Benzimidazoles and Cogeneric Tricyclic Compounds, Part 2 (The Chemistry of Heterocyclic Compounds, Volume 40)

Benzimidazoles and Congeneric Tricyclic Compounds IN TWO PARTS PART TWO This is (he fortieth volume in the series TH...

Author: P. N. Preston

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Benzimidazoles and Congeneric Tricyclic Compounds

IN TWO PARTS

PART TWO

This is (he fortieth volume in the series

THE CHEMISTRY OF lurrEROcYCLIC coMPouNDs

THE CHEMIsLaY OF HEIEROCYCLK COMPOA

SERIES OF MONOGRAPHS

ARNOLD WEISBERGER and EDWARD C. TAYLOR Editors

BENZIMIDAZOLES AND CONGENERIC TRICYCLIC COMPOUNDS PART 2 Edited by

P. N. PRESTON DEPARTMENT OF CMEMISTRY. HERIOT-WATT UNIVERSITY. EDINBURGH. SCWILAND

With contribufions b y

M. F. G . STEVENS DEPARTMENT OF PHARMACY,

DEPARTMENT OF CHEMISTRY.

UNIVERSITY OF ASTON.

UNIVERSITY OF EDINBURGH.

BIRMINGHAM.

EDINBURGH.

ENGLAND

SCOnAND

AN IMFRSCIENCE

@

JOHN WILEY & SONS

New York

G . TENNANT

PUBLICATION

. Chichater . Brisbane . Toronto

An Interscience @ Publication Copyright @ 1980 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. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc.

Ubrary of Coaprees Cataloging im Poblicatioa Data: Main entry under title: Benzimidazoles and congeneric tricyclic compounds. (The Chemistry of heterocyclic compounds; 40, pt. 1 ISSN 0069-3154) “An Interscience publication.” Includes index 1. Benzimidazoles. I. Preston, P. N. QD401.BM 547.593 80-17383 ISBN 0-471-03792-3 (v. 1) ISBN 0-471-08189-2 (v. 2)

-v.

The Chemistry of Heterocyclic Compounds The chemistryof heterocycliccompounds is oneof the most complex branches of organic chemistry. It is equally interesting for its theoretical implications,for the diversity of its synthetic procedures, and for the physiological and industrial significance of heterocyclic compounds. A field of such importance and intrinsic difficulty should be made as readily accessible as possible, and the lack of a modern detailed and comprehensive presentation of heterocyclic chemistry is therefore keenly felt. It is the intention of the present series to fill this gap by expert presentations of the various branches of heterocyclic chemistry. The subdivisions have been designed to cover the field in its entirety by monographs which reflect the importance and the interrelations of the various compounds, and accommodate the specificinterests of the authors. In order to continue to make heterocyclic chemistry as readily accessible as possible, new editions are planned for those areas where the respective volumes in the first edition have become obsolete by overwhelmingprogress. If, however, the changes are not too great so that the first editions can be brought up-to-date by supplementary volumes, supplements to the respective volumes will be published in the first edition. ARNOLD WEISSBERGER Research Laboratories Eosmtan Kodak Company Rochester, New York Princeion University Princeton, New Jersey

EDWARD C. TAYLOR

Preface to Part 2 More than 25 years have elapsed since the publication in this series of Imidazole and Its Derivatives by Klaus Hofmann. In updating this work, Leroy Townsend has undertaken the task of editing a volume on monocyclic imidazoles, and the present book covers the chemistry of benzimidazole and its dihydro derivatives, as well as congeneric tricyclic compounds that contain a condensed benzimidazole moiety. Because many ring systems are covered, it has proved necessary to divide the volume into Part 1 (Chapters 1 to 5) and Part 2 (Chapters 6 to 10). Chapters 1 to 3 on benzimidazoles, benzimidazole N-oxides, and dihydro derivatives update the book of Hofmann through Volume 87 of Chemical Abstracts. The chemistry of tricyclic compounds containing a condensed benzimidazole moiety is covered comprehensively from early literature through the same Volume 87 of Chemical Abstracts. Chapters 4 to 9 on the condensed ring systems are organized in terms of the position and s u e of the ring fused to the benzimidazole skeleton (denoted “6-5”). Thus Chapters 4 through 8 are concerned with compounds in which fusion of the third ring is at the benzo and imidazole rings respectively. Chapter 9 deals with the chemistry of tricyclic compounds in which a benzimidazole moiety may be considered to be formally annulated from N-1 to c-7. The growth of benzimidazole chemistry in the past 25 years has paralleled that of purines and stems from the determination of the partial structures of nucleic acids in the early 1950s. Benzimidazoles and congeneric compounds are substrates that might act as inhibitors in nucleic acid biosynthesis, and their relative ease of preparation and low cost make them attractive as potential pharmacological agents. The variety of marketed products described in chapter 10 bears witness to the large commitment to benzimidazole chemistry. I hope that this book will stimulate further research, particularly on the synthesis of new tricyclic derivatives and related condensed analogs. I am indebted to a number of friends and colleagues who have contributed to this book. It has been a pleasure to collaborate with David Smith and with Malcolm Stevens and George Tennant, and I thank them for their large collective contribution. Information on commercially marketed products is difficult to obtain, but my task was simplified with the generous assistance of Colin C. Beard, Gerald Farrow, Janet M. Shether, Brian K. Snell, and Ian S. Swanson. I also thank my wife, Veronica, who carried out an initial estimate of the magnitude of literature on benzimidazoles and

...

Vlll

Preface to Part 2

congeneric tricyclic compounds. Thanks are due also to Susan Bobby who typed part of the manuscript, Anthony F. Fell who translated a number of documents from Russian, and my former research students Alex Davidson and Ian E. P. Murray who helped to check the manuscript. Finally, I express my appreciation of the help and enthusiasm of the Series Editors, Edward C. Taylor and Arnold Weissberger, of Stanley F. Kudzin, and of the staff of John Wiley and Sons, Inc.

P. N. PRESTON Edinburgh, Scotland January 1981

Contents PART TWO 6. Condensed Bemimidazoles of Type 6 - 5 5

1

G . TENNANT 7. Condensed Benzimidazdes of Type 6-5-6

257

G. TENNANT 8. C~adeasedBeazinddozdes of Type 6-5-7 a d Higher Horndogs

463

M. F. G. STEVENS 9. Condensed BeazhDiQzdes Bridged Between N-1 a d C-7

505

M. F. G . STEVENS

10. commereirrl Applications of Benzimidazdles

531

P. N. PRESTON

AptborIndex

543

Subject I d e x

567

PART ONE

1. Benzimidazoles P. N. PRESTON

1

Co-ntents

X

2. Benzimidazde N-Oxides

287

D. M. SMITH 3. Mhydrobenzimidazoles, Benzimidazdones, Benzimidazdethiones and Related Compounds

331

D. M. SMITH 4. Condensed Benzimidazdes of Type 5-6-5

391

G. TENNANT 5. Condensed Benzimidazoles of Type 6-6-5

483

P. N. PRESTON AND G. TENNANT

Autbor Index

645

Subject Index

675

Chemistry of Heterocyclic Compounds, Volume40 Edited by P. N. Preston Copyright 0 1980 by John Wiley & Sons, Ltd.

CHAPTER 6

Condensed Benzimidazoles of Type 61.515 G. TENNANT 6.1 Tricyclic 6-5-5 Fused Benzimidazoles with No Additional Heteroatoms . . . . 6.1.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ring-closure Reactions of Benzimidazole Derivatives . . . . . . . . Ring-closure Reactions of Other Heterocycles . . . . . . . . . . . 6.1.2 Physicochemical Properties . . . . . . . . . . . . . . . . . . . . Spectroscopic Studies . . . . . . . . . . . . . . . . . . . . . Infrared Spectra . . . . . . . . . . . . . . . . . . . . . . . Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . . . Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . Mass Spectra . . . . . . . . . . . . . . . . . . . . . . . . General Studies . . . . . . . . . . . . . . . . . . . . . . . . 6.1.3 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions with Electrophiles . . . . . . . . . . . . . . . . . . Protonation . . . . . . . . . . . . . . . . . . . . . . . . . Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . Halogenation. Nitration. Nitrosation. Diazotization. and Diazo Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . Hydroxylation . . . . . . . . . . . . . . . . . . . . . . . . Amination . . . . . . . . . . . . . . . . . . . . . . . . . Halogenation . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . Oxidation .......................... Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.4 Practical Applications . . . . . . . . . . . . . . . . . . . . . . Biological Properties . . . . . . . . . . . . . . . . . . . . . . Dyestuffs . . . . . . . . . . . . . . . . . . . . . . . . . . . Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Tricyclic 6-5-5 Fused Benzimidazoles with One Additional Heteroatom . . . . 6.2.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ring-closure Reactionsof Benzimidazole Derivatives . . . . . . . . Ring-closure Reactions of Other Heterocycles . . . . . . . . . . . 6.2.2 Physicochemical Properties . . . . . . . . . . . . . . . . . . . . Spectroscopic Studies . . . . . . . . . . . . . . . . . . . . . Infrared Spectra . . . . . . . . . . . . . . . . . . . . . . .

1

2 3 3 29 38 38 38 41 44 55 56 57 57 58 60 64 67 72 72 74 75 78 79 80 84 84 84 84 84 86 86 140 144 144 144

2

Condensed Benzimidazoles of Type 6-5-5

Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . . . Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . Massspectra . . . . . . . . . . . . . . . . . . . . . . . . General Studies . . . . . . . . . . . . . . . . . . . . . . . . Crystallography . . . . . . . . . . . . . . . . . . . . . . . Dipole Moments . . . . . . . . . . . . . . . . . . . . . . . Ionization Constants . . . . . . . . . . . . . . . . . . . . . 6.2.3 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions with Electrophiles . . . . . . . . . . . . . . . . . . Protonation . . . . . . . . . . . . . . . . . . . . . . . . . Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . Halogenation . . . . . . . . . . . . . . . . . . . . . . . . Nitrosation and Nitration . . . . . . . . . . . . . . . . . . . Diazo Coupling . . . . . . . . . . . . . . . . . . . . . . Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . Deprotonation ....................... Hydroxylation and Related Reactions . . . . . . . . . . . . . Amination . . . . . . . . . . . . . . . . . . . . . . . . . Reactions with Anionic Reagents . . . . . . . . . . . . . . . Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.4 Practical Applications . . . . . . . . . . . . . . . . . . . . . . Biological Properties . . . . . . . . . . . . . . . . . . . . . . Dyestuffs . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Tricyclic 6-5-5 Fused Benzimidazoles with Two Additional Heteroatoms . . . 6.3.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ring-closure Reactionsof Benzimidazole Derivatives . . . . . . . . Ring-closure Reactions of Other Heterocycles . . . . . . . . . . . 6.3.2 PhysicochemicalProperties . . . . . . . . . . . . . . . . . . . . Spectroscopic Studies . . . . . . . . . . . . . . . . . . . . . . Infrared Spectra . . . . . . . . . . . . . . . . . . . . . . . Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . . Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . General Studies . . . . . . . . . . . . . . . . . . . . . . . . Dipole Moments . . . . . . . . . . . . . . . . . . . . . . . 6.3.3 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . Oxidation and Reduction . . . . . . . . . . . . . . . . . . . . 6.3.4 Practical Applications . . . . . . . . . . . . . . . . . . . . . . . 6.4 Tricyclic 6-5-5 Fused Benzimidazoles with Three Additional Heteroatoms . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

154 158 171 178 178 178 178 179 179 179 182 186 197 202 204 207 207 207 209 211 215 216 217 217 219 219 221 221 229 230 230 233 234 239 239 242 242 242 244 244 244 244 245

6.1. TRICYCLIC 6-5-5 FUSED BENZIMIDAZOLES WITH NO ADDITIONAL HETEROATOMS Union of a five-membered carbocyclic ring in 6-6-5 fashion with benzimidazole involves fusion across the N(1)-C(2) bond in the latter and gives rise to a single structural type corresponding to the pyrrolo[ 1.2.albenzimi d. azole ring system (Scheme 6.1). The latter is encountered in 1H (6.1), 3H

6.1. Fused Benzimidazoles with No Additional Heteroatoms

3

R (6-3)

(6.2), and 4 H (6.3) tautomeric forms as well as in the guise of 1H-2,3dihydro (6.4) and 1H-2,3,3a,4-tetrahydro (6.5) structures (Scheme 6.1 and Table 6.1). Of these the 4H system (6.3) has attracted most attention because of its potentially aromatic character. TABLE 6.1. TRICYCLIC 6-5-5 FUSED BENZJMIDAZOLE RING SYSTEMS WITH NO ADDITIONAL HETEROATOMS Structure'

Name'

(6.1) (6.2)

1 H-Pyrrolo[ 1.2-a]benzimidazole 3H-Pyrrolo[ I ,2-a]benzimidazole JH-Pyrrolo[ 1.2-a]benzimidazole 2,3-Dihydro- 1 H-pyrrolo[ 1.2-albenzimidazole 2.3.3a.4-Tetrahydro- 1 H-pyrrolo[ 1,2-a]benzirnidazole

(6.3) (6.4) (6.5)

Cf. Scheme 6.1.

' Based on the Ring Index. 6.1.1. Synthesis Ring -closure Reactions of Benzimidazole Deriuatiues of ortho-phenylenediamine (6.6) and its derivatives The c~ndensation'-~ with maleic anhydrides (6.7) to give pyrrolo[ 1.2-a]benzimidazol-l-ones (6.10) (Scheme 6.2 and Table 6.2) is plausibly explained in terms of the

qNH2+ Rfi Hz

R2

(6.6)+ (6.15)

(6.14) Scheme 6 .2

4

VI

G

Yield

184 258 (decomp.)

2 76 57

a

Yield not quoted. Solvent not specified. Reaction conditions not specified. Melting point not quoted. Crystal form not specified.

-

Red powder

Orange-red crystals Red solid Red needles

J

-

Brown needles

Crystal form

5

4 2

3 2

1 1

1

Ref.

hr; E = AcOH/(reflw)(40min)

Acetonechloroform Ethanol Dimethylfor mamide-water Dimethylformamideacetic acid

at 250"; D =heat at 180-190"/0.5

3 16 (decomp.)

169

7

-b

-c

-

186

-

Solvent of crystallization

m.p. ("C)

85

-*

-b

(YO)

A =heat in the melt; B =heat in a high b.p. solvent or in the melt; C = heat F = AcOH/(room temp)(l2 hr); G = AcOH/(room temp)(2 hr).

(6.6)+ (6.14; R = NO,, R' = OH)

E F

(6.10; R' = R2 = Ph) (6.10;R' = R2 = Ph) (6.10; R' = R2 = Me) (6.10; R' = OMe, R2= Ph) (6.10; R' = R2 = Ph) (6.10; R' = OH, R2 = Ph) (6.10; R' =OH, R2 = P-NO~C~H,)

B C -d D

(6.8; R' = R2 = Ph) (6.9; R' = R2 = Ph) (6.6)+ (6.7; R' = R2 = H) (6.6)+(6.7;R1=OMe. R2 = Ph) (6.6)+ (6.14; R = H, R ' = Ph) (6.6)+ (6.14; R = H. R' = OMe)

(6.10; R' = R2 = Ph)

A

(6.6)+ (6.7; R' = R2 = Ph)

Product

Reaction conditions"

Starting materials

TABLE 6.2. SYNTHESIS OF lH-PYRROL0[1,2-a]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF BENZIMIDAZOLE DERIVATIVES AND RELATED PROCESSES.

6


formation and thermal cyclization of 2-benzimidazolylacrylic acid intermediates (64,thus justifying the inclusion of such reactions under the present heading. Indeed, the thermal cyclization (Scheme 6.2) of the acid (6.8; R' = R2 = Ph) to the pyrrolo[ 1,2-a]benzimidazolone (6.10;R' = R' = Ph) (albeit in unspecified yield) has been demonstrated.' Equally, however, ring-closure reactions of the type [Scheme 6.2; (6.6)+ (6.7)+ (6.10)]may involve the corresponding N-(2-aminophenyl)maleimides (6.9) as intermediates, since it has also been shown' that the compound (6.9;R' = R2 = Ph) undergoes thermal cyclization at 250" to afford the pyrrolo[l,2-a]benzimidazol-1-one (6.10;R' = R' = Ph) in high yield (Table 6.2). Information on the general scope and efficiency of 1H-pyrrolo[ 1,2-a]benzimidazole syntheses based on the condensation of ortho-phenylenediamines with maleic anhydrides is lacking, and in view of their simple character such reactions merit more detailed study. Of particular interest is the possibility of isomer formation when unsymmetrically substituted maleic anhydrides are employed as substrates. Thus, irrespective of whether a benzimidazole derivative or an N-(2-aminophenyl)maleimideis involved as intermediate ring-closure using an unsymmetrically substituted maleic anhydride, (6.7; R' # R2) should lead to two possible isomeric pyrrolo[ 1,2-a]benzimidazol-lones. In the only extant example' of this situation the condensation of orthophenylenediamine (6.6)with the methoxy-substituted anhydride (6.7;R' = OMe, R2 = Ph) led exclusively to the 3-methoxypyrrolobenzimidazolone (6.10;R' = OMe, R2= Ph), whose formation is consistent with either preferential initial [Scheme 6.2; (6.6)+ (6.7; R' = OMe, R' = Ph) + (6.8; R'=OMe, R2=Ph)] or final [Scheme 6.2; (6.9; R'=OMe, R Z = P h ) + (6.10;R' = OMe, RZ= Ph)] condensation between an amino group and the carbonyl group not deactivated toward nucleophilic attack by the methoxyl substituent. The nature of ortho-phenylenediamine-maleic anhydride condensations is such that the products are of necessity lH-pyrrolo[l,2-a]benzimidazol-1-ones (6.10) and not the isomeric 3H-pyrrolo[ 1,2-a]benzimidazol-3-ones (6.11). 1H-Pyrrolo[ 1,2-a]benzirnidazol-l-ones are also the end-products of the reactions of ortho-phenylenediamines with cyclobutene-3,4-diones in acetic acid [Scheme 6.2; (6.6)+ (6.14)+ (6.10)].2*4*5 This type of condensation gives very poor yields (Table 6.2) when 1,2-diphenylcyclobutene-3,4-dione(6.14;R = H,R' = Ph) is used as substrate: whereas employing 2-aryl-l-hydroxycyclobutene-3,4-diones (6.14;R' = OH)leads"' to the corresponding 2-aryl-3-hydroxy-1H-pyrrolo[1,2-a]benzimidazol-l-ones(6.10;R' = OH,R' = phenyl or p-nitrophenyl) in good yield (Table 6.2). The latter reactions are suggested' to follow a course (Scheme 6.2) involving the formation and ring expansion-ring contraction of a quinoxaline intermediate [Scheme 6.2; (6.6)+ (6.14; R' = OH) (6.15)+- (6.13)+- (6.12)--* (6.10)J.The reactions (Scheme 6.3) of 2-azido-1-methylbenzimidazole(6.16) with acetylenic esters (methyl propiolate, dimethyl acetylenedicarboxylate) in acetonitrile under reflux as well as resulting in the expected cycloaddition to the azido group, are

6.1. Fused Benzimidazoleswith No Additional Heteroatoms

(6.16)

SeLemO 6.3

7

(6.17)

reported6 to afford mQderate to high yields of products formulated as the lH-pyrrolo[ 1,2-a]benzimidazole derivatives (6.17; R = H or CO,Me), though probably inadvertently, since the combustion analysis and mass spectral properties" of the supposed diester product (6.17;R = C0,Me) are consistent with a C14 rather than a CISstructure. Moreover, the 'H NMR spectra reported" for these products lack signals attributable to the C(1) methylene protons in the structures (6.17; R = H or C0,Me). Closer scrutiny of the structures of these compounds is in any case warranted in view of their unorthodox mode of formation (i.e., annelation of the imidazole ring in preference to the anticipated exclusive cycloaddition to the azido group). 3H-Pyrrolo[ 1,2-a]benzimidazoles are readily accessible, usually in high yield (Table 6.3), by the thermal condensation of onho-phenylenediamine and its derivatives with y-ketocarboxylic acids [Scheme 6.4; (6.6)+ (6.18)+ + (6.20)l."' The probable intermediacy of the corresponding 2-benzimidazolylethyl ketones in these reactions is supported by the ready thermal cyclization of 4-(2-benzimidazolyl)-2-butanone(6.19;R' = Me, R2 = R3 = R4 = H) to l-rnethyl-3H-pyrrolo[1,2-a]benzimidazole(6.20;R' = Me, R2= R3=R4=H).' In some instances the y-keto acid can be replaced by a suitable y-ketonitrile, in which case condensation is conducted under acidic conditions (Table 6.3).9 Reaction (Scheme 6.4)of onho-phenylenediamine (6.6)with 1,2-diaroyl-1,2-diphenylethylenes(6.23)in refluxing methanolic acetic acid affords high yields (Table 6.3) of 1,2,3,3-tetraary1-3H-pyrrolo[1,2-a]benzimidazoles (6.20;R' = R3= Ar, R2 = R4 = phenyl).'" These reactions are readily explained'" in terms of initial condensation to give benzimidazole derivatives convertible by cyclization and subsequent vinylogous Wagner-Meerwein rearrangement into the observed products [Scheme 6.4;

(6.6)+ (6.23)+ (6.22)+ (6.21)+ (6.2011.

1-Substituted 2-alkylbenzimidazoles [Scheme 6.5; (6.24)]are quaternized by 01 -halogeno ketones to give benzimidazolium salts (6.25),which are smoothly cyclized by base treatment to afford the corresponding 4Hpyrrolo[ 1,2-a]benzirnidazoles (6.27) in high yield (Table 6.4)."-" This highly versatile synthetic method has been exploited"-" for the synthesis of a wide variety of 4H-pyrrolo[ 1,2-a]benzimidazoles bearing alkyl or aryl substituents at all three possible sites in the pyrrole nucleus (Table 6.4). The cyclization step [(6.25)--* + (6.27)]in these syntheses is most commonly effected by simply heating the isolated benzimidazolium salt (6.25)under

00

C C

B

A

A

A

A

A


7.8 7.8

116-1 18

110-111

80 80

206' 246'

10 10

9

7.8

154-156

73

180-189

7.8

210-212

87

71

7,8

205-207

R2 = R3= R4 = H)b (6.20; R' = R3 = Me, R2= R4 = H)' (6.20; R' =Me, R2= R4= H. R3 = Et)" (6.20; R' = Me, R2 = R4 = H, R3 = Pr")' (630; R' = Me, R2 = R4 = H, R3 = B u " ) ~ (6.20; R' = R3 = R4 = Me, R~ = H) (6.20; R ' = R2 = R3 = R4 = Ph) (6.20; R' = R3 = p-MeOC6H4, R2 = R4 = Ph)

88

Ref.

(6.20; R' = Me,

m.p. ("C)

Yield (96)

Product

* A = 80-200"; B = HCllreflux; C = AcOH, MeOH/(reflux)/(2 hr). Forms a hydrochloride, m.p. 281-283'. Forms a hydrochloride, m.p. 260-263". dForms a hydrochloride, m.p. 147". 'Yield not quoted. f Forms a hydrochloride, m.p. 204-206". ZForms a hydrochloride, m.p. 210-213". Crystallized from methanol-acetic acid.

(6.6)

+ (6.18; R' = Me, R2 = R3 = R4 = H) (6.6) + (6.18; R' = R3 = Me, R2 = R4= H) (6.6) + (6.18; R' = Me, R2= R4 = H, R3= Et) (6.6) + (6.18; R' = Me, R2 = R4 = H, R' = Pr") (6.6) + (6.18; R' = Me. R2 = R4 = H, R3= Bu") (6.6) + (6.18; R' = R3 = R4 = Me, R2= H, CN for C02H) (6.6) + (6.23; Ar = Ph) (6.6) + (6.23;Ar = p-MeOC,H,)

Starting materials

TABLE 6.3. SYNTHESlS OF 3H-PYRROLO[ I,~-u]BENZIM~DAZOLES BY RING CLOSURE REACTIONS OF ORTHOPHENYLENEDIAMINE

- a,ql

aNH2 COR' ~I H R *

/

NH2

(6.6)

+

/

R4CR3 I C02H

R3

(6.1%)

(6.19)

R' R3

(6.26)

R4

/

RZ

(6.27) srkmc 6.5 9

H

R4

R

0

+

C

D

E

F

(6.25; R' = R3 = R4 = Me, R2 = H)

(6.25; R' = R3 = R4 = Me, R2 = H)

(6.25; R' = R' = R4 = Me, R2 = H)

(6.25; R' = R2= R' = R4 = Me)

(6.25; R' = CH,Ac, R2= R4 = H, R' = Me) (635; R' = Me, R2 = R4 = H, R3 = Ph)

R4 = Pr") (6.25; R' = R' = Me, R2 = Ph, R4= H) (635; R' = Et, R2 = R4 = H, R' = Me) (6.25; R' = Et, R2 = H, R3 = R4 = Me) (6.25; R' = Et, R2 = H, R3 = Me, R4= Ph) (635; R' = R3 = Me, R2=R4=H)'

E

E

E

E

E

E

E

E

B

(6.25; R' = R2 = R3 = Me, R4 = H)

(6.25; R' = R3 = Me. R2 = H,

A

(6.25; R' = R3 = Me, R2 = R4 = H)

Dimethylformamidewater Ethanol Ethanol

207-208 169-1 7 1

(decomp.) 109-1 11

90

95

Acetone-water 139- 140

82

74

Water

138-140 78

R2 = R4= H. R' = Me) (6.27; R' = Me, R2 = R4 = H, R3 = Ph)"

Ethanol

177-178

-k

Ethanol

Acetone

Ethanol

Ethanokther

Isopropanol

Methanol

Methanol

Ethanol

Solvent of crystallisation

152-153

136-138

165- 166

114-116

96

96

99

90

m.p. ("C)

86

70

39

74

65

69

50

46

Yield

(Yo)

(6.27; R' = CH2Ac,

R2 = H, R4 = Pr") (6.27; R' = R3 = Me, R2 = Ph, R4= H)' (6.27; R' = Et, R2 = R4 = H, R3 = Me)' (637; R' = Et, R2 = H, R3 = R4 = Me)' (6.27; R' = Et, R2 = H, R3 = Me, R4 = Et)' (637; R' = R3 = Me, R2 = R4 = H)'."

(637 ; R' = R3 = Me,

R2 = R4 =H)b (6.27; R' = R2 = R' =Me, R4 = H)' (637; R' = R3 = R4 = Me, R~ = H )' (6.27; R' = R3 = R4 = Me, R~ = H) (6.27; R' = R' = R4 = Me, R2 = HY (6.27; R' = R2 = R3 = R4 = Me)'

(6.27; R' = R3 = Me,

Reaction conditions" Product

15

-h

Colorless solid

11

19

15

-h

-h

15

11

15

15

14

15

13

12

12

12

Ref.

-h

-h

-h

-h

Colorless crystals

Colorless plates Colorless platesd Colorless platesf Colorless platesf -h

Crystal form

SYNTHESIS OF 4H-PYRROLO[ 1,2-a JBENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF BENZIMIDAZOLE DERIVATIVES

Starting material

TABLE 6.4.

-

w

(6.26; R' = Me, R2 = R4 = H, R3 = p-NO2C6H4) (6.25; R ' = Me, R2 = R4 = H, R' = m -N02C,H4) (6.26; R' =Me, R2 = R4 = H, R3 = m-NO,C,H,) (6.25; R' = Me, R2 = R4 = H, R3 = p-MeC,H4) (6.25; R' =Me, R2 = R4 = H, R' = p-MeOC,H,) (6.25; R' = Et, R2 = R4 = H, R3 = p-BrC,H,) (6.25; R' = Et, R2 = R4 = H, R3 = p-NOZCbH4) (6.25; R' = Et, R2 = R4 = H, R3= 2-thienyl) (6.25; R' = Me, R2 = R4 = H, R3 = Ph)' (6.25; R ' =Me, R2 = R4 = H, R' = p-BrC,H,)' (6.25; R ' = CH2Ph, R2 = R4 = H, R3 = p-MeOC,H,)

(6.25; R' = Me, R2 = R4 = H, R' = Ph) (6.25; R' = Et, R2 = R4 = H, R3 = Ph) (635; R' = CH,Ph, R2 = R4 = H, R3 = Ph) (6.25; R' = Me, R2 = R4 = H, R3 = p-BrC6H4) (6.25; R' = Me, R2 = R4 = H, R' = p-N02C,H4)

E

E

E

E

E

E

E

E

G

E

G

E

E

E

E

A

(6.27; R' = Me, R2 = R" = H. R3 = p-N02C6H4) (6.27; R' = Me, R2 = R4 = H. R' = m -N02C6H4) (6.27; R' = Me, R2 = R 4 = H, R3 = m -N0,C6H4) (6.27; R' = Me, R2 = R4 = H, R3= p-MeC,H,) (6.27; R' = Me, R2 = R4 = H, R' = p-MeOC,H,) (6.27; R' = Et, R2= R4 = H. R3 = p-BrC,H,)' (6.27;R'=Et,R2=R4=H, RJ = p-BrC,H,&' (6.27; R' = Et, R2 = R4= H, R3 = 2-thienyl)' (6.27; R' = Me, R2= R 4 = H, R3 = Ph)" (6.27; R' = Me, R2 = R4 = H. R" = p-BrC&)" (6.27; R' = CH,Ph, R2=R4=H, R3 = p-MeOC,H4)

(627; R' = Me, R2 = R4= H, R3 = Ph)" (6.27; R' = Et, R2 = R4 = H, R3= Ph)P (6.27; R' = CH2Ph, R2 = R 4 = H. R3 = Ph) (6.27; R' =Me. R 2 = R4 = H, R3 = P - B ~ C ~ H , ) ~ (6.27; R ' =Me, RZ= R4 = H. R' = p-N02C,H4) 123-124 (decomp.) 155- 156 180-182

92 86 90

95

82

149- 1SO 98

Acetone-light petroleum Water

Ethanol

Ethanol

Ethanol

-

Dimethylformarnide

-

Ethanoldimethylformamide

Ethanol

Ethanol

Ethanol

Ethanol

Dimethylformamide Dime thyl203-204 formamide Dimethyl159-160 formamide (decomp.)

178-1 79

79

123-124

95

118-121

141-142

84

81

131-132

170.5171.5 -

67

96-98

92

-

119-120

97

96-98

114

-k

11

Red crystals

15

-h

11

1s

15 15

17

Colorless solid Red crystals -h

-h -h -h

11

13

-h

16

16

-

-

I1

11

17

11

12

Colorless solid Red crystals

Colorless needles Colorless solid -h

(Continued)

R' =Me, R' = Ph, R'= m-NO,C,H,, R4 = H) (6.225; R' = RZ= Me, R3= Ph,

R4 = H) (6.25; R' = R2 = Me, R3 = Ph, R 4 = H) (6.25; R' = R2 = Me, R' = p-BrC6H4, R4 = H) (6.25; R' = R ' = Me, R' = p-NO,C,H,, R4 = H) (6.25; R ' = R4 = Me, R' = H, R3 = Ph) (6.25; R' = R4 = Me, R2 = H, R3 = Ph) (6.25; R' = R4 = Me, R2 = H, R3= p-PhC6H4) (6.25; R' = R' = R4 = Me, R' = Ph)

(6.25;

E

E

E

H

E

E

E

D

E

E

(6.25; R' =Me, R2 = Ph,

R' = p-N02C6H4, R4 = H)

E

E

E

R' = p-N02C6H4, R4 = H) (6.27; R' =Me, R' = Ph, R' = m -N02C6H4,R4 = H) (6.27; R' = R' = Me, R3 = Ph, R4= H) (6.27 R' = R2 =Me, R3= Ph. R4 = H)' (6.27; R' = R' = Me, R3 = p-BrC,H,, R4 = H) (6.27; R' = R' =Me, R3= p-N02C6H4,R4 = H) (6.27; R' = R4 = Me, R2= H, R3 = Ph)" (6.27; R' = R4 = Me, R2 = H. R' = Ph) (6.27; R' = R4 = Me, R' = H, R3 = p-PhChH4) (6.27; R' = R' = R4 = Me, R' = Ph)'

(6.27; R' =Me, R' = Ph,

87

91

84

85

83

91

172- 173

191-192

141-142

145-146

143-144

162-163

136-137

36'

66 97

170-172

184-185

156-158

157-158

157-159

m.p. ("C)

97

92

99

(6.27; R' =Me, R' = Ph,

R3 = p-BrC,H,, R4 = H)

94

96

Yield

R4 = H) (6.27; R' = CH,Ph, R' = R3= Ph, R4 = H)

(637; R' =Me, R2 = R3 = Ph,


(6.25; R' = Me, R' = Ph, R' = p-BrC6H4, R4 = H )

(6.25; R' = Me, R'

= R3= Ph, R4 = H) (6.25; R' = CH,Ph, R' = R3 = Ph, R4 = H)

Starting materials

TABLE 6.4

Dimethylformamide Ace tone-w ater

Ethanol

Dirnethylformamide Dimethylformamide Dimethylformamide Methanol

Dimethylformamide Ethanoldimethylformamide Ethanoldimethylformamide Ethanoldimethylformamide Dimethylformamide Ethanol


15

-h

15

15

-k

15

-h

12

15

-h

Yellow plates

15

12

-h -h

15

11

17

11

Ref.

-h

Red crystals

Colorless solid

-h

Colorless solid

Crystal form

w

F

E

= R4 = H,

K K

K

R' = Et, R2= C0,Et)

(6.28;

(6.28;R' = Me, R2= CN) (6.28; R' =Me, R2 = CN)

K

K

(6.28; R' =Me, R ' = C0,Et)

= C0,Et)

K

R' = Me, R2= C0,Et)

(6.28;

R' = Me, R'

J

R' = Me, R2 = CN)

(6.24;

(6.28;

1

R' = Me, R2 = C0,Et)

E

E

R' = p-BrC,H,COCH,, R2 = Me, R3= p-BrC6H4, R4 = H) (6.27; R' = Me, R ' = C0,Et. R3= Ph, R4=H) (637; R' = Me, R2 = CN, R3= Ph, R4= H)

R3= Et) (6.29; R' = Me, R2 = C02Et, R3= Ph) (6.29; R' = Et, R ' = CO,Et, R3= Me) (6.29; R' = R3= Me, R2 = CN) (6.29; R' =Me, R2= CN, R3= Et)

(6.29; R' = R3= Me, R' = C02Et) (6.29; R' = Me, R2 = C0,Et.

74 58

63

32

40

67

45

41

-k

67

259 158-1 59

162-163

156

110-111

153-154

160-161

94-95

167-169

188-189

196-197

-k

E

180-181

164-166

(decomp.)

160-161

238-240

68

47

-k

98

(6.27;

(6.27; R' = p-BrC6H4COCH2, R' = R4= H, R3= p-BrC6H4)

(6.27; R' = CH,COPh, R2=R4= H, R3= Ph) (6.27; R' = CH2COPh, R'= R4 = H, R3=ph)"

E

(6.24;

R'

(6.25;

R' = p-BrC6H4COCH2, = Me, R3 = p-BrC,H4, R4= H)

(6.25; R' = CH,COPh, R2 = R3= Ph, R4= H)'

R2 = R4 = H, R3= p-N02C6H4) (6.25; R' = p-BrC,H,COCH,, R2 = Ph, R3= p-BrC6H4,R4 = H)

(6.25; R' = p-NO2C6H4COCH2,

(6.25; R' = p-BrC6H4COCH2, R2 = R4 = H. R3= p-BrC6H4)

E

E

R3= Ph) (6.25; R' = CH'COPh, R ' R3= Ph)'

(6.25; R' = CH,COPh, R2 = R4 = H,

Ethanol lsopropanol

Ethanol

Ethanol

Ethanol

Methanoldimethylformamide Isopropanol

Methanoldimethylformamide Ethandldimethylformamide Dimethylformamide Ethanoldimethylformamide Methanoldimethylformamide Ethanoldimethyl formamide Ethanol

EthanoI

19

-

19

18

20 20

21 21 21 21 21 21

-h -h -h -h -h -h -k -h -h -h

-h

18

19

-h h

19

18

-h

-h

P

(Continued)

187- 188

70

(6.34; R' = Me, RZ= Ph)' (6.34;R' = Et, R2 = Ph)' (6.34:R' = H. R2 = Ph)"

M

M

M

(6.30; R' = Me, R2 = Ph) (6.30;R' = Et, R2 = Ph)

(6-35)

22 22

22

22 22

21 21

Yellow prisms 22

-h

-h

21

Ref.

D = NaOEt,

a

Na,SO,, H20/(80-90')(2 hr); B = 0.7% Na,CO,, Na,SO,, H20/(90-95')(40 min); C - 0.7% Na,CO,, H20/(800)(1.5 hr); Na,SO,, EtOH/(reflux)(ZO min); E = NaHCO,, H20/(reflux)(2-8 hr); F = Na,CO,, Na,SO,, H20/(100')(2.5 hr); G HzO/ (reflux)(15-30 min); H = 0.8% Na2C0,, H20/(9O0)(1 hr); I = PhCOCH,Br, acetone/(reflux)(96 hr); J = PhCOCH,Br, acetone/(reflux)(4 hr); K = (R3CO)20, Et,N/(130-14O0)(1 hr); L = NaHCO,, NaHSO,, HzO/(reflux)(4 hr); M = KOH, THF/room temp.)(4-14 hr). Forms a perchlorate, colorless needles, m.p. 199-200'. Forms a picrate, yellow plates, m.p. 164" (from ethanol) and a perchlorate, m.p. 212" (from water). Turn green in air. ' Forms a perchlorate, colorless needles, m.p. 178' (from ethanol). f Turn red in air. R Forms a picrate, m.p. 151-153" (from water). Crystal form not specified. ' Hydrochloride; free base forms colorless crystals which rapidly turn red in air; forms a perchlorate, colorless crystals, m.p. 194-195" (from acetic acid then ethanol). Picrate.

81

76 73

41

(6.34;R' = R2 = Me)

L

88-89 90-100 (decomp.) 178-1 79 (decomp.) 151-152 132-133 (decomp.) 64-65 Ethanol-water

32 30

lsopropanol Isopropanol

-h

Ethanol

246 207-208

Crystal form


55 41

(6.30; R' = R2 = Me)

A = 0.7% Na,CO,,

m.p. ("C)

Yield (Yo)

R3 = Me) (6.29;R' = R3 = Me, R2 = Ph) (6.29; R' =Me, R2 = Ph, R3 = Et) (6.34;R' = Me, R2 = H) (6.34;R ' = Et, RZ= H)

(6.29; R' = Et, R2 = CN,

L L

K

K

K


(6.30; R' = Me, R2 = H) (6.30; R' = Et, R2= H)

(6.28; R' = Me, R2 = Ph) (6.28;R' = Me, R2 = Ph)

(6.28; R' = Et, R2 = CN)

Starting materials

TABLE 6.4

Yield not quoted. 5,6-Dimethyl derivative. 6,7-Dimethyl derivative. Forms a picrate, m.p. 202" (from acetone). Forms a hydrochloride, m.p. 273" (from water) and a hydriodide. yellow needles, m.p. 276". Forms a picrate, m.p. 192-194". Forms a picrate, m.p. 200-201" (from acetic acid). Forms a picrate, m.p. 205-207" (from acetic acid). Forms a picrate, m.p. 185-186" (from acetone). This m.p. differs widely from that cited in Ref. 15. Forms a picrate, m.p. 155-156" (decomp.) (from water). Forms a picrate, yellow needles , m.p. 185" (from ethanol), a perchlorate, yellow crystals, m.p. 208" (from aqueous hydrochloric acidhand a hydriodide, yellow needles, m.p. 245" (from aqueous hydriodic acid). Forms a picrate, yellow prisms, m.p. 251-253" (from ethanol).

16


TABLE 6.5. THE EFFECT OF VARYING THE BASIC CATALYST ON THE EFFICIENCY OF THE CYCLIZATION OF I,2-DIMETHYL-3PHENACYLBENZIMIDAZOLIUM BROMIDE (6.25; R' =Me, R2= R4 = H, R3 = Ph) TO 4-METHYL-2-PHENYL-4H-PYRROLql,2-a]BENZIMIDAZOLE (6.27; R' = Me, R2= R4 = H, R3= Ph) Basic catalyst'

Yield (YO)

Basic catalyst"

Yield (YO)

Sodium ethoxide Sodium methoxide Sodium hydroxide Calcium hydroxide Potassium carbonate Sodium carbonate Sodium hydrogen carbonate Ammonium carbonate

93 86 91 95 86 91 95 35

Calcium carbonate Sodium phosphate Sodium acetateb Triethylamine Ammonia Di-n-butylamine n-Butylamine Pyridineb

18 70 7 50 91 36 70 19

Reaction conditions: H20or EtOH/(reflux)(S hr). Reaction conditions: H20or EtOH/(reflux)(20 hr).

reflux for a few hours with aqueous sodium hydrogen arbo on ate""^-'^"^ or aqueous sodium arbo on ate'^"^"" with or without the addition of sodium s~lfite"-'~ to inhibit the subsequent oxidation of the 4H-pyrrolo[1,2-a]benzimidazole products, which tends to occur making purification difficult. Other bases that have been used successfully to catalyze the cyclization of benzimidazolium salts of the type (6.25) to 4H-pyrrolo[l,2-a]benzirnidazoles (6.27) include alkali metal hydroxide^"^'"'^ and alk~xides,'~*"*'~ ammonia,16 benzyltrimethylammonium hydroxide,16 and amines (primary, secondary, and tertiary).l2*I6 A detailed study16 of the variation in the efficiency of the cyclization of 1,2-dimethyl-3-phenacylbenzimidazolium bromide (6.25; R' = Me, RZ= R4 = H, R3 = Ph) to 4-methyl-2-phenyl-4Hpyrrolo[l,2-a]benzimidazole (6.27; R' = Me, R2 = R4 = H, R3= Ph), using different catalysts, reveals (Table 6.5) that ammonium and alkaline earth metal carbonates, sodium acetate, and certain amines (e.g., di-n-butylamine, pyridine) are inefficient catalysts for transformations of this type. The probable intermediacy of benzimidazolium betaines [Scheme 6.5; (6.26)] in the cyclizations of the benzimidazolium salts (6.25) is demonstrated'6 by their isolation under suitable conditions and their ready transformation (Table 6.4) into the corresponding 4H-pyrrolo[ 1,2-a]benzimidazoles (6.27) merely on warming with water or on attempted crystallization from organic solvents. Where the 2-alkyl group in the original benzimidazole (6.24) is activated by a substituent such as ethoxycarbonyl o r cyano, simply warming in acetone solution with the a-halogeno ketone is sufficient to accomplish direct conversion into the 3-ethoxycarbonyl or 3-cyano-4H-pyrrolo[ 1,2-a]benzimidazole (6.27; R 2 = C 0 2 E t or CN) thus opening up routes to the otherwise difficultly accessible 3-carboxylic acids of the series.*' In a further synthetically useful variant, 1-substituted 2-methylbenzimidazolium salts bearing a benzyl, ethoxycarbonylmethyl, or cyanomethyl substituent at N(3)


nTqR2

17

R3

I R1

R’

(6.28)

Scheme 6.6

COR~

(6.29)

[Scheme 6.6; (6.28; R2= Ph, C02Et, or CN)] have been shown” to condense with acid anhydrides in the presence of a base such as triethylamine to afford in a single step, moderate to good yields (Table 6.4) of 4H-pyrrolo[ 1,2-a]benzimidazoles with an acyl substituent at C(3) and a phenyl, ethoxycarbonyl, or cyano substituent at C(1) (6.29;RZ= Ph, CO,Et, or CN). 2-Methylated 4H-py~olo[1,2-a]benzimidazoles are also the end-products of the sodium hydrogen carbonate-sodium hydrogen sulfite, or potassium hydroxide-mediated cyclizations of 1-substituted 2-alkyl-3-(2-propynyl)benzimidazolium bromides [Scheme 6.7; (6.30)].z2These transformations are reported22to proceed in moderate to excellent yield (Table 6.4) and are

(6.32)

(6.33)

Me

(6.34)

(6.35) Scheme 6.7

Condensed Benzimidazoles of Type 6 - 5 5

18

rationalized by a course (Scheme 6.7) involving the formation and cyclization of an allenylbenzimidazolium betaine intermediate [(6.30)+ (6.31)+ (6.32)+ (6.33)+(6.34)].The enhanced yields (Table 6.4) observed in the cyclizations of the 2-benzylbenzimidazolium salts (6.30;R’ = Ph) are consistent with stabilization of the proposed carbanion intermediate (6.32)by the phenyl substituent. Similar carbanion stabilization also accounts for the high yield (Table 6.4) base-catalyzed cyclization of 2-benzyl-l-(2-propynyl)benzimidazole (6.35) to 2-methyl- 3-phenyl-4H-pyrrolo[ 1,2- a ]benzimidazole (6.34;R‘ = H,R2= Ph).z2 4H-Pyrrolo[1,2-afienzimidazoles are isolated in very low yield (Table 6.6) from the reactions (Scheme 6.8) of 1-substituted 3-acylmethylbenzimidazolium bromides (6.36)with acetylenic esters under basic condit i o n ~ . ” *These ~ ~ transformations are readily in terms of the in situ formation of benzimidazolium ylid intermediates and their 1,3-dipolar cycloaddition to the acetylenic ester to afford dihydropyrrolo[ 1,2-a]benzimidazoles convertible by oxidation in the reaction medium into the observed products [Scheme 6.8; (6.37)+ (6.38)4(6.39)]. 4H-Pyrrolo[1,2-a]benzimidazoles are also formed in low yield (Table 6.6) in the cycloaddition

pJj’ / N

I

CH2COR2

a j ’ CHCOR~

3%

I

(6.39)

S&eme 6.8

6.1. Fused Benzirnidazoleswith No Additional Heteroatorns

I

H

19

CH2C02Me

(6.40)

C02Me

(6.41)

sebeme 6.9

reactions of simple benzimidazole derivatives with acetylenic esters.2s-2Y Thus, prolonged heatiw of benzimidazole with methyl propiolate in acetonitrile gives the adduct [Scheme 6.9; (6.41)]in 10% yield.2s In contrast, 1,2-disubstituted benzimidazoles react with dimethyl acetylenedicarboxylate to give low yields of L)H-pyrrolo[1,2-a]benzimidazoles [Scheme 6.10; (6.4S)l derived by loss of the C(2) substituent?G28 These deep-seated transformations are accounted for (Scheme 6.10) by reaction of the benzimidazole derivative with two molecules of the acetylenic ester to give a zwitterionic intermediate convertible by cyclization and subsequent fragmentation into the 4H-pyrrolo[ 1,2-a]benzimidazole products [Scheme 6.10; (6.42)+ (6.43)+ (6.44)+ (6.431. On the other hand, the reaction2’ of ethyl 2-(N-methylbenzimidazolyl)acetate with dimethyl acetylenedicarboxylate to give the 4H-pyrrol4 1,2-a]benzimidazole tricarboxylic ester [Scheme 6.11 ; (6.50)] is best accommodated by a course (Scheme 6.1 1)”

~1

w-

C0,Me

/

C02Me

R2

-u;q A

RI

Meme 6.10

C02Me

C0,MeC02Me

(6.45)

-CO,Me

R’ RZH (6.44)

/I

h~ 0

(6.36; R’ = Me, R2 = Ph)

(6.36; R ’ = Et, R2 = OMe)

(6.36; R’ = Me, R2 = OMe)

(6.36; R’ = CH2Ph, R2 = Ph)

(6.36; R ’ = Et. R2 = p-BrC,H,)

(6.36; R’ = Et, R2 = Ph)

(6.36; R’ = Me, RZ= p-BrC,H,)

(6.36; R’ = Me, R2 = Ph)

Starting material

Reaction conditions‘

Methanol Ethanol Ethanol

224 155-157 186 175- 178

ins 160 130-131

5

4 4 17 5 2 11

R”=H) (6.39; R i = R4 = Et, R2=p-BK6H4,R 3 = H ) (6.39; R’ = CH,Ph, R2 = Ph, R” = H, R4 = Et) (639; R ’ = Me, RZ= OMe, R3=H, R4=Et) (639; Ri = Et. R2 = OMe, R” = H, R4 = Et) (6.39; R’ = R4 = Me, R2 = Ph, R” = C0,Me)

164

4

(6.39; R’ = Me, R2 = Ph, R” = H, R4 = Et) (6.39; R’ = Me, R2 = p-BrC,H,, R3 = H,R4 = Et) (6.39; R’ = R4 = Et, R2 = Ph,

Ethanol

Ethanol

Ethanol

Ethanol

Ethanol

m.p. (“C)

Yield (90)

Product


Colorless needles Colorless needles Colorless needles Colorless needles Colorless crystals Colorless needles Colorless needles Colorless needles

crystal form

23

23

23

24

23

23

23

23

Ref.

TABLE 6.6. SYNTHESIS OF 4H-PYRROLO[ I,~-cI]BENZIMIDAZOLES BY CYCLOADDITION REACTIONS OF BENZIMIDAZOLE DERIVATIVES WITH ACETYLENIC ESTERS

1 I (6.50)

0.2 3

10

(6.45; R = CHMHC0,Me)

I I (6.45; R = MeO,CC=CHCO,Me)

2 36

(6.45; R = Me) (6.45: R=CHCCHCO,Me)

G H

237-239 140

-

183 203

182

198

134-135

177- 178

2 12-2 13

Rods

Methanol

Methanol Methanol

Rods Plates

-

-

Methanol

Methanol

Ethanol

Ethanol

Colorless crystals Colorless PColorless PIiSmS Colorless needles Colorless needles

Dichloroethane

28 29

28

21 28

26

25

23

23

24

a A = HG=CCO,Et, K2C03, dimethylformamide/(room tempJ(2 days); B = HC=6CCO,Et, Et,N, benzene/(reflux)(3 hr); C = MeO,COCCO,Me, K,CO,, dimethylformamide/(room tempJ(3 days); D = MeO,CG=CCO,Me, Et,N, benzene/(room tempJ(24 hr); E = H(3fCC02Mc, MeCN/(reflux) (5-7 days); F = MeO,CgCCO,Me, THF or ether/(room tempJ(7 days); G = MeO,CXkCCO,Me, MeCN/(reftux)(S hr); H = MeO,CC=CCO,Me, MeCN/(reflux)(lZ hr); I = MeOzCC=CCOzMe, MeCN/(reflux)(S-10 days).

16.46)

R'=RZ=Ph) I (6.42; R = MeO,CC--CHCO,Me)

(6.42; R = Me. R' = Ph, RZ= H) (6.42: R=CH--%HCO,Me, R' = Ph, R2= H) (6.42; R = CH%HCO,Me,

8

10

2

7

8

(6.45; R = Me)

E

(6.40)

(6.39; R' = CH,Ph, R2= Ph, R3 = CO,Me, R4= Me) (6.39; R' = R" = Me, R2 = OMe, R3 = C0,Me) (6.39; R' = Et, R2 = OMe, R3= C0,Me. ' R = Me) (6.41)

F

C

(6.36; R' = Et, R2 = OMe)

RZ= H)

C

(6.36; R' = Me, RZ= OMe)

(6.42; R = R' = Me,

D

(6.36; R' = CH,Ph, R2 = Ph)

22


I CHzCOzEt Me (6.46)

Me (6.47)

(6.49)

(6.50) scbane 6.11

initiated by the formation of the zwitterionic intermediate (6.48) cyclization of which affords a dihydropyrrolo[ 1,2-a]benzimidazole (6.49) readily oxidiz-

able to the observed product (6.50). 2,3-Dihydro- 1H-pyrrolo[l,2-a]benzimidazoles [Scheme 6.12; (6.54)] are readily synthesized in moderate to high yield (Table 6.7) by the basecatalyzed cyclization of 2-(y-halogenopropyl)benzimidazoles (6.55; X = C1 or Br).30*31 The ready formation of 2-(y-chloropropyl)benzimidazoles (6.55; X = C1) by chlorination of the corresponding 2-( y-hydroxypropy1)benzimidazoles (6.53) provides the basis for an improved version32 of such cyclizations, in which the hydroxy compound (6.53) is heated with thionyl chloride in dimethylformamide to give directly moderate to high yields of the requisite 2,3-dihydro- 1H-pyrrolo[l,2-a]benzimidazoles (6.54). Products of the latter type are also formed even more directly, if less efficiently (Table 6.7), by the thermal cyclization [Scheme 6.12; (6.53) --* (6.54)] of 2-(yhydroxypropyl)benzimidazoles, which can either be preformed33 or generated in situ by the condensation of ortho-phenylenediamine derivatives with y-lactones [Scheme 6.12; (6.51)+(6.52) + (6.53)].3535It is interesting to


23

NH2

R4

NH2 (6.51)

R

(6.54)

R'

R'

\

NH2

R2 (6.51)

R5

(6.56)

(6.57)

SeLemc 6.12

compare the low yields of 2,3-dihydro-1H-pyrrolof1,2-a]benzimidazoles (Table 6.7) obtained in the cyclizations of 2-(y-hydroxypropyl)benzimidazoles (6.53) with the uniformly high yields of such products (Table 6.7) claimed36 for the acid-catalyzed ring-closures of 2-(y-aminopropyl)benzimidazoles accessible in isolated form or by the in siru reaction of orthophenylenediamine derivatives with pyrrolidin-2( 1H)-ones [Scheme 6.12; (6.51) + (6.56) -+ (6.57)]. Formation of 2,3-dihydro- lH-pyrrolo[ 1,2-a]benzimidazoles by cyclization of y-functionalized 2-propylbenzimidazoles (cf. Scheme 6.12) unlike the alternative synthetic approach of ring-closure of N(ortho-substituted pheny1)pyrrolidines (see later) is unambiguous in relation to the site of substituents in the pyrrolidine nucleus of the final products. However, the use of nuclear-substituted benzimidazole precursors in such cyclizations can lead, by ring-closure in two possible senses, t o isomer which in some cases can be successfully sepamixtures (Table 6.7),32*.16 rated.32 In other instances, single isomers, often of unestablished orientati or^,^^ are produced. In the context of the latter situation, Freedman, Payne, and Day have shown32 that, irrespective of the electronic bias of the substituent, ring-closure of 5(6)-substituted 2-(y-chloropropyl)benzimidazoles occurs preferentially at the nitrogen atom para to the occupied site in

P

E E

E

(6.53; R' = NO,, R' = R' = R4 = H)

E

E

E

E

D

D

A

A

+

R3= R4 = H) (6.54; R' = R2 = R3 = R4 = H)'

(6.54; R' = R' = MeO,

(6.54; R' = R2 = Me, R' = R4 = H)

RZ= Cl)

(6.54; R' = R3 = R4 = H,

176- 177

40

Ether-benzene

45

50

61

133-135

194-196

177-179

Benzene

Ethyl acetate

Ethyl acetate

32

32

32

32

133- 134 49

96-98

32

Ethyl acetate 209-210 60

48

32 32

Ethyl acetate Ether-hexane

30

30

115 144-145 44 43

93-95

30 236-238

40 38

30

188-189

31

85

72

(654; R' or RZ= CI

A

-

-

31

30

quant.

(6.54; R' = R2 = R3 = R4 = H)d.r

C

n-Heptane

30

Ethyl acetate

115.5-1 16.5 115-1 17

Ref.


m.p. ("C)

236-237

43

(654; R' = R2= R3 = R4 = H)d.e

B

or H, R3=R4=H)b.f (6.54; R' = R2 = R4 = H, R3 = Me)b4 (6.54; R' or R2 = CI or H, R' = Me, R4 = H)b.' (6.54; R' = R2 = R4 = H, R' = n-C,H,S)b (6.54; R' or R2=CI or H, R'= n-C,H,,, R4=H)b*f (6.54; R' = R2 = R' = R4 = H) (6.54: R' = R3 = R4 = H, R2 = Me) (6.54; R' = R3 = Rq = H, R2= NO,) (6.54; R' = Cl, R2=R3=R4= €4)

70

(6.54; R' = R2 = R3 = R4 = H)'

A

Yield (YO)

Product

Reaction conditions'

R' = Me)b (655; R ' = R 2 = R 4 = H , R3 = n-C,HI5, X = Cl)b (6.55; R' = X = CI, R2 = R4 = H, R3 = o-C;H,,)~ (6.53; R' = R2 = R3 = R4 = H) (6.53; R' = Me, R2 = R3 = R4 = H)

(6.55; R' = R2 = R3 = R4 = H, X = Br) (6.55; R' = X = CI, R2 = R3 = R4 = H) (6.55; R' = R2 = R4= H, R3 = Me, X = ClIb (6.55; R' = X = Cl, R2 = R4 = H,

X = Br)

(6.55; R' = R2= R3 = R4 = H, x = Cl)b (6.55; R' = R2 = R' = R4 = H,

Starting materials

TABLE 6.7. SYNTHESIS OF 2,3-DIHYDRO- lH-PYRROLO[1,2-a]BENZIMIDAZOLESBY RING-CLOSURE REACTIONS OF BENZIMIDAZOLE DERIVATIVES AND RELATED PROCESSES

I

+

(6.58; R = H)

(6.56; R3 = R4 = R5 = H)

+

(6.51; R' =Me, R2 = H)

(6.56; R3 = R4 = H, R5 = Me)

+

(6.56; R3 = R4 = RS= H) (6.51; R' = R2 = H)

+

(6.51; R' = R 2= If)

(6.52; R3 = Me, R4 = H) (6.57; R' = R2= R3= R4= Rs= H) (6.57; R' = R2 = R3 = R4= R5 = H)

1

I I

(652; R3 = Me, R4 = H) (6.51; R' = R2 = Cl)

+

(652; R3 = H, R4 = Me) (6.51; R' = CI, R2 = H)

+

(6.52; R3 = R4 = H) (6.51; R' = R2 = H)

+

R3 = Me) (6.53; R' = R2 = Cl, R3 = Me, R4 = H) (6.51; R' = R2 = H)

(6.53; R' = R2 = R4 = H,

0

N

N

N

h4

L

.

1

(6.60; R = H)'

(6.54; R' = R3 = R4 = H,

(6.54; :;:iR4=H) R' = Me,

[

('54; R' = R2 = R3 = R4= H)

R2=R3=R4=H)

(6.54; R' =Me,

+

R2 = Me)

43

71

72

74

73

85

76

149

15

(6254;R' = R2 = Cl, R3 = Me,R4= H) (6.54; R ' = R2= R3 = R4 = H) (6.54; R' = R2= R3= R4 = H) '(6.54; R' = R3 = R4 = H,

3

K

101-103

16

(6.54; R', R2 = CI or H, R3=Me,R4=II)i

I

170-171

nitrnhrnrrnr

Ethanol or

-

-

4

Ethyl acetate

-

Ethyl acetate

-

118

-P

118"

-

n-Heptane

n-Hept=

-

m

Ethyl acetate'

n-Heptane

-k

115

10

147-149

35-40

I

18

43

29

(6.54; R' = R2 = R4 = H. R3 = Me)' (654; R' = R2 = CI, R3 = Me, R4 = H)

H

G

F

19

37. 38,

36

36

36

36

36 36

33

33

34

35

33

33

(Continued)

85 85 85

(6.63; R = H) (6.63; R = OMe) (6.63; R = NMe,)

78 68

-

62

Yield (YO)

(6.60; R = H)' (6.61)' (6.60; R = OAc)'

(6.60; R = H)' (6.60; R = H)'

Product

200-20 1 121- 122 (decomp.) 195 250 252

-

171-172 172-175

m.p. ("C)

Dichloroethane Methanol Ethanol

Ether or nitrobenzene Chloroform Ether

-q


44 44 44

41 42 40

38, 43 39.40

Ref.

'

'

a A = NaOEt, EtOH/(reflux)(2 hr); B = KOH, EtOH/(room temp.)(20 min); C = NaOEt, EtOH, high dilution/(room tempJ(20 min.); D = NaOEt, EtOH/(room temp.)(2 hr); E = SOCI,, dimethylformamide/(reflux)(45 min); F = ~-methylbutyrolactone/(125")(5hr); G = a-methylbutyrolactone/ (reflux)(8 hr); H = 270°, autoclave/7 hr; Z = 270°/3 hr; J = reRux/5.5-8 hr; K = Montmorillonite catalyst/(290-31O0)(10 hr); L = 85% H,P0,/(300")(12 hr); M = methanesulfonic acid/(300-320°)(10 hr); N = 85% H,P0,1(300")(2-4 hr); 0 =sublimation at 230-240O; P = 95-130"/30 min; Q = dicyclohexylcarbodiimide, pyridine, dimethylformamide/(5-10")(10-12 hr); R = POCI,, dimethylformamide/(room tempJ(24 hr); S = crystallization from acetic acid. Hydrochloride. Forms a hydrochloride, colorless, hygroscopic crystals, m.p. 235-237" (from ethanol-ether). Colorless prisms. Forms a picrate, yellow needles, m.p. 222-222.5 (from 2-methoxyethanol). 'Position of the chlorine substituent not determined. * Free base has m.p. 68.5-70". 4.7-Dimethoxy derivative. ' 5.8-Dimethoxy derivative. Colorless crystals. Purified by distillation. Purified initially by distillation, b.p. 130"/0.2 mm Hg. Brown oil. characterized as the picrate, yellow prisms, m.p. 222-224' (from ethanol). " b.p. 148-150"/0.2 m m Hg. O Isomer mixture not separated. Oil, b.p. 143-145'/0.2 m m Hg. Purified by sublimation. ' Yield not quoted.

S S S

(6.62; R = H) (6.62; R = OMe) (6.62; R=NMe,)

Q

R P

P

0

Reaction condition"

(6.58; R = H) (6.58; R = H) (6.58; R = OH)

(6.59) (6.58; R = H)

Starting Materials

TABLE 6.7


21

the nucleus. For example,32 cyclization of the benzimidazole derivatives (6.55; R' = Me or NO2, R2 = R3 = R4 = H, X = CI) leads to the single 2,3dihydro-lH-pyrroIo[l,2-a Jbenzimidazoles (6.54; R' = R3 = R4 = H, R2 = Me or NO2), albeit in only moderate yield (Table 6.7). In contrast, ring-closure of the chloro derivative (6.55; R ' = X = C I , R 2 = R 3 = R 4 = H ) affords a separable mixture of the 6-chloro- and 7-chloropyrrolo[ 1,2-a)benzimidazoles (6.54; R' or R2 = CI, R2 or R' = R3 = R4 = H).32The aforementioned preferential cy~lization'~of the methyl-substituted benzimidazole (6.54; R' = Me, R2 = R' = R4 = H) to the single pyrrolo[ 1,2-a]benzimidazole isomer (6.54; R' = R3= R4= H, R2 = Me) stands in contrast to the isomer mixture obtained3' (cf. Table 6.7) in the analogous cyclization of the 2 - ( y aminopropyl)benzimidazole (6.57; R' = R5 = Me, R2 = R3 = R4 = H). This latter result casts some doubt on the specificity of the cyclization of electronically biased 5(6)-substituted benzimidazoles by preferential ring-closure at the nitrogen atom para to the substituent. 2,3-Dihydro- 1H-pyrrolo[ 1,2-a]benzimidazol- 1-ones [Scheme 6.13; (6.60)J are readily available as products of the dehydrative c y ~ l i z a t i o n ~ 'o~f *342benzimidazoly1)propionic acids [Scheme 6.13; (6.58) + (6.60)] or, less orthodoxly, in the parent case by the thermal ring-contraction of a benzodiazepinedione [Scheme 6.13; (6.59) --* (6.60; R = H)].38*43The former cyclizations proceed in moderate to good yield (Table 6.7) and can be effected

H

(J-J~=Q-JO

CHNMe,

R

(6.60)

(6.61)

Br (6.62)

Br Scheme 6.13

(6.63)

Condensed Benzimidazolcs of Type 6-5-5

28

t h e r m a l l ~ ~ 'or - ~ ~in the presence of a dehydrating agent such as acetic or dicyclohexylcarbodiimide.4' The use of phosphorus oxychloride in conjunction with dimethylformamide as the dehydrating agent results in Vilsmeier-Haack condensation (see later) subsequent to cyclization, the product then being the corresponding dimethylaminomethylene derivative [Scheme 6.13; (6.58; R = H)+ (6.60; R = H) 4(6.61)]."' 1-Aryl2-bromo-l,2-dihydro-3H-pynolo[l,2-a]benzimidazol-3-ones result (Table 6.7) on attempted crystallization of the dibromo adducts of 2-cinnamoylbenzimidazoles [Scheme 6.13; (6.62) --* (6.63)]." 2,3,3a,4-Tetrahydro-1H-pyrrolo[l,2-a fienzimidazoles, more commonly encountered as the reduction products of 2,3-dihydro-lH-pyrrolo[1,241bernzimidazoles (see later) are also formed in low yield by the in siru cycloaddition reactions of N-acylmethylenebenzimidazolium ylids with electron-deficient alkenes [Scheme 6.14; (6.64; R' = Me or CH2Ph, RZ= Ph

(6.67)

(6.66)

(m.p. loti",from ethanol)

(oil)

COPh

NH2

CO2H

H (6.68) (i) (ii) (iii) (iv)

(6.69)

(6.70)

Et,N, benzene or pyridine/SO" CHp=CHCN/(room temp.) (24 hr, then reflux 3 hr) PhCOCHSHCOPh; pyridine/5O0 rellux/24hr !kheme 6.14


29

or OEt)+(6.65; R’=Me or CH2Ph, RZ=Ph or OEt)-,(6.66) or (6.67)p5.“ and in a single instance3’ by the thermal condensation of orthophenylenediamine with a y-keto carboxylic acid [Scheme 6.14; (6.68)+ (6.69) + (6.70)].

Ring-closure Reactions of Other Heterocycles Substituent i n t e r a ~ t i o nin~ ~N-(orfho-substituted pheny1)pyrrolidines is a rich source of 2,3-dihydro- 1H-pyrrolo[1,2-a]benzimidazoles. Thus, N-(2aminopheny1)pyrrolidine~~~~’ or their N-acyl derivative^^^*^^^^ are smoothly cyclized by peroxytrifluoroacetic a~id~’.~’ or performic (in both cases generated in siru from the corresponding carboxylic acid and hydrogen peroxide) to afford uniformly high yields (Table 6.8) of the corresponding 2,3-dihydro- ltl-pyrrolo[ 1,2-a]benzimidazoles [Scheme 6.15 ; (6.71; R3= H or COR) -+ (6.74)]. The mechanism involved in these ringclosures has been the subject of some controversy.47~49*52*s3 However, support for the proposa147*49v52 that cyclization involves the initial formation and subsequent Polonovski rearrangement of a pyrrolidine N-oxide intermediate [Scheme 6.16; (6.79) +(6.80) + (6.81)+ (6.82) + (6.83)+ (6.84)] is provided by the dem~nstration~~ that N-(2-benzamidophenyl)pyrrolidine N oxide (6.79; R = NHCOPh) cyclizes readily under acidic conditions to afford 2,3-dihydro-lH-pyrrolo[ 1,2-a]benzimidazole (6.84) in good yield (Table 6.8). Less compelling evidence is afforded by the analogous reductive ring-closureS3 of N-(2-nitrophenyl)pyrrolidine N-oxide [Scheme 6.16; (6.79; R = NO2)+ + + (6.84)], since this transformation could be the result of deoxygenation followed by reductive cyclization (see later) of the N-(2-nitrophenyl)pyrrolidine produced. The utility of the Hg(II)-EDTA complex as an oxidizing agent for effecting the high yield (Table 6.8) cyclization of N-(2-aminophenyl)pyrrolidine and its N-acyl derivatives to 2,3-dihydro-1H-pyrrolo[ 1,Za)benzimidazoles has recently been emphasi~ed.~~.” The acid-catalyzed cyclization of N-(2-benzamidophenyl)pyrrolidin-2-one is reporteds6 to afford 2,3-dihydro- 1H-pyrrolo[1,2-a]benzimidazole, albeit in unspecified yield. 2,3-Dihydro- 1H-pyrrolo[ 1,2-a]benzimidazoles are also the end-products of the thermolysis of N-(2-azidophenyl)pyrolidines in high-boiling solvents such as nitrobenzene or diethyleneglycol dimethyl ether [Scheme 6.15; (6.72)+(6.74)].57-59 Ring-closure of this type is generally less efficient (Table 6.8) than peracid-mediated cyclization of the corresponding amines (see before) and is believed to occur by cyclizative insertion in a nitrene intermediate followed by oxidation of the 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazole produced [Scheme 6.17; (6.72) + (6.85) + (6.86)3 (6.74)]. This pathway to product is supported by the demonstration5’ that thermolysis of N-(2-azidophenyl)pyrolidin-2-oneleads to 2,3,3a,4-tetrahydro- 1H-pyrrolo[ 1,2-a]benzimidazol-l-one [Scheme 6.18; (6.87) + (6.88)]


30

(6.7 1)

(6.73)

/

R)-JNj ' J /

R2

/ (6.75)

\

(6.74)

\

Rn-v (6.76)

/

0(6.77)

n=p-Tolyl]

N/

R2

0

scbeae 6.15

~

3

(6.78)

in high yield (Table 6.9). The thermal conversion of the sulfonyl azide [Scheme 6.15; (6.73; R' = H, R2 = NO,)] into the pyrrolobenzimidazole derivative (6.74; R ' = H , R 2 = N 0 2 ) is consideredm to be initiated by Curtius rearrangement in a sulfonyl nitrene intermediate. Interaction between an aromatic nitro substituent and the C(2) methylene center in an ortho-situated pyrrolidine ring is observed under a variety of conditions and almost invariably leads to 2,3-dihydro-lH-pyrrolo[ 1,2-a]benzimidazoles as the major prod~cts.4~ In the context of such ring-closures, the reductive cyclization of N-(2-nitrophenyl)pyrrolidines [Scheme 6.15 ;

(6.85) S c h n e 6.17

Scheme 6.18

31

h,

w

R' = R2= R3= H) R' = R2 = R' = H) R' = R2 = H, R3 = Ac) R' = R2 = H, R3= COPh) R ' = R 3 = H , R2=C1)

R3 = Ac) (6.71; R' =NO2, R2 = H, R3=Ac) (6.71; R' = NHAc, R2 = H, R3 = Ac) (6.71; R' = H, R2 = NHAc, R3 = Ac) (6.71; R' = H, R2 = C0,Et. R3 = CHO) (6.79; R=NHCOPh) (6.79; R=NO,) (6.71; R' = R2 = R3 = H) (6.71; R' = R2 = H, R3 = CONH,) (6.72; R' = R2= H) (6.72; R' = H, R2 = Cl) (6.72; R' = H, R2 = Br) (6.72; R' = H, R' = F) (6.72; R' = R2 = H)' (6.72; R' = R2 = Cl) (6.72; R'=H, R2=Me)

(6.71; R' = R' = H, R2 = Me) (6.71; R' = R3 = H, R2 = NO,) (6.71; R' = H, R2 = NO,,

(6.71; (6.71; (6.71; (6.71; (6.71;

B

R' R' R' R' R' = H,

R2 = Cl)

= R2 = H)

= R2= H) = R2 = H) = R2 = H)

G G G

G G G G

F F

E

R' = H, R2 = F) R' = R2 = H)* R' = R2 = a) (674; R' = H.R2 = Me)

= R2 = H)

= R2 = H) = R' = H) = R2 = H) = R2 = H)' R' = H, R2 = Cl) R' = H, R2 = Br)

R' R' R' R' R'

8

8

z.

-

-e -

71 50 quant. 85 68 46

62

(6.74; R' = H,R2 = C0,Et)

B (6.74; (6.74; (6.74; (6.74; (6.74; (6.74; (6.74; (6.74; (6.74; (6.74

43

(6.74; R' = H, R2 = NHAc)

B

D

91

80-90

86 72 80-90

85-95 92 74 85 75

(6.74; R' = NHAc, RZ= H)

(6.74; R' = NO,, R2 = H)

(6.74; R' = H, R2 = Me) (6.74; R' = H, R2 = NO,) (6.74; R' = H, R2 = NO,)

(6.74; (6.74; (6.74; (6.74; (6.74;

81

(6.74; R' = R2 = H)

1

Yield (Oh

Product

B

B

B

A A

A

B

B C

A

(6.71; R' = R2 = R3 = H)

~

Starting material

~~


~

146

115 114 115 131 150 128 122 215

114-1 15

-

139

256

236

205

144 209-2 10 208

115 115 115 115 133-134

114-115

m.p. ("C)

b

b

b

b

d

Benzene-n-hexane b -

Cyclohexane Ether

-b

52 53 54 54 51 58 58 58 58 58 58

41

51

-

b

51

47

48 48 50

49 41 49 49 48

48

Ref.

-b

-b

-

Benzene-light petroleum 2-Butanone 2-Butanone

-

Benzene-light petroleum


TABLE 6.8. SYNTHESIS OF 2,3-DIHYDRO-lH-PYRROLO[1.2-o]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF N42SUBSTITUTED PHENYL)PYRROLIDINES AND RELATED PROCESSES

w w

3)

R' = H, R2= SO,N

~~~~

L L

I I

K

1

G G G G H H I J 1 J

G

R3= Ac)'

(6.77; R' = H, RZ= C0,H) (6.77; R' = H, R2= CF,) (6.78; R' = RZ= R3= H) (6.78; R' = H, R2= NO,,

61 33 67 68

70 13 32 16

78

quant. quant. 51

-e -e

-

-

-
250 207-209 242 246 202 282 230

J

140 220 198 1 33- 1 34

m.p. ("C)

TABLE 6.19. ALKYLATION REACTIONS OF 2,3-DIHYDRO-lH-PYRROL~2,3-a]BENZIMlDAZOLES, 2,3,3a,4-TETRAHYDRO-1 HPYRROLq1,2-a]BENZIMIDAZOLES,AND lH-PYRROLq1,2-a]BENZIMIDAZOLES

68 58 58 82 59 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58

Ref.

16

10

G G

-m

-m

-

-

110 I10 110

110

110 110 95

-

-"

' -'

-

-' -'

-'

-'

-

-

-

-

F

a

CI CI C0,Et CO,H Br

-

Et (CH,),OH Me Et Et Et Et -

O-NOZC~HJ (6.150) (6.151) -

(6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.149; Ar = Ph) (6.149; A r =

A = MeCI; B = MeI; C = Etl; D = TSO,EI; E = PhCH2CI; F = HO(CH,),Br; G = CH 2 N 2' Without cosolvent. Under reflux. Acetone. Sealed tube conditions. f T = toluene-p-sulfonyl. * Melting point not specified. Yield not specified. ' Nitromethane. I Methanol. Ethanol. Needles from ethanol. Room temp. " Tetrahydrofurane. Orange-red crystals from acetone-chloroform. P Crystallized from ethanol.

5

2

E

E

16 16 2

16 16

2

4

C

C

C

C

B

C F

-

-

-

-

H H H H H H H -

CI CI Cl CI CN CN CN

-

-

-

I I

1

I I I I

63

44

-h

-h -h

-h

-h

-

-h -h -

76

58 58 58 58 58 58 58 76

(decompJ76 169" 2 1 77p 2

110-122'

>250 >250 250 230 >250 >250 280 132-133'

64


ACYLATION. The high degree of aromatic character and susceptibility to electrophilic attack of the 4H-pyrrolo[ 1,2-a]benzimidazole ring system (see before) is demonstrated by the ability of its simple alkyl and aryl derivatives to undergo Friedel-Crafts type reactions with acylating Acylation occurs preferentially at the more reactive C(1) position and only takes place at C(3) when the former site is occupied by a substituent. FormylationI3 is readily achieved in moderate to high yield (Table 6.20) under Vilsmeier-Haack conditions (POC13-DMF) and provides a useful general method for the synthesis of 4H-pyrrolo[l,2-a]benzimidazole-1- and 3carboxaldehydes [Scheme 6.29; (6.152; R' = H) and (6.153; R' = H)]. A~etylation'~*'~ occurs even more simply on heating with acetic anhydride allowing synthetic access, again usually in good yield (Table 6.20), to 1- and 3-acetyl-4H-pyrrolo[ 1,2-a]benzimidazoles [Scheme 6.29; (6.152; R' = Me) and (6.153; R' = Me)]. Correspondingly, benzoyl chloride in the presence of pyridine effects the smooth transformation of suitable 4H-pynolo[ 1,2-a]benzimidazole substrates in good yield (Table 6.20) into the C(1) and C(3) benzoyl derivatives [Scheme 6.29; (6.152; R' = Ph) and (6.153; R' = Ph)].13 4H-Pyrrolo[l,2-a]benzimidazolesare also acylated at the C(l) and C(3) positions in good yield (Table 6.20) by aryl and acyl isocyanates and isothiocyanates, the products of these synthetically useful reactions being the corresponding carboxamide and thiocarboxamide derivatives [Scheme 6.29; (6.152; R' = NHR), (6.153; R' = NHR), (6.154), and (6.155)].74*81 The protic salts (e.g., perchlorates) of 4H-pyrrolo[ 1,2-a]benzimidazoies are activated at C(1) and C(3) toward aldol-type condensation with aldehydes. Reactions of this type have been utilized" for the synthesis of rnethine dyestuffs containing a 4H-pyrrolo[ 1,2-a]benzimidazoIe chromophore, as

TABLE 6.20. ACYLATION REACITONS OF ZOLE DERIVATNES

4H-PYRROLO[ 1,2-a]BENZIMIDA-

Reaction conditions" Product R'

(%)

m.p. ("C)


Ref.

35 64 61 60 78 53 75 52 77 61 53 50 47 71

140 142 222 184 157 132 147 199* 188 173' 145 211 192 219

Cyclohexane Cyclohexane 2-Propanol Ethanol Ethanol Ethanol Ethanol Ethanol Ethanol Ethanol Ethanol Ethanol Ethanol Ethanol

13 13 13 13 13 13 13 12 13 12,13 13 13 13 13

A A A A B B B B B B

c C C C

(6.152) (6.152) (6.152) (6.153) (6.152) (6.152) (6.152) (6.152) (6.152) (6.153) (6.152) (6.152) (6.152) (6.152)

H

H H

H

Me Me Me Me Me Me Ph Ph Ph Ph

R2

R'

Me Ph Me Me Me Et

H

Ph

Me Ph Me Me Ph Me Ph

H

Me Me

H H H

Me Me Me

H

H Me Me

Yield

TABLE 6.20 Reaction conditions'

(Continued) R'

R2

R'

(Yo)

m.p. (T)

(6.153) (6.152)

Ph NHPh

Me Me

Me H

87 31

168 Ethanol 171-172 Ethanol or

D

(6.152)

NHPh

Ph

H

67

D

(6.152)

NHPh

Me

Me

66

D

(6.153)

NHPh

Me

Me

80

E

(6.154)

Ph

Me

H

49

E

(6.154)

Ph

Ph

H

61

E

(6.154)

Ph

Me

Me

58

E

(6.155)

Ph

Me

Me

70

F

(6.152)

NHCOPh Me

H

76

F F F F

(6.152) (6.152) (6.152) (6.153) (6.154)

NHCOPh NHCOPh NHCOPh NHCOPh COPh

Ph Me Ph Me Me

H Me Me Me H

81

G G G G

(6.154) (6.154) (6.154) (6.155) (6.157) (6.158)

COPh COPh COPh COPh

Ph Me Ph Me

H

80 79 82

_

69

C

D

G

H H

-

-

_

Yield


Product

Me Me Me

80

93 83 75

80

41

'A = POCI,,

dimethylformamide 182-183 Ethanol or dimethylformamide Ethanol or 218 dimethylformamide Ethanol or 220 dimethylformamide 162-163b Ethanol or dimethylformamide 177-178' Ethanol or dimethylformamide 170' Ethanol or dimethylformamide 176177' Ethanol or dimethylformamide 193-1 94' Ethanol or nitromethane

Ref.

13 81 81

81 81

81 81 81 81 74

191-192 -d 196197 -d 192-193 -d 169-170 -d 168-169' Ethanol or nitro-

74 74 74 74 74

165-166 -d 165-166 -d 181-182 -d 183-184 -d 232 Ethanol 236 Ethanol

74 74 74 74 12 12

methane

dimethylformamide/(room tempJ(0.5 hr), then warm briefly at 50-60"; B = Ac20/(100")(5 min); C = PhCOCI, pyridine/(10O0)(5 min); D = PhN=C=O/(I00". sealed tube)(l5 rnin); E = PhN=C=S/(lOO", sealed tube)(l5 min); F = PhCON-0, ether/(room temp.)(few min); G = PhCON-==, ether/(room temp.)(few min); H = p-Me,NC,H,CHO, Ac,O/(reflux)(few min). Colorless needles. Yellow solid. Solvent of crystallization not specified. ' Red crystals.

65

66


(6.152)

(6.153)

a+--JN"' Q)---qR R2

T

Me

I

R3

RZ

Me CSNHR'

(6.154)

Scheme 6.29

(6.155)

exemplified by the transformations [Scheme 6.30; (6.156) +(6.157) or (6.158)J (Table 6.20)." The C(3) center in 2,3-dihydro-lH-pyrrolo[ 1,2-a]benzimidazole [Scheme 6.31; (6.159)] is sufficiently activated by the adjacent azomethine center to undergo acylation under relatively mild conditions. For example, treatment of 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole (6.159)with acetic anhydride in the presence of zinc or with benzoyl chloride in ~ y r i d i n e ~ ~

I

Me

(6.156)

Me

Me

(6.157)

schcw 6.30

NMez (6.158)


67

results in specific acylation at C(3) with formation of enol esters of the type (6.160; R = Me or Ph). In the benzoylation of (6.159) using benzoyl chloride in alkaline solution,56 enol ester formation is accompanied by ring-opening to the product (6.161) (Scheme 6.31). Not unexpectedly, quaternization of the N(4) center in 2,3-dihydro-lH-pyrrolo[ 1,2-a]benzimidazole (6.159) enhances the reactivity of the C(3) position toward acylation. As a consequence, C(3) acylative condensation reactions of N(4)-aIkyl-2,3-dihydro- 1H pyrrolo[ 1,2-a]benzimidazolium salts, e.g. [Scheme 6.32; (6.162) + (6.163)] have found widespread uses8."* for the construction of methine dyestuffs incorporating a 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole nucleus. The lack of reactivity toward base-catalyzed aldol-type condensation reported41 for 2,3-dihydro-lH-pyrrolo[ 1,2-a]benzimidazol- 1-one (6.164) (Scheme 6.32) is surprising and contrasts with enhanced reactivity of the sulfur analog [Scheme 6.32; (6.1631 in such processes (see later).

~--~*y-J--qe ? Rr I*

(6.159)

COPh (6.161)

R

(6.160)

(m.p. 139")

m.p. ("C)

126.5 231 (i) Ac20. ZnC12/(reRux)/(3 hr) (ii) PhCOCl, pyridine/(lOO")/(15 min) (iu) PhCOCI, 1S0/o NaOH/(mm temp.)(lO min) SCLeac 6.31 Me

Ph

The orthodox behavior of amino substituents in the aromatic nucleus of 2,3-dihydro- lH-pyrrolo[1,2-a]benzimidazoles toward acylationsx has been exploited for the synthesis of fused systems as illustrated by the transformationS3 shown in Scheme 6.33. AND DIAZO HALOGENATION, NITRATION, NITROSATION, DIAZOTIZATION, COUPLING. With the exception of the reportedR4chlorination of the aromatic nucleus in 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole by sulfuryl chloride, examples of electrophilic halogenation reactions of pyrrolo[ 1,241benzimidazoles of the various structural types are surprisingly lacking. In contrast, the behavior of both 4H-pyrrolo[l,2-a]benzimidazoles and 2,3dihydro- 1 H-pyrrolo[ 1,Za]benzimidazoles toward nitration is reasonably well documented. The attempted nitration'" of alkyl- and aryl-substituted 4H-pyrrolof 1,2a]benzimidazoles with fuming nitric acid results in the formation of nitrates,


68

(6.162)

NMez (6.163)

0J;1:Q

(6.164) (6.165)

R H

X TSO,

a1

X -

Yield (%) 15

20

m.p. ("C) 250-251 (dec0mP.) 317 (decomp.)

(i) Me,NC,H,CHO, pipendine, EtOH/ (reflux)/(0.5-2 hr) [T = toluene-p-sulfonyl] Mew 6.32

CH,

s

which resist further nitration. On the other hand, treatment of 1- and 3acetyl-4H-pyrrolo[1,2-a]benzimidazoles with fuming nitric acid in acetic acid" results in the nitrative replacement of the acyl substituent to give the corresponding 1- and 3-nitro-4H-pyrrolo[1,2-a]benzirnidazoles [Scheme 6.34; (6.166; X=NOz) and (6.168; X=NO,)], albeit in only low yield (Table 6.21).Subsequent nitration of the benzene nucleus is not observed, presumably as a result of conjugative deactivation by the nitro group already present in the C(1) or C(3) position [cf. Scheme 6.34; (6.166; X = NOz) c* (6.167) and (6.168; X = NO,) c* (6.169)]. The presence of such conjugative

0

H

(m.p. 260")

(i) ethyl polyphosphate/( 165OM0.75hr) Scheme 6.33

o-qx

6.1. Fused Benzimidazoleswith No Additional Heteroatoms +X-NOI+

'

N ' I Me R' (6.166)

R2

9-

";q*o'

he X

-of

(6.168)

R2

N I ' 1 Me (6.167)

Me T,

69

c

(6.169)

(6.170)

Scbcme 6.34

(6.171)

interaction is supported by the exceptionally low frequency7' of the IR bands due to the nitro groups in these molecules. In contrast, 2,3-dihydro1H-pyrrolo[ 1,2-a]benzimidazoles containing a C(6) or C(7) amino substituent or a C(6) halogeno substituent are smoothly nitrated by "mixed acid" at low temperature to give the corresponding C(7) or C(6) nitro derivatives [Scheme 6.34; (6.170) or (6.171)] in high yield (Table 6.21).58,7' In contrast to their resistance to nitration (see before) simple C(1) and C(3)-unsubstituted 4H-pyrrolo[1,2-a]benzimidazoles are rapidly nitrosated7' at room temperature by sodium nitrite in acetic acid to give the C(1) or C(3) nitroso derivative [Scheme 6.34; (6.166; X = N O ) or (6.168; X = NO)] in excellent yield (Table 6.21). As in the case of acylation the nitrosation of 4H-pyrrolo[ 1,2-a]benzimidazoles takes place preferentially at C(1) and only occurs at the C(3) position when the C(1) position is substituted. 4H-Pyrrolo[l,2-a]benzimidazolesalso couple readily at the C(1) and C(3) positions with arenediazonium cations giving the respective azo derivatives [Scheme 6.34; (6.166; X = N=NAr) or (6.168; X = N=NAr)] in very high yield (Table 6.21)." Amino substituents in the benzene nucleus of 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidzoles can be diazotized under standard condition^^^"^ to give diazonium salts which undergo the usual displacement reactions (see later).

0

4

(6.166) (6.168) (6.166) (6.166) (6.166) (6.168) (6.166)

(6.166)

(6.166)

C

D D D D D

D

D

C

C

B

(6.166) (6.166) (6.166) (6.166) (6.168) (6.166)

Product

A A A A


p-Et,NC,H,N=N

p-EtzNC,H,N=N

NO NO N=NPh N=NPh N=NPh N=NF'h p-Et,NC6H4N=N

X

R

Me

H

Me Me H

Me

Ph

56

82

180

191

155 161

207 245 141 176 180

74 87 58 60 65 51 62 Me' Me' Me Ph Me8 Me Me

Me Me

H H

229 304 276 274 254 276

32 30 36 40 17 93

Me Ph Me Ph Me Meb

H H Me Me Me H

m.p. ("C)

(YO)

R2

R'

Yield

Nitromethane Nitromethane Nitromethane Nitromethane Nitromethane Ethanol-perchloric acid Ethanold Ethanold Ethanol' Ethanol' Ethanol' Ethanol' Dimethylformamide waterf Dimethylformamide waterf Dimethylformamide waterf


70

70

70

70

70 70 70 70 70

70 70 70

70

70 70

Ref.

TABLE 6.21. NITRATION, NITROSATION, AND DIAZO-COUPLING REACTIONS OF ~H-PYRROL~I,~-U]BENZIMIDAZOLES AND 2,3-DIHYDRO-lH-PYRROLO[ 1.2-a]BENZIMIDAZOLES

4

w

(6.166)

D

-

-

-

p-O*NCBH,N=N

p-HOZCC,H,N=N P-HO~CC~H,N=N p-OzNC,H,N=N

3r CI F NHAc NHAc

-

-

-

-

-

Me

H

H

H

-

-

Me

Me Ph Ph

75

75

74

-h -h

46

86 78 75

201 203 236 212 208

262

241 208 253

Ethanol' Ethanol'

-'

-'

Ethanol' Ethanol' Dimethylformamidewater' Dimethylformamidewater' Ethanol

58 58 58 71 71

70

70 70 70

A = HNO,(S.G. 1.52), AcOH/(room temp.)(short period); B = HNO,(S.G. 1.52), AcOH/(100°)(30 min); C = NaNO,, AcOH/(room NaOAc, AcOH/(5-lO0)(short time); E = HNO,(S.G. 1.42), conc. H,SO,/(O-S")(short time); F = HNO,(S.G. 1.5). ternp.)(lO min); D = conc. H,SO,/(O")(lO min, then room temp.)(] hr). Perchlorate, yellow needles. Forms a hydrochloride, yellow-orange needles, m.p. 260" (from water). Forms green crystals. Forms a perchlorate, orange-yellow needles, m.p. 244" (from acetic acid). Forms red needles. Forms a perchlorate, m.p. 281" (from nitromethane). Yield not quoted. ' Solvent of crystallization not specified. Forms yellow needles.

F F

E

E

E

(6.170) (6.170) (6.170) (6.170) (6.171)

(6.166) (6.166) (6.166)

D D

D


72

Reactions with Nucleophiles

HYDROXYLATION. The lability, toward hydrolytic cleavage, of the pyrroline ring in simple 3H-pyrrolo[ 1,2-a]benzimidazoles is illustrated (Scheme 6.35) by the reportedg ring-opening of 1,3,3-trimethyl-3H-pyrrolo[l,2-~]benzimidazole (6.172)to the N-(2-aminophenyl)pyrrolinone (6.173) merely on attempted crystallization from hydroxylic solvents. O n the other hand, the Me

(6.172)

(6.173) Sckme 6.3s

inertness toward hydroxylation, and consequent stability to hydrolysis of the pyrrole ring in 4H-pyrrol~1,2-a]benzimidazoles, is indicated by the demon~tration'~ that ~ ' ~C(1) and C(3) acetyl substituents in such molecules are removable by forcing acidic hydrolysis, leaving the parent ring system intact. The similar stability to hydrolysis of the pyrrolidine ring in 2,3-dihydro-lHpyrrolo[ 1,2-~Jbenzimidazolesis illustrated (Table 6.22) by the survival of the ring system under acidic and basic conditions which serve to demethylate

TABLE 6.22. HYDROLYTIC REACITONS OF ~ . ~ - DIHYDRO-~H-PYRRO~~,~-Q]BENZIDAZOLE DERIVATIVES 2,3-Dihydro- lH-pyrrol~1,2-a]benzimidazoie Hydrolysis conditionsa Substrate A

B B

C C C a

Roduct

5 ,CDimethoxy5,8-Dihydroxy6-AcetamicJo-7-nitro- 6-Amino-7nitro7-Acetamido-6-nitro- 7-Amino-6nitro6-Ethoxycarbonyl6-CarboxyI-Ethoxycarbonyl8-Carboxy6-Ethoxycarbonyl-7- 6-carboxy-7chlomchiom-

Yield m.p. (%)

("0


50

305-306 Ethanol 275 2-Ethoxyethanol (decamp.) 320 2-Ethoxyethanol (decamp.) quant. 300 Acetic acid-water 310-311 -d d >270

-

-

Ref. 32 71 71 58 58 58

A = conc. HCUlOO", pressure; B = conc. HQ/(reflux)(l hr); C = 2.5 M NaOH, EtOH/(reBuxM mh). Yield not quoted. Forms red prisms or needles. Solvent not specified.

6.1. Fused Benzimidazoles with No Additional Meteroatoms

kH2Ph C1(6.174)

73

I

CH2Ph (6.175)

(6.176)

=ao CHNMe,

(6.178)

(rn.p. 170-171O)

(6.179)

(i) 4 M NaOHl(heat)/(1 rnin) (ii) Na,C03 aq./beat (iii) 3% HCI, EtOH/(roorn temp.)(3 hr) sebcnc6.36

methoxy sub~tituents,’~deacetylate acetamido groups,71 and hydrolyze ethoxycarbonyl s u b s t i t u e n t ~ ,giving ~~ the corresponding phenols, amines, and carboxylic acids, usually in good yield (cf. Table 6.22). C(3)-Acyl substituents in 2,3-dihydro- 1H-pyrrolo[ 1,2-u]benzimidazoles are also hydrolytically removed under alkaline conditions without disruption of the ring system.s6 On the other hand, the presence of a quaternary or a carbonyl center at N(4) and C(l), respectively, confers hydrolytic instability on the 2,3-dihydro- 1H-pyrrolo[ 1,2-u]benzimidazole ring system as demonstrated by the ring-opening reactions [(6.174) -+ (6.175)p9 and [(6.176)+(6.177)]37 portrayed in Scheme 6.36. However, the successful acid-catalyzed hydrolysis (Scheme 6.36)42 of the dimethylaminomethylene derivative (6.178) to the hydroxymethylene product (6.179) shows that 2,3-dihydro- 1H-pynolo[ 1,2a]benzimidazoles can be manipulated in protic media provided the conditions are mild enough. As in the case of 2,3-dihydro- 1H-pyrrolo[ 1,2-u]benzimidazole (see before), the hydroxide-catalyzed ring-opening of 1H-pyrrolo[ 1,2-a]benzimidazol-1-ones [Scheme 6.37; (6.180)] as initiated by attack at the carbonyl group, and affords 2-benzimidazolylacrylic acids of the type (6.181; R = Ph)’ or [in the case of 3-hydroxy substrates, e.g. (6.180; R = OH)] by subsequent decarboxylation, the 2-benzimidazolyl ketone [e.g. (6.182)]., The presence

74

a;,qoh ax Condensed Benzimidazoles of Type 6-5-5

H

R

R

(6.180)

(6.181)

/R

H (6.182)

(i) 30% KOH aq.. EtOH/(rmm temp.)/(lO min) Seheme 6.37

of the bridgehead quaternary center in 2,3,3a,4-tetrahydro-lZf-pyrrolo[1,2a]benzimidazolium salts such as (6.183)(Scheme 6.3% promotes hydroxide ion attack at the C(3a) position with concomitant ring-opening to eightmembered carbinolamines [e.g. (6.184)], which coexist in equilibrium with the open-chain aminoaldehydes [e.g. (6.185)].76

CH2Ph

(6.183)

CH,Ph

KJ

CH2Ph

(6.184)

I

I CHO PhCH2 (6.185)

(i) NaOH aq./room temp sebcme 6.38

AMINATION. The nucleophilic addition of amines to the C(l)-C(2) double bond in 1,3,3-trimethyl- 1H-pyrrolo[ 1,2-a]benzimidazole [cf. Scheme 6.35; (6.172)]to give adducts of the type (6.186)(Scheme 6.39) is briefly reported in a patent.”


75

nuB H N 300 167- 168

-

-

45 79

141-142 110 239-240 108-109

("C)

m.p.

70

42

-

-

-c

(Yo)

Yield

Ethanol

Ethanol

-

-d Dimethylformamide Ethanol-water Ethanol-water

-d

-

-

Me thanol-water -d MethanolTwater

-J


106

106

106

106

103

128 123 123

128

124 94 125 123 123 123 123 125 125

Ref.

BY RING-CLOSURE REACTIONS OF 2-BENZIMISYNTHESIS OF 2,3-DIHYDROTHIAZOLO(3,2-a~ENZIMIDAZOLES DAZOLETHIONE DERIVATIVES

Starting materials (R'-+R6 unspecified = H)

TABLE 6.29.

0

w

+

+

(6.239;R' = CH,CI, X = CI)

+

(6.239; R' = CF,, X = Br) (6338)

+

(6.239;R' = Pr', X = Cl) (6.238)

+

(6.239; R' = Et, X = Br) (6.238)

+

(6.239; R' = Me, X = Cl) (6.238)

(6.238)

(6.239;X = CI)

G

G

M

1 1 l G l G 1 . l G l G

(6339;X = CI) (a238, R3= R6= Me)'

+

(6339;X=Cl) (6.238; R4 = RS = Me)

+

(6.239;X = CI, CH(OEt), for COR') (6.238;R4 = RS = Me)

lL

K

(6.240;CH(OEt), for COR') (6.238)

+


Starting materials (R'-+R6 unspecified = H)

TABLE 6.29 (Continued)

94-96

109-111

138-139

18 1-184

-c -c -c -

(6.241;R' = Et) (6.241;R' = Pr') (6.241;R' = CF,) (6.241;R' = CH,CI)

(-P.)

19 1.5- 193.5

111-1 12

89

(decomp.)

202-205

(decomp.)

185-202

Acetonitrile, acetone or ethanol-water


Acetonitrile, acetone, or ethanol-water

Acetonitrile, acetone, or ethanol-water

Diethyl ether

Tetrah ydrofurane

Ethanol

Tetrahydrofurane

Methanol

-

200-202


m.p. ("C)

97

(6.241;R' = Me)

(6.241; R3 = R" = Me)

92

88

(6.241;R4 = (6.241;R4 = RS = Me)'

89

(6.241)' = Me)

82

(%)

Yield

(6.241)'

Product (R'+R6 unspecified = H)

108

108

108

108

103

103

106

103

94

106

Ref.

VI

g

+

I

+

+

for COR')

+

for COR') (6.240; R' = Ph, R2 = CHzC02Et)"

(6.239; Rz = Ph, X = Br, CH(OMe),

(6.238)

P

lH lo

H

0

i

(6339; R2 = Me, X = Br, CH(OEt),

(6.238; R4 = RS= Me)

for COR')

(6.239; RZ= Me, X = Br, CH(OEt),

(6.238)

+

(6.241; R' = Ph,

R2= CH,CO,Et)'

R2= R4 = R' = Me)

(6.241; RZ= Ph)

(6.241;

(6.241; RZ= Me)"

(6.241; R2 = Me)

67

82

90

96

90

quant.

-

Rs= NO,)

(6.241; R2 = Me)"

(6.241; R' = CF,,

G

-

-'

-

Rs= NO,)

R' = cyclohexyl)

(6.241;

(6.241; R' = Me,

R' = CH2SPh)

(6.241;

G

G

G

I N

I

X = Br, CH(OEt),

X = Br)

I

R2= Me, X = Br, CH(OMe),

for COR')

(6.239;

(6.239; R2 = Me, for COR') (6.238)

+

(6.239; R' = CF,, (6.238)

+

(6.239; R' = Me. X = Cl) (6.238; Rs = NO,)

i-

(6.239; R' = cyclohexyl, X = Cl) (6.238; Rs = NO,)

+

(6.239; R' = CH,SPh, X = C1) (6.238)

(6.238)

129-131

195.5- 196.5

230-231

196-197

198-200

201-203

206.5-208.5

122-124

155-156

138-139

Acetone

Methanol

Dimethylformamide

Ethanol-water

Methanol

Tetrahydrofurane





102, 109

107

106

106

107

103

108

108

108

108

+

+

+

R' = p-CIC6H4,

I

T

R

Yield

(6.241; OEt for OH)'

(6.241; R' = p-CIC6H4, R2 = CH2C02H)q

78

75

55

53 83

44

R2 = CH,CO,Me) (6.241; R' = p-CIC6H4, 95 RZ= CH,CO,Et, R4 or Rs= N 0 2 ) P

(6.241; R' = Ph, R2 = CH,CO,Me)" (6.241; R' = p-CIC6H4, R2= CH,CO,Et) (6.241; R' = P - C I C ~ H ~ ,

(6.241; R' = Ph, Rz = CH,CO,Me)"

(6.241; R' = Ph, R2= CHZCO2Me)" 99

(%)

102.5-103.5

Ethanol-water

Dioxane-ace tonitrile

Benzene-acetonitrile

9Y-101 163-165

Acetone

Acetone Acetone

Acetone

Acetonitrile


132- 134

145-147 140-142

145-147

-'

m.p. ("C)

106

102, 109

102, 109

102, 109

102 102, 109

109

109

Ref.

a

A = CI(CH,),CI, NaHCO,, 20% NaOH, Pr'OH/(reRux)(3hr); B = Br(CH,),CI, NaOH, EtOH/(reRux)(3hr); C = CI(CH,),CI, NaHCO,, KOH, Pr'OH/(reflux)(3hr); D = KOH, MeOH, H20/(reflux)(3hr); E = toluene/(reRux)(30rnin); F = SOC12/(reflux)(7-10min); G = 2-butanone/(reflux)(2-8hr); H = HzO/(reflux)(3-4hr); I = EtOH/(reflux)(4hr); I = dimethylformamide/(60-65'')(1 hr, then 100°)(10rnin); K = 36% HCl/(reflux)(l.Shr): L = 5M HCl/(reflux)(3hr); M = 50% EtOH-H,O/(reflux)(l hr); N = 20% HCl/(reRux)(SOrnin); 0= 4 M HCl/(reflux)(7-13hr); P = NaHCO,, H,O, benzene or CHCl,/(room temp.)(few rnin); Q = MeOH/(reflux)(Shr); R = AcOH/(100°)(1-3hr); S = H,O/(room tempJ(5 hr); T- POCl,/(reflux)(l.S hr). Forms a methiodide, m.p. 185-187" (decomp.). Yield not quoted.

(6.240; CH(OEt), for COR')

RZ= CH,CO,H)

(6.239;

(6.238)

P R2 = CH,CO,Me) (6.240; R' = P-CIC~H~, P R2 = CH,CO,Et, R4 or R' = NOz)

R2= CHzC02Et)

(6.240; R' = p-CIC,H,.

S S

0

Reaction Product conditions" ( R ' 4 R " unspecified = H)

lR

(6340; R' = Ph, R2 = CH2C02Me)" (6340; R' = p-CIC6H4,

X = Br)

(6339; R' = Ph, R2 = CH,CO,Me,

(6.238)

CH,CO,Me, X = Br)

(6.239; R' = Ph, R2 =

(6.238)

Starting materials (R' 3 R6 unspecified = H)


-4

0

c

Solvent of crystallization not specified.

'

'

8

f

Forms a hydrobromide, m.p. 219-220" (decomp.) (from aqueous hydrobromic acid), and a picrate, rn.p. 230-231" (from acetic acid). Hydrochloride. Hydrochloride monohydrate; free base has m.p. 243-245" (from water). i Hydrochloride, free base has m.p. 180-205" (decomp.) (from dioxane). Forms a hydrochloride, m.p. 184-186" (decomp.) (from dioxane-water) and a picrate, yellow needles, m.p. 225-226" (decornp.) (from ethanol). Forms a hydrochloride, m.p. lY8". Forms a picrate, m.p. 275-280' (decornp.) from ethanol. Cisltrans isomer mixture. " Forms a picrate, yellow crystals, m.p. 179-180" (decomp.) (from ethanol-water). Hydrobromide. P Position of nitro substituent not established. Forms a hydrobromide m.p. 203-205". ' Melting point not quoted. Forms a picrate, yellow needles from ethanol, m.p. 209-211" with resolidification and remelting at 235-236'.

' Forms a hydrochloride m.p. 217-219".

108


products of such cyclizations would appear desirable. Heating in polyphosphoric acid is reported9' to effect the cyclization of 2-(2-allylthio)benzimidazole in low yield (35%) to 3-methyl-2,3-dihydrothiazolo[3,2-a]benzimidazole (m.p. 168-170") by a process which is presumably related mechanistically to the foregoing 2-(~-halogenoalkylthio)benzimidazolecyclizations. General synthetic access to 2,3-dihydrothiazolo[3,2-a]benzimidazole derivatives is also provided by the halogenative-dehydrohalogenative ringclosure induced in N ( l)-(~-hydroxyalkyl)-2-benzimidazolethiones by treatment with thionyl chloride [Scheme 6.55; (6.255)- (6.256)]. The excellent yields achievable (Table 6.29) coupled with the ready availability of the N (p-hydroxyalky1)benzimidazolethione starting materials (6.255) from 2chlorobenzimidazoles (by N-alkylation with a p-halogeno alcohol followed by treatment with thiourea) makes this type of 2,3-dihydrothiazolo[3,2-a]benzimidazole synthesis an attractive alternative to that through 243ha1ogenoalkylthio)benzimidazoles (see before). Moreover, unlike ringclosure of the latter type, the nature of the cyclization step [(6.255)-, (6.256)] in N-(p-hydroxyalky1)benzimidazolethione cyclizations is such that, provided the orientation of the starting material is secure, ring-formation is unambiguous in terms of the ultimate site of substituents in the benzene nucleus.'28 As already briefly discussed, 2-(/3-oxoalkylthio)benzimidazolesare capable of coexisting in ring-chain tautomeric equilibrium with the corresponding 3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazoles [cf. Scheme 6.51; (6.240) S (6.241)]. Careful IR and 'H NMR s t ~ d i e s ' ~ ~of" ~such * equilibria reveal that 2-(~-oxoalkylthio)benzimidazoles containing bulky or electronwithdrawing substituents, which can conjugate with the carbonyl group, exist preferentially in the open-chain form (6.240) both in the solid state and in solution. Conversely, the presence of sterically undemanding, electrondonating substituents incapable of conjugating with the carbonyl group favor the ring-closed form to the extent that, in the solid state at least, the molecule exists essentially as the 3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazole (6.241). Simple, unsubstituted, and C(2) or C(3) alkyl or C(2) aryl-substituted 3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazoles (6.241; R' = H or alkyl, R2= H, alkyl or aryl) are therefore synthetically readily accessible (Scheme 6.51) in high yield (Table 6.29) by the condensation of 2-benzimidazolethiones (6.238) with a-halogeno ketone^^^^^^^^.^^^ and aldehydes' 03*106 under neutral conditions or with a-halogeno aldehyde aceta~s94.103.106. 107 in acidic media. 3-Aryl-3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazoles (6.241; R' = aryl) are generally inaccessible by this route being usually unstable relative to the open-chain 2-(2-benzimidazolylthio)acetophenone tautomers (6.240; R' = aryl), though the presence of certain a-substituents in the latter [e.g. (6.240; R1 = aryl. R2 = CH,CO,R)], somewhat unexpectedly, favors formation'"2*'w of the ring-closed isomer (6.241; R' = aryl, R2= CH2C02R)in high yield (Table 6.29). Acid-catalyzed cyclization'06 of the preformed acetal [Scheme 6.5 1; (6.240; R' -,R6= H, CH(OEt), for COR')] gives 3-hydroxy-2,3-dihydrothiazolo[3,2-albenzimid-

6.2. Fused Benzimidazoles with One Additional Heteroatom

109

azole (6.241; R' -+ R6 = H) in good yield (Table 6.29) through the presumed intermediacy of the corresponding 2-(~-oxoalkylthio)benzimidazole (6.240; R' + R6 = H). Conversely, phosphorus oxychloride-mediated ring-closure of the acetal (6.240; R' + R6 = H, CH(OEt), for COR') leads to 3-ethoxy-2,3dihydrothiazolo[3,2-a Jbenzimidazole (6.241; R' +R6 = H, OEt for OH) also in good yield (Table 6.29).'06 The preferential alkylation of benzimidazolethiones by a-halogeno carbony1 compounds and their acetals at sulfur rather than nitrogen, and the consequent 3-hydroxy structure [Scheme 6.5 1; (6.241)] for the resulting ring tautomeric products, rather than the alternative 2-hydroxy formulation (6.241; R2=OH, H for OH), follow from the ~ x i d a t i o n " ~of the parent system (6.241; R' 3 R" = H) to 2,3-dihydrothiazolo[3,2-u-Jbenzimidazol-3one whose orientation has been firmly established (see later). O n the other hand, the orientational preference governing the ring-closure reactions of 2(fboxoalky1thio)benzimidazoles to 3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazoles substituted in the benzene ring has not been investigated beyond the qualitative demonstration of single isomer formation.'02*'0s 2,3-Dihydrothiazolo[3,2-a]benzimidazol-3-onesare generally accessible by a logical extension of the foregoing 2-(/3-oxoalkylthio)benzimidazole cyclizations involving the acylative ring closure of 2-benzimidazolylthioacetic acids and esters [Scheme 6.56; (6.257; R6 = H or alkyl)+(6.259)].

RS

(6.259)

(6.260)

(6.261)

(6.262) !3cbeau 6.56

,-.

(6.257; R' (6.257; R' (6.257; R' (6.257; R' (6.258) (6.258) (6.263; R'

= Me)

= Et) = h") = Bu") = R3 = R4 = Me)

(6.257; R2 = RS = Me) (6357; R' = Me) (6.257; R' = Me)

(6357; R2 or RS = Me) (6.257; R3 or R 4 = MeO) (6.257; R3 or R4=C1) (6.257; R3 or R4= NO,) (6.257; R3 = R4 = Me) (6.257; R' = R4 = Me)

A

K

H J

B

B

B

I

A B

H

A A A A A

A

C D E E F G

181 180 181 180 178 181 181 178-181 179-180 181 > 300 183-184

64 55 67-69 66 65 98 93 40 25 25 40 70

172-173 101 204

74 79 43 82 78 75 99 59 28 78

(6.259; R2 = R5 = Me) (6.259; R' = Me) (6.259; R' =Me) (6.259; R'= Et) (6.259 R' = PI") (6.259; R' = Bu") (6.259; R' = R3 = R4 = Me) (6359; R' = CH,CO,H) (6.259; R' = CH,CO,H) (6.264; R' = Me)

255

-

-

58 90 123-124

-c

(decomp.)

(decomp.)

191-192 154 183-184 220 1 77- 1 78 175-176

65 48 64 70 76 80-82

(decomp.)

m.p. ("C)

Yield (% )

(6.259; R2 = Me) (6.259; R4 = OMe) (6359; R4 = CI) (6.259; R4= NO,) (6.259; R' = R4 = Me) (6.259; R3 = R* = Me)

(6.259) (6.259) (6359) (6359) (6.259) (6359) (6359) (6.259) (6359) (6359) (6.261) (6359; R4 = Me)

A A A A

(6.257) (6.257) (6.257) (6357) (6.257) (6357) (6.257; R6 = Et) (6357: R6 = Et) (6.257: R6 = Et) (6.257; R6 = Me or Et) (6.257) (6.257; R3 or R" = Me)

B



Starting material (R1+R6 unspecified = H)

-b -b

b

-

Methanol Methanol Ligroin

Ethanol Methanol -h

Ethanol Ethanol Benzene Benzene-ethanol Ethanol Ethanol

Ethanol Ethanol Methanol o-dichlorobenzene Ethanol Ethanol Ni trobenzene Ethanol

-h

Ethanol-benzene

h

Ethanol

-

94 94 94 134 144 147 129

133 94 101

133 97 98 136 133 134

129 131 132 101 135 137 94 138 134 140 130 133

Ref.

REACTIONS OF 2-


TABLE 6.30. SYNTHESIS OF 2,3-DIHYDROTHIAZOL0[3,2-a]BENZIMIDAZOL-3-ONES BY RING-CLOSURE BENZIMIDAZOLETHIONE DERIVATIVES

R' =Me, R2= NO,)

(6.263; R' = Ph) (6.263; R' = Ph. RZ= NO,) (6.257; R'= COMe, R6 = Et) (6.258) (6.258) (6.258) (6.258) (6.258) (6.258) (6358) (6.258) (6.257) (6.257) (6.257) + (6.257) c + (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6.257) (6357) (6.257) (6.257)

(6.263;

N 0 0 N 0 N 0 N 0 N 0 N 0

0

N

0

N 0 N

0

N

0

N

N 0

M M M M M

M

L M M

A A

A

R' = Me, RZ= NO,)

(6.264; R' = Ph) (6.264; R' = Ph, R2= NO,) (6.260; X = C(Me)OAc) (6.260: X = CHPh) (6.260; X = O-HOC~H~CH) (6.260; X = CHCH = CHPh) (6.260; x = ACNHC,H,CH)' (6.260; X = rn -02NC,H,CH) (6360; x = 2-HOCIOH6CH) (6.260; X = p-MeOC,H,CH) (6.260; X = p-NOZC,H,CH) (6.260; X = CHPh) (6.260; X = CHPh) (6.260; X = p-CIC,H,CH)' (6.260; X = p-CIC,H,CH) (6.260; X = P - N O ~ C ~ H ~ C H ) ~ (6.260; X = p-NO&H,CH) (6.260; X = p-MeC6H,CH)h (6.260; X = p-MeC,H,CH) (6.260; X = p-MeOC,H,CH)h (6.260; X = p-MeOC,H,CH) (6.260: X = p-BrC,H,CH) (6360; X = p-BrC,H,CH) (6.260; X = p-IC,H,CH) (6.260; X = p-IC,H,CH) (6.260; X = p-HzNC,H,CH) (6.260: X = p-NCCeH,CH) (6.260; X = p-NCC,H,CH) (6.260; X = p-Me,NC6H,CH) (6360; X = p-Me,NC,H,CH) (6360; X = 2-thienyl CH) (6360; X = 2-thienyl CH) (6.260; X = 2-fury1 CH) (6.260; X = 2-fury1 CH) (6.260; X = CHCH=CHPh) (6.260; X = CHCH=CHPh)

(6.264;

81 94 68 81 85 96 89 96 81 89

x5

92 83 94 80 93 78 90

81

44 62 -d 18 34 5s 27 62 58 52 37 82 90 84 95 85 98

235.5-236 242-243 -

-

169.5

-

169

-

294-295 19-3- 195 269

__

238-239 269-272

-

315 250.5-25 1

-

238 (decomp.) 222 22 1 192-194 2 14 178 234 172 230 236 238 280 226 286-287

-

Acetic acid

Dimethylformamide

-

-

Chloroform Dimethylformamide Ethanol Acetic acid

-

Dimethylformamide

-

Dimethylformamide

-

Acetic acid

-

Dimethylformamide Dimethylformamide Acetic acid

-

Acetic acid

Xylene -b Benzene

b

i29 129 141 149 149 149 149 149 149 149 149 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148

129

h)

c c

( 6 a . X = 0) (6.265; X = NH) (6.265; X = p-(QCH~CH,),NC6H,CH) (6.260; CHC0,Me) (6.260; CHC02Me) (6.260; CHC0,Et) (6.260; R' or R2= Me, X = CHC0,Me)' (6.260; R' or R2= NO,, X = CHC0,Me)' (6.260; R' or R2= C1, X = CHC0,Me)' (6.260; R' or R2= CO,H, X = CHC0,Me)' (6.260; X = NPh) (6.260; X = p-02NC6H4NHN) (6360; X = p-MeOC6H4NHN) (6.260; X = p-MeC6H4NHN)


71 47 52 53

66

73

66

26 73

-d

45 40 69 96

163-165 249-250 202-204 263

238-240

190-194

243-245

245 283 218 175-176 192-193 145-150 180-183

~-

Ethanol-water Diox an e Dioxane Dioxane

Acetone

Acetone

Benzene

Ethanol Ethanol Acetic acid Acetone Acetone Methanol Benzene


151 151 151 151

145

145

145

148 148 132 145 147 145 145

Ref.

a

A = Ac,O.

'

pyridine/(100")(5-15 min); B = Ac,O, pyridine/(100°)(3-48hr); C = dicyclohexylcarbodiimide, pyridine/(5-10")(12 hr); D = ethyl poIyphosphate/(100")(2hr); E = ortho-dichlorobenzene/(reflux)( 1 hr); F = sodium sand, benzene/(reflux)(0.5 hr); G = SOCI,, pyridine, benzene/ (wam)(lO min); H = A~O/(reflux)(4-8min); I = Ac20, pyridine/(room tempJ(48 hr); J = maleic anhydride, dioxane/(reflux)(24hr); K = maleic anhydride, glyme/(l6O0)(reaction time not specified); L = Ac20/(reflux)(3 hr); M = NaOAc, AcOH/(reflux)(2-3 hr); N = ArCHO, KOAc, Ac20/(130140")(15min); 0 = ArCHO, pyridine/(120")(10 min); P = phthalic anhydride or phthalimide, Ac,0/(140")(15 min); Q = piperidine, EtOH/(reflux)(4 hr); R = MeO,CKkCCO,Me, or EtO,CC%CCO,Et, MeOH/(reflux)(l-2 hr); S = PhN=C(CI)COCI, Et,N, benzene/( 100°)(3hr); T = ArNHN=C(CI)COCI, Et,N, benzene-dioxane/(reflux)(3 hr). Solvent of crystallization not specified. Oil. (I For details of the ortho and meta isomers cf. Ref. 148. Yield not quoted. For details of the ortho isomer cf. Ref. 148. Crystallized from ethanol, dioxane, or acetic acid. ' Single isomer obtained; site of substituent not established. f Position of the AcNH substituent not specified.

T T T

R

(6.258; R' or R2 = C02H)

S

R

(6.258; R' or R2 = Cl)

(6.258) (6.258) (6.258) (6.258)

R


(6.258; R' or R2 = NO,)

(6.257) (6357) (6.257; R6 = Et) (6.258) (6.258) (6.258) (6.258; R' or R2 = Me)

Starting material ( R ' 4 R " unspecified = H)



113

This mode of thiazolo[3,2-a]benzimidazole ring formation normally proceeds in high yield (Table 6.30) and is most efficiently achieved by the action of dehydrating agents, such as acetic anhydride (usually in conjunction with pyridine)94,97.98. 101.129- I 3 6 or dicyclohe~ylcarbodiimide,'~~ on 2-benzimidazolylthioacetic acids (6.257; R6 = H) readily accessible by the condensation of 2-benzimidazolethiones with a -halogeno carboxylic acids. The cyclization of 2-benzimidazolylthioacetic acids by heating with thionyl chloride in pyridine tends to afford dimeric products of the type (6.261) (Scheme 6.56) rather than simple 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-0nes.'~''The ring-closure of ethyl 2-benzimidazolylthioacetate (6.257; R' --* RS= H, R6 = Et), which occurs only in low yield by heating in 1,2-di~hlorobenzene'~~,~~~ or with sodium in ben~ene,'~" gives 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-one (6.259; R' 4R5= H) in high yield (Table 6.30) when catalyzed by hot ethyl polyph~sphate.'~The extension of the acetic anhydridepyridine mediated cyclization of 2-benzimidazolylthioaceticacids to a -alkyl derivatives (6.257; R' = alkyl) afford^^^*'"'*'^^ moderate to high yields (Table 6.30) of 2-alkyl-2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones(6.259; R' = alkyl), molecules previously reported'29 to be inaccessible by ringclosure of this type. Treatment14' of ethyl 2-(2-benzimidazolylthio)acetoacetates [Scheme 6.56; (6.257; R' = COMe, R6 = Et)] with acetic anhydride in the absence of pyridine leads to ring-closure through the ester group (and not the acetyl substituent as observed in the presence of pyridine-see before) the products being the enol acetates [6.260; X = C(OAc)R] which are presumably derived by subsequent acetylation of initially formed 2acetyl-2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones (6.259; R' = COMe). The interesting sodium hydride catalyzed tran~formation'~~ of the benzimidazolylthiopropanone derivative [Scheme 6.56; (6.262)] into 2-acetyl-2,3dihydrothiazolo[3,2-a]benzimidazol-3-one (6.259; R2 Rs= H, R' = COMe) is rationalized in terms of the intermediacy of phenyl 2-(2-benzimidazoly1thio)acetoacetate (6.257; R' = COMe, R2+ R5 = H, R6 = Ph), whose formation by facile N-P C acyl shift provides a model for enzymemediated transcarboxylation involving carboxybiotin. The acetic anhydridepyridine promoted cyclization of N(1)-substituted 2-benzimidazolylthioacetic acids [Scheme 6.57, (6.263; R' =Me or Ph)] leads to anhydro products having interesting tricyclic mesoionic structures (6.264;R' = Me or Ph).'29 The chemistry of these molecules has not been investigated to any e ~ t e n t , " ~

-

N

COZH

I

I R' (6.263)

R'

(6.264) scbeec 6.57

114


despite current widespread interest in mesoionic compounds in general.'43 As for other cyclizations leading to thiazolo[3,2-a]benzimidazole derivatives (see before), ring-closure of 2-benzimidazolylthioaceticacids and esters unsymmetrically substituted in the benzene ring can give rise to two possible products by alternaisomeric 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-one tive ring-formation at the two nonequivalent benzimidazole nitrogen atoms. The fact that this situation leads to structural ambiguity when single pro' ' ~ ' in ducts are formed has been ignored in some i n s t a n c e ~ , ' ~ ~ while others, 144~145 though recognized, has not been resolved. In other s t u d i e ~ ~ ' *a ~choice ~ ~ ' ~between ~ possible C(6) and C(7) orientations for monosubstituted 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-oneshas been made on the basis of the 'H NMR splitting patterns of the protons at C(5) and C(8), which can be differentiated (with allowance for the perturbing effect of the substituent) by the enhanced deshielding of the former as a result of the anisotropic effect of the proximate C(3) carbonyl group. The C(6) orientations a ~ s i g n e d ~ " ~on' * ~this ' ~ ~ basis indicate that ring-closure takes place preferentially at the nitrogen atom mera rather than para to the substituent, irrespective of whether this is chloro, methyl, or methoxy. The orientational preference exhibited by the latter two substituents is particularly surprising, implying as it does that a presumed electrophilic (acylative) cyclization process involves ring-closure at the predictably less basic of the two available nitrogen centers. In view of this unexpected result, further detailed studies of the factors governing orientational preference in 2-benzimidazolylthioacetic acid cyclizations would appear to be warranted. by the The formation of 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones direct condensation of 2-benzimidazolethiones with a-halogeno carboxylic acids does not appear to have been described, the reported reaction'46 of 2benzimidazolethione itself with chloroacetic acid in the presence of sodium having been acetate to give 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-one shown'32 to be incorrect. On the other hand, the uncatalyzed condensation of 2-benzimidazolethione with maleic anhydride to give the acetic acid derivative [Scheme 6.56; (6.259; R' = CH2C02H,R2+ R5= H)], albeit in low yield (Table 6.30) appears to be well enough authenti~ated.'""~' In closely related 2-benzimidazolylthioacetic acid reacts with phthalic anhydride or phthalimide in acetic anhydride in the presence of potassium acetate to afford moderate yields (Table 6.30) of the 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-onederivatives [Scheme 6.58; (6.265; X = 0 or NH)]. The fact that 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-onescondense with aromatic aldehydes under a variety of conditions (see later) to give the corresponding 2-arylidene derivatives [Scheme 6.56; (6.260; X = CHAr)] makes them plausible intermediates in the formation (Table 6.30) of analogous products when 2-benzimidazolethione is allowed to react with aromatic aldehydes and chloroacetic acid in acetic acid containing sodium acetate.'4Y However, the possibility that the aldol condensation' involved in these ring-closures occurs prior to and not subsequent to ring-formation is


115

Scheme 6.58

suggested by the rep~rted’~’ cyclization of a 2-arylidene derivative of 2benzimidazolylthioacetic acid to the corresponding 2-arylidene-2,3-dihydrothiazolo[3,2-a]benzimidazol-3-one [Scheme 6.56; (6.260; R’ = R2 = H, X = CHAr)] simply on attempted crystallization. That 2-benzimidazolylthioacetic acid and its ethyl ester can function as substrates for the synthesis of 2-arylidene-2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones is readily demon~trated‘”~~~’ by their smooth acetic anhydride or pyridine promoted condensation with aromatic aldehydes to give the anticipated arylidene products (6.260; R’ = R2 = H, X = CHAr). 2-Alkylidene-2,3-dihydrothiazolo[3,2-a Jbenzimidazol-3-ones of the type (6.260; X = CHC0,R) are also formed in moderate to high yield (Table 6.30) as the end-products of the uncatalyzed condensation reactions of 2benzimidazolethiones with acetylenic e ~ f e r s . ~ ~ A ~ ~recent ‘ ~ ’ ~study14’ ~ ’ ~ is concerned with the knotty problem of product orientation in cycloaddition of this type and has confirmed by chemical and crystallographic means the 3-OX0 structure (6.260; R ’ = R 2 = H , X=CH,CO,Me) (as opposed to a 2-0x0 or six-membered formulation) originally assigned’” to one of the major products of the reaction of 2-benzimidazolethione with dimethylacetylenedicarboxylate in acetic acid or methanol. Similar problems of product orientation are encountered in the base-catalyzed condensation reactions of 2-benzimidazolethiones with 2-arylimino and 2-arylhydrazono chloroacetyl chlorides which afford moderate yields (Table 6.30) of monoarylimines and monoarylhydrazones of 2,3-dihydrothiazolo[3,2-a]benzimida~ole-2,3-diones.~’~ These condensates appear to have been assigned”’ the C(3)-0XO orientations [Scheme 6.56; (6.260; X = NAr or NNHAr)] (as opposed to the alternative 2-0x0 structures) purely on the basis of analogy with similar products derived by coupling reactions at the reactive C(2) position in preformed 2,3-dihydrothiazolo[3,2-aJbenzimidazol-3-ones (see later) yet apparently without the demonstration of common product formation. More rigorous evidence in support of the 3-OX0 formulations (6.260; X = NAr or NNHAr) for the benzimidazolethione derived products would therefore be desirable. Synthetic access to the rare 1H,3H-thiazolo[3,2-a]benzimidazole ring system is dependent on the spontaneous thermal cyclization (Scheme 6.59)

Condensed Benzimidazolesof Type 6-5-5

116

TABLE 6.31 SYNTHESIS OF l-IMINO-lH,3H-THIAZOL0[3,4-a]BENZIMIDAZOLE DERIVATIVES BY RING-CLOSURE REACIlONS OF 2-(a -CHLOROALKYL)AND 2-(a-THIoCvANOALKYL)BENZIh4IDAZOLES" Starting material (R'+R3 unspecified = H)

Product Reaction (R'+R3 conditionsb unspecified = H)

(6.266; c1 for SCN) A (6.266) B (6.266; R3 = Me, CI for S C N ) A (6.266; R' or R2= C1, CI for S C N ) (6.266; R' or RZ= Me, CI for S C N )

C

C

Yield

(YO)

(6.267) (6.267) (6.267; R3 =Me) (6.267; RZ=CI)

42 40 23 59

(6.267; R' = Cl) (6.267; R*=Me)

-' 19

From Refs. 152 and 153. MeOH/(reflux)(l hr); B = MeOH/(reflux)(1hr); arnide/(SO")(3.5 hr). Yield not specified. a

A = NH4SCN,

m.p.

("0


169-170

Methanol

-

-

117-1 18 Light petroleum 156-158 Diethyl ether

161-162 152-153

Diethyl ether Diethyl ether

C = NH4SCN, dimethylform-

of 2-(a-thiocyanoalkyl)benzimidazoles (6.266) either preformed or generated in situ by the action of ammonium thiocyanate on 2-(a-chloroalkyl)The only moderate yields (Table 6.31) of l-iminobenzimidazoles. lH,3H-thiazolo[3,4-a]benzimidazoles(6.267) so obtained are offset by the convenience in practice of such cyclizations based as they are on 2-(achloroalkyl)benzimidazole starting materials readily available by the reaction of ortho-phenylenediamine derivatives with a-chlorocarboxylic acids. Ring-closure failslS3 for 2-(a-thiocyanoalkyl)benzimidazolesubstrates having strongly electron-withdrawing substituents (e.g., nitro) in the C5(6) position presumably due to the diminished nucleophilicity of the imidazole ring nitrogen atoms. Cyclization of 2-(a -thiocyanoalkyl)benzimidazoleswith less electronically demanding substituents (e.g., chloro, methyl) at the C5(6) position proceeds readily but affords mixtures of both possible ring-closed products [i.e. (6.267; R' = C1 or Me) and (6.267; R2= C1 or Me)), which at least in the examples d e s ~ r i b e d , ' ~ *are * ' ~amenable ~ to separation (Table 6.31) and characterization on the basis of their respective 'H NMR absorption. The ring-closure of 2-(a-mercaptomethyl)benzimidazole to 1H,3Hthiazolo[3,4-a]benzimidazol-1-one (m.p. 212-214") [Scheme 6.59; (6.266;

'


117

R' +R3= H, H for CN)+ (6.267; R' + R3= H, 0 for NH)] using phosgene in the presence of pyridine has been briefly described'53 but without experimental details. The cycloaddition reactions'54 (Scheme 6.60) of the 1-methylbenzimidazolium 3-imine (6.268) with activated alkenes (e.g., methyl acrylate, acrylonitrile) afford, in unspecified yield, oily intermediates assigned 2,3,3a,4tetrahydro-lH-pyrazolo[2,3-a]benzimidazolestructures of the type (6.269; R = C02Me or CN).These transforniations appear to be the only examples of pyrazolo[2,3-a]benzimidazole synthesis involving ring-closure in benzimidazole derivatives.

=a-

C02Et

@ $ -

I

-N

Me I

/

CO2Et

Me I H R

(6.268)

(6.269) [R= CN or CO,Me]

Synthetic routes to imidazo[ 1,2-a]benzimidazoies of the various structural types are based almost exclusively on cyclization reactions of 2-aminobenzimidazole precursors (cf. Tables 6.32, 6.33, 6.34, 6.35, and 6.36). For example ring-closure in N( 1)-(p-oxoalky1)- or 2-(P-oxoalkylamino)benzimidazoles affords general synthetic access to variously substituted 1Hand 9H-imidazo[ 1,2-a]benzimidazoles (Scheme 6.6 1). 2-Alkyl- and 2-aryl N-unsubstituted 1(9)H-imidazo[l,2-a]benzimidazoles(6.275; R' = alkyl or aryl, R2= H) or (6.276; R' = H, R2 = alkyl or aryl) in particular are readily prepared in high yield (Table 6.33) by the smooth cyclization of 2-aminoN( 1)-(P-oxoalky1)benzimidazoles r(6.272) S (6.273); R' or R2= alkyl or aryl, R2 or R' = HI achieved thermally in alcoholic ~ o l v e n t s ' ~or~ "in~ ~ hydrochloric acid'" or, in the form of their hydrobromides, using methanolic alkali.'55*'56Moreover, the 2-amino-N( 1)-(p-oxoalkyl)benzimidazoles required as substrates need not be preformed but can be prepared and ring-closed in situ by the reaction of .2-chloro-N( 1)-(/3-oxoalkyl)benzimidazoles with ammonia [Scheme 6.61 ; (6.270) (6.272; R2= H) (6.275; R2= H)],'18a*158 or more conveniently, but in lower yield (Table 6.33) by heating 2-aminobenzimidazoles with a-halogeno carbonyl comsolution [Scheme 6.61 ; pounds in a l ~ o h o l i c ' ~or~ dimethylf~rrnamide'~~ ~'~~ (6.271; R' = R2 = H) (6.273; R' = H) (6.276; R' = H)]. Correspondingly the in situ condensation of 2-aminobenzimidazole with bromoacetaldehyde

-

-

-

-

TABLE 6.32 SYNTHESIS OF lH-IMIDAZ0[1,2-a]BENZIMIDAZOLES(6.275) BY RINGCLOSURE REACTIONS OF 2-CHLORO-1-(80XOALKYL)BENZIMIDAZOLES (6.270).O Reaction conditions* R A A A A

H H H H H H H H H H H H H H H H H H H

Product R'

(6.275)

Yield (To)

R2

Me Me Me Me Me Me Me Me Me Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph

87 67 93 57 Ph 54 m -MeC,H,' ~ - M I ? C ~ H , ~ 64 85 p-MeOC,H,d 53 p-EtOC6H,d 47 a-naphthyl' Me**' 88 83 (CH2)ZOH 70 (CH2)2NEtzR Bu' 82 66 C6H, I' 92 CH,Ph 71 Ph 71 m-MeC,H, 65 p-MeC,H, 50 p-HOC6H4

H H H

Ph Ph Ph p-MeOC,H,

p-MeOC,H, p-EtOC6H,d a-naphthyl H

88 87 45 83

H H H

p - M e w , H, p-MeOC,H, p-BrC,H,

(CHz)zOH Phd H

80 82 64

A

H H H H H

p-BrC,H, p-BrC,H, p-BrC,H, p-BrC6H, 2-thienyl

(CH2)ZOH Bu' Ph p-MeC,H," H

81 77 72 85 34

A A A A A

Me Me Me Me Me

Me Me Ph Ph Ph

CH2Ph Ph (CHJzOH Bun Ph

83 75 59 54 51

B

A

B

A

B A A A A A

A A A

A A A A A A A

B

A A A

B B

H

(CHz)@H CH,CH=CH,' CH2Ph

m.p. ("C)


Water 167-169 224-226 Dioxane 128-1 30 Acetone-water 143-145 Acetone-water 204-206 Methanol 111-113 Acetone-water 113-1 15 Acetone-water 122-124 Acetone-water 180-182 Methanol 127 Ethanol 166-168 Methanol-water 192-194 Acetic acid 207-209 Methanol 203-205 Methanol 130-132 Methanol-water 204-206 Methanol-water 188-190 Acetone-water 188- 190 Acetone-water 348-350 Dimethylformamide(decomp.) water 205-207 Methanol 149-151 Acetone-water 212-214 Acetone-water 295-297 Dimethylformamide(decomp.) water 188-190 Acetone-water 125-127 Acetone-water 316-3 18 Dimethylformamide(decomp.) water 184- 186 Acetone-water 225-227 Dioxane 182- 184 Acetone-water 188- 190 Acetone-water 281-283 Dimethylformamide(decomp.) water 192-194 Acetone-water 198-200 Acetone-water 163-165 Acetone-water 21 1-213 Methanol 154- 156 Ace tone-water

From Refs. 118a, 157, and 158. A = R'NH,, MeOH/( l4O-18Oo, autoclave)(6 hr); B = R'NH,, dimethylformamide/(reflux)(4 hr); " Picrate; free base is an oil. Monohydrate. ' Also obtained in quantitative yield from (6.272; R = H, R' = Ph, R2 = Me) by treating with conc. HCI under reflux for 2 hr. Forms a hydrochloride, m.p. 243" (decomp.) (from ethanol-ether or acetone-methanol). Dipicrate. 118

R' = Br) (6.271; R = R2 = H, R' = CH,Ph) (6.273; R = H, R' = CH,Ph, R2 = Me) (6.279; R = CH,Ph) (6.278; R' = H, R2 = Br) (6.278; R' = Br. R2 = H) (6.273; R = H, R' = (CH,), NEt,, R2= Me) (6.279; R = CH,C%CH) (6.280; R = CH==C=CH2) (6.273; R = R' = H. R2 = Ph)*

(6.279; R = Et) (6.279; R = Et) (6.278; R = Et, R' = H.

R2 = Me)

E

1

E E

D

E E

c

D

H

E

C E

G

F

R2 = Me)R (6.276; R = H, R' = CH,Ph, R2 = Me) (6.281; R = CH,Ph) (6.281; R = CH,Ph) (6.281; R = CH,Ph) (6.276; R = H. R' = (CH,), NEt,, Rz = Me)h (6.281; R = CH==C==CH,)' (6.281; R = CH=C=CH,) (6.276; R = R' = H,R2 = Ph)

(6.267; R = H, R' = CH,Ph,

(6.277; R = Me) (6.276; R = H, R ' = Et, R2 = Me)' (6.281; R = Et) (6.281; R = Et) (6.281; R = Et)

(6.281; R = H) (6.281; R = H) (6.276; R = H, R' = R2 = Me)d (6.281; R = Me) (6.281; R = Me)

50 72 85

94 85-90 85-90 90

269-270 (decomp.)

67-69

-

-'

111-112

-

Methanol

Ethanol-water

-

-

95

170 170 155, 156

169 169 169 162b

166

166

111 87

170 170 165 169 169 171 161

156

156

155

Ref.

169 169 169 Ethanol-water

Light petroleum -

-

Benzene -

Methanol

Methanol


236 -

93 85-88 85-90

J

95 85-88 52

88

-

C

(6.279; R = H) (6.280; R = H) (6.273; R = H, R' = R2 = Me) (6.279; R = Me) (6.279; R = Me) (6.274; R ' = Me, R2 = COMe) (6.273; R = H, R ' = Et,

83 16

30

B

(6.271; R = R' = R2 = H)

c D c

251-253 (decomp.) 195- 196 200 94 85 236-238

16

(6.276; R = R2 = H,

B

R' = CH,COMe)b (6.276; R = R' = H, R2 = Me)

190 (decom p .) 208-210

95

(6.276; R = R ' = R2= H)

A

m.p. ("C)

CH(OEt), for COR') (6.271; R = R' = R2 = H)

(6.273; R = R' = H,

Yield

(%I

Product


Starting material

TABLE 6.33. SYNTHESIS OF ALKYL AND ARYL 9H-IMIDAZ0[1.2-a)BENZIMIDAZOLESBY RING-CLOSURE REACTIONS OF 2-AMINOBENZIMIDAZOLE DERIVATIVES

0

w

(6.273;R = H, R' = Me, R2 = Ph)b (6.273;R = H, R' = Me, R2 = Ph) (6.273;R = H , R'=Me. R2 = p-BrC6H4) (6.273;R = H, R' = Me, R2 = 0-02NCbH.J (6.273;R = H, R' = Me, R2 = m -02NC6H4) (6.273;R = H, R ' =Me, R2 = P-O$'%H.+) (6.273;R = H, R' = Me, R2 = 2-naphthyl) (6.274;R1 = Ph, R2 = COMe) (6.273; R = H, R ' = Et, R2 = Ph)

(6.273;R = R ' = H , R 2 = p CIC6H4)b (6.273;R = R' = H, R2 = paC6H4) (6.273; R = R' = H, R2= PBrC6H4)b (6.273;R = R' = H, R2 = pBrCbH4) +.(6.271;R = R' = R~ = H)

(6.273;R = R' = H, R2 = Ph) (6.273;R = R ' = H, R2 = Ph) (6.270; R = H, R' = Ph)

Starting material


D G

N

N

D

G

D,G

D, G

M

L

I

I

I

I

D K

I (6.276;R = R1= H, R2 = pCIC6H4) (6.276;R = R' = H, R2 = pCIC6H4) (6.276;R = R' = H, RZ= pBrC6H4) (6.276;R = R ' = H . R 2 = p BrC,H4) (6.276;R = R' = H, R2 = 2-(5-nitrothienyl)) (6.276;R = H, R' = Me, R2 = Ph)b (6.276;R = H, R' =Me, R2= Ph)k (6.276;R = H, R' = Me, R2 = p-BrC6H4) (6.276;R = H,R' = Me, R2 = o-02NC6H4) (6.276;R = H, R' = Me, R2= m-02NC6H,) (6.276;R = H, R' = Me, R2 = p-O2NC&J (6.276;R = H, R' = Me, R2 = 2-naphthyl)' (6.277;R = Ph) (6.276;R = H,R' = Et, R2 = Ph)"

(6.276;R = R' = H, R2 = Ph) (6.276;R = R' = H, R2 = Ph) (6.276;R = R' = H, R2 = Ph)


Yield

51 87

a3

82

70

52

66

92

44

24

90

96

90

92

91 87

J

(Ole)

9393.5

117-1 ia

I

-

192

225

118

153

301-304 (decomp.) 120

300

-

279-2ao (decornp.)

Octane Ethanol-water

Ethanol-dirnethylformamide Ethanol

Methanol

171 161

164

163

163

163

162a

162a

Ethanol-water Methanol

167

159

155

155, 156

155

155, 156

156 157 118a. 158

Ref.

Methanol

Methanol-chloroforrn

Dime thylformamide

Dimethylforrnarnide

Dirneth y lformamide Acetic acid

-

310 285-287 (decomp.) 275-276 (decornp.) -


m.p. ("C)

-

I-

N

D

(6.273;R = H, R' = Et, 0 R2 = p-BrC,H,) (6.273;R = H, R' = Et, 0 R2 = m -O2NC,H,) (6.273;R = H,R' = Et, 0 R2 = p-O,NC,H,) (6373;R = Me, R' = Et, G R2 = P-O~NC~H,) (6.273;R = H, R' = CH2Ph, D, G R2 = Ph) (6373;R = H,R' = CH2COPh. 3 R2 = Ph)b (6.273;R = H, R' = CH2COPh, D R2 = Ph) (6.273; R = H, R' P-CI3 C&COCH,, R2= p-CIC,H,) (6.273;R = H, R' = p-Br3 c&coCH2, R2 = p-BrC,H,) (6373;R = H, R' = D (CH,),NEt,, R2 = Ph) (6.273; R = H, R' = (CH,),NEt,, P R2= P-CIC,H*)~ (6373;R = H, R' = I (CHz),NEt,, R2 = P - C I C ~ H ~ ) * (6.273;R = H, R' = P ( C H 2 ) 2 m t 2 , R2 = p-BrC&4)h (6373;R = H, R' = 3 (CH,),NEt,, R2 = p - B r c ~ H , ) ~ (6273;R = H, R' = P (CH,),NMe,, R2 = P-CIC~H,)~ (6373;R = H, R' = P (CH,),NMe,, R2 = p-BrC,H,)" (6276;R = H, R' = Et, R2 = p-BrC,H,)" (6.276;R = H,R' = Et. R2 = m-O,NC,H,)" (6.276;R = H , R'=Et, RZ= p-02NC,H4)P (6.276;R = Me, R' = Et, Rz = p-O,NC,H,) (6.276;R = H, R' = CH,Ph, R2= Ph) (6.276;R = H, R' = CH,COPh, R2= Ph)4 (6.276;R = H, R' = CH,COPh, R2= Ph)' (6376;R = H, R' = p-CIQH4COCH2, R2 = p-CIC,H,)' (6.276; R = H, R' = p-BrC6H4COCH2, R2 = p-B&&)' (6.276;R = H, R' = (CH2),NEt2, R2 = Ph)" (6376;R = H, R' = (CH2),NEt2, R2 = p-CI320 255 82 267 84 -c 214-215 >300 5s 80-90 210 75 167

92 9s 25 -

Yield

(%I

Xylene Acetic acid

-d

Chlorobenzene Ethanol Xylene Xylene Xylene Ethanol

-d

Ethanol Xylene Xylene Acetic acid -d Acetic acid

-d

Benzene Xylene Acetic acid

Hexane

-


TABLE 6.62. ACYLATION AND RELATED REACTIONS OF 2,3-DIHYDROTHIAZOL0[3,2-a]BENZIMIDAZOLES AND 2,3DIHY DROTHIAZOL0[3,2-a]BENZIMIDAZOL-3-ONES

103 103 129 138 130 101 133 136 133 134 101 23 1 101 23 1 133 133 136 136 130 101 138 231

Ref.

J

G I

D

E

D

E

F

E

H

D

B

r D % G G G

E

F

E

F

E

Reaction conditions’

TABLE 6.62

Unsubstituted Unsubstituted 6-Me6.7-di-MeUnsubstituted Unsubstituted Unsubstituted 6.7-di-MeUnsubstituted Unsubstituted

Unsubstituted Unsubstituted

Unsubstituted 6-Me6,7-di-Me6,7-di-MeUnsubstituted Unsubstituted 6,7-di-Me6.7-di-Me6,7-di-Me-

(6.399)

0

0

0

0

0 0 0 0 0 0

0 0

0 0 0 0 0 0 0 0 0

X

Substrate

(Continued)

Y

Unsubstituted Unsubstituted 6-Me6,7-di-MeUnsubstituted Unsubstituted Unsubstituted 6.7-di-MeUnsubstituted Unsubstituted

Unsubstituted Unsubstituted

Unsubstituted 6-Me6,7-di-M~6.7-di-MeUnsubstituted Unsubstituted 6,7-di-Me6,7-di-Me6,7-di-Me-

(6.399)

0 0 0 0 0 0 0 0 0 0

0 0

0 0 0 0 0 0 0 0 0

X

Y

4-Me,NC6H4CH 4-Me,NC6H,CH 4-Me,NC6H,CH 4-Me,NC6H4CH PhCHSHCH MeCHSHCH 2-Furfurylidene 2-Furfurylidene Me,C H0,CCH

4-Me,NC,H,CH 4-Me2NC,H4CH

4-MeOC6H,CH 4-MeOC6H4CH 4-MeOC6H4CH 4-MeOC,H4CH 3-02NC6H4CH 4-02NCbHaCH 2-02NC6H4CH 3-02NC6H4CH 4-OZNC6H4CH

Product

-c

-

76 50

-c

45

90 40 81 86

45

-c

70 72 60

-c

40 70 74 49 80

-

269 267-268 tdecomp.) 269 270 273-274 >320 234-235 212 231-232 260-261 181.5-182

236 195 257-258 238-239 254 >300 246-247 259-260 318-319

Yield m.p. (“C)

(%)

-d

Acetic acid Methanol

-d

-d

-d

1-Propano1 Acetic acid Ethanol Xylene

-d

Acetic acid Acetic acid Dimethylformamide Ethanol

d

-

-d

Ethanol Xylene PfOH

-d


131 101 133 133 130 101 130 134 131 147

129 130

101 133 133 134 101 130 134 134 134

Ref.

K

z

7-NH2 Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted

Unsubstituted Unsubstituted Unsubstituted Unsubstituted 6,7-di-Me-

0 0 0 0 0

H, H, H, H. H,

H H H H H

0 0 0 0 0 H, H 0 0 0 0 0 0 0 0 0 0

Unsubstituted Unsubstituted Unsubstituted Unsubstituted 6.7-di-Me7-AcNH Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted

H, H PhNHCSNH, He 2-MeC6H,NHCSNH, He 3-MeC6H,NHCSNH, H' 4-MeC6H,NHCSNH, He 2-CIC,H,NHCSNH, He 3-CIC6H,NHCSNH, H' 4-ClCbH4NHCSNH. H' 2-BrC,H4NHCSNH, He 3-BrC6H4NHCSNH, H' 4-BrC,H4NHCSNH, He

EtOCH Me2NCH MeCON(Ph)CH 4-Me2NC,H,N 4-Me2NC,H,N

58 65

60

100 60 65 58 59 62 61 59

93 39

55

46 77

243-245 220-221 195-197 198-200 175-177 202-204 215 21 1 189 189 165-166

167-169 255-256 195 256 300-302

-d

d

-

-d -d

d

d

-

-d -d -d -d

Ethanol Acetic acid Ethanol Chloroform Ethanol4ichloroethane Water

128 235 235 235 235 235 235 235 235 235 235

129 2 34 135 131 134

a

A = Ac,O/(room temp.)(l4 hr); B = ArCHO, Et,N, EtOH/(reflux)(lO min); C = ArCHO, piperidine, BunOH/(reflux)(2 hr); D = ArCHO. NaOAc. AcOH/(reRw)(reaction time unspecified);E = ArCHO, NaOAc, AcOH/(reflux)(2-4 hr); F=ArCHO. piperidhe. EtOH/(100'="1-2 hr); G = M H o , AcOH/(reflux)(ZOmin-1 hr); H = ArCHO, piperidine, EtOH/(room temp.)(l hr); I = M e 2 C 4 , piperidine/(reflux)(6hr); J = HO,CCHO, AcOH (reaction conditions not specified); K = (EtO),CH, A%O/(reflux)(20min); L = POCI,, dimethylformamide/(Oo)(30min), then (50°)(5 hr); M = PhNHCH-NPh, Ac,O/(reflux)(30 min); N = 4-Me2NC&N0, EtOH/(reflux)(ZO min); 0 = 4-Me,NC6H,N0, piperidine, EtOH/(reflux)(2 hr); P = Ac20/(reflux)(l.5 hr); Q = ArN=C=S, EtOH/(reflux)(S hr). Colorless oil. Yield not quoted. Solvent of crystaiiization not specified. ' Hydrochloride.

c , Q

Q Q Q Q Q Q Q Q Q

P

0

M N

L

190


provide the means for the construction of methine d y e ~ t u f f s ' ~ ~incor*~~*,~~~ porating the 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-one nucleus. The methylene reactivity of 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-one toward carbon-based electrophiles is further exemplified by its reaction129with ethyl orthoformate in the presence of acetic anhydride to afford the C(2)ethoxymethylene derivative, albeit in only moderate yield (Table 6.62) and by its ready aminoalkenylation at the C(2)-position by dimethylformamide in the presence of phosphorus oxychloride (the Vilsmeier-Haack condensat i ~ n ) .In~ reactions ~ ~ closely related to those with aromatic aldehydes (see before), 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-onesundergo uncataly~ed'~'or base (sodium arbo on ate'^^'^^^ or piperidine'") catalyzed condensation with nitrosoarenes to give moderate to excellent yields (Table 6.62) of 2-arylimino-2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones. Amino- and hydroxy-substituted 2,3-dihydrothiazolo[3,2-a]benzimidazoles behave in an orthodox manner toward acylation as illustrated by the straightforward acetylation of nuclear amino substituents12" and by the reaction of C(2) amino groups with aryl isothiocyanates to afford the corresponding thioureas (Table 6.62).235 In accord with their ring as opposed to open-chain tautomeric structures (see page IOS), 3-hydroxy-2,3dihydrothiazolo[3,2-a]benzimidazoles acetylate in standard fashion giving high yields (Table 6.62) of the corresponding acetoxy derivative^.'"^*'^^ Acylation (Table 6.63) of l-imino-1H,3H-thiazolo[3,4-a]benzimidazole (6.400;X = NH, Y = H2) by acetic anhydride or acid chlorides under basic conditions occurs at both N(4) and at the imino substituent, demonstrating the ability of this molecule to react in the 4H-tautomeric form (6.401; X = NH, Y = H).'" In contrast, the reaction of l-imino-lH,3H-thiazolo[3,4-a]benzimidazole (6.400; X = NH, Y = H2) with isocyanates and isothiocyanates is confined to the imino substituent and leads to moderate yields (Table 6.63) of the simple ureas and t h i o u r e a ~ . 'The ~ ~ mobility of the hydrogen atoms in the C(3)-methylene group of l-imino-lH,3H-thiazolo[3,4-a]benzimidazole manifest in the tautomeric character of this molecule (see before) is also apparent in its uncatalyzed condensation with aromatic aldehydes to give moderate yields (Table 6.63) of the corresponding 3arylidene derivatives (6.400;X = NH, Y = ArCH).'" The tendency for 4H-pyrazolo[2,3-a]benzimidazoles to undergo electrophilic attack at the C(3) position is demonstrated by their smooth reaction with aromatic aldehydes under basic conditions to afford high yields (Table 6.64) of 3-arylidene-3H-pyrazolo[2,3-albenzimidazolederivatives (6.403;X = ArCH).I9' Analogous condensation reactions with enamides and related substrates are widely used for the synthesis of 3H-pyrazolo[2,3-a]benzimidazole cyanine dyestuffs.lg8The susceptibility of 4H-pyrazolo[2,3albenzimidazoles to electrophilic attack at the C(3) position is further demonstrated by their specific aminoalkenylation at this site under VilsmeierHaack conditions (i-e., reaction with dimethylformamide-phosphorus

H, H H. H H, H H, H H, H H. H H.H H, H H, H H. H H,H H,H H, H H, H

NH NH NH NH NH NH NH NH

NH PhNHCON PhNHCON PhNHCON PhNHCON 0

MeCO PhCO 4-CIC,H,CO Et0,C PhCH20,C 4-MeC,H4SO, H, H H, H H, H MeCO PhCH 2-Furfurylidene 2-Thienylidene 2-Thienylidene

(6.400) 4-N02C,H,NHCON (6.401) PhNHCON (6.400) PhNHCON (6.400) PhNHCON (6.400) PhNHCON (6.400) 0

H. H

Y

MeCON PhCON 4-CIC,H4CON Et0,CN PhCH20,CN 4-MeC6H,S0,N (6.400) PhNHCON (6.400) C1,CCONHCON

(6.401) (6.401) (6.401) (6.401) (6.401) (6.401)

(6.000) MeCON

x

77 63 33 42 35

50

87 50 65 27 25 20 43 33

30

(Yo)

Yield

260-262 153-155 221-224 230-234 256-258 21 1-212

258-261 232-234 220 162-163 168-170 197-198 160d 180-182

195-197

m.p. ("C)

Acetone Benzene Dimethyl sulfoxidewater Pyridine Ethyl acetate Chloroform-ether Chlorofom-ether Ether Chloroform

-'

Ether-light petroleum Chloroform Ethyl acetate Pyridine Benzene


a

From Ref. 152. A = A ~ O / ( l O ~ ) / ( l . S - lmin); S €3 = Ac,O, NaOAc/(100")(0.25 hr); C = PhCOCI, pyridine, ethyl acetate/(reflux)(0.5hr); D = 4-CIC6H4COCl, Et,N, ethyl acetate/(reflux)(20 min); E = RCO,Cl/(reflux, neat)(l.5 hr); F = 4-MeC,H4S0,CI, pyridine, benzene/(room temp.)(48 hr); G = RN=C=O, ethyl acetate/(reflux)(l hr); H = ArCHO/(reflux, neat)(3 min). ' Solvent of crystallization not specified. With resolidification at 195-197'.

H H H H

A

G

G G

E F

E

D

c

B

H, H

NH

(6.400) Y Product

A

Reaction Substrate conditionsb X

DERIVATIVESa TABLE 6.63. ACYLATION REACTIONS O F 1H,3H-THIAZOL0[3,4-a]BENZIMIDAZOLE

SO,H SO,H H H S03H

NH, H H H H

NH,

Ph C17H3, Me Ph Ph

Ph

Me Ph Ph

NO NH, NH,

H H S03H

S03H

R3

RZ

R'

Substrate (6.402)

NHCOPh C,?H,, Me Ph Ph

(6.402) (6.403) (6.403) (6.403) (6.403) S03H S03H H H S03H

NHCOEt

NHAc NHAc NHAc

(6.402) H (6.402) H (6.402) S03H

(6.402) SO,H

R2

Product R'

-

-

Ph

-

Ph

Me Ph Fll

R'

4-Me2NC&,CH Me,NCH Me,NCH 4-EtZNCeHdN

-

x

m.p.

-


-

51-68 220 Methanol-water (decomp.) 61 >350 Methanol-water -b 90 -' b 59 216 b 235 -b 43 >315 (decomp.)

b 68 293-293.5 89 295-296 Methanol 61-72 go0/,) by lithiation of a 2,9-disubstituted 9H-imidazo[ 1,2-a]benzimidazole at the C(3) position followed by carboxylation with carbon The reactivity of the C(3) position in 2,9-disubstituted 9H-imidazo[ 1,2-a]benzimidazoles to electrophilic substitution also extends to formylation under Vilsmeier-Haack conditions (reaction with dimethylformamide-phosphorus oxychloride). Acylation of this t ~ p e ' ~ ~proceeds .'~' in high yield (Table 6.65) and allows direct access to the synthetically useful 3-formyl derivatives, which are less conveniently prepared by lithiation of 2,9-disubstituted 3bromo-9H-imidazo[l,2-a]benzimidazolesfollowed by reaction with dimethylf~rmamide.'~'The failure'" of 1H-imidazo[ 1,2-a]benzimidazoles to undergo acylation with acetic anhydride, acid chlorides, or the VilsmeierHaack reagent (dimethylformamide-phosphorus oxychloride) demonstrates, in accord with theoretical predictions (see before), the lower reactivity of the imidazole ring in such molecules to electrophilic attack. 2,9-Disubstituted 3acetyl-9H-imidazo[l,2-a]benzimidazolesare converted under VilsmeierHaack conditions into the 3-ethynyl derivatives in high yield (Table 6.65) via isolable p-chlorovinyl aldehyde intermediate^.^'^ C(2) and C(3) amino substituents in 9H-imidazo[l,2-a]benzimidazoles are readily acetylated under standard conditions (Table 6.65).174*175 Prior lithiation at the C(3) position is a prerequisite of the successful reaction of 9H-imidazo[ 1,2-a]benzimidazoles with aldehydes, which allows access, albeit in variable yield (Table 6.65), to the corresponding C(3) secondary alcohol derivatives.'64 C(2) methyl substituents in 9H-imidazo[1,2-a]benzimidazoles are sufficiently activated to electrophilic attack to

2-PhN(Me)-3-MeCO-9-Mc-

2,9-di-Me-3-(PhGCCO)2-Ph-3-(PhC%CCO)-9-Me-' 3,9-di-Me-2-MeCO3.9-di-Me-2-PhCO2-Ph-3-MeC0NH-9-PhCH22.9-di-Me-3-CHO-8 2-Ph-3-CHO-9-Me2-( ~ - B I C , H , ) - ~ - C H O - ~ - M ~ - ~

2-Ph-9-Me-

2.9-di-Me2-Ph-9-Me3.9-di-Me3.9-di-Me2-Ph-3-NH2-9-PhCH22,9-di-Me2-Ph-9-Me2-(p-BrC,H4)-9-Me-

F

G G D

J J J

1

H

2-Ph-3-[2-(5-nitro-2-furyl)acryloyl]-9-Me-

2-Ph-9-Me-

E

2,9-di-Me-3-(PhCH=CHCO)-

2-Ph-9-Me-

2-PhN(Me)-9-Me2.9-d i-Me -

2-PhN(COMe)-3-MeCO-9-Me2-{p-0,NC,H4N(COMe)]-3-MeCO-9-Mc2-[p-CIC,H4N(COMe)]-3-MeCO-9-Me2-(p-Et0,CC,H4NH)-9-Me-d 2-[p-Et0,C,H4N(COMe)]-3-MeCO-9-Me-

E

E

P DD

D D c

2.9-di-Me2-Ph-9-Me2-PhNH-9-Me-d 2-(p-0,NC,H,NH)-9-Me-d ~-(P-CIC,H,NH)-~-M~-~

B C D

70 88 40

-d

58

40 47 80

53

-d

-d -d

70 76 77 84 88 78

50

85

2-(p-BrC,H4)-3-MeCO-9-Me-

2-(p-BrC,H4)-9-Me-

A

2,9-di-Me-3-PhCO2-Ph-3-PhCO-9-Me-

87 89 92

2,9-di-Me-3-MeCO-b 2.9-di-Me-3-MeCO2-Ph-3-MeCO-9-Me-'

Yield

(Yo)

2,9-di-Me2.9-di-Me2-Ph-9-Me-

Product

1(9)H-imidaz~l,2-a]benzimidazole

A A

A

Reaction conditions" Substrate

2 10 (decomp.) 304-305 (decomp.) 203-204 195-196 177 140-142 2 12-2 13 186 147 199-201

225

179-180

158

156 215 171 27 1 194 174

197

178 178 212

m.p. ("C)

Ref.

Ethanol Ethanol Acetone Acetone Ethanol-water Methanol Dioxane Ethanol

164 164 171 17 1 175 165 165 164

Dimethylformamide 214

Ethanol-water 173 Ethanol 172 172 Ethanol-dimethylformamide Ethanol-limethyl172 formamide 172 Benzene 172 Ethanol Ethanol 174 Dimethylformamide 174 Heptane 174 Ethanol 174 174 Ethanol Ethanol-dirnethyl214 formamide Ethanol-dimethyl214 formamide Ethanol 214


TABLE 6.65. ACYLATION REACTIONS OF I(9)H-IMIDAZO[ 1,2-a]BENZIMIDAZOLES AND 2,3-DIHYDRO-1(9)H-IMIDAZO[ 1,2-0] BENZIMIDAZOLES

2-Ph-3-MeCO-9-Me-

2-Me-3-MeCO-9-PhCH22-Ph-3-MeCO-9-[Et,N(CH2)J2-Ph-3-MeCO-Y-Me: 2-Ph-3-Br-9-Me2-Ph-3-Br-9-Me-

K

K

K

r

2.9-di-Me-3-MeCO2,9-d i- Me - 3- MeCO-

2.9-di-Me-3-MeCO2-Ph-3-MeCO-%Me-

2-Ph-3-MeCO-9-Me2-Ph-3-MeCO-9-Me2-Ph-3-MeCO-9-Me2-Ph-3-MeCO-9-Me2-Ph-3-MeCO-9-[Et2N(CH,),I2,9-di-Me-3-NH29-Me-2.3-dihydro-2-one

P

P P

P P P P P

Q Q

P

2,9-di-Me2,9-di-Me2.9-di-Me-3-MeCO-

0 0 P

0

s o

N N

M N

L

2-Ph-3-Br-9-Me2,9-di-Me-3-Br2.9-di-Me2,9-di-Me-

2-Ph-9-PhCH22-Ph-6.7-di-Me-y-Et2,9-di-Me-3-MeCO-

J J

K

2-(2-naphthyl)-9-Me-

J 98 90 70-85

80

254-255

Ethanol-dimethylformamide Ethanol Ethanol Light petroleum

153-154 215-216 2,9-di-Me-3-(HC%C)117-118 (decomp.) 2-Ph-3-(HC=C)-Y-Me70-85 127-128 Light petroleum (decomp.) 2-Me-3-(HC=C)-9-PhCH270-85 170 Ethanol 2-Ph-3-(H&C)-9-[Et2N(CH,),I-' 70-85 -m 155-156 Light petroleum 81 147 Dioxane 72 192 Dimethylformarnide (decornp.) 2-Ph-3-(p-Me2NC6H4CHOH)-9-Me55 181-182 Ethanol 193 Ethanol 2.9-di-Me-3-(p-Me2NC,H,CHOH)22 90 2-(PhCH=CH)-9-Me215 Ethanol 2-(p-OzNC,H,CH==CH)-9-Me72 22 1 Dimethylformamide (decomp.) 2-( o-HOC,H,CH=CH)-9-Me98 297 Dimethylformamide 2-(p-Me,NC6H4CH=CH)-9-Me63 2x2 Ethanol 2,9-di-Me-3-(PhCH=CHCO)-P 179- 180 Ethanol-dimethyl90 formamide 2,9-di-Me-3-(p-MeOC,H4CH=CHCO)91 18 1 Ethanol 2,Y-di-Me-3-(m-02NC,H4CH==CHCO)94 243-244 Ethanol-dimethyl(decomp.) formamide 2,9-di-Me-3-( p-O,NC,H,CH=CHCO)95 292 Dimethylformamide 2-Ph-3-(PhCH=CHCO)-9-Me-q 94 225 Ethanol-dimethylformamide 2-Ph-3-(p-MeOC,H4CH==CHCO)-Y -Me90 211-212 Ethanol 90 2-Ph-3-(m -02NC,H4CH=CHCO)-9-Me323 Dimethylformamide 2-Ph-3-(p-0,NC6H,CH=CHCO)-9-Me95 288 Dimethylformamide 2-Ph-3-(p-Me2NC,H,CH=CHCO)-9-Mc73 208 Ethanol 2-Ph-3-(p-MeOC,H4CH=CHCO)-9-[Et2N(CH2),]88 149-150 Ethanol 2,9-di-Me-3-( p-02NC,H4CH=N)78 230-232 Ethanol 3-(p-0,NC,H4CH=)-9-Me-2,3-di hydro-2-one 74 317 Dimethylformamide 2-Ph-3-CHO-9-PhCH2-'

2-Ph-3-CHO-6.7-di-Me-9-Et-k

2-(2-naphthyl)-3-CHO-9-Me-'

214 214 2 1.4 214 214 175 180

214 214

214 214

165 214

165

164 164 165 165

213 213 213 165 164

213

164 164 213

164

Q\

\o

c

l-Me-2,3-dihydro-2-one 2,3-dihydro-l(9)H-

9-PhCH2-2,3-dihydro-2-one

Yield

(%I

1-guanyl-2,3-dihydro-

31

3-(o-02NC6H4CH=)-9-Me-2,3-dihydro-2-one 6 2 3-(p-0,NC6H4CH=)-9-PhCH2-2,3-dihydro-2-one 70 1-Me-3-(p-0,NC,H4CH=)-2,3-dihydro-2-one 70

Product

l(9)H-imidazdl ,2-a]benzimidazole

9-Me-2,3-dihydro-2-one

Substrate

(Continued)


~~

262 Dimethylformamide 300-301 Dimethylformamide 284 270-272 Water (decornp.)

m.p.

("a

180 180 180 176

Ref.

'

J

aA

= Ac,O/(reflux)(1-3 hr); B = PhCOCI, benzene/(room temp.)(l hr); C = PhCOCI, pyridine/(80")(2-3 rnin., then boil briefly); D = A%O, NaOAc/ (reflux)(3-3.5 hr); E = RCH=CHCOCI/(40-80")(reaction time not specified); F = 2-(5-nitro-2-furyl)acryloyl chloride/( 100-12O0)(reaction time not specified); G = Ph-C COCl/(40°)(20 rnin); H = PhCOCI, pyridinel(1 10-120°)(10 rnin); I = A%O/(reflux)(brief); J = POCI,, dimethylformamide/(room temp.)(30 min, then 100")(20 min-2 hr); K = POCI,, dimethylformamide/(room tempJ(30 min, then 60-70")(2 hr, then treat with KOAc)/(60-70") (1-1.5 hr); L = POCI, dimethylformamide, KOAc/(lV)(reaction time not Specified); M = Bu"Li, toluene-ether/(-75")(5 hr, then dimethylformamideether)(-75")(1 hr, then 20")(3 hr); N = Bu"Li, toluene/(-75")(5 hr, then ArCHO. ether)(-75')(1 hr, then room temp.)(l4 hr); 0 = ArCHO, melt/ (65-100')(5-10 min); P = ArCHO, 40% NaOH aq., EtOW(warm)(few rnin); Q = ArCHO, AcOH or Ac20/(reflux)(15-20 min); R = p-O,NC,H,CHO, A%O/(reflux)(l hr); S = 2,S-dimethyl-l-guanyIpyrazole,EtOH/(reflux)(4 hr). * Forms a 2,44initrophenyIhydrazone,dark brown needles, m.p. 260-261" (fromdimethylformamide), and a hydrochloride. colorless needles, m.p. 276" (from ethanol). Forms a hydrochloride, m.p. 217" (from ether-ethanol). Hydrochloride. ' Yield not quoted. f Forms a 2,44initrophenyIhy&azone, red crystals, m.p. 272" (from dimethylformamide). * Forms a 2,4-dinitrophenylhydrazone,black crystals, m.p. 288" (from dimethylformarnide), and an oxime, m.p. 265" (from ethanol-water). Forms a 2,4-dinitrophenylhydrazone,m.p. 307-308" (from dimethylformamide). ' Forms a 2.4-dinitrophenylhydrazone,m.p. 330" (from dimethylformamide). Forms a 2,4-dinitrophenylhydrazone,m.p. 248-250" (from dimethylformamide). Frorns a 2,4-dinitrophenylhydrazone,m.p. 288" (decornp.) (from dimethylforrnamide). ' Forms a dipicrate, m.p. 168-169'. In Oil. " Forms a 2,4-dinitrophenylhydrazone,red needles, m.p. 304" (from dimethylformamide). " Forms a hydrochloride, m.p. 134" (from ethanol). P Forms a 2,4-dinitrophenylhydrazone,red crystals, m.p. 228-229' (decomp.) (from dimethylformamide). Forms a 2.4-dinitrophenylhydrazone.red crystals, m.p. 259-260" (decornp.) (from dimethylformarnide). ' Solvent of crystallization not specified

S

R

Q Q


TABLE 6.65


197

undergo uncatalyzed condensation with aromatic aldehydes affording moderate to excellent yields (Table 6.65) of the C(2) styryl derivative^.'^' Despite the strongly electron-donating (and hence deactivating) character of the 9H-imidazo[ 1,2-a]benzimidazole ring system, attached C(3) acetyl groups participate in orthodox aldol-type condensation reactions with aromatic aldehydes giving high yields (Table 6.65) of the anticipated apunsaturated keto derivative^.^'^ The condensation of C(3) amino substituents in 9H-imidazo[ 1,2-a]benzimidazoles with aromatic aldehydes leads to Schiff base formation in good yield (Table 6.65)."' As a result of the lower reactivity of their component C(3) methylene groups, 2,3-dihydro1H- and BH-imidazo[ 1,2-a]benzimidazo1-2-onesare much less able than 2,3-dihydrothiazolo[3,2-a]benzidazol-3-ones (see before) to take part in aldol-type condensation reactions and only form C(3) arylidene derivatives (Table 6.65) with the more reactive aromatic aldehydes (e.g., p-nitrobenzaldehyde). 4H-Imidazo[ 1,5-a]benzimidazoles are readily acylated at the C(1) and C(3) positions under a variety of conditions, thus substantiating theoretical predictions224 of the susceptibility of these sites to electrophilic attack. Acetylation at the C(1) and C(3) positions in 4H-imidazo[l,S-a]benzimidazoles is achieved smoothly and in high yield (8696%) (Table 6.66) simply by heating with acetic anhydride in the presence of sodium acetate.192,193,215 Formylation under Vilsmeier-Haack conditions likewise affords excellent yields (Table 6.66) of 4H-imidazo[ 1,5-a]benzimidazole 1~ ~1)-Unsubstituted ~~~~*~~~ 4H-imidazo[ 1,5-a]and 3 - ~ a r b o x a l d e h y d e s . ~C( benzimidazoles also react readily with aqueous formaldehyde to give high yields (Table 6.66) of the corresponding C(1)-hydroxymethyl derivative^.^" In contrast, the reaction of C(3)-unsubstituted 4H-imidazo[ 1,5-a]benzimidazoles with aqueous formaldehyde leads not to the anticipated C(3)hydroxymethyl derivatives but to dimeric products (Table 6.66) formed by their self-c~ndensation.'~~ 4H-Imidazo[ 1,5-a]benzimidazoles are readily 5,221 at the C(1) position under Mannich conditions (conamin~alkylated~' densation with secondary amines in the presence of formaldehyde) (Table 6.66),and undergo cyanoethylation at the same site on treatment with acrylonitnle (Table 6.66).21'

HALOGENATION. Reagents such as bromine in

or N-bromosuccinimide in acetone122 effect the bromination of thiazolo[3,2-a]benzimidazoles at the electron-rich C(2) position giving moderate to high yields (Table 6.67) of the corresponding C(2)-bromo derivatives. Bromine readily adds to the carbon-carbon double bond in 2-arylidene-2,3-dihydrothiazolo[3,2-a]benzimidazol-3-onesgiving vermilion colored dibromo adducts in moderate to high yield (Table 6.67).'0','33 The transformation shown in Scheme 6.86 represents what appears to be the sole example of the halogenation of the 4H-pyrazolo[2,3-a]benzimidazole ring ~ y s t e m , " ~and illustrates the reactivity of the C(3) position in the latter to electrophilic attack.

90 76

I

H

(1,4-di-Me-3WH2( l-Ph-4-Me-3f5CH21-(Me2NCH,)-3-Ph-4-Me-

( l,4-di-Me-3fzCH2-

1,4-di-Me1,4-di-MeI-Ph-4-Me3-Ph-4-Me-

H

G

n8 99

249.5-252 114.5-1 16.5 Ether

-

Ethanol-water

Ethanol Ethyl acetate

190-192 159-160 (decomp.) 201-203 100

9n

1-Ph-3-CHO-4-PhCH2-d 1-HOCH2-3-Ph-4-Me-

Ethanol Ethanol Ethanol Ethanol Benzene Ethanol

209-2 10.5 223.5-225.5 247-249 182- i n 3 178-179 199.5-200.5


94 n4 n9 96 72 92

("a

m.p.

1- M c C O - ~ - P ~ - ~ - M C 1.4-di-Me-3-MeCOl-Ph-3-MeCO-4-Me1-Ph-3-MeCO-4-PhCH21 -CHO-3,4-di-Meb1-CHO-3-Ph-4-MeC-

( O h )

Yield

l-Ph-4-PhCH23-Ph-4-Me-

3-Ph-4-Me1,4-di-Me1-Ph-4-Me1-Ph-4-PhCH,3.4-di-Me3-Ph-4-Me-

~

Product

4H-lmidazo[ 1,5-a]benzimidazole

Substrate

~

E F


ACYLATlON REACTIONS OF 4H-IMIDAZO[l ,S]a]BENZlMIDAZOLES

~-

TABLE 6.66.

192 192 192 215

215 192 192 193 216 215, 216 193 215

Ref.

3-Ph-4-Me-

K

n

1-(MeN NCH2)-3-Ph-4-Me-' 96 l-f l-[NC(CH,),]-3-Ph-4-Me-6 32 184-186

220-223 Ethanol

Ether-ethanot

215

221

'

'

HCHO aq., EtOH/(rwm tempJ(l2 hr); J=MeNnNH, 30% HCHO aq., EtOH/(room temp.)(S ht); K = Lf CH,=CHCN, Roddionov reagent/(reflux)(8 hr). * Forms an oxime. yellow crystals, m.p. 260-261.5 (decornp.) (horn ethanol), and a thiosemicarbazone, yellow crystals, m.p. 225.5-226" (dccomp.) (from methanol). Forms an oxime, yellow crystals, m.p. 214-214.5" (decomp.) (from ethanol), and a thioscmicarbazone, m.p. 215-216" (decomp.) (from acetic acid). Forms an oxime. colorless crystals, m.p. 191-193' (from ethanol). and a thiosemicarbazone, yellow needles, m.p. 225.5-227.5" (decornp.) (from ethanol). ' Solvent of crystallization not specified. Dihydrochloride. * Forms a picrate, m.p. 187-188".

a A = Ac,O, NaOAc/(eflux)(2-3 hr); B = Ac,O, NaOAc/(90-100")(1.5 hr), then (120")(30 min); C = POCI,, dimethylformamide/(room temp.)(several days); D = POCt,. dimethylformamide/(2So)(4 hr); E = ma,, dimethylformamide/(room temp.)(l5 hr); F = 30% HCHO aq.. H,O/(reflux)(4 hr); G = 30% HCHO aq., H,O/(reflux)(30 min); H = 40% Me,NH aq., 30% HCHO aq., EtOH. H,O/(room tempJ(24-48 hr); I = 15%

3-Ph-4-Me-

J

0 0

a

A = N-bromosuccinimide,acetone/(room temp.)( 14-15 hr);

B

B

B

B

B

B

B

B

B

t 4 B

2-Br-2-[PhCH(Br)]-6,7-di-Me-2,352 2-(PhCH=)-6,7-di-Me-2,3-dihydro-3-one dihydro-3-one 80 2-(p-HOC6H,CH=)-2,3-dihydro-3-one 2-Br-2-[p-HOC6H,CH(Br)]-2,3dihydro-3-one 2-(p-MeOC6H,CH=)-2,3-dihydro-3-one 2-Br-2-[p-MeOC6H,CH(Br)]-2,350 dihydro-3-one 2-(p-MeOC6H,CH=)-6-Me-2,3-dihydro-2-Br-2-[p-MeOC,H4CH(Br)J-6-Me-2,3- 45 dih ydro-3-one 3-one 2-(p-MeOC6H4CH=)-6,7-di-Me-2,3-di 2-Br-2-[p-MeOC6H,CH(Br)]-6,7-di-Me-2,362 hydro-3-one dihydro-3-one m-O,NC6H4CH(Br)]-2,32-(m-O2NC,H,CH=)-2,3-dihydro-3-one 2-Br-24 80 dih ydro-3-one 2-(p-Me,NC,H4CH=)-2,3-dihydro-3-one 2-Br-2-[p-Me,NC6H4CH(Br)]-2,358 dihydro-3-one 2-(p-Me,NC,H,CH=)-6-Me-2.3-dihydro-2-Br-[p-Me,NC6H,CH(Br))-6-Me-2,348 %one dih ydro-3-one 2-(p-Me,NC6H,CH=)-6,7-di-Me-2,3-di2-Br-[p-Me,NC6H4CH(Br)]-6,7-di-Me-2,3-68 hydro-3-one dihydro-3-one 2-(p-CIC6H4CH=)-6-Me-2,3-dihydro-2-Br-[p-CIC,H,CH(Br)]-6-Me-2,340 %one dih ydro-3-one 2-(p-C1C6H,CH==)-6,7-di-Me-2.3-di2-Br-[p-CIC,H4CH(Br)]-6,7-di-Me-2,3- 59 hydro-3-one dihydro-3-one

B

B = Br,, CHCI,/(0-5")(2 hr).

101

-b

133

133

133

133

101

133

-b

-b

133

101

-b -b

101

133

101 133

122

122

Ref.

-b

213-214 -b (decornp.) -b 262-263 (decomp.) -b 180 (decomp.) 267-268 -b (decomp.)

190

244-246 (decomp.) 208-209 (decomp.) 258

240

>300

207 -b 285-286 -b (decomp.) -b 217-218

Solvent of crystallization not specified,

2-Br-2-[PhCH(Br)]-2,3-di hydro-2-one 50 2-Br-2-[PhCH(Br)]-6-Me-2,3-dihydro-3-one48

2-(PhCH-)-2,3-dihydro-3-one 2-(PhCH=)-6-Me-2,3-dihydro-3-one

B B

}

Benzene-ethyl acetate

245

14

2,8-di-Br-3-Ph-6,7-di-Me-

3-Ph-6.7-di-Me-

A

Acetone Ethanol

208 220

61 28

2-Br-3-Ph2-Br-3-Ph-6.7-di-Me-

Solventof crystallization

2.3-DIHYDROTHIAZOLq3,2-a]-

Yield m.p. ("C)

(%)

3-Ph-

Product

OF THIAZOLq3,2-aJBENWMIDAZOLES AND

A

Thiazolo[3,2-a]benzimidazole Reaction conditionsP Substrate

REA(X1ONS BENZIMIDAZOL-3-ONES

TABLE 6.67. BROMINATION


201

CI

c1

I H

I H (i) SO,CI,, NaOAc, AcOH/(40")(15 min)

C17H35 a

(m.p. 115-1 16")

C(3)-Unsubstituted imidazo[ 1,2-a]benzimidazoles are readily brominated under mild conditions to give uniformly high yields (Table 6.68) of the C(3)-bromo derivative^.'^^",^^^*^^ The facility of these transformations is a measure of the high-electron localization at the C(3) position in the 9Himidazo[ 1,2-a]benzimidazole ring system (see before). The resistance of the imidazole ring in lH-imidazo[ 1,2-a]benzimidazoles to electrophilic attack (see later) does not apply to bromination, which occurs readily and affords the C(3)-bromo derivatives in high yield (Table 6.68).15' Not unexpectedly, of 2,3-dihydroimidazo[ 1,2-a]benzimidazoles occurs at the bromination'66*1M0

TABLE 6.68. BROMINATION REACTIONS" O F 1H- AND 9H-IMDAZq1,2-a]BENZIMIDAZOLES 1 H- or YH-lmidazo[ 1 . 2 4 Jbenzimidazole

Substrate

Product

Yield (%)

89 98

m.p.("C)


Ref.

274 Ethanol-ether 164 245 162a (decomp.) 2-(p-02NC,H,)-9-Me- 2-(p-02NC,H,)-3-Br-9-Me-h,' 90 268 Dimethylformamide163 2-(p-BrC6H,)-9-Me- 2-(p-BrC6H,)-3-Br-9-Me65 170 Ethanol-dimethyl 163 formamide 2-Ph-6,7-di-Me-9-Et- 2-Ph-3-Br-6.7-di-Me-9-Et-b.g 90 >220 163 (decomp.) 2-Ph-9-PhCHZ2-Ph-3-Br-9-CH2Ph-h.h n8 244 Ethanol 164 2-Ph-9-[Et,N(CH2),]- 2-Ph-3-Br-9-[Et2N(CH,),]-".' 82 167-168 Ethanol-ether 164 I-Me-2-PhI -Me-2-Ph-3-Br-'.' quant. 259 Ethanol 157 (decomp.) 2,9-di-Me2-Ph-9-Me-

2,9-di-Me-3-Br-b.C 2-Ph-3-Br-9-Me-b3d

Br,, CHCI,/(20')(60 min). Hydrobromide. Free base has m.p. 148" (from ethanol). Free base has m.p. 148" (from ethanol). ' Solvent of crystallization not specified. Free base has m.p. 256" (from dimethylformamide). * Free base has m.p. 158" (from ethanol). Free base has m.p. 172" (from ethanol). ' Free base is an oil. Free base has m.p. 205" (from ethanol).

'

'

Condensed Benzimidazolesof Type 6 - 5 5

202

TABLE 6.69. BROMINATION REAOIONS' OF 4 H - I M I D A Z q 1,5-a]BENZIMIDAZOLE DERIVATIVES 4H-lmidazo[ 1.5a]benzimidazole

CC)

Substrate

Product

Yield ('10)

m.p.

I-Ph-4-Me3-Ph-4-Me-

1-Ph-3-Br-4-MeI-Br-3-Ph-4-Me-

24 72

152-154 191-194


Ref.

ether methanol

192 22 1

N-Bromosuccinimide, CC14/(reflux)(2hr).

unspecified sites in the benzene ring and not in the imidazoline nucleus. 4HImidazo[ 1,5-a]benzimidazoles are brominated in moderate to high yield (Table 6.69) at the electron-rich C(1)221and C(3)192 positions by heating with N-bromosuccinimide in carbon tetrachloride. AND NITRATION. The ready conversion of C(3)-unsubstituted NITROSATION 4H-pyrazolo[2,3-a]benzimidazoles into C(3)-nitroso derivatives by treatment with sodium nitrite in hydrochloric or sulfuric acids (Table 6.70)'9y9200 is a further illustration of the susceptibility of the C(3)position in the 4Hpyrazolo[2,3-a]benzimidazole ring system to electrophilic attack. 9-Alkyl-2-aryl-9H-imidazo[ 1,2-a]benzimidazoles react with sodium nitrite in acetic acid to give the corresponding C(3)-nitroso derivatives in high In contrast, the C(3)-nitrosation of 2,9-dimethylyield (Table 6.7 1).175*227 9H-imidazo[ 1,2-a]benzimidazole is followed by ring-opening to an iminobenzimidazoline derivative (Scheme 6.87).227Analogous ring-opening occurs on attempted nitrosation of 9-methyl-2,3-dihydro-9H-imidazo[ 1,2-a]benzimidazol-2-one (Scheme 6.87)."" The failure of 1H-imidazo[ 1,2-a]benzimidazoles to undergo nitro~ation'~'is a measure of the low reactivity

TABLE 6.70. Reaction conditions" A A A A

n B

NITROSATION REACTIONS OF 4H-PYRAZOL0[2,3-a] BENZIMIDAZOLE DERIVATIVES

4H-Pyrazolo[2,3-a]benzimidazole Substrate

Product

2-Me2-Ph2-Ph-6-SO3H2-CONHZ2-COzH2-COZH-6-SO3H-

2-Me-3-NO2-Ph-3-NO2-Ph-3-NO-6-SO3H2-CONH2-3-NO2-COzH-3-NO2-COZH-6-SO3H-

Yield

m.p.

Solvent of

(Oh)

("C)

crystallization Ref.

-

c

-d

-

c

-d

-

b

-b 98

260

-d

b

-

c

-d

b

-

c

-d

b

-

c

-d

-

" A = 10% NaNO,, 20% H2S04 aq./-5 to +5"; €3 = 10% NaNO,, 20% HCI aq./O-lO". Yield not quoted. Melting point not quoted. Solvent of crystallization not specified.

199 I99 200 199 199 199

t3

w 0

271-272 297-298

70 87 YO

2-( p-O,NC,H,)-9-Me-X-NO,-'

2-Ph-%Me-

2-(p-0,NC6H,)-9-Me2,9-di-Me-3-NH2-

D

D 2,9-di-Me-3-[ 1-(2-hydroxynaphthyl-azol. -

75

2-(p-02NC,H,)-9-Me-X-N0,-' quant.

235-236

-

Ethanol Dimethylformamide Ethanol Dimethylformamide Dimethylformamide Dimethylforrnamide Dimethylformamide Ethanol


Dark-green plates. Forms a hydrochloride, red solid, m.p. 194-195". Nitrate. " Forms a monohydrate, m.p. 22 I". ' Position of the second nitro group not established.

'Green solid.

Forms a hydrochloride, red needles, m.p. 208-200".

Green needles.

A = NaNO,, AcOH, H2O/(20")(short time); B = NaNO,, AcOH, H,O, EtOH/(70-80°)(15-20 min); C = conc. H,SO,/(-S -lOo)(l hr); D = KNO,, conc. H,SO,/(-5 to -12")(1 hr); E = NaNO,, H' then treatment with @-naphthol in NaOHaq.

E

2-(p-BrC,H,)-3-N02-9-Me-

2,Y-di-Me-3-N02-

2.9-di-Me2-(p-BrC6H,)-9-Me-

D D

24Xh

88

2,9-di-Me-3-N02-

2,9-di-Me-R

100

c

94

2-Ph-3-NO-9 -PhCH,-'" 2-Ph-3-NO-6,7-di-Me-9-Et-b

247 244 (decomp.) 215 265

2-Ph-Y-PhCH22-Ph-6,7-di-Me-9-Et-

B

A A

92 a4

Yield (YO) m.p. (T)

2-Ph-3-NO-9-Me-h.' 2-(p-BrC,H4)-3-NO-9 -Me-d

9H-Imidazor ______ I ,2-n]benzimidazole _.__ Product

2-Ph-9-Me2-(p-BrC,H4)-9-Me-

Substrate

A


TABLE 6.71. NlTROSATION AND NITRATION REACTIONS OF 9H-IMIDAZ0[1,2-a~ENZIMIDAZOLE DERIVATIVES

to

163 175

163

163 163

163

175 175

227 175

Ref.


204

N-OH

I

I

Me

Me

(i) NaN02, conc. HCI. EtOH/(0’)(30 min) (ii) NaN02, AcOH/(room tempJ(48 hr) .sdnune 6.87

of the imidazole ring in such molecules to electrophilic attack. 3-Amino9H-irnidazol 1,2-a]benzimidazoles, when stable, can be diazotized to give diazonium salts which undergo orthodox diazo-coupling reactions with substrates such as &naphthol (Table 6.71).”’ 9H-Imidazo[ 1,2-a]benzimidazoles can be nitrated at the C(3) position under standard conditions. For example, treatment of 2,9-dimethyl-9Himidazo[l,2-a]benzimidazole with potassium nitrate-concentrated sulfuric acid affords the C(3)-nitro derivative in high yield (Table 6.71).’63 The same compound is obtained in lower yield (Table 6.71) by rearrangement of the nitrate salt of 2,9-dimethyl-9H-imidazo[l,2-a]benzimidazolein concen2-(p-Bromophenyl)-9-methyl-9H-imidazo[1,2-a]trated sulfuric benzimidazole also nitrates at the C(3) position in the imidazole ring giving the corresponding nitro derivative in high yield (Table 6.7 1).163In contrast, the nitration’63 of 9-methyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole affords a dinitro product derived by substitution at the para position in the phenyl substituent and at an unestablished site in the fused benzene ring. The lack of substitution in the imidazole ring in this instance can be attributed to preferential initial nitration of the phenyl substituent with consequent deactivation of the C(3) position to further attack. The benzene nucleus in 9H-imidazo[ 1,2-a]benzimidazoles has been shown2I4 to nitrate less readily than an attached furan substituent. The reactivity of the imidazole ring in 4H-imidazo[ 1,5-a&enzimidazoles toward electrophilic substitution extends to nitrosation, which is readily accomplished by treatment with sodium nitrite in acetic acid at room temperature or below, and affords high yields of C(1)2’s and C(3)’” nitroso derivatives (Table 6.72). DIAZOCOUPLING. The activated methylene substituent in 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones couples readily with aryldiazonium salts


205

TABLE 6.72. NITROSATION REACTIONS OF 4H-IMIDAZq1,5-aJBENZ IMIDAZOLE DERIVATIVES

Reaction

4H-lmidazo[ 1,5-a]benzimidazole Yield

conditions" Substrate

(Yo)

Product

A

3-Ph-4-Me- l-N0-3-F?1-4-Me-~ 83

B B

1,4-di-Me- 1,4-di-Me-3-N0-' 95 1-Ph-4-Me- l-Ph-3-NO-4-Me-d 75

A = NaNO,. AcOH/(5")(15min); Dark-green needles. Colorless needles. Yellow crystals.

m.p. ("C) 222-222.5 (decomp.) 125.5-126.5 148-151


Ref.

Ethanol

215

Water Ligroin

192 192

B = NaNO,, AcOH/(room tempJ(l5 min).

under weakly acidicz3' or b a s i ~ conditions ~ ~ to ~ give * high ~ ~yields ~ ~ (Table 6.73) of C(2)-arylhydrazono derivatives. The spectroscopic properties of these products (see page 152) suggest their existence to a significant extent in the tautomeric azo form [Scheme 6.88; (6.404; A S B)]. 4H-Pyrazolo[2,3-a]benzimidazolescouple at the electron-rich C(3) position with a wide range of aryl and hetaryldiazonium salts giving the corresponding azo derivatives usually in high yield. Reactions of this type TABLE 6.73. DIAZO COUPLING REACTIONS OF 2.3-DIHYDROTHIAZOLO[3,2-a> BENZIMIDAZOL-3- ONES Reaction

2,3-Dihydrothiazolo[3,2-a]benzimidazol-3-oneYieldm.p.

conditions" Substrate

Product

A

Unsubstituted

2-(PhNHN=)-

B

Unsubstituted

2-(PhNHN=)-

B B

Unsubstituted Unsubstituted Unsubstituted Unsubstituted

2(p-MeC,H4NHN=)2-(m-MeC6H,NHN=)2-(p-CIC6H,NHN=)2-(p-O2NC6H,NHN=)-

C

Unsubstituted Unsubstituted Unsubstituted 6,7-di-Me-

C

6,7-di-Me-

2-(p-H2NSO2C,H,NHN=)2-(p-H02CC6H,NHN=)2-(p-HS0,C6H,NHN=)2-(p-MeOC6H,NHN=)6,7-di-Me2-(p-BrC6H,NHN=)6,7-di-Me-

B

A A

A A

(Yo)

("C)

70

255.5-256 (decomp.) 74-80 255 (decomp.) 74-80 261-263 74-80 252 74-80 284 73 283-284 71

72 66 24

Solvent of crystallization Ref. Methanol Acetic acid Acetic acid Acetic acid Acetic acid 1-Propanol

131, 211 231 231 231 231 131, 211 211 211 21 1 134

242-245 307.5-308 >330 228-229

Ethanol Ethanol Water Dioxane

262-263

Dimethylform- 134 amide

A = Ar&,O-,NaOAc, AcOH, MeOH, H,0/(10-15°) (reaction time not specified); B =Arfi2CI-, NaOAc, MeOH, H,O (temp. and reaction time not specified); C = Arfi2CT, NaOAc, Ac,O, AcOH, MeOH/(18-20")(18-48 hr).

a

~

N

2-(p-CIC,H,NH)-3-(p-BrC,H4N=N)-9-Me96 2-(p-Et02CC,H,NH)-9-Me-b 2-(p-EtO2CC,H,NH)-3-(p-BrC,H4N=N)-9-Me- 87

2-[PhN(Me)l-9-Me-b

D

195

186-187 221-223 183-184

3-Ph-4-Me1-(p-MeOC,H4N=N)-3-Ph-4-Me- 43 1-Ph-4-PhCH2- 1-Ph-3-(p-BrC,H,N=N)-4-PhCH2- 46 1-Ph-4-PhCH2- l-Ph-3-(p-MeOC,H,N=N)-4-PhCHz-30

-*

Methanol-waterdimethylformamide Ethanol Dimethylformamide

Solventof crystallization


'A = Arh2Cl-, AcOH, MeOH (20") (12 hr); B = Ar&,CI-, Ac,O, AcOH, MeOW(20") [7 days (in the dark)].

B B

A

200-201

50

1-(p-BrC,H4N=N)-3-Ph-4-Me-

3-Ph-4-Me-

A

Yield m.p. ("C)

(Yo)

4H-Imidazo[ 1,S-a]benzimidazole

product

Substrate

DIAZO COUPLING REACTIONS OF 4H-IMIDAZO[l.S-alBENZIMIDAZOLE DERIVATIVES

Reaction contitions'

TABLE 6.75.

(I

22 1 193 193

221

Ref.

174

174 174

174 174

227 227

Ref.

NaOAc,

Benzene Dimethylformamide Ethanol Dimethylformamide Benzene Dimethylformamide Ethanol


A = p-BrC6H,&2CI-, AcOH/( 1OOo)(5-10+min); B = p-HO,CC,H,~,CI-, ethanol, H,O/(room tempJ(0.5 hr); C = p-BrC,H,k,CI-, AcOH/(room temp.)( 1 hr); D = p-BrC,H,N,CI-, NaOAc, H,O/(room temp.)( 1 hr). Hydrochloride.

54

193 245

2-(p-CIC6H,NH)-9-Me-*

C C 2-[PhN(Me)l-3-(p-BrC,H,N=N)-9-Me-

244 302

67 92

2-PhNH-3-(p-BrC6H,N=N)-9-Me2-(p-0,NC,H,NH)-3-(p-BrC,H4N=N)-9-Me-

2-PhNH-9-Me-b 2-(p-02NC,H,NH)-9-Me-b

C C

295 306

84 77

2-Ph-3-(p-BrC6H,N=N)-9-Me2-Ph-3-(p-HO2CC,H,N=N)-9-Me-

2-Ph-9-Me2-Ph-9-Me-

B

A

("C)

(YO)

m.p.

Yield

Product

9H-Imidazo[ 1,2-a]benzimidazole

Substrate


TABLE 6.74. DIAZO COUPLING REACTIONS OF 9H-IMIDAZ@l,2-a]BENZIMIDAZOLEDERIVATIVES


~

A

~

N

H

~~~~

A

~

207

-NAr

B

A (6.404) %heme 6.88

have been principally exploited for the synthesis of azo dyestuffs containing the 4H-pyrazolo[2,3-a]benzimidazolenucleus.198~199~205~230*240 C(2)-Arylzz7and C(2)-amin0”~9H-imidazo[ 1,2-a]benzimidazoles couple with aryldiazonium salts at the C(3) position under weakly basic or neutral conditions affording the anticipated arylazo derivatives in good to excellent yield (Table 6.74). The lower tendency of the imidazole ring in 1H-imidazo[ 1,2-a]benzimidazoles to undergo electrophilic substitution (see before) accounts for the f a i l ~ r e ’ ~of’ 1-methyl-2-phenyl-1 H-imidazo[ 1,2albenzimidazole to couple at the C(3) position with aryldiazonium salts. The coupling reactions of 4H-irnidazoE 1,5-a]benzimidazoIes with aryldiazonium salts in weakly acidic or basic solution are apparently less efficient than those of their 9H-imidazo[ 1,2-a]benzimidazole counterparts and result in only moderate yields (Table 6.75) of the expected C(1)221 or C(3)193 arylazo products.

Reactions with Nucleophiles The generally electron-rich character of 6-5-5 fused benzimidazoles with one additional heteroatom is not conducive to nucleophilic substitution. The ring systems in such molecules tend therefore to be inert to nucleophilic reagents or, if subjected to forcing conditions undergo ring scission rather than simple substitution. Attached substituents generally exhibit orthodox behavior toward nucleophilic attack.

DEPROTONATION. The dehydration of readily accessible 4H-imidazoC 1 3 a]benzimidazole C(1) and C(3) carboxaldoximes using acetic anhydride alone or in the presence of sodium acetate allows the synthesis in high yield (Table 6.76) of the respective nit rile^.'^^*^'^ HYDROXYLATION A N D RELATEDR E A ~ I O NThe S . stability of the 2,3to hydrolysis is implicit in its survival under aqueous alkaline conditions, which serve to convert an attached amide substituent into a carboxyl group.” The alkaline hydrolysis of thiazolo[3,2-a]benzimidazole-2-carboxylicesters to give the corresponding carboxylic acids in high yield”’ likewise testifies to the inertness of the thiazolo[3,2-a]benzimidazole ring system to hydrolytic attack. On the other

dihydrooxazolo[3,2-a]benzimidazole ring system


208

TABLE 6.76. DEHYDRATION OF 4H-IMIDAZql,5-a]BENZIMIDAZOLE C(1)AND C(3)-CARBOXALDOXIMES TO C(1)- AND C(3)-CYANO-4HIMIDAZq 1,5-a]BENZIMIDAZOLES Reaction conditions' A

A

B

4H-Imidazo[ 1,5-a]benzirnidazole Substrate

Product

Yield

m.p.

(%)

("C)

Solvent of crystallization Ref.

179-179.5

Ethanol

216

192-194

Acetone

216

204.5-206

Acetic acid

193

l-(HONdH)-3,4- 1-CN-3.497 di-Medi-MeI-(HON=CH)-3I-CN-3-Ph88 Ph-4-Me4-Mel-Ph-3-(HON=CH)- 1-Ph-3-CN-4- 91 4-CH7PhCH,Ph-

'A = Ac,O, NaOAc/(reRux)/(2.5hr); B = Ac,O/(reflux)/(3 hr).

hand, the C(3) carbonyl substituent in 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones confers hydrolytic instability, which, under alkaline conditions, leads by cleavage of the C(3)-N(4) bond to 2-benzimidazolylthioacetic acid derivati~es.'~~*'~~*'~~*~~~ Conversely, the acidic hydrolysis of 2,3dihydrothiazolo[3,2-a]benzimidazol-3-ones occurs at the N(9)-C(9a) bond giving good yields of N-(2-arninophenyl)thia~olidine-2,4-diones.'~~~'~~ The contrasting stability of lH,3H-thiazol0[3,4-a]benzimidazol-2-ones to acidic hydrolysis is demonstrated by their formation from 1-imino- 1H,3Hthiazolo[3,4-a]benzimidazoles in acid media.'5z*'53 EsterZo6and a c y l a m i n ~ substituents ~ ~ ' ~ ~ ~ can be hydrolytically removed from 4H-pyrazolo[2,3-a]benzimidazoleswithout disruption of the ring system. 9H-Imidazo[l,2-a]benzimidazoles are likewise moderately stable to acid- and base-catalyzed hydrolysis under conditions that effect the removal of an N(1)- quaternary methyl group'65 or promote the loss of ester,173 a ~ y l , ' and ~ ~ hydroxyalkyl'w ~ ' ~ ~ side- chains from the C(2) or C(3) positions. ~ ~N(1) However, the presence of a C(3) nitroso s u b ~ t i t u e n t ' * ~or* ~an quaternary center'6z"*zz7renders the 9H-imidazo[ 1,2-a]benzimidazole ring system susceptible to hydrolytic cleavage at the N(l)-C(2) bond with formation of a 2-iminobenzimidazoline derivative or the 2-benzimidazolone formed by its further hydrolysis. The carbonyl substituent in 2,3-dihydro9H-imidazo[ 1,2-a]benzimidazol-2-onesacts as a focal point for both acid and base-catalyzed hydrolysis, which again leads to 2-iminobenzimidazoline or 2-benzimidazolone formation, respectively.'" The acid- or basepromoted cleavage of the imidazolinone ring in 2,3-dihydro-9H-imidazo[1,2-a]benzimidazol-3-ones,on the other hand, results in the formation of (2-benzimidazoly1)aminoacetic acid derivatives.6*18z 2,3-Dihydro-9 Himidazo[ 1,2-a]benzimidazole-2,3-dionesare selectively hydrolyzed at the C(3)-N(4) bond under alkaline conditions giving the respective 2-oxalylaminobenzimidazoles. lS5 Though stable to alkaline hydrolysis, 4H-imidazo[ 1,5-a]benzimidazoles are cleaved at the C(l)-N(9) bond in acidic media with formation of 2-(2-


209

aminoalkyl)benzimidazole

derivative^.^'^ lH,3H-Imidazo[3,4-afienzimidazoles are effectively N,N-acetals of formaldehyde and as such are also hydrolyzed under acidic conditions to 2-(2-arninoalkyl)benzimidazole~.~** C(1)-Cyano groups in 4H-imidazo[ 1,5-a]benzimidazoles undergo orthodox triethylamine catalyzed addition of hydrogen sulfide to afford the corresponding thioamides [Scheme 6.89; (6.405)] in essentially quantitative yield .2

I

'

Me R (6.405)

R Yield

Me Ph

(%) m.p. ("C) (from AcOH)

99 quant.

242-244 249.5-250.5

sehew 6.89

AMINATION. 2,3-DihyQothiazolo[ 3,2- a]benzimidazol-3-ones exhibit amide-like behavior toward carbonyl reagents such as hydrazineZ3l and phenylhydra~ine'~'.~~' undergoing ring-opening to 2-benzimidazolylthioacethydrazides rather than condensation at the carbonyl group. C(2)Acetyl derivatives of thiazolo[3,2-a]benzimidazoles, on the other hand, form the usual condensates (oximes, etc.) with carbonyl reagents. 1 1 ' Acid chlorides of the thiazolo[3,2-a]benzimidazole series are also aminated in standard fashion to carboxamide derivative^."^ The 4H-pyrazolo[2,3-a]benzimidazole ring system is stable to forcing aminolysis under conditions'w that convert an ester substituent in high yield (Table 6.77) into a primary carboxamide group. 3-Acylamino-4H-pyrazolo[2,3-a]benzimidazoles are oxidatively aminated at the C(3) position to afford moderate yields (Table 6.77) of 3,3-diamino-3H-pyrazolo[2,3-a]benzimidazoles (6.407), which are convertible by base-catalyzed elimination of the acylamino substituent into azomethine dyestuffs of the type (6.408).200.242 C(3)-Bromo substituents in 9H-imidazo[ 1,2-a]benzimidazoles are somewhat surprisingly, prone to nucleophilic displacement and react readily with secondary amines to give high yields (Table 6.78) of the corresponding 3-amino-9H-imidazo[ 1,2-a]benzimidazole derivatives.'62a Despite the electron-donating (and hence deactivating) character of the 924-imidazo[ 1,2-a]benzimidazoIe ring system, f0rmy1'~~and nitrosoZz7substituents at the C(3) position participate in orthodox condensation reactions with arylamines affording the expected anils and azo compounds in moderate to high yield (Table 6.78).

TABLE 6.77. AMINATION REACTIONS OF 4H-PYRAZOL0[2,3-a]BENZIMIDAZOLE DERIVATIVES

R3

HSO,

Ph

(6.406)

NEt,

(6.408)

(6.407)

Starting material


(6.406; R' = C02Me, (6.406; R'= Ph,

R2=R3=H)

Product

(%)

m.p. ("C)

Ref.

A

(6.406; R' = CONH,,

90

272b

199

B

(6.407;

54

230 200, (decomp.) 242 220 200, (decomp.) 242 >315 200, 242 200, 242

R2 = NHCOMe, R3 = S03H) (6.406; R' = Ph, B R2 = NHCOEt, R3= SO,H) (6.407; R = COMe) C (6.407; R = COEt)

Yield

NEt,

R2=R3=H)

R = COMe) (6.407;

R = COEt)

57 78

(6.408)

c

78

'A = 25% NH,OH/(80-85", autoclave)(8 hr); B = p-Et2NC6H,NH,, H,O/(room temp.)(l hr); C = NaOMe, MeOH/(lOO")(few min). * Crystallized from methanol.

30% H,O,,

Na2C03,

TABLE 6.78.. AMINATION REACTIONS OF YH-IMIDAZq1.2-a JBENZIMIDAZOLE DERIVATIVES Reaction conditions" A

B C C C D E

9H-lmidazo[ 1,2-albenzimidazole

Yield

m.p.

Substrate

Product

(Yo)

("C)

2-Ph-3-Br9-Me2-Ph-3-Br9-Me2,9-di-Me3-CHO2-Ph-3-CHO9-Me2.9-di-Me3-CHO2-Ph-3-CHO9-Me2-Ph-3-NO9-Me-

2-Ph-3-(l-piperidyl)9-Me2-Ph-3-( I-morpholiny1)9-Me2.9-di-Me-3( 0- HOC,H,NECH)2-Ph-3-(o-HOC6H4N=CH)-9-Me2,9-di-Me-3-(p-0,NC,H4N=CH)2-Ph-3-(p-O,NC,H,N=CH)-9-Me2-Ph-3-(p-H02CC6H,N=N)-9-Me-

100

134-135


Ref. 162a

38

Light petroleum 212-213 Light petroleum 292 Dimethyl(decomp.) formamide 245 Benzene

98

142

Ethanol

165

76

230

Benzene

165

57

305-306

Dimethylformamide

165

90 83

162a 165 I65

dimethylformamide/(reflux)(2 hr); B = morpholine, dimethylformamide/(reflux) (2 hr); C = ArNH,, EtOHl(reflux)(2-10 hr); D = p-O2NC6H,NH2&15O0 (melt)](5 hr); E = pHO,CC,H,NH,, AcOH/(reflux)(2 hr).

'A = piperidine,

210

211

6.2. Fused Benzimidazoles with One Additional Heteroatom TABLE 6.79.

REACTIONS OF 2,3-DIHYDROTHIAZOL0[3.2-a]BENZIMlDAZOL-3ONE DERIVATIVES WITH CARBANIONIC REAGENTSa

Starting material

Reaction conditionsb Product

Yield (70)

m.p. ("C)'

(6.409; Ar = Ph) (6.409; Ar = Ph)

A A

78 51

165-166 134

(6.409: Ar = p-MeOC,H,)

A

66

-

(6.409; Ar = Ph) (6.409; Ar = p-CIC,H,) (6.409; Ar = o-CIC,H,) (6.411) (6.411) (6.411) (6.409; Ar = o-MeOC,H,) (6.409: Ar = o-EtOC,H,) (6.409; Ar = o-CIC,H,)

A A A

a

From Ref. 231.

B B B

C C C

(6.410; R = Ar = Ph) (6.410; R = p-MeOC,H,, Ar = Ph) (6.410; R = Ph, Ar = pMeOC,H,) (6.410; R = Et, Ar = Ph) (6.410; R = Ph, Ar = p-CIC,H,) (6.410; R = Ph, Ar = o-CIC,H,) (6.412; R = Et) (6.412; R = Ph) (6.412; R = p-MeC,H,) (6.413; Ar = o-MeOC,H,) (6.413; Ar = o-EtOC,H,) (6.413; Ar = o-ClC,H,)

A = RMgX, benzene, ether/(reflux)(2 hr); ether, chloroform/(room temp.)( 12 hr).

76 79 70 60 71 65

80 70 74

120 1SO

160-161 205-207 202-203 190-191 138-140 140-142 I41

B = RMgX, benzene/(reflux)(20 min); C = CH,N,,

Crystallized from ethanol.

REACTIONS WITH ANIONIC REAGENTS. The mode of reaction (Table 6.79) of 2,3-dihydrothiazolo[3,2-~~enzimidazol-3-one derivatives with Grignard reagents is markedly dependent on the nature of the substitution at the C(2) position. C(2)-Arylidene derivatives (6.409) react by addition to the carbon-carbon double bond rather than the carbonyl group giving Michael adducts of the type (6.410).23'In contrast, 2-imino-2,3-dihydrothiazolo[3,2a]benzimidazol-3-ones such as (6.411), €or which Michael addition is precluded, undergo preferential reaction at the carbonyl group affording good yields (Table 6.79) of the hydroxy products (6.412).231The of C(2)-arylidene 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones(6.409) with

212


diazomethane to give high yields (Table 6.79) of methylated products (6.413) can be rationalized by a course (Scheme 6.90) involving initial Michael addition r(6.414) +(6.415)] followed by nitrogen loss and ketonization of the enol intermediate produced [(6.415) +(6.416) +(6.417)].

[GCH. (6.414)

/ c___

Ar (6.416)

(6.415)

?Me

(6.417) Scheme 6.90

The electrophilic reactivity of attached carbonyl and nitroso substituents appears to be little diminished by the electron-rich and hence potentially deactivating character of the 9H-imidazo[ 1,2-a]benzimidazole ring system. C(3) Formyl and acetyl substituents react readily'64 with Grignard reagents giving the anticipated carbinols in good to excellent yield (Table 6.80), and participate efficiently (Table 6.80) in aldol-type condensation reactions with active methylene compounds of various type^.'^'''^^ The base-catalyzed condensation of 3-nitroso-9H-imidazo[ l72-a]benzimidazoles with substrates such as phenylacetonitrile likewise leads to azomethine formation in moderate yield (Table 6.80).'" Both carbonyl substituents in 9-benzyl-2,3-dihydro9H-imidazo[ 1,2-a]benzimidazole-2,3-dione react with ethylmagnesium bromide giving 9-benzyl-2,3 -diethy1-2.3 -dihydroxy - 2,3-dihydro- 9H-imidazo[l,2-~]benzimidazole in moderate yield (Table 6.8O).ls5 Heating 3-bromo-9H-imidazo[ 172-a]benzimidazoles with sodium or potassium nitrite in dimethylformamide results in replacement of the halogen substituent to give the corresponding 3-nitro-9H-imidazor 1,2-a]l-Bromo-4-methyl-3benzimidazoles in high yield (Table 6.8 1). phenyl-4H-imidazo[ 1,5-ulbenzimidazole is likewise converted in high yield (92%) into l-nitro-4-methyl-3-phenyl-4H-imidazo[l,5-a]benzimidazole (m.p. 233-234.5') by heating with sodium nitrite in dimethyl sulfoxide.22' The ease of these presumed nucleophilic displacement reactions is surprising when viewed in the light of the electron-rich character of the C(3) and C(1) positions in the 9H-imidazol[ 1,2-a]benzimidazole and 4H-imidazor 13a]benzimidazole ring systems. The ready replacement of the halogen atom

89

34

2-Ph-3-p-MeOC,H4COCH==CH-9-Me-

2-Ph-3-rn-OZNC6H,COCH=CH-9-Me-

2-Ph-3-CHO-9-Me-

2-Ph-3-CHO-9-Me-

C

C

88

2,9-di-Me-3-p-MeOC,H4COCH-=CH-

85

80

2.9-di-Me-3-PhCOCH=CH-

2-Ph-3-PhCOCH=CH-9-Me-

2.9-di-Me-3-CHO-

2-p-BrC6H4-3-PhC(OH)Me-9-Me-

2,9-di-Me-3-PhmCC(OH)Me2,3-dihydro-2,3-di-Et-2,3di-OH-9-CH2Ph-

C

C

C

B A

2.9-di-Me-3-PhC(OH)Me2-Ph-3-PhC(0H)Me-Y -Me-*

57 71

70 85 63 55 52

w

L

2.9-di-Me-3-COMe2-Ph-3-COMe-9-Me2-p-BrC,H,-3-COMe-9-Me2.9-di-Me-3-COMe2.3-dihydro-9-CH,Ph2,3-dione 2.9-di-Me-3-CHO-

2-Ph-3-PhbCCH(OH)-9-Me-

2.9-di-Me-3-PhC%CCH(OH)-

90 75 75 70 90 63 75

A A A

2.9-di-Me-3-CHO2-Ph-3-CHO-9-Me-

B B

2,9-di-Me-3-PhGCCH(OH)-

2.9-di-Me-3-PhCH(OH)-

2,9di-Me-3-p-MeZNC,H4CH(OH)2-Ph-3-p-EtOC6H,CH(OH)-9-Me-* 2-p-BrC,H4-3-PhCH(OH-9-Me-' 2-~-naphthyl-3-PhCH(OH)-9-Me-~ 2-Ph-3-PhCH(OH)-9-CHZPhe

Yield

(Yo)

68

2,9-di-Me-3-CHO2.9-di-Me-3-CHO2-Ph-3-CHO-Y-Me2-p-BrC6H,-3-CHO-9-Me2-a-naphthyl-3-CHO-9-Me2-Ph-3-CHO-9-CHZPh2.9-di-Me-3-CHO-

A A A A A A A

Product

h ) B

Substrate

9H-Imidazo[ 1,2-a]benzimidazoIe

204-205 (decomp.) 216-217 (decomp.) 168-169 (decomp.) 178- 179 (decomp.) 272-273 (decomp.)

192- 193 (decomp.) 208-209 (decomp.) 160- 16 1 156-157 137-138 122-123 112

-

199 193 174-175 183- 184 197-199 171-172 197-198 (decomp.)

("a

m.p.

REACTIONS OF 9 H - I M I D A Z q 1.2-aIBENZIMIDAZOLES WITH CARBANIONIC REAGENTS


TABLE 6.80.

Dimethylformamide Ethanol-dimethylformamide Dimethyl formamide

Ethanol

Ethanol Ethanol Ethanol Ethanol Chloroform-light petroleurn Ethanol

Ethanol

Ethanol

-

Ethanol Ethanol Ethanol Ethanol Ethanol Ethanol Benzene-light petroleum


214

214

214

214

214

185

164 164 164 164

164

164 164

164 i64 164 164 164 164 164

Ref.

h)

2-Ph-3-CHO-9-Me2-Ph-3-NO-9-Me-

D 2-Ph-3-02NCH=CH-9-Me2-Ph-3-PhC(CN)=N-9-Me -h

2-Ph-3-h -naphthoyl)CH=CH-9-Me-

2-Ph-3-(2-furoyl)CH=CH-9-Me47 50

84 98

Yield

(56)

189-189.5 183- 184 (decomp.)

164-165 221-222

m.p. ("C) Ethanol Dimethyl formamide Ethanol Dioxane-ether


165 227

214 214

Ref.

'

" A = RMgX, tetrahydrofurane/(reflux)(3hr); B = P h D C M g B r , ether/(reflux)(4 hr); C = ArCOMe, 40% NaOH aq., EtOH/(warm), then (room temp.)(few hr); D = MeNO,, NH40Ac/(reAux)(40hr); E = PhCH,CN, 5% NaOH aq.. EtOH/(reflux)(20-30 min). * Forms a hydrochloride, m.p. 286-287" (decomp.) (from ethanol). Forms a hydrochloride. m.p. 300' (decomp.) (from ethanol). Forms a hydrochloride. m.p. 290-293" (decomp.) (from ethanol). Forms a hydrochloride. m.p. 276-277" (decomp.) (from ethanol). 6,7-Dimethyl derivative. Forms a hydrochloride, m.p. 285" (decomp.) (from ethanol). Monohydrate.

E

2-Ph-3-CHO-9-Me2-Ph-3-CHO-9-Me-

C C

Product

9H-Imidazof1,2-afbenzimidazole

Substrate



6.2. Fused Benzimidazoleswith One Additional Heteroatom TABLE 6.81. NITRODEBROMLNATION REACTIONS BENUMIDAZOLE DERIVATIVES Reaction conditions" A

B B B

YH-Imidazo[ 1.2-a]benzimidazole Substrate

Product

Yield (Yo)

2-Ph-3-Br2-Ph-3-NO,80 9-Me%Me65 2-p-BrC,H42-p-BrC,H4-33-Br-9-MeNO,-%Me2-p-02NCbHA- 2-p-02NCbH4-3- 75 3-Br-%MeNO,-%Me2-Ph-3-BrY-Et-h

2-Ph-3-N029-Et-b

95

m.p. ("C) 205

OF

215

9H-IMIDAZ0[1,2,a]-


Acetoneethanol 271-272 Dimethylformamide 237 Ethanoldimethylformamide 234-235 Dimethyl (decomp.) formamide

Ref. 162a 163 163 163 ~~

dimethylformamide/(reflux)(lhr); B = KNO,, dimethylformamide/(reflux)(reaction time not specified). 6.7-Dimethyl derivative. A = NaNO,,

in the 3-bromo-4H-imidazo[ 1,5-a]benzimidazole by nitrite ion becomes even more intriguing when compared with its inertness to reagents such as ethanolic sodium hydroxide or ethanolic sodium ethoxide.''' Further information on the mechanism of the nitrodebrominations undergone by 3bromo-9H-imidazo[ 1,2-a]benzirnidazoles and l-bromo-4H-imidazo[ 1,sa]benzimidazoles would therefore be welcome.

Oxidation The stability of the 2,3-dihydrothiazolo[3,2-a]benzimidazolering system to oxidation by chromium trioxide-pyridine is implicit in the use of this reagent for the oxidation of 3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazoles to 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-0ne~.~~~~~~ The attempted peracid oxidation of 2,3-dihydrothiazolo[3,2-a]benzimidazol-3ones to the corresponding sulfones results in scission to 2-benzimidazolone

derivative^.^^ '

Permanganate oxidation of gH-imidazo[ 1,2-a]benzimidazoles and their 2,3-dihydro derivatives leads either to complete disruption1h6 of the molecule or to the formation of azobenzimidazole The stability of 9H-imidazo[ 1,2-a]benzimidazoles to manganese dioxide oxidation, on the other hand, provides the means for their ~ynthesis'~'from 2,3dihydro-9H-imidazo[ 1,2-a]benzimidazoles and for the oxidation of propargyl alcohols of the 9H-imidazo[ 1,2-a]benzimidazole series to the respective ketone^.'"^ 2-Phenyl-2,3-dihydro-1H-imidazo[l,2-a]benzimidazoleis reported16" to be stable to dehydrogenation with reagents such as chloranil or N-bromosuccinimide. The attempted selenium dioxide oxidation of 2methyl-9H-imidazo[1,2-a]benzimidazolesto the corresponding aldehydes

216


leads to complex mixtures of products.'6s 4H-Imidazo[ 1,5-a]benzimidazoles are notorious for their ease of oxidation by atmospheric oxygen to unidentified blue s u b s t a n c e ~ . ' ~ ~ * ~ ~ ~

Reduction The redu~tion'"~"'~ of 2-acylthiazolo[3,2-a]benzimidazoles to the corresponding carbinols in high yield (Table 6.82) using sodium borohydride, demonstrates the stability of the thiazolo[3,2-a]benzimidazole ring system to reducing agents of this type. The 2,3-dihydrothiazolo[3,2-a&enzimidazole ring system is likewise stable to reduction'28 by hydrazine in the presence of Raney nickel under conditions (Table 6.82) that generate an amino group from a C(7)-nitro substituent. The reductive scission23s of 2-phenylhydrazono-2,3-dihydrothiazolo[3,2-a]benzimidazol-3-one to 2amino-2,3-dihydrothiazolo[3,2-a]benzimidazol-3-onein moderate yield (Table 6.82) represents a potentially general method for the synthesis of such amino derivatives. The catalytic reduction of readily accessible 3-nitroso-4H-pyrazolo[2,3a]benzimidazoles provides a general for the synthesis in moderate to high yield (Table 6.83) of 3-amino-4H-pyrazolo[2,3-a]benzimidazoles. Metal-proton donor reagents such as zinc and acetic acid, and tin or stannous chloride in combination with hydrochloric acid reduce 3-nitrosoand 3-nitro-9H-imidazo[ 1,2-a]benzimidazoles to the corresponding a r n i n e ~ . ' These ~ ~ , ~ tend ~ ~ to be unstable relative to their open-chain nitrile tautomers but in some cases (Table 6.84) can be isolated in the free form or as hydrochlorides. 9-Benzyl-2-methyl-9H-imidazo[1,2-a]benzimidazoleis debenzylated by sodium in liquid ammonia to afford 2-methyl-9H-imidazo[ 1,2-a]benzimidazole in quantitative yield (Table 6.84). 166 In the analogous TABLE 6.82. REDUCTION OF THIAZOL0[3,2-a]BENZIMlDAZOLEDERIVATIVES

A A A

B C

2-COMe2-MeCH(OH)2-COMe-3-Me- 2-MeCH(OH)3-Me2-C02Et-3-Me- 2-CH20H-3-Me-

85 87

116-1 18 227-228

86

194-195

7-N02-2,3dihydro2-(PhNHN=)2,3-dihydro3-one

57 57

7-NH2-2.3dihydro2-NHZ-2.3dihydro-3-one

103 1 I5

229-230

Benzene Dimethylformamide Ethanolwater Water

185

Ethanol

235

A = NaBH,, EtOH/(retlux)(Zhr); B = Raney-Ni, 80% N,H,.H,O,

C = N+S20,, EIOH, H,O/(reRux)(30 min).

103 128

EtOH/(retlux)(30min);


217

TABLE 6.83. REDUCTION” OF 3-NITROSO-4H-PYRAZOLO[2,3-a]BENZIMIDAZOLE DERIVATIVES

3-Nitroso-4H-pyrazolo[2,3-a]benzimidazole Yield Substrate Product (Yo) 2-Me-

2-Me-3-NH,-

54

2-Ph2-COZH2-CONH2-

2-Ph-3-NHI2-COZH-3-NH22-CONH2-3-NH,-’

67 64

2-Ph-6-SOTH-

2-Ph-3-NH2-6-SOJH-

89

2,6-di-C02H-

2,6-di-C0,H-3-NH2-

69

2-CO2H-6-SO3H-

2-COZH-3-NH2-6-SOTH-

62

52

m.p. (“C)


Ref.

>175 (decomp.)

Water

199

-c -c

Methanol

199 199 199

-

200

2-Propanol

199

-

199

-b -b

220 (decomp.) 260 (decornp.) >260 (decornp.) 280 (decornp.)

c

“ H,,

Raney-Ni, 25% NH,OH aq., MeOH or pr’OH/5O0, 50 atm. Melting point not quoted. Solvent of crystallization not specified. Sulfate.

sodium and liquid ammonia reduction of 9-benzyl-2-phenyl-9H-imidazo[ 1,2-a]benzimidazole 166 debenzylation is accompanied by reduction of the C(2)-C(3) double bond giving a mixture of 2-phenyl-9H-imidazo[ 1,2-a]benzimidazole and its 2,3-dihydro derivative in good overall yield (Table 6.84). The reduction of both carbonyl substituents in 2,3-dihydro-9Himidazo[ 1,2-a]benzimidazole-2,3-dionesby lithium aluminum hydride provides a method for the synthesis of 2,3-dioIs of the 2,3-dihydro-9Himidazo[ 1,2-a]benzimidazole series.185 C(7)-Nitro substituted 2,3-dihydro~ the corresponding 1H-imidazo[ 1,2-a]benzimidazoles are ~ o n v e r t e d ” into amines (Table 6.84) by orthodox catalytic hydrogenation or by reduction with hydrazine in the presence of Raney nickel. 6.2.4. Practical Applications

Biological Properties 2,3-Dihydrooxazolo[3,2-a]benzimidazolederivatives are to enhance the antibiotic activity of penicillins and cephalosporins and are also therapeutic agents” for certain disorders of the central nervous system. Thiazolo[3,2-~]benzimidazolederivatives exhibit antibacterial activity”‘ and their quaternary salts have been patented244 as hypoglycaemic agents. 2,3-Dihydrothiazolo[3,2-u]benzimidazolederivatives are associated with a particularly wide range of biological properties including a n t i t ~ m o r , ” ~ * ~ ~ ’

Q,

80

yo

1-CHPh2-7-NO2-2,3-dihydro- 1HY-Me-2,3-dihydro-9H-2,3-dione

1-CHPh,-7-NH2-2.3-dihydro1H34 2.3-di-OH-9-Me-2.3-dihydro-YH60 9-CH2Ph-2,3-dihydro-9H-2,3-dione 2,3-di-OH-9-CH2Ph-2.3-dihydro-9H- 70

1-PhCH(Me)-7-NOZ-2,3-dihydro-lH1-PhCH(Me)-7-NH2-2,3-dihydro1H-

zz:dihydro-lH-

9

quant.

-c

62

-e

(Yo)

Yield

228-230 235-236 184

221 123-125

192.5 217 (decomp.) 211 (decomp.) 194 (decomp.) 310

ec)

m.p.

Dimethylformamide Ethanol Chloroformligroin Ligroin Ethanol Ethanol

Benzene

I

Ethanol-water

Benzene Ethanol-water


176 185 185

176

166

166

175

175 175

Ref.

a A = SnCl,, H a , EtOH/(reaction temp. and time not specified); B = Zn, AcOW(room tempJ(2-2.5 hr); C = Na, NH, liqJ10-15 min; D = H,, Raney/Ni EtOH/55 psi; E = 100% N,H,, H,O, Raney/Ni, EtOH, dimethylformamide/(lOOo)(l hr); F = LiAlH,, etherl(reflux)(4hr). Forms a dihydrochloride, m.p. 297" (from ethanol-ether). Hydrochloride. dForms a picrate, m.p. 188" (decomp.) (from acetic acid), and a monoacetyl derivative, m.p. 212-213" (from ethanol-water). Yield not quoted. Forms a picrate, m.p. 280-281.5" (from acetic acid).

F F

E

D

z c

{

2-Me-9-CH2Ph-9H-

C

2-Ph-9-CHzPh-9H-

2-p-BrC,H,-3-NH,-9-Me-9H-c*f

2-p-BrC6H,-3-NO-9-Me-9H-

B 2-Me-9H-

2,9-di-Me-3-NH,-9H-b

B

2-Ph-3-NH2-9-CH,Ph-9H-c.d

Imidaz0[1.2-a&enzimidazoIe Product

2,9-di-Me-3-N02-9H2-Ph-3-NO-9-CHZPh-9H-

Substrate

A


TABLE 6.84. REDUCTION OF IMIDAZ0[1,2-a]BENZIMIDAZOLEDERIVATIVES

6.3. Fused Benzimidazoles with Two Additional Heteroatoms

219

antiviral,246and antitubercular"' activity, as well as having a depressant effect on the central nervous ~ystem."~2,3-Dihydrothiazolo[3,2-a]benzimidazol-3-one derivatives are also central nervous system depresants'^' and exhibit marked a n t i c o n v u l ~ a n t , ~ ~an~ tispasmodic, ~ ~ ~ ' ~ ~ ~ ~ 139*'41 and hyp~tensive'~' activity. In addition, 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-one derivatives are r e p ~ r t e d " to ~ be effective antibacterial herbicidal,' 15b insecticidal,248 and agents. The f~ngicida1,~*'~'.'~~*~~'*~~~ plant-gr~wth-regulating'~~ properties of thiazolo[3,2-a]benzimidazoles and their 2,3-dihydro derivatives have also been reported. lH,3H-Thiazolo[3,4a]benzimidazole derivatives have been patented'" as parasiticides and rodentocides. 4H-Pyrazolo[2,3-a]benzimidazole derivatives have attracted attention236.237 as central nervous system stimulants. Depending on the nature of the substituents, 9H-imidazo[ 1,2-a]benzimidazoles can exert either a stimulating or a depressant effect on the central nervous system,24' and consequently have useful sedative and analgetic proper tie^.'^^-'^^ Certain 1H- and 9H-imidazo[ 1,2-a]benzimidazole derivatives are associated with marked cardiovascular, and in particular hypotensive activity.162b,164.177.214.2S0 9H-Imidazo[1,2-a]benzimidazoles have also been patented as antiviral agents.'56 Derivatives of the 4H-imidazo[ 1,5-a]benzimidazole ring system are of interest because of their antitubercular activity.216

Dyestuffs The thiazolo[3,2-a]benzimidazole ring system has been employed as a 2,3-dihydrothiazolo[3,2-a]benzichromophoric unit in cyanine midazol-3-0nes~~'*~~' having found particular application in this respect. The utility of 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-onederivatives as photographic sensitizing agents is emphasized in a number of publications.Z28.Z32,252 The 4H-pyrazolo[2,3-a]benzimidazole ring system has been used extenaz0,230*240 ~ . ' ~ ~ and metal comsively as a chromophore in a ~ o m e t h i n e , ~ ~ p l e dyes. ~ ~4H-Pyrazolo[2,3-a]benzimidazole ~ ~ derivatives are also the subject of patents relating to photographic developer^,^^*^^^ and color coupling198,204,205,256 and photosensitizingz1' agents. 6.3. Tricyclic 6-5-5 Fused Benzimidazoles

with Two Additional Heteroatoms

6-5-5 Fused benzimidazole structures incorporating two additional heteroatoms (Scheme 6.91) and Table 6.85) include the unique, siliconcontaining, 2-sila-3H-thiazolo[3,2-a]benzimidazole(6.418) and 3-sila-2Himidazo[ 1,2-a]benzimidazole (6.419) frameworks, and the sulfur-containing

R (6.419)

(6.418)

8

5

8

4

9

(6.420)

(6.421)

(6.422)

(6.423)

R

R

(6.425)

(6.424)

R

R

(6.427)

(6.426)

(6.428) sebew 6.91 220

R


22 1

TABLE 6.85. TRICYCLIC 6-5-5 FUSED BENZIMIDAZOLE RING SYSTEMS WITH TWO ADDITIONAL HETEROATOMS

Structure" (6.418) (6.419) (6.420) (6.421) (6.422) (6.423) (6.424) (6.425) (6.426) (6.427) (6.428) a

Nameb

2-sila-3H-thiazo10[3.2-a]benzimidazole 3-sila-2H-imidazo[1,2-a~nzimidazole 1,2,4-thiadiazolo[2,3-a)benzimidazole 1,2,4-thiadiazoIo[4,5-a Jbenzimidazole 4a,5,6,7,8,8a-hexahydro1,3.4-thiadiazolo[3,2-a]benzimidazole lH-1.2.3-triazolo[1.5-albenzimidazole 1 H-1.2,4-triazolo[4,3-a Jbenzimidazole 9,9a-dihydro-1 H - 1,2,4-triazol0[4,3-a~nzimidazole 9H- 1,2,4-triazol0[4,3-a]benzimidazole 2,3-dihydro-9H1,2,4-triaz010[4,3-a]benzirnidazole 1 H - 1,2,4-triazol0[2,3-a]enzimidazole

Cf. Scheme 6.91. Based on the Ring Index.

1,2,4-thiadiazolo[2,3-a]benzimidazole (6.420), 1,2,4-thiadiazolo[4,5-a]benzimidazole (6.421), and 1,3,4-thiadiazolo[3,2-ulbenzimidazolering systems, the latter being known only in the 4a,5,6,7,8,8a-hexahydro form (6.422). Fully nitrogen-containing 6-5-5 fused benzimidazoles having two additional heteroatoms are represented by the 1H-1,2,3-triazolo[ 1,5-a]benzimidazole (6.423), 1H- (6.424) and 9 H - (6.426) 1,2,4-triazolo[4,3-a]benzimidazole ring systems and their 9,9a- (6.425) and 2,3- (6.427) dihydro derivatives, and by the 1 H-1,2,4-triazolo[2,3-a]benzimidazolering system (6.428). 6.3.1. Synthesis

Ring- Closure Reactions of Benzimidazole Derivatives Derivatives of the 2-sila-3H-thiazolo[3,2-a]benzimidazole ring system are accessible257(Scheme 6.92) by the base-catalyzed cyclization of condensates (6.431) derived by the reaction of 2-benzimidazolethiones (6.429) with bromomethyldimethylchlorosilane (6.430). Ring-formation of the type [(6.431) + (6.432)1 is akin to that of 2,3-dihydrothiazolo[3,2-a]benzimidazoles from 2-(~-halogenoalkylthio)benzimidazoles(see page 101) and is effected in good yield (Table 6.86) using 1,8-bis(dimethyIamino) naphthalene as the basic catalyst. As in the closely related 2-(&halogenoalkylthio)benzimidale cyclizations (see page 101) the factors governing the direction of ring-closure in substrates (6.431)unsymmetrically substituted in the benzene ring are as yet unknown.*" The uncatalyzed condensation (Scheme 6.92) of bromomethyldimethylchlorosilane (6.430)with 2-aminobenzimidazoles (6.433) occurs at N(1)rather than at the amino group to

ax< H

R

+

Me Cl-Si-CH2Br I

I

Me

I

H

(6.429)

/

(6.430)

H

(6.432)

(6.431)

+

(6.430)

(6.433)

R (6.434)

(6.435)

H

Scheme 6.92

TABLE 6.86. SYNTHESIS OF 2-SILA-3H-THIAZOLq3,2-a]BENZIMIDAZOLES AND 3-SILA-2H-IMIDAZqI ,2-a]-BENZIMIDAZOLES BY RINGCLOSURE REACHONS OF BENZIMIDAZOLE DERIVATIVES Starting materials

(6.431;R = H) (6.431;R=NO,) (6.433; R = H) (6.433; R-Me) (6.433;R = Ci) (6.433; R = NO,)

Reaction conditions‘ A

A

B B B B

Product

(6.432;R = H) (6.432;R = (6.435; R = H) (6.435; R=Me) (6.435; R = Ci) (6.435; R = NO,)

Yield (%)

m.p. (“C)

Ref.

>so

181-182 165 (decomp.) 62-64 123-125 107-109 192-195

257 257

65

48 70 82 68

258 258 258 258

A = 1,8-bisdimethylaminonaphthaIene, tetrahydrofurane/(rom tempJ(24 hr); B = tetrahydrofurane/(room tempJ(2-4 days). Position of the nitro substituent not established.

222


223

afford via presumed silylated intermediates (6.434), moderate to good yields (Table 6.86) of 3-sila-2H-imidazo[1,2-a]benzimidazolederivatives (6.435).258The structures of these compounds follow from their mode of ring-opening on reaction with acetic anhydride (see later). The uncatalyzed character of 3-sila-2H-imidazo[l,2-a]benzimidazoleformation compared with the base-catalyzed nature of 2-sila-3H-thiazolo[3,2-a]benzimidazole synthesis reflects the difference in basicity of the nitrogen centers involved in these related ring-closure reactions.258 Readily accessible 2-thioacylaminobenzimidazoles are oxidatively cyclized, mainly in high yield (Table 6.87), to 1,2,4-thiadiazolo[2,3-a]benzimidazole derivatives [Scheme 6.93;(6.436) +(6.437)] by treatment259with bromine or m -chloroperbenzoic acid in chloroform solution. Reactions of this type have been principally exploited for the synthesis of 2-hetarylsubstituted 1,2,4-thiadiazolo[2,3-a]benzimidazoles(6.437) (Table 6.87).259 TABLE 6.87. SYNTHESIS O F 1,2,4-THIADIAZOLq2,3-a]BENZIMIDAZOLE DERIVATIVES (6.437) BY OXIDATIVE RING-CLOSURE O F 2THIOACYLAMINOBENZIMIDAZOLES(6.436)" Starting material (6.436)

Reaction conditionsb

Ph p-MeC,H, pBu'C,H, P-F,CC,H, p-CIC,H, 2-Naphthyl 2-Furyl 2-Thienyl 3-Thienyl 2-Thiazolyl 4-Thiazolyl 5-Thiazolyl

Product (6.437)

Yield (YO)

A A A A A A A A A A A A

Ph p-MeC,H, p -Bu'C,H, P-F3CC,H4 p-CIC,H, 2-Naphthyl .2-F~vl 2-Thien yl 3-Thienyl 2-Thiazolyl 4-Thiazolyl 5-Thiazolyl

60 50 90

2-Pyridyl 3-Pyridyl 2-Pyrazinyl 3-Isothiazolyl 4- Isothiazolyl

B

2-Pyridyl 3-Pyiidyl 2-Pyrazinyl 3-Isothiazolyl 4-Isothiazolyl

-d

5-1sothiazolyl 1,2,3-ThiadiazoI-4-y1

A

A

5-Isothiazolyl 1,2,3-Thiadiazol-4-yl

75 80

A

1,2,5-Thiadiazol-3-y1

60

A

R A A

70

60

85

50 70 20

60 90 90 50 85

95

80

m.p. (YJC 235-236 251.5-253 217.5-21 8 249-250 230-232 258-259 203-204.5 22%230 2 18-2 18.5 244-244.5 252.5-254.5 227 (decomp.) 258-260 258 245-246.5

-

225.5-226 (decomp.) 245-245.5 256-251 (decomp.) 226.5-229.5

OFrom Ref. 259. A = Br,,CHCl,/(room temp.)(3 hr); €3 = m-chloroperbenzoic acid, CHCI, (roomtempJ(l5 hr). Solvent of crystallization not specified. Yield not quoted. ' Melting point not quoted.


224

S

H H (6.436)

seheme 6.93

(6.437)

The orthodox thermal condensation (Scheme 6.94) of benzimidazole-2sulfonamide (6.438) with ethyl orthoformate provides an efficient method for the synthesisz6' of the 1,2,4-thiadiazolo[4,5-a]benzimidazole sulfone (6.439). Unfortunately, attempts to generalize this straightforward synthetic procedure were unsuccessful. A more general if less orthodox synthetic approach (Scheme 6.94) to 1,2,4-thiadiazolo[4,5-a]benzimidazolederivatives (6.442) is provided by the uncatalyzed condensation of 2-thiocyanatobenzimidazoles (6.440) with imidazole derivatives (6.441).261Despite the course followed in these reactions, the structures of the

(6.438)

(6.439) (m.p. 332-335')

R'

qRscN H (6.440)

+

y--JI R2 H (6.441)

(i ) (EtO),CH,freflux)(30min) (ii) acetone or acetonitrile/(room temp.)(l4 hr) Scheme 6.94

.R2


22s

products (6.442) are established beyond doubt by X-ray of the parent compound (6.442; R' = Rz= H). Transformations of the type [(6.440) + (6.441)+ (6.442)] suffer from the disadvantagez6' of giving rise to isomer mixtures when unsymmetrically substituted thiocyanatobenzimidazoles or imidazoles are used as reactants but merit further study in terms of their possible application to the general synthesis of 1,2,4-thiadiazolo[4,5-a]benzimidazoles containing substituents other than imidazolyl. Further study of such reactions in a mechanistic sense is warranted by the lack of information on the nature of the formal S+ N shift and oxidation required to account for 1,2,4-thiadiazolo[4,5-a]benzimidazole formation. What would appear to be the only reported example of 1,2,3-triazolo[1,5a]benzimidazole formation26z is represented (Scheme 6.95) by the N bromosuccinimide mediated ring-closure of the hydrazone (6.443) to the hydrobromide (6.444),which affords the parent base (6.445) on treatment with aqueous pyridine. Syntheses of the isosteric 1H- and 9H-1,2,4-triazolo[4,3-a]benzimidazole ring systems in contrast are well documented and are invariably effected by ring-closure of 2-benzimidazolylhydrazinederivatives (Scheme 6.96 and Table 6.88).263-268 lH-1,2,4-Triazolo[4,3-a]benzimidazole formation is illustrated by the acid-catalyzed cyclization of the hydrazone (6.447) [readily accessible by the reaction of the 2-benzimidazolylhydrazine (6.446) with ethyl orthoacetate] in moderate yield (Table 6.88) to 1,3-dimethyl-lH-l,2,4-triazolo[4,3-aJnzimidazole

(6.443)

(6.444)

(m.p. 19Y)

J (ii)

(88%)

Ph (6.445) (m.p. 148") (i) N-bromosuccinimide, EtOAc/room temp. (reaction time not specified) (ii) pyridine-water

scbeam 6.95

N N Q\

E

F F

(6.446; R = Me, R' = H) (6.446; R = CH,Ph, R' = H) (6.446; R = Ph, R' = H)

R = H, R' =Me) R = H.R' = Me) R = H, R' = Me) R = H, R' = Et)

(6.449; R = Me) (6.449; R = CH,Ph) (6.449; R = Ph)

(6.449; R = H)

(6.449; R = H)

(6.450; R = R' = Me) (6.449; R = H)

(6.448) (6.450; (6.450; (6.450; (6.450;

Product

quant. quant. 68

95

59

42

-

40 93 84 92 79

Yield (X)

177 284 (decomp.) 275 (decomp.) 282-283 (decomp.) 263-265 2 16-2 18 237-241

73-74 231-232 233 260

m.p. eC)

Ethanol-water Ethanol-water Dimethylformamidc-water

Ethanol-water

-d

Ethanol-water

-b

Butanol

-b

Butanol

-b


267 267 268

267

265

263 264 265 263 264, 265 263 266

Ref.

Purified by sublimation. Yield not quoted. Purified by precipitation from sodium hydroxide solution with acetic acid.

A = toluene-p-sulfonic acid, xylene/(reflux)(4hr); B = (EtO),CMe, xylene/(reflux)(4-5 hr); C = (EtO),CEt, xylene/(reflux)(34 hr); D = CS,, KOH, EtOH/heat until H,S evolution ceases; E = P h N d - S , trichlorobenzene/(reflux)(2.5 hr); F = CS,, dioxane or pyridine/(reflux)(l-2 hr); G = CS,, pyridine/(reRux)(4hr).

G

F

(6.446; R = R' = H)

(6.446; R = R ' = H )

(6.446; R = R' = H)

B B B C

A

B D

R = R ' = H) R = R' = H) R = R' = H) R = R' = H)


(6.446; R = Me, R' = H)

(6.447) (6.446; (6.446; (6.446; (6.446;

Starting material

TABLE 6.88. SYNTHESIS OF 1H-AND 9H-1,2,4-TRIAZOLO[4,3-a)BENZIMIDAZOLES BY RING-CLOSURE OF 2-BENZIMIDAZOLYLHYDRAZINEDERIVATIVES


I R

I H

I Me (6.447)

1

227

R’-H

JI

R (6.450)

sebcme 6.96

(6.448).263The oxidative ring-contraction (Scheme 6.97) of the 1,2,4triazolo[4,3-a]quinoxaline (6.451) to the 9,9a-dihydro-lH-1,2,4-triazolo[4,3-a]benzimidazole derivative (6.453) is suggested269to occur by initial oxidation to the intermediate (6.452) followed by hydrolytic scission at the C(4)-N(5) bond and then recyclization at C(1). 9 H -1,2,4-Triazolo[4,3-u]benzimidazole derivatives are readily synthesized in moderate to high yield (Table 6.88) by the direct thermal ring-closure of 2-benzimidazolylhydrazine (6.446; R = R ’ = H ) and its ring N-alkyl derivatives with ortho esters [Scheme 6.96; (6.446; R = H or alkyl, R’ = H)+ (6.450; R = H or alkyl, R’ = alky1)].26*265Correspondingly, reaction of 2-benzimidazolylhydrazine and its ring N-alkyl and aryl derivatives with carbon disulfide in the presence of potassium hydroxide266 or pyridine,267*268 or with phenyl isothiocyanateZ6’results in the formation (Table 6.88) of tautomeric 2,3dihydro-9H-1,2,4-triazolo[4,3-a]benzimidazole-3-thiones [Scheme 6.96; (6.446; R = H,alkyl, or aryl, R’ = H)-+ (6.449; R = H, alkyl, or aryl)]. The

Condensed Benzimidazoles of Type 6 - 5 5

228

(6.451)

(6.452)

(6.453)

(m.p. 210") (i) O,,light petroleum/(reflux)(8hr) Scheme 6.97

acylative cyclization of readily synthesized N-acylamino 2-aminobenzimidazoles, using acetic or propionic anhydrides, or benzoyl chloride, provides a general, high yield (Table 6.89) route to C(2)-substituted N-acyl1H-1,2,4-triazolo[2,3-a]benzimidazoles, deacylation of which affords the The parent heterocycles [Scheme 6.98; (6.454) + (6.455) --* (6.456)J."' position of the acyl substituent in the immediate products of these cyclization reactions was not established, the N ( 1) formulation (6.455) being assigned on a purely arbitrary basis.270 TABLE 6.89. SYNTHESIS OF 1H-~,~.~-TRIAZOL~[~.~-U~ENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF 1,2-DIAMINOBENZIMIDAZOLE DERIVATIVES" Reaction Starting materialb conditions'

Product

(6.454; (6.455; (6.454; (6.455; (6.454; (6.455;

(6.455; (6.456; (6.455; (6.456; (6.455; (6.456;

R = Me) R = Me) R = Et) R = Et) R = Ph) R = Ph)

A

B

A

B

C D

Yield (YO) m.p. ("C) R = Me) R = Me) R = Et) R = Me) R = Ph) R = Ph)

71 80 71 66 83 60

154-155 258-259 111-113 198-200 230-232 310-315

Solvent of crystallization Acetonitrile Acetonitrile -d

Ethyl acetate Acetonitrile Ethanol

From Ref. 270. Hydrobromides. A = (RCO),O/(refluxl(S hr); B =cone. HCl/(reflux)(2hr); C = PhCOCl/(reflux)(Shr); D = 10% NaOH aq./(reflux)(2hr). Solvent of crystallization not specified.

a


,NHCOR

229

,COR

NH2 (6.454)

(6.455)

/ (6.456) Scheme 6.98

Ring-closure Reactions of Other Heterocycles Ring-closure reactions of heterocyclic substrates other than benzimidazole derivatives to 6-5-5 fused benzimidazole frameworks having two additional heteroatoms are rare. Perhaps the best documented2” process in this category is the brominative cyclization (Scheme 6.99) of 2-(2-cyclohexenylamin0)- 1,3,4-thiadiazole derivatives (6.457) to give the hydrobromides of 4a,5,6,7,8,8a-hexahydro-1,3,4-thiadiazolo[3,2-u]benzimidazoles (6.458) in good yield. Ring-closure of this type represents the only method for the construction of the 1,3,4-thiadiazolo[3,2-a]benzimidazole ring system reported to date.

H (6.457)

(6.458)

R

Me

CHZCHZCOZH CHZPh

Ph

(i) Br,, CHCl,/(O”)(few min)

Yield (YO) m.p. (“C) 69 78 79 60

159-160 194-195 124-125 181-182

230


6.3.2. PhysicoehermcPl -Roperties

Spectroscopic Studies

INFRARED SPECTRA. The infrared spectra (Table 6.90)2s8 of 3-sila-2H-

imidazo[ 1,2-a]benzimidazole derivatives (6.459) contain NH absorption at 3400-2800 cm-' and characteristic bands in the ranges 1435-1430 and 1261-1254 cm-' attributable to the asymmetric and symmetric Me-Si stretching modes, respectively. The NH-substituent in N(9)-unsubstituted TABLE 6.90. INFRARED SPECTRA" OF 3SILA-2H-IMIDAZq 1.2-aE BENZLMIDAZOLE DERIVATIVES (6.459Ib

H (6.459)

(6.459)R H Me

CI

NO,

NH 3400-2800 3400-2800 3400-2800 3400-2800

v,,(cm-') SiMe'

SiMed

1430 1435 1431 1432

1261 1258 1254 1257

Measured for solid dispersions in KBr. From Ref. 258. Asymmetric stretching vibration. Symmetric stretching vibration.

9H- 1,2,4-triazolo[4,3-a]benzimidazolesgives rise to broad 1R absorption The acyl substituent in N(Table 6.91) in the range 3400-2600 m-'.263,272 acyl- lH-1,2,4-triazol~2,3-albenzimidazolesis associated with uniform JR carbonyl absorption at 1700 9H-1,2,4-Triazolo[4,3-a]benzimidazoles give rise to IR C==N absorption (Table 6.91) at lower frequencies (1650-1620 cm-') than that (1660 cm-') (Table 6.91) of lH-1,2,4-triazolo[4,3-a]benzimidazoles, thus allowing the differentiation of the two structural types. The presence of NH absorption at ca. 3100 cm-' and C=S absorption at 1517-1488 cm-'in the IR spectra (Table 6.91) of 2,3-dihydro-9H-l,2,4triazolo[4,3-a]benzimidazole-3-thionesis consistent with the preferential existence of these molecules in the thione tautomeric form (6.462) both in the solid state and in solution.

c

w

h)

Me H H

C J-H --*(

Me

(6.462)

May be reassigned to NH def. Measured for a solution in CS,. ' Measured for a suspension in Nujol.

(6.462)

H Me H H H H

Me Me Me Me Me Me Me Me MeS H Me

H H

-

-

RZ

R'

(6.460) (6.461) (6.461) (6.461) (6.461) (6.461) (6.461) (6.461) (6.461) (6.461) (6.462) (6.462)

Compound

R3

R4

Nujol

Nujol

KBr KBr KBr KBr KBr KBr KBr KBr KBr Nujol CS,, Nujol CS,, Nujol

Medium

(6.461)

-

c

3283' 3078'

-

3100 3100 3160-2600 3089 3400,3210 3060-2630

-

3060-2650

-

NH

1512

1488 1649

1494' 1517, 1494'

-

-

-

C=S

1652

1651 1650' 1652'

-

1660 1630 1630 1620 1650 1625 1640 1620"

C=N

v,,(cm-')

(6.462)

-

-

-

-

-

-

1620 1520,1340 1540, 1340

-

Others

267

267

263 263 263 11 11 11 272 272 272 267 267 267

Ref.

TABLE 6.91. INFRARED SPECTRA OF 1 H- AND 9 H -1,2,4-TRIAZOL0[4,3-a]BENZIMlDAZOLE DERIVATIVES (6.460). (6.461), AND (6.462)

TABLE 6.92. ULTRAVIOLET SPECTRA OF 1H-AND 9H-l,2,4TlUAZOL0[4,3-~]BENZIMIDAZOLE DERIVATIVES (6.463). (&a), (a&), AND (6.466).

R

I

I

R'

R

I

(6.465)

(6.4663

Compound

R

R'

(6.463)

H

Me Dioxane

(6.464) (6.464) (6.464) (6.464) (6.462)e (6,464) (6.463)e

(6.464 (64G4) (6.463) (6.463) (6.463)

(6.463) (6.463) (6.463) (6.464) (6.464)

(6.464) (6.464)

Solvent

A,,(nm)(log~)

222(4.49), 232 sh (4.30). 237 sh (4.24), 257(3.91), 263 sh (3.87), 293(3.67), 301 sh (3.62) 215(4.55), 230sh (4.10), 240sh (3.72), H Me EtOH 289(3.70), 294(3.70) H Me MeOH 214(4.78), 232(4.29), 288(3.69), 293(3.70) 212(4.56). 286(3.52). 290(3.52) H Me H,O 29 l(3.49). 295(3.49) H Me CHCI, H Me EtOH-HCI 275(3.60), 28 lS(3.68). 292.5(3.46), 297.5(3.45) 269(3.62), 276(3.67), 287(3.46), H Me CF,CO,H 295 sh (3.40) 214(4.79), 232(4.30), 288(3.74), H Et MeOH 294(3.75) Me Me Dioxane 225(4.38), 236(4.20), 241(4.18), 261(3.95), 266(3.97), 287 sh (3.41), 296(3.54), 306(3.49) 216 sh (4.45). 220(4.45), 233 sh (3.93), Me Me EtOH 237 sh (3.91). 253(3.72), 260(3.71), 291(3.30), 300(3.28) 214sh (4.43), 219(4.44), 234 sh (3.90), Me Me H,O 250(3.59), 256 sh (3.58), 289(3.20), 296(3.20) 295(3.30), 303(3.26) Me Me CHCI, Me Me EtOH-HCI 267(3.33), 275(3.54), 282.5(3.57), 292 sh (2.63) Me Me CF,CO,H 264 sh (3.33), 272(3.50), 278(3.54), 287 sh (2.67) Me Me Dioxane 224(4.31), 234(4.10), 251 sh (3.80), 300(3.84) 216(4.48), 231 sh (3.80). 245 sh (3.52). Me Me EtOH 29 1(3.49), 297(3.50) Me Me H,O 215(4.49), 288(3.32), 296(3.32) Me Me EtOH-HCI 276(3.43), 283(3.55), 297(3.48)

232

Ref. 226 263 265 263 263 273 273 265 226 263 263 263 273 273 226 263 263 273


233


(6.463)

I

R

(6.465)

(6.466)

R' Solvent

Compound

R

(6.464) (6.465)

Me Me CF,CO,H Me Me EtOH

(6.465)

Me Me CF,CO,H

(6.465)

Me Et

EtOH

(6.465)

Me Et

CF,CO,H

(6.465)

Et

Me

EtOH

(6.465)

Et Me Me Me Me Et Et

Me Me Me Et Et Me Me

CF,CO,H EtOH CF,CO,H EtOH CF,CO,H EtOH CF,CO,H

(6.466) (6.466) (6.466)

(6.466) (6.466) (6.466)

A,,,(nm)(log

E)

272.5(3.45), 279(3.55), 295(3.34) 263 sh (3.42), 277(3.65), 284(3.67), 297 sh (2.72) 265 sh (3.53). 274(3.68), 281(3.69). 303 sh (2.74) 269 sh (3.43), 277(3.62), 284(3.66), 296 sh (2.51) 267 sh (3.49), 274(3.63). 282(3.68), 300 sh (2.18) 265 sh (3.35). 277(3.64), 284(3.68), 300 sh (2.61) 267 sh (3.49), 274(3.65), 282(3.69) 293(3.63). 300(3.62) 294(3.53), 302(3.50) 297(3.65), 301(3.64) 295(3.59), 303(3.63) 295(3.64), 302(3.65) 295(3.55), 304(3.52)

Ref. 273 273 273 273 273 273 273 273 273 273 27 3 273 273

ULTRAVIOLET SPECTRA. The UV spectra (Table 6.92) of 1(9)H-1,2,4triazolo[4,3-a]benzimidazoles and their N(1) and N(9) alkyl derivatives are

typified by a series of intense absorption bands indicative of the delocalized aromatic character of these molecules. In accord with their more extensively conjugated structures, N(9)-alkyl 9H-1,2,4-triazolo[4,3-a]benzimidazoles tend to absorb more intensely at longer wavelength than their N(1)-alkyl 1H- 1,2,4-triazolo[4,3-a]benzimidazole counterparts. This distinguishing feature has been for the study of the tautomeric equilibrium in 3-methyl-1(9)H-l,2,4-triazolo[4,3-a]benzimidazole, the position of which is to be markedly sensitive to solvent effects, nonpolar media (e.g., dioxane) favoring the N(l)H tautomer, and polar media (e.g., ethanol,


234

water) the N(9)H isomer. P r ~ t o n a t i o nof~ 3-methyl-1(9)H-l,2,4-triazolo~~ [4,3-a]benzimidazole and its N(l) and N(9) methyl derivatives has a dramatic, though not unexpected effect (Table 6.92) on the U V absorption of these %molecules, the bands at shorter wavelength disappearing and those at longer wavelength suffering a marked reduction in intensity. Alkylation of the N(1) position in N(9)-alkyl-9H-1,2,4-triazolo[4,3-a]benzimidazoleshas a similar effect (Table 6.92) which is heightened by quaternization of these molecules at the N(2) position. The site of N-alkylation in 9-alkyl-9H1,2,4-triazolo[4,3-a~enzimidazoles can therefore be established unambiguComparison of the UV spectra (Table 6.92) ously using UV of model N(1) and N(2) alkyl 3,9-dimethyl-9H-1,2,4-triazolo[4,3-a]benzimidazolium cations with the UV spectra of 3-methyl-1(9)H-1,2,4-triazolo[4,3-a]benzimidazole and its N(1) and N(9) methyl derivatives in acidic media (Table 6.92) likewise allows the site of protonation in these molecules to be determined (see NUCLEAR MAGNETIC RESONANCE SPECTRA.The protons of the dimethylsilyl substituent in 3-sila-2H-imidazo[ 1,2-a]benzimidazoles resonate as a welldefined six proton singlet at S 0.15-0.19 (Table 6.93), while those of the C(2) methylene group give rise to uniform singlet absorption in the range 62.44-2.49.258 The enhanced deshielding260of the C(3) proton in 1,2,4thiadiazolo[4,5-a]benzimidazole sulfone [d. page 224, Scheme 6.94; (6.439)], which absorbs as a singlet at S 9.05, is consistent with the combined effects of delocalization in the 1,2,4-thiadiazol0[4,5-a]benzimidazolering system and electron-withdrawal by the sulfone substituent. The successful analysis274of the 'HNMR spectra (Table 6.94) of 3methyl-1(9)H-1,2,4-triazolo[4,3-a]benzimidazole and its N(1) and N(9) TABLE 6.93. 'H NMR SPEmRAa** OF 3-SILA-2H-IMIDAZ0[1,2a IBENZIMIDAZOLE DERIVATIVES (6.46S)c

(6.4591 (6.459)

H

R

ArH

NH

CH,

Si(Me)

Others

H

7.00-7.50111 7.12 7.33 7.61

3.87 3.83br 3.70br 3.81

2.48 2.44 2.49 2.49

0.15 0.17 0.19 0.17

-

Me CI NO,

8 in ppm measured for solutions in (CD,),SO from TMS.

2.22

-

-

Signals are sharp singlets unless denoted as br = broad; m = multiplet. From Ref. 258.

H H H H H H H H H H Me Me Me Me Me Me COMe COMe

R'

H H

H

H H H H H Br H NO, H H H H H H H

R2

NH, NH, H H H H H H H H

NO,

H H H D Br Br NO,

C

A

C

A A

C

A A

B

A

B B

B

B

A A A A

Solvent'

R2

H(5)

R'

= 0.95-1.13 ' J7.8= 8.16-9.30

H(8) 2.73 2.73 2.74 2.72 3.07 3.04 3.22 3.30 2.65 2.93 2.66 2.7 1 2.68 2.65 2.68 2.76 2.74' 2.82'

Me(3)

'

'

' 8 values not quoted. These signal assignments may be interchanged. COMe.

J6.8

Hz. Hz. Hz.

H(7)

J6.7 = 7.41-7.67

H(6)

R2

-

-

-

3.73 3.74 3.84 3.60 3.64 3.71

-

-

-

NMe

Others

R3Y7J--MeR3y7---Me 274 272 263 272 272 212 212 272 272 272 214 263 263 274 263 263 263 263

Ref.

1H- AND 9H-1,2,4-TRIAZOL0[4,3-a]BENZIMIDAZOLE DERIVATIVES (6.467A)AND (6.467B)

R3

Of

" 6 in pprn measured from TMS. Signals are sharp singlets unless denoted as m = multiplet ' A = (CD,),SO; B = CF,CO,H; C = CDCI,. J5,6= 8.00-8.03 Hr. ' I s , , = 1.17-2.00 Hz. J5,8= 0.50-0.67 Hz.

(6.4678)

(Urn)

(6.467B)

(6.467B)

*

*

* * *

(6.467A)e (6.4678) (6.467A)== (6.467B) (6.467A) (6.4618) (6.467A) (6A67B) (6.467A)e (6.467B) (6.467A) (6.467B) cn (6.467A)e(&4618) (6.467A) 1-( (6.467A) (6.467B) (6.46714)e (6.467B) (6.467A) (6.467A) (6.467A) (4.467B)

Compound

TABLE 6.94. 'H NMR SPECTR

(6.470)

(6.468) (6.469) (6.470)

(6.468)

(6.468) (6.468) (6.468)Z (6.468) (6.468)s (6.468)

(6.469)

=(6.469) =(6.469) (6.469) = (6.469)

Compound

Me

Me Me Me Me Me

H H H

H

H

R1

Me

Me

H H H

D NO, NO, H

H H

R2

144.0

B

A

B

A

B

A

B

139.0 138.9 145.5 137.2 144.0 140.3 144.8 140.7

139.1

-d

C(3)

A A

B

A

Solvent'

123.4

123.4 123.9 123.4 125.6 124.2 121.7 123.2 121.4

123.5 123.6

C(4a)

114.5

111.7 114.4 111.6 108.8 111.7 110.9 114.1 111.9 114.7 112.4

C(5)

126.8

139.8 142.5 118.1' 126.7 120.3 126.2 123.7

-

119.4 126.5

C(6)

129.9

124.5 130.7 124.4 120.6 126.0 123.9 130.0 124.8 130.4 127.0

C(7)

113.7

114.0 116.5 116.7 117.5' 115.9 110.1 113.3 113.6

114.1 116.0

C(8)

139.6

142.5 152.8 142.7 150.1 137.5 138.4 139.4 137.7

142.7 137.7

C(8a)

147.7

155.8 158.5 152.2 154.7 148.0 156.0 151.4 146.2

-d

156.0

C(9)

11.9

11.4 11.6 11.6 11.4 11.5 11.3 11.2 11.2

11.3 11.4

Me

37.9' 3 1.98

30.5g

34.0b 36.9' 29.0' 31.3' 36.6'

-

-

-

-

-

NAlk

DERIVATIVES (6.46% (6.469), (6.470). TABLE 6.95. I3C NMR S P E n R A " OF 1H- AND 9H- 1,2,4-TRIAZOL0[4,3-a]BENZIMIDAZOLE AND (6.471)b

h)

4

w

"6 in ppm measured from TMS. ' From Ref. 273. A = (CD,),SO; B = CF,CO,H. " Not observable. ' These signal assignments may be interchanged. Me(1). Me (9). Me of Et group. ' CH, of Et group. ' Me (2).

A

Me

Et

(6.471)

142.5

141.8

A

Et

Me

(6.471)

143.5

B

Me

Me

(6.471)

142.5

A

Me

Me

(6.47 1)

141.0

140.9

Me

Et

(6.470

A

A

Et

Me

(6.470)

126.6

121.4

1 12.0

111.7

115.2

122.4

122.4

125.2

122.3

111.8

121.4 123.3

123.8

123.7

112.5

112.4

121.7

121.5

128.1

128.0

130.7

128.0

127.1

127.0

114.5

114.3

113.0

114.3

113.7

113.5

136.9

137.8

139.6

137.7

136.7

137.8

150.4

151.4

152.8

151.0

145.7

145.8

10.7

10.5

12.0

10.7

11.1

11.2

30.7K 14.4h 44.6' 36.5' 14.Sh 39.2' 29.P 38.2' 30.8Y 39.5' 29.gK 14.1h 46.1' 38.2' 13.0'' 39.6'


238

methyl derivatives using the L A W N program in conjunction with nuclear Overhauser effects (NOE) allows the assignment of chemical shifts and coupling constants to the benzenoid protons in these molecules. The attempted i n v e ~ t i g a t i o n ~of' ~the tautomeric equilibrium in 3-methyl-1(9)H-1,2,4triazolo[4,3-~]benzimidazole by 'H NMR spectroscopy was unsuccessful. However, this equiIibrium is readily s t ~ d i e d " ~by means of I3CNMR spectroscopy (Table 6.95) which demonstrates the predominance of the 9H-tautomer (6.469; R' = R2 = H) to the extent of 60-70% in dimethyl sulfoxide. The value of the 13CNMR method for the investigation of such

TABLE 6.96.

'H NMR SPECTRA".b OF 1 H- I ,2,4-TRIAZOL0[2,3-o]BENZIMIDAZOLE DERIVATIVES (6.472)c

(6.472) (6.472) R'

a

R2

Solvent" H(5)

H(6)

-

H(7)

m

H Me COMe Me

A

H COEt

Et Et

A

H COPh

Ph Ph

B B

c--- 7.54 rn -7.37 111-8.43

CH,Ph

Ph

C

-7.20111-

-7.50 -7.40

m-

. -< -7.55

7.55m-* m-8.55'

B B

S in ppm measured from TMS.

*-

H(8)

Me

CH,

2.50' 8.50 inf 2.83' 2.468 i.4a,th.' 2.85qI.l 1.37th.' 2.9aqi.' 1.42 tk.' 3.40qk,' 8.00 m" mf 7.54 m"' 8.04 mn 5.38" 7.30111"' 7.82p

Signals are sharp singlets unless denoted as t = triplet; q = quartet; m = multiplet. From Ref. 270. A = CD,CO,D; B = CDCI,; C = CCI,. ' Me (2). May be reassigned to H(5). COMe. Me of Et group. Coupling constant not quoted. CH, of Et group. Me of COEt group. CH, of COEt group. Ph (2). " COPh. CH,Ph. CH2Ph.

'

Others

6.3. Fused Benzimidazoles with Two Additional Heteroatorns

239

tautomeric equilibria resides in its applicability in solvent systems inappropriate for UV spectroscopic studies (see before) or dipole moment measurements (see later). The site of protonation and quaternization in 1H- atld 9H- 1,2,4-triazol0[4,3-a Ibenzimidazoles can be determined on the basis of the consequent shielding effect of ca. 10 ppm on the 13C chemical shifts (Table 6.95) of carbon atoms adjacent to the nitrogen centers involved.273 The enhanced deshielding of one of the benzenoid protons [ H ( 5 )or H ( 8 ) ]in l-acyl-1H-1,2,4-triazolo[2,3-a]benzimidazoles (Table 6.96) is attributedz7' to a long-range anisotropic effect of the N-acyl substituent.

General Studies DIPOLE MOMENTS. Dipole measurements provide a useful means for the study of tautomeric equilibria in 1(9)H-1,2,4-triazolo[4,3-a]benzimidazoles. For example, comparison of the dipole moments (Table 6.97) of 1,3-dimethyl1H-1,2,4-triazolo[4,3-a]benzimidazole (6.473; R = Me) and 3,9-dimethyl9H-1,2,4-triazolo[4,3-u]benzimidazole (6.474; R = Me) measured in dioxane taken in the with that of 3-methyl- 1(9)H-1,2,4-triazolo[4,3-a~enzimidazole same solvent, indicates the tautomeric equilibrium of the latter compound in dioxane to favor the 1H-tautomer (6.473; R = H). The contrasting predominance of the 9H-tautomer (6.474; R = H) in ethanol revealed by UV studies (see before), is a reflection of the solvent-dependent nature of the equilibrium process [(6.473; R = H) (6.474; R = H)].

*

'TABLE 6.97. DIPOLE MOMENTS" OF 1H- AND 9H-1.2.4TRIAZOLO[4,3-a]BENZIMIDAZOLE DERIVATIVES (6.473) AND (6.474)h

R

R (6.474)

(6.473)

Compound

R

I.L (D)

(6.473) (6.473) (6.474)

H Me Me

3.20 3.55 5.12

=(6.474)

Measured in dioxane at 25".

' From Ref. 226.

0

E

E

D

C C

3-Me-l(9)H-

B

i

+

3,9-di-Me-9H1,3-di-Me- 1H-

+

1,3-di-Me-lH-

-2,3-dihydro-9H-3-thione

3

2.9-di-CH2N3 -2.3-dihydro-9H-3-thione

2,3-Dihydro-l(9)H-3-thione 2,9-di-CH2N

2,3-Dihydro-l(9)H3-thione

3,9-di-Me-9H2,3-Dihydro-l(9)H-3-thione 3-MeS-9-Me-9H9-Me-2.3-dihydro3-MeS-9-Me-9H9H-3-thione 3-Me-9-COMe-9H3-Me- 1(9)H-

3-Me-l(9)H-

l(9)H- 1.2,4-Tnazolo[4,3-a Ibenzimidazole Substrate Product

A

Reaction conditionsa

quant.

134-136

144-146

214-216

-c 90

104-105

I

Ethanol

Ethanol

-d

-

Ethanol-water

-

-

-


-

-

177

73-74

m.p. (“C)

30 90 90

45 70

55

Yield

(Yo)

TABLE 6.98. ALKYLATION AND ACYLATION REACTIONS OF 1(9)H-1,2,4-TRIAZOL@4,3-alBENZIMIDAZOLES

272

272

263

267 267

263

263

Ref.

h)

9-CH2Ph-2,3-dihydro1(9)H-3-thione 9-CHqNMe,-2,3-dihydro1(9)H-3-thione

E

\p-2.3-dihydro-9H-3-thione

-2.3-dihydro-9H-3-thionc

3 n

dihydro-9H-3-thione

9-CH,NMe,-2-CH,NMe,-2,3-

9-CH,Ph-2-CH2N

9-CH,Ph-2-CH,N

quant.

80

80

Ethanol

Ethanol

167-168 153-154

Ethanol

Ethanol

Ethanol

Ethanol

171-173

176-178

146-148

152-154

A = MeI, NaOEt, EtOH/(reflux)(7 hr); B = Me2S0,, NaOH, H,O/(reflux)(6 hr); C = MeI, EtOH/(reflux)(lO-lS min); D=Ac,O, pyridine (reaction temp. and time not specified). E=R,N, 400?' HCHO aq. (reaction temp. and time not specified). Purified by sublimation. ' Yield not quoted. Solvent of crystallization not specified.

E

9-CH,Ph-2,3-dihydro1(9)H-3-thione

E

80

9-Me-2-CH2Nq2.3-diiyb-9H-3-thione

9-Me-2.3-dihydro-l(9)H3-thione

E

W

90

9 - M c - 2 - C H 2 N 3 -2,3-dihydro-9H-3-thione

9-Me-2,3-dihydro- l(9)H3-thione

90

E

\b-2,3-dihydro-9H-3-thione u

2,9-di-CH2N

2,3-Dihydro- 1(9)H3-thione

E

272

272

272

272

272

272

242


63.3. Reactions

The brevity of the following account is a measure of the general lack of information on the chemical behavior of the several 6-5-5 fused benzimidazole ring systems having two additional heteroatoms.

Reactions with Electrophiles Changes in the UV and 13CNMR a b ~ o r p t i o n ' o ~f~ 1H- and 9H-1,2,4triazolo[4,3-a]benzimidazoles with decrease in pH are consistent with the ready protonation and hence basic character of these molecules. In the case of 1,3-dimethyl-1H-1,2,4-triazolo[4,3-a]benzimidazole these changes are inte~pretable'~~ in terms of exclusive protonation at N(9). The UV and 13CNMR spectra of 3-methyl- l(9)H- 1,2,4-triazolo[4,3-u]benzimidazole and its N(9)-methyl derivative in acidic media, on the other hand, indicate the presence of a mixture of the two monocations derived by competing protonation at N(1) and PI(^)."^ The product (m.p. 130-132"), obtained in moderate yield (50%) by the sodium hydride-mediated ben~ylation'~~ of 2-phenyl- 1H-1,2,4-triazolo[2,3a]benzimidazole has been arbitrarily assigned an N(1)-benzyl structure, though the N(3) or N(4) position for the benzyl group appears equally likely. In accordance with its tautomeric character, 3-methyl- l(9)H- 1,2,4triazolo[4,3-a]benzimidazole undergoes competing base-catalyzed methylat i ~ n at ' ~ the ~ N(l) and N(9) positions in good overall yield (Table 6.98). The uncatalyzed reaction267 of 2,3-dihydro-1(9)H-1,2,4-triazolo[4,3-a]benzimidazole-3-thione with methyl iodide results in methylation at both sulfur and nitrogen giving 9-methyl-3-thiomethyI-9H-1,2,4-triazolo[4,3-~]benzimidazole in high yield (Table 6.98). "C NMR spectroscopy provides a highly sensitive method for determining the site of quaternization in 1Hand 9H- 1,2,4-triazolo[4,3-a]benzimidazolederivatives.273 3-Sila-2H-imidazo[ 1,2-a]benzimidazoles are unstable to acetylation which promotes cleavage of the silicon-nitrogen bond in these molecules giving unstable silyl carboxylates convertible by hydrolysis into isolable siloxanes [e.g., Scheme 6.100; (6.475) +(6.476) +(6.477)].258Acylative ring-opening of this type serves to establish the gross structure of the 3-sila2H-imidazo[ 1,2-a]benzimidazole ring system. The 1(9)H-1,2,4-triazolo[4,3-a]benzimidazole ring system is stable to ring-opening by reagents (e.g., acetic anhydride-pyridine), which effect acetylation at the N(9) position (Table 6.98).263 2,3-Dihydro-9H-1,2,4-triazolo[4,3-a]benzimidazole-3thiones are aminoalkylated in high yield (Table 6.98) at the N(2)and N(9) positions under the conditions of the Mannich reaction.272 The nitration of 3-( 1-imidazo1yl)-1,2,4-thiadiazol0[4,5-a]benzimidazole occurs at both the benzene nucleus and the imidazole substituent giving


243

(6,477) (i) Ac,0/(50-559(1 hr) Memt

6.100

isomer mixtures of unestablished constitution.26' 3-Methyl- 1(9)H-1,2,4triazolo[4,3-~]benzimidazoleundergoes bromination and nitration sequentially at the C(6) and C(8) positions in the benzene ring in good yield (Table 6.99).2'2 The amino substituent in 6-amino-3-methyl- l(9)H- 1,2,4-triazolo[4,3-u]benzimidazole can be d i a z o t i ~ e d ~under ' ~ standard conditions (Table 6.99) to afford a diazonium salt which exhibits orthodox chemical reactivity (e.g., toward hypophosphorus acid reduction-Table 6.99).272 TABLE 6.99. BROMINATION, NITRATION, AND DIAZOTIZATION REACTIONS OF l(9)H-~,~,~-TR~AZOLO[~,~-CI]BENZIM~DAZOLE DERIVATIVES

(%)

m.p. ("C)

Solvent of crystallization Ref.

3-Me-6-Br- l(9)H-

51

288

-b

3-Me-6,8-di-Br-l(9)H3-Me-6-N02- 1 (9)H3-Me-6,8-di-N02- l(9)H3-Me-6-D- 1(9)H-

49 86 86 80

>300

Reaction l(9)H- 1,2,4-Triazolo[4,3-aJbenzimidazole conditionsa Substrate Product

Yield

~~

A

B

C D

3-Me-I(9)H3-Me- 1(9)H3-Me- 1 (9)H3-Me-6-NH2- 1(9)H-

~

1272

>350 >350 230

Methanol

-' -'

-'

212 212 212

A = Br,, NaOAc, AcOH/(Oo) then (room temp.)(S hr); B = conc. HNO,, conc. H,SO,/(-lO to -So) (0.5 hr); C- conc. HNO,, conc. H,SO,/(-10 to -5")(3 hr); D = NaNO,, DCI/(-lO")(l hr), then a

H,PO,, D,O/(room temp.)(4 hr). Purified by sublimation. Solvent of crystallization not specified.

244


Reactions with Nucleophiles The 1H-1,2,4-triazolo[2,3-a]benzimidazole270 and 1(9)H-1,2,4-triazolo[4,3-a]ben~imidazole~~~ ring systems are stable to acidic and basic conditions suitable for the hydrolytic removal of N-acyl substituents. Routine transformations of this type apart, the behavior of the various 6-5-5fused benzimidazole ring systems having two additional heteroatoms to nucleophilic attack, has not been investigated.

Oxidation and Reduction Information on the stability of 6-5-5 fused benzimidazoles with two additional heteroatoms toward oxidation and reduction is very limited. In one the 1,2,4-thiadiazolo[2,3-a~en~imidazole ring system, and specifically its component sulfur atom, have been shown to be unaffected by peracid oxidation under conditions that convert a thiomethyl substituent into the S-oxide. The conversion261of 3-(1-imidazoly1)-1,2,4-thiadiazolo[4,5-a]benzimidazole into 2-mercaptobenzimidazole on treatment with lithium aluminum hydride, on the other hand, illustrates the susceptibility of 1,2,4-thiadiazolo[4,5-a]benzimidazoles to reductive ring scission. In contrast, 3-methyl-6-nitro-l(9)H-1,2,4-triazolo[4,3-a~enzimidazole can be catalytically reduced in high yield (90%) to the amine (m.p. 172O) without disruption of the ring system?72

Derivatives of the 1,2,4-thiadiazolo[2,3-a]benzimidazole~591,2,4thiadiazol0[4,3-a]benzimidazole,~~~ 1,2,4-thiadiazolo[4,5-a]benzimidazo1e,261 and 1,2,4-triazol0[4,3-a]benzimidazole,~'~ring systems have found application as antifungal agents. 1(9)H-1,2,4-Triazolo(4,3-a]benzimidazole derivatives have been patented as antifogging agents for photographic e m u l ~ i o n s . ~ " ~ ~ ~ ~

6.4. Tricyclic 6 - 9 4 Fnsed Bendmidazoles

with Three Additional Heteroatoms

The ephemeral tetrazolo[l,5-a]benzimidazolering system [Scheme 6.101; (6.478)] is the sole representative of the class of 6-5-5fused benzimidazoles having three additional heteroatoms. To date, tetrazolo[ 1,5-a]only as the unstable ring tautobenzimidazoles have been mers in azidoazomethine-tetrazole equilibria279 involving 2-azido-

References

R (6.478)

245

R

(6.479)

\

bare

R=H

(6.480) Scbeme 6.101

benzimidazoles [e.g., Scheme 6.101; (6.478; R = COMe) (6.479; R = COMe)] or as stable anions2'" derived by deprotonation and spontaneous ring-closure of N-unsubstituted 2-azidobenzimidazoles [Scheme 6.101; (6.479; R = H) (6.478; R = H) + (6.480)].

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248. H. J. Scholl, E. Klauke, F. Grewe, and I. Hammann, Ger. Patent, 2,062,348; Chem. Absrr., 77,114391 (1972). 249. S . V. Ivanovskaya, Sb. Nauch. Rab. Volgograd. Gos. Med. Inst., 22, 139 (1969); through Chem. Abstr., 75. 47311 (1971); G. V. Kovalev, I. S. Morozov, and I. N. Tyurenkov, Farmakol. Toksikol. (Moscow), 37, 558 (1974); Chem. Abstr., 82, 361 (1975). 250. S. V. Ivanovskaya, Sb. Nauch. Rab., Volgograd. Med. Inst., 21, 175 (1%8) through Chem. Abstr., 73, 75494 (1970); Sb. Nauch. Rab. Volgograd. Gos. Med. Inst., 22, 142 (1969); through Chem. Abstr., 75.33574 (1971); Sb. Nauch. Rab., Volgograd. Gos. Med. Inst., 23, 228 (1970); through Chem. Abstr., 75, 47283 (1971); G. V. Kovalev, S. M. Gofman, S. V. Ivanovskaya, M. V. Panshina, V. I. Petrov, A. M. Sirnonov. and I. N. Tyurenkov, P h m o l . and Toxicol. (Moscow), 36, 88 (1973); Farmakol, and Toksikol. (Moscow), 36, 232 (1973); Chem. Abstr., 78, 154693 (1973); M. V. Panshina, Mater., Pouolzh. Konf. Fiziol. Uchasriern Biokhim., Farmakol. Morfol. 6th 2.49 (1973); through Chem. Abstr., 82, 80662 (1975); I. N. Tyurenkov, Muter.. P m l z h . Konf. Fiziol. Uchastiem Biokhim., Farmakol. Morfol. 6th 2, 63 (1973); through Chem. Abstr., 82, 118900 (1975). 25 1. J. D. Kendall and G. F. Duffin, Brit. Patent, 730,489; Chem. Abstr., 49, 15580b (1955); Brit. Patent, 734,792; Chem. Abstr., 50,1502h (1956); J. D. Kendall, G. F. Duffin, and H. R. J. Waddington, Brit. Patent, 743,133; Chem. Abstr., 51, 899b (1957); J. D. Kendall and G. F. Duffin, Brit. Patent, 749,189; Chem. Abstr., 51, 904g (1957); Brit. Patent, 749,190; Chem. Abstr., 51,902e (1957); Brit. Patent, 749,193; Chem. Abstr., SO, 16492f (1956); H. R. J. Waddington, G. F. Duffin, and J. D. Kendall. Brit. Patent, 785,334; Chem. Absrr., 52, 6030g (1958); G. F. D u f i , D. J. Fry, and J. D. Kendall, Brit. Pcuenr, 785,939; Chem. Abstr., 52, 10777e (1958); E. J. Poppe. VeroeflentL Wiss. Phofo-Lob. Wolfen, 10, 115 (1965); Chem. Abstr., 65. 9995b (1966). 252. Belgian Patent, 668,594; Chem. Abstr., 65,3213b (1966); E. J. Poppe, East Ger. Patent, 49,396; Chem. Abstr., 66, 50702 (1967); Ger. Patent, 1,235,738; Chem. Abstr.., 66, 110064 (1967). 253. T. V. Bobkova and I. A. Soloveva, Tr. Vses. Nawh.-Issled. Prwkt. Inst. Khim. Fotogr. Prom.,1968, 60; through Chem. Abstr., 74, 127523 (1971). 254. Brit. Patent, 927,614; Chem. Abstr., 62, 2853d (1965); R. Mersch and F. Muenz, Ger. Patent, 1,225,320; through Chem. Abstr., 66. 3810 (1967): B. Sohngen and A. Brack. Ger. Patent, 2,415,055; Chem. Abstr., 84, 32599 (1976). 255. G. Schaum and K. H.Menzel, Ger. Patent, 1,158,836; Chem. Abstr., 60,6388b (1964); H. Vetter, W. Pueschel, A. Melzer, and M. Peters, Ger. Patent, 2,505.248; through Chem. Abstr., 85, 200531 (1976). 256. K. H. Menzel and H. Ulrich, Ger. Patent, 1,127,220; Chem. Abstr., 57, 16811d (1962); M. Iwama, I. Inoue, and T. Hanzawa, Ger. Patent, 1,804.167; Chem. Abstr., 73, 16321 (1970); K. Shiba, M. Hinata, S. Kubodera, Y. Hayakawa, and S. Moriuchi, Ger. Porent, 2,323,462; Chem. Abstr., SO, 114771 (1974); M. Fujihara, Y. Takai, T. Endo, and T. Masukawa, Jap. Patent, 74 53,435; through Chem. Abstr., 81,162088 (1974); K. Shiba, M. Hinata, R. Oki, and T. Shishido, Ger. Patent. 2,414,869; Chem. Abstr., 82, 9976 (1975); A. Arai, K. Shiba, M. Yamada, N. Furutachi, and K. Nakamura, Ger. Patent, 2,528,845; Chem. Abstr., 85, 134259 (1976); A. Arai, K. Nakamura, M. Yamada, and N. Furutachi, Ger. Pafent, 2,532,225; Chem. Abstr.. 85, 134266 (1976); T. Endo, S. Sato, S. Kikuchi, K. Takabe, H. Imamura, T. Kozima, and T. Usui, Ger. Patent, 2,607,040; Chem. Abstr., 85, 200534 (1976); T. Endo, S. Sato, S. Kikuchi, K.Takabe, H. Imamura, T. Kozima, and T. Usui, Ger. Patent, 2,607,648; Chem. Absrr., 85,184815 (1976); T. Kojima, S. Sato, K. Takabe, T. Endo, H. Sugita, and H. Imamura, Jap. Patent, 76 112,341; through Chem. Abstr., fl6, 56766 (1977); K. Takabe, S. Sato, T. Kojima, T. Endo, and T. Usui, Jap. Patent. 76 112,344; through Chem. Abstr., 86, 56765 (1977); E. Boeckly, W. Himmelmann, E. Meier, W. Sauertag, I. Boie, and P. Bergthaller, Ger. Patent, 2,517,408; Chem. Abstr., 87. 76356 (1977). 257. H.Alper and M. S. Wolin, 1. Org. Chem.. 40,437 (1975).

References

255

258. H. Alper and M. S. W o k . 1. Organomefal. Chem., 99, 385 (1975). 259. C. C. Beard, Ger. Patent, 2,446,119; Chem. Abstr., 83, 28234 (1975); US. Patent, 3,976,654; Chem. Absrr., 86, 5464 (1977); US. Parenr, 4,009,164; Chem. Absrr., 86, 189943 (1977). 260. B. Stanovnik and M. Tisler, Arch. P h m . , 300, 322 (1967); Chem. Abstr., 67, 82161 (1967). 261. (a) R. D. Haugwitz, B. Toeplitz, and J. 2.Gougoutas, Chem. Cornmun., 1977, 736; (b) R. D. Haugwitz and V. L.Narayanan, US.Patenr, 3,864,353; Chem. Abstr., 82,156323 (1975). 262. A. Messmer and A. Gelleri, Angew. Chem. Int. Edn., 6, 261 (1967). 263. J. De. Mendoza and J. Elguero, Bull. Soc. Chim. France, 1974, 1675. 264. J. A. Van Allan, US.Parenr, 2,891,862; Chem. Abstr., 54, 4224a (1960). 265. G. A. Reynolds and J. A. van Allan, J. Org. Chem., 24, 1478 (1959). 266. J. D. Bower and F. P. Doyle, J. Chem. Soc.. 1957, 727. 267. N. P. Bednyagina and I. N. Getsova, J. Org. Chem. USSR, 1, 135 (1965); Zh. Organ. Khim., 1, 139 (1965); Chem. Abstr., 62, 16234d (1965). 268. G. N. Tyurenkova and N. P. Bednyagina, J. Org. Chem. USSR, 1, 132 (1965); Zh. Organ. Khim., 1, 136 (1965); Chem. Abstr., 62, 16234e (1965). 269. H. Daniel, Chem. Ber., 102, 1028 (1969). 270. R. I. Fu Ho and A. R. Day, J. Org. Chem., 38, 3084 (1973). 271. G. S. Chekrii and I. V. Smolanka, Ukr. J. Chem., 40.39 (1974); U&r. Khim. Zh., 40,262 (1974); Chem. Absrr., 80, 133355 (1974). 272. J. De Mendoza, P. Rull, and M. L. Castellanos, Afinidad, 35, 197 (1978); Chem. Absfr., 89, 129455 (1978). 273. R. Faure, E. J. Vincent, J. Elguero, J. De Mendoza. and P. Rull, Bull. Soc. Chim. France, 1978, 11, 273. 274. J. De Mendoza and M.C. Pardo, An. Quim., 71,434 (1975); Chem. Abstr., 83,205356 (1975). 275. Y. Yasuda, Y. Soeda, A. Ueda, S. Kano, and Y. Kato, Jap. Patent, 74 08,852; through Chem. Abstr., 81, 164732 (1974). 276. Y. Yasuda, Y. Soeda, A. Ueda, S. Kano, and K. Kato, Jap. Patent, 74 11,063; through Chem. Abstr., 83, 73454 (1975). 277. Belgian Patent, 559.022; through Chem. Abstr., S4, 132a (1960). 278. E.Alcalde and R. M.Claramunt, Terrahedron Len., 1975,1523; cf. also J. D. Bower and F. P. Doyle, J . Chem. Soc., 1957, 727. 279. R. N. Butler, Chem. I d . , 1973, 371.


CHAPTER 7

Condensed Benzimidazoles of Type 6416 G.TENNANT 7.1 Tricyclic 6-5-6 Fused Benzimidazoles with No Additional Heteroatom . . . . 7.1.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ring-closureReactionsof Benzimidazole Derivatives . . . . . . . Ring-closure Reactions of Other Heterocycles . . . . . . . . . . 7.1.2 Physicochemical Properties . . . . . . . . . . . . . . . . . . . . Spectroscopic Studies . . . . . . . . . . . . . . . . . . . . . Infrared Spectra . . . . . . . . . . . . . . . . . . . . . . . Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . . . Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . Mass Spectra . . . . . . . . . . . . . . . . . . . . . . . . 7.1.3 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions with Electrophiles . . . . . . . . . . . . . . . . . Protonation . . . . . . . . . . . . . . . . . . . . . . . . . Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic Substitution Reactions . . . . . . . . . . . . . . Reactions with Nucleophiles . . . . . . . . . . . . . . . . . Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . 7.1.4 Practical Applications . . . . . . . . . . . . . . . . . . . . . . Biological Properties . . . . . . . . . . . . . . . . . . . . . . Dyestuffs . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 Tricyclic 6-5-6 Fused Benzimidazoles with One Additional Heteroatom . . . 7.2.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ring-closureReactionsof BenzimidazoleDerivatives . . . . . . . Ring-closure Reactions of Other Heterocycles . . . . . . . . . . 7.2.2 Physiuxhemical Properties . . . . . . . . . . . . . . . . . . . . Spectroscopic Studies . . . . . . . . . . . . . . . . . . . . . Infrared Spectra . . . . . . . . . . . . . . . . . . . . . . . Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . . . Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . Mass Spectra . . . . . . . . . . . . . . . . . . . . . . . . General Studies . . . . . . . . . . . . . . . . . . . . . . . . Crystallography . . . . . . . . . . . . . . . . . . . . . . . Ionization Constants . . . . . . . . . . . . . . . . . . . . .

257

. . .

. . .

.

. . .

.

258 260 260 277 294 294 294 298 299 320 320 320 320 321 321 327 330 333 336 339 341 341 341 341 345 345 381 389 389 389 394 398 410 411 411 411


258

Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions with Electrophiles . . . . . . . . . . . . . . . . . . Protonation . . . . . . . . . . . . . . . . . . . . . . . . . Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic Substitution Reactions . . . . . . . . . . . . . . Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . Hydroxylation and Related Reactions . . . . . . . . . . . . . Amination . . . . . . . . . . . . . . . . . . . . . . . . . MiscellaneousReactions . . . . . . . . . . . . . . . . . . . Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.4 Practical Applications . . . . . . . . . . . . . . . . . . . . . . Biological Properties . . . . . . . . . . . . . . . . . . . . . . Dyestuffs . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3 Tricyclic 6-5-6 Fused Benzimidazoles with Two Additional Heteroatoms . . . 7.3.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ring-closureReactionsof BenzimidazoleDerivatives . . . . . . . . Ring-closure Reactions of Other Heterocycles . . . . . . . . . . . 7.3.2 PhysicochemicalProperties . . . . . . . . . . . . . . . . . . . . SpectroscopicStudies . . . . . . . . . . . . . . . . . . . . . Infrared Spectra . . . . . . . . . . . . . . . . . . . . . . . Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . . . Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . General Studies . . . . . . . . . . . . . . . . . . . . . . . . Ionization Constants . . . . . . . . . . . . . . . . . . . . . 7.3.3 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions with Electrophiles . . . . . . . . . . . . . . . . . . Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic Substitution Reactions . . . . . . . . . . . . . . Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.4 Practical Applications . . . . . . . . . . . . . . . . . . . . . . Biological Properties . . . . . . . . . . . . . . . . . . . . . . Other Applications . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.3

411 411 411 412 414 417 417 417 420 420 420 426 426 426 427 427 429 429 445 445

445

445 447

448 451 451 451 451 451 453 453 453 454 454 454 455 455

7.1 Tricyclic 6-5-6 Fused Benzimidazoles with No Additional Heteroatom Benzimidazole-derived 6-5-6 fused heterocycles with no additional heteroatoms conform to a single skeletal type (Scheme 7.1 and Table 7.1) represented by the fully unsaturated pyrido[ 1.2.a]benzimidazole ring system (7.1) and its various dihydro (7.2)-(7.7), tetrahydro (7.8)-(7.10), and hexahydro (7.11) derivatives. The chemistry of pyrido[ 1.2.a]benzimidazole derivatives was briefly reviewed by Mosby in 1961.Ia

pJ-/-?J2 3

7 \

6

4

6

Y S

4

R

(7.3)

8a-2

(7.4)

3

7 \

6

5

4

(7.5)

R

(7.7)

:Q/D; 6

R (7.9)

5

(7.10)

R (7.11)

seheme 7.1

259

4


260

TABLE 7.1. TRICYCLIC 6-5-6 FUSED BENZIMIDAZOLE RING SYSTEMS WITH NO ADDITIONAL HETEROATOMS

(7.1)

(7.2)

(7.3)

(7.4) (7.5) (7.6) (7.7) (7.8) (7.9) (7.10) (7.11) a

Pyridd1 . 2 4 lbenzimidazole 1,2-Dihydropyrido[ 1,2-afbenzimidazole 1,4-Dihydropyrido[1,2-o)benzimidazole l,S-Dihydropyrido[1,2-afbenzimidazole 3,4-Dihydropyrido[ 1,2-a)benzimidazoIe 3,5-Dihydropyrido[ 1,2-a]benzimidazole 4a,S-Dihydropyrido[ 1,2-a]benzimidazole 1,2,3,4-Tetrahydropyrido[1,2-a]benzimidazole 1,2,3,5-Tetrahydropyrido[1.2-a Jbenzimidazole 6,7,8,9-Tetrahydropyridd1,2-a]benzimidazole 1.2,3,4,4a,S-Hexahydropyrido[1,2-albenzimidazole

Cf. Scheme 7.1. Based on the Ring Index.

7.1.1. Synthesis Ring-closure Reactions of BenzimidazoZe Derivatives Pyrido[ 1,2-a]benzimidazole derivatives are formed as minor products (Table 7.2) of the uncatalyzed thermal reactions of benzimidazoles with acetylenic esters [methyl propiolate, dimethyl acetylenedicarboxylate (DMAD)].Ib Benzimidazole in particular reacts with three molecules of DMAD to give a 1,5-dihydropyrido[ 1,2-a]benzimidazole derivative [Scheme 7.2; (7.12; R = R' = H) --., (7.13; R = Me02Ck=CHC02Me)].2 In the analogous reaction of 1-methylbenzimidazole with DMAD, the 1,5dihydro product (7.13; R = Me) is accompanied by the 4a,5-dihydro isomer (7.14; R = Me, R' = C02Me, RZ= H) formed by a subsequent methoxycarbonyl ~ h i f t . ~Low . ~ yields (Table 7.2) of separable mixtures of unrearranged (7.14; R = R' = alkyl, R2 = C0,Me) and rearranged (7.14; R = R2= alkyl, R' = C0,Me) 4a,5-dihydropyrido[ 1,2-a]benzimidazoles are likewise produced in the thermal cycloaddition reactions of DMAD with simple 1,2dialkylbenzimidaz~les.'~*~~ l-Methyl-2-benzylbenzimidazole,on the other hand, reacts' with DMAD to give both the direct cycloadduct (7.14; R = Me, R' = CH2Ph, RZ= C02Me) and the 1,5-dihydropyrido[l,2-a]benzimidazole derivative [Scheme 7.3; (7.16; R' = Me, R2 = Ph, R4 = R5 = C02Me)] resulting from the involvement of the benzyl substituent. Addition involving the side chain also intervenes in the thermal reactions (Scheme 7.3) of acetylenic esters (methyl propiolate, DMAD) with benzimidazoles (7.15; R = H or Me, R 2 = C 0 2 E t or CN) having an active methylene

t4

F I

H

(7.15; R2 = CN) (7.15; R2 = CN)

(7.15; R' = Me, R2 = CN) (7.15; R' = Me, R2 = CN)

F

H

F

(7.12: R = C W H C O , M e ,

(7.15; R2 = CN)

G

(7.12; R = Me, R' = CH,Ph)

F

F

(7.12; R = Me, R' = Pr')

R' = Bu') (7.12; R = C W H C 0 2 M e , R' = Ph)

D

E

(7.12; R = Et, R' = Me)

(7.12; R = Me. R' = Et)

D

C

(7.12; R = Me)

= Me)

B

(7.12; R = M e )

R = R'

A

(7.12)

(7.12;


Starting material (R --* R5 unspecified = H)

R=

+

I

(7.16; R' =Me, R2 = CN, (7.16; R' = Me, R2 = CN, R3 = R4 = R5 = C0,Me)

R4= C0,Me)

(7.17; R2 = CN, R4 = C02Me) (7.18: R2 = CN, R3 = C0,Me)

19 11

5 32

171.5-172.5 213.5-215.5

255-256 290-292

263-266

0.16

+

(7.18; R' = CHLCHCO,Me, R2 = CN)

1

Methanol

159-160 2.6

269-271

+

Methanol

190-191

14

Methanol Dimethylformarnide Methanol Methanol

Methanol

Methanol

Methanol

200-201

Methanol Methanol

29

-

19

= Bu',

1

1 15-1 17d 133 175

Methanol

Methanol Methanol

}

Methanol Methanol Methanol

Methanol


65 13.6

-

146-147

161-162 144-146

0.6 9

-h

138-139

-

225-226 173-174

191-192

1 .5

23 3 11

8

Yield (YO) m.p. ("C)

(7.17; R' = CItlCHCO,Me, R2 = CN)

R'

R2 = C02Me) (7.14; R = CHACHCO,Me, R' = CO,Me, RZ= Ph) (7.16; R' = W C H C O , M e , R2 = CN, R4 = C02Me)

{

(7.14; R = Et, R' = C0,Me. R2 = Me) (7.14; R = Me, R' = Pr', R2 = C02Me) (7.14; R = Me, R' = CH2Ph, R2 = C0,Me) (7.16; R' = Me, R2 = Ph. R3 = R" = R5 = CO,Me) (7.14; R = C W H C O , M e ,

+

R2 = C0,Me) (7.14; R = Et, R' = Me, R2 = C0,Me)

(7.14; R = R2 = Me, R' = C0,Me) (7.14; R = Me, R' = Et,

{

{

MeO,CF=CHCO,Me) (7.13; R = Me) (7.14; R = Me. R' = C0,Me) (7.14; R = Me, R' = CO,Me) (7.14; R = R' = Me, R2 = C0,Me)

(7.13;

Product (R + R4 unspecified = H)

TABLE 7.2. SYNTHESIS OF PYRIDO[ 1,2-a]BENZIMIDAZOLE DERIVATIVES BY RING-CLOSURE REACTIONS OF BENZIMIDAZOLES WITH ACETYLENIC ESTERS AND METHYL VINYL KETONE

6 6

6 7

6

1, 4

1. 4

5

4

2. 3

2, 3

2, 3

2,3 3

2

Ref.

h) o\ h)

n

F

(7.15; R' = Me. R2 = C0,Et)

(7.15; R' =Me, R2 = C02Et)

R2= C1)

K

J

166-168 232-233 (decomp.) 2 13-2 14

16 26

[ (7.30; R'=Ph)

(7.31; R = H)' or (7.31; R = Et)' (7.30; R'=Et, R2=CI)

37

21

202 (decomp.) 119-121 18

R3= R4= Rs = C O2Me) (7.30; R' =Me)

+

13 15

292-293 146-147

172-1 74

260 (decomp., 212-213 (decomp.) 223-224

239

m.p. ("C)

(7.17; R ' =Me, R3 = C02Me) (7.16; R' =Me, R2 = C02Et.

{ 25

(7.16; R' = Me, R2 = C02Et, R4 = C02Me)

+

16

(7.18; R2 = CO,Et, R3 = C02Me)

7.8

6

30

Yield (X)

1

I

Ethanol Ethanol acetonitrile Ethanol

Acetic acid

Ethanol

Methanol Methanol

Dimethylformamide Methanol

Methanol

Dimethylformamide Methanol


11

11

11

6

6

7

6

6

7

Ref.

" A = M e 0 2 C m C 0 2 M e , benzene/(reflux)(l6 hr); B = Me02CG=CC02Me, acetonitrile/(reflux)(l4hr); C = Me02CCkCC02Me, toluene/(0")(4 hr), then (room tempJ(5 days); D = Me02CG=CC02Me, tetrahydrofuran/(room tempJ(2-4 days); E = Me02CC%CC02Me, acetonitrile/(room temp.) (4 days); F = MeO,CCkCCO,Me, acetonitrile/(reflux)( 1-5 days); G = MeO,CGKCO,Me, acetonitrile/(reflux)(5 hr); H = HC%CCO,Me/(reflux)(8-12 days); 1 = Me02CC%CC02Me. dimethylformamide/(100")(0.5-1hr); J = MeCOCH=CH2, acetonitrile/(room temp.)(2-4 weeks), then pyridinel boil 1 min, and treat with HCIO,; K = MeCOCH=CH,, acetonitrile/(room temp.)( 10 days), then 2,6-lutidine/(boil 1 min, and treat with HCIO,). * Mixture not separated. Yield not quoted. With remelting at 127-126. By-product using acetic acid in the workup. By-product using ethanol in the workup.

(7.29; R' = Ph)

(7.29; R' = Et,

J

I

(7.15; R2 = C02Et)

(7.29; R' = Me)

(7.16; R2 = C02Et, R' = R4 = R' = C02Me)

F

(7.15; R2 = C02Et)

= C02Me)

(7.17; R' = CH&CHCO,Me,

H

(7.15; R2 = C02Et)

R'

(7.18; R' = Me, R2 = CN, R' = C0,Me)

I

(7.15; R' = Me, R2 = CN)



Starting material (R + Rs unspecified = H)


/ RI

I R (7.12)

R'

C02Me (7.13)

R5

CH2C02Me

scbeme 7.2

(7.14)

\ R2 (7.18)

(7.16)

R4

(7.17)

Scheme 7.3

263

R3

264


substituent at the C(2) p o ~ i t i o n . ~Depending ,~ on the nature of the benzimidazole substrate, the acetylenic ester used as reagent, and the reaction conditions, three types of pyrido[ 1,2-a]benzirnidazole product result in low yield (Table 7.2) from such reactions. Broadly, reaction with DMAD in acetonitrile affords 1,5-dihydropyrido[ 1,2-a]benzimidazoIes of the type (7.16; R Z = C 0 2 E t or CN, R3+R'=C02Me),6 whereas the use of dimethylformamide as the solvent leads to products formulated on the basis of their 'H NMR absorption as pyrido[ 1,2-a]benzimidazol- l(5H)-ones (7.18; R2 = C 0 2 E t or CN, R3 = C02Me).7 In further contrast, reaction with methyl propiolate in acetonitrile: tends to convert 2-ethoxycarbonylmethyland 2-cyanomethylbenzimidazoles into pyrido[l,2-a]benzimidazol-3(5H)ones (7.17, though an exception is provided by 2-cyanomethyl- l-methylbenzimidazole, which under these conditions yields the 1,5-dihydropyrido[ 1,2-a]benzimidazole derivative (7.16; R' = Me, R2 = CN, R3 = R5 = H, R4 = C02Me).6 The reaction6 of 2-cyanomethylbenzimidazole with methyl propiolate in acetonitrile is also apparently exceptional in giving the 1,5dihydropyrido[ 1,2-a]benzimidazole (7.16; R' = CH=CHC02Me, R2 = CN, R3 +R5= H) and the pyrido[ 1,2-a]benzimidazol- 1 (5H)-one (7.18; R' = CH = CHC02Me, R2 = CN, R3 = H) as well as the anticipated pyrido[ 1,241benzimidazol-3(5H)-one (7.17; R' = CH=CHCO,Me, R2 = CN, R3 = R4 = H). The reaction of the benzimidazole derivatives (7.15; R ' = H or Me, R2 = C 0 2 E t or CN) with acetylenic esters to give 1,5-dihydropyrido[ 1,2a]benzimidazoles (7.16) and pyrido[1,2-a]benzimidazol-3(5H)-ones (7.17) is explicable (Scheme 7.4) in terms of the formation of a common zwitterionic intermediate (7.20), which can cyclize directly [Scheme 7.4; (7.20) + (7.22) --* (7.24) + (7.17)] or after reaction with a second molecule of acetylenic ester [Scheme 7.4; (7.20) + (7.21) + (7.23) +(7.16)] giving the observed products. Pyrido[ 1,2-a]benzirnidazol- 1(5H)-one formation, on the other hand, is the obvious outcome of initial Michael addition of the methylene center in the benzimidazole at the acetylenic triple bond, followed by cyclization of the adduct produced [Scheme 7.4; (7.15) + (7.19) + (7.18)]. The reason for preferential pyrido[ 1,2-a]benzimidazol-l(5~-one formation (and hence Michael addition) in dimethylformamide' compared with 1,5-dihydropyrido[ 1,2-a]benzimidazole or pyrido[ 1,2-a]benzimidazol3(5H)-one (and hence zwitterion) formation in acetonitrile6 is not clear but may be a consequence of the greater basicity of the former solvent compared with the latter. The reactions (Scheme 7.5) of benzimidazolium ylides of the type (7.25) with methyl propiolate or dimethyl acetylenedicarboxylate are reported to give low yields of products variously formulated as pyrido[ 1,2-a]benzimidazol- 1(SH)-ones (7.26)8*9 or benzimidazolium betaines (7.27).9 However, more recent evidence'" that the product of the reaction of the ylide (7.25; R = Et, R ' = M e ) with DMAD is in fact the pyrroloquinoxalinone (7.28) implies similar structures for the remaining products (Scheme 7.5) of such reactions. The prolonged reaction (Scheme 7.6) of 1alkyl-2-ethoxycarbonylmethylbenzimidazolium perchlorates (7.29) with

265

7.1. Fused Benzimidazoles with No Additional Heteroatom

(7.15)

\

I

k R

R

H

R

(7.19)

R

\

(7.20)

I

I

(7.18)

(7.22)

I

I

R

crJ$40

(7.21)

k R

CH,CO,Me

H

(7.24)

N R R (7.23)

I

I

R

(7.17)

(7.16) !3cheme 7.4

methyl vinyl ketone (MVK) at ambient temperature in acetonitrile affords low yields (Table 7.2) of condensates formulated on the basis of their 'H NMR absorption as 5-alkyl- 1,2-dihydropyrido[ 1,2-a]benzimidazolium perchlorates (7.30)." The orientation of these products suggests that the initial step in their formation involves either aldol-type condensation between the carbonyl group in MVK and the C(2) methylene center in the benzimidazolium salt or more probably addition of N ( 3 ) in the latter at the double

266


(7.25)

R'

Me CH,Ph Me Et

(7.27) (R= Me or CH,Ph)

R2 COzEt C0,Et C0,Me C0,Me

R'

(7.26)

H H C02Me C0,Me

(7.28) sekmc IS

bond in MVK. Competing Michael addition between the C(2) methylene center in the benzimidazolium salt and MVK is indicated by the isolation of the adducts (7.31; R = H or Et) when the reaction mixture derived from the benzimidazolium perchlorate (7.29; R' = Me, R2 = H) is subjected to aqueous or ethanolic workup." Pyrid~1,2-a]benzimidazoles variously substituted in both the benzene and pyridine rings are generally accessible in high yield (Table 7.3) by the

I

+

')}

(7.33;R4 = CN)

+

(7.33;R4 = CN) (7.32; R' = R3 = Me. 1 R2 = CH,CO,Et)

+

(7.33; R4 = CN)' (7.32;R' = R2 = R3 = Me)

+

(7.33;R4 = CN)* (7.32;R' = R3= Me)

+

A

A

lA l A

(7.33;R4= CN. R5 = C0,Me) (7.32; R' = R3 = M

+

(7.33; R4 = CN, R5 = OMe) (7.32;R' = R3= Me)

A

A

A

A


i'l A

(7.33;R4 = CN, R5 = CI) (7.32; R' = R3 = Me)

+

(7.33;R4= CN, Rs= Me) (7.32; R' = R3 = Me)

+

(7.33; R4 = CN) (7.32;R' = R3= Me)

+

(7.33;R4= CN) (7.32; R' = R3 = Me)

+

(7.32; R3 = Me)

Starting materials (R + RS unspecified = H)

65 90

(7.34;R' = R3= Me, R4 = CN, R5 = OMe) (7.34; R' = R3 = Me, R4 = CN, R5 = C02Me)

49 62

(7.34;R' = R2 = R3 = Me, RJ = CN) (7.34;R' = R3= Me, R2= CH,CO,Et, R4= CN)

57

40

(7.34;R' = R3= Me, R4 = CN, R5 = C1)

(7.34;R' = R'= Me, R4 = CN)'

39

(7.34;R1 = R3= R5 = Me, R4 = CN)

44

92

(7.34;R' = R3 = Me. R4= CN)

(7.34;R' = R3 = Me, R4 = CN)"

59

Yield (%)

(7.34;R3= Me, R4 = CN)

Product (R -+ RS unspecified = H)

206-207

285-286

304

295-297

295-305

214-215

212-218

204

235-237

218-219

m.p. ("C)

12

Dimethylformamidewater

12 12

Dimethylformamidewater Dimethylformamidewater

12

12



12

12 Dimethylformamidewater


12

12

Dime t hylformamidewater


12

Ref.



TABLE 7.3. SYNTHESIS OF PYRIDq1.2-a]BENZIMIDAZOLEDERIVATIVES BY RING-CLOSURE REACTIONS OF BENZIMIDAZOLES WITH 8-DICARBONYL COMPOUNDS AND RELATED PROCESSES

(Continued)

+

00

+

(7.37)

+I

(7.33;R4 = CN)' (7.36)

+

(7.33;R4 = CN)* (7.32;R' = Me, R3 = Ph)

+

(7.33;R = Me, R4 = CN)' (7.32;R' = Me, R' = C0,Me)

+

(7.33;R = Me, R4 = CN)" (7.32;R' = R2 = R3=

+

(7.33;R" = CN) (7.32;R' = R3 = Me)

I

(7.33;R" = CN) (7.32;R' = OEt. R3 = C0,Et)'

+

(7.33;R4 = CN) (7.32;R' = OMe. u R3 = CH,CO,Me)

0

I

~

(7.33;R4 = NO,) (7.32;R' = Me. R3 = OEt)

+

(7.33;R" = CN) (7.32;R' = R3 = Me)

+

(7.32;R2 = NO,)

~

Starting materials (R+ R5 unspecified = H)

TABLE 7.3

I

D


(7.39)

(7.35;R' = Ph, R3 = Me, R 4 = CN)

(7.35;R' = Me, R3 = Ph, R4 = CN)

1

62

57

28

86

91

(7.35;R' = R2 = R' = Me, R4 = CN) (7.35;R' = Me, R ' = CO,Me, R4 = CN)

88

(7.35;R' = R3 = Me, R' = CN)

89

85

(7.34:R' = OH, R' = C02Et, R4 = CN) (7.34;R' = OH, R3 = CH,CO,Me, R4 = CN)

89

48

(7.34;R' = R3 = Me, R4 = NO,) (7.34;R' = O H , R3 = Me, R" = CN)

75

Yield (%)

(734;R2 = NO,, R4 = CN)

Product (R-r R5 unspecified = H)

161-163

232-23gh

265-267

246

249-250

275

293

16

Nitromethaneethanol

Ethanol

18

16

16

Nitromethaneethanol

Ni tromethaneethanol

16

15

15

14

13

12

Ref. -

Nitromethaneethanol

Dimethylformamide

-c

300 (decamp.)

Acetonitrile

Dime thylfonnamidewater


248-250

-d

m.p. ("C)

m \o

N

J

J

J

(7.44: R' = Mc)

R' = CI)

R' = OMe)

(7.44:

(7.44:

R' = Me)

R' = RZ= Me) R = Me) R = R' = Me) R = Me, R' = Ph) R = R' = R2 = Me)

R' = Me)

R' = Pr') R' = R2= Me)

17.491

(7.48; R = CO,Et)

M

(7.54: R = C0,Et)

(7.47; R' = Et)

L

(7.44)

+

(7.47; R3 = Me)

K

(7.44)

R2= C0,Me)

(7.47;

J

97

73

76

61

30

54

(7.47; R' =NO,) (7.47: RZ= NO,)

92

90

225-227

134

94

163

144-148

212-214

159-161

163

120-124

148-150

89 92

88-90 77-79 77-79 77-79 100-102 109-110 171-172 157-159

78 84 73 84 34 72 32 65

RZ= OMe)

(7.47:

(7.47: R2 = CI)

(7.47:

(7.47)

(7.43: (7.43: (7.43; (7.43: (7.43; (7.43: (7.43; (7.43;

(7.44; R' = C0,Me)

J

J

(7.44)

(7.40; R' = M e ) (7.40: R' = Pr') (7.40: R'= RZ= Me) (7.42; R' = R2 = Me) (7.40: R = M e ) (7.40: R = R' = Me) (7.40; R = Me, R' = Ph) (7.40: R = R' = R2 = Me)

20 20 20

Benzene-light petroleum Benzene-ligh t petroleum Benzene-light petroleum

20

Benzene-ligh t petroleum

21

20


Benzene (decomp.)

20



20

20

Benzene-ligh t petroleum


19 19 19 19 19 19 19 19

Diisopropyl ether Diisopropyl ether Diisopropyl ether Acetone Acetone Acetone Acetone Acetone

2 0

(Continued)

+

R = CN)

+

+I

+

R = COMe)

R = H)

(7.51) (7.59) (7.62)

P

c?

(7.57)

(7.57)

(7.54;

R = CN)

(7.54; R = CONH,)

Product

(R+ RS unspecified = H)

M

0

M

N

M


79

10

50

91

Yield (YO)

165

217-219

315

273-275 (decomp.)

m.p. (OC)

Ethyl acetatelight petroleum

Acetone

Ethanol

Acetic acid-water


23

22

21

21

21

21

Ref.

A = NaOEt, EtOH/(100")(2 hr); B = 70% HCIO, aq./(reflux)(l5 min); C = piperidine, methanol/(3W0')(1 hr), then (reflux)(l4 hr); D = piperidine, ethanol, dimethylformamide/(reflux)(lO hr); E = Et,N, methanol, dimethylformamide/(reflux)( 10 hr); F = 14O-18O0/15-Y0 min; G = cthanol/(rcflux)(4 hr); H = toluene-p-sulfonic acid/(250-27O0)(20-30 min); Z = toluene-p-sulfonic acid/(260")(15 min); J = AGO, Et,N/(reflux)(l6 hr); K = (EtCO),O, Et,N/(reBux)(l6 hr); L = (Pr"CO),O, Et,N/(reflux)(l6 hr); M = AcOH/(room temp.)(3-5 days); N = AcOH/(room temp.)(l4 hr); 0 = AGO/(room temp.) (4 days); P = PCI, (reaction conditions not specified). Q = AcOH/(75')(2 hr). 9-Amino-7-chloro derivative. ' 7,8-Dichloro derivative. Melting point not quoted. Solvent of crystallization not specified. Sodium salt. Perchlorate. Isomer mixture.

(7.60)

(7.49) (7.58)

(7.49) (7.55;

(7.49) (7.55;

I

R = CONH,)

(7.49) (7.55; R = H )

(7.49) (7.48;

(7.48;

Starting materials (R+ R' unspecified = H)

TABLE 7.3

27 1

ql

7.1. Fused Benzimidazoleswith No Additional Heteroatom

COR' CHR2 I + R5{

I

COR~

(7.32)

CH2R4

R (7.33)

RS (7.34)

!kkme 7.7

(7.35)

clo;

-

base- or acid-catalyzed condensation of P -dicarbonyl compounds with Nunsubstituted benzimidazoles having an active methylene substituent at the C(2) position [Scheme 7.7; (7.32)+ (7.33; R4= CN or NO,) (7.34; R4= CN or Effective catalysts for these reactions include sodium ethoxide,'2 ~ i p e r i d i n e , ' ~ triethylamine," .'~ and perchloric acid.I3 The use of unsymmetrically substituted benzimidazoles or P-dicarbonyl compounds in condensation reactions of the type [Scheme 7.7; (732)+ (7.33)+ (7.34)] is complicated by the possibility of isomer formation as a result of the availability of several modes of ring-closure. In the few examples of such reactions only a single pyrido[ 1,2-a]benzimidazole product was isolated and its orientation assigned without unequivocal proof of structure. Obviously, more extensive studies of the scope and orientational preference of these synthetically useful reactions are warranted. N-Substituted benzimidazoles having an activated C(2) methylene substituent also condense readily with P-dicarbonyl compounds under acidic conditions, the products of these reactions being pyrido[ 1,2-a]benzimidazolium salts. For example, 2-cyanomethyl-1-methylbenzimidazolium perchlorate reacts smoothly on heating with a variety of 6-dicarbonyl compounds giving high yields (Table 7.3) of the corresponding 4-cyano-S-methylpyrido[ 1,2-a]benzimidazolium perchlorates [Scheme 7.7; (732)+ (7.33; R = Me, R4= CN, R5= H)+ (7.35; R4= CN)].I6 The orientation of the pyrido[ 1,2-a]benzimidazoIium salts obtained when unsymmetrically substituted p-dicarbonyl compounds are employed as substrates indicate that the structure of the final product in these reactions is dictated by preferential initial condensation between the C(2) methylene substituent in the benzimidazole and the more electrophilic carbonyl center in the 0-dicarbonyl compound. A general synthesis of pyrido[ 1,2-a]benzimidazoIe derivatives involving the condensation of C(2)

272


aNH2 ,,A NH2

+ I- SMe

+

(7.36)

(7.37)

[afipj-=Aph 7

Ph

(7.39)

(7.38)

srhem~7s

unsubstituted benzimidazoles with ethoxymethylenemalononitrile and related reagents has recently been described.” 1,3-DiphenyIpyrido[1,241benzimidazole is the end-product of the reaction (Scheme 7.8) of orrhophenylenediamine with the thiapyrilium salt (7.37).18This transformation proceeds in good yield (Table 7.3) and may be rationalized in terms of the intermediate formation and cyclization of the benzimidazole derivative

(7.38).

Cyclic p-enaminoketones derived from orrho-phenylenediamine cyclize in the presence of a catalytic amount of toluene-p-sulfonic acid to provide a moderately efficient (Table 7.3) general route to otherwise rarely encountered 3,4-dihydropyrido[ 1,2-a]benzimidazole derivatives [Scheme 7.9; (7.40)+ + +(7.43)1.19Omission of the acid catalyst in the cyclization of

(7.40)

(7.42)

/ weme 7.9

(7.41)

(7.43)


273

the compound (7.40; R = H, R'= R2 = Me) results in the formation of the 2(6-oxoalky1)benzimidazole(7.42; R = H, R' = R2 = Me), which is smoothly cyclized by treatment with toluene-p-sulfonic acid to give the 3,4-dihydropyrido[ 1,2-a]benzimidazole (7.43; R = H, R' = R2 = Me). These observations prompt" a mechanism (Scheme 7.9) for 3,4-dihydropyrido[ 1,2-a]benzimidazole formation involving initial ring-closure to and subsequent ring-opening of a spiro-benzimidazole intermediate (7.41) followed by cyclization of the 2-(6-oxoalkyl)benzimidazole (7.42) produced. Pyrido[ 1,2-a]benzimidazol- l(4H)-ones are generally available, mostly in high yield (Table 7.3), by the acylative ring-closure of readily accessible 2-(@-0xopenty1)benzimidazole derivatives with acid anhydrides in the presence of triethylamine or sodium acetate as catalyst [Scheme 7.10; (7.44)4 (7.47)].'" Ring-formation in these reactions may be envisaged as occurring either by cyclization of a mixed anhydride intermediate (7.45) or by aldol condensation in an N-acyl derivative (7.46). In either case the use of substrates (7.44) unsymmetrically substituted in the benzene ring can lead to two possible products, depending on which of the benzimidazole nitrogen atoms is involved in the final ring-closure of (7.45) or the initial N-acylation to give (7.46). In practice" ring-formation occurs almost exclusively through

(7.44) 1(R~CH2C0,*0

1

r

R' CHMe,

CHMe, (7.45)

I (7.47) !3&esne 7.10

(7.46)

274


condensation at the benzimidazole nitrogen atom para to the benzene substituent irrespective of whether this is electron-donating or moderately electron-withdrawing. The latter result is surprising, implying as it does that acylative attack occurs preferentially at the apparently less basic of the two available nitrogen centers. Only in the case of the powerfully electronwithdrawing nitro substituent does competing ring-closure at the nitrogen atom metu to the substituent predominate, and even here condensation

(7.54) !3cbeme 7.11


275

through the para nitrogen atom still occurs to a marked extent.*” The reaction of benzimidazoles containing an active methylene center at the C(2) position with diketene in acetic acid solution provides a convenient method for the synthesis in moderate to high yield (Table 7.3) of pyrido[l,2a]benzirnidazol-l(5H)-ones [Scheme 7.1 1; (7.48; R = CO,Et, CONHI, or CN)+ (7.49) + + (7.54; R = CO,Et, CONH,, or CN)].‘’ Pyrido[1,2-a]benzimidazole synthesis by this means bears an obvious relationship to that through C(2)-methylene-~ubstitutedbenzimidazoles and P-dicarbonyl compounds (see before) and is suggested” to occur via aldol-type ring-closure in an initially formed betaine intermediate [Scheme 7.1 1; (7.48) + (7.49) ---* (7.50) + (7.51) + ---* (7.54)]. A similar benzimidazole betaine intermediate is postulated” to account for the annelation of C(a)-unsubstituted benzimidazoles by diketene in acetic acid or acetic anhydride which provides synthetic access, albeit in only low yield (Table 7.3), to 4a,5-dihydropyrido[ 1,2-a]benzimidazol-l,3(2H,4H)-diones [Scheme 7.12; (7.55) + (7.49) + (7.56) -+ (7.57)].

-

R

(7.55)

(7.49)

0

0

COMe (7.57)

COMe (7.56) Scheme 7.12

1,2,3,4-Tetrahydropyrido[1,2-~]benzimidazolesare simply and often efficiently obtained by acylative or alkylative ring-closure in benzimidazoles suitably functionalized at the C(2) position. Acylative processes of this type are illustrated (Scheme 7.13) by the phosphorus pentachloride-mediated cyclization of the 2-benzimidazolylbutyric acid derivative (7.58) to give the 3,4-dihydropyrido[ 1,2-a]benzimidazol-l(2H)-onederivative (7.59) in good yield (Table 7.3).” The transformation (Scheme 7.14)23of the diamide (7.60)

276


(7.58)

(7.59)

FZ

sebane 7.w

in good yield (Table 7.3) into the 3,4-dihydropyrido[1,2-a]benzimidazoll(2H)-one (7.62) simply on warming in acetic acid is explicable in terms of the intermediate formation and cyclization of the 2-benzimidazolylbutyramide (7.61) and demonstrates the facility of such acylative ringclosure. Alkylative ring-closure (Scheme 7.15) in 4-(2-benzimidazolyl)-1butanol (7.65) provides a simple rationale for the reaction of ortho-phenylenediamine (7.63) with 6-valeronitrile (7.64) to give 1,2,3,4-tetrahydropyrido[ 1,2-a]benzimidazole (7.67).24 Despite the low yield obtained (Scheme 7.15), this transformation represents probably the most convenient method for the synthesis of the tetrahydropyrido[ 1,2-a]benzimidazole

aJJ H9

I c,*HZ

0

I

H

O

(7.61)

I

NHCOzCHzPh (7.62) sckac 7.14


(7.63)

(7.64)

277

(7.65)

1

(7.67)

(7.66)

ax

(m.p. 101-102")

CHzCHzCl

hPA &(17%) f !+,--)Q

CHzCl (7.68)

(7.69)

CN

(m.p. 215-217")

(i) 230"/16 h (ii) KOH, EtOH/(room temp.)(20 min) (iii) PhCH,CN, NaNH,, tolutne/(room temp.) 30 min., then (reflux)(6 hr) Scheme 7.15

(7.67), which is also accessible in high yield (87%) by the potassium hydroxide catalyzed cyclization (Scheme 7.15) of 2-(4-bromobutyl)benzimidazole (7.66)." The latter synthetic approach, unlike that based on 142substituted ary1)piperidine cyclizations (see later), is applicable to the unequivocal synthesis of 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazoles substituted in the piperidine ring. The sodamide-induced dehalogenative ringclosure (Scheme 7.15) of 1-(2-chloroethyl)-2-chloromethylbenzimidazole (7.68), though inefficient, is of interest in affording a 1,2,3,4-tetrahydropyrido[ 1,2-u]benzimidazole (7.69) useful as the precursor of a compound related to the drug DemeroL2'

Ring-closure Reactions of Other Heterocycles Fully unsaturated pyrido[ 1,2-a]benzimidazoles nitrated in the benzene ring (7.74; R' and/or R2=NOz) are obtained in moderate to high yield (Table 7.4) by the thermal cyclization (Scheme 7.16) of 2-(2-nitroary1amino)pyridines (7.72; R' and/or R2= NO,) which can be preformed or prepared in sifu by the condensation of 2-nitrochlorobenzene derivatives (7.70; R' and/or RZ= NO2)with 2-aminopyridines (7.71).27-29 Cyclization of

00

2

(7.86) + (7.87; (7.91)

(7.86) + (7.87; (7.86) + (7.87;

R' = R2 = Br)

R' = Br) R1= RZ= Br)

(7.88) (7.86) + (7.87; R2 = Me) (7.86) + (7.87; R2= Me) (7.86) + (7.87; R' = NO,) (7.86) + (7.87; R' = Br)

(7.81) (766) + (7.87)

R4 = NO,) R3 = NO,) R' = Me, R2 = NO,) R2= NO,, R3 = Me) R2 = C0,Et) R' = R3= Me, R2 = C0,Et)

R4 = Me) R2 = NO,) R2 = NO,)

R2 = NO,) R' = R2 = NO,) R' = R2 = NO,, R3 = Me)

+

P S

P R

P 0 R

(7.90; R' = R2 = Br) (7.92)'

(7.90; R' = Br) (7.90; R' = R2 = Br)'

(7.90) (7.90; R2 = (7.90; R2= Me) (7.90; R' = NO,)' (7.90; R' = Br)'

0

N

(7.83)' (7.90)'

R2 = CO,Et)d

(7.74; R2 = NO,) (7.74; R' = R2 = NO2 ) (7.74; R' = R2 = NO,, R' = Me) (7.80) (7.80) (7.80; R 4 = Me) (7.80; R2 = NO,) (7.80; R 2 = N 0 2 ) (7.85) (7.80; R4 = NO,) (7.80; R3 = NO,) (7.80; R' =Me,R2 = NO,) (780; R2 = NO,, R3 = Me (7.80; R2= CO,Et)d (7.80; R' = R3 = Me,

(7.74; R2 = NO,)

(7.74; R' = NO,

Product

(R-., R4 unspecified = H)

M N

L L L L L

K

J

r

G G H

D E F

C

B

A

(7.72; R' = NO,) (7.70; R2 = NO,)

(7.71) (7.72; (7.72; (7.72; (7.75) (7.75) (7.75; (7.75; (7.75; (7.84) (7.75; (7.75; (7.75; (7.75; (7.75; (7.75;

React ion conditions"

Starting materials (R + R4 unspecified = H)

Ethanol or heptane Ethanol

-

-

30 74

17

37

80 48 46 30 73

181-182

-

159-160

-

219-220 148-149

-

235-237

>300 95-96

223-225 228-230 215-2 17 240-242 233-235 271-271.5

-

c

-

-

Ethanol Light petroleum (b.p. 100-120") Light petroleum (b.p. 100-120")

c

-

-

Ethanol Ether-light petroleum

Methanol Ethanol Acetone Acetone

-

Ethanol/water

-

-

118-120 237-239

-

82 65

c1

(1

5-10 70 90 12 10 50 56 8 20 28

-b

Nitrobenzene Nitrobenzene Ethanol

-

Ethylene glycol monoethylether

Nitrobenzene


>300 256-260 179

-

212

12 32 83

262-263

m.p. ("CJ

76

Yield (7'0)

37 38

37 37

37 37 37 32,37 37

36 37

21 30 30 30 32 31, 34 32 33, 35 35 31 31 33 33, 34, 35

21

29

29

28

Ref.

TABLE 7.4. SYNTHESIS OF PYRIDO[ 1,2-o]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF PYRIDINE DERIVATIVES

4

\o

N

'

'

+

R' = Me)

R2= Et)

(7.101; R' = R3= Me)

(7.101;

(7.101; R3 = Me)

+

62

58

45

10

(7.101;

R' =Me)

61

-b 69

I -b

70

(7.101; R2 = Me)

(7.95; R2= Me) (7.101)

(7.95;

(795)m

124-125

127-128

106-107

186-187

167-168

222" 152- 153

260 (decornp.) 273"

I

Methanol Light petroleum (b.p. 40-60") tight petroleum (b.p. 40-60') tight petroleum (b.p. 40-6V) Light petroleum (b.p. 40-60") tight petroleum (b.p. 40-60") Light petroleum (b.p. 40-60")

Methanol

41

41

41

41

40

39

39

A = naphthalene or dipheny1/300-310" (reaction time not specified); B = CaCO,, ethylene glycol monoethyl ether/(reflux)(l6 hr); C = ethylene glycol monoethyl ether/(reflux)( 16 hr); D = N,N-dimethylaniline/(reflux)(2-5 hr); E = phenol, xylene/heat (reaction conditions not specified); F = polyphosphoric acid/(150°)(reaction time not specified); G = hv, Pyrex filter, EtOH/24 hr; H = 98% orthophosphoric acid/(16O0)(30 rnin); I = pyrophosphoric acidheat (reaction conditions not specified); J = 0.67 M HCI, EtOH/(reflux)(l8 hr); K = pyrophosphoric acid/(110-160°)(15 min); L = pyrophosphoric acidl(l40180")( 15 rnin); M = NaNO,, H,SO, aq./(5-2Oo)(16 hr, then reflux 45 min); N = no solvent/(reflux)( 15 min); 0 = hydrogen bromide-acetic acid/(room temp.)(l hr); P = Na2C03, EtOH/(reflux)(3-18 hr); Q = no solvent/(120-130")(2 hr); R = EtOH/(reflux)(26 hr); S = P20, (reaction conditions not specified); T - AcOH, H,O/(reflux)(S min); U = LiCiO.,, acetonitrile/(0.55 v)(4 hr). Yield not quoted. Solvent of crystallization not specified. Methiodide. ' Forms a picrate, m.p. 196198" (decomp.). 'Forms a hydrate (in air) m.p. 56-58", and a picrate. m.p. 256-258" (from ethanol-acetic acid). Hydrochloride; free base has m.p. 85-87". Forms a dihydrate, m.p. 60-61" (from water) and a picrate, m.p. 155-158 (from ethanol). ' Forms a picrate, m.p. 216-219" (decornp.) (from ethanol-acetic acid). Forms a hydrochloride, m.p. 260-262", and a picrate, m.p. 264-265" (decomp.) (from acetic acid). Forms a picrate, m.p. 167-169" (from ethanol-acetic acid). Forms a methiodide, m.p. 246-247". Forms a hydrochloride, m.p. 243" (decomp.). " Purified by sublimation. " These m.p. assignments may be reversed.

U

U

R2= Et)

(7.96) + (7.98;

+ (7.98; R' = R3= Me)

U

R' = Me)

(7.96) + (7.98;

(7.96)

U

(7.96) + (7.98; R2 = Me)

T

U

R = Me) + (7.94)

T

(7.97) + (7.98)

(7.93

(7.93) + (7.94)


280

(7.70) R'

/

(7.71)

H

R'

(7.72)

(7.73)

k2

(7.74)

SCLCW 7.16

the isolated 2-(2-nitroarylamino)pyridine(7.72)is achieved by heating in the in a high-boiling medium such as nitrobenzene or N,N-dimethylaniline,*' naphthalene or diphenyl,28 or ethylene glycol monoethyl ether,29 in sirw formation of the nitropyridoor with phenol in ~ y l e n eConversely, .~~ [1,2-a]benzimidazole (7.74;R' and/or R2= NO2) is accomplished by heating the nitrochlorobenzene and aminopyridine components in ethylene glycol monoethyl ether in the presence of calcium carbonate.29 Ring-closure of the 2-(2-nitroarylamino)pyridine is logically explained in terms of the intramolecular nucleophilic displacement of the ortho-nitro substituent by the NH center in an iminopyridine tautomeric form [Scheme 7.16; (7.72)e (7.73)-+ (7.74)].Pyrido[ 1,2-a]benzimidazole derivatives are also formed in low yield (Table 7.4) when 1-(2-pyridyi)benzo-l,2,3-triazolesare heated in polyphosphoric acid under the conditions of the Graebe-Ullmann as ionic processes reaction.*3s These transformations may be involving ring-opening to diazonium intermediates convertible by intramolecular displacement of the diazonium substituent into the observed products [Scheme 7.17; (7.75)-+(7.76)* (7.78)+(7.80)]. By way of contrast, the photolytic conversion of 1-(2-pyridy1)benzo-1,2,3-triazoles into pyrido[ 1,2a]benzimidazoles proceeds in high yield (Table 7.4) and is formulatedm as a radical-mediated process [Scheme 7.17; (7.75)-+(7.77)f* (7.79)+(7.80)l. The formation and cyclization of a diazonium cation intermediate accounts for the diazotative conversion (Scheme 7.18) of the 2-arylaminopyridine


281

(7.75)

(7.77)

(7.76)

+

1

H R'

R' (7.80) Scheme 7.17

derivative (7.81)in high yield (Table 7.4)into the pyrido[ 1.2-albenzimidazolium salt (7.83).36The direct cyclization (Scheme 7.19) of the 2-arylaminopyridine derivative (7.84) to the pyrido[ 1,2-a]benzimidazole (7.85) under acidic on the other hand, is unusual in that the displacement of an amino substituent from a deactivated benzene nucleus appears to be involved. Pyrido[ 1,2-a]benzimidazoles are also the end-products of amine-carbonyl condensations in a variety of pyridine derivatives. 6,7,8,9-Tetrahydropyrido[1,2-a]benzimidazoles in particular, are generally accessible in moderate yield (Table 7.4) by the reaction of 2-aminopyridine derivatives with 2chlorocyclohexanone in boiling ethanol, alone, or in the presence of sodium

282

Condensed Bendmidazoles of Type 6-5-6

N I Me (7.81)

I

Me (7.82)

a-

(7.83)

srheme 7.18

A

(7.85)

(7.84) Scheme 7.19

carbonate [Scheme 7.20; (7.86)+(7.87) .--* -+ (7.90)].”*” The intermediacy of tautomeric 2-pyridylaminocyclohexanone derivatives [(7.88)S (7.89)] in these reactions is indicated by the successful acid-catalyzed cyclization of the compound (7.88; R’= R2= H) to the parent 6,7,8,9-tetrahydropyrido[1,2albenzimidazole (7.90; R’ = R2 = H)in high yield (Table 7.4).37 Pyrido[ 1,2a]benzimidazole itself is efficiently formed (Table 7.4) by the cyclodehydration of 1-(2-aminophenyl)pyridin-2(1H)-one using phosphorus pentoxide [Scheme 7.21; (7.91)- (7.92)].38 2-Aminopyridine is reported” to condense with 1,4-benzoquinones in hot aqueous acetic acid to give good yields (Table 7.4) of 8-hydroxypyrido[1,2-a]benzimidazoles [Scheme 7.22; (7.93) + (7.94) -+ (7.95)]. The position of the hydroxyl group in these products, if correct, is indicative of preferential initial condensation between the amino substituent of 2-aminopyridine with one of the carbonyl groups of the quinone. Alkyl-substituted pyrido[l,2-a]benzimidazole derivatives are formed in good yield (Table 7.4) when 2,4,6-tri-tert.-butylanilineiselectrolytically oxidized in the presence of pyridine and its C(3) and C(4) alkyl deri~atives.4~’~’ These reactions are suggested4l to involve the in siru formation of 2,4,6-tri-tert.-butylphenylnitrenium ion [Scheme 7.23; (7.96) -+ (7.97)] and its nucleophilic substitution by the alkylpyridine to afford a

7.1. Fused Benzimidazoles with No Additional Heteroatorn

(7.86)

J

(7.87)

H

J

(7.91)

(7.93)

283

Sckme 7.21

(7.94)

(7.89)

(7.92)

(7.95) sebaw 7.22

cationic intermediate (7.99) convertible by cyclization into an unstable dihydro product (7.100) and thence by further oxidation into the observed alkylpyrido[ 1,2-a]benzimidazole (7.101). Consistent with this mechanism is the finding4' that pyridol 1,2-a]benzimidazole formation fails for pyridines having a single C(2) alkyl group, thus demonstrating steric inhibition of electrophilic attack by the nitrenium cation on the piperidine derivative.

284


(7.99)

/

(7.100)

(7.101)

General synthetic access to 1,2,3,4-tetrahydropyrido[l,2-u]benzimidazoles is provided by the cyclization of variously ortho-substituted l-arylpiperidine derivatives (Scheme 7.24) using a range of reagents and reaction conditions (Table 7.5).42 Analogous ring-closure reactions of orrhosubstituted 1-arylpyrrolidines to 2,3-dihydro-1H-pyrrolo[ 1,2-u]benzimidazoles are discussed in detail in Chapter 6 (cf. section 6.1.1, “Ring-closure Reactions of Other Heterocycles”). Perhaps the simplest mode of cyclization of an ortho-substituted 1-arylpiperidine to a 1,2,3,4-tetrahydropyrido[1,2a Ibenzimidazole derivative is represented by the acid-catalyzed conversion43 of the piperidinone derivative (7.102; R’ 3 R’ = H) in unspecified yield (Table 7.5) into 1,2,3,4-tetrahydropyrido[1,2-~]benzimidazole(7.105; R’ -+ R3= H).However, a more convenient general procedure giving good yields (Table 7.5) of 1,2,3,4-tetrahydropyrido[1,2-u]benzimidazoles involves the oxidative cyclization of 1-(2-arninophenyl)piperidines or their N-acyl derivatives [Scheme 7.24; (7.103; R = H, alkyl, or acyl) --f (7.105)].42*44-49 The reportedly successful use of persulfuric acid4’ to effect such oxidative .~~~ oxidative ring-closure is cyclizations could not be s u b ~ t a n t i a t e dHowever, readily accomplished using pertrifluoroacetic acid?’ or performic in each case generated in sitw by the reaction of trifluoroacetic acid or

285

7.1. Fused Benzimidazoles with No Additionid Heteroatom

NHCOPh

(7.102)

NHR

/

\

J

(7*103)

(7.104)

yy (7.106)

R3 R2 R

b NO*D \

(7.107)

-R1ny-) R2

I

0(7.108)

scheme 7.24

‘

N’

(7.109)

OR

formic acid with hydrogen peroxide. The oxidative cyclization of 1-(2aminopheny1)piperidines by peracids may be viewed4’ as involving the initial formation of nitroso intermediates convertible by subsequent cyclodehydration into the observed 1,2,3,4-tetrahydropyrido[1,241benzimidazoles. Tentative support for this mechanism is provided by the reaction (Scheme 7.25) of nitrobenzene (7.110) with N-lithiopiperidide (7.111) to give 1,2,3,4-tetrahydropyrido[l,2-u]benzimidazole (7.114) via the plausible intermediacy of 1-(2-nitrosophenyl)piperidine (7.112).” As in the case of ortho-aminated 1-arylpyrrolidines (cf. Chapter 6, section 6.1.1, “Ring-closure Reactions of Other Heterocycles”), the oxidative transformation of ortho-aminated 1-arylpiperidines by peracids into 1,2,3,4-tetra~ ~terms ’ ~ ~ of hydropyrido[1,2-u]benzimidazoles may also be r a t i o n a l i ~ e d in the initial formation and subsequent Polonovski rearrangement of a piperidine N-oxide intermediate. Support for the involvement of the latter has been adduced from the successful reductive cyclization of 1-(2-nitropheny1)piperidine 1-N-oxide (7.113) to 1,2,3,4-tetrahydropyrido[1,241benzimidazole (7.114)in good yield (Table 7.5).’l However, this result is rendered irrelevant by the probable reductive removal of the N-oxide

%

h)

A

(7. 102) (7. 103) (7. 103; R = COPh) (7. 103) (7s 103; R = COPh) (7. 110)+ (7.111) (7. 113) (7. 113) (7. 103) (7. 103; R = COPh) (7. 103;R=CHO) (7. 103; R = COMe) (7, 103; R = CONH,) (7. 107) (7. 107) (7. 104) (7. L23) (7. 103; RZ= Me) (7. 107; R2 = Me) (7. 107; R2 = Me) (7. LW; R2 = CF,) (7. L07; R2= Me) (7. 107; Rz = Me) (7. L07; R2 = CF,) (7. 107; R2 = CFJ (7. 104; R2 = CF,) (7. ,04; R2=CF3) (7. 103; R2= Cl)

B

J

H M N

L

H H

L

H

€3

K

J

I

H

G G G G G

E F

D

B B C C

Reaction conditions”

Starting materials (R + R3 unspecified = H) (7.105) (7.105) (7.105) (7.105) (7.105) (7.114) (7.114) (7.114) (7.105) (7.105) (7.105) (7.105) (7.105) (7.105) (7.105) (7.1OS)e (7.125) (7.105; R2 = Me) (7.105; R2= Me) (7.105; R2= Me) (7.185; ~2 = CF,) (7.105; R2= Me) (7.105; R2= Me) (7.185; R2= CF,) (7.105; R2= CF,) (7.105; R2= CF,) (7.105; R2= CF,) (7.105; R2= Cl)


Cyclohexane

100-101

101

66

-b -b

Cyclohexane

99-100

58 35 85-95 85-95 16 82 34 quant. quant. 89 33 76 62 83 77 92 60 55 quant. 65 55 quant. 65 65

Cyclohexane

126 126 126 140 126 126 140 134-135 140-141 152

-

Cyclohexane

d

-

-d -d -d

d

-

-d -d -d

Ethyl acetate

-c

-d

-d -d

-

101-102

-c

100

-

-

-d -d

Cyclohexane

-c

-b -c -c

-d

m.p. (“C)

Yield (%)


43 45 45 46 46 50 51 51 52 52 53 53 53 54 55 29 60 45 54 44b 54 54 44b 54 58 58 60 45

Ref.

TABLE 7.5. SYNTHESIS OF 1.2,3.4-TETRAHYDROPYRIDO[1.2-a]BENZIMIDAZOLES AND 1.2.3.4.4a. 5-HEXAHYDROPYRIml.2- a]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF N-(2-SUWITUTED PHENYL)PIPERIDLNEDERIVATIVES

!$

(7.105; R' = N (7.105; R2 = CN) (7.105; R2 = CN) (7.105; R2 = CN) (7.105; R2 = C02H) (7.105; RZ= C0,Et) (7.105; R2= C0,H)

S

M N

(7.104; R' = N

(7.107; R2=CN) (7.104; R2 = CN) (7.104; R2 = CN) (7.107; R2 = C0,H) (7.107; R2 = C0,H) (7.104; R2 = COiH)

, R2 = N02)

N J

3

J

(7, 104; R'=CI) (7. 107; R' = Cl) (7. 107; R2 = Br) (7. !04; R2 = F) (7. 104; R' = R2 = Cl) (7. .27) (7. 34; R = F) (7. ,03; R2 = NO,) (7. .03; R = COMe, R2 = NO,) (7. 103;R2= NO,) (7. L07; R2= NO,) (7. .07; R2 = NO,) (7. 107; R2 = NO,) (7. 104; R2 = NO,) ; = COMe, R' = NO,) (7. ~ 0 3R (7. 104; R' =NO,) (7. 104)8

0

N

H M

J

I C

R

P Q B C Q H L

J J J

a , R2 = N02)

(7.105; R' = Cl) (7.105; R' = CI) (7.105; R2 = Br) (7.105; R2 = F) (7.105; R' = R2 = C1) (7.125; R = a) (7.125; R = F) (7.105; R2 = NO,) (7.105; R2= NO,) (7.105; R2 = N o d (7.105; R2 = NO,) (7.105; R2 = NO,) (7.105; R2 = NO,) (7.105; R2 = NO,) (7.105; R' =NO,) (7.105; R' = NO,) (7.105)K.h

(7.105; RZ= CI) (7.105; R2 = Cl). (7.105; R2= C1) (7.105; R' = CI)

H

(7.107; RZ= Cl) (7.104; R2 = Cl) (7.104; R2 = Cl) (7.103; R' = Cl)

J J C

(7.105; R2 = Cl)

C

(7.103; R2 = Cl)

b

-b -b

88

b

65

-b -

24

-b -b

80 80-90

-b

60 5 95 80-90 50 82 55

b

b

-

-

-b -b

-b

-b

70 82

b

-

176 298 125 298

175

-

137- 140

107-108

-c

146 146 163 110 184 188 164 219-220 219 219-220 209 220-222 219-220 218.5-219.5 218

152 153-154 153 148

150

Diglyme

-d

-d

-d -d -d

Methyl ethyl ketone

Light petroleum b.p. 80-100"

-d -d

Benzene or ethanol Chlorobenzene

-d . -d

Benzene or ethanol

-d

Methyl ethyl ketone

-d -d -d -d

-d -d

Light petroleum (b.p. 100-120")

-d

Ethylene dichloride

-d

Light petroleum (b.p. 100-120")

58 58 60 54 58 58

29

54 44b 43 29 47 58 29

44a

60 60 67 64 45 47

60

49 60 57

49 54 29 60

V V V W

W W W

X

(7.118;Ar = 2-CIC6H,) (7.118; k = 4-aC6Hd (7.118; Ar = 2-C1-5-OZNC&)

(7.117)

U U

s

T

T

86 90 80

(7.122;Ar = 2-CIC,&)" (7.122; Ar = 4-CICeHJ (7.122;Ar = 2-C1-5-O2NC6H4)

-b

61 27 20 84

(7.108)' (7.108;R2 = Cl) (7.108;R2= NO,)' (7.122; Ar = Ph)

(7.121)

50 73 85

10

60 14

84

b

-

40

60

-b

Yield (YO)

(7.195;R3 = Me) (7.189;R = H) (7.189; R = COMe)

3,'

(7.132; R = N

(7.1@5;R' = NHCOMe) (7.132; R = Me)

H

J C

(7.105;R2 = NHCOMe) (7.105;R2 = NHCOMe) (7.105;R' = NHCOMe)

(7.105;R2 = NHCOMe)

H

C

(7.105; R2 = SO,N

J

3)

Product (R+ R4 unspecified = H)


(7.107) (7.107; RZ= Cl) (7.107; RZ= NO,) (7.118; Ar = Ph)

(7.104; R3 = Me) (7.107) (7.107;RZ= NO,)

(7.131; R = N

3)

(7.103; R = COMe, R2 = NHCOMe) (7.107; RZ= NHCOMe) (7.104;R2= NHCOMe) (7.103; R = COMe, R1 = NHCOMe) (7.107;R' = NHCOMe) (7.131; R = Me)

Starting materials (R-r R3 unspecified = H)


202-204 131 228 288 (decomp.) 244-246 252 243 (decomp.) > 300 (decomp.)

98 170 160

231-232

238 263-264

222 218-220 238

222

229

m.p. (T)

Acetic acid-water

-I

Ethyl acetate Ethyl acetate -light petroleum b.p. 60-80" Ethyl acetate Ethyl acetate Ethyl acetate

-d

Chloroform-light petroleum

Methanol

d

-

-d

Chlorobenzene

d

-d -d


61

63 63 63

63

55 55 55

59 56 56

66

54 66

54 29 48

48

60

Ref.

(7.106; R2= NO,) (7.106; R2= NO,) (7.116)

75 50-60 69

quant.

quant.

38

34

137-138

-

-

129

304-306 (decomp.) 119

(decamp.)

360

-

Ethanol - water

-

Ethyl acetate light petroleum Ethyl acetate - light petroleum -

d

-

Water

52

58 58

58

58

65

62

J

'

A = 2M H,SO&eflux)(2 hr); B = 30% H202. CF,CO,H, CH,Cl2/(reflux)(l5-3O rnin); C = 30% H,O,, 98% HCO2H/(l00")(1Ck15rnin); D = ether/(-50")(70 rnin); E = Sn, HCO,H/(reflux)(3 hr); F = Zn, NH4CI, H,O/(mom tempJ(6 hr); G = HgO. EDTA, EtOH-H,O (1 :l)/(room temp.)(S30 rnin); H = sand/(220-24W)(0.5-4 hr); I = hu, HCI aq., MeOH/(room temp.)(66 hr); J = PhN0,/165-175" (reaction time not specified);K = conc. HCI, w EtOH/(reflux)(4hr); L =TiCI,. conc. HCI/(W)(l hr); M = (EtO),P/(reflux)(8-10 hr); N = diethylene glycol dimethyl ether/(reflux)(lOmin); 0 = electrolysis in aqueous ethanol; P = SO,Cl,/room temp. (reaction time not specified); 0 = H,O,, conc. H,S04/(room ternpJ(20 hr); R = SnCI,, conc. HCI/(room temp.)(24 hr); S = PhN0,/(170-18O0)(0.5 hr); T = hv, CHCI,; U =Ac,O, ZnCl,/(reflux)(4 hr); V = conc. HCV(110-160°)(7-72 hr); W = conc. H a , EtOH/(room temp.)(l4 hr); X = alloxan, conc. HCI, EtOH/(room temp.)(14-72 hr); Y = SO,, H,0/(70")(0.5 hr), or conc. H a , EtOWwarm; 2 = hu. benzene/(room tempJ(l8 hr). Yield not specified. Melting point not quoted. Solvent of crystallization not specified. ' Forms a picrate. m.p. 229-230" (from ethylene glycol rnonoethyl ether). 'Forms a hydrochloride, m.p. 295-296 (from water). 8 6-Nitro derivative. Forms a hydrochloride, m.p. 258-260". Benzenesulfonate salt; free base has m.p. 191". Hydrochloride hydrate. Hydrochloride. ' Precipitation from ethanol by acetone. Hemihydrate. " Hydrate.

N

2

(7.104; R2= NO,)

M G

(7.106)

N

(7.104)

(7.1@4;R2= NO,) (7.107; R2= NO,) (7.115)

(7.130)

Y

(7.129)

(7.106; R2= NO,)

(7.Ul)"

X

(7.117)

290


U (7.110)

(7.111)

(7.112)

(7.113)

(7.114)

I

Men NHCOPh

a

(7.115)

COPh

(7.116)

sekmc 1.25

substituent prior to ring-closure, and the propensity of 1-(2-nitropheny1)piperidines to undergo reductive cyclization to 1,2,3,4-tetrahydropyrido[ 1,2-a]benzirnidazoles under standard conditions (see later). 1-(2Aminopheny1)piperidine and its N-acyl derivatives are cyclized to 1,2,3,4tetrahydropyrido[1,2-a]benzimidazole in essentially quantitative yield (Table 7.5) by oxidation with mercuric oxide in combination with ethyleneThe similar oxidative ring-closure of diaminetetraacetic acid (EDTA).52*S3 the methyl-substituted pipendine derivative (7.11S),on the other hand, affords the 1,2,3,4,4a,5-hexahydropyrido[1,2-a]benzimidazole (7.116) in good yield (Table 7.5).52 A number of useful methods for the synthesis of 1,2,3,4-tetrahydropyrido[ 1,2-a]benzimidazoles are based on the ring-closure of l-(Znitropheny1)piperidine derivatives under a variety of conditions. For example, 1,2,3,4-tetrahydropyrido[1,2-albenzimidazoles (7.105) are formed in moderate to good yield (Table 7.5) simply by heating the corresponding 1-(2nitropheny1)piperidinederivatives (7.107)in sand at 220-240°.s4 Cyclization of this type is promoted by the presence of electron-withdrawing groups in the benzene nucleus of the 1-(2-nitrophenyl)piperidine substrate. Conversely, the presence of electron-donating groups results in longer reaction


291

times and lower yields. The thermal transformation of 1-(2-nitrophenyl)piperidine derivatives into 1,2,3,4-tetrahydropyrido[l,2-a]benzimidazoles can be shown not to involve nitrene intermediates and is suggested54 to occur by cyclodehydration to the corresponding 1,2,3,4-tetrahydropyrido[1,2-a&enzimidazole 5-N-oxides [Scheme 7.24; (7.107) + (7.108)] followed by thermal deoxygenation. 1,2,3,4-Tetrahydropyrido[1,2-a]benzimidazole 5-N-oxides are in fact formed in moderate yield (Table 7.5) by the cyclodehydration of 1-(2-nitrophenyl)piperidine derivatives in hot concentrated hydrochloric acid.” In contrast, the photolysis of 1-(2-nitrophenyl)piperidine in methanolic hydrochloric acid results in complete deoxygenation giving 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole in high yield (Table 7.5).5s 4-Acetoxy- or 4-hydroxy-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazoles are formed in good yield (Table 7.5) when 1-(2-nitrophenyl)piperidine derivatives are heated under reflux with zinc chloride in acetic anh~dride.’~ These cyclization reactions are explicables6 in terms of the intermediacy of 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole 5-N-oxides convertible into the observed products by further reaction with acetic anhydride with or without accompanying hydrolysis. 1,2,3,4-Tetrahydropyrido[ 1,2-a]benzimidazole 5-N-oxides are also postulated44b as intermediates in the reductive cyclization of 1-(2-nitrophenyl)pipridine derivatives to tetrahydropyrido[l,2-a]benzimidazoles using titanous chloride. These reactions proceed cleanly and in high yield (Table 7.5), and represent probably the most convenient method for the synthesis of 1,2,3,4-tetrahydropyrido[ 1,2-a]benzirnidazoles. The reductive formation of the latter from 1-(2-nitrophenyI)piperidines can also be effected electrolyticallys7 or using reducing agents such as stannous and under these conditions is believed to involve the formation and cyclodehydration of transient 1-(2-nitrosophenyI)piperidine intermediates. 1-(2-Nitrophenyl)piperidine derivatives are also reductively cyclized in high yield (Table 7.9, via isolable 1,2,3,4,4a,5-hexahy&opyrido[ 1,2-a]benzimidazole intermediates, to 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazoles using trimethyl phosphite as the reducing agent [Scheme 7.24; (7.107) +(7.106) +(7.105)].58In related processes (Scheme 7-24), 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazoles (7.105) are formed in high yield (Table 7.5) by the thermolysis of 1-(2azidopheny1)piperidine derivatives (7.104) in high-boiling solvents such as n i t r ~ b e n z e n e ~ ~and . ~ ~diethylene ,~’ glycol dimethyl ether.” These reactions may be viewed as involving cyclizative insertion in initial nitrene intermediates to give 1,2,3,4,4a,S-hexahydropyrido[1,2-a]benzimidazoIe derivatives (7.106), which in some instances” can be isolated, but in most cases are spontaneously oxidized to product (7.105). 1,2,3,4-Tetrahydropyrido[1,2-a]benzimidazoles are also the end-products of a miscellany of reactions which share the common feature of ring-closure between an unsaturated onho-substituent and the C(2) methylene center in the hetero ring of a 1-arylpiperidine derivative. Cyclization reactions of this type are exemplified (Scheme 7.26) by the acid-catalyzed formation of the

292


(7.117)

I

9 a: OHNV YNHO

K

0 (7.119)

(7.118)

1-

(7.120)

J

1 CH2Ar C1-

HNKNH 0

(7.122)

(7.121)

betaine (7.121)from 1-(2-aminophenyl)pipridine (7.117) and alloxan via the presumed intermediacy of the azomethine (7.119),61*62 and by the transformation in high yield (Table 7.5) of 1-(2-arylideneaminophenyl)piperidines (7.118) under acidic conditions into 1,2,3,4-tetrahydropyrido[1,2-a~enzimidazoliumsalts (7.122).63Labeling suggest that the acid-catalyzed ring-closure of the azomethines (7.118) and (7.119) to the tetrahydropyrido[1,2-a]benzimidazoies (7.122)and (7.121)involves the formation and disproportionation of 1,2,3,4,4a,5-hexahydropyrido(1,2-a]benzimidazole intermediates of the type (7.120). Interaction between an ortho-diazo substituent and the C(2) methylene center in the hetero ring of

R

so,a2,

R

(7.127)

R

R

N4O2

(7.128)

NHSO;

(7.130)

(7.129)

n

pip-

hv

phsR o 2 N n N dNS0,Ph

(7.131)

scheme 7.27

293

(7.132)

-


294

1-arylpiperidines provides a further mode of ring-closure leading to 1,2,3,4tetrahydropyrido[ 1,2-a]benzimidazoles. Representative of such reactions (Scheme 7.27) are the acid-catalyzed conversion of the azobenzene derivative (7.123; R = H)in high yield (Table 7.5) into 1,2,3,4-tetrahydropyrido[ 1,2-a]benzimidazole (7.125; R = H),6l and the unusual formatiod4 (Table 7.5) of its tetrafluoro derivative (7.125; R = F ) by the reaction of the piperidine N-oxide (7.124; R = F) with hydrazine, a transformation to involve the diimide intermediate (7.126). Cyclization of the latter type is further illustrated by the acid-catalyzed conversion of the diazo sulfonate (7.129) in moderate yield (Table 7.5) into the 1,2,3,4-tetrahydropyrido[ 1,2-a]benzimidazole 5-N-imine (7.130).65Other processes leading to 1,2,3,4-tetrahydropyrido[l,2-a]benzimidazoles include the photocyclization of quinonediimines [Scheme 7.27; (7.31) --* (7.132)]66and the ring-closure of 1-(2-aminophenyl)piperidine using thionyl chloride [Scheme 7.27; (7.127; R = H) + +(7.125; R = C1)],6' the latter reaction involving the possible intermediacy of the sulfonylamine derivative (7.128).

7.1.2. Physicochemical Properties Spectroscopic Studies

INFAREDSPECTRA(Tables 7.6 and 7.7). The NH tautomeric form of 1,5and 3,5-dihydropyrido[1,2-a]benzimidazoles (7.136; R' = H), (7.138; R' = H), and (7.139; R' = H)is substantiated by the presence in their IR spectra (Table 7.7) of well-defined NH absorption in the range 3480-3255 cm-'. The exceptionally low IR stretching frequencies (ca. 2190 cm-') (Table 7.7) of C(4) cyano groups in 1,5-dihydropyrido[1,2-a&enzimidazoles are attributed6 to resonance interaction with the imidazole ring [Scheme 7.28; (7.141) (7.142)]. In contrast, C(4) cyano substituents in pyrido[ 1,2-a]benzimidazol-1(5H)-ones6~7*21 and pyrid~1,2-a]benzimidazol-3(5H)-ones6 exhibit normal IR absorption (Table 7.7) as a result of competing resonance interaction between the imidazole ring and the C(1) or C(3) carbonyl substituent, e.g. [Scheme 7.28; (7.143; R2= CN) f* (7.144; R2= CN)]. It follows that the C(1) and C(3) carbonyl groups of pyrido[l,2-a]benzimidazol- 1(5H)-ones6.'**' and pyrido[ 1,2-a]benzimidazol-3(5H)-ones6are associated with very low IR carbonyl absorption (ca.1680-1640 cm-')(Table 7.7). Pyrido[ 1,2-a]benzimidazol-1(4H)-ones,20on the other hand, are distinguished by IR carbonyl absorption at significantly higher frequencies (ca 1700m-') (Table 7.7). Resonance interaction of the type [Scheme 7.28; (7.141) ++ (7.142)] also accounts for the low IR carbonyl stretching frequencies of C(4) ester substituents in 1,5-dihydropyrido[l,2-~~enzimidazoles (Table 7.7).6 Bands at ca. 1650-1640 cm-' attributable to C=N absorption are characteristic of the IR spectra (Table 7.6) of fully unsaturated pyrido[1,2-~]benzimidazolederivatives.

-

N

H H Me Me Me Ph Me

H

H

C0,Et C02Et C0,Me

H H

H

H H Ph H Me H Me

H Me H

(7.133) (7.133) (7.133) (7.133) (7.133) (7.133) (7.133) (7.133) (7.134) (7.134) (7.134) (7.134) (7.134)

H

R2

R'

Compound

H H H NH2 CO,H NO2 NO2 NO2 Me Ph Me Me C0,Me

R'

H H Ph H Me H H Me H H H H C0,Me

R4

R' (7.133)

H Ph H H C0,Me

-

-

-

-

RS

CIO, I CIO, C10, CIO,

-

-

X

Nujol

-

-

-

3430.3180 3500-2800br

-

-

-

NH,OH

x-

KBr KBr Nujol Nujol KBr Nujol Nujol Nujol KBr Nujol

KBr KBr

Medium

R' (7.134)

R'

q--

1740 1740 1740

-

-

1650

-

1640 1640 1640 1657 1645

-

1645 1640 1645

1680

G N

c--O

Vm.,(CII-')

TABLE 7.6. INFRARED SPECTRA OF PYRID0[1,2-a]BENZIMIDAZOLEDERIVATIVES (7.133) A N D (7.134)

30 30 18 32 35 31 31 31 lla 18 1 la lla 2

Ref.

TABLE 7.7. INFRARED SPECTRA OF DIHYDROPYRI~~,~-U]BENZIMIDAZOLE

CHMe,

(7.l35)

(7.136)

(7.137)

~

R4

R'

R2

R3

(7.135) (7.135) (7.135) (7.135) (7.136) (7.136) (7.136) (7.136) (7.136)

Me Me Et

H C0,Et C02Et C0,Et C0,Me C0,Me C0,Me CN

Me Me Me Me C0,Me C0,Me CO,Me H H

(7.136) (7.l36)

Me H

C0,Et C0,Et

H C0,Me

H C0,Me

(7.136)

Me

C0,Et

C0,Me

C0,Me

C0,Me

C0,Me

Compound

R

(7.136) (7.137) (7.137) (7.138) (7.138)

Ph

Me Me0,C -CHCO,Me MeO, HCH,CO,Me Me CH a H C 0 , M e

&-

Me

CN

CN

-

-

C02Me C0,Me C0,Me CH2C0,Me H

-

-

-

CH *HC02Me H

CN

-

CN

H Me

-

H Me COMe H H

CN CN CN C0,Et C0,Et

C0,Me C0,Me C0,Me Me C0,Me

(7.138)

COMe

C0,Et

C0,Me

-

(7.138) (7.139) (7.139) (7.l39) (7.139)

H CH k H C 0 , M e H Me CH a H C 0 , M e

CONH,

-

H

Me H H C0,Me C0,Me

(7.140)

Me

Me

C0,Me

-

(7.140) (7.140)

Me Me

Et C0,Me

C0,Me H

(7.138) (7.138) (7.138)

(7.138)

(7.138)

a

CN

CN H

8-Chloro derivative. &N or c;---C.

296

-

-

-

-

-

H C0,Me H H

-

DERIVATIVES (7.135)-(7.140)

(7.138)

RS

(7.139)

(7.140) %&m-l)

Medium KBr KBr KBr KBr Nujol Nujol Nujol Nujol Nujol

NH

C=N

C-0

-

-

-

-

-

2190 2200

Nujol Nujol

-

Nujol

-

Nujol KBr KBr Nujol KBr Nujol Nujol Nujol KBr Nujol Nujol

KBr Nujol Nujol Nujol Nujol

2192

-

2222 2240

2214 2220 2224

-

-

-

-

2214 2220

-

Nujol

-

Nujol Nujol

297

1735 1725 1740 1740,1730 1740,1700 1740,1730 1748,1669 1733,1723, 1671 1747,1683 1753,1742, 1709 1770,1734, 1720 1142,1717 1695 1700 1733,1686 1670 1724.1660 1734,1668 1730,1678 1683,1640 1744,1732, 1696 1746,1725, 1692,1662 1660 sh, 1645 1716,1647 1736,1668 1703,1655 1740,1707, 1649 1730,1710, 1690 1730,1690 1740,1705

C=N

C==C

Ref.

1640

-

1 la lla 1 la

-

-

1630’1664’ 1625’

lla 2 2 2 6 6

t- 1662‘1660b 1624b

6 6

1670b

1643b

6

1626b

6 20 20 6 21

-

1670 1680 1680

-

1664b

-

1640

-

-

-

-

-

-

-

c- 1656”-

-

-

7 7 7 21 7

-

-

7

-

21 6 6 6 6

c-- 1652’-

-

t--

-

1625’-

-

1620‘-

-

-

-

2

-

-

2 2.3


298

R R

‘

N \ I

R

R

N (7.141)

N(7.142)

(7.143)

(7.144) schuoe 7.28

ULTRAVIOLET SPECTRA.The highly delocalized nature of the ring system in fully unsaturated pyrido[ 1,2-a]benzirnidazoles is illustrated by their UV spectra (Table 7.8), which are typified by a series of intense absorption maxima in the range 240-390 nm. Not unexpectedly, the presence of unsaturated substituents at the C(1) and C(3)positions of the pyrido[l,2-a]benzimidazole ring system results in a uniform shift of the U V maxima to longer wavelength (Table 7.8). On the other hand, quaternization of the N ( 5 ) position in pyrido[1,2-a]benzimidazoles appears to have little effect on the UV absorption (Table 7.8). The UV spectra (Table 7.9) of 1,5-dihydropyrid~1,2-a]benzirnidazoles feature three intense UV bands in the ranges 240-250, 300-320, and 390-430 nm.2*5*6 Preferential protonation of 1,5-dihydropyrido[l,2-afienzimidazoles at the C(4) position [Scheme 7.29; (7.156)4(7.157)] is indicated by the similarity of their UV absorption in acidic media (Table 7.9) to that of the benzimidazolium ~ation.~.’.~ The largely similar UV absorption of pyrido[ 1,2-a]benzirnidazol-l(5H)-ones (7.149)6*7 and pyrido[ 1,2-a&enzimidazol-3(5H)-ones (7.1SO)6in both neutral and acidic media (Table 7.9), on the other hand, is consistent with the presence in these molecules of resonance interaction of the type [Scheme 7.28; (7.143) t* (7.144)]. The UV absorption (Table 7.9) of pyrido[ 1,2-a]benzimidazol-3(SH)-ones(7.150)6is distinguished from that of pyrido[ 1,2-a]benzimidazol- 1(5H)-ones (7.149)6*7 in being generally less complex. The ready protonation of 4a,5-dihydropyrido[ 1,2-a]benzirnidazoles (7.151) accounts for the reduction in the complexity, and the hypsochromic shift, of the UV absorption of these molecules (Table 7.9) on changing from neutral to acidic The UV absorption of 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazoles (Table 7.10), as might be expected, resembles that of simple benzimidazole derivatives.


299

TABLE 7.8. ULTRAVIOLET SPECTRA OF PYRIDO[ 1,2-a]BENZIMIDAZOLE DERIVATIVES (7.14947.147)

R2

3RJ / - -Jf

Q i ) -& w

f

1-

R'

t-Bu

(7.145)

Compound R'

R'

Me

(7.146)

(7.147)

R2 R3

R4

Solvent"

X,,,(nrn)(logE)

Ref.

240(4.45), 245(4.46), 258(3.99), 266(3.29) 240(4.54), 245(4.53), 254(4.1 l), 266(4.00) 217(3.75), 270(4.06), 315(3.60), 355(3.54) 225(4.04). 272(3.95),317(3.84), 355(3.70) 248(4.64), 255(4.78),265(4.34), 274(4.26), 296(3.56), 308(3.70), 320(3.74), 344(3.60), 358(3.68), 375(3.64), 396(3.37) 254(4.77), 264(4.38), 272(4.23), 294(3.57), 305(3.72), 317(3.69), 349(3.74). 364(3.72), 283(3.43) 249(4.60), 256(4.75), 266(4.36), 275(4.31), 295(3.58), 307(3.70), 319(3.59), 35W3.62). 370(3.57) 256(4.74),266(4.31), 275(4.17), 299(3.51), 31 1(3.68), 324(3.77). 358(3.69),374(3.66), 394(3.36) 249(4.61), 256(4.75), 266(4.38), 275(4.33), 295(3.60), 307(3.71), 319(3.61), 354(3.66), 368(3.6 1) 256(4.73), 273(4.13), 308(3.69), 321(3.74), 350(3.76), 363(3.73) 249(4.55), 315(3.81), 328(3.85) 228(4.52). 298(4.47), 333(3.98), 351(3.85),389(3.41) 212(4.03), 257(4.64). 265(4.41), 275(4.42), 304(3.66). 317(3.56)

30

(7.145)

H

H

H

H

A

(7.145)

Me

H

H

H

A

(7.145)

H

Ph

H

Ph

A

(7.147)

_

_

_

-

A

(7.146)

H

H

H

-

B

(7.146)

Me

H

H

-

B

(7.146)

H

Me H

- B

(7.146)

H

H

Me

- B

(7.146)

H

Et

H

-

B

(7.146)

Me

H

Me

-

B

(7.145) (7.145)

H H

H H

NO,

H H

-b

(7.145)

CN Me

H

Me

-b

NH,

A

~

~~~~

30 18 18 40 41 41 41 41 41 32 31,32 12

~~~~~

A =ethanol; B = cyclohexane. Solvent not specified.

NUCLEAR MAGNETICRESONANCESPECTRA.Conjugative interaction with N ( 5 ) would be expected to confer enhanced electron deficiency on the C(1) and C(3) positions in fully unsaturated pyrido[ 1,2-a]benzimidazoles. In accord with this expectation H(1) in pyrido[ 1,2-a]benzimidazole derivatives resonates uniformly at lower field (Table 7.11) than the other pyridine protons, followed closely by H ( 3 ) . Predictably H ( 6 ) is the most deshielded

MeO,CC=CHCO,Me

(7.148)

MeO,CCHCH,CO,Me Me

Me

Me

Me CH&HCO,Me

CHaHC0,Me

H

H

Me

Me

(7.148) (7.148)

(7.148)

(7.148)

(7.148) (7.148)

(7.148)

(7.148)

(7.148)

(7.148)

(7.148)

I

Me

(7.148)

I

R'

Compound

(7.148)

C02Et

C0,Et

C0,Et

C0,Et

CN

CN CN

CN

C0,Et

C0,Me C0,Et

C0,Me

C0,Me

RZ

C0,Me

C0,Me

C0,Me

C0,Me

H

C0,Me

C0,Me

C0,Me

C0,Me

H

CH,CO,Me

CH,CO,Me

CH,C02Me

CH,CO,Me

CH,C02Me

CH,CO,Me CH,CO,Me

H

H

H H

CH,CO,Me

H

H

H CH,CO,Me

H

H

R5

CH,CO,Me

C0,Me H

C0,Me

C02Me

R4

H

H

C0,Me H

C0,Me

C0,Me

R3

(7.149)

B

A

B

A

B

B A

A

B

A A

A

A

Solvent'

(7.150)

2

254(4.03),316.5(4.47),400(4.29)

2 242 inf (3.85),265 inf (3.70). 309(4.16),403(4.03) 250.5 inf (3.93),316.5(4.41),397(4.21) 2 213(4.38), 250(4.11),273 inf (3.84), 6 315(4.58),398(4.35) 211(4.41),267 inf (3.92),315(4.58), 6 398(4.35) 211 inf (4.26),220(4.37), 248(4.24), 6 262 inf (4.06),298.5(4.31),409(4.34) 6 216 inf (4.28),276(4.27) 213(4.51), 242(4.38), 259(4.37), 6 280(4.42),293 inf (4.23),428(4.53) 206(4.49), 268 inf (4.27),282(4.29), 6 365(3.69) 211(4.26), 217 inf (4.24),225 inf (4.19), 6 248(4.18), 308(4.58),412(4.29) 215 inf (4.25).247(3.92),265(3.82). 6 272(3.84),28 1(3.82), 307(4.07) 208(4.25). 228(4.19). 286(4.43), 6 330(4.30), 398(3.63) 210(4.53), 236(4.17),269(4.15), 6 283 inf (4.00)

Ref.

(7.151) Amax (nm) (log c)

TABLE 7.9. ULTRAVIOLET SPECTRA OF DlHYDROPYRIDq1,2-a]BENZIMIDAZOLE DERIVATIVES (7.148k(7.151)

c

g

CN

H

Me

Me CHaHC0,Me

CHkHC0,Me

H

COMe H

Me

COMe

Me

Me

CWC0,Me

CHACHC0,Me

CUCHC0,Me

CH-ICHCO,Me

H

(7.148)

(7.148) (7.149)

(7.149)

(7.149)

(7.149) (7.149)

(7.149)

(7.149)

(7.150)

(7.150)

(7.150)

0.150)

(7.150)

(7.150)

(7.150)

CN

CN

CN

H

H

H

CN

COZEt

CN

CO,Et

CN

Ph CN

Ph

CN

Me

(7.148)

CN

Me

(7.148)

H

H

H

C0,Me

C0,Me

C0,Me

C0,Me

C0,Me

C0,Me

C0,Me C0,Me

C0,Me

H

C0,Me H

C0,Me

C0,Me

C0,Me

C02Me

H

H

H

H

H

H

-

C0,Me

-

C0,Me

C0,Me

C0,Me

CH,CO,Me -

CH,CO,Me

CH,CO,Me

CH,CO,Me

A

B

A

A

A

A A

A

B

A

B

A

B

A

211 inf (4.09),22N4.30).283(4.56), 6 314 inf (4.10),323(4.22),400(3.50) 233(4.16),268(4.07),287(4.11), 6 305 inf (3.92),321 inf (3.85) 5, 6 220 inf (4.51).275(4.20),281(4.19), 315(4.18).480(4.25) 275(4.22). 282(4.19) 5, 6 21 1(4,41), 224(4.46),258(4.37), 6 281(4.32),358 inf (4.27),371(4.39), 400(3.46) 242(4.44),259(4.39),269 inf (4.33), 6 304(3.70), 354 inf (4.23),365(4.32). 402 inf (3.36) 228(4.26), 241(4.30). 273(4.00), 7 298(4.45),357(4.2 1) 236(4.31), 299(4.20),359(4.18) 7 228(4.28),255(4.37), 284(4.33), 7 387(4.00) 229(4.35). 253(4.40),295(4.33), 7 385(4.04) 223(4.28), 247(4.24),264(4.25), 7 377(4.03) 212(4.42). 230(4.34),261(4.67), 6 306 inf (3.97).315(4.09),336(3.97) 210 inf (4.08).217(4.11),258 inf (4.29),6 267(4.31),307(3.77),316 inf (3.76) 6 211(4.39), 219 inf (4.35).259(4.63), 280 inf (4.29),290 inf (4.22), 327(4.38) 220 inf (4.31),251(4.53), 262(4.50), 6 275(4.44),329(4.20) 6 211(4.39), 249(4.62),256 inf (4.51), 274(4.29),283(4.27),3M(4.34) 212(4.49), 249(4.48),261(4.44), 6 282(4.32),323(4.09) 211(4.29),230 inf (4.13).270(4.47), 6 283 inf (4.41).308 inf (4.00).416(3.92)

0, .-

w

H

Me

Me Me

Me Me Me Me

Me CHLCHC0,Me CH-%HCO,Me Me

Me

Me Me

(7.150)

(7.151)

17.151) (7.151)

(7.151) (7.151) (7.151) (7.151)

(7.151) (7.151) (7.151) (7.151)

(7.151)

(7.151) (7.151) C0,Me C0,Me

C0,Me

CHzPh Bu' Bu' C0,Me

Et i -Pr i-Pr CH,Ph

Me Et

Me

CN

R2

A = MeOH;

B = MeOH-70% HC104 aq. UV data available in a supplementary publication.

R'

(7.148)

(Conrinued)

Compound

~~~

TABLE 7.9

Ph Ph

H

H

C0,Me C0,Me C0,Me

C0,Me C0,Me C0,Me C0,Me

C0,Me COiMe

C0,Me

H

R3

(7.149)

-

-

-

_.

-

-

-

-

-

-

-

-

-

-

B

A

B

A

B B B

A

B

A

B

A

B

A

B

-

Solvent"

RS

-

-

C0,Me

R4

(7.150)

-b -b

236(4.24), 271.5(4.19), 301(4.01), 437(3.95) 234.5(4.44), 236.5(4.43), 269(4.06), 299.5(3.95), 345(3.90), 436(3.97)

b

-

-b

224 inf (4.38), 254(4.22), 317(3.88), 450(3.88) 244(4.27), 296(4.00)

-b -b

(nm) (log E )

215 inf (4.32), 233(4.28), 256(4.51), 271(4.55), 291 inf (4.09), 390(4.02) ZZO(4.31). 256(4.18). 316(3.88), 441(3.96) 243(4.27), 295(4.02) 220(4.29), 254(4.17), 332.5(3.83), 457(3.90) 253(4.27), 296(4.03)

A,,,

(7.151)

4 4

2

2

5

4 4

2 4 4 5

2 2

2

6

Ref.

TABLE 7.10. ULTRAVIOLET SPECTRA OF TETRAHYDROPYRID0[1,2-a]BENWMIDAZOLE DERIVATIVES (7.152)-(7.155)

R'

NHSO;

(7.152)

(7.155)

HNYNH 0 (7.153)

RZ

Solvent" Amax (nm)(log E )

H

A

H

H H

A A

(7.152) (7.152) (7.152) (7.152)

Me C1 NO, Me

H H H NHS0,Ph

A A A A

(7.152)

Me

NHS0,Ph

B

NHS0,Ph

A

213(4.61),258(3.88), 299(4.01)

66

NHS0,Ph

B

307(4.03)

66

-

-b

H

-b -b

NO* Br

-b

Compound R' (7.152) (7.152) (7.152)

(7.152) (7.152)

H

H

N Z N

(7.153) (7.154)

-

(7.155) (7.155) (7.155) (7.155)

H

a

3

H H Br

Br

Ref.

248.5-251(3.76),254(3.78). 276.5(3.75), 24.50 283(3.81) 249(3.76), 275(3.75), 282(3.76) 45 213.1(4.42), 254.6(3.71), 276.2(3.71), 48 282.4(3.73) 249(3.76),275(3.75), 282(3.76) 45 249(3.76), 275(3.75), 282(3.76) 45 24l(4.29) 45 262(3.95), 285(3.90),288(3.90), 66 295(3.91) 288(4.24), 304(4.01) 66

249.5(4.34),270.5(3.95),277243.93) 206(4.01),245.4(3.50), 269.6(3.52), 276.4(3.51) 235(4.45), 281(3.62), 316(3.66) 245(4.45), 302(3.68), 332(3.70) 281-283(4.36) 245(4.45), 290(3.68), 325(3.70)

C

A

A = EtOH; €3 = EtOH-NaOH aq.; C = H,O.

Solvent not specified.

R

R

R H R

(7.156)

(7.157) !WMmlt 7.29

303

R

63 65

37 37 32 37

5?

w

H(3)

2.9d

-

-i

D

B C

(7.159; R' = R3 = Me) (7.160; R' = R3 = Me,

x = (30,)

7.97"*' 9.42d"

B

i

-

2.22d

6.66d.O 6.54'mf 6.54'*' 2.28d 6.53'*O

8.30'*"*" 8.19"'" 8.35' 8.14"*' 8.25's"

B B B B

-

3.54 2.w

(7.158; R2 = Me, R3 = NO,) (7.158; R3 = NO,, R4 = Me) (7.158; RZ= R* = Me, R3 = CO,H) (7.159) (7.159; R' = Me) (7.159; R2= Me) (7.159; R3= Me) (7.159; RZ= Et)

D D

8.9d'

-

10.10d'

D

-

6.78

-' .*

7.25f*"*P 7.68"."*P 6.99f*"*" 2.60d 2.34d 7.38O.l 7.Ogp 7.57P 1.27" 7.44-O 2.66" 6.85-I 2.56d 2.6d -i

2.6Y

-i

8.2dk

-i

-

(7.158; R3= NO,)

9.26d'

-

2.60d 7.018.11m

9.31d'

A

7.908.23m 8.41qh

(7.158; R2= NO,)

9.62d'

D

7.50m 7.40 2.36d

(7.158; R' = NO,)

6.96 6.32br

H(4)

H(5)

H(6)

H(8)

-

4.04'

-7.88

7.38d'

7.49dl 7.43d' 7.43d' 7.454' 7.44di c---i-8.54d"

1.65q

1.67q 1.67q 1.62" 1.66" 1.66q

1.40"

1.42" 1.41" 1.40" 1.42" 1.429

7.02-7.48m

i

c - -i

c

-

-

-

7.50m

8.407.90-8.23m8.60m8 7.85 7.20-7.8.03m 8.501~1~ 7.70-8.00rn-

8.30-7.40m -7.01-8.11m-

H(7)

H(9)

7.564'

7.67d' 7.61d' 7.68d' 7.63d' 7.61d'

-

-

-

-

-

-

41 1la

40 41 41 41 41

31 31 35

31,32

-

35

35

30 30 19

-

-

-

-

Others Ref.

* 8.40'

7.708.00m'

7.908.23mg

8.29

-- -H(2)

B

9.04 8.95 2.88d

H(1)

A

A

Solvent'

(7.160)

(7.158)

(7.159)

RJ

R'

OF PYRID0[1,2-o]BENZIMIDAZOLEDERIVATIVES (7.158H7.160)

(7.158) (7.158; R' = Me) (7.158; R2 = R4 = Me)

(R'+ RS unspecified=H)

Compound

TABLE 7.11. 'H NMR

8

w

x = CIO,)

D

D

c--

-= 2.52'

-

C--I-

2.99'

2.57'

2.46'

-

-

-

-

-'

4

4

4

4.03'

4.35'

'

a

le0HZ

N(Me).

" Me of Et group. " CH, of Et group. "J = 7 Hz.

= l.o HZ

IJMe(2)-H(1)=

"M(3)-H(4)

1.0-1.2 Hz.

= 9.5 Hz.

'J*(,)-H(3)=

But.

A = Me,SO; B = CDCI,; C = (CD,),SO; D = .CF,CO,H. *ti values in ppm measured from TMS. .. Signals are sharp singlets unless denoted as: d = doublet; q = quartet; m = multiplet. C(Me).

(7.160;R' = RS= Me, R2= CN, R3= CO,Me, x = CIO,)

X=CIO,)

(7.160;R' = R ' = Me, R2= CN,RS= Ph.

-'

2.98'

-I

2.63' +

-'

9.904"

C

2.88'

2.67'

7.82d"

9.70d"

6.7-8.3m

-

C

D

(7.160;R' = R ' = RS= Me, D R2= CN, X = CIO,) (7.160;R' = R' = R4= RS= D Me, R2= CN, X = CIO,) (7.160;R' = RS=Me, D R2= CN,R' = Ph.

R2= C02Et, R ' = Me, X = CIO,)

R2= CO,Et, X = C10,) (7.160;R' = Ph, X = CIO,

= Rs= Ph. X = I) (7.160;R' = R ' = Me,

R '

(7.160;R'=Me,

-

-

I

-

I

-

-

P

-'

6.7-8.3m

b

b

b

*

+

- -

16

-

16

16

-

-

16

16

1l a

1l a

18

-

-

-

-

-

TABLE 7.12.

'H NMR SPECTRA"*bOF DIHYDROPYRIDO[l,2-a]BENZIMIDAZOLE

Me

6

Compound (R1+R5 unspecified = H)

R'

6

(7.161)

(7.162)

(7.165)

(7.166)

Solvent'

H( 1)

H(2)

H(3)

H(4)

(7.161;R' = Me) (7.161; R' =Me, R2 = C02Et) (7.161;R' = Et, RZ= C02Et, R3 = CI) (7.161;R' = Ph, R2 = C0,Et) (7.162) (7.162;R2 = Me) (7.162;R' = OMe) (7.162;R' Cl) (7.162;R' = C02Me) (7.162;R' = NO,) (7.162;R2 = NO,) (7.162;R3 = Me)

A

4.40t" 4.60td

2.851' 3.001'

2.2v 2.44e

6.7 m

€3

B

4.261'

3.02td

2.36'

-

(7.162;R3 = Et)

C

(7.163;R' = Me, R2 = R3 = R4 = C02Me)

C

6.26

I (7.163;R' = Me02CC = CHCO,Me, RZ= R3 = R4-- C02Me)

C

6.31

-

-

C

6.24

-

-

~~

I

(7.163; R' = Me02CCHCH,202Me, R2 = R3 = R4 = C0,Me)

c---------

2.22'

1.22th*' 2.75qh*"

-

P

-8

2.95mh-' 1.35dh*' 2.75mh.J 1.35dh.'

1.70'

1.70'

DERIVATIVES (7.161)-(7.167)

(7.163)

(7.164)

17.167)

-

3.86' 3.90'

-

8.10dh

8.20' b

-8

4

7.75m 7.55dh 7.30d' 7.80~11 8.55d' n.3od' 7.80dh

-

7.70ddh*' 7.30m 7.20ddh*'

-

7.30m

-

7.00ddh.' 7.35ddh*' 8.15dd h.' 8.30ddh.'

-

-

8.30m 8.20d' 8.25dh 8.30dh 8.40d 8.55dh 9.2od'

*

8.33ddh.' 7.35-8.40111

4

7.38-8.40111

3.71"

*

7.37111

b

6.63"

4

7.39111

b

5 .76dd0J'

4

7.26111

b

307

b

-

1l a 1la 1l a

-

1l a 20 20 20 20 20 20 20 20

-

20

-

3.02 3.71 3.77 3.97 3.67 3.71 3.78 3.80 3.90 3.92 3.50 3.70 3.70 3.77 3.80 3.94

2

2

2

TABLE 7.12

(conrid)

R'

Me

6

6

(7.161)

(7.162)

' l e d &

R3

R'

R2

6

(7.165) Compound ( R ' 4 R ' unspecified = H)

Solvent'

(7.163; R' = Me, R2 = CN, R4 = CH,CO,Me) (7.163; R' = CH&HCO,Me, R2 = CN, R4 = CH,CO,Me)

C

(7.163; R' = Me, R2 = CO,Et, R4 = CH2C02Me)

C

C

(7.163; R2 = C02Et, R3 = R4 = C02Me, B RS= CH,CO,Me)

(7.163; R' = Me, R2 = CO,Et, C R3= R4= CO,Me, RS= CH2C02Me)

(7.166) H(l) 6.05tq 2.73P' 6.08tq 2.76der 6.09tq 2.502.95mq*'+' 3.18d"" 3.556"

3.15

H(2)

W3)

-

7.53

-

7.52

-

8.17

-

-

-

-

4.27qmh 1.21th.1 4.19qh.'"

1.30th2' 4.13qh." 7.20-

7.35111 3.21

-

-

(7.164; R' = CHA=CHCOzMe,

C

-

6.30dh

7.95dh

(7.164; R2 = C02Et, R3 = Me)

C

-

6.07

2.60'

(7.164; R2 = CN, R3 = Me)

D

6.95

2.80'

(7.164; R2 = CONH,, R3 = Me)

D"

-

6.92

2.90'

R2 = CN)

1.201.50ml

(7.163; R' =Me, R2 = Ph, C R' = R4= CO,Me, R5= CH,CO,Me) (7.163; R' = Me, R2 = CN, C R3 = R4 = CO,Me, R5 = CH,C02Me)

W4)

308

(7.163)

(7.164)

R3

(7.167)

-

3.96'

4

7.15-7.60m

-

7.30-7.80~1-

-

-

+

7.33-7.70111

4

7.30-7.80m

4.041

4

6.80-7.30m

3.77'

4

7.20-7.35rn

4.801

4

6.80-7.40111

4

7.40-8.10m -8.81rn

4

7.40-7.55111-8.72-

3.83'

8.6Od'," 6.76d n*s 12.0612.40br"

-

-

-

7.07111

-

7.50-7.92rn-8.444

7.50-7.95m -8.50-

8.97111 8.73111 8.75111

309

3.53 3.78 3.55 3.82 3.90 3.51 3.82

6 6 6

3.42 3.62 3.76 3.76 3.38 3.40 3.74 3.78 2.84 3.43 3.66 3.66 3.60 3.75 3.80 3.86 3.85

6

-

21

-

21

-

21

6

6

5

6


Compound (R'+Rs unspecified = H) -~

(7.164; R2 = CN, R3= C02Me) (7.164; R' = COMe, R2 = C02Et, R3 = C02Me) (7.165; R2= Me) (7.165; R' = R2 = Me) (7.165; R2 = W) (7.165; R' = Me) (7.165; R' =Me, R2 = Ph) (7.165; R2 = R3= Me) (7.165; R' = R2 = R3= Me) (7.166; R' = Me, R3= C02Me) (7.166; R' = CH-CO,Me,

R3 C02Me)

B

(7.166)

-

8.80 8.89

C

(7.167; R' = R3=Me, R2 = C0,Me)

C

(7.167; R' = Me, R2 = Et, R3= C0,Me)

C

(7.167;

R' = Me, R2 = Pr', R3= C02Me)

C

(7.167; R' = CH*HCO2Me,

C

B

H(2) 6.40 6.37

-

2.48br' 2.54br' 2.48dC.' 2.43br'

(7.167; R' = R2 = Me, R3= C02Me)

Rr= But, R3= C02Me)

(7.165)

2.50br'

C

RZ=CN)

(7.162)

2.48br' 2.45bf

(7.166; R2 = CN, R4= C02Me) (7.166; R' = CHaHCO,Me,

6

(7.161)

SolventC H(1)

n

R'

Me

6

3.95' 8.83dd

3 10

5.12m 5.09m 5.22m 5.21m 5.35m 5.08m 5.00m 3.98X 6.53 6.54dd

H(3) 3.90' 3.86'

H(4)

4.22q

(7.163)

(7.164)

R3

(7.167)

7 7

*

-Y

-

b

-

-Y

4

7.20-7.80111 7.35-7.90111

< 4

*

7.30-7.80m 7.85-8.30m 7.40-7.70m 6.55-7.10m

4

c

3.081

6.654

6.77td

0.7 6td.' 2.04qd,"

3.17

c -6.50-7.20m

0.901'

3.14

1.05""

5.81"*' 7.95d'J

-

6.54d,

4

7.03td

6.60-6.80,

6.75-7.45m-

311

b

7.20d

*

7.1Om

-

-

-

-

3.90 4.00 8.63m 3.82

3.14 3.77 3.81 4.04 3.72 -3.80 3.7~

3.78 3.83 4.08 3.77 3.80 3.83 4.09 3.79 3.79 3.82 3.85 4.10

19 19 19 19 19 19 19 6 6

6 6 2

3

2

4

1b.4


0

R'

Me (7.161)

Compound (R1-R5 unspecified = H)

6

(7.162)

H(1)

H(2)

H(3)

H(4)

C

-

-

-

-

(7.167; R' = Me, R2 = C0,Me)

C

8.26

-

-

-

(7.167; R' = CH*HCO,Me, R2= CO,Me, R3= Ph)

C

7.60

(7.167; R' = Me, R2= CH,Ph, R3= C0,Me)

Solvent'

S values in ppm measured from TMS. Signals are sharp singlets unless denoted as br = broad; d =doublet; dd =double doublet; t =triplet; q =quartet; m = multiplet. A = CD,CN; B = (CD,),SO: C = CDCl,; D = CF,CO,H. dJ=7.5-8.1 Hz. C(Me). N(Me). *S values not specified. '-I= 7.10Hz. '-I= 1 - 3 H ~ . I CHMe,. 'CHMe,. ' Me of Et group. CH, of Et group. C=CHCO,Me. CHC0,Me. p I = 4 and 10Hz.

'.1,--,-,(,,=5.1-5.2HZ. ' CH,CO,Me.

312

(7.163)

(7.164)

R'

(7.167)

~~~

2.90d 3.32d

3.10

-

3.11'

5.48dn*' 7.97'3

~

~~~

~

6.80-7.40m 6.30-6.70m

4

6.67-7.19

5.54ddd*'

6.60m

7.00m

5

3.53 3.72 3.78 3.98 * 3.72 3.80 3.80 3.91 7.16ddd.' 3.40 3.75 3.75 3.88 3.93

P

2

lb, 4

~~

J = 12.0-14.0 Hz. CH4. " JSem= 13.9-14.2 Hz. ' NH. 6 Values in ppm measured from sodium 3-trimethylsilyl-1-propane sulfonate. OMe. Other signals in the ranges 6 0.93-3.86 and 6 7.10-7.88 not assigned. JM.(L)-H(Z,

Bu'.

313

314


of the benzenoid protons in pyrido[ 1,2-a]benzimidazoles (Table 7.11). C(1) and C(3) methyl substituents in pyrido[l,2-a]benzimidazoles, as expected, are more deshielded (Table 7.11) than their C(2) and C(4) counterparts. Allylic coupling (H = 1.0 Hz) is observed (Table 7.1 1) for methyl substituents at the C(2), C(3), and C(4) positions in pyrido[l,2-a]benzimidazoles. The enhanced deshielding (Table 7.12) of the N ( 5 ) methyl substituent in the 1,5-dihydropyrido[1,2-a]benzimidazole [Scheme 7.30; (7.177)] is attributed' to resonance interaction involving the nitrogen atoms of the imidazole ring [Scheme 7.30; (7.177) (7.178)]. H(2) in pyrido[l,2-a]benz-

-

(7.177)

seb€lnt 7.30

H C0,Me

Me (7.178)

imidazol-l(SH)-ones (7.164) and pyrido[1,2-a]benzimidazol-3(5H)-ones (7.166) absorbs at higher field (Table 7.12) than H(3) or H(1), respectively, the particularly low field resonance of the latter being explained6 in terms of deshielding associated with resonance interaction of the type [Scheme 7.28; (7.143) t,(7.144)]. Pyrido[ 1,2-a]benzimidazol- 1(4H)-ones (7.162) and pyrido[ 1,2-a]benzirnidazol-l(5~-ones (7.164) are readily differentiated from their C(3)-keto counterparts on the basis of the enhanced deshielding of H(9) (Table 7.12) as a result of the anisotropic effect of the C(1)carbonyl €YOUP* H ( 1) in 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazoles (7.168) resonates (Table 7.13) at lower field (6 3.8-4.4) than H(4) (6 2.9-3.2), and both H(1) and H(4) are more deshielded than H(2) or H(3) (6 1.8-2.6). The anisotropic effect of the N-oxide substituent in 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole 5-N-oxides results in a deshielding of H(4) (Table 7.13), while both H ( 1) and H(4) in 1,2,3,4,-tetrahydropyrido[l,2-a]benzimidazolium salts (7.170) resonate at somewhat lower field (Table 7.13) compared with H(1) and H(4) in the parent 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazoles. Ring-chain tautomerism [Scheme 7.3 1; (7.179) S (7.180)] accounts for the presence in the 'H NMR spectrum of the l-hydroxy1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole derivative (7.179), of signals attributable to the open-chain keto isomer (7.180).19 I3C NMR (Table 7.14) allows the unambiguous assignment of structure to 1,5-dihydro- and 4a,5dihydropyrido[ 1,2-a]benzimidazoles derived by the cycloaddition of dimethyl acetylenedicarboxylate to benzimidazole derivatives3

(7.168)

ks

3

(7.168; R' =NO,; N(S)-oxide) (7.168; R' = NO,; RZ=Cl)

B

A

3.824.121' 4.44brt' 3.954.26t'

B

1.80-2.26m 4

1.85-2.20m + 2.903.17t' c 1.96-2,37m 4 3.35brt' c 1.85-2.30m --. 2.973.271' t

+-

2.903.17' 3.20brt'

B

4

(7.168; R' = C l , N(S)-oxide) (7.168; RZ= Cl)

c 1.85-2.20111

e 2.00--2.30111 + 3.27brt'

4.32brt' 3.824.121' 4.15brt'

A B

(7.168; N(5)-oxide) (7.168; R' = a)

H(4)

H(2)

H(3)

(7.173)

R

kHC02CHzPh

Solvent' H(1)

(7.172)

COPh

(7.169)

0

-

-

8,48ddO

8.71dP 8.22

-

7.10-7.75m

7.90ds

-

7.27-7.39m

-

-7.10-7.75m

H(7) H(8) c---7.63-7.76m

H(6)

COMe (7.174)

X-

-

-

-

H(4a)

(7.170)

7.98dh 7.40

H(9)

-

-

55 49

49

55

-

55 49

Ref.

-

Others

0

(7.171)

'H NMR SPECTRAab OF TETRAHYDRO- AND HEXAHYDROPYRIDq1,2-a]BENZIMlDAZOLEDERIVATIVES (7.168)(7.174)

Compound (R' 4 RSunspecified= H)

R'

RZ$&.---j$

TABLE 7.13.

QI

c

w

(7.168)

R'

(7.lm

R'=N3>

R2 = NHS0,Ph)

(7.168; R' =Me,

R2= NHCOMe) (7.168; R' = NO,, RZ= N,)

5

(7.168; R' = CI, R2 NO,) (7.168;R' = NO,, R2= NH,) (7.168;R' =NO,,

1

B

B

B

B

B

B

4.04tf

c-2.31111

- -

c 2.00-2.35111 + 4.321' 3.92c 1.85-2.10m-+ 4.25111 4.35-2.15-2.42md 4.60111 4.40c 2.15-2.60m 4 4.70111 4.04t' 2.05br

4.06

H(3)

3.01tf

3.053.351' 2.983.18111 3.303.55111 3.353.60m 3.08tf

H(4)

(7.173)

RI H

-

-

-

-

I

H(4a)

:k.:

H(2)

(7.169)

Solvent" H(1)

(7.172)

COPh OPh

x&q:

Compound (R'-rRs unspecified= H)

R'

TABLE 7.13 (Confinucd)

COMe

- - - -

-

H(7) H(8)

(7.174)

7.20-7.80m'

7.20-7.70m'

7.70

8.80

7.7s

7.80

~

H(9)

- - 8.59

9.08

8.55

8.02

H(6)

(7.170)

X-

O

0

49

-

8.32brl

66

1.88' 66 6.60br'

49

49

49

2.50'

-

-

Ref.

-

-~ --

Others

(7.171)

K 0

w

1

4

I-

W

1.80'

C

E

B

(7.173;R = 2-CI-S-O,NC,H,CHz) (7.174)

B B

E E F

(7.171) (7.171) (7.170;R' = NHSO;) (7.172) (7.173;R = H)

c

-

-

+-2.00-2.70m-t

-

-

2.35m -1.35br 3.32m 2.56q'"

-

-

-

5.15brtf 6.26br

-

3.023.95m

2.70 3.60brd'

-

-

3.13br 3.23m 3.00brtf

4.85br

4.50m

3.38m 3.38m 3.30m

2.23t" 5.10tr 2.68t0*' 2.13m 5.10m 2.80m 3.4Om

2.21br 2.35br

-2.20-2.80rnd

-1.94111 -1.80111 -1.90m

-1.92m-

3.00m

1.94q'

2.21br 2.35br

4.34br -2.27br 4.42m -2.33m 3.78brd 1.70quin4.10f 2.15qf 2.88tf

1.87

4.58m 4.52m 4.54m

4.50m

A A A

(7.170;R' = R ' = Me, R2= CO,Et, D R4 = OEt, X = (30,)

(7.170;R' = 2-ClC6HaCH2, X = Cl) (7.170;R' = 4-CIC,H4CH,, X-CI) (7.170;R' = 2-CI-5-O,NC6H,CH,, X=Cl) (7.170;R' = R3= Me, R2= CO,Et, R4= OH, X = (30,)

A

(7.170;R' = CH,Ph, X = CI)

-

3.95t'

B

B

4.0lbrt' 4.28br

B

B

(7.169)

(7.168;RS= OH) (7.168;R' = NO,, R2= OCOMe) (7.168;RS= COPh)

.

7.50-8.30m

-

-6.10-7.70m

4.15qq

-

62 62 62

62

23

52

21

62

1.23t'a" l l a 3.9Y 4.20qw*" 5.40br" 1.07'*' lla 1.19'*" 2.89qws 3.68qwJ' 4.03" 4.25q"*" 60 63 7.80' 65 52 3.70br' 58

5.32" 6.10' 5.699 7.32' 5.759 5.639 5.73q

-

7.90-8.40m 2.61'

7.50-7.83m 7.20-8.30m -6.97-7.73m, 8.20mi6.33m 6.60m

- --7.60m-

7.50-8.20m

-

*

-6.80-7.90m' -6.70-7.90m' -6.70-7.90m'

7.20-7.90m

+---7.30-8.60111

-

8.03' -7.00-7.75m'-

7.80m -7.10-7.40m7.30br" 56 6.56d' 8.16ddS." 7.43d6 2.19' 56

5.88-7.10-7.50m--, 6.62m

3.94t

4.50brY

-

-

-

-

-

-

-

-

-

-

-

00

c

w

A = D,O: B = CDCI,; C = CD,CN; D = (CD,),SO: 6 values in ppm measured from TMS.

E = CF,CO,H; F = C,D,N (deuteriopyridhe).

' '

19.0Hz.

Signals are sharp singlets unless denoted as br = broad; d = doublet; dd = double doublet; t =triplet; q =quartet; m = multiplet. Hydrochloride hydrate. I = 5.5-6.0 Hz. ' J value not quoted. I = 1.5-2.3 Hz. I = 9.1-9.5 Hz. ' COMe. 1 Includes Ph. C(Me). NH. OH. "H(3) of keto form. H(3) of enol form. PH(6) of keto form. CH,. ' PhH. ' Hemihydrate. ' Me of Et group. " J = 7.0 Hz. " NMe. CH, of Et group. J = 7.0 and 9.0 Hz. Y Resolved at 100 MHz into a doublet of doublets, J = 9.0 and 3.0 Hz. I = 12.0 Hz.

a

(Foomotes to Table 7.13)

R/fiMe=ay , Me

OH

&Me

(7.179)

Me sdeme 7 3 1

Me

(7.180)

TABLE 7.14. l3CNMR SPECTRA" OF DIHYDROPYRID0[1,2-a]BENZIMIDAZOLE DERIVATIVES (7.175) AND (l.176)b

(7.175)

(7.176)

Compound

Solvent' C(Ar)

(7.175)

A

109.4 110.0 123.4 123.6

(7.176; R' = H, R2 = C0,Me)

B

(7.176; R' = C02Me, R~ = H)

B

(7.176; R' = Me, RZ= C0,Me)

C

111.0 112.1 120.7 127.3 108.2 110.7 121.3 127.3 131.7 144.1 109.0 113.6 119.8 125.0 131.4 143.9

6 values in ppm measured from

TMS.

C(CO,Me)d G O

OMe

NMe

Others

97.1 123.6 129.0 133.9 149.9 149.0 103.9 119.0 130.4 139.8 104.0 110.6 136.4

162.4 163.2 167.2 167.9

50.3 51.3 51.8 52.6

34.9

53.5'

165.0 165.2 165.9 168.3 165.0 165.5 168.5

52.6 53.1 53.3 54.4 50.8 52.8 53.2 53.5

33.2

17.2' 85.78

34.9

863 136.4'

104.8 150.5

165.8 167.6 168.1

51.5 52.2 52.6 52.9

33.8

17.7' 84.99 143.9'

From Ref. 3. ' A = (CD3),SO-CDCI, ( 1 : 1); B = CD,NO, ; C = CDCI,. Includes unidentified signals. = C(1). Me(4a). C(4a).

' Me(1). 319


320

TABLE 7.15. MASS SPECTRA OF DIHYDROPYRIDql,2-a]BENZIMIDAZOLE DERIVATIVES (7.181k(7.183)0

...

,CH2C02Me n-

f (7.181)

k0,Me

R

702Me

CN

CN

(7.182)

(7.183) m* (metastable transition)

Comuound

m/c kel. abundance %) (assignment)

(7.l81;R2 = CN,

339(6.2)(M+), 266(100)(M - CH2C02Me)

-

485(9)(M+), 454(3.3) (M-OMe), 426(100) (M- C02Me), 41 2( 12) (M = C&CO,Me)

425.5, 375, and 343 (485-D 454,485-* 426, and 485 -D 412)

(7.181; R' =Me,

502(4) (M+), 443(100) (M-CO,Me), 429(30) (M-CH2C02Me), and 398(5.6) (M - CH2C02Me- OMe)

391 and 367 (502+443 and 502 + 429)

(7.181; R'=Me, R 2 = W .

455(5) (M+), 396(100) (M-C02Me) 382(18) (M - CH,CO,Me), and 364(7) 293(100) &I 265(2) +) (M ,-CO), 262(9.5) (M- OMe), and 234(17) (M - C0,Me) 267(100) (M+), 239(13) (M-CO), 236(10) (M - OMe), and 208(20) (M - C02Me)

345 and 335 (445-396 and 396-r 364) 240 and 187 (293-* 265 and 293 + 234) 214 and 208 (267+239 and 267 + 236)

R3=R4=H) (7.181; R' = H, R2 = C02Et, R3 = R4 = C0,Me) R2 = C02Et. R3 = R4 = C02Me) R3 = R" = C0,Me)

(7.182)

(7.183) From Ref. 6.

MASSSPECTRA. The Mass spectra (Table 7.15) of 1,5-dihydropyrido[1,2albenzimidazoles (7.181) contain weak molecular ion peaks and base peaks Loss of the C(1) ester corresponding to the loss of a C(1) ~ubstituent.~.~ substituent from substrates of the type (7.181; R4= C0,Me) on electron Primary loss of impact results in the formation of stable aromatic CO is a characteristic feature of the mass spectra (Table 7.15) of pyrido[ 1,2a]benzimidazol-1(5H)-ones [e.g. (7.182)] and pyrido[ 1 ,2-a]benzimidazol3(5H)-ones [e.g. (7.183)]. The mass spectra of fully unsaturated pyrido[ 1,2a ]benzimidazoles,"o*41 1,5-dihydropyrido(1,2-~&enzimidazoles,~ and 1,2,3,4tetrahydropyrido[1,2-a]benzimida~oles~~ have also been recorded. 7.1.3. Reactions

Reactions with Electrophiles

PROTONATION.The basicity of pyrido[ 1,2-a]benzimidazoles2' and their 1,2,3,4-tetrahydro derivative~~~ is demonstrated by the ready solubility of


32 1

these molecules in dilute mineral acids and their recovery unchanged on basification. The similarity of the UV spectra of 1,5-dihydropyrido[1,2-a]benzimidazoles in acidic solution to that of the benzimidazolium cation is indicative of preferential protonation of the former molecules at the C(4) position .2 ALKYLATION. The presence of the acidic NH-center in N(5)-unsubstituted pyrido[ 1,2-a]benzimidazol- 1(5W)-ones renders these molecules susceptible to orthodox methylation under basic conditions giving good yields (Table 7.16) of the corresponding N(5) methyl derivatives [e.g. Scheme 7.32, (7.184)].' and their The uncatalyzed alkylation of pyrido[ 1,2-a]benzimidazole~'~.'~.'~.~~ 1,2,3,4-tetrahydro derivative^^^.^"."^ also occurs at the N ( 5 ) position and affords good yields (Table 7.16) of the corresponding quaternary salts (7.185)and (7.186).Alkylation of this type can be achieved by heating with or alkyl halide^'^,^^.^^.^^.^^ and sulfatesI6 in the absence of solvent'8~29~3'~60~62 in solvents such as acetone6" or nitromethane.'6'6"

q * ; =.?$ C02Me

Me I

(3

Me

(7.184)

R'

(7.185)

R' I

(7.186)

X-

X-

srbcw 7.32

ACYLATION. H y d r ~ x y land ~ ~ amino2y'32substituents in fully unsaturated pyrido[ 1,2-a]benzimidazoles behave in orthodox fashion toward acetylation, giving the corresponding acetoxy and acetamido derivatives, respectively (Table 7.17). The activation of C(3)methyl substituents in N(5)-substituted pyrido[ 1,2-a]benzimidazolium salts toward acylative condensation has been exploited for the synthesis of cyanine dyestuffs. Condensation reactions of this type are illustrated (Scheme 7.33) by the reaction of the pyrido[l,2-a]benzimidazolium salt (7.187) with the benzothiazole derivative (7.188)to afford the cyanine (7.189)."' N(5)-unsubstituted pyrido[ 1,2-a]benzirnidazol-l(SH)-ones undergo orthodox acetylation at nitrogen with reagents such as acetyl chloride giving good yields (Table 7.17) of the N ( 5 ) acetyl derivatives.' In contrast N ( 5 ) unsubstituted pyrido[ 1,2-a]benzimidazol- 1(5H)-ones are formylated under

w

E

I D J F D D D D

H

F G

E

B D

B B

C

B

A B B

Alkylating agent"

1

10 3.5

3 3 4 5 15 16 2 15 15 15 15

30 15 1

-

-

110 120 120 110 110 110 100

-k -k -k -k

110 100

-k

100

-8

-k

-B

100 100

1.5 16

-

Reaction temp. ("C)

Reaction time (hr)

h

-n -

Acetone Acetone Acetone Acetone

-c

Acetone

-c

-

Trichloroethylenenitromethane

-c

-h

Dimethyl formamide

-c

Solvent

(7.186;R' = (CH,),OSO;) (7.186;R' = (CH,),SO,NHCOMe, X = Br) (7.186;R' = (CH2),S02NHCOMe, X = Br) (7.186; R' = (CH2),C0NHSO2Me, X = Br) (7.186; R' = Et, R2 = C1, X = I) (7.186;R' = (CH2),C0,H, RZ= CI, X = Br) (7.186; R' = (CH,),OSO;, R2 = Cl) (7.186;R' = Et, R3 = c1,X = I) (7.186;R ' = E t , R*=F, X = I ) (7.186;R' = Et, R2 = Br. X = I) (7.186;R'= Et, R' = CN, X = 1)

(7.185;R2 = R4 = Me, R' = CO,Et, X = I) (7.186;R' = Me, X = I) (7.186; R' = Me, X = I) (7.186;R' = Et, X = I) (7.186; R' = CH2Ph. X = C1)

(7.184) (7.185;X = I) (7.185;R3 = CO,Et, X = I) (7.185; R2 = R4 = Ph, X = I) (7.185;R' = CN, R2 = R4= Me, X = MeSO,)

Product ( R ' 4 R 4 unspecified = H)

TABLE 7.16. ALKYLATION REACTIONS OF PYRID011.2-alBENZIMIDAZOLEDERIVATIVES

-d -d -d

d

-

-d

70 70

c

-

C

-

56

(YO)

Yield

271-271.5 220-221" 210 246 288O (decomp.) 260 >260 206-208 238 >250 228 >260 250 >250 > 250 306

239' 246-247' 233-235' 280-282 207'

m.p. ("C)

60 60 60 60 60 60 60 60 60 60 60

33 29 60 60 62

7 29 33 18 16

Ref.

3

15

16

D

D

D

3 15 15

110 110 -k 110 110

110

100

110

-k

n

-

-

Acetone

-

-

-n

Acetone Nitromethane

-

O

" A = Mel, NaH; B = MeI; C = Me,SO,;

D = Etl; E = PhCH,CI; MeSO,NHCO(CH,),Br; J = HO,C(CH,),Br; K = HO(CH2),Br. Crystallized from dimethylformamide. No cosolvent. Yield not quoted. ' Crystallized from water. Reaction time not specified. Reaction temperature not specified. Reaction solvent not specified. ' Crystallized from acetone. Room temperature. Ir Reflux. ' Crystallized from ethanol. Crystallized from acetone-methanol. " Sealed tube conditions. Crystallized from ether-ethanol.

D D

r

K

4

15 1.5

B

D

X=I)

-d

0,

R2= So,

d

-d -d

-

F= 0 -

I

(CH2)3-0

I

so, ;

G = MeCONHSO,(CH,),Br;

>250 >250 >260 >250 >250

>250

>260 270 260

H = MeCONHSO,(CH,),Br;

(7.186; R ' = E t , R 2 = R 3 = C I , X = l ) -d (7.186; R' = (CH,),OH, R2 = R3 = CI, X = Br) -d (7.186; R' = (CH,),CONHSO,Me, X = Br) -d (7.186; R' = Et, R2 = CI, R3= CN, X = I) -d (7.186; R'=Et, R 2 = F . R3=CN, X = I ) -d

(7.186; R' = Et,

(7.186; R' = Et, R'= CN, X = I) (7.186; R' = Me, R2= CF,, X = I) (7.186; R ' = Et, R2 = CF,, X = I)

I=

60 60 60 60 60

60

60 60 60

g

W

*

>300

>zoo

320 (decomp.) 300 >350

144-146

14

14

-

C

14 14 C

-

14

-c -c -c

7

7

39

B = AeO.AcOH/(reflux)(reaction time not specified); C = A130/(100")(2 hr); D = AcCI, dimpropyla-

2-CHO-3-Et02C-4-CN-1(SH)-one54 2-CHO-3-BunO,C-4-CN-1(SH)-one73

2-CHO-3,7-di-Me-4-CN-l(5H)-one 98 2-CHO-3-Me-4-H2NCO-1(5H)-one 80

96

60

296-298

32 29 39

Ref.

Benzene Benzene-light petroleum (b.p. 60-80") Benzene-light petroleum (b.p. 60-80") Dichloromethaneethanol Ethanol

c

c

-


f

mine/(room temp.)(l hr); E = POCI,, dimethylforrnamide, CHCl,/(30-8Oo)(1 hr); F = POCI,, dimethylformamide, N-methylpyrrolidone/(10°)(30min), then (30-60")(1 hr), and finally (70°)(45min). Yield not specified. Solvent of crystallization not specified. Hydrate; the anhydrous base has m.p. 142-144". = Mixture. These m.p. assignments may be reversed.

A = Ae01(4Oo)(reaction time not specified);

F F

3,7-di-Me-4-CN-l(5H)-one 3-Me4H2NCO-l(5H)sne 3-Et02C-4-CN- l(SH)-one 3-Bun02C-4-CN-l(5H)sne

3-Me-4-CN- l(5H)-one

I(SH)-one 2-CHO-3-Me-4-CN- 1(5H)-one

E

F F

15

203-2041

230-231 106-108 209 139-14d

-b -b quant. 30

m.p. ("C)

Yield (%)

3-Me02C-4-CN-5-MeCO-1(5H)-one 73

3-MeO,C-4-EtO,C-l(5H)-one 3-Me0,C-4-EtO2C-5-MeC0-

3-MeO2C-4-CN-l(5H)-one

D

7-Me-8-MeC0,-

2-MeCONH6-MeCONH-d 8-MeC0,6-Me-8-MeCO2-

Product

D

7-Me-8-HO-

6-Me-8-HO-

2-NHZ6-NHZ-

r-+1

Substrate

Pyriddl,2 -a]benzimidazole

ACYLATION REACTIONS OF PYRID@~,~-u~BENZIMIDAZOLE DERIVATIVES

C

C

B

A

Reaction conditionso

TABLE 7.17.

7.1. Fused Benzimidazoles with No Additional Heteroatorn

/Ph

Me Ph

325

CO&t c10;

Et

I

(7.187)

COMe

Cl0;

(7.188)

(0 (26%)

CH=CH-CH

(7.189)

iJ3 I

Et

C10;

(m.p.288")

(i) 1,5-diazabicycl~3,2,2)nonane, MeCN/(room temp.)(lO min)

sckme 7.33

Vilsmeier-Haack conditions at the C(2) position thus providing high yield (Table 7.17) synthetic access to pyrido[ 1,2-a]benzimidazol- 1(5H)-one 2car box aldehyde^.'^ The application of acylative condensation of this type to the synthesis of dyestuffs is illustrated by the reaction (Scheme 7.34) of the pyrido[ 1,2-a]benzimidazol- 1(5H)-one (7.190) with the cyclic imide chloride (7.191)to give the condensate (7.192).68

I

(7.190)

(i) (84%)

(i) PhNO,/IO"

(7.192)

sebcae 7.34

(7.191)


326 TABLE 7.18.

ACYLATION REACTIONS OF ~,~,~,~-TETRAHYDROPYRIDO(~,~-U] BENZIMIDAZOLE DERIVATIVES

1,2,3,4-Tetrahydropyndo[1,2-a]benzimidazole Reaction conditions" Substrate A

B

C

D E F

Yield

(YO) m.p. ("C)

Product

7-NHZ9-NHZUnsubstituted Unsubstituted 8-02N-

7-MeCONH9-MeCONH-

-'

4-PhCO-

-

-'

-

72

77

4-CN-1,3-dione 2-(PhNHCH=)94 4-CN-1,3-dione

219.5-220 236-237 185-187 168-169 188 >300

Solvent of crystallization Ethyl acetate Ethanol -d -d


-d

Ref. 29 29 42,52 50,52 43 70

a A = Ac,O,AcOH/reRux (reaction time not specified); B = Ac20 (reaction conditions not specified); C=PhCOCI, 10% NaOH aq./room temp. (reaction time not specified); D = PhCOCI, 10Y0 NaOH aq. (reaction conditions not specified); E = PhCOCI, 15% NaOH aq. (reaction conditions not specified);F = PhNH,, (EtO),CH, ethylene glycol/(150-180°)(20min). Yield not quoted. 4,5-Dibenzoyl-1,2,3,5-tetrahydropyrid~1,2-a]benzimidazole. Solvent of crystallization not specified. 4,5-Dibenzoyl-8-nitro- 1,2,3,5-tetrahydropyrido[1.2-a]benzimidazole.

The typical behavior of nuclear amino substituents in 1,2,3,4-tetrahydropyrid~1,2-a]benzimidazoles toward acylation (Table 7. 18)29has been utilized in the synthesis of fused ring systems based on the 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole nucleus. In particular (Scheme 7.35) 7-amino-1,2,3,4tetrahydropyrido[ 1,2-aJbenzimidazole (7.193) condenses smoothly with @-keto esters [e.g. (7.194)] in the presence of ethyl polyphosphate giving COMe I +

H2N

YMe

COzEt (7.193)

(7.194)

Me (7.195) (i) ethyl polypho~phate/(165~)(0.75 hr) sebew 735


327

(7.1%)

I

PhCWOH

COPh

(7.198)

(7.197)

(7.199)

scbarc 7.36

the corresponding fused pyridin-4( 1H)-ones [e.g. (7.195)] in good yield.69 The reaction (Scheme 7.36)of 1,2,3,4-tetrahydropyrido[1,2-albenzimidazoles (7.196) with benzoyl chloride under alkaline as well as resulting in ring-opening to 1-(2-benzamidophenyI)piperidin2( 1H)-ones (7.197), affords products (Table '7.18) variously formulated as dibenzoyl derivatives (7.1!W2 and enol benzoates (7.1!J9).43

ELECTROPHILIC SUBSTITUTION REACTIONS. Information on the reactivity of pyrido[ 1,2-a]benzimidazoles toward electrophilic substitution is relatively sparse. Electrophilic halogenation, for example, appears to have been studied only in the single. instance of the bromination of a 4a,5-dihydropyrido[ 1,2-~]benzimidazole to give a monobromo derivative of unestablished constitution.2 Nitration (Table 7.19), on the other hand, has been more extensively investigated and in the case of pyrido[ 1,2-a]benzimid a ~ o l eaffords ~ ~ the 8-nitro derivative in good yield. The nitration of 1,2,3,4-tetrahydropyrido[1,2-a]ben~imidazoles~~*~~*~" IS . also readily accomplished in good yield (Table 7.19) using nitric acid or potassium nitrate in conjunction with concentrated sulfuric acid and, depending on the substitution pattern of the benzene ring in the substrate, occurs at the C(7) or C(8)

00

29 49 49

d

-d -d -

60

Methyl ethyl ketone Ethanol Ethanol

184 264 199-200 204 220

180

-d

49 60 49 60

60

Ethanol

171 194

29

Ref. Methanol

-d


271-272

-c

Yield (%) m.p. ("C)

8-OzN59 8-0,N-1,2,3,4-tetrahydro-b 7-CI-8-O2N-1,2,3,4-tetrahydro-b 7-CI-8-02N-1,2,3,4-tetrahydro-b 7-02N-8-C11,2.3,4-tetrahydro-b 7-Br-8-0,N1,2,3,4-tetrahydro-b 7-F-8-OZN-1,2,3,4-tetrahydro-b 7-MeCONH-8-OZN-l,2,3,4-tetrahydro84 7-MeCONH-8-02N-1,2,3,4-tetrahydro-88 8-MeCONH-7-O2N-1,2,3,4-tetrahydro85

Pyrid~l.2-n)bendmid~k Product

Unsubstituted 1,2,3,4-tetrahydro7-CI-1,2,3,4-tetrahydro7-CI-1,2,3,4-tetrahydro8-C1-1,2,3,4-tetrahydro7-Br-1,2,3,4-tetrahydro7-F-1,2,3,4-tetrahydro7-MeCONH-1,2,3,4-tetrahydro7-MeCONH-1,2,3,4-tetrahydro8-MeCONH-1,2,3,4-tetrahydro-

Substrate

'

" A = conc. HNO,, conc.H,SO4/(O-15")1 hr 20 min), then (40-500)(15 min); B = conc.HNO,,conc. H,SO.,/(CrSO) (reaction time not specifid);C = KNO,, conc. HzS0.,/(O-50), then (room temp.)(l hr); D = conc. HNO,, conc. H2S0,/(-10 to -So), then (Oo)(l hr). Yield not quoted. Melting point not quoted. Solvent of crystallization not specified.

B D C C

B

C

B

A B C


Table 7.19. N I T R A T I O N REACllONS OF PYRIDOl1.2-alBENZIMIDAZOLEDERIVATIVES


329

OH

NO2

(7.200)

(i)

KNO,, conc. HzS0J(20-25")16 hr)

(7.201)

[m.p. 235" (decomp.)]

scbcpe 7.37

position. Nitration (Scheme 7.37) of the oxazolo-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole (7.200) is accompanied by ring scission, the product being a nitro derivative (of unestablished orientation) of 8-acetamido-9hydroxy-l,2,3,4-tetrahydropyrido[1,2-a]benzimidazole(7.201).48 Amino substituents in the benzene ring of pyrido[ 1,241b e n ~ i m i d a z o l e s and ~ ~ *their ~ ~ 1,2,3,4-tetrahydro derivative^^^*^^.'^*^^ can be diazotized under standard conditions to afford diazonium salts, which in some instances can be isolated, and in general undergo reactions (e.g., deamination) typical of such intermediates. The reactivity of the C(2) position in pyrido[ 1,2-a]benzimidazol- 1(5H)-ones toward diazo coupling has been exploited for the synthesis of a wide range of azo dyestuff^.^^ The amination (Scheme 7.38) of pyrido[ 1,2-a]benzimidazole (7.202; R = H) by 0-toluene-p-sulfonyl hydroxylamine is reported" to occur at the N ( 5 ) position giving 5-aminopyrido[ 1,2-a]benzimidazolium tosylate (7.203) in good yield. In contrast, the product derived by reaction (Scheme 7.38) of a

I

NH2 TSO; (7.203) (m.p. 195-196')

(7.204)

a-

[m.p. 163' (decomp.)]

(i) N H z O S 0 2 T , C H 2 C 1 2 / (ternp.)(0.25 ~ hr) (ii) ~ z ~ , ~ c 1 3 / ( 1 0 - 2 0 0 )hr) (48 [T= p-tolyl] sckre 7.38


330

hydroxypyrido[ 1,2-a]benzimidazole (7.202; R = OH) with chloramine is formulated as the N(10) amino derivative (7.204).73 The sulfonation and chlorosulfonation (Scheme 7.39) of pyrido[ 1,2-a]benzimidazol- 1(5H)-ones occurs preferentially at unestablished sites in the benzene ring.

HSO, (679cl. (i)

k $ C 0HI 2 E CONH2 t

(7.205)

(7.206) (m.p. > 340")

slJ$ HI

a

(-302

& , A m

CH2COzEt

(7.207)

2C02Et

(7.208) (m.p. > 300")

(i) 23% oleum/(W)(2 hr). (ii) C1SO3H!(8O0)(4hr). (iii) morpholme. N-methylpyrrolidone/(20-30°)(I hr)

scicw 7.39

Reactions with Nucleophiles The ring systems in fully unsaturated pyrido[ 1,2-a]benzimidazoIes and their 1,2-dihydro- and 1,2,3,4-tetrahydro derivatives are stable to acidic conditions suitable for the hydrolysis (Table 7.20) of acetamido subs t i t u e n t ~ , ~or~ *of~ nitriles ~ * ~ ~ to carboxylic acids" or for the hydrolytic removal of ester substituents."' The ring system in pyrido[ 1,2-a]benzimidazole 1(5H)-ones likewise remains intact under acidic and basic conditions, which serve to convert ester or cyano substituents into carboxyl or carboxOn the other hand, 1,2,3,4-tetrahydroamide groups, re~pectively.'~*'~ pyrido[ 1,2-a]benzimidazoles quaternized at N ( 5 ) are susceptible to nucleophilic ring-opening under alkaline condition^.^' Processes of this type are illustrated (Scheme 7.40) by the reaction of 1,2,3,4-tetrahydropyrido[l,2albenzimidazole (7.209) with benzoyl chloride in the presence of aqueous sodium hydroxide to afford 1-(2-benzamidophenyl)piperidin-2(1H)-one (7.212).43This transformation is r a t i o n a l i ~ e din~ ~ terms of the intermediate

1.2.3-tri-Me-4-CN-

1,3-di-Me-2-HO,CCH2-4-CN-

2-NO2-4-CN-

1,3,7(8)-tri-Me-4-CN-

A

A

A

A

3,5-di-Me-4-C02Et-, perchlorate 3-MeO2CCH,-4-CN- 1,Sdihydro1(5H)-one 3-Me-4-CN- 1.5-dihydro- 1(5H)-one

3-C02Et-4-CN- 1,Sdihydro- l(5 H)-one

D

E

C

3-CO2Et-4-CONH,- 1.5-dihydrol(SH)-one

3,5-di-Me-. perchlorate 3-H02CCH2-4-CN-1.5-dihydrol(SH)-oneb 3-Me-4-CONH2-1,5-dihydro1(SH)-one

1,3-di-Me-4-CO2H-7,8-di-CI-

1,3-di-Me-4-CN-7,8-di-C1-

A

B

96

1,3-di-Me-4-CO2H-7-CI-9-NH, -

1,3-di-Me-4-CN-7-CI-9-NH2-

A

-c

93

-

55

82

80

1.3-di-Me-4,7(8)-di-CO2H-

1,3-di-Me-4-CN-7(8)-C0,H-

A

91

1,3-di-Me-4-CO2H-7(8)-CI-

1,3-di-Me-4-CN-7(8)-CI-

56

80

86

95

66

95

75

1,3-di-Me-4-CO2H-7(8)-MeO-

1,3,7(8)-tri-Me-4-CO2H-

2-N02-4-C0,H-

1,3-di-Me-4-CO2H-

3-Me-4-C02H-

Yield

(Yo)

A

1,3-di-Me-4-CN-7(8)-MeO-

1,3-di-Me-2-HO,CCH,-4-C0,H-

1,3-di-Me-4-CN-

A

w : A

1,2,3-tri-Me-4-C02H-

3-Me-4-CN-

A

Product

PyridoE1,2-a lbenzimidazole

Substrate

Reaction conditions’ Solvent of crystallization

270 (decomp.) >290

14 15

-d

1l a 15

12

12

12

12

12

12

12

12

12

12

12

Ref.

-d

Dimethylformamidewater 253 Dimethylformamidewater 242-243 Dimethylformamidewater 268 Dimethylformamidewater 176 Dimethylformamidewater 240 Dimethylformamide (decomp.) water 244 Dimethylformamidewater 305 Dimethylformamide water 345 Dimeth ylformamide (decomp.) water 280 Dimeth y lformamide (decomp.) water 258 Dimethylformamide (decomp.) water 240-245 Ethanol >310° -

240

m.p. (“C)

TABLE 7.20. HYDROLYTIC AND RELATED REACTIONS OF PYRIDq1,2-a JBENZIMIDAZOLE DERIVATIVES

w

3

4-PhC0,NH- 1,2,3,4-tetrahydro-1-one 4-NH,- 1.2,3,4-tetrahydro-1-one

7-MeCONH-8-NO2-1,2,3,4-tetrahydro- 7-NH2-8-N0,- 1,2,3,4-tetrahydro7-NO2-8-MeCONH-1,2,3,4-tetrahydro- 7-NO,-8-NH2- 1,2,3,4-tetrahydro-

Yield

83

147

253 310

-c -c

52 86 83

93

-c

m.p. ("C) >170 (decomp.) 315 (decomp.) 206-210 285-287 146-148 266-267

81

(%)

15

-d

23

49 49

1la 26 26 29

15

-d

Ethanol-acetonitrile Ethanol-water Hexane Ethylene glycol monoethyl ether Ethanol-water Ethylene glycol monoethyl ether Ether-me thanol

Ref.


" A = conc. H2S04, AcOH, H,0/(150")(20 hr); B = conc. HCI, dimethylacetarnide/(reflux)(40-60 min); C = 50% NaOH sq./(2O-4O0)(14 hr); D = 80% H2S04 aq./(lOO")(lhr); E = 85% H2S04 aq./(100-11Oo)(4hr); F = Bu"OH, 96% H2S04 aq./(reflux)(30hr); B = Bu"NH2, toluene-p-sulfonic acid/(reflux)(8hr); H = conc. H2SOJ(145-15Oo)(2 hr); I = HCl gas, EtOH/(room temp.)@ days); J = 2 M HCl/(reflux)(lSmin); K = conc. HCl/(reflux)(lhr); L = 25% HBr-AcOH/(room temp.)(l6 hr). Sodium salt. Yield not quoted. Solvent of crystallization not specified. ' Forms a hydrochloride, m.p. 304" (decomp.).

L

K K

J

1

H

B

3-C02Et-4-CN- 1,5-dihydro-l(SH)-one

G

3,4-di-C02Bu"- 1,s-dihydro-1(5H)-one

3- CONHBu" -4-CN- 1,s-dihydrol(SH)-one 3.5-di-Me-4-C0,Et- 1,2-dihydro3,5-di-Me-1,2-dihydro4-CO2H-4-Ph-1,2,3,4-tetrahydro4-CN-4-Ph- 1,2,3,4-tetrahydro4-COzH-4-Ph-1,2,3,4-tetrahydro4-CO2Et-4-Ph-1,2,3,4-tetrahydro7-MeCONH-8-N02- 1,2,3,4-tetrahydro- 7-NH,-8-N02- 1,2,3,4-tetrahydro-'

3-C02Et-4-CN- 1,s-dihydro-l(SH)-one

F

Pyridd 1,2-albenzimidazole Product

Substrate




333

formation and ring-opening of 5-benzoyl- 1,2,3,4-tetrahydropyrido[1,241benzimidazolium chloride [Scheme 7.40; (7.210) 4(7.211) 4(7.2l2)I.

(7.209) (7.210)

NHCOPh (7.212) COPh (7.211) !k!baue 7.40

1,2,3,4-Tetrahydropyrido[1,2-albenzimidazole 5-N-oxide unlike its 2,3dihydro-lH-pyrrolo[l,2-a]benzimidazolecounterparts (cf. Chapter 6, sec-

tion 6.1.3, “Reactions with Nucleophiles”) gives only tars on attempted nucleophilic halogenation with acid halides.74 O n the other hand, nuclear diazonium salts derived from 1,2,3,4-tetrahydropyrid~l,2-u)benzimidazoles behave like the corresponding 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzirnidazole derivatives (cf. Chapter 6, section 6.1.3, “Reactions with Nucleophiles”) in undergoing replacement by cyanidem and azide*’~~~ ion affording methods (Table 7.21) for the synthesis of cyano- and azido1,2,3,4-tetrahydropyrido[1,2-a]benzirnidazoles. Azidopyrido[ 1,2-a]benzimidazoles are likewise accessible from the corresponding diazonium

Oxidation The pyrido[ 1,2-a]benzimidazole ring system is relatively stable to oxidation under a variety of conditions. Thus, bromine effects the oxidative dimerisation (Scheme 7.4 1) of the N-aminopyrido[ 1,2-albenzimidazolium salt (7.213) to the azo compound (7.214);’ and also promotes the dehydrogenation (Table 7.22) of a 1,5-dihydropyrido[1,2-a]benzirnidazole to the corresponding benzimidazolium cation.2 Pyrido[ l,Za]benzimidazoles are also formed as the stable end-products of the palladium-charcoal catalyzed dehydrogenation (Table 7.22) of 1,2-dihydro-,”” 1,2,3,4-tetrahydr0-,’~ and

W W

7-NH2-8-NO,-1,2,3,4-tetrahydro-7-N,-8-NO,-1,2,3,4-tetrahydro-

C

7-NO2-8-NH,-1,2,3,4-tetrahydro- 7-NO2-8-N,-1,2,3,4-tetrahydro-

-

-

194 (decomp.) 195 (decomp.)

194 212 210 253 167 (decomp.) 132

m.p. ('C)

-d

-d

Light petroleum, b.p. 80-100" Light petroleum b.p. 100-120'

-c

c c

c

-


49

49

27

60 60 60 60 27

Ref.

a A = NaN02, HCl aq./(o"), then CuCN. KCN, Na,CO,/(room temp.)(30 mh), and finally (50-60")(15 min); B = NaNO,, H,SO,. H,PO,/(lo"), then treat with NaN,; C = NaNO,, HCI aq./(o"), then treat with NaN,. Yield not quoted. Solvent of crystallization not specified. Decomposes on attempted crystallization.

C

6,8-di-N3-1,2,3,4-tetrahydro-

-

A A B

A A

6,8-di-NH2-1,2,3,4-tetrahydro-

-

Yield (%)

B

pYrid~l,2-o]benzimidazole Product

-

Substrate

8-MI,- 1,2,3,4-tetrahydro8-CN-1,2.3,4-tetrahydro7-CI-8-NH2-1,2,3,4-tetrahydro- 7-CI-S-CN-1,2,3,4-tetrahydro7-Br-8-NH,-1,2,3,4-tetrahydro- 7-Br-S-CN-l.2,3,4-tetrahydro7-F-8-NH,-1,2,3,4-tetrahydro- 7-F-S-CN-l.2.3.4-tetrahydro6,8-di-NH26,8-di-N,-


TABLE 7.2 1, DISPLACEMENT REACTIONS OF PYRIDO[l,2-a]BENZIMIDAZOLE DIAZONIUM SALTS

U

w w

1,2,3,4-tetrahydro6,7,8,9-tetrahydro2-NO,-6,7,8,9-tetrahydro-

Unsubstituted Unsubstituted 2-NO2-

1,2,3,4-tetra-C02Me-5-Me-, perchlorate 1,3-di-Me-

3-Me-4-C02Et-5-Ph- perchlorate

3,5-di-Me-, perchlorate 3,5-di-Me-4-C02Et-, perchlorate

Pyrido[ 1.2-9 Ibenzimidazole Product

3,5-di-Me-l,Z-dihydro-, perchlorate 3,5-di-Me-4-C02Et- 1,2-dihydro-, perchlorate 3-Me-4-C02Et-5-Ph-l ,2-dihydro-, perchlorate 1,2,3,4-tetra-C02Me-5-Mel,S-dihydro-, perchlorate 1.3-di-Me-3.4-dihydro-

Substrate

4

-* -

57

75

50

54

58

178-179 176-177 240-241

113-115

188-189

240-245 242-245 (decomp.) 230-232

Yield ('10) m.p. ("C)

Methanol (trace of HCIO,) Light petroleum b.p. 30-70" Chlorobenzene Benzene Ethanol

Ethanol

Ethanol Ethanol


DEHYDROGENATION REACTIONS OF DIHYDRO- AND TETRAHYDROPYRIDO[l,2-a]BENZIMIDAZOLE DERIVATIVES

29 37 32

19

2

1l a

1l a 1l a

Ref.

a

A = 10% PdC, dimethylacetamide/(reflux)(l hr); B = Br,, HCIO,, AcOH/(100")(30 min); C =MnO,, benzene/(reflux)(2 hr); D = PdC/(306")(20 min); E = PdC/(300°)(6 hr); F = chloranil, xylene/(reflux)(44hr). Yield not quoted.

F

D E

C

B

A

A

A


TABLE 7.22.

336


I NH2 TSO; (7.213) (7.214) (i) Br,/(room temp.)(few min) CT = p-tolyl]

sdwre 7.41

6,7,8,9-tetrahydropyrido[1,2-a]benzirnida~oles.~~ The dehydrogenation of molecules of the latter type can also be accomplished using chloranil as the oxidant.32 The stable aromatic character of pyrido[ 1,2-a]benzimidazoles is further illustrated by their synthesis in good yield (Table 7.22) by the manganese dioxide oxidation of readily accessible 3,4-dihydropyrido[ 1,243benzimidaz~les.’~The 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole ring system, in contrast, is relatively stable to oxidants such as manganese dioxide, hydrogen peroxide, lead tetraacetate, and chloranil, as demonstrated by the utility of these reagents for the conversion of 1,2,3,4,4a,Shexahydropyrido[l,2-a]benzimidazole derivatives into 1,2,3,4-tetrahydropyrido[ 1,2-a]benzimidazoles (Table 7.22).’“ The lead tetraacetate oxidation (Scheme 7.42) of the benzenesulfonate salt of the 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole derivative (7.215) gives a pink solution, whose spectroscopic properties are consistent with the presence of the cation (7.216).66

(7.215)

(i) Pb(OAc),. AcOH/(room tempJ(l2 br)

(7.216) (Am.= 540 nrn)

sekrpc 7.42

Reduction The fully unsaturated and 1,s-dihydropyrido[ 1,2-a]benzimidazole ring systems are stable to reduction (Table 7.23) with iron and hydrochloric

w

Y

-

-c

8-NHZ-

J

8-NHz- 1,2,3,4-tetrahydro-

-c

K K

J

1

90

85

-c

66

73

6-NHZ-8-NOz4-Me-6-NH,-8-NOz6,8-di-NH24-Me-6,8-di-NH21,2,3,4-tetra-C02Me-5CO,Me-S-(MeO,C&==CHCO,Me)- (MeCHCH,CO,Me)- 1,SdihydroI 1,S-dihydrd7-NH,-8-NO2- 1,2,3,4-tetrahydro8-N02- 1,2,3,4-tetrahydro6-NHZ6-NH,- 1,2,3,4-tetrahydro7-N02-1,2,3,4-tetrahydro7-NH2-1,2,3,4-tetrahydro8-NO2-1,2,3,4-tetrahydro8-NH,- 1,2,3,4-tetrahydro-

-e -c -c

6,8-di-NO24-Me-6,8-di-NOz6,8-di-NO24-Me-6,8-di-NO21,2,3,4-tetra-

G G F F H

93 81 80

89 88 60

C

-

195-197

217-219 176-177 218-220 19&200

>280 269-270 204-205 130' 173-174

260-262 260-262 220 (decomp.) 133134 229-230 185-187

-

178-179

162

179

-

-c -c -

50

71

6-NOz8-NOz4-Me-8-N026-NHZ8-NH24-Me-8-NH2-

4-Me8-NOZ4-Me-8-N022-NHz-

4-Me-6,8-di-N26-NHZ-8-NOz4-Me-6-NH,-8-NO22-NOZ-

+

Unsubstituted Unsubstituted Unsubstituted Unsubstituted 4-Me-

8-yHz8-N,-, sulfate 6,8-di-rH26,8-di-N,4-Me-8-h2-

Yield (%) m.u. ("C)

E F F

D

A A

B

B C B B

A

Product

qrlido[l.2-a&enzimidazole

REDUCTION OF PYRID0[1,2-a]BENZIMIDAZOLEDERIVATIVES

Reactions conditions" Substrate

TABLE 7.23.

Methanol Ethyl acetate Methanol Ethyl acetatemethanol Ethyl acetatemethanol

Benzene Xylene Light petroleum (b.p. 100-120") Nitrobenzene Xylene Ethanol Benzene Methanol

-

Pyridine Xylene

-

Light petroleum (b.p. 40-60')

-d -d

-

b

-


29

29 29 29 29

27 27 27 27 2

29 27, 28 27

27 27 27 32

28 21 27 27 27

Ref.

W W W

5-(2-CI-S-O2NC6H,CH,)- 1,2,3,4tetrahydro-, chloride

0

-

C

-c -

quant.

-'

1,2,3,4,4a,S-hexahydro5-(2-CI-5-0,NC6H,CH,)- 1,2,3,4,4a,5hexahydro-

7-F-8-NHZ-1,2,3,4-tetrahydro7-NH,-8-(l-piperidyl)-1.2,3,4-tetrahydro--'

7-Br-8-NH2-1,2,3,4-tetrahydro-

9-NH,- 1,2,3,4-tetrahydro7-CI-8-NH2-1,2,3,4-tetrahydro-

9697

119

186-187 210 217 199 189-191

Yield (%) m.p. ("C)

29 60 60 60 29

Ref.

Ethyl acetate58 light petroleum Light petroleum 62

Ethyl acetate

J

-f

J

Benzene


a

A = NaNO,, H,SO,, H3POI/(-S0), then EtOH, H,O/reflux (reaction time not specified); B = EtOH, H,O/reflux (reaction time not specified); C=NaNO,, HCI aq./(o"), then A1 powder, EtOH/reflux (reaction time not specified); D = H,, 5% PdUroom temp., atm press; E = F e , AcOH, H,O/(reRux)(3 hr); F = H,, PtO,, EtOH/70", 3-5 arm; G = Na,S, S, acetone. H,O/(reflux)(2 hr); H = H,, PdC, MeOH/(room temp., 3-5 atm)(l7hr); I = NaNO,, HCI aq./(3-5'), then H,P0,/(39")(30 min); I = H,, hO,, MeOH/(90-100', 60 atm)(3 hr); K = H,, Raney-Ni, MeOH/(50-6O0)(5atm); L = Fe, NaOAc, HCI, AcOH, HzO/(reflux)(3.5hr); M = H,, Raney-Ni, ethyleneglycol monomethyl ether/room temp., atm. press; N = LiAlH,, ether/(reflux)(Sdays); 0 = NaBH,, H,O/(room temp.)@ min). * Purified by crystallization from light petroleum (b.p. 4060"). followed by sublimation. Yield not quoted. Purified by sublimation. Melting point indefinite. f Solvent of crystallition not specified.

N

K

7-F-8-N02- 1.2,3.4-tetrahydro7-N02-8-(1-piperidyl)-1,2,3,4tetrahydro1,2,3,4-tetrahydro-

7-Br-8-NO2-1,2,3,4-tetrahydro-

9-NO2-1,2,3,4-tetrahydro7-CI-8-NOZ-1,2,3,4-tetrahydro-

Product

Pyridoll,2-aIbenzimidazole

M

M

M

L

Reactions conditionsa Substrate



339

acidz9 or hydrogen over p l a t i n ~ m or ~~’~~ catalysts at atmospheric pressure or somewhat above (1-5 atm.) under conditions which serve to convert nitro into amino ~ u b ~ t i t u e nort ~saturate ~ ~ - ~unsaturated ~ ~ ~ ~ side chains.2 However, the hydrogenation (Table 7.23)29 of pyrido[ 1,2-a)benzimidazole derivatives over a platinum catalyst at elevated temperature (90-lOO0) and pressure (50-60 atm.) results in reduction of the pyridine ring giving the corresponding 1,2,3,4-tetrahydropyrido[l,2-a]benzimidazoles. The stability of the 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole ring system to catalytic reduction thereby demonstrated is further substantiated by the utility of hydrogenation over Raney nickel at atmospheric pressure6’ or abovez9as a means for the conversion of nitro- 1,2,3,4-tetrahydropyrido[1,2a]benzimidazoles into the corresponding amines (Table 7.23). On the other hand, 1,2,3,4-tetrahydropyrido[l,2-a]benzimidazole derivatives are readily reduced (Table 7.23) to 1,2,3,4,4a,5-hexahydropyrido[1,2-a]benzimidazoles using lithium aluminum hydridess or sodium borohydride.62 The reductive removal of diazonium substituents from pyrido[ 1,2-a]benzimidazoles or their 1,2,3,4-tetrahydro derivatives is accomplished in an orthodox manner using hypophosphorus acid2’ or simply by heating with ethan01.*~*~~ Selective reduction of the C(6) nitro substituent in a 6 3 dinitropyrido[ 1,2-a]benzimidazole can also be achieved in classical fashion using sodium p ~ l y s u l f i d e . ~ ~

Miscellaneous Reuctions The thermolysis of azido- 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazoles under different conditions provides the basis for the synthesis of tetracyclic structures containing a 1,2,3,4-tetrahydropyrido[l,Za]benzimidazole nucleus. Annelation reactions of this type are represented by the oxazolopyrido[ 1,2-a]benzimida~oIe~~ and oxadiazolopyrido[1,2-a lben~imidazole~~

afJ (7.217)

(7.218)

-im3 (i)

N3

\

/

(7.219)

Me

(7.220)

(i) plyphosphoric acid, AcOH/(reRux)(:! hr) sebemc 7.43

I

NH2

(7.226)

(7.227)

Ph N+N

Ph (7.228)

!atme 7.45

340

(7.229)

N’

7.2. Fused Benzimidazoleswith One Additional Heteroatom

34 1

syntheses outlined in Schemes 7.43 and 7.44. The oxidative transformation (Scheme 7.45)75of the fused N-amino- 1,2,3-triazole (7.226) in the presence of phenyl azide into the isomeric 1,2,3-triazolopyrido[1,2-a]benzimidazoles (7.228) and (7.229) is indicative of the intermediacy of the benzyne derivative (7.227). 7.1.4. Practical Applications

Biological Properties Analgetic activity7' apart, the biological properties of pyrido[ 1,2-a]benzimidazoles appear to have attracted little attention.

Dyestuffs Pyrido[ 1,2-a]benzirnidazole derivatives have found widespread use as components of azomethine,' azo,' 5*7 ' * 7 8 and cyaninem dyestuffs, and as photographic sensitizing agents.79

7.2. Tricyclic 6-5-6 Fused Benzimidazoles with One Additional Heteroatom The known oxygen-containing structures in the title category (cf. Scheme 7.46 and Table 7.24) include the 3,4-dihydro-2H-[ 1,3]oxazino[3,2-a]benzimidazole (7.232), the 3,4,4a,5-tetrahydro-lH-[l,3]oxazino[3,4-albenzimidazole (7.234), and the 3,4-dihydro- 1H-[ 1,4]oxazin0[4,3-a]benzimidazole (7.237) ring systems. Derivatives of the corresponding, parent, unsaturated 2H- and 4H-[ 1,3]0xazino[3,2-a]benzimidazole ring systems (7.230) and (7.231), the 1H-[1,3]oxazino[3,4-a]benzimidazole ring system (7.233) and the 1H- and 10H-[ 1,4~xazino[4,3-a]benzimidazolering systems (7.235) and (7.236) do not appear to have been described to date. Tricyclic 6-5-6 fused benzimidazole frameworks having sulfur as an additional heteroatom are represented (Scheme 7.47 and Table 7.24) in the literature by the 2H-[ 1,3]thiazino[3,2-a]benzimidazole ring system (7.238), its 4 H isomer (7.239) and 3,4-dihydro derivative (7.240), and by the 1H[1,4]thiazino[4,3-a]benzimidazole ring system (7.242), its 10H isomer (7.243),and 3,4-dihydro (7.244) and 10,lOa-dihydro (7.245) derivatives. A search of the literature has failed to reveal any reference to the 1H-[1,3]thiazino[3,4-a]benzimidazole ring system (7.241) or its derivatives.

(7.230)

(7.231)

(7.232)

(7.233)

an

1

6

(7335)

R

(7.234)

8'-"? N

b

I

lt (7.236)

(7.237) sekme 7.46

TABLE 7.24. TRICYCLIC 6-5-6FUSED BENZIMIDAZOLE RING SYSTEMS WITH O N E ADDITIONAL HETEROA T O M (OXYGEN O R SULFUR) Structure"

(7332) (7.234) (7.237) (7.238) (7.239) (7.240) (7.242) (7343) (7.244) (7.245) a

Nameb

3,4-Dihydro-2H-[ 1,3]oxazino[3,2-a]benzimidazole 3,4,4a,S-Tetrahydro1H-[ 1,3]oxazino[3,4-a]benzimidazole 3,4-Dihydro-1 H-[l,4]oxazino[4,3-a]benzimidazole 2H-[1,3miazin0(3.2-a ]benzimidazole 4H-[1,3~iazino[3,2-o]benzimidazole 3,4-Dihydro-2H-[ 1,3]thiazinO(3,2-a]benzimidazole 1 H-[ 1,4JThiazinO(4,3-a]benzirnidazole 1 OH-[ 1,4JIl1iazino[4,3-a]benzimidazole 3,4-Dihydro1 H-[ 1,4]thiazinO(4,3-a]benzirnidazole 10,lOa-Dihydro1H-[ 1,4]thiazin~4,3-a]benzimidazole

Cf.Schemes 7.46 and 1.47.

* Based on the Ring Index.

342

7.2.

Fused Benzimidazoles with One Additional Heteroatom

(7.238)

(7.239)

(7.240)

(7.241)

343

6

9

10

1

R

(7.242)

(7.243)

R

(7.244)

(7.245) Schane 7.47

Fully nitrogen-containing tricyclic 6-5-6 fused benzimidazoles having one additional heteroatom comprise some 16 ring systems (Scheme 7.48 and Table 7.25). Of these, the pyrimido[ 1,2-a]benzimidazole ring system (7.247) and its various dihydro (7.248)-(7.252), tetrahydro (7.253), (7.254), and (7.256), and hexahydro (7.257) derivatives have been most extensively studied. The chemistry of pyrimido[ 1,2-a]benzimidazoles was briefly reviewed in 1961."'

(7.246)

(7.247)

R

R

(7.248)

(7.249)

R

(7350)

(7.251)

R (7352)

(7353)

R

(7.255)

(7.254)

R

(7.256)

(7.257)

R

(7.258)

(7.259)

(7.262) scheme 7.48

344

R


345

Though the reduced frameworks (7.256) and (7.257) have been described in the literature, derivatives of the fully unsaturated pyrimido[3,4albenzimidazole ring system (7.255) have yet to be reported. TABLE 7.25. TRICYCLIC 6-5-6FUSED BENZIMIDAZOLE RING SYSTEMS WITH O N E ADDITIONAL HETEROATOM (NITROGEN) Structure"

Name"

(7.246) (7.247) (7.248) (7.249)

Pyridazino[2,3-a]benzimidazole Pyrimido[1 ,Z-a]benzimidazole l,Z-Dihydropyrimid~l.2-a]benzimidazole 1 ,4-Dihydropyrimido[ 1,2-a]benzimidazole 3,4-Dihydropyrimido[ 1,2-a]benzirnidazole 2,lO-Dihydropyrimidd1,2-a]benzimidazole 4,10-Dihydropyrimido[1,2-a]benzimidazole 1,2,3,4-Tetrahydropyrimido[1,2-a]benzirnidazole 2,3,4,lO-Tetrahydropyrimid~l,2-a]benzimidazole 1,2,3,4-Tetrahydropyrimido[3,4-a~enzimidamle 1,2,3,4,4a,5-Hexahydropyrimido[3,4-a]benzimidazole Pyrazino[1,2-aIbenzimidazole 4,10-Dihydropyrazino[ 1,2-a]benzimidazole 1,2,3,4-Tetrahydropyrazino[l,2-a]benzimidazole 2,3,4,1O-Tetrahydrop yrazino[1,2-a]benzimidazoIe 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]benzimidazole

(7350)

(7.251) (7352) (7353) (7.254) (7.256) (7.257) (7258) (7.259) (7360) (7.261) (7.262)

" Cf.Scheme 7.48.

* Based on the Ring Index. 7.2.1. Synthesis

Ring-closure Reactions of Benzimidazole Derivatives The 3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazolering system is most readily constructed by the base-catalyzed ring-closure of 2benzimidazolones having a suitably y-functionalized propyl side chain at N(1). Ring formation of this type involves the intramolecular nucleophilic displacement of a leaving group at the y-position of the propyl side chain by the C(2) 0x0 group of the imidazolone ring and is exemplified (Scheme 7.49) by the sodium ethoxide catalyzed cyclization of 1-(3-hydroxypropyl)benzimidazol-2(3H)-one tosylate (7.264; X = p-MeC,H,SO,O) to 3,4dihydro-2H-[ 1,3]oxazino[3,2-a]benzimidazole (7.265) in good yield (Table 7.26)." The sodium hydride catalyzed condensation of 2-benzimidazolone (7.263) with 1,3-dibromopropane to afford 3,4-dihydro-2H-[ 1,310xazino[3,2-a]benzimidazole (7.265) in unspecified yield (Table 7.26)"*83 may likewise be rationalized in. terms of the intermediate formation and basecatalyzed cyclization of 1-(3-bromopropyl)benzimidazol-2(3H)-one(7.264; X=Br). The products, formed in good yield (Table 7.26) by the reaction


346

a 300

Acetic acidwater

121

(7315;R' = Ph, 50 R, = H)

>330

Ethanol

122

(7315; 25 R1 = R2 = Me)

325-330

Ethanol

122

248-250

Formic acidwater

119

120

(7315;R' = H, 30 R2= C0,Et) (7315;R ' = H , R2 = C02Et)

36

270-272

Dimethylformamide

(7.315;R ' = H , RZ= CN)

95

>350

Cyclohexanone I 1 9

J

" A = no cosolvent/l8O0 (reaction time not specified); B = AcOH or EtOH/reflux (reaction time not specified); C = no cosolvent/reflux (reaction time not specified); D = no cosolvent/(l2O0) 1.25 hr). * Yield not quoted.

Pyrimido[1,2-~]benzimidazolesynthesis of this type is readily accomplished by heating the reactants together in the absence of solvent" 1.120.122-125*127 or in ethanol, 11 1.l21,127 acetic acid,'" or dimethylformamide." ' In some instances (Table 7.3 1) condensation catalysts such as sodium ethoxide,'" toluene-p-sulfonic acid,"' and polyphosphoric acid126are employed with advantage. The p-keto ester components in condensation reactions of this type can be replaced (Table 7.31) by p-keto amides1I6or nitriles128aand in the specific case of ethyl acetoacetate by ethyl p-aminocrotonateL'1*122 or

w

M N N

0

D

P 0

R

(7.299)

(7399; R'=CI)

(7.299; R'=CI)

(7.299; R' = R2 = Me) (7310; R = Me) (7.299; R = Me)

(7.299; R = Me, R' = Br)

(7.299; R = Me, R2 = Br)

+

+

(7.299)

(7.299)

(7.299)

K

I J

E F G H

L

(7.299) (7.299)

(7.299) (7.299)

(7.299)

(7.299) (7.299)

305-310 29 1-294 165-167 231.5-232.5 224-225.5 261.5-263.5

21 36 97 21 7 4

(7.302; R = R4 = Me, R' = Br) (7.302; R = R4 = Me, RZ= Br)

(7.302; R' = CI, R4= Me) (7.302; R' = R2 = R4 = Me) (7.313) (7.302; R = R4 = Me)

(7.302; RZ= CI, R4= Me) (7.302; R' = CI, R4 = Me)

312-316

14 60 90

294 (decomp.) 292-296 287-288 298-302 (decomp.)

-

306-308 287-288 292-296

-

50

(7.302);R' = c1, R4 =

(7.302; R4 = Me) (7.302; R4= Me) (7.302; R4 = Me)

b

-

32 20 40 73 80 73 38 60

-b

(7.302; R4= Me) (7.302; R4= Me) (7.302; R4 = Me) (7.302; R4 = Me) (7.302; R4 = Me) (7.302; R4 = Me) (7.302; R4 = Me) (7.302; R4 = Me) (7.302; R4 = Me) (7.302; R4 = Me)

C D

(7.299) (7.299)

280 294 (decomp.) 280 292-296

-b -b

(7.302; R4 = Me) (7.302; R4 = Me)

B

A

(7.299) (7.299)

m.p. (T)

Yield (%)

Product (R -+ R4 unspecified = H)


~

Starting materials (R- R2 unspecified = H)

~~~

Methanol

Methanol

I

Ethanol Ethyl acetate Methanol

Dimethylformamide

Ethanol

Ethanol Methanol Dimethylformamidewater

Ethanol

-

Ethanol-water Methanol Ethan oI

-

Ethanol Ethanol

Ethanol Ethanol


TABLE 7.31. SYNTHESIS OF PYRIMID~[~,~-u]BENZIM~DAZOL-~( 10H)-ONES BY RING-CLOSURE REACTIONS OF 2AMINOBENZIMIDAZOLE DERIVATIVES

125

111 120

111

121

111 127 115

124 111 111 111 111 121 127 111 111 122

120, 123 122

Ref.

%

0

(7.299) (7.299) (7.299) (7.299) (7.299) (7399) (7.299)

B

Y Z

(7.299; R = Me) (7.299)

Y F

E

X

H

W

€4

R

V

I

S C

(7.299) (7.299) (7299) (7399) (7.299; R = Me) (7.299) (7.299; N=CHNMe, for NH,) (7.299) (7.299) (7.299) (7.299) (7.299) (7.299; R' = CI)

0

D S

U

U H

0

T

(7.299) (7.299)

T

S

(7.299) (7.299)

= CH,OEt)

R3 = C0,Et)f (7.302; R = Me, R3 = C0,Et) (7.302; R3=CN)

(7.302; R4 = Ph) (7.302; R4 = Ph) (7.302; R4 = F'h) (7.302; R4 = Ph) (7.302; R = Me, R4 = Ph) (7.302; R4 = 2-furyl) (7.302; R3 = COMe) (7.302; R3 = C0,Et) (7.302; R3= C02Et) (7.302; R3 = C0,Et) (7.302; R3= C02Et) (7.302; R3 = C0,Et) (7.302; R' or R2=CI,

R'

(7.302; R3=CN, R4=Me) (7.302; R3= C1, RJ = Me) (7.302; R3 = Ph) (7502; R4 = CH,CI) (7.302; R4 = CF,) (7.302; R4 = CH,CO,Et) (7.302; R'= OEt,

R4 =Me)

(7.302; R3 = Pr", R4 = Me) (7.302; R' = CH,COPh,

(7.302; R' = R4 = Me) (7.302; R3 = Et, R4 = Me)

b

97 14

80

95

60 40 91 60 37 51 95

-

46

40

-b

80 48 87 47 14 43 81

31

-b

b

60

-

190 358-362 (decomp.)

3 15-3 17 309-3 11 2!26-297 309-3 11 2 18-2 19 318-320 276-278 270-27 1 292-294 292-295 > 280 309-310 > 350

293-295 342 295-297 300 3 15-3 18 202-204 223225

330 284 (decomp.) 253 286-288

Acetic acid

-

130 120

121 124 127 116 127 121 129 119 120 127 130 131 119

121 128a 121 126 Ill 121 121

122 121

121 122

(Footnotesowrleaf)

Chloroform Cyclohexanone Ethanol Acetic acid Acetic acid Dmethylformamide Dimethylformamide Acetic acid Formic acid

-

Ethanol Ethanol Methanol

Ethanol Ethanol-water Ethanol lsoamyl alcohol Ethanol

e

1-Butanol

-

Benzene-e thanol 1-Butanol

Cyclohexanone Benzene-ethanol

5

0

, benzenelroom temp.

polyphosphoric acid/(14O0)(30-40min); V = PhCOCH,CONH, (no cosolvent)/l4O0 (reaction time not specified); W =

k?

CH, xylene/(room temp.)(l-2 hr), then (140")(few min); X = EtOCH=C(CO,Et), (no cosolvent)/(l10")(0.5hr); Y = EtOCH=C(CO,Et),, 1,2,4-trichlorobenzenelreflux (reaction time not specified); Z = EtOCH==C(CN)CO,Et (no cosolvent)/(120°)(1.25 hr). * Yield not quoted. Isomer mixture not separated. * Mixture. Solvent of crystallization not specified. f C(7) or C(8) position for the benzene substituent not established.

(R')CO,Et,

QCH2 (reaction time not specified), or benzene/(reflux)(7 hr); 0 = R4COCH(R3)CO2Et,EtOH/(reflux)(l hr), then (140-1SOo)(fewmin); P = MeCOCH,CO,Et, dimethylformamide/(100°)(6hr); Q = MeCOCH,CO,Et (nocosolvent)/(160")(21 hr); R = R4COCH,C0,Et (nocosolvent)/(l40-160")(5 hr); S = R4COCH(R3)C0,Et. EtOHlreflux (reaction tine not specified); T = MeCOCH(R3)C0,Et (no cosolvent)/l30-140" (reaction time not specified); U = R4COCH-

solvent)/heat (reaction conditions not specified); M = MeCH==C(NH,)CO,ET (no cosolvent)/(130")(0.2hr); N =

A = MeCOCH,CO,Et (nocosolvent)/(lOO')(12 hr); B = MeCOCH,CO,Et or EtOCH=C(CO,Et), (no cosolvent)/heat(reactionconditionsnotspecified); C = MeCOCH,CO,Et (no cosolvent)/(l50-17O0)(15-20 min); D = R4COCH(R3)C0,Et/(130-1350)(1.25 hr); E = MeCOCH,CO,Et or EtOCH= C(CO,Et),, EtOH/(reflux)(S-45hr); F = MeCOCH,CO,Et or EtOCH==C(CO,Et),, dimethylformamide/(80-100°)(3 hr); G = MeCOCH,CO,Et, NaOEt, EtOH/(reflux)(18 hr); H = R4COCH(R')C02Et or EtOCH-C(CO,Et),, AcOH/reflux (reaction time not specified); I = MeCOCH,CO,Et/(reflux)(3 hr); J = MeCOCH,CO,Bu'/(l35")(1.5 hr); K = MeCOCH,CO,Bu', toluene-p-sulfonic acid, benzene/(reflux)(20hr); L = MeCH=C(NH,)CO,Et (no co-

(Foomotes to Table 7.31)


365

diketene.Iz7 Additionally, the use of a-alkylated121*122 or arylated'21 or a-diazo'23 acetoacetic esters affords the corresponding C(3) functionalized pyrimido[ 1,2-a]benzimidazol-4( lOZf)-ones (Table 7.31). In this context it is noteworthy that the reaction"' of 2-aminobenzimidazole with ethyl 2cyanoacetoacetate affords 3-cyano-2-methylpyrimido[1,2-a]benzimidazol4(10H)-one (7.302; R' = R2 = H, R3 = CN, R4 = Me) in good yield (Table 7.31) thus demonstrating the apparent lack of involvement of the cyano (7.299; R = Me, R' = R2= H) substituent. 2-Amino-1-methylbenzimidazole and 2-methylaminobenzimidazole (7.310; R = Me) condense thermally with 6-keto esters to afford high yields (Table 7.31) of the anticipated l-methyland 1pyrimido[ 1,2-a]benzimidazol-4( l0Zf)-ones (7.302; R = Me)125*127 methylpyrimido[1,2-a]benzimidazoI-4(1H)-ones [e.g. (7.313)], respectively. The reactions of p-keto esters with N(1)-unsubstituted 2-aminobenzimidazoles unsymmetrically substituted in the benzene ring is variously reported to lead to isomer mixtures"' or single products of unestablished orientation.'*' The C(4)-0XO as opposed to alternative C(2)-0xo structures assigned in general to the products of the condensation reactions of 2aminobenzimidazoles with p-keto esters and related substrates have been firmly established by 'H NMR studies.' * 17'27 The product formed in high yield (Table 7.3 1) by the reaction12' of the 2-formamidinobenzimidazole (7.299; R = R' = R2 = H, N=CHNMe, for NH,) with diketene has also been assigned a pyrimido[ 1,2-u]benzimidazol-4( 10H)-one structure (7302; R = R' = R2= R4 = H, R3 = COMe). 3-Acylpyrimido[ 1,2-a]benzimidazol4(1OH)-ones and related compounds of this type [e.g. (7.302; R3 = C02Et or CN)] are generally accessible in high yield (Table 7.31) by the more straightforward thermal condensation of 2-aminobenzimidazoles with substrates such as diethyl ethoxymethylenemalonate"9~'20~'27~'30*'31 and ethyl ethoxymethylenecyanoacetate'20 in the absence of solvent"" or in ethano1,Iz7 acetic acid,"" dimethylf~rmamide,'~'or trichloroben~ene.'~~ as opposed to C(2)-0xo formulations for the products of these The C(~)-OXO reactions are substantiated by the results of 'H NMR 2Aminobenzimidazole derivatives also condense readily with malonic esters on heating the reactants alone or in solvents such as ethanol or acetic acid giving moderate to high yields (Table 7.32) of tautomeric 2-hydroxypyrimido[1,2Products, a]benzimidazol-4( 10H)-ones [Scheme 7.59; (7.303)].116*12'*'32 also assigned 2-hydroxypyrimido[ 1,2-a]benzimidazol-4( 10H)-one structures (7.303) are formed in high yield (Table 7.32) by the reaction of 2-aminobenzimidazoles with carbon ~ u b 0 x i d e . I ~ ~ In contrast to the formation of C(4)-0XO products observed with P-keto esters (see before), the thermal condensation (Scheme 7.62) of 2-aminobenzimidazole with ethyl cyanoacetate is reported'24 to afford the C(2)-0xo product (7321), albeit in unspecified yield (Table 7.33). The possible intermediacy of the amide (7.318), formed by preferential initial condensation between the amino group of 2-aminobenzimidazole and the ester substituent of ethyl cyanoacetate, is indicated by its smooth base-catalyzed

366


1H)TABLE 7.32. SYNTHESIS OF 2-HYDROXYPYRIMIDq1,2-a]BENZIMIDAZOL-4( ONES BY RING-CLOSURE REACTIONS OF 2-AMINOBENZIMIDAZOLE DERIVATIVES Starting material (R+R2 unspecified = H)

Product Reaction (R + R' conditionsa unspecified = H)

(7.299) (7.299) (7399) (7.299; R1= Me)

A

(7.299; R=Me) (7.299; R = Et) (7.299; R=Pr") (7.299; R = Bun) (7.299) (7.299) (7.299) (7.299) (7.299)

C C

B C C

C

C

D E F

G H

Yield m.p. ("C)


Ref.

>340 330 >310 283-285

Formic acid-water Aniline Ethanol Ethanol

121 132 133 133

262-264 281-283 253-255 245-246 284-285 278 337 285 >330

Ethanol Ethanol Ethanol Ethanol Formic acid Acetic acid-water Nitrobenzene Formic,acid-water Ethylene glycol

133 133 133 133 121 116 132 116 121

(%)

53 (7.303) 100 (17.303) 92 (7.303) (7.303; R' or 85 R2 = Me)b (7.343; R = Me) 88 (7.303; R = Et) 90 (7.303; R = Pr") 85 (7.303; R = Bu") 86 (7.303; R'= Et) 42 (7.303; R3= Bun) (7.303; R'= CH2Ph)d 95 (7.303; R3= Ph) (7.303; R'=CO,Et) 80

'A = CH,(CO,Et),, EtOH/(reflux) 1 hr, then 140-15O0)(fewmin); B = (2,4-Cl,C6H302C)2CH2(no cosolvent)/(125")(3min); C = C,O,, acetone-benzene/60-70n (reaction time not specified); D = EtO,CCH(Et)CO,Et, EtOH/(reflux)(1 hr), then (140-150")(few min): E = EtO,CCH(Bu")CO,Et (no cosolvent)/(l80")(30min); F = (2,4-Cl,C,H,0,C)2CHCH2Ph/[2600 (melt)](S min); G = EtO,CCH(Ph)C02Et (no cosolvent)/(180")(30min); H = EtO,CCH(CO,Et)CO,Et, EtOH/(reflux)(lhr), then (140150")(few min). C(7) or C(8) position for the benzene substituent not established. Yield not quoted. Sublimes at 300".

c y ~ l i z a t i o n 'to ~ ~the aminopyrimido[ 1,2-afbenzhidazole (7.321). General synthetic access (Scheme 7.62) to pyrimido[ 1,2-a]benzimidazol-2( 1H)-ones (7.319)is provided by the condensation reactions of 2-aminobenzimidazoles with acetylenic esters (e.g., ethyl and methyl propiolate, ethyl phenylacetylenedicarbo~ylate).~~"~~~~.~ propiolate, and dimethyl Pyrimido[ 1,2-a]benzimidazol-2( lH)-one formation of this type is simply accomplished in moderate to high yield (Table 7.33) by heating the reactants together in solvents such as acetone,"" e t h a n ~ l , ' ~ ~ ,d' i~~"x *a n~e~, ' ~ or ' tetrahydr0f~rane.I~~ The products of these reactions are assigned C(2)-0xo structures (7.319)as opposed to alternative C(4)-0XO structures on the basis of their 'HNMR absorption.120*127~130~135~136 Preferential cyclization to C(2)0x0 products is consistent with a mechanism'27 for pyrimido[ 1,2-a]benzimidazol-2( 1H)-one formation involving Michael addition of the aminobenzimidazole to the acetylenic ester through a ring nitrogen atom (as opposed to via the amino group) followed by ring-closure of the adduct produced.


367

R

I

I

Me H (7.317)

I

H (7.318)

H

Me (7.322)

(7321)

sebew 7.62

However, the observed mode of ring-closure could also be the result of initial condensation between the amino substituent of the aminobenzimidazole and the ester group of the acetylenic ester, followed by cyclization of the resulting amide. The feasibility of the latter pathway is demonstrated by the cyclization (Scheme (7.62)of the acetylenic amide (7.320) or its vinyl bromide precursor (7.317) to the pyrimidor 1,2-a]benzimidazol2( 10H)-one (7.322) in high yield (Table 7.33). The reaction (Scheme 7.63)of N ( 1)-unsubstituted 2-aminobenzimidazoles (7.323) with halogenoalkyloxiranes (7.324) to afford admittedly low yields (Table 7.34)of 3-hydroxy- 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoIes (7.32S)'37*13R nonetheless represents probably the most general method available for the synthesis of simple 1,2,3,4-tetrahydropyrimido[1,241benzimidazole derivatives. Condensation reactions of this type are readily accomplished by heating the reactants under reflux in 2 - b ~ t a n o n e or ' ~ ~with sodium hydroxide in The orientation established unambiguously


368

TABLE 7.33. SYNTHESIS OF PYRIMIDo[l,2-~]BENZrMIDAZOL-2(lH)-ONES BY RINGCLOSURE REACTIONS OF 2-AMINOBENZIMIDAZOLE DERIVATIVES. Starting material ( R - DR~ unspecified = H)


Product (R + R' unspecified = H)

Yield (46)

m.p. ("C)

(7321) (7321) (7.319)

-b -b

-

-

42

336-339

Dimethylformamide Acetic acid

338-340 (decomp.) > 300 Dimethylformamide-water 3 13-3 15 Dimethylformamide 178- 180 Ethyl acetate -c 178 -c 214 Methanol 300 -c > 300 235 Chloroform -c 222

(7316) (7318) (7316)

A B

(7316)

D

(7.319)

29

(7316)

E

(7.319)

56

(7316)

F

(7.319)

69

(7316;R' = Me) (7316;R' = Me) (7316;R2= Me) (7.316) (7316) (7.316;R2= Me) (7.316;R2= Me) (7.320;R = Ph) (7317;R = Ph) (7.316)

G E

18 56 31 21 46 31 94 83 83 73

(7.316)

N

(7319;R' = Me) (7319;R' = Me) (7322) (7319;R = Ph) (7319;R = Ph) (7.322;R = Ph) (7.322;R = Ph) (7322;R = Ph) (7322;R = Ph) (7319; R = C0,Me) (7319; R = C0,Me)

C

E

H I J

K

L L M

52

303-305

Solvent of crystallization Ethanol

-

-

221

Dimethylformamide Ether-dimethylformamide

229

Ref. 124 124 120 134 130 127 120 130 130 127 130 127 136 136 136 127 135

' A = EtO,CCH,CN (no cosolvent)/(l4O")(l5min); B = NaOH aq./room temp. (reaction time not

specified); C = H C e C q 2 E t , acetone/(reflux)(4.5hr); D = HC%CC02Me, EtOH/(reflux)(lS min); E = HC=CCO,Et, Me4NOH-, EtOH/(reflux)(6hr); F = HC=CCO,Et, EtOH/(reflux)(0.5-3 hr); G = HC=CCO Et, acetone/(reflux)(2Ohr); H = PhC=CCOzEt, EtOH/(reflux)(O.5-3 hr); I = PhCB 5 CCO,Et, Me4NOH-. EtOH/(reflux)(6hr); J = PhCBCCO,Et, EtOH/(reflux)(3hr); K = P h C r CCOCI, pyridine, tetrahydrofuranel(- 10°)(20 min), then (room temp.)(6 hr); L = NaOEt, EtOH/(reflux)(O.Shr); M = Me02CC=CCOzMe, EtOH/(reflux)(O.5-3 hr); N = Me02Cc=--CC02Me, dioxane/(32-35")(6hr). * Yield not quoted. Solvent of crystallization not specified.

for the products of these reactions by spectroscopic means,137is consistent with a course for their formation involving initial ring N-alkylation followed by epoxide ring-opening in the N ( 1)-epoxyalkylbenzimidazole produced, and subsequent recycluation. Reaction also succeeds with N( 1)-alkyl-2aminobenzimidazoles, but here the eventual product (Table 7.34) is a lO-alkyl-2,3,4,1O-tetrahydropyrimido[ 1,Zalbenzimidazole [e.g., Scheme 7.63; (7.323; R' = Me, Rz = CHzPh)+ (7.324; R2= R3= R"= RS= H) -P (7.326)].'38The base-catalyzed condensation"' (Scheme 7.64)of 2-aminobenzimidazole (7.327;R = H) with @-unsaturated carboxylic acid chlorides


R

(7324)

(7.323)

R' (7325)

369

Me

H

srkemc 7.63

I

CHzPh (7.326)

affords low yields (Table 7.34) of products whose 'H NMR absorption is consistent with their as 3,4dihydropyrimido[ 1,2-a]benzimidazol-2( 1H)-ones (7328; R = H).Formation of these compounds can be rationalized in terms of the initial acylation of the amino group in the aminobenzimidazole followed by Michael-type ring-closure in the ap unsaturated amide intermediate produced. This course is supported by the

H

R3

I

R2

I

R

(73%)

Scheme 7.64

2

I I

I

I I I

I

(7327; (7327; (7327; (7327) (7327; (7327)

R = C0,Me)

R = C0,Me) R = C0,Me) R = C0,Me)

(7324; R2 = R3 = Me, X = Br) (7327)

+

(7324; R4 = Me, X = Br) (7323)

+

(7324; R4 = Me, X = Br) (7323; R’ =Me)

+

(7324; R5 = Me, X = Br) (7323)

+

(7324; X=Cl) (7323)

+

(7324; X = Br) (7323: R = CH,Ph, R’ = Me)

+

(7324; X=Cl) (7323; R’ =Me)

.t

(7324; X = Br) (7.323)

+

(7323)

Starting materials (R 4RS unspecified = H)

(7.325; R’ =Me)

A

(7328) (7.328) (7328) (7328) (7328; R’ = Me) (7328; R’ = Me) (7328; R2=Me)

C

D E

I

15 82 29

260-26 1 44 18 6

264-266 260-262 260-262

-

261-262

240-242

260 (decomp .)

35

24

10

(7.325; R’= R4 = Me)

230 (decomp.)

230-232

258-260

82 23

175 (decomp.)

158-160

205 (decomp.)

m.p. (“C)

31

80

17

7

(7325; R2 = R3 = Me)

F G H

Yield (OIO)

(7325; R4 = Me)

A

A

A

A

(7.325; R’ = Me)

(7325)c

B

B

(7.325)

= H)

Product (R -B RS unspecified

A

Reaction conditions‘

Ethanol-water Ethanol Ethanol

-

-

Dimethylformamide Ethanol

-b

-b

-b

-b

Ethanol-ether

-b

-d

b

-


TABLE 7.34. SYNTHESIS OF TETRAHYDROPYRIMIDO[1,2-a]BENZIMIDAZOLESBY RING-CLOSURE REACTIONS OF 2AMINOBENZIMIDAZOLE DERIVATIVES

139 139 139 120 139 120

120

137

137

137

137

138

137

138

137

Ref.

3

I-

M

N

(7327;R = C0,Me)

(7330) (7332) (7.334;Ar = p-MeOC,H,)

0

(7.334;Ar = p-Me,NC,H,)

(7329) (7331) (7333) (7335;R = COCHPh,. R' = RZ= Ph, Ar = p-MeOC,H,) (7335;R = COCHPh,, R' = R2= Ph, Ar = p-O,NC,H,) (7335;R = COCHPh,, R' = R2= Ph, AX' = p-Me,Nc,H,) (7335;R' = COMe, Ar = p-Me2NC6H,) (7.336;R' = Et, R2= Bu") (7.336;R' =Me, R2 = Ph) (7.336;R = CO,Me, R' = R2= Me)

(7328;RZ= Me) (7328;R2 = R' = Me) (7328;R2= Ph) [7328;R = (CH2),CO,H]

46

-8

-8

66

84

75

81

50

25 86

55

97 33 93

300 300 164-166

233235

237-239

217-218

216-217 170-171 206-208 223-224

256-257 244-246 289-290 245-246

Cyclohexane

-d -d

-d

-d

-d

-d

-1

Water Ethanol

Ethanol Ethanol Ethanol Ethanol

116 116 142

129

141

141

136 135 141

139

139 139 139

Purified by chromatography. Yield not quoted.

' Hydrochloride.

, benzene/(reflux)(Shr); R = (EtO,C),C(Bu")Et (no cosolvent)/(180")(30min);

CH2 (no coso~vent)/(180")(30 min); T = (CICO),CMe,, K,CO,, CHCl,/(room temp.)(72hr).

OQ

Forms a hydrochloride, m.p. 214-216" (from ethanol-ether). Solvent of crystallization not specified.

* Not crystallized,

s = (EtO,C),C(Ph)Me

(50°)(2 hr); P = Ph,C==C=O, xylene/(reflux)(lOhr); Q =

a

A = methyl ethyl ketone/(reflux)(l-4 days); I3 = NaOH, H,O, EtOH/(reflux)(3hr); C = CH24HCOCI, Et3N, MeCN/(room temp.)(l.5 hr); D = CH,=CHCO,H, dimethylformamide/(reflux)(6hr); E = CH,=CHCO,H, pyridine/(reflux)(2hr); F = Cl(CH,),CO,H, NaOMe, MeOH, dimethylformamide/(room temp.)(2 hr), then (100°)(2hr); G = CH2=C(Me)COCI, Et,N, tetrahydrofurane/(room tempJ(5 hr); H = CH,=C(Me)CO,H (no cosolvent)/(140-180")(2hr); I = MeCH==CHCOCI, Et,N, acetone, tetrahydrofurane/(room temp.)(6 hr 15 min); I = MeCH=CHCO,H (no cosolvent~/~l40-l8O0)~2 hr); K = Me,C=CHCO,H (no cosolvent)/(l50-200")(2hr); L = PhCH=CHC02H (no cosoIvent)/(l50-200")(2hr); M = CH,=CHCO,H (no cosolvent)/(l40-190")(2hr); N = pyridine, EtOH/(reflux)(6-8hr); 0 = dicyclohexylcarbodiimide, dioxane/(room temp.)(2 hr), then

T

S

R

P

(7.334;Ar = p-Me,NC,H,)

(7327) (7327) (7327;R = C0,Me)

P

(7.334;Ar = p-O,NC,H,)

0 P

L

K

J

(7327;R = C0,Me) (7327;R = C0,Me) (7327;R = C0,Me)

+{

372


Ph

Ph

Me H (7330)

Me (7.331)

mN-Me

n N-Me

u

CON R

G

O

H z

H

CON

W

-aAko I

I Me (7332)

Me (7333) sehcme 7.65

demon~tration'~~ of the smooth base-catalyzed cyclization (Scheme 7.65) of the ap-unsaturated amide (7.330) to give the 3,4-dihydropyrimido[1,241benzimidazol-2(10H)-one (7.331) in high yield (Table 7.34). 3,4-Dihydropyrimido[1,2-a]benzimidazol-2(1H)-ones are also formed in high yield (Table 7.34) by the thermal condensation of 2-methoxycarbonylaminobenzimidazole with ap-unsaturated carboxylic acids [Scheme 7.64; (7.327; R = COzMe)+ (7328; R = H)].'39 3,4-Dihydropyrimido[1,2-a]benzimidazol-2(lH)-one synthesis of this type is in some instances complicated by concomitant addition of the reagent to the NH group in the tautomeric product with consequent formation of a mixture of 3,4-dihydropyrimido[1,2-afbenzimidazol-2(lH)-one and 3,4-dihydropyrimido[1,2-a&enzimidazol-2(10H)-one isomers [e.g., Scheme 7.64; (7.327; R = C02Me)+ CH2 = CHCOZH * (7.328; R = (CHJ,CO*H, R' = R2 = H) + (7329)].'39 The cyclization [Scheme 7.65; (7.332) --* (7.333)]represents an alternative if synthetically limited (Table 7.34) approach to 3,4-dihydropyrimido[1,241benzimidazol-2(lH)-~nes.'~'Products, formulated as 2,3-dihydropyrimido[1,2-a&enzimidazol-4(10H)-onederivatives,are obtained in high yield (Table 7.34) by the cycloaddition of diketene129and diphenylketene'40"41 to 2arylideneaminobenzimidazoles[Scheme 7.66; (7.334) --+ (7335)l.Conversely, 1H,3H)-diones are formed in more pyrimido[1,2-aIbenzimidazole-2,4( orthodox fashion (Table 7.34) by the condensation of 2-aminobenzimidazole derivatives with q a -disubstituted malonic esters116 or malonyl [Scheme 7.66; (7327; R = H or C02Me)+ (7.336; R = H or C02Me)].


373

R

H

(7.335)

(7334)

R

H (7.327)

(7336) sebew 7.66

With only one exception (see later) methods for the construction of the elusive pyrimido[3,4-a Jbenzimidazole framework are based on ring-closure reactions of 2-(p-aminoethyl)benzimidazole derivatives. Typical of such methods is the general synthesis (Scheme 7.67) of I-aryl- 1,2,3,4-tetrahydropyrimido[3,4-a]benzimidazoles (7.338) in high yield (Table 7.35) by the sodium hydroxide catalyzed condensation of 2-(p-aminoethyI)benzimidazole (7.337; R = H)with aromatic a 1 d e h ~ d e s . IOpen-chain ~~ benzylideneamino structures for the products of these reactions can be excluded o n the basis of their 'H NMR a b ~ o r p t i o n . ' ~ Ring-closure ~ of 2-(P-aminoethyl)benzimidazole can also be effected by base-catalyzed reaction with carbon disulfide, the product formed in good yield (Table 7.35) being 3,4-dihydropyrimido[3,4-a]benzimidazole-1(2H)-thione (7.339; X = S).143 In related

,H

(7338)

(7.339) sebcme 7.67

4 P

w

A =R m O , 1

~~

39 45 67

-c

(XI

Yield

M NaOH/(80-90")(15 rnin); B = no cosolvent/(170°)(75rnin);

NaOH, H,O, EtOH/(reflux)(ZOhr). Dihydrochloride. Yield not quoted. Solvent of crystallization not specified. Hydrochloride.

0

D

A A C

x x

(7338; R = 2-thienyl) (7338; R = 4-pyridyl) (7339; = 0) (7339; = 0 ) (7339; X = S )

(7.337; R = H)b (7.337; R = H)b (7.337 ; R = CO2Et) (7.337; R = C0,Et)' (7337; R = H)b A

(7338; R = H) (7338; R = Ph) (7.338; R = p-ClCeH4) (7338; R = p-BrC,H,) (7338; R = m-02NC,H4) (7338; R = p-Me,NC,H,) (7338; R = 2-furyl)


(7.337; R = H)b (7337; R = H)b (7.337; R = HIb (7.337; R = H ) ~ (7.337; R = H)b (7337; R = H)b (7337; R = H)b

Starting materials

c=Na,CO,,

Dimethylformamide

Ethanol

-d -d

d

-

-d -d -d

d

-

Methanol-water

-d


143 143 144 144 143

143 143 143 143 143 143 143

Ref.

H,O/(reRux)(few rnin); D = cs,,

216 (decomp.)

-

197-199 156-157 190-191 221-222 189-190 225-226 184 (decomp.) 224-225 160-161 245-248

m.p. (OC)

BY RING-CLOSURE TABLE 7.35. SYNTHESIS OF 1,2,3,4-TETRAHYDROPYRIMIDq3,4-~]BENZIMIDAZOLES REACTIONS OF 2-(f3-AMINOALKYL)BENZIMLDAZOLE DERIVATIVES


375

transformations (Scheme 7.67)the readily accessible 2-(@-ethoxycarbonylaminoethy1)benzimidazole (7.337; R = C0,Et) thermal or sodium carbonate catalyzed ring-closure to afford, albeit in only moderate The yield (Table 7.35)3,4-dihydropyrimido[3,4-a]benzimidazol-l(2H)-one. - thione [Scheme 3,4,4a, 5 - tetrahydropyrimido[ 3,4- aJbenzimidazole - 1(2H) 7.68; (7.342)] is claimed145 to be the somewhat unexpected end-product (obtained nevertheless in high yield-cf. Scheme 7.68)of the uncatalyzed reaction of orrho-phenylenediamine (7340)with the keto isothiocyanate

(7.341).

o-\"" \

NH,

+

C ,N=C=S

Me, Me

/ \ CH,COMe

H

(7.342)

(m.p. 230-232') (i) xylene/(reflux)(4 hr)

sebaw 7.68

Most synthetic routes to pyrazino[3,4-a]benzimidazoles are dependent on ring-closure reactions of N(l),C(2)-bifunctionaIized benzimidazole derivatives. For example (Scheme 7.69),derivatives of the fully unsaturated pyrazino[4,3-a]benzimidazole ring system (7.344)are generally accessible in high yield (Table 7.36) by the ammonium acetate-mediated ring-closure of readily available 1-(2-oxoalkyl)-2-acylbenzimidazoles (7.343;X2= Y, = 0) or the corresponding acetals (7.343;X, or Y, = 0,Y or X = OR).146*'47 The

(7.343)

sebanc 7.69

(7.344)

R'

376


TABLE 7.36. SYNTHESIS OF PYRAZIN@4,3-a]BENZIMlDAZOLES BY RING-CLOSURE REACTIONS OF BENZIMIDAZOLE DERIVATIVES Starting material

(7.343;R = R2 = H, R' = Ph, X, = 0, Y = OBu") (7.343;R = R' = H, R2 = Ph, X = OEt, Y, = 0) (7.343; R = H, R' = R2 = Ph, x, = Y, = 0) (7.343; R = Me, R'= R2= Ph, x, = Y,= 0) (7.343;R = H, R' = CO,Et, R2 = Ph, x, = Y, = 0) a


Yield (%)

m.p. ("C)

Solvent of crystalljzation Ref.

A

(7.344;R = R 2 = H , R' = Ph)"

79

218-219 -' (decomp.)

146

B

(7.344;R = R ' = H , R2 = Ph)

91

170-172

Ethanol

147

A

(7.344;R = H , R' = RZ= Ph)

91

223-224

Acetone

146

A

(7.344;R = Me, R' = R2= Ph)

91

227-228

Acetone

146

B

(7.344;R = H. R' = CO,Et, R2= Ph)

91

170-172

Ethanol

147

A = NH,OAc, AcOH/(reflux)(l-2 hr);

* Hydrochloride.

B = NH,OAc, AcOH/(reflux)(lS min).


less obvious thermolytic cyclization (Scheme 7.70) of 2-azidoalkylbenzimidazoles (7.345) having an a@-unsaturated acyl side chain at N(1) affords pyrazino[4,3-a]benzimidazol-4(1OH)-ones (7.347) in good yield (Table 7.37).14' These transformations are plausibly rationalized (Scheme 7.70) of the intermediate formation and subsequent breakdown of tetracyclic 1,2,3triazoline derivatives (7.346).148 Construction of the 1,2,3,4-tetrahydro-

0

CHN3

I R

(7-345)

0

(7.347)

/

Wane 7.70

(7.346)

2 4

A

A

A

A

(7,345; R = H, Ar = o-CIC,H,)

(7.345; R = H, Ar = 1-naphthyl)

(7.345; R = Me, Ar = Ph)

(7.345; R = Me, Ar = o-CIC,H,)

G

F

(7352; R = CH,Ph) (7.352; R = CH,Ph)

C

B B

(7358; R = CH,Ph. X = Cl) (7.350; R = CH,Ph, X = Br)

(7350; R = Me, X = Cl)c (7350; R = CH,Ph, X = Cl)

65

-d

54 70

27 22 37 41 40 28

(7.349; R = CI, R' = Bun) (7.349; R = NO,, R' = Bu") (7.349; R = CO,Et, R' = Bu") (7.349; R = H, R' = CH,Ph) (7.349; R = H, R' = (CH,),Ph) (7.349; R = H, R' = (CH,),CI)

B B B

D E

R = Cl) R = NO,) R = C0,Et) R = H) R=H)b R = H, R' = (CH,),CI)

(7.346; (7.348; (7.348; (7.348; (7.348; (7351;

38

65

(7.349; R = H, R' = Bu")

(7347; R = Me, Ar = 1-naphthyl)

50

67

(7.347; R = Me, Ar = Ph) (7.347; R = Me, Ar = o-ClC,H,)

30

49

50

Yield (%)

(7347; R = H, Ar = 1-naphthyl)

(7.347; R = H, Ar = o-CIGH,)

(7.347; R = H, Ar = Ph)

Product

B

(7.348; R = H) (7.348; R = H)

R = H)b

(7.348;

A

A

(7.345; R = H, Ar = Ph)

(7.345; R = Me, Ar = 1-naphthyl)


Starting material

(decomp.)

187-1 89

-

(decomp.)

233-235 193-194

127- 129 106-109 128-1 30 124-125 108-1 11 90-93

92-94

226-228

215-216

217-21 8

200-202

217-219

207-209

("c) m.p.

Ethanol-ether

Ether-light petroleum 2-Propanol Ethanol-ether

-d -d -d -d

Ethanol-dimethyl sulfoxide Ethanol-dimethyl sulfoxide Ethanol-dimethyl sulfoxide Ethanol-dimethyl sulfoxide EthanoMimethyl sulfoxide Ethanol-dimethy1 sulfoxide Ether-light petroleum (b.p. 30-60°) Ether


TABLE 7.37. SYNTHESIS OF DIHYDROPYRAZIN0[4.3-a]BENZIMIDAZOLESAND TETRAHYDROPYRAZIN0[4,3-a]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF BENZIMIDAZOLE DERIVATIVES

149 149

149 149

26 26 26 26 26 26

26

148

148

148

148

148

148

Ref.

R = H) R = CH,Ph) R = Bun) R = cyclohexyl) R = CH,Ph) R = p-MeC,H,) R = cyclohexyl) R = cyclohexyl)

(7358; R = p-MeOC,H,) (7.568) (7361)

L

M N

(7359) (7.359)

R = p-MeC,HJ

(7.356; R = p-MeOC,H,)

75 60

82

85

305-306 294-296

160

185-187

148-150

200-20 1 188-190 265-267 215-216 278-280 297-299 168- 170

292-294

-

m.p. ("C)

Ethanol Ethanol-water Ethanol Ethanol Ethanol Dimethylformamide Benzene-light petroleum Benzene-ligh t petroleum Benzene-light petroleum Benzene-light petroleum Acetic acid-water Dioxane

Water


152 152

151

151

151

150 150 150 151 151 15 1 151 151 151

Ref.

" A = toluene/(reflux)(l hr); B = RNH,, benzene/(room tempJ(44 hr), then (lOOo, pressure)(6 hr); C = Bu"NH,, benzene/(room tempJ(32 hr), then looo, (pressure)(l2 hr); D = Me&H, acetone/(reflux)(lOmin); E = PhCH,NHMe, acetone/(reflux)(10 min), then Pr'OH/(reflux)(6 hr); F = SOCI,, then PfOH/(reflux)(6 hr); G = PBr,, CHC1,/(80-8S0)(2 hr), then WOH/(reflux)(6 hr); H = aziridine, HCI, EtOH/(100". pressure)(8 hr); I = SOCI,, dimethylformamide/(O-5°), then (reflux)(:! hr); I = ClCH,COCI. Et,N, tetrahydrofurane/(mom temp.)(l hr), then (reRux)(3hr); K = PhCH(CI)COCl, Et,N, tetrahydrofurane/(room temp.)(l hr), then (reflux)(3hr); L = (COCI),, Et,N, tetrahydrofurane/(V)(l hr), then (room temp.)(l hr); M = conc. H,SO,, AcOH/(65")(1.5 hr); N = conc. NH, aq.. EtOH/(30")(2 weeks). Hydrochloride. Hygroscopic. Solvent of crystallization not specified. Yield not quoted.

(7.356;

(7.358;

(7358; R = CH,Ph)

R = CH,Ph) R = Bu", R' = H) R = cyclohexyl, R' = H) R = CH,Ph, R' = H) R = p-MeC,H,, R' = H) R = cyclohexyl, R' = Ph) R = cyclohexyl) 61

28 65 79 38 52 47 25 63 79

R = H)

(7355; (7.355; (7355; (7357; (7357; (7357; (7357; (7.357; (7358;

R = H)

Yield (%)

Product

L

L


R = p-MeCeHJ

(7356; R = CH,Ph)

(7353) (73%; (7354; (7356; (7356; (7356; (7356; (7.356; (7356;

Starting material



R/j&J--../LN\

319

R'

(7351)

(7.352) Scheme 7.71

pyrazino[4,3-a]benzimidazole ring system is accomplished in more orthodox fashion (Scheme 7.7 1) by the aminolytic ring-closure of conveniently synthReacesized 1-(2-chloroethyl)-2-chlorornethylbenzimidazoles(7.348).26.'49 tion of the latter with aliphatic primary amines requires elevated temperature and pressure and affords only low to moderate yields (Table 7.37) of 2-alkyl- 1,2,3,4-tetrahydropyrazino[4,3-afienzimidazoles (7.349; R = alkyl).26 Nor is the alternative approachz6 of dehydrohalogenative ringclosure [e.g., Scheme 7.71; (7.351; R = H, R' = (CHz)zCI)+ (7.349; R = H, R'=(CH,),CI)] any more efficient (Table 7.37). On the other hand, the ring-closure (Scheme 7.71) of 1 -(2-chloroethyl)-2-chloromethylbenzimidazoles (7.348) with secondary aliphatic amines gives good yields (Table 7.37) of the corresponding 2,2-dialkyl-1,2,3,4-tetrahydropyrazino[4,3-u]benzimidazolium chlorides (7350).'4vProducts of the latter type are also efficiently synthesized (Table 7.37) by the halogenative-dehydrohalogenative cyclization (Scheme 7.71) of readily accessible 1-(2-hydroxyethyl)2-aminomethylbenzimidazoles (7.352), using reagents such as thionyl chloride or phosphorus t r i b r ~ m i d e . 'Heating ~~ with thionyl chloride in dimethylformamide also effects the analogous ring-closure (Scheme 7.72) of benzimidazole-2-(N-hydroxyethyl)carboxamides(7354) to 3,4-dihydropyrazino[4,3-a]benzimidazol-I(2H)-ones (7355) in good yield (Table 7.37).l5O The parent 3,4-dihydropyrazino[4,3-a]benzimidazol-1(2H)-one (7355; R = H ) is also conveniently prepared, though only in low yield

380


0 (7.355) Sckme 7.12

(Tat.,: 7. 7) by the acid-catalyzed condensation of ethy 2- "enzimidazolecarboxylate (7.353) with aziridine at elevated temperature and pre~sure.'~" The triethylamine catalyzed condensation of 2-(alkylaminobenzyl)benzimidazole derivatives with a -chlorocarboxylic acid chlorides provides a convenient general method for the synthesis in moderate to good yield (Table 7.37) of 1,2-dihydropyrazino[4,3-a]benzimidazol-3(4H)-ones[Scheme 7.73; (7.356) + (7357)].'" The assignment of C(~)-OXO as opposed to structures to these products is based on their IR alternative C(~)-OXO carbonyl absorption and their relative stability to hydroly~is.'~'2-(Alkylaminobenzyl)benzimidazoles (7356) also react readily with oxalyl chloride in the presence of triethylamine to good yields (Table 7.37) of pyrazino[4,3a]benzirnidazole-3,4( 1H,2H)-diones (7.358).'" Pyrazino[4,3-a]benzimidazole-l,3(2H,4H)-dione, on the other hand, is accessible in high yield

Ph

Ph (7357)

H

H scheme 7.73

Ph H (7.358)

R

7.2. Fused Benzirnidazoles with One Additional Heteroatom

(7.359)

381

0 (7.360)

(Table 7.37) by the simple sulfuric acid catalyzed hydrolytic ring-closure of l-(ethoxycarbonyImethyI)-2-cyanobenzimidazole [Scheme 7.74; (7.359)+ (7.360)].'52The tautomeric C( 1)-imino derivative [(7.361)S (7.362)]of the latter compound is likewise obtained in good yield (Table 7.37) by the aminolytic cyclization of the benzimidazole derivative (7.359).lS2

Ring-closure Reactions of Other Heterocycles Ring-closure reactions of N-(2-substituted pheny1)morpholine derivatives provide the basis of a variety of methods (Table 7.38) for the general synthesis of 3,4-dihydro-lH-[1,4]oxazino[4,3-a]benzimidazoles.Transformations of this type are essentially analogous to those already discussed in detail for the synthesis of 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazoles (cf. section 7.1.1, "Ring-closure Reactions of Other Heterocycles"), and consequently merit only brief comment under the present heading. Perhaps the simplest example of the ring-closure of an N-arylmorpholine derivative to a 3,4-dihydro- 1 H - [ 1,4]oxazino[4,3-a]benzimidazole is provided by the acid-catalyzed cyclodehydration of 1-(2-benzamidophenyl)morpholin2(1H)-one to 3,4-dihydro- 1H-[1,4]oxazino[4,3-a]benzimidazole [Scheme 7.75; (7.363).--,(7.364)].42O f greater utility for the general synthesis in high yield (Table 7.38) of 3,4-dihydro- 1H-[ 1,4]oxazino[4,3-a~enzimidazoles is the oxidative cyclization of 1-(2-aminophenyl)morpholinesor their Nacyl derivatives, using reagents such as performic acid4M8*1s3.1s4 pertrifluoroacetic or mercuric oxide in conjunction with EDTA.s2 In the sulfuryl chloride promoted cyclization of 1-(2-aminophenyl)morpholines,3,4dihydro- 1H-[ 1,4]oxazino[4,3-~]benzimidazole formation (Table 7.38) is ac' ~ ~ thermolysis companied by perchlorination of the benzene n u ~ l e u s . " ~The

TABLE 7.38. SYNTHESIS OF ~,~-DIHYDRO-~H-[~,~~XAZIN~[~.~-O~ENZIMI [4,3-alBENZIMIDAZOL.FS (7368) BY RING-CLOSURE REACTIONS OF

(7.366)

(7.365) Substrate (7.365) R

R'

RZ

NHZ NHCHO NHCOMe NHCOPh NHZ N3

H H H H H H

H H H H H H

NHZ N3

NH, NHCOMe NHCOMe N3 NHCOMe NHCOMe NHZ N3 NHZ NH2 NO2

H H H H H H H H NH2 H H H H


R

A B B B C D

(7.366) (7.366) (7.366) (7.366) (7.366) (7.366)

H H H H H H

H

A

(7.366)

H

H

H

E

H H H H NO2 H H NHCOMe OEt CI H H H

H H H H H H H H H H H H H

A D A B B D B B B D F F G

H H

H H H

H I I

(7.367) (7.367) (7.367)

H

H

H

K

(7.367)

H H

H H

H L

H

H

L

R3

R4

H H

H

H H H H H H

H

H H H

H

382

He

Bu' CF,'

( 7 s ) AND (7.367). AND 1,2,3,4,10,1Oa-HEXAHYDR~1,4~XAZINON-ARYLMORPHOLINE DERIVATIVES (7365)

I

0-

H (7.368)

(7367)

Yield (Yo)

m.p. PC)


129-130

Cyclohexane -c

R'

R2

R'

R4

H H H H H H

H H H H H H

H H H H H H

H H H H H H

73 85-95 85-95 85-95 47 69

H

Me

H

H

61

170-171

H

CF,

H

H

46

130-132

H H H H NO2 H H NHCOMe OEt CI CI c1 H

H H H H

62 50 76 80-90 80-90

196 200-200.5 214-215 217 205 186 210 258

H H H

CI CI NO, H NO, H H CN H H NHCOMe H H NO2 H H C I c1 CI CI CF, H NO,

H H H

H

H H CI CI H

-d 17

67

-

d

-d 50 30 15

-b -b -b

129-130 130

-b

192 143 156-158 196

-

-

26-30 55 3

-

-

-

12

146-148

-

20 1 136-138

(decomp.)

-

E

-

c

light petroleum (b.p. 40-60") Benzene-cyclo hexane Chloroform- n hexane Ethyl acetate Ethyl acetate Methyl ethyl ketone

-

-c -c -c C

-e

-c -c -c Ethyl acetatelight petroleum (b.p. 60-80") Ethyl acetate Ethyl acetate Chloroform -hexane Methanol-ether

(decomp.)

-

-

13 75

2 15-2 18 125

-

-

75

155

383

Ref.

Ethyl acetate Ethyl acetatelight petroleum Ethyl acetatelight petroleum

45 46 46 46 52 59 45 154 45 29, 60 45 47 47 60 48 48 153 60 67 154 56 55 55 155

155 55 58 58

(Footnotesoverleaf)

384


(Foomofes lo Table 7.38) a A = 30% H,O,, CF,CO,H, CH,Cl,/(reflux)(l5-30 min); B = 30% H,O,, 98% HCO,H/(10O0)(10-15 min); C = HgO, EDTA, 50% ethanol-water/(room tempJ(l50 min); D = nitrobenzene/ (165-175")(0.5 hr); E = 30% H,O,, 88% HCO,H/(60-75")(15 min); F = SO,C1,/Oo, room temp. (reaction time not specified); G = ZnCI,, Ac,O/(reflux)(4 hr); H = conc. HC1/(110-15O0)(12-20 hr); I = hv, conc. HCI, MeOH/(roorn tempJ(80 hr); I = 20% HCI/(I 10")(28 hr); K = 20% HCl/(reflux)(20 hr) L = diethylene glycol dimethyl ether/(reflux)(lO min). Melting point not quoted. Solvent of crystallization not specified. Yield not quoted. ' Hydrochloride. Monohydrate.

of 1-(2-azidophenyl)morphoIinesin n i t r o b e n ~ e n e ~provides ~ ' ~ ~ * an ~ alternative method to oxidative cyclization for the synthesis in high yield (Table 7.38) of 3,4-dihydro-1H-[ 1,4]0xazino[4,3-~]benzimidazole derivatives. The thermal cyclizations8 of 1-(2-azidophenyl)morpholines in nonoxidizing solvents such as diethylene glycol dimethyl ether affords the corresponding 3,4,10,10a-tetrahydro-1 H-[1,4]oxazino[4,3-~]benzimidazoles (Table 7.38)

kOPh (7.363)

(7.364)

(i) 2 M H,S04/(reflux)(2 hr) scheme 7.75

thus demonstrating the probable intermediacy of the latter in the nitrobenzene-promoted thermolyses. The acid-catalyzed therma15s~'s4*'s5 and photocherni~al~~ cyclizations of 1-(2-nitrophenyl)morpholines afford low yields (Table 7.38) of 3,bdihydro-1 H-[ 1,4]oxazino[4,3-~]benzimidazole 10-N-oxides as opposed to the parent 3.4-dihydro- IH-[ 1,4]oxazino[4,3-a]benzimidazoles. 8-Nitro-3,4-dihydro-1H - [ 1,4]oxazino[4,3-a]benzimidazole 10-N-oxide is also a plausible intermediate in the zinc chloride-acetic anhydride-mediated cyclization of 1-(2,4-dinitrophenyl)morpholine to 1acetoxy-8-nitro-3,4-dihydro-lH-[1,4]oxazin~4,3-a~enzimidazole (Table 7.38).56Other isolated examples (Scheme 7.76) of 1-arylmorpholine to 3,4dihydro-1H-[ 1,4]oxazino[4,3-~]benzimidazolecyclizations include the acidcatalyzed conversion of the benzylidene derivative (7.369) into the salt


P

O

N-7

a N J iG% \

N

I

(7370)

(7369)

(7371)

385

(m.p. 183")

I

(7.372)

(ii) (62%)

(7.373)

(rn.p. > 360") (i) mnc HCI, EtOH/(room tempJ(l4 hr) (ii) conc. HCI, EtOH/(room temp.)(3 days) Scheme 7.76

(7.370)62 and the related acid-catalyzed condensation of 1-(2-aminophenyI)morpholine (7.371) with alloxan ( 7 3 7 2 ) to afford the betaine (7.373).63 The polyphosphoric acid-catalyzed transformation (Scheme 7.77) of 1-(3pyridazinyl)benzo-l,2,3-triazole (7.374) in good yield into 2-hydroxypyridazino[2,3-~]benzimidazole( 7 3 7 5 ) represents what appears to be the only reported s y n t h e ~ i s 'of~ ~the pyridazino[2,3-u]benzimidazole ring sys~ ~ 1-(2-pyrimidyl)benzo- 1,2,3-triazole tem. The analogous t h e r r n o l y s i ~ 'of


386

I

I

N===N

(7.375)

(7.374)

(m.p. 320")

IQ=N

(7,376)

(7.377)

(m.p. 192")

(i) poiyphosphoric acidll50" (time not specified) 7.77

(7.376)in polyphosphoric acid exemplifies an alternative method to 2aminobenzimidazole/malondialdehyde diethyl acetal condensation (cf. section 7.2.1, "Ring-closure Reactions of Other Heterocycles") for the synthesis in high yield of pyrimido[1,2-a]benzimidazole (7.377). The acidcatalyzed nature of the cyclizations r(7.374)+(7375)l and [(7.376)+ (7.377)],which are akin to those of 1-(2-pyridyI)benzo-172,3-triazolesdescribed in section 7.1.1 ("Ring-closure Reactions of Benzimidazole Derivatives") is indicated by the higher temperatures required to achieve product formation in aprotic media."" The thermal cyclization (Scheme 7.78)of 2(2,4,6-trinitrophenylamino)pynmidines(7.380)preformed or prepared in sinc by the condensation of 2-aminopyrimidines (7.379)with 2,4,6-trinitrochloroR'


387

TABLE 7.39. SYNTHESIS OF NITROPYRIMIDqI ,2-a]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF 2-(N-2,4,6TRINITROPHENYLAMIN0)PYRIMIDINE DERIVATIVES" Startingmaterial (7.374)

+

Reaction conditionsb

I A

(7.375; R' = R2 = H) (7.376; R' = Me, R2 = H) B (7.376; R' = Me, R2= NH,) C (7.376; R' = Me, C RZ= NHCOMe) a

Yield Product

(YO)

(7.377; R' = R2= H)

15

(7377; R' = Me, R2= H) 24 (7.377; R' =Me, R2= NH,) -d (7.377; R' =Me, 69 RZ= NHCOMe)

m.p. ("C) 196 (decomp.)' >3OOc >33OC 323-325

From Refs. 157 and 158. A = benzene/( 100")(2 hr); B = nitrobenzene, phenol/heat (reaction temp. and time not

specified); C = phenol, benzene/heat (reaction temp. and time not specified). Solvent of crystallization not specified. Yield not quoted.

benzene (7.378), is reported'" to afford moderate yields (Table 7.39) of 7,9-dinitropyrimido[ 1,2-a]benzimidazoIe derivatives (7.381). However, the yields claimed for these transformations could not be substantiated.lS8The rearrangement [Scheme 7.79; (7.382) -+ (7.383)]"9 exemplifies a mechanistically interesting if synthetically limited method for the construction of the 2,3-dihydropyrimido[ 1,2-a]benzimidazol-4( 1H)-one ring system. The reductive cyclization (Scheme 7.79) of the pyrimidine derivative (7.384)

H (7.383)

(7.382)

(7.384)

(7.385)

(i) 270" (no co-solvent)/few min (ii) H,, 10% PdC, AcOH/(room temp.)(atrn. press) scheme 7.m

g

u

CH,Ph Me Me Ph Ph P-CIC~H~ p-Cic& O-MeC6H4 o-MeC6H, m-MeC6H4 m-MeC6H, Me

C0,Me H NO, H NO, H NO, H NO, H NO, NO,

D E

D

D D D D D

D

C D D

C

B

A A

(7.387) (7.388) (7.388) (7388) (7.388) (7.388) (7.388) (7.388) (7.388) (7.388) (7.388) (7.389)

(7.387) (7.387) (7.387) (7.387)


(7.387)

-

H NO,

NO2 H NO2

H

C0,Me H NO, H NO2

H C0,Me

H

c1

R'

-

CH,Ph Me Me Ph Ph p-Clc& p-ClC6H4 o-MeC6H4 o-MeC6H4 m-MeC6H4 m-MeC6H4

C0,Et C0,Et COMe Me

R2

(Yo)

75

-

6 29 24 20

Yield

149-150 90 103 70 70 105 117 88 142 130 100 175

126-127 129-131 140- 141 158-160

m.p. I"C)

(7388)

-'

c

Ethyl acetatelight petroleum

-

I

?.

-r -* -e -e -c

Ethyl acetate Ethyl acetate Acetone-zther Ethyl acetatehexane


-

145 205 168 95 157 110 105 153 175 140

160 161. 161 161 161 161 161 161 161 161 161 58

29 29 149 160

-

Ref.

m.p. ("C) (picrate)

(7389)

E = diethylene glycol dimethyl ether/(reflux)(l2min). Yield not quoted. Yields 15-30%. Crystallized from ethyl acetate-chloroform. Purified by chromatography.

" A = nitrobenzene/170-180° (reaction time not specified); B = nitr0benzene/(l80-183~)(10 min); C = (EtO),P/(180")(2hr); D = 20% HCl/(reRux)(ZShr);

NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 N3

NO2

NO* NO2

NO2

C0,Et C0,Et COMe Me

H CI H C0,Me

N, N3

N3

R2

R'

R

Substrate (7.386)

( 7 s )

TABLE 7.40. SYNTHESIS OF 1,2,3,4-TETRAHYDROPYRAZIN~4,3-a]BENZIMIDAZOLES (7.387) AND (7.388). AND 1,2,3,4,10,10aHEXAHYDROPYRAZIN0[4,3-a]BENZIMIDAZOLES(7.389) BY RING-CLOSURE REACTIONS OF N-ARYLPIPERAZINE DERIVATIVES (7.386)


389

provides a simple, though relatively inefficient means for the synthesis of pyrimido[3,4-a]benzimidazole-1,3(2H,4H)-dione (7.385).'44 1,2,3,4-Tetrahydropyrazino[473-a]benzimidazoles, like their 3,4-dihydro1H-[1,4]oxazino[4,3-a]benzimidazole and tetrahydropyrido[1,2-~]benzimidazole counterparts (cf. this section and section 7.1.1, "Ring-closure Reactions of Other Heterocycles"), are synthetically accessible albeit in low yield (Table 7.40) by the thermolytic cyclization of 1-(2-azidophenyl)piprazines in nitr~benzene.'~.'~~ In accord with their intermediacy in these transformations, 1,2,3,4,10,10a-hexahydropyrazino[4,3-a]benzimidazolesare the products (Table 7.40) of the thermolytic decomposition of 1-(2-azidophenyl)piperazines in nonoxidizing solvents such as diethylene glycol dimethyl ether.sx 1,2,3,4-Tetrahydropyrazino[4,3-u]benzimidazole derivatives are also formed in low yield (Table 7.40) by the triethyl phosphite catalyzed cyclization of 1-(2-nitrophenyI)pipera~ines.'~"Cyclization of the latter in hot concentrated hydrochloric acid, on the other hand, leads to the formation, again in low yield (Table 7.40) of 1,2,3,4-tetrahydropyrazino[4,3-a]benzimidazole 10-N-oxides.'"' The transformations outlined in Scheme 7.80 exemplify less orthodox routes to tetrahydropyrazino[4,3-~]benzimidazole derivatives.'62

wT

(77%)

(7390)

\

" Y C H O

SMe H (7.391)

(rn.p. 267")

(7.392)

(7.393)

(rn.p. 267-269") (i) Mel, 2 M NaOH/(roorn ternp.)(2 hr) (ii) 2 M NaOH/(room ternp)(few rnin) sdlcme 7.80

7.2.2. Wysicochemid Properties

Spectroscopic Studies INFRARED SPECTRA.In accord with their lactone-like structures, the 3,4derivative (7.394) and the dihydro- 1 H-[ 1,4]oxazin~4,3-~]benzimidazole


390

TABLE 7.4 1. INFRARED SPECTRA OF OXAZINOBENZIMIDAZOLONEDERIVATIVES (7.394) AND (7.395)

(7.394)

(7.395)

Compound

R

Medium

C=O

(7.394) (7395) (7.395) (7.395) (7.395) (7395) (7395)

COMe COMe COCHPh, COCHPh, S0,Me S0,Me

KBr Nujol CHCl, Nujol CHCl, KBr CHCI,

1740 1768, 1764, 1756, 1763, 1758 1764

1686 1670 1678 1668

C=C

Ref.

1662

87 86 86 86 86 86 86

-

1640 1657 1640

3,4,4a,5-tetrahydro- 1H-[1,3]oxazino[3,4-a]benzimidazoles (7395) exhibit high-frequency IR carbonyl absorption in the range 177CL1750 cm-' (Table 7.41). The relatively low frequency (2180 cm-') for the IR cyano absorption of the IOH-[ 1,4]thiazino[4,3-a]benzimidazole derivative [Scheme 7.81 ; (7.412)] is attributed" to resonance interaction between the cyano substituent and the imidazole ring. Comparison of the IR stretching frequencies (Table 7.42) of the ring carbonyl substituents in the 4W-[ 1,3]thiazino[3,2a]benzimidazol-4-one (7.396; R' = Me, R2= H, X = 0) and the 2H[1,3]thiazino[3,2-a]benzimidazol-4(3H)-ones(7397) demonstrates the marked effect of conjugation in the former molecule. The carbonyl group in 1H-[1,4]thiazino[4,3-a]benzimidazol-4(3H)-one[Scheme 7.8 1; (7.413)] absorbs in the IR at 1728 cm-'.lo3

(7.412)

(7.413) Scheme 7.81


391

TABLE 7.42. INFRARED SPECTRA OF [~,~]THIAZIN~[~.~-U]BENZIMIDAZOLE DERIVATIVES (7.3%) AND (7397)

(7396)

Compound R' (7396) (7396) (7.397) (7.397) (7397) (7397) (7.397) (7397) (7397)

CN Me

H H H

R' R2 OH H

H H

H H NO2 H Me Me H H

a

H H H H H H

p-CIC,H,CO

(7.397)

X

Medium

CHC0,Me

KBr KBr

0

a

2

KBr KBr Nujol KBr KBr KBr

C=C

3200-2200br

1740,1720 1620 1690 1670 1731 1630 1733 1724 1680 1725,1680 -

Comparison of the IR carbonyl absorption (Table 7.43) of N-unsubwith that of specifically N( 1)stituted pyrimido[ 1,2-albenzimidazol-2-ones and N(10)-methylated derivatives demonstrates the N-unsubstituted molecules to exist in the solid state and in solution predominantly in the pynmido[ 1,2-a]benzimidazol-2(lH)-one tautomeric form (7.398; R' = H).I3' A similar IR study13"of pyrimido[ 1,2-a]benzimidazol-4-onederivatives (Table 7.43) demonstrates the pyrimido[ 1,2-a]benzimidazol-4( 10H)one tautomeric form (7.401; R = H) to predominate in the case of N-unsubstituted compounds. N ( 1)-substituted 3,4-dihydropyrimido[ 1,2-a]benzimidazol-2( lH)-ones [Table 7.44; (7.403)] are readily differentiated from their N(10)-substituted isomers [e.g. (7.404)] on the basis of the lower IR carbonyl stretching frequencies (Table 7.44) in molecules of the latter type as a result of increased conjugation. The close similarity of the IR frequencies (Table 7.44) of the ring carbonyl substituents in N-unsubstituted 3,Cdihydropyrimido[ 1,2-a]benzirnidazol-2-ones and their N( 1)-substituted derivatives indicates the former molecules to exist predominantly in the 3,Qdihydropyrimido[ 1,2-albenzimidazol-2( lH)-one tautomeric form (7.403;R' = H).The IR carbonyl absorption (1680-1670 an-') reported133 for N(10)-substituted pyrimido[ 1,2-a]benzimidazole-2,4(3H,l0H)-diones [Scheme 7.82; (7.414)] appears anomalous when compared with the IR carbonyl stretching frequencies (Table 7.44) of the 2,3-dihydropyrimid~l,2-albenzimidazol-4(1H)-one (7.405; R = R3= R4= H,R' = R2= Me) [v,,,,, (C=O) = 1730 cm-'1, on the one hand, and the 3,4-dihydropyrimido[1,2-a]benzimidazol-2( 10H)-one (7.404) [ vmsx(C=O) = 1625 cm-'I, on the

Ref.

91 93 101 103 92 105 106 104 108

TABLE 7.43. INFRARED SPECTRA OF PYRIMID0[1,2-a]BENZIMIDAZOLONES(7.398)7.401)

b'

P he

R'

(7.3%)

(7.399)

R

Me

(7.401)

(7.400)

Compound R (7.398) (7.398) (7.398) (7.398) (7.399) (7.398) (7.398) (7.398) (7.399) (7.399) (7.398) (7.398) (7.398) (7.400) (7.401) (7.401) (7.401) (7.401) (7.401) (7.401) (7.401) (7.401) (7.401) (7.401) (7.401) (7.401) (7.401) (7.401) (7.401)

-

H

-

Ph Ph

R' H H

H Me

-

H H Me -

R2 H H H H

-

Ph Ph Ph

-

-

H H

-

-

Me

C0,Me

-

- -

H H Me H H Me H Me Me Me Me Me Me Me H CH,CI H Ph Me Ph H H H H Me H H H H H

C0,Me CO'Me

-

H H H H H Hb

H '

H H H C0,Et CO2Et CO@ CO,H CN

vmU (cm-9

Medium

NH

KBr KBr Me,SO KBr KBr KBr KBr KBr KBr CHCI, KBr Nujol

C=O 1675 1680 1680 1670 1630 1650 1675 1675 1685 1615 1740,1690 1745,1690, 1680 1750,1685 1670 1678 1690 1690 1680 1685 1680 1680 1682 1680 1670 1720,1645 1650 1653 1725

CH,CI, KBr KBr KBr

-a

KBr KBr KBr KBr KBr KBr KBr KBr KBr KBr Nujol Nujol

-d

~~

a

CKN

Medium not specified. C(7) bromo derivative. C(8) bromo derivative. vmax(C=O)not specified.

392

C=N

Ref. 127 130 130 130 130 127 130 127 127 136 127 135 135 130

130 130 111 127 125 125 125 126 127 127 127 130 120 120 120

eyi ' mJLoQLko

Me p-Me,NC,H, p-MeOC,H, p-Me2NC6H, p-O,NC,H,

(7.405) (7.405) (7.405) (7.405) (7.405)

" May also be assigned to NH def.I3'

-

H H COCHPh, COCHPh, COCHPh,

(7.404)

(7.403)

Me

H H H Me H H H H Me Me

(7.402) (7.402) (7.402) (7.402) (7.403) (7.403) (7.403) (7.403) (7.403) (7.403)

-

R'

(7.402)

H

I

N A N

Compound R

\

(7.405)

Me H H H H

H H H Me H H Me Me C0,Me CONH(CH,),NMe, n C o d a b l e

R*

(7.403)

R'

I

H COMe Ph Ph Ph

-

H Me H H

R'

H H Ph Ph Ph

-

H H Me H

R4

CHCI, Nujol KBr KBr KBr KBr

CHZCI,

KBr KBr KBr KBr Nujol KBr Nujol KBr Nujol CH,CI,

~~

C=O

-

3150

-

1625 1730 1729, 1715 1733, 1681 1733, 1678 1737, 1691

1650 1657 1614 1614 1618

-

1695, 1660 1620

1620 1620

-

1620" 1627" 1628" 1632"

C==N

-

(7.405)

R

136 159 129 141 141 141

135

137 137 137 137 120 139 120 139 135 135

Ref.

X LI y - i

338O-2500br 3350-2550br 3350-2600br 3400-2600br 1680 1659-1640 1680 1690 1735, 1695 1700, 1685

Medium NHlOH

(7.404)

Me I

TABLE 7.44. INFRARED SPECTRA OF TETRAHYDROPYRlMlDO[1,2-a]BENZIMlDAZOLE DERIVATIVES (7.402)-

394


mY , ~ o 0

R (7.414)

0

(7.415)

(7.416)

(7.417) Sdleme 7.82

other. Pyrimido[3,4-a]benzimidazol-l,3(2H,4H)-dione [Scheme 7.82; (7.415)] exhibits IR carbonyl absorption (1750, 1722 cm-') typical of a diacyl amide ~ t r u c t u r e . ' ~ ~ The ester substituent in the pyrazino[4,3-~]benzi1nidazolederivative [Scheme 7.82; (7.416)] gives rise to IR carbonyl absorption at 1720 cm-'.I4' The IR carbonyl absorption (1630 cm- I ) of pyrazino[4,3-a]benzimidazol4( l0H)-ones (7.417)"* is consistent with the highly conjugated nature of the carbonyl substituent in these molecules. 1,2-Dihydropyrazin0[4,3-a]benzimidazol-3(4H)-ones [Table 7.45 ; (7.407)] are readily distinguished from their 4(3H)-one counterparts [e.g. (7.408)] on the basis of their significantly lower IR carbonyl stretching frequencies (Table 7.45).

ULTRAVIOLET S P E ~ R The A . similarity of the UV absorption4' of simple 1,4~xazino[4,3-~]benzimidazoles to that of benzimidazole 3,4-dihydro- 1H-[ is consistent with the saturated nature of the fused oxazine ring in the former molecules. On the other hand, the conjugative unsaturation present in the thiazine ring of [1,3]thiazino[3,2-a]benzimidazol-4-ones[Table 7.46; (7.418)] accounts for the presence in their UV spectra (Table 7.46) of two intense maxima at 219-229 and 245-265 nm. The UV spectra (Table 7.47) of fully unsaturated pyrimidd1,2-u]benzimidazoles (7.420) and pyrimido[ 1,2-~]benzirnidazoliumsalts (7.421) are typified by the presence of a single intense maximum at ca. 240 nm accompanied by two lower intensity bands at longer wavelength. The UV spectrum (Table 7.48) of pyrimido[ 1,2-a]benzimidazol-2( 1H)-one (7.422; R' = R2= H), on the other hand, contains two intense absorption maxima at 236 and 250 nm and two lower intensity bands at 262 and 298 nm. Protonation of the molecule has the effect of suppressing the bands at 250 and 262 nm and inducing a hypsochromic shift in the long-wavelength band. Deprotonation,

TABLE 7.45. INFRARED SPECTRA OF 1,2,3,4TETRAHYDROPY RAZINO[~,~-CI]BENZIMIDAZOLE DERIVATIVES (7.406)-(7.411)

Compound

R

Medium

(7.406) (7.406) (7.407) (7.407) (7.407) (7.408) (7.409) (7.410) (7.411)

H CH,Ph Bu" Cyclohexyl CH2Ph

KBr KBr

Cyclohexyl

-

(7.411)

CH,Ph

-

NH

-a -a -a -

-

Nujol Nujol

3220, 3115 3250

-

0

-

-

a

0

C==O

Ref,

1680 1660 1660-1645 1660-1645 1660-1645 1710 1740, 1700 1650 1740- 1730. 1685-1 680 1740-1 730, 1685-1 680

150 150 151 151 151 151 152 152 151 151

TABLE 7.46. ULTRAVIOLET SPECTRA OF [ 1,3mIAZINq3,2-a]BENZIMIDAZOLE DERIVATIVES (7.418) AND (7.419)

(7.418)

(7.419)

Compound

R

Solvent"

A,

(7.418) (7.418) (7.418) (7.418) (7.418) (7.419)

H Me CI NO2 CO,H

A A A A A

223(4.17), 263(4.34) 224(4.19), 266(4.42) 219(4.28), 265(4.38) 22 l(4.25). 245(4.32) 229(4.46), 259(4.41) 295-297 (4.10-4.30)

a

A = methanol;

B

B =ethanol. 395

(nm) (log E )

Ref. 93 93 93 93 93 92

TABLE 7.47. ULTRAVIOLET SPECTRAa OF PYRIMID0[1,2-a]BENZIMIDAZOLES (7.420) AND PYRIMID0[1.2-a]BENZIMIDAZOLIUM SALTS (7.421)

i'

(7.420) Compound R'

(7.428) (7.420) (7.420)

(7.421) (7.421) (7.421)

H

H

(7.421)

RZ

R3

H

-

H

Ph Me Ph

H

Me Me

Me Me

Ref.

20X4.37).245(4.62),320(3.79),365(3.38) 247(4.14),285(3.30),315(2.30) 236sh. 247(4.50).256(4.48),263sh. 310(4.11),370sh 240(4.15),300(3.66),345(3.51) 240(4.51),294(3.%), 330(3.73) 240(4.37), 330(4.00),365sh

-

Me NH,

COZEt

La(nm) (log e )

156 114 120 114 114 114

Measured for solutions in ethanol.

TABLE 7.48. ULTRAVIOLET SPECTRA OF PYRIMIDq1,2-a]BENZIMIDAZOLONES (7.4223-47.4B)

QLkom.kQ.yR2a. I

R' (7.422)

Compound R

(7.424)

Me 1 (7.425)

Solvent"

A,,

H

H

A

H

H

21 1(4.41),236(4.51), 250(4.26), 262(3.93),298(4.06) 239(4.47), 248sh, 264sh,298(4.03) 236(4.48),289(3.96) 253(4.7l), 268sh(4.06) 23q4.22).294(4.05) 21 l(2.05). 237sh(4.24),248(4.03), 263(4.66),283(4.79) 249(4.47). 263(4.20),290(3.95) 2 t2(4.32),227sh(4.lo),248(4.36), 263sh(4.11),290(3.%) 242(4.46), 305(4.03) 212(4.76),239(4.76),297(4.30) 252(4.00), 2%(3.00) 251(4.00).298(4.00)

(7.422) (7.422) (7.422) (7.422) (7.422)

-

-

H H H H

(7.422) (7.422)

-

(7.422) (7.422) (7.422) (7.422)

-

(7.423)

R'

R2

-

-

R I

R'

(7.422)

-

Me I

B

H H H H

-b -

Me Me

H H

B A

H

Ph Ph Ph Ph

B A

H

Me Me

E

B

A

B

C

3%

(nm)(log E )

Ref.

134 120 1 20 120 127 130 120 130 127 130 127 127


elkoa1Loaxy:a.y Me I

R I

(7.423)

(7.424)

I

R'

(7.422)

Me i

(7.425)

RZ

Solvent'

A,,

-

R' Me H H

C0,Me C0,Me

Ph

D A

-

Me

C0,Me

A

(7.423) (7.423) (7.423) (7.423) (7.424)

H

-

-

-

A

Ph Ph Ph H

(7.424)

253(4.00), 288(3.00) 213(4.35), 239(4.42) 207(4.52), 243(4.40), 262(4.07), 310(3.85) 212(4.5 l), 250(4.36), 264sh(4.08), 270sh(4.02),306(3.80) 215(4.33), 237(4.52). 303(4.09) 24 l(4.00). 307(3.00) 240(4.00), 29S4.00) 242(4.00), 294(3.00) 228(4.33), 250sh(4.07), 321(4.02), 331(4.05) 228(4.36), 25Osh(4.10), 324(4.1l), 337(4.15) 254(4.47), 288(4.22). 3433.97) 255(4.00), 287(4.00), 347(3.00) 254(4.00), 29N4.00) 253(4.00), 287(4.00), 348(3.00) 231sh. 247sh, 276sh. 331(4.26), 341(4.26), 358sh 248(4.31), 273(4.11). 291(4.01) 220(4.38), 243sh(4.21), 264(3.87), 275sh(3.73),331(4.27), 342(4.26) 217(4.45), 240(4.19), 267(3.68), 276(3.64), 326(4.33), 343(4.31) 210(4.38), 231(4.25). 265sh(3.72), 273(3.56), 334(4.29), 342sh(4.28) 228(4.42), 248sh. 256sh, 330(4.23), 342(4.21) 218(4.41), 241(4.17), 269(3.66), 334(4.23), 244sh(4.19) 228sh(4.34). 244sh(4.28), 264sh. 276sh. 284sh. 296sh, 322(4.24), 345(4.23) 233(4.22), 248sh(3.99), 316(3.45) 229(4.12). 244sh(3.94), 306(3.51) 231sh(4.21), 250sh(3.%), 318(3.44) 228(4.41), 240(4.37), 329(4.011)

Compound

R

(7.422) (7.422) (7.422) (7.422)

B

B

H

H

C D A

Me

H

H

A

(7.424) (7.424) (7.424) (7.424) (7.424)

H Me Me Me H

Ph Ph Ph Ph H

H H H H C0,Et

B B

(7.424) (7.424)

H H

H

C0,Et C0,Et

B

(7.424)

Me

H

C0,Et

A

(7.424)

COMe H

C0,EI

A

(7.424)

H

H

CO,H

B

(7.424)

Me

H

CO,H

A

(7.424)

H

H

CN

B

(7.425) (7.425) (7.425) (7.425)

Me Me Me Me

Me Me Me H

H H H CO,Et

H

c D

B

A

B

-b E

._

B

(nm)(log E )

= MeOH; B = EtOH; C = 0.1 M NaOH, EIOH; D = 0.1 M HCI, EtOH. Measured at pH = 1. ' Measured at pH = 13. aA

397

R'

Ref. 127 127 135 135 130 127 127 127 130 130 127 127 127 127 120 127 130 130 130 120 130 120 120 120 120 120


398

TABLE 7.49. ULTRAVIOLET SPECTRA OF 1.2,3,4-TETRAHYDROPYRIMIDO[1,2-aJBENZIMLDAZOLEDERIVATIVES (7.426) AND (7.42'7)

R'

I

(7.426)

Compound

R'

RZ

(7.426) (7.426) (7.426) (7.427) (7.427) (7.427) (7.427) (7.427) (7.427) (7.427) (7.427) (7.427)

H H Me H H H Me Me Me H H H

H Me Me H H H H H H Me Me Me

I

H Solvent"

" A =ethanol.

H

(7.427) A,,,

(nm) (log c)

228(3.72),253(3.69), 291(3.72) 233(3.69),250(3.62),299(3.67) 231(3.61), 256(3.51), 302(3.57) 252(4.06).260 sh, 28q4.12). 292(4.13) 234(4.13),279(4.15),287(4.18) 263(3.89), 272(3.87), 302(4.32) 251(4.05),258sh. 284(4.13).291(4.13) 234(4.14),279(4.16). 287(4.19) 263(4.00), 272(3.97),302(4.35) 252(4.06),2-h. 285(4.13), 292(4.14) 234(4.14). 279(4.16), 287(4.19) 262(4.lo), 272(4.07), 303(4.37)

Ref.

137 137 137 120 120 120 120 120 120 120 120 120

Measured at pH = 1. Measured at pH= 13.

on the other hand, causes the disappearance of the bands at 236 and 298 nm and produces a small but significant bathochromic shift in the remaining maxima at 250 and 262 nm. Pyrimido[ 1,2-a&enzimidazol-4( lOH)-ones [Table 7.48; (7.424)] can be differentiated from pyrimido[ 1,2-a&enzimidazol-2(1H)-ones (7.422) on' the basis of their generally longer wavelength UV absorption (Table 7.48). UV studies"' demonstrate the preferential existence of pyrimido[ 1,2-a]benzimidazol-4-onesin the 10Htautomeric form (7.424; R = H). Not unexpectedly, the UV absorption (Table 7.49) of simple 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole derivatives is similar to that of 3,4-dihydro- 1H-[ 1,4]oxazino[4,3-~]benzimidazoles (see before) and benzimidazole. The UV spectra of 1,2,3,4-tetrahydropyrazino[4,3-a'jbenzimidazoles are likewise similar to those of 2-

(dialky1aminomethyl)benzimidazoles.'41

NUCLEAR MAGNETIC RESONANCE SPECTRA. The protons at the C(1) position in 3,4-dihydro- 1H - [ 1,4]oxazino[4,3-a]benzimidazoles resonate at consistently lower field (Table 7.50) compared with the protons at the C(3) or C(4) positions due to the cumulative deshielding effect of the oxygen atom and the azomethine substituent. In 3,4-dihydro-2H-[ 1,3]thiazino[3,2-a]benzimidazole derivatives [Table 7.5 1; (7.434)], on the other hand, H(4)

3

w

R

(74293

l

b-

E

C B D

B

A

A A A

Solvenf

9

4

-

5.45br 5.47br 5.355.55m 7.28 2.19 5.38 5.08 5.40 5.31

H(1)

H(4)

CH2Ph.

'JHO)-,,*= 10.5 Hz.

a

HB. "6 values not specified.

7.88 8.93 7.85

H(6)

(7.431)

-

H(7)

-4.55 6.25i.i

4.20

4.50

4.42 4.27

4.63k.i.l 5.05"*J*'

4.60

-

8.6Sf

8.93 9.23 8.55

-n

7.69-7.83111 8.22ddeSf 7.62d' 7.40-8.3Om ___* 7.50--8.00m

8.28dde*,

P

8.49df

4

7.53'

-

-

H(8) H(9)

HNKNH 0

0*d-

8 \

- -- -

-4.42-4.65m + 4.43-4.65m + +4.40-4.70m 4 t

H(3)

(7.4%)

6 values in ppm measured from TMS. Signals are sharp singlets unless denoted as d = doublet; dd = doublet; m = multiplet. ' A = CDCl,; B = D,O; C = CF,CO,D; D = CF,CO,H; E = (CD3),S0. COMe. 'IH,3,-Ha = 4.0 Hz. 'I=9.1-9.5 Hz. J = 2.0-2.1 Hz. k H A Hydrochloride. 'IHAvH,= 13.5 Hz.

(7.429)' (7.429;R = NO2)* (7.430) (7.431) (7.432)

(7.428;R' = OCOMe, R2= NO,)

(7.428;R2= NO,, R3= NH,) (7.428;RZ= NO,, R3 = NHCOMe) (7.428;R2 = NO,, R3= N,)

(R+ R' unspecified = H)

Compound

(7.428)

R'

6

5.82'

-

-

-

-

H(10)

TABLE 7.50. 'H NMR SPECTRAGb OF 3,4-DIHYDRO-1H-[1,4]OXAZINq4,3-a]BENZIMIDAZOLE DERIVATIVES (7.428H7.432)

55 55 62 63 87

56

49 49 49

Ref.

P 0 0

A

(7.433) (7.434;R' = R2= H) (7.434;R' = H,R2= Me)' (7.434; R' = OH,R2 = H) (7.434;R' = OH, RZ= HI' (7.434;R' =OH, R2 = Me) (7.435;R' = R2= H) (7.435;R' = CI, R2= H) (7.435;R' = H, RZ= NO,) -J-

6.44 2.75111 1.80-2.60111 5.25m 5.05m 5.15-5.35m 3.38111 3.29111

H(3)

- -

2.04' 3.70" 3.501' 3.80m 3.78' 3.80111

H(2)

~

-

4.48t' 4.1Sm 4.64111 4.54t' 4.50-4.70111

-

H(4)

~~

(7-434)

7.50% 8.12111 8.12dh 8.7Yk

7.25%

4

H(6)

~

-~

"

JH(6bH(7)

= Hz. ' JH(7)-H(V) = 2 Hz. ' 8 values not quoted. Multiplicity not specified.

These signal assignments may be reversed.

' Hydrochloride.

J value not quoted.

'C(Me).

6 values in ppm measured from TMS. Signals are sharp singlets unless denoted as d = doublet; dd = double doublet; t = triplet; rn = multiplet. ' A = (CD,),SO; B = D20; C = CF,C02H; D = CDCl,.

A D A

C

B

c

B B

Solvent'

(7.433) H(8)

8.23"

7.68-8.25m 7.66 1.2Sd 7.17 7.67-

~~

-2.52-' -7.291117.30ddh*'

-

-

H(7)

(7.435)

__

'H NMR SPECTRA"sb OF [I ,3]THIAZINq3,2-a]BENZIMlDAZOLE DERIVATIVES (7.433H7.435)

Compound

TABLE 7.5 1 .

7.42% 7.56111 7.60d' 7.68"

+

7.15%

H(9)

~~

93 98 98 98 98 98 106 105 106

Ref.

~


40 1

resonates at lowest field, the observed order of shielding (Table 7.5 1)for the thiazine ring protons being H(3)> H(2) > H(4). The deshielding effect of the C(4) carbonyl substituent in 2H-[1,3]thiazino[3,2-a~enzimidazol4(3H)-ones [Table 7.51; (7.435)] results in similar chemical shifts for H(2) and H(3) in such molecules (Table 7.51). H(6) in 2H-[1,3]thiazino(3,2-a]benzimidazol-4(3H)-ones absorbs at lower field (Table 7.5 1) than the other aromatic protons as a result of the anisotropic deshielding effect of the C(4) carbonyl substituent. The olefinic proton at the C(3) position in 4H[ 1,3]thiazino[3,2-a]benzimidazol-4-ones [e.g., Table 7.5 1; (7.433)] gives rise to singlet absorption in the range S 2.45-2.55.93 H(4) and H(9) are the most deshielded (Table 7.52) of the pyrimidine ring and benzenoid protons, respectively, in fully unsaturated pyrimido[ 1,2albenzimidazole derivatives (7.436). The C(2) and C(4) methyl substituents in 2,4-dimethylpyrimido[1,2-a]benzimidazole(7.436; R' = R2= Me) can be differentiated"' on the basis of the lower field resonance (Table 7.52) of the protons in the latter and their appearance as a doublet (J=0.9 Hz) due to coupling with H(3). Consequently, the lack of splitting (Table 7.52) associated with the protons of the methyl substituent in the pyrimido[ 1,241benzimidazole derivative obtained"' by condensing 2-aminobenzimidazole with acetoacetaldehyde dimethyl acetal (cf. section 7.2.1, "Ring-closure Reactions of Benzimidazole Derivatives") supports its formulation"' as 2methylpyrimido[ 1,2-a)benzimidazole (7.436; R' = Me). Conversely, the deshielded nature of the methyl group in the major product derived'I4 by the reaction of 2-aminobenzimidazole with methyl P-chlorovinyl ketone in the presence of perchloric acid (cf. section 7.2.1, "Ring-closure Reactions of Benzimidazole Derivatives"), requires its adjacency to the quaternary bridgehead nitrogen in the product, and hence indicates the latter to be 4methylpyrimido[ 1,2-a]benzimidazolium perchlorate. ' l4 The finding1I4 that the free base of this compound and the presumed 2-methylpyrimido[l,2-a]benzimidazole from 2-aminobenzimidazole and acetoacetaldehyde dimethyl acetal (see before) are apparently identical, reveals a possible flaw in one or other of the 'H NMR interpretations involved. H(3) and H(4) in pyrimido[ 1,2-a]benzimidazol-2( 1H or 1OH)-ones [Table 7.53; (7.437) and (7.438)] resonate uniformly at 6 5.8-7.0 and 6 8.0-8.9, respectively, with JH(3tH(4) = 7.5-8.0 Hz. Correspondingly, H(2) is considerably more deshielded (Table 7.53)than H(3) in pyrimido[ 1,2-a]benzimidazol-4(10H)-ones (7.439). A noteworthy feature of the 'H NMR absorption (Table 7.54) of the latter molecules and their N(1)H isomers (7.440) is the enhanced deshielding of H(6) as a consequence of the anisotropic effect of the proximate C(4) carbonyl substituent. This feature is of course lacking in the 'H NMR spectra (Table 7.53) of pyrimido[l,2-a]benzimidazol-2-ones (7.437) and (7.438) and therefore permits the differentiationll 1.120.130 of the two structural types. The normality of the NMR absorption (Table 7.55) of H(6) in 3,4-dihydropyrimido[ 1,2-a]benzimidazol-2(1H)-ones (7.441) is consistent with the C(2) position for the

h,

8

H H Me CI NH(CH,),NMe, NH2

B

A A

A A A

8.89ddd' 2.62' 2.53' 2.32' 2.42' 1.55tk.' 4.66qm.'

7.2Oddd.' 7.00d' 6.76 5.85 6.05 9.39 J J

-

9.49dde.' 9.33df 2.Y7dh.' 7.80mg 7.Wm 8.20m 8.48m

7.901~10 7.90111.

' '

8.00m

7.50m

- -t

+-7.50m + 8.30111. c 7 . 5 0 m 4 8.30mg t7.40m 8.10mg c-- 7.50m -+

6 values in ppm measured from TMS. Signals are sharp singlets unless denoted as d = doublet; dd = double doublet; t = triplet; q = quartet; m = multiplet. 'A = (CD,),SO; B = CF,CO,H. JH(Z)-H(3) = 4.0 Hz. "H(2FH(4) = 2.0 HZ. JH(3tH(4) = 6.5 Hz. These signal assignments may be reversed. C(Me). 1JH(3)-&fe(4)= O.' HZ i 6 values not quoted. Me of Et group. J value not specified. CH2 of Et group.

a

H Me Me Me Me C0,Et

R2

TABLE 7.52. 'H NMR SPECTRAOb OF PYRIMID0[1,2-all3ENZIMIDAZOLEDERIVATIVES (7.436)

111

111 120

111 111 111

$

P

C C

C 6.37' 6.39

6.00

7.OOdd 6.05d' 6.13' 6.9& 6.12dd 6.15' 5.81 6.15 6.26 6.50 6.50 6.60 6.20

8.08' 7 .30-7.80rni

2.75"

8.86dd 8.7W 8.71' 8.83dd 8.00dd 8.02' 6.60-7.70m' 7.29-7.90m' 7.25-7.70111' 3.70' 4.101 4.10' 4.95d1*' 5.80tm.'

"6 values in ppm measured from TMS. Signals are sharp singlets unless denoted as d = doublet; t = triplet; m = multiplet. A = CF3COzH; B = (CD,),SO; C = CDCI,. ' J = 7.5-8.0 Hz. * J = 5.0 Hz. Multiplicity not specified. * NMe. S vdues not quoted.

(7.438; R' = Me, R2 = H) (7.438; R' = Me, R2= Ph)

RZ= Me)

(7.437; R' = (CH2),NMq.

Bh

B B B

C C

B

C A C C

B

A

R'

(7.437)

-

-

7.90'

-h

-

CH,OH CH,OH; exchangeable with DzO. " NCH,. a C(Me).

'Spectrum taken at 100".

MeO.

' ArH.

7.30-7.70m 7.30-7.80m t -

c-----7.10-7.9Om

-

7.86m 7.10-8.00ni c--- 7.20-8.10m c - 7.97m 7.10-7.80m 7.10-7.80rn 6.60-7.70m 6.65m7.29-7.90111 7.25-7.70m7.05-7.75111 7.10-7.65m 7.15-7.70m ___.* 7.15-7.85m 4

R' (7.4361

R2

'H N M R SPECTRAab OF PYRIMI~I,~-u]BENZIMIDAZOL-~-ONES (7.437) AND (7.438)

(7.437; R' = R2= H) (7.437; R' = RZ= H) (7.437; R' = R2 = H) (7.437; R' = Rz = H) (7.437; R' =Me, R2 = H) (7.437 R' = Me, R2 = H) (7.437; R' = H, Rz = Ph) (7.437; R' = H, R2 = Ph) (7.437; R' = Me, R2 = Ph) (7.437; R' = H, R2= C0,Me) (7.437; R' = H, RZ= C0,Me) (7.437; R' = Me, R2= C0,Me) (7.437; R' = Me, R2 = CH,OH)

TABLE 7.53.

130 127

135

120 130 127 130 127 127 135 135 135

130 134

120 127

P P

0

(7.439) (7.439 R' =Me) (7.439; R2= Me) (7.439; R2= Me) (7.439; R*= R2= Me) (7.439; R' = R2= Me)' (7.439; R' = R2= Me)' (7.439; R2= Ph) (7.439; R' =Me, R2= Ph) (7.439 R2= C0,Et)

-

Compound (R' R3 unspecified = H)

TABLE 7.54. 'H N M R

C

B

A

A C B B B

A B

Solvent'

H(1)

-

7.99d 7.92d 2.32'*' 2.70' 2.36' 2.34' 2.36' 7.45-8.21111' 7.35-8.10111' 9.21

H(2)

(7.439)

R'

0

6.03d 6.08d 5.81 6.45 5.97 5.99 6.00 6.70 6.65 1. 5 4 P d 4.63q".d

H(3)

H(8)

H(7)

-

H(9)

7.13ds 7.35-7.50111

c------ 7.30-7.75m 8.47m 8.52111 7.10-7.50m7.50111 8.40m 8.30m t-------- 7.70-8.00m7.17-7.44111 8.57ddSeh 7.54dds.h 8.75h 7.35-7.50m 8.43d' 8.35m 7.45-8.21111 7.35-8.10m 8.40 7 7.88111 8.72m

H(6)

(7.440)

Me

0

OF PYRIMIDq1,2-a]BENZIMIDAZOL-4-ONES (7.439) AND (7.440)

3.90

-

3.72' 3.72' 3.70'

-

H(10)

130 130 111 127 125 125 125 127 127 120

Ref.

R’= Me)

C

-

4.13’

-

_.

-

-

8.67 8.78 8.75 8.79 9.22 8.89 2.13’ 8.40

8.70

1.30t”’.d 8.20111 4.30qn.d 8.50111 8.63111 -n 8.52111 8.36111 8.80m 8.72111 6.67 8.72m 8.571~1 +

*

7.80-8.00m7.92m 7.85m 7.30-7.90m-

c - 7.39111-

7.40-7.50m-

c----.7.20-7.70m-

7.30-7.60m

- - -

6.90-7.60111

- -

6 values not quoted.

” CH, of Et.

Me of Et.

‘ ArH.

” 6 values in ppm measured from TMS Signals are sharp singlets unless denoted as d = doublet; dd = double doublet; t = triplet; q = quartet; m = multiplet. A = (CD,),SO; B = CDCI,; C = CF3C0,H; D = CDCL,+CD,),SO; E = KOD-D,O. Multiplicity not specified. C(Me). Singlet at 500 Hz, which resolves to a doublet ( J = 0.6 Hz) at 50 Hz. ’J = 8.5-9.0 Hz. hJ=2.0Hz. ’ NMe. C(7)bromo derivative. Ir C(8) bromo derivative.

(7.440; R2= C0,Et)

(7.440;

(7.439; R’ = C0,Et) (7.439; R’= Me, R3= C0,Et) (7.439; R’= COMe. R3= C0,Et) (7.439; R’ = CO,H) (7.439; R’= Me, R’ = CO,H) (7.439; R3= CN)

(7.439; R3= CO,Et)

-

-

130 130 130 120 130 120 120 130

127

H H

H

H H

H

H

H

H Me

H

Me

R2

8 m H H

R'

H

NMe H

U

CON

n

Ph

H

Me

Me H

H

H

Me CH20H

H H

H

R4

H H H

R3

2.65-3.35mS.'."

3.10-3.40111

3.55"

2.90 2.84q-" 3.3 1qp.O

1.58d'*' 3.30-3.70111 3.00-3.800ct'

c---3.95-4.42111

3.43td 4.15t'

H(3)

3.38"

-

-

-

2.6 1-2.8Od 2.82-3.1 ImY

-

-

SolventC H(1)

+

5.35dd~' 2.35"' 2.26-2.60111" 3.40-3. 75m"

1.72'.' 5.00-5.70111 1.56' 4.78111 3.681114 5.21t' 5.50-5.80111

4.W5.000ctk

4.721" 2.90t=

H(4)

H(7) 7.68

H(8)

b

b

139 139

+ 120

H(9) Ref.

c---6.90-7.75111

7.00-7.401~1-

7.35 7.00-7.70111

c---7.73

7.67

135

139

+ 139 135

120

1 20

- - -

c----h

-7.15

H(6)

-

TABLE 7.55. 'H N M R SPECTRA".b OF 3.4-DIHYDROPYRIMIDO[1,2-~]BENZ1MIDAZOL-2(1H)-ONES (7.441)

'

Me

NHMe CONHMe

H D

Jgem- l3Hz. Hz; lgern- l7 HZ

- l o Hz;

JH(3)irans-H(4)-7

Hz.

1.5 HZ.

Hz;

Hz; JH(3tH(4)trom

3.55"

3.40-3.65rn" 2.30m" 4. W . 4 0 m Y

3.40-3.65111'" 2.90m' 9.00mY

-7.10-8.00111-

6 values in ppm measured from TMS. Signals are sharp singlets unless denoted as d = doublet; dd = double doublet; t = triplet; q = quartet; Oct = octet; m = multiplet. 'A = CF3C0,H; B = (CD3),SO: C = CDCI,; D = C,D,N. J = 7-8 HZ. J values not specified. CH,CO,H. NCH,. 6 vdues not specified. ' C(Me). ' I = 7 Hz.

' JH(3kir-Hw)-2

Ir JH(3bH(4)n$- 8

"NMe. = 7.5

= 16.5 HZ.

nJH(3)320 (decornp.) 226227 (decomp.) 224-225 203-205 225-226 203-204 >360

77 79 87 49 55 63 42

66

(7.4%; R = H)

(7.504; (7.504; (7.504; p (7.504; w QO (7.504; (7.504; (7.4%;

Dimethylfonnamide

>360 250-253 Toluene (decornp.) 245-246 Toluene

Dimethylformamide

305-306


72

38

b

-

42 73 78

Yield m.p. ("C)

(O/O)

(7.505; R = OPh. R' = p-n-CSHI,CnH, (7.505; R=OPh, R' = p-CIC6HJ (7.505; R = OPh, R' = p-BrCnH,) (7.505; R = OPh, R' = p-O,NC,H,) (7.505; R = NH,, R' = Ph) (7.505; R = NH,, R' = p-CIC,H,) (7.505; R = NH,, R' = p-O,NCbH,) (7.498; R = NH,)'

R = Ph) R = Ph) R = Ph)

D

R = H) R = H)

(7.498; (7.498; (7.498; (7.498; (7.498;

B C D

A

Reaction conditionse Product

E

(7.504 R = OPh)

(7.497; R = R' = H, X = NH) (7.497; R = R' = H, X = NH) (7.497; R = R' = H. X = NH) (7.497; R = H, R' = COPh, X = NH) (7.497; R = H, R' = CSNHCOPh, X = NH) (7.504; R = OPh)

Starting material

TABLE 7.72. SYNTHESIS OF 1,3,5-TRIAZINq1,2-a]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF 2AMINOBENZIMIDAZOLE DERIVATIVES

187 187 187 187 186

187

187 187 187

184

187 187 187 187 187 187 183

187

187

185 185 186 186 186

Ref.

I

Q

Q

Q

Q

R

R

(7.508;R = R' = H)

(7.508; R = R' = H)

(7.508;R = R' = H)

(7.508;R = R' = H)

(7.508;R = R' = H)

P Q

0 0 0 0

P

0

(7.510;R = p-MeC,H,)

(7.509;R' = p-MeOC,H,, R2= p-BrC6H4) (7.509;R' = p-MeC,H,, R2 = p-02NC6HJ (7.509;R' = p-MeOC,H,, R2 = p-OzNC,H,) (7.509;R' = 2-naphthyl, R2 = p-OZNCbH,) (7.510;R = Ph)

46

41

43

56

58

50

81 34

-b -b -b -b

71 74

-b -b -b -b

78

(7.502)

N (7.513;R = Me) (7.513;R = Et) (7.513;R = p r (7.513;R = Pr') (7.513;R = Bun) (7.513;R = Bu") (7.513;R = Bu') (7.513;R = Bu') (7.513;R = CH2Ph) (7.513;R = Ph) (7.513;R = Ph) (7.509;R' = P-O~NC~H,, R2 = Ph)

78

0 0 0 0

-

>360

308-309

238-240

>360

>360

268-269

138 167-168 130-132 112-1 14 109 109-1 10 138 143 145-146 196-197 152-153 224-226

Dimethylforrnamidewater Dimethylformamidewater Dirnethylformamidewater Dimethylformamidewater Dimethylformamidewater Dimethylforrnamidewater Dirnethylformarnidewater

-f

-r

J -f J

J n-Hexane m -Xylene

J J J

187

187

187

187

187

187

190 190 190 190 190 195 190 190 190 190 195 187

186

-

186 188 189 143 186 186 186

-

Pyridine Dirnethylformamide Dirnethylforrnarnide Dimethylformamide

-

-

323 46 311 94 294-295 quant. >360 78

28

-

(7.502)

(7.499) (7.500)' (7.500) (7.501) (7.502) (7.502)

N

N

M

L

K

J

(7.508;R = R' = H)

(7.497;R = H, R' = COPh, X = 0) (7.4%; R = H) (7.4%; R = H) (7.497;R = R' = H, X = NH) (7.497;R = R' = H. X = NH) (7.497; R = H, R' = CONHCOPh, X = NH) (7.497;R = H. R' = CONHCO,Et, X = NH) (7.497;R = H, R' = CSNHCO,Et, X = NH) (7.512;R' = R2 = H) (7.512;R' = R2 = H) (7.512;R' = R2= H) (7.512;R' = R2 = H) (7.512; R' = R2= H) p (7.512;R' = R2 = H) $ (7.512;R' = R2 = H) (7.512;R' = R2= H) (7.5U;R' = R2 = H) (7.5l2;R' = R2= H) (7.512;R' = R2 = H) (7.508;R = R' = H)

$

(Continued)

(7.511) (7.511) (7.511; (7.511; (7.503; (7.515; (7.515; (7.515;

S T S S U V W V

U

V

Y

V

(7.4%; R = H) (7.512; R' = R2= H)

(7.497; R = H , R'=Bu", X = O )

R' = H, R2= Me)

(7.512;

X

V

(7.4%; R = H )

(7.512; R' = H,

R2= Me)

+

(7.515; R = Bun, R' = H, R2 = Me)

(7.503; R = H, R' = Bun) (7.515; R = Bun, R' = Me, R2 = H)

(7.503; R = H, R' = Bun) (7.515; R = Bun. R' = R2 = H)

'

(7.515: R = Pr', R' or R2= H or Me)* (7.503; R = H,R = Bun)

18

54 17

87 78

84

50

41

R = Pr', R' = R2 = H)

V

(7.512; R' = R2 = H)

(7.515;

53

(7.515; R = Pr".R' = R2 = H)

V

84

R' = R2= H)

(7.512;

>350

>350

rn.p. (OC)

255

280 310

285-287 280

282

325

300

285-287

325-326

>320 quant. 348 -b >320 -b >320 >350 70 93 >350 >360 44 320 56

-

V

R = Me)' R = CI)' R = H, R' = Me) R = Me, R' = R2= H) R = Me, R' = R2= H) R = Me, R' or R2 = H or Me)' (7.515; R = Et. R' = R2 = H)

(7.510;

40

Yield (46)

R = m-CIC,H.,)

~

35

~

(7.510; R = p-CIC6H.J

R

R


(7.512; R' = R2 = H)

R=H) R = Me) R = CI) R = H) R' = R2 = H) R = Me, R' = R2 = H) R' = H, R2 = Me)

R = H)

= H)

R = R'

(7.508;

(7.507; (7.507; (7.507; (7.507; (7.496; (7.512; (7.514; (7.512;

= H)

R = R'

(7.508;

Starting material

TABLE 7.72

I

Dioxane or dimethylformamide Acetic acid Dioxane or dirnethylformamide Dioxane Dimethylforrnamidewater Dioxane

Dioxane or dimethylformarnide Dioxane or dimethylforrnarnide Dioxane or dimethylformamide Dirnethylformarnide

Dimethylforrnarnide J

d

h

Acetic acid -

Dimethylformamidewater Dirnethylformarnidewater Acetic acid Dioxane-water Acetic acid


199

199

200 199

199

199

199

199

199

197 186 197 197 200 199 199 199

187

187

Ref.

+

(7.503; R = H, R ' = NMe,) (7.503; R = H, R' = CH,CO,Me)

V

Z Z

(7.512; R' = R2= H)

-b

79

87

67 15 93

-h

in

I

>330 252

340

-h

--i

201,202 20 I

199

199 199 199 199

199

Dioxane

270

Dioxane Dioxane Dioxane Dioxane-water Dioxane or dimethylformamide Dioxane or dimethylfonnamide

199

-d

315

205 320 305 250 340

199

Dioxane

315

199

Dioxane

300

''

A = HCO,Et, MeOH/(reflux)(48 hr); B = 1,3,5-triazine, piperidine, EtOH/(reflux)(lO hr); C = PhCON+S, pyridine/(reflux)(24 hr); D = pyridine/(reflux)(lS hr); E = R'CO,H, toluene/(reflux)(3 hr); F = dicyandiamide/(l25-2OW)(6 hr); G = R'CHO. toluene/(reflux)(l-3 hr); H = PhCON==C=O, pyridine/(reflux)(48 hr); I = pyridine/(reflux)(24 hr); J = PhCON=C=S, pyridine, benzene/(room temp.)( 16 hr); K = PhCON=C=S, pyridine, benzene/(room temp.)(24 hr); L = PhCHO, KOH, EtOH/(reflux)(S hr); M = PhCON=G=O, EtO,CN=C=O, or EtO,CN-C-S, Et,N, dioxane/(80")(3 hr). N = dimethylformamide/(reflux)(few min); 0 = RNH, 35% HCHO aq., CH,C1,/(38°)(1 hr); P = RNH, 30-37% HCHO aq., dioxane/(70-90")( 1-5 hr); Q = R'N===CHR', dimethylfonnamide/(130")(1hr); R = RN=C=O, dimethylformamide/(130°)(1-2 hr); S = BrCN, KHCO, EtOH/(5O-6O0)(few min); T = EtO,CN=C=O, Et,N/(80")(4 hr); U = MeNHCON(Me)COCI or PhNHCON(Bu")COCI, Et,N, acetone/(reflux)(2-3 hr); V = RN=C=O, Et,N, toluene/(reflux)(8-16 hr); W = Et,N, toluene/(reflux)(l2 hr); X = Bu"N==C=O. PhNMe,, methyl isobutyl ketone/(reflux)(2 hr); Y = COCI,, Et,N, toluene/(room temp.)(2 hr), then (reflux)(8 hr); Z = (PhO),C=O, PhOH, PhCN/(160°)(24 hr). Yield not quoted. Nitrate. Not crystallized. ' Pyridinium salt; free base has m.p. 310" (from dioxane). Solvent of crystallization not specified. C(7) or C ( 8 ) position for the substituent in the benzene ring not established. Purified by precipitation from alkaline solution with dilute acid.

(7.49: R = H . R'=NMe,. X = R) (7.497: R = H, R' = CH2C0,Me, X = 0)

(7.515; R = Ph, R' = R2 = H)

V V V V

(7.512; R' = H. RZ= CI\ (7.512; R' = R2 = Me) (7.512; R' = RZ= C1) (7.4%; R = H)

(7.515; R = Bun, R' = H, R2 = OMe) (7.515; R = Bun. R' or R2 = H or C1)* (7.515; R = Bu". R ' = R'- = Me) (7.515; R = Bun, R' = R2= Cl) (7.503; R = H, R' = Ph)

V

(7.512; R' = H, RZ= OMe)

1

V

(7.512; R' = H. RZ= Bu" 1

+

V

(7.512; R' = H, R2 = Et)

-b (7.515; R = Bun, R' or R2 = H or CF,)* 35 (7.515; R = Bun. R' or R2 = H or EtIs (7.515; R = Bun. 43 R' or R2= H or (7.515; R = Bun, R' = OMe, R2 = H) 26

V

(7.512; R' = H. R2 = CF,)

442


(7.497; X = S). The direct conversion of a 2-aminobenzimidazole derivative into a 1,3,5-triazino[1,2-a]benzimidazole is exemplified by the thermal reaction of 2-aminobenzimidazole with dicyandiamide to give, depending on yields (Table 7.72) of 2,4the temperature used, m ~ d e r a t e " ~to diamino- 1,3,5-triazino[1,2-a]benzimidazole (7.498; R = NH,). 2-Amino1,3,5-triazino[l,2-a]benzimidazole(7.498; R = H) is likewise formed in good

yield (Table 7.72) by the acylative ring-closure of N-(2-benzimidazolyl)guanidine (7.497; R = R ' = H , X = N H ) with ethyl formate or less orthodoxly with 1,3,5-triazine in the presence of piperidine."' 2-Amino-4phenyl- 1,3,5-triazino[1,2-a]benzimidazole (7.498; R = Ph) is the somewhat unexpected product obtained in high yield (Table 7.72) by the pyridine catalyzed condensation of N-(2-benzimidazolyl)guanidine (7.497; R = R' = H, X = NH) with benzoylisothiocyanate.ln6 The first-formed intermediate in this transformation is the N-benzoylthiourea derivative (7.497; R = H, R' = CSNHCOPh, X = NH) which can be isolated and shown'86 to be convertible in the presence of pyridine into the 1,3.5-triazino[1,2-a]benzirnidazole (7.498; R = Ph) (Table 7.72), or thermally, in the absence of catalyst, into the N-benzoylquanidine derivative (7.497; R = H, R' = COPh, X = NH). The demonstrable pyridine catalyzed cyclization of the latter (Table 7.72) then accounts satisfactorily for the original formation of the 1,3,5-triazino[1,2-a]benzimidazole (7.498; R = Ph) from N-(2-benzimidazolyl)guanidine (7.497; R = R' = H, X = NH). Ring-closure reactions (Scheme 7.99) of 2-amino-l(iminoacy1)benzimidazoles(7.504) constitute an alternative general synthetic approach to derivatives of the fully unsaturated 1,3,5-triazino[1,2-a]benzimidazole ring sy~tem.'~'Processes of this type are exemplified by the thermal reactions of the imidate (7.504; R = OPh) and the amidines (7.504; R = NR,) with aromatic carboxylic acids to give good yields (Table 7.72) of 2-aryl-4-phenoxy- and 4-amino-2-aryl- 1,3,5-triazino[1,2-a]benzimidazoles (7.505; R = OPh or NR2, R' = aryl), re~pectively.'~'The related thermal ring-closure reactions of the imidate (7.504; R = OPh) and the amidines (7.504; R = NR2) with aromatic aldehydes"' afford efficient (Table 7.72) general methods for the synthesis of 1,2-dihydro- 1,3,5-triazino[1,2-a]benzimidazoles of the type (7.506; R=OPh or NR,, R'=aryl). In ring formation (Scheme 7.99) akin to that affording 2-amino-4-phenyl- 1,3,5triazino[ 1,2-a]benzimidazole (7.498; R = Ph) (see before), 4-phenyl- 1,3,5triazino[ 1,2-a]benzimidazol-2( lH)-one (7.499) is obtained'86 in moderate yield (Table 7.72) by the pyridine catalyzed cyclization of the N-benzoylurea derivative (7.497; R = H, R' = COPh, X = 0),which can be preformed or prepared in siru by the reaction of 2-aminobenzimidazole with benzoylisocyanate. 4-Phenyl- 1,3,5- triazino[ 1,2-a]benzimidazole- 2( 1H)-thione (7.500) is likewise formed in moderate yield (Table 7.72) by the ring-closure of 2-aminobenzimidazole with benzoylisothiocyanate or ethoxycarbonyli ~ o t h i o c y a n a t e . ' ~ ~The " ~ ~ potassium hydroxide catalyzed condensation (Scheme 7.98) of N-(2-benzimidazolyl)guanidine (7.497; R = R' = H, X = NH) with benzaldehyde to give the 1,3,5-triazino[ 1,2-a]benzimidazole de-


R

443

I

(7304)

(7.505)

H (7.506)

(7.510)

H

!wlew 7.99

rivative (7.501)'43 exemplifies an efficient {Table 7.72) and potentially general method for the synthesis of 3,4-dihydro- 1,3,5-triazin~1,2-a]benzImidazoles. 2-Amino- 1,3,5-triazino[l,2-a]benzimidaz01-4(3H)-one(7.502) is the end-product (Table 7.72) of a series of thermal ring-closure reactions originating in N-acyl derivatives (7.497; R = H, R' = CONHCO,Et, CONHCOPh, or CSNHC02Et) readily accessible by the

444

Condensed Benzirnidazoles of Type 6-5-6

reaction of N-(2-benzimidazolyl)guanidine (7.497; R = R' = H, X = NH) with benzoyl- or ethoxycarbonylisocyanate or ethoxycarbonylisothiocyanate.Ia6 Simple 1,2,3,4-tetrahydro-1,3,5-triazino[1,2-a]benzimidazole derivatives are generally available in high yield (Table 7.72) by the Mannich-like condensation reactions of 2-methoxycarbonylaminobenzimidazoles with amines in the presence of aqueous formaldehyde [Scheme 7.100; (7.512) +(7.513)].'90-'96 In an alternative method (Scheme 7.99), 2-amino1-cyanobenzimidazole (7.508; R = R' = H) is thermally ring-closed with arylideneimines to afford low to moderate yields (Table 7.72) of 1,2dihydro-1,3,5-triazino[ 1,2-a]benzimidazole-4(3H)-imines(7.509; R' = R2 = a r ~ l ) . ' *The ~ related thermal condensation (Scheme 7.99) of 2-amino- 1cyanobenzimidazole (7.508; R = R' = H)with aryl isocyanate~'~'provides synthetic access, though in low yield (Table 7.72) to 1,3,5-triazino[ 1,243benzimidazole-2,4(1H,3H)-dione 4-imines (7.510; R = aryl). 2-Amino- 1cyanobenzimidazoles (7.508; R' = H) are plausible intermediates in the potassium hydrogen carbonate catalyzed ring-closure reactions of orthophenylenediamine derivatives with cyanogen bromide to give N-unsubstituted 1,3,5-triazino[l,2-a]benzimidazole-2,4(1H,3H)-dionesin unspecified yield [Scheme 7.99; (7.507)- (7.508; R' = H)-* (7.511)],19' The parent 1,3,5-triazino[1,2-a]benzimidazole-2,4( 1H,3H)-dione is obtained'86 in quantitative yield (Table 7.72) by the triethylamine catalyzed reaction of 2-aminobenzimidazole with ethoxycarbonylisocyanate via the probable intermediacy of an N-ethoxycarbonyl N-(2-benzimidazolyl)urea derivative [Scheme 7.98; (7.496; R = H)+ (7.497; R = H, R' = C02Et, X = O)].The thermal ring-closure of 1-cyano-2-(cyanoamino)benzimidazolewith n-butylamine to give 3-n-butyl-1,3,5-triazino[1,2-a]benzimidazole-2,4(1H,3H)diimine [Scheme 7.99; (7.508; R = H, R' = CN)+(7.510; R = Bu", NH for R

- n,

R' = R=

I

(7.512)

C0,Me (7.513)

R'

,CONHR

R2x A N H C 0 2 M e I

H

(7.514)

(7.515) %heme 7.100


445

0)]”8 represents a potentially useful method for the synthesis of molecules of this type. 3-Substituted 1,3,5-triazino[l,2-a]benzirnidazole-2,4(1H,3H)diones are generally accessible, often in high yield (Table 7.72) by the triethylamine catalyzed ring-closure of 2-aminobenzimidazole derivatives with isocyanates’””or allophanoyl chlorides,200via the possible intermediacy of urea derivatives, which can likewise be cyclized by thermal treatment with diary1 carbonates20**202 or by triethylamine catalyzed condensation with phosgene”’ [Scheme 7.98; (7.496)- (7.497; X = 0)-(7.503)]. Alternatively the ring-closure of 2-aminobenzimidazoles with isocyanates and allophanoyl chlorides involves N-carboxamide intermediates, which can be preformed and cyclized under basic conditions to afford 3-substituted 1,3,5-triazino[l,2-albenzimidaole-2,4(1H,3H)-diones[e.g., Scheme 7.100; (7.512) -+ (7.514) + (7.515)]?03 thoughonly in low yield (Table 7.72).

Ring-closure Reactions of Other Heterocycles The dehydrative ring-closure (Scheme 7.10 1) of 2-(2-aminophenyl)-l,2,4triazine-3,5(2H,3H)-diones(7.516) which gives 1,2,4-triazino(2,3-a]benzimidazol-2(1l-f)-ones (7.517) in good yield, represents the sole reported example of a reaction in the title category.

(7.516)

(7.517)

(i) AcOH/(refluxHlOhr)

COZH

76

CN

71

260-265 (decomp.) >360

sebeme 7.101

7.3.2. Wysicochemical Properties

Spectroscopic Studies INFRAREDSPECTRA.The NH substituents in the tetrahydro-l,2,4-triazino[4,3-a]benzimidazole derivative [Scheme 7.102; (7.536)] give rise to welldefined IR NH absorption at 3230 cm-l. Compared with the IR carbonyl stretching frequencies (ca. 1700 cm-’) of simple 1,2,4-triazino[2,3-a]benzimidazol-2(1H)-ones [e.g., Table 7.73; (7.518; R = Me or Ph)] that

446


!kkm? 7.102

(1670 cm-I) for the cyano derivative (7.518; R = CN)is abnormally low. The IR stretching frequency (1693 cm-I) of the ring carbonyl group in an N-unsubstituted 1,2,4-triazino[4,3-a]benzimidazol-4-one”6is consistent with the existence of such molecules in the N(1O)H as opposed to the N(1)H tautomeric form. The more conjugated ring carbonyl substituent in 1,2,4-triazino[4,5-a]benzimidazol1(5H)-ones [e.g., Table 7.74; (7.520)] absorbs in the IR at lower frequencies than that in 1,2,4-triazind4,5-a)benzimidazol- 1(2H)-ones [Table 7.74; (7.521)]. The similar IR frequencies (Table 7.74) of the ring carbonyl substituents in N-unsubstituted 1,2,4triazino[4,5-a]benzimidazol-1-ones [TabIe 7.74; (7.521; R’= H)] and specifically N(2)-substituted derivatives [e.g., Table 7.74; (7.521; R’ = Et)] are indicative of the preferential existence of the former molecules in the N(2)H as opposed to N(5)H tautomeric form. The ring carbonyl substituent in 1,2,4-triazolo[4,5-a]benzimidazol-4(3H)-ones [Table 7.74; (7.522)] absorbs uniformly in the IR at 1680 cm-’. 1,3,5-Triazino[1,Z-albenzimidazole-2,4( 1H,3H)-dione 4-imines [Table 7.75; (7.526)] exhibit IR NH absorption at 3350-3340 cm-’, carbonyl absorption in the range 17451735 cm-’and well-defined C=N absorption at 1655-1645 cm-I. The IR TABLE 7.73. INFRARED SPECTRA OF ~,~,~-TRIAZIN~[~,~-U]BENZIMIDAZOL3(4H)-ONES (7.518)

H

(7.518)

R

Medium

OH,NH

Me

-a

-

Ph

CO,H CN C(NH,)=NOH a

0

Nujol Nujol Nujol

Medium not specified.

3465,3365

e N -

-

2242

-

C=O

C=N

Ref.

1700 1700 1732,1714 1670 1705

-

172a 172a 206 206 206

1640 1628 1638


447

TABLE 7.74. INFRARED SPECTRA OF 1,2,4-TRIAZINq4,5-a]BENZIMlDAZOLE DERIVATTVES (7.519H7.522)

(7.519)

(7.520)

(7.521)

(7.522) vmaX(cm-9

Compound

(7.519) (7.519) (7.519) (7.520) (7.521) (7.521) (7.521) (7.521) (7.521) (7.522) (7.522) (7.522) (7.522) (7.522)

R'

RZ

Medium

NH,OH

C==O

Ref.

OEt OCOCMe OCOCH,CI

C0,Et C0,Et C0,Et

-

1735

H H H Et Et H H Me CH,OH (CH,),CN

C0,Et C0,Et CONH, C0,Et C0,Et H Me H H H

Nujol Nujol Nujol Nujol Nujol MeCN Nujol Nujol MeCN Nujol Nujol Nujol Nujol Nujol

7 7 7 7 7 7 7 7 7 181,in2 181,in2 182 207 207

-

-

-

3180

-

-

3200 3200

-

-

inoo, 1740

1800,1730 1700,1676 1735,1720 1730 1735,1635 1734,1710 1734,1710 1680 1680 1680 1680 1680

spectra (Table 7.75) of 3-substituted 1,3,5-trimin4 1,2-u]benzimidazole-2,4(1H,3H)-diones (7.527) are typified by the presence of two bands in the carbonyl region in the ranges 1745-1715 and 1705-1680 cm-'. Bands in the ranges 1696-1670 and 1650-1630m-' in the IR spectra of 1,2-dihydro1,3,5-triazino[1,2-a]benzimidazoles [Table 7.75; (7.524)] are attrib~ted'~' to C=N absorption. ULTRAVIOLET SPECTRA. The UV spectra (Table 7.76) of derivatives of the fully unsaturated 1,2,4-triazino[4,5-a]benzimidazole ring system [Table 7.76; (7.530)] are characterized by the presence of three intense absorption maxima in the range 2 2 3 3 3 5 nm. Comparison of the UV absorption (Table 7.76) of specifically N(2) and N ( 5 ) alkylated 1,2,4-triazino[4,5-a]benzimidazol-1-ones [e.g., Table 7.76; (7.531) and (7.532; R' = Et, R2= CO,Et)] with that of N-unsubstituted 1,2,4-triazino[4,5-a]benzimidazol-lones [e.g., Table 7.76 (7.532; R' = H)] clearly demonstrates molecules of the latter type to exist preferentially in the N(2)H tautomeric form. Correspondingly, the essential coincidence of the U V spectra (Table 7.76) of Nunsubstituted and N(3)-methyl-1,2,4-triazino[4,5-a]benzimidazol-4(3H)ones [Table 7.76; (7.533; R' = H or Me)] and their dissimilarity from that of


448

TABLE 7.75. INFRARED SPECTRA OF 1,3,5-TRlAZINO[ 1,2-o)BENZIMIDAZOLE DERIVATIVES (7523)-(7.527)

(7.523)

Compound R

(7.524)

R'

R2

Medium OH,NH

Aql

-O

C=N

-

1680-1640 187 1650 185 1675-1635 187 1670.1620 184 1696-1670, 187 1645- 1630 1695-1680 187 1650-1635 1620 190 1655-1645 187 20 1

(7.523) (7.523) (7.523) (7.523) (7.524)

-

OPh H NH, NH, OPh

(7.524)

-

NR,

Avl

-"

3160-3140

-

(7.525) (7.526) (7.527)

Bun Aryl CH,CO,Me

-

-

-a -a

-

KBr

-

(7.527)

CH,CO,Bu"

-

-

KBr

-

(7.527)

CHZCOzPh

-

-

KBr

-

(7.527)

NMe,

-

-

KBr

-

1745 1745-1735 1755,1740, 1695 1740,1715, 1680 1765,1738, 1690 1745,17051695

O

-

-

NH, KBr Aryl NH, KBr A v l -a

-

C=O

3335,3250 3400-3300 3190 3200-3100

3350-3340

1690

-

-

-

Ref.

-

20 1

-

20 1

1640-1620

201, 202

Medium not specified

the 0-methyl derivative [Table 7.76; (7.530; R' = H, RZ= OMe)] demonstrates the existence of the N-unsubstituted compounds in the keto as opposed to hydroxy form. NUCLEAR MAGNETICRESONANCE SPEW. The protons of the C(3) and

C(4) methylene substituents in 1,2,3,4-tetrahydro-l,2,4-triazino[4,3-a]-

benzimidazole [Scheme 7.102; (7.536)] resonate as triplets centered at


449

TABLE 7.76. ULTRAVIOLET SPECTRA OF 1,2.4-TRIAZINOBENZIMIDAZOLE DERIVATIVES (7.528t(7.533)

(7.528)

(7.529)

(7.531 Compound

(7.530)

(7.532)

R'

(7.528) (7.529)

-

(7.530) (7.530)

H Me

(7.530) (7.530) (7.530) (7.530) (7.530) (7.530) (7.531) (7.532)

H H Me OEt OCOMe

-

RZ

H

Solvent"

-

A A

H

-

C0,Et

*

Amax (nm) (log c)

Ref. 172b 206

B B

202(4.54), 270(4.38). 375(4.01) 214(4.51), 265(4.54), 279(4.58), 286(4.60) 343(3.96) 246(4.40), 316(3.78) 226(4.18), 245(4.40), 320(3.98), 335(3.90) 255(4.36), 268(4.34), slS(4.07) 223(4.27), 258(4.28), 334(3.84) 25 1(4.43), 268(4.40), 315(4.02) 227(4.21), 250(4.49), 320(3.77) 243(4.34), 324(3.92) 243(4.34), 326(3.92) 245(4.24), 265(4.26), 359(4.07) 2 18(4.37), 244(4.37), 326(3.93)

179 182 195 7 7 7 7 7

A A

H

Ph OMe Ph COzEt C0,Et OCOCH2CI C02Et

-

(7.533) ~~

A A A

B B

B

179 179

(7.532)

H

C O N 2 B

230(4.3 I), 246(4.22), 320(4.05)

7

(7.532) (7.533) (7.533) (7.533) (7.533)

Et

C0,Et H

247(4.39), 332(3.97) 250(4.49), 295(3.94), 305(3.92) 25 l(4.46). 295(3.97), 305(3.96) 247(4.43), 295(3.99), 39543.99) 245(4.44), 297(3.97)

7 182 182 207

H

Me CHZOH

H

A = ethanol;

H H

Me

B

C A A A

182

B = methanol; C = dioxane.

8 3.90 and 4.40, re~pectively."~The signal due to H(1) which appears at 6 10.2 (Table 7.77) in fully unsaturated 1,2,4-triazino[4,5-a]benzimidazole derivatives [Table 7.77; (7.534)] is shifted upfield to ca. 89.3 in 1,2,4triazino[4,5-a]benzimidazol-4(3H)-ones [Table 7.77; (7.535)]. H(9) in the latter molecules resonates at lower field than the other benzenoid protons (Table 7.77).

$

R' = R2 = H) R' = H, R2 = Ph) R' = Me, R2 = Ph) R = R' = R2 = H) R = R' = R2 = H) R = R2 = H,R' = NO,) R = R' = H, R2 = NO,) R = CH20H, R' = R2 = H) R = (CH,),CN, R' = R2 = H)

Solvent'

9

9.30 9.34

-e -

10.20dd 10.20 3.1Y 9.30

(7.534)

R'

3.82' 3.23tk.' 4.7 5 trnJ

-

R'

0

t

4

t

7.97m 8.17d' 8.78d'

'

'

8.30m 9.4M' 9.43dh

8.03-8.69m 8.07m. 8.62m. 8.82m 8.16-8.43m 7.60m 7.60m 8.48ddh.' 8.42ddh.' 8.15-8.43m 8.16-8.44m

+

(7.535)

++NAN

'H NMR SPECTRAab OF 1,2.4-TRIAZIN0[4.5-a] BENZIMIDAZOLE DERIVATIVES (7.534) AND (7.535)

"6 values in ppm measured from TMS. Signals are sharp singlets unless denoted as d = doublet; dd =double doublet: t = triplet; m = multiplet. A = Me,SO-CCI,; B = Me2SO; C = CF,CO,H; D = Me,NCHO. J = 2.0 Hz. ' 6 values not quoted. PhH. C(Me). J = 8.8-10.0 Hz. ' J = 2.0-2.3 Hz. CH20H. NCH,. ' I value not quoted. rn CH2CN.

(7.534; (7.534; (7.534; (7.535; (7.535; (7.535; (7.535; (7.535; (7.535;

TABLE 7.77.

179 179 195 207 182 182 182 207 207

-

-

Ref.

45 1


General Studies IONIZATION CONSTANTS. The pK, value (5.32 f 0.02) measured spectroscopically in aqueous ethanol for 2-cyano- 1,2,4-triazino[2,3-a]benzimidazol3(4H)-one indicates this molecule, as expected, to be a weak N-acid.206

7.3.3. Reactions

Reactions with Electrophiles ALKYLATION. In accord with their N(2)H as opposed to N(5)H tautomeric structures, 1,2,4-triazino[4,5-a]benzimidazoll(2H)-ones are alkylated in high yield (Table 7.78) at N ( 2 ) under basic condition^.^ Correspondingly, the base-catalyzed alkylation of 1,2,4-triazino[4,5-a]benzimidazol-4(3H)ones takes place at N(3) also in high yield (Table 7.78).'x22.207 In contrast, the uncatalyzed thermal methylation of 1,2,4-triazino[4,5-a]benzimidazol4(3H)-one takes place at oxygen giving 4-methoxy- 1,2,4-triazino[4,5-a]benzimidazole in good yield (Table 7.78).lx2 1,2,4-Triazino[4,5-a]benzimidazol-4(3H)-one is cyanoethylated in good yield at N(3) under basic conditions [Scheme 7.103; (7.537)+(7.538)].207 The reaction of 1,3,5-triazino[ 1,2-a]benzimidazole-2( 1H)-thione with ethyl iodide in the presence of

TABLE 7.78. ALKYLATION REACTIONS OF 1,2,4-TRIAZIN0[4,5-a IBENZIMIDAZOLONES Reaction conditions"

1,2.4-Triazin~4,5-a]benzimidazolone

m.p. ("C)


Ref.

66

161-162

Ethanol

7

64

207

Ethanol

Yield

(Yo)

Substrate

Product

B

4-C02Et1(2H)-one 4(3H)-one

2-Et-4-C02Et1(2H)-one 4-OMe

C

4(3H)-one

3-Me-4(3H)-one

83

C

l-Me-4(3H)-one 1,3-Me2-4(3H)-one 84

C

4(3H)-one

3-Et-4(3H)-one

42

D

4(3H)-one

3-CH2Ph-4(3H)one

57

A

181, 182 308-310 Dimethylform- 181, amide 182 241-243 181, Ethanol I82 232 Ethanol 181, 182 289-290 Dimethylform- 207 (decomp.) amide

A = Etl. NaH. dimethylformamide/(I00")(18 hr): B = Me2S0,, PhN0,/(130-140")(45 min.): C = Me1 or Etl, NaOEt, EtOH/(reflux)(4.5 hr); D = PhCH,CI, KI, NaOEt, EtOH dimethyl sulfoxide/ (reBux)(7hr).

0 (7.537)

(7.538)

(7.539)

(m.p. 277-278')

(m.p. 35 1-352")

(i) CH,=CHCN, Triton W/(reflux)(3 hr) (ii) HCHO aq., EtOH/(reBux)(3.5 hr) Schaue 7.103

TABLE 7.79. ALKYLATION REACTIONS OF 1,3,5-TRIAZINO[ 1.2-aBENZIMIDAZOLE DERIVATIVES Reaction conditions" A A

B

c A

B

c A A

D

1,3,5-Triazino[ 1,2-albenzimidazole Substrate 2,4(1 H,3H)-dione 2,4( lH,3H)-dione 2,4(1H,3H)-dione 2.4( lH,3H)-dione 3-Bun-2,4(1H.3H)dione 3-Me-2,4(1 H,3H)dione 3-Ph-2,4( lH.3H)dione 3-Et-2,4( 1H,3H)dione 3-Ph-2,4(1H,3H)dione 4-Ph-2( 1Hbthione

Product

Solvent of m.p. ("C) crystallization

199 199 199 199 199

1,3-M%-2,4(1H,3H)-dione 232 1,3-Et2-2,4( lH,3H)-dione 156 1,3-Bu;-2.4(1H,3H)-dione 116-117 1,3(CH2Ph),-2,4(1H,3H)-dione 200-202 1-Me-3-Bun-2,4(lH.3H)-dione 150-151

1-Bun-3-Me-2,4(1H,3H)-dione 180

Acetonitrile

l-Me-3-Ph-2,4( 1H,3H)-dioneb 222-224

+

190

2-SEt-4-Ph-

199 199

280-28 1 1-Prn-3-Et-2,4(1H,3H)-dione 170-175

2-OMe-3-Ph-4(3H)-oned

l-Pr"-3-Ph-2,4(lH,3H)-dione185-192

Ref.

199 -b

199

Ethanol

188

A = NaOMe, MeOH, benzene/(room tempJ(30 min. then R1. dimethylformamide)/(80°)(1 hr); B = NaH, dimethylformamide/(room tempJ(l0 min), then BunBr)/(1200)(1 hr); C = Mel, K,CO,, dimethylformamide/( looo)(1 hr); D = Etl, NaOH, MeOH(room temp.)(l6 hr). Solvent of crystallization not specified. Yield 26%. Yield 546. * Purified by chromatography. a

452

7.3. Fused Benzimidazoles with TWO Additional Heteroatoms

453

sodium hydroxide is reported'88 to occur at sulfur giving a thioethyl derivative (Table 7.79) in unspecified yield. N(3)-Substituted 1,3,5-triazino[ 1,2albenzimidazole-2,4( 1H,3Zf)-diones undergo orthodox alkylation at N ( 1) under basic condition^.'^^ ACYLATION. 1,2,4-Triazin0[4,5-a]benzimidazol-l(2H)-onesare acylated at oxygen rather than nitrogen by acid chlorides under basic conditions [e.g., Scheme 7.104; (7.540)-,(7.541)].7 O n the other hand, the reaction of 1,2,4-triazino[4,5-a]benzimidazol-4(3H)-onewith formaldehyde results in hydroxymethylation at N(3) [Scheme 7.103; (7.537)--* (7.53!l)].207 Also, the acylation of N(3)-substituted 1,3,5-triazinoC1,2-aJbenzimidazole-2,4(lH,3H)-diones by acid chlorides and acid anhydrides occurs at N(l) rather than at oxygen (Table 7.80).'99

0

C02Et (7.540)

C02Et R

H

CI (1)

(7.541)

Yield (%)

m.p. ("C)

76

150-151 188- 190

-

MeCOCI, (Pr'),NH, CH,Cl,/(room temp.)(:! hr) Scheme 7.104

ELEC~ROPHILIC SUBSTITUTION REACTIONS. The nitration of 1,2,4-triazino[4,5-a]benzimidazol-4(3H)-oneby mixed acid affords the %nitro derivative [m.p. 338" (decornp.)] in 70% yield.'82 This appears to be the only reported example of electrophilic substitution in a tricyclic 6-5-6fused benzimidazole ring system of the type under consideration.

Reactions with Nucleophiles The stability of the 1,2,4-triazin~2,3-a]benzimidazol-4(3H)-one ring system to acidic hydrolysis is demonstrated by the conversion of 2-cyano1,2,4-triazin~2,3-a]benzimidazol-3(4H)-one in hot concentrated hydrochloric acid into the corresponding carboxylic acid [m.p. 260-265" (decornp.)] in 71% yield.2M In contrast, the fused triazine ring in fully unsaturated 1,2,4-triazino[4,5-aJbenzimidazole~,~.'~~ and in 1,2,4-triazino[4,5-a]3H)]benzimidazol- 1(2ti)-onesZo8 and 1,2,4-triazin~4,5-uJbenzimidazol-4( ones182 is readily opened under both acidic and basic conditions giving

454


TABLE 7.80. ACYLATION REACTIONS OF 1,3,5-TRIAZINO[1,2-a]BENZIMIDAZOL2,4(1H,3H)-DIONESa

1,3,5-Triazin~1,2-a]benzimidazole Reaction conditionsb Substrate Product

l-COMe-3-Et-2,4(lH,3H)225 dione 203 3-pr"-2,4(1H,3H)-dione l-COMe-3-P1''-2,4(lH,3H)dione 3-Pf-2,4( 1H,3H)-dione 1-COMe-3-W-2,4(1H,3H)208 dione 148-1 52 3-Bun-2,4(1H,3H)-dione 1-CO2Et-3-Bun-2,4(1H,3H)dione 3-Bun-2,4(1H,3H)-dione 1-C0,Ph-3-Bun-2,4(1H.3H)170-172 dione 3-Ph-2,4(1H,3H)-dione 1-CONHMe-3-Ph-2.4(lH.3H)- 350 dione 3-Bu"-2,4(1H,3H)-dione 1-CONHBu"-3-Bun280 2,4( 1H,3H)-dione 3-Ph-2,4(1H,3H)-dione 1-CONHPh-3-Ph-2,4(1H.3H)- 330-345 dione

3-Et-2,4(1H,3H)-dione

Solvent of

m.p. ("C) crystallization

-

C

-c -c Acetonitrile Benzene Dimethylformamide -c -c

From Ref. 199. A = Ac,O/(reflux)(2-7 hr); €4 = ClC0,Et or CICO,Ph, Et,N, tetrahydrofurane/(6S0)(2hr): C = RN=C=O, Et,N, toluene/(reflux)(Shr). Solvent of crystallization not specified.

benzimidazole derivatives. The 1,3,5-triazine ring in 1,3,5-triazin41,2-a]benzimidazoles is also susceptible to base-catalyzed r i n g - ~ p e n i n g . ~ ~ ~ Oxidation Investigations of the behavior of the various 6-5-6 fused benzimidazole ring systems with two additional heteroatoms toward oxidation have been limited to the ~ t u d y " ~ of the electrochemical oxidation of 1,4-dihydro1,2,4-triazino[4,3-a]benzimidazolederivatives and the demonstration of the dehydrogenation18' of 1,2-dihydro- 1,3,5-triazino[ 1,2-a]benzimidazoles to fully unsaturated 1,3,5-triazino[ 1,2-a]benzimidazole derivatives. 73.4. Practical Applications

Biological Properties 1,3,5-Triazino[1,2-a]benzimidazole derivatives of various types have found widespread application as antiparasitic agents'*lw*'w and as and herbicides.'"" fungicides,190- 193,196,199,201-203,209 pesticides,'YY*202

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Orher Applications 1,3,5-Triazino[ 1,2-a]benzimidazole-2,4(1H,3H)-dione has been patented’” as a photographic emulsion stabilizer.

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168. H. 0.Hankovszky, K. Hideg, and S. Pacsa, Hung, Teljes, 10,396;through Chem. Abstr., 84, 135623 (1976). 169. W. P. Langsdorf, S. African Patenr, 7,005,123;through Chem. Abstr., 76.21955 (1972). 170. K. Murobushi, Y. Kuwabara. S. Baba, and K. Aoki, J. Chem. Soc. (Tokyo), 58, 440 (1955); through Chem. Abstr., 49, 14544i (1955); Y. Kuwabara and K. Aoki, Konishiroku Reu., 6, 1 (1955)through Chem. Abstr., 49, 11473f (1955);Y. Kuwabara and K. Aoki, Yakugaku Zasshi, 77,906 (1957);through Chem. Abstr., 51, 1615% (1957);Y. S . Moshkovskii and M. V. Deichmeister, Trudy Vsesoyuz. Nauch, Issledovate1 Kinoforoinsr.. 1960. 74; through Chem. Abstr., 56, 8208h (1962). 171. W. L. Mosby in Systems with Bridgehead Nifmgen, Paa 2, IThe Chemisfry of Heterocyclic Compounds. A. Weissberger, (Ed.), Wiley-Interscience, New York, 1961, Chap. 7, pp. 907-910. 172. (a) R 1. Fu Ho and A. R. Day, J. Org. Chem., 38,3084 (1973);(b) A. V. Zeiger and M. M. Joullie, J. Org. Chem., 42, 542 (1977). 173. M. V. Povstyanoi, E. V. Logachev, and P. M. Kochergin, Chem. Heterocycl. Compd.. 1976,603; Khim. Gererotsikl. Soedin., 1976, 715; Chem. Abstr., 85, 94322 (1976). 174. Y. I. Beilis, M. V. Povstyanoi, E. V. Logachev, and A. V. Shikarev, J. Gen. Chem. USSR 46.420 (1976);Zh. Obshch. Khim., 46,426 (1976);Chem. Abstr., 84. 142548 (1976);P. M. Kochergin and M. V. Povstyanoi, USSR Parent, 384.821; Chem. Abstr., 79, 105299 (1973). 175. M. V. Povstyanoi, E. V. Logachev, and P. M. Kochergin, Ukr. Khim. Zh., 43, 746 (1977);through Chem. Abstr., 87, 167984 (1977). 176. D. J. Le Count and A. T. Greer, 1. Chem. Soc. Perkin Trans. I, 1974, 297. 177. M.V. Povstyanoi, P. M. Kochergin, E. V. Logachev, E. A. Yakubovskii. A. V. Akimov. and V. P. Kruglenko, Chem. Heterocycl. Compd. 1976, 1180;Khim. Geterorsikl. Soedin, 1976, 1424;Chem. Absrr., 86. 55350 (1977). 178. M. V. Povstyanoi, P. M. Kochergin, E. V. Logachev, and E. A. Yakubovskii, Chem. Heterocycl. Compd. 1975. 371;Khim. Geterotsikl. Soedin., 1975,422;Chem. Abstr., 83, 28197 (1975). 179. Z.A. Pankina and M. N. Shchukina, Chem. Pharm. J., 6,633 (1972);Khim. Farm. Zh., 6,8 (1972);Chem. Abstr., 78,92396 (1973). 180. J. Slouka, Monatsh. Chem., 100, 91 (1969);Chem. Abstr., 70, 96766 (1969). 181. Z.A. Pankina and M. N. Shchukina, Chem. Heterocycl. Compd., 1970, 228; Khim. Geterotsikl. Soedin., 1970, 245; Chem. Absrr., 72, 111426 (1970);Chem. Heterocycl. Compd., 1968, 281; Khim Geterotsikl. Soedin., 1968, 380; Chem. Abstr., 69, 96680 (1968). 182. Z.A. Pankina, M. N. Shchukina, N. P. Kostyuchenko, and Y. N. Sheinker, Chem. Pharm. J., 4, 314 (1970);Khim. Farm. Zh., 4, 12 (1970);Chem. Abstr., 73, 56068 (1970). 183. H.Schlaepfer and J. Bindler, U.S.Patent, 3,309,366;Chem. Abstr., 67,21939(1967). 184. A. Kreutzberger and A. Tantawy, Chem. Ber.. 111, 3007 (1978). 185. A. Kreutzberger, Arch. Pharm., 309,794 (1976);Chem. Abstr.. 86, 72588 (1977). 186. L. Capuano, H. J. Schrepfer. M. A. Jaeschke, and H. Porschen, G e m . Ber., 107, 62 (1974). 187. M. Augustin and K. R. Kuppe. Tetrahedron, 30,3533 (1974). 188. R. Sgarbi. Chim. Ind. (Milan). 48, 18 (1966);Chem. Absa., 64,9727e (1966). 189. L. Capuano and H. J. Schrepfer. Chem. Ber., 104, 3039 (1971). 190. A. Roechling and K. Haertel, Ger. Patent, 2,224,244;Chem. Abstr., 80,59970(1974). 191. H. Roechling and K.Haertel, Ger. Patent, 2,308,067;Chem. Absrr., 81, 152284 (1974). 192. H. Roechling and K. Haertel, Ger. Parent, 2,349,911;Chem. Abstr., 83,97387(1975). 193. H.Roechling, and K. Haertel, K. Kirsch, and D. Duewel, Ger. Parent, 2,356,258;Chem. Abstr., 83, 97395 (1975). 194. H. Roechling, R. Kirsch, and D. Duewel, Ger. Parent, 2,452,365;Chem. Abstr., 85, 63096 (1976).

References

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195. G. Kempter, W. Ehrlichmann, and R. Thornann, 2. Chem., 17, 262 (1977); Chem. Abs tr.. 87, 167987 (1977); E. Ger. Paten? 118,881; Chem. Abstr., 86, 106666 (1977). 196. C. C. Beard, J. A. Edwards, and J. H. Fried, South Afncan Parent. 7,603,751; through Chem. Abstr., 89, 43516 (1978). 197. N. Heimbach and R. H.Clark, U.S. Parent 2,444,609; C h e m Abstr., 42,7180i (1948). 198. E. R. White, E. A. Bose, J. M. Ogawa, B. T. Manji, and W. W. Kilgore, Agr. Food Chem.,21, 616 (1973). 199. L.Schroeder, W. Ost, and K . Thomas,Ger. Parent, 2,144,505; Chem. Abstr., 78, 159686 (1973). 200. H. G. Werchan, G. Dittrich, and P. Held, E. Ger. Patent, 127,636; Chem. Abstr., 88, 136680 (1978). 201. W. Daum and P. E. Frohberger, Ger. Parent, 2,527,677; Chem. Abstr., 86. 155704 (1977). 202. W. Daum, W. Behrenz, I. Hammann, H. Scheinpflug, and W. Brandes, Ger. Parent. 2,528,623; Chem. Abstr., 86, 155796 (1977). 203. E. A. Bose and E. R. White, US.Patent, 3,725,406; Chem. Abstr., 79,62595 (1973). 204. A. h b r u s and E. Hargitai, Enoiron. Qual. Saf. SuppL. 3, 113 (1975); Chem. Abstr., 85, 117793 (1976). 205. J. P. Calmon and D. R. Sayag, J. Agric. Food Chem., 24,314 (1976). Chem. Abstr., 84, 131467 (1976). 206. J. Slouka, Collect. Czech. Chem. Commun., 42, 894 (1977); Chem. Abstr., 87, 102271 (1977). 207. Z. A. Pankina and M. N. Shchukina, Chem. P h . J., 3,440 (1969); Khim. Farm. Zh., 3, 15 (1969); Chem. Absrr.., 72. 55412 (1970). 208. J. Slouka and M. Budikova, Acta Uniu. Palacki Olomue., Fac. Rerum Nat., 45, 113 (1974); Chem. Abstr., 82, 125360 (1975). 209. B. Sachse, F. Schwerdtle, and H. Roechling, Meded. Fac. Londbouwwet., Rijksuniu. Gent., 40,723 (1975); through Chem. Abstr., 84, 131292 (1976); K. Haertel, B. Sachse, and F. Schwerdtle, Ger. Patent, 2,519,520; Chem. Abstr., 86, 26911 (1977).


CHAPTER 8

Condensed Benzimidazoles of Type 6417 and Higher Homologs M .F.G.STEVENS 8.1 Tricyclic Benzimidazoleswith No Additional Heteroatom 8.1.1 Synthesis . . . . . . . . . . . . . . . . . . .

.

..........

........

Cyclization of orrhebubstituted N-Aryl Heterocycles . . . . . . . . Cyclization of 1- and 2-Substituted Benzimidazoles . . . . . . . . Photolysis of Phenazine N-Oxides . . . . . . . . . . . . . . . . 8.1.2 Physicochemical Studies . . . . . . . . . . . . . . . . . . . . . Infrared Spectra . . . . . . . . . . . . . . . . . . . . . . . . Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . . . . Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . . Mass Spectra . . . . . . . . . . . . . . . . . . . . . . . . . General Propexties . . . . . . . . . . . . . . . . . . . . . . . 8.1.3 Reactions . . . . . . . . . . . . . . . . . . . . ........ Reactions with Electrophiles . . . . . . . . . . . . . . . . . . Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . Photochemical and Thermal Reactions . . . . . . . . . . . . . . Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2 Tricyclic Benzimidazoles with One Additional Heteroatom . ........ 8.2.1 Synthesis . . . . . . . . . . . . . . . . . . . . ........ 8.2.2 Physicochemical Studies and Reactions . . . . . . . . . . . . . . . 8.3 Tricyclic Benzimidazoles with Two Additional Heteroatoms . . . . . . . . . 8.3.1 Synthesis and Reactions . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

464 464 464 471 475 477 477 478 480 482 482 484 484 484 489 490 491 492 496 498 499

502

Tricyclic benzimidazoles of the 6-5-7 arrangement. and larger ring homologs. have not been extensively studied and most efforts in this area have been directed toward the development of synthetic methods with little systematic examination of the physical and chemical properties of the system . Three main synthetic routes can be recognized: 1. Interaction of an ortho substituent (generally amino. substituted amino. azido. or nitro) with the cr-methylene group of a saturated heterocyclic 463

464

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

(heteroalicyclic) ring. Yields are, in general, high and the mechanistic details and scope of this reaction in benzimidazole chemistry-"the t-amino effect"-have been reviewed by Meth-Cohn and Suschitzky.' 2. Cyclization of 1- or 2-substituted benzimidazoles. Included in this type are the controversial reactions of 2-substituted benzimidazoles with acetylenic esters, which afford azepinol 1,2-a]benzirnidazoles in meager yields, and more efficient syntheses of tricyclic systems bearing additional heteroatoms in the 7(8) ring. 3. Photolysis of phenazine N-oxides. Although of mechanistic interest, this approach is limited to the formation of benzimidazoles fused to an azepinone fragment.

8.1. TRICYCLIC BENZIMIDAZOLES WITH NO ADDITIONAL HETEROATOM

8.1.1. Synthesis Cyclization of ortho-Substituted N- Aryl Heterocycles Oxidation of N-(0-aminopheny1)hexahydroazepine (8.1) with peroxytrifluoroacetic acid yields the azepinobenzimidazole (8.2) in high yield.* De-

8.1. Tricyclic Benzimidazoles with No Additional Heteroatom

465

TABLE 8.1. AZEPINO[ I,2-a]BENZIMIDAZOLES (8.3) FORMED BY PERACID OXIDATION OF N-(o-AMIN0PHENYL)HEXAHYDROAZEPINES OR THEIR N-ACETYL DERIVATIVES Substituents R

R'

Oxidant

Yield (%)

m.p. ("C)

Ref.

H C0,Et NHAc H NO," Hb

H H H NHAc H NO,

CF,C0,H/H202 HC02H/H202 HCO2HIH202 HCOzH/H,O2 HCOzH/H202 HC02H/H202

91 58 68

124-125

2 3 4

108

252 222 177 196

66

-c -

4

5

5

" Starting material: N-(2-acetylamino-4-nitrophenyl)hexahydroazepine.

Starting material: N-(2-acetylamino-5-nitrophenyl)hexahydroazepine. Yield not recorded.

rivatives of (8.1)substituted in the benzene ring3 or bearing an acetylated oaminophenyl group4*' similarly form substituted azepinobenzimidazoles (83) with performic acid being the oxidant of choice (Table 8.1). Cyclization of the unsubstituted amine (8.1)can also be accomplished by sulfuryl chloride.6 The first step is probably formation of the tetrachloro derivative (8.4), followed by conversion to sulfonylamine (8.5). Cyclization to the tricycle (8.6) may occur either by way of a nitrene (following loss of sulfur dioxide) or by intramolecular H-abstraction and cyclization.' Diazotization of (8.1) in hydrochloric acid followed by treatment with sodium sulfite-sulfur dioxide yields a diazosulfonate (8.7), which cyclizes to a benzimidazolium sulfamate (8.8) with excess sulfur dioxide at 70°.'

c1

466


A series of anils (8.9), prepared from amine (8.1)and aromatic aldehydes, cyclize in ethanolic hydrochloric acid to benzimidazolium salts (8.10)(Table 8.2) together with an equal proportion of the benzylamines (8.11).' In one case-the anil from 2-chloro-5-nitrobenzaldehyde-the product is a red insoluble dihydrobenzimidazole (8.12), which is transformed to a benzimidazolium salt in boiling ethanolic hydrochloric acid. A similar anil cyclization is probably involved in the synthesis of betaine (8.13)when (8.1) is reacted with alloxan in acid." Labeling experiments with the deuterated piperidine analog of (8.9; R = C,H,CI-o) show that deuterium is incorporated into the benzylic positions of both the benzimidazolium salt and benzylamine by-product.' The anils probably react by way of their subsequent cyclization of the immonium ions (8.14) mesomeric forms (8.9~);

c1-

(8.12)

(8.13)


467

TABLE 8.2. AZEPINO[ 1,2-a]BENZIMIDAZOLES FORMED BY CYCLIZATION OF ANILS (8.9) IN ETHANOLIC HYDROCHLORIC ACID" Compound

R

Yield (YO) m.p. ("C)

8.10 8.10 8.10

Ph 2-ClC,H4 4-CIC6H4

84 86 90

8-10 8.12 8.13

-

2-C1.5-NOzC,H,b

80 94 -

-

288 (decomp.) 244-246 252 (hemihydrate) 243 (decomp.) 144 >300

" From Ref. 9.

From compound (8.12) and ethanolic hydrochloric acid. Yield not recorded.

gives the protonated dihydrobenzimidazoles (8.15). The flexible 7membered ring of the latter allows for a bimolecular transition state between protonated and free dihydrobenzimidazole (8.16) in such a way that hydride transfer can occur (Scheme 8.1). N-(o-Azidopheny1)hexahydroazepines(8.17) thermolyze in nitrobenzene to afford the tricyclic benzimidazoles (8.19; R = H,(3).The role of the

(8.9)

-

H' c1CN-CHR

(8.14)

(8.9a)

(8.15)

I

(8.16)

(8.11) scbeme 8.1

468


(8.18)

(8.17)

(8.19)

R = H,CI,NO,

nitrobenzene is twofold: it initiates the thermal decomposition and oxidizes the intermediate dihydrobenzimidazoles (8.18).” A dihydro intermediate (8.18; R = NO,) can be isolated when the solvent is hot diglyme and further transformed to the aromatic product (8.19; R = NO,) by a range of oxidizing agents.” Physical characteristics of azepino[ 1,2-~]benzimidazolesprepared by this route are recorded in Table 8.3. TABLE 8.3. AZEPINq1,2-a]BENZIMDAZOLES PREPARED BY THERMOLYSIS OF N-(o-AZIDOPHENYL)HEXAHYDROAZEPINES (8.17) Compound

R

NO,

Yield (YO) m.p. (“C)

H

75 85

8.19

c1

72

8.19 8.19

NO,

-a

8.18 8.19

NO,

lo@

119 125-126 232-234 (methiodide) 107-109 25 9-26 1 (hydrochloride) 273-273 (methiodide) 174-175

-

Ref.

12 11 11 11 11 11 11

12

By decomposition of (8.17; R = NO2) in nitrobenzene; yield not recorded. By oxidation of (8.18; R = NO,).

a

Although reductive cyclization of N-cyclohexyl-o-nitroaniline(8.20) to azepinobenzimidazole (8.2) can be achieved by heating the substrate in either ferrous oxalate (21% yield) or sand (15%),13 this type of cyclization is more effectively accomplished by trivalent phosphorus deoxygenating agents.I4 Conveniently, only the o-nitro substituent of N-(2,4-dinitrophenyl)hexahydroazepine (8.21) reacts in boiling trimethyl phosphite,’* giving the dihydrobenzimidazole (8.18; R = NO2) in 5 0 4 0 % yield; triethyl phosphite is a less satisfactory agent. Deoxygenation of the N-acetyl-o-nitrodiphenylamine (8.22) with triethyl phosphite in boiling cumene affords the azepinobenzimidazole (8.23) in 11% yield.15 Although 6H- or l0H-isomers are compatible with the spectral data the 6H-arrangement is preferred, since it


(8.21)

469

LJ

accords with its (presumed) formation via an intermediate o-nitrene --.* azanorcaradiene 4azepine transformation. Conversion of benzimidazoles to their N-oxides cannot normally be accomplished by direct oxidation (see Chapter 2, section 2.2.1). However, when N-(o-nitropheny1)hexahydroazepines or their higher ring homologs (8.24) are refluxed in 6N-hydrochloric photolyzed in methanolic hydrochloric or reduced with titanous chloride in hydrochloric acidIg either tricyclic N-oxides (8.27) or their deoxygenated counterparts (8.28) are formed. In the acid cyclization the reaction is believed to proceed via nitronic acid species (8.25),which abstract a hydrogen atom from the a-methylene group (Scheme 8.2);the products are hydrochloride salts of N-oxides (8.26).The reaction can be exploited for the attachment of larger heteroalicyclic rings (Table 8.4):however, in the case of the 13-membered N-aryl heterocycles (8.24; R = H or Cl, n = 11) only 2-(o-chlorododecylSurprisingly, in the amin0)nitrobenzenes (8.29)are formed in 90% ~ie1ds.l~ photocyclization route both N-oxides (8.27) and benzimidazoles (8.28) appear to be formed by different pathways””* and the product distribution is exquisitely sensitive to the basicity of the tertiary nitrogen and the electronic influence of the substituent in the phenyl ring. In the titanous chloride-hydrochloric acid reduction of N-(o-nitropheny1)hexahydroazepine (8.24; R = H, n = 5) the reaction probably involves an intermediate N-oxide, which is deoxygenated to the benzimidazole (8.28; R = H, n = 5 ) by the second equivalent of reducing agent.19 With zinc chloride-acetic anhydride the reaction takes a different course and the zinc salt of the 6-hydroxyazepinobenzimidazole(8.30) is formed.20 Similar treatment of N-(2,4-dinitrophenyl)hexahydroazepine yields the acetoxyazepine (831).Comparable rearrangements have been noted in 1,2-dimethylbenzimidazole-3-0xide.~~

(8.26)

(8.27)

(8.28) R = H.c1,NO, !acme 8.2

RaNo2 \

(8.29) NH(CH2)12Cl

410

R = H,Cl


471

TABLE 8.4. AZEPINO[ I.~-u]BENZIMIDAZOLE-~-OXIDES (8.27). A Z E P I N ~ ~ , ~ - U ] BENZIMIDAZOLES (8.28), (8.30). AND (8.31). AND HIGHER HETEROALICYCLIC HOMOLOGS FORMED FROM N-(aNITR0PHENYL)HETEROCYCLES(8.24) Conditions Synthetic No. of hrl method" temp. in "C

Yield

Compound

R

n

8.27

H

S

A

401110

74

8.27

CI

s

A

4811 10

62

8.27

NO,

5

B A

241 20 121150

79 76

8.27

CI

6

A

7211 10

61

8.27

CI

7

A

72/110

52

8.28

H

S

B

241- 20 1I80 241 20 241 20 3/ 140 2.51140

81 100 86 23 70 87

8.28 8.28 8.30 8.31

H CI

-

-

11 11

-

-

C B

B

D

E

-

-

(YO)

m.p. ("C)

Ref.

16. 17 212 (hydrochloride) 17 129 (dihydrate) 17, 18 188 17 16 206 (hydrochloride) 17 125 (hydrate) 17 110 (hydrate) 17, 18 126 124 19 111 17 129 17 182 20 205 20

A = Nitro compound in 6N-hydrochloric acid; B = Nitro compound photolyzed by a 200 W Hanovia medium-pressure lamp (Pyrex cooling jacket) in aqueous AnalaR methanol and hydrochloric acid deaerated with nitrogen; C = Nitro compound and titanous chloride (2 mol. equiv.) in ION-hydrochloric acid; D=Nitro compound and zinc chloride ( 1 mol. equiv.) in acetic anhydride; E = Nitro compound and zinc chloride (2 mol. equiv.) in acetic anhydride.

Cyclization of 1- and 2-Substitufed Benzimidazoles The simplest cyclization of this type involves the ring-closure of osubstituted 2-alkylbenzimidazoles. 2-(5-Bromopentyl)benzimidazole(832a) cyclizes in sodium ethoxide to the azepinobenzimidazole (8.2) in 94% yield;22 heating the corresponding amine (83213)at 300" is less efficient.23 Trimer (8.33) prepared from o-phenylenediamine and adipoyl cyclizes to an azepinone (8.34) in moderate yield on sublimation. The action

(8.32)

a, R = Br b, R = NH,

472

Condensed Benzimidazolesof Type 6-5-7and Higher Homologs

~ H c o ( c H 2 i 4 c o N H

l-m'm

O.ImmHu

(8.33)

0

(8.34)

35 '10

of phosphoryl chloride on the diamide (8.35) gives 9-(benzimidazol-2y1)nonanoic acid (8.37) possibly by way of the 11-membered heterocycle

(8.36).24 A methyl or activated methylene group in the 2-position of benzimidazoles can be elaborated into a 7-membered ring by reaction with acetylenic esters. 1,2-Dimethylbenzimidazole(8.38; R = Me) and the 1-ethyl analog react with excess dimethyl acetylenedicarboxylate (DMAD) at room temperature to afford complex mixtures: minor components of the mixtures are the azepino[ 1,2-a]benzimidazoles (8.39).Tetrahydrofuran is the solvent of Significantly the ethyl group in 2-ethyl- I-methylbenzimidazole will not participate in formation of a 7-membered ring. The first step in the reaction is the attack of DMAD at the vacant 3-position of the benzimidazole to give a zwitterion @.a)which , can react further by proton transfer from the reactive methyl-but not ethyl-group. The carbanionic intermediate (8.41) thus generated traps a further mole of DMAD (Scheme

"K

R I

EH E

(8.38)

(8.39) R = Me,Et; E = C0,Me

8.1. Tricyclic Benzimidazoles with No Additional Heteroatorn

473

(8.39)

(8.41) R = Me,Et; E = C0,Me Srsew 8.3

8.3). A similar mechanism has been advanced to explain the formation of azepines in the reactions of 2-alkylthiazoles and acetylenic esters.26 When 2-methyl- and 2-benzylbenzimidazole substituted with a transacrylate substituent in the 1-position (8.42) react with DMAD products are formed, which were originally claimed to be azepino[ 1,2-a]benzimidazole~;~’ this assignment has been correctedz8 and the overall position clarified.*’ For example, structure (8.43) originally proposed” as the product from (8.42; R = Me) has been reassigned the cyclobuta[4,5]pyrrolo[ 1,2a]benzimidazole structure (8.44) on the basis of its 13C N M R spectrum and

I E

(8.42) R = Me; Benzyl

a&E HE

E

H E

(8.43)

H (8.44) E = C02Me

474


other spectroscopic properties:2Mthese are similar to an adduct formed from 6-bromo-2-methylquinoline and DMAD on which an X-ray diffraction analysis has been Benzimidazole-2-acetonitrile(8.45) with DMAD in refluxing acetonitrile gives a small yield of the 6-cyanoazepino[ 1,2-a]benzimidazole (8.46), whereas the main product from 1-methylbenzimidazole-2-acetonitrileis now considered to be a cyclobutapyrrolobenzimidazole(8.47)2Mrather than the 10-cyanoazepinobenzimidazole (8.48) as originally

H

E

CN (8.47)

H E (8-48)

E = C0,Me

Azepinobenzimidazoles of two types are formed irom 2-benzyl- 1methylbenzimidazole (8.49) and acetylenic esters.33 The “normal” products of this type of cyclization (8.50) are accompanied by more conjugated

a x I

Me

(8.49)

CHzPh

CGE €1

E H E (8.50)


Me R - CI - I p h

E

W E

475

/Me q

&

P

h

E W

E E

E

(8.51)

E

(8.52) E = C0,Me.C02Et

triesters (8.52): the latter compounds may be formed from starting benzimidazole by successive additions of ester and proton transfers, which generate dipolar species (8.51), followed by loss of the elements of methyl or ethyl formate. Physical characteristics of azepinobenzimidazoles prepared from benzimidazoles and acetylenic esters are compiled in Table 8.5. TABLE 8.5. AZEPIN~~.~-U]BENZIMIDAZOLES FROM 2-SUBSTITUTED BENZIMIDAZOLES AND ACETYLENIC ESTERS Starting benzimidazole

Product

Compound R

Compound R

Me Et

8.38 8.38 8.45

-

8.49 8.49 8.49 8.49

Me Et

E

Reagent"

Reaction Yield m.p. solvent (%) ("C)

C0,Me C0,Me C0,Me

DMAD DMAD DMAD

THF THF CH,CN

13 17 360

268 (decornp.) >300 >360

>350

210 245-246

-

-

-

-

1

1

1

1

1 1

6 6 6 6 7 8 9 1 1 1 1

carboxylic acid; reflux; I = amine (9.1)and acetic acid-acetic anhydride; J = amine (9.4)and carboxylic acid; reflux in hydrochloric acid; K = vacuum sublimation of the 6-mercaptoethyl compound [9.3 R = R' = H, R2 = (CH,),SH]. Yield not recorded. Ammonium oxalate not oxalic acid. Malonamide not malonic acid.

aA

= arnine (9.1)and carboxylic acid; reflux until effervescence ceases; B = amine (9.1) and carboxylic acid; reflux in 4N-hydrochloric acid; C = amide (9.2)with FQCI,/P,O,; reflux in xylene; D = arnide (9.2)with P20,; reflux in benzene; E = amide (9.2)with poCI,/PCI,; reflux; F = amine (9.1)and acid chloride; reflux in benzenopyridine; G = amine (9.1)and phthalic anhydride; heat until effervescence ceases; H = dihydrochloride salt of amine (9.1)and

~

9.6

9.6

9.6

9.6

9.6 9.6

9.3 9.3 93 9.3 9.3 9.5 9.5 9.6 9.6 9.6 9.6

TABLE 9.2. SUBSTITUTED 8-METHOXY-5,6-DIHYDRO-4H-IMIDAZq4,5,1ii& QUINOLINES (9.8) AND (9.9) FROM AMIDE DERIVATIVES OF 8-

AMINO-6-METHOXYQUINOLINE(9.7)

ComDound

R

R’

R2

Yield (%)

m.p. (“C)

Ref.

H H H H H H H H H H 7-NHz 7-OMe

H Me H H H H H H H H H H

CH20H Me CH,NEt, (CH2)zCOzH (CH,),Me (CHz)zCONEtZ (CH,),,Me Ph CH,Ph CH(0H)Ph Me Me

21 48 53 31 98 64 52 45 48

190-192 140-142 78-81 221.5-223.5 83-84 73-74 67.5-72.5 237-238 94.5-97 230.5-236 369-170 161-163 239-240

4 4 4 4 10 10 4 4 4 4 4 4 4

~~

9.8 9.8 9.8 9.8 9.8 9.8 9.8 9.8 9.8 9.8 9.8 9.8 9.9

-

-

-

(9.10)

44 17.5 13 43.5

(9.11) x = 0,s

0 II

(9.13)

(9.12) NHC0,Et NH \

0 (9.14)

(9.15) 510

93%


(9.16)

511

L-tH Me

Me

(9.17) 67%

Physical characteristics of 2-aminobenzimidazoles, benzimidazolin-2-ones, and 2-thiones prepared as above are recorded in Table 9.3 (see also section 9.1.3.“Reactions with Nucleophiles”). TABLE 9.3.

IMIDA~4,S,l-ij]QUINOLINESAND A PYRROLO[ 1,2,3-cd]BENZIMIDAZOLE FROM 8-AMINO-l,2,3,4-TETRAHYDROQUMOLINES AND SUBSTITUTED 6-METHOXYQUINOLINES

Compound

R

9.10

H

9.10

8-OMe

9.11

H

9.11

8-OMe

9.11 9.11 9.15

H 8-OMe

-

9.17

-

a

X

-

Cyclization method“ CNBr under N,

Yield

(YO) m.p. (“C)

Ref.

40

1, 2, 11

201-202

(picrate: >320) CNBr under N,

229-230

(hydrobromide:

0 ClCOCl in AcOH H,NCONH, at 140* 0 CICOCI in AcOH -d S CS, in EtOH S CS, in pyridine

- -

- CS, in

39

75 97 49 76 5 32

97 93

pyridine’

67

266-268) 213-214 210-21 1 234-235 234-235 234-235 2 14.5-2 15.5 >2ao 280-3 I 5

4 1, 2 3

4 4 4 1. 2 12 13

(decomp.) 2 10-21 2

12

From 8-amin~1,2,3.4-tetrahydroquinoline(s) unless otherwise stated. From the dihydrochloride salt of &amino- 1.2.3.4-tetrahydroquinoline. From urea (9.13) in 4N-hydrochloric acid. From urethan (9.12) and hydrogen over 20% platinum on carbon; in acetic acid. From urethan (9.14) at 19W. From (9.16).

Cyclizution of N-(o-Acy1amino)phenyl HeterocycIes Decomposition of the pyrrolidine (9.18)in polyphosphoric acid at 145150” affords a product identical to the tricycle (9.19),independently prepared by cyclization of the diacetyltetrahydroquinoline(9.20), and different

Condensed Benzimidazoles Bridged Between N-1 and C-7

512

,

Pdyphosphoric

acid

NAc

H

(9.18)

Me

(9.21)

Me

(9.19)

(9.20)

(9.22) 509/0

from the anticipated imidazobenzazepine (9.22),itself readily prepared from (9.21).This decomposition embodies features of the “t-amino effect”” (see Chapter 8, section 8.1.1 “Cyclization of orfho-Substituted N-Aryl Heterocycles”) and occurs with a range of anilides substituted in the ortho position with heteroalicyclic group^'^.'^: the mechanism is summarized in Scheme 9.1. The first step is thought to be conversion of the anilide (9.23)t o iminopolyphosphate (9.24), which cyclizes to the spiro-benzimidazolium salt (9.25).Fission of the salt yields the polyphosphate (9.27)via the (incipient) carbonium ion (9.26).Elimination of polyphosphoric acid then generates an olefin (9.28),which under the prevailing Friedel-Crafts conditions cyclizes at the penultimate carbon atom of the chain to yield the observed benzimidazoles (9.29). Yields of cyclic products are highest (Table 9.4) when R = H, Me or Ph; n = 5, but no cyclization occurs with electron-withdrawing R substituents (CF, or CICH,) or bulky groups (CMe,). Similarly, cyclization .is completely inhibited when the heteroalicyclic ring is morpholine, piperazine, or an N-substituted piperazine, and the rate of disappearance of starting material (9.23)is suppressed as the ring size increases ( n = > 5). Cyclization of the hepta- or octamethyleneimine homologs (9.23);R = Me, n = 7 or 8) does not involve the penultimate carbon of the polymethylene chain: rather, cyclization only takes place after the primary carbonium ion has rearranged to contain a tertiary carbonium ion.I6 Thus the heptamethyleneimine gave product (9.30)in 35% yield and the octamethyleneimine analog gave a mixture of at least three components.

(9.27)

(93)

sekme 9.1 TABLE 9.4.

CONDENSED BENZIMIDAZOLES (9.29) FORMED FROM N-(oACYLAMIN0)PHENYL HETEROCYCLES (9.23) IN POLYPHOSPHORIC ACID AT 145-150"

Starting materii (9.23) R n

Heating time (hr)

Product (9.29) R n

H Me Ph H Me Ph H Me Ph Me

0.5 6 0.5 1 1 1 1 1 1 1.5

H Me Ph H Me Ph H Me Ph

4 4 4 5 5 5 6 6 6 7

-e

Yield (Oh)

m.p. or b.p.

of base [K)/mml

4 4 4 5 5

27 21 10 58

90 55

(15712) 117 130

6

10 3.5 14 35

120 102

5

6 6

" Picrate.

Methiodide. Compound (9.30). 513

(125/O.5) 140

-

-

96

m.p. of' derivative CC)

Ref.

175" 14 219" 14 180" 14 220". 150b 14 195". 163b 14 224b 14 214" 14 165' 14 14 16

Condensed BenzimidazolesBridged Between N-1 and C-7

514

(9.30) Cyclization of 2-Methylbenzimidazole

The only recorded example of this type of annelation is the interaction of 2-methylbenzimidazole (9.31) and the diester (9.32) at 200" to afford the imidazoquinolone (9.33)."

(9.32)

(9.31)

(9.33) 34%

9.1.2. PhysieocaemicPl S h d k Absorptions at 1690 and 1215cm-' in the IR spectra of the products from 8-amino-1,2,3,4-tetrahydroquinolineand phosgene or carbon disulfide'-2 confirm that the cyclic compounds exist in the 2-one or 2-thione tautomeric forms (9.34;X = 0 or S), respectively." The related derivative cyclized with cyanogen bromide, although originally considercd" to be the imine (9.34; X = NH) on the basis of misinterpreted IR and UV spectral comparisons with model compounds, is now known to exist predominantly as the 2-amino tautomer (9.35; X = NH).3*'8 In chloroform solution the IR spectrum shows bands at 3504 and 3412cm-' for the asymmetrical and symmetrical NH stretching modes: after partial deuteration a new band emerges at 3458cm-'. This new band is an uncoupled NH stretching

(9.34)

(9.35) X=O,S,NH

(936)

9.1. Tricyclic Benzimidazoleswith No Additional Heteroatorn

515

absorption arising from the NHD group, and such a triplet cannot be explained by invoking a partially deuterated imine contribution." The UV spectra of 2-substituted 5,6-dihydro-4H-imida0(4,5,1-ij]quinolines closely resemble the spectra of 1,Zdialkylbenzimidazoles. The only notable exception is the spectrum of the methylene-bridged benzimidazole (9.6; X=CHJ, which has an additional absorption in the visible region indicative of conjugation through the methylene group (9.36).' The UV spectra of representative benzimidazoles bridged between N-1 and C-7 are recorded in Table 9.5. Reports of 'H N M R spectra of bridged benzimidazoles are rare,','" and only in those compounds (9.29) formed by cyclization of N - ( 0 acy1amino)phenyl heterocycles (9.23), which involve a contraction of the polymethylene chain, has N M R been important in structure determinati~n.'~*'~

TABLE 9.5. ULTRAVIOLET SPECTRA OF BENZIMIDAZOLES BRIDGED BETWEEN N-1 AND C-7 X

Compound R

R' R2

X

9.3 9.3

H H

H H

H Me

- - -

A

9.3 9.3 9.3 9.5 9.6

H H H Me

H H H

CHZOH Ph 4-bridyl

- -

A

9.10 9.11 9.11 9.11 9.17 9.29

-

- - -

H H H 8-NHz -

-

-

(or n ) Solvent"

- -

- - - CH, - -

A A A A A

B

0 -

A

S

-

A A

c'

s -

H

- - -

- -

-

(4)

9.29

Me

- -

-

(4)

c

9.29

Me

- -

-

(5)

c

9.29 9.29

Ph Me

- - -

-

(5) (6)

c

- -

D

1.2-Dimethyl benzimidazole

-

-

A

C

Amax (log&)

257(3.78) 274(3.65) 283.1(3.59) 1 255.2(3.73) 273.6(3.63) 1 282.4( 3.62) 259(3.83) 276(3.77) 285(3.63) 1 240(4.19) 290(4.22) 1 250.7(3.95) 306(4.21) 1 219(4.01) 294(3.84) 322(3.81) 8 258(4.14) 276(4.11) 284.8(4.09) 1 360(3.12) 257b 2x8 3 225-234(3.82) 284(3.76) 1 225(4.27) 247.6(4.26) 304.8(4.47) 1 226(3.90) 293(3.91) 322(3.86) 12 223' 262 335 12 212(4.13) 254(3.79) 275(3.70) 14 282(3.70) 214(4.77) 257(3.80) 275(3.70) 14 283(3.69) 213(4.59) 257(3.87) 276(3.68) 14 284(3.62) 215(4.76) 244(4.12) 291(4.12) 14 215(4.51) 259(3.79) 276(3.67) 14 284(3.63) 250.5(3.79) 274(3.78) 28N3.80) 19

" A = 95% EtOH; B = Dioxan; C = MeOH; D = 0.01 N-KOH.

' Log

Ref.

E not recorded. Measured as picrate salt against a blank of picric acid of the same molar concentration.

516


The pK, values for 9-substituted imidazo[4,5,1-ijJquinolines(9.3;R = OPh, Me, NEt2, R’= R2= H) measured in 5% aqueous ethanol’ are 5.0, 6.03, and 6.90, respectively. These values lie in the range where the Chichibabin reaction is possible (see section 9.1.3 “Reactions with Nucleophiles”).

9.1.3.

Repctions

Reactions with Electrophiles Nitrat ion of unsubstituted 5,6-dihydro-4H-imidazo[4,5,1ijlquinoline with 50% nitric acid at -15” affords a mixture (81%) of three mononitro derivatives.’ Controlled nitration of 9-methylimidazoquinolines (9.37);R = H, Me) in nitric-sulfuric acid at -10% affords 8-nitro compounds (9.38; R = H,Me, R’= &NO2), whereas more vigorous treatment at 80” yields the 7,8-dinitro derivatives (see Table 9.6). The o-diamine (9.39)prepared by stannous chloride reduction of the corresponding dinitroimidazoquinoline can be transformed to the tetracyclic imidazole (9.40;X = CH) or triazole (9.40;X = N) with formic or nitrous acids, respectively.’ Me

19.37)

(9.39)

Me

(9.38)

(9.40)

X = CH (100%) X = N (51%)

Quaternization of imidaz0[4,5,1-ij]quinolines~~~-~~ or benzimidazoles bearing a larger methylene bridge,14 with methyl iodide, affords the N-1 met hiodides.


517

TABLE 9.6. NITRO- AND AMINOSUBSTITUTED 9-METHYL-S,6-DI-

HYDR0-4H-IMIDAZq4,S,l-ij]-

QUINOLINES (9.38)" R

R'

Yield

H H Me Me Me Me

%NO2 7,8-Di-N02 8-NO2 8-NH, 7,8-Di-N02 7.8-Di-NH2

no

88.5 83 97 67 90

(O/O)

m.p. ("C)

232-233 202-204 164-165 142-143 209-210 151-152

" From Ref. 5.

Reactions with NucleophiIes Tricyclic benzimidazolin-2-ones (9.41); R = H, OMe) are transformed to reactive chloro compounds (9.42) with phosphorus o ~ y c h l o r i d e ' ~ the : chloro group can be displaced by sodium methoxide to yield ether (9.43; R=H)'.' or by a range of secondary and tertiary amines3-' to provide amines (9.44) (Table 9.7).The chloro group of the quaternary iodide (9.45) is particularly reactive toward nucleophile~:~ it is displaced with (aqueous) ammonia or methylamine in absolute ethanol to yield amines (9.46; R = H, Me), which are isolated as hydroiodide salts; with aqueous methylamine the 1-methylbenzimidazolin-2-one(9.47) is formed. The UV spectra of imines (9.46) differ qualitatively from the spectra of representative 2-aminobenzimidazoles (9.44).3 R

wo-Ryyc, R

rn NaOMe

OMe (9.41)

(9.42)

I

(9.43)

R'R'NH

(9.44)

R = H, OMe R'R2 = H,Me; Me,Me; C,H,,

Me

Me

R=H,Me

(9.45)

TABLE 9.7. PRODUCTS OF NUCLEOPHILIC SUBSTITUTION REACTIONS OF SUB!VXTUTED 5,6-DIHYDRO-4H-1MIDAZq4.5,1-ijJQUINOLINES Compound R 9.42

H

9.42 9.43 9.44 9.44 9.44 9.44 9.46 9.46 9.47 9.49 9.49 9.49 9.49 9.49 9.49 9 4

OMe H H H OMe OMe H Me H 8-OMe 7-OMe 8-OMe 8-OMe 8-OMe 9-Me

9.49 9.49 9.50 9.50 9.51 9.51 9.51

9-OPh 9-NEtz 9-Me 9-NEtZ H 7-OMe 8-Me

Picrate. Hydrochloride. Hydrate.

RZ Yield (%) m.p. (T)

R’

75-76 75-76 132-1 34 Oil 222-223 63-64’ 189-191 71-73 91-92 93-95 120-121 199-200 229-230 234-235 229-230 227-228 234-235 258-259 (decomp.) 249-250 124-125 213-214 153-154 214-215 223-224 210-211

60 82 68 100 92 94 22 57 83 61 55 47 75 75 75 50 40 70 60 45 58 33 85

91 90 *(

Hydroicdide. Nitrobenzylidene derivative. 518

m.p. of derivative (“C)

Ref.

1, 2 3 4 154-15S9, 212-214b 1, 2 3 3 175 (decomp.)”

-

>305d 284-285*

-

151-153‘ 210-211‘

-

210-21 1’

-

4

4 3 3 3 20 20 3 20 3 3

5

9.1. Tricyclic Benzirnidazoles with No Additional Heteroatorn

5 19

Despite the generally accepted view that only n-deficient heterocycles undergo the Chichibabin reaction, a range of imidazoquinolines (9.48)react with sodamide in dimethylaniline at 120°.3*’*20Nucleophilic substitution in the 2-position can also be achieved by fusing imidazoquinolines with potassium hydroxide or sulfur.’ Yields of 2-aminobenzimidazoles (9.49),benzimidazolin-2-ones (9.50)and 2-thiones (9.51)formed by the latter methods (Table 9.7) compare favorably with those from S-amino-1,2,3,4tetrahydroquinolines and 1-carbon donors (see section 9.1.1).

(9.49)

(9.50)

(9.51)

Hydrolysis of the 1: 7-trimethylimidazobenzazepinium iodide (9.52)in aqueous alkali affords a quantitative yield of the ring-opened product (9.53).14 1-

-

2N NaOy

H

H

Me

Me

(9.53)

(9.52)

100%

Oxidation Although the imidazobenzazepine (9.54)has a potentially vulnerable 2-methyl group, oxidation with potassium permanganate only involves the

520


(9.54)

(9.55) 25%

tertiary CH group, and the product is the alcohol (9.55).14However, freshly sublimed selenium dioxide or, less efficiently, manganese dioxide effects the side-chain oxidation of hydroxymethylbenzimidazoles (9.56).6 The aldehydic products (9.57)can also be formed from the corresponding 2-methylbenzimidazoles with selenium dioxide. The aldehydes form oximes and participate in crossed aldol reactions with either acetophenone6 or other 2methylbenzimidazoles.*' For example, reaction between the tricyclic aldehyde (9.58) and the dimethylbenzimidazolium iodide (9.59)yields the luminophore (9.60).6-21 Physical properties of aldehydes (9.57)and their derivatives are shown in Table 9.8.

I-

Me.

(9.58)

(9.59)

(9.60) 66%

9.1. Tricyclic Benzimidazoleswith No Additional Heteroatom

521

TABLE 9.8. ALDEHYDES (9.57) OF THE IMIDAZ0[4,5,1-ij]QUINOLINE SERIES PREPARED BY SELENIUM DIOXIDE OXIDATION OF 2-HYDROXYMETHYLBENZIMIDAZOLES ( 9 . 5 6 ) O

R'

Yield

H

H

81

179-180

8-Me 8-OMe 9-Me

Me Me H

66 58 62

102-103 136-138 111-112

R

m.p. (OC)

(%)

m.p. of derivatives (T)

255 (decomp.)", 208-209,' 285-287 (decompJd 163-164 (decomp.)" 140-141 (decompJb 156157 (decomp.)", 179-180"

From Ref. 6. Oxime. ' Derivative with acetophenone. Compound (9.60). a

Reduction l-Methyl-5,6-dihydro-4H-imidazo[4,5,l-~~]quinolinium iodide (9.61;X =

I) yields a benzimidazoline (9.62)on treatment with sodium borohydride:"

reoxidation with moist silver nitrate regenerates the quaternary salt [isolated as the perchlorate (9.61;X = ClO,)]. The benzimidazoline (9.62)is a powerful reducing agent and the main product from its reaction with benzoyl chloride is the quaternary chloride (9.61;X = Cl) (65%) together with the tetrahydroquinoline (9.63;R = Bz): in the process the benzoyl chloride is reduced to benzaldehyde. Oxidation of the benzimidazoline with sulfur or selenium affords high yields of the 2-thione or 2-selenone (9.64;X = S, Se). Interaction of benzimidazoline (9.62)and its 1-methiodide salt leads to disproportionation and the formation of the benzimidazolium iodide (9.61;

s&Jx-

(9.61)

(9.63)

+ /*e

/Me

S&&H

(9.62)

(9.64)

H

522


TABLE 9.9. l-hlEXHYL-5,6-DIHYDRO-4H-IMIDAZO[4,5,1-ij]QUINOLINIUMSALTS (9.61), BENZIMIDAZOLINE (9.62), A N D ITS DERIVATTVESa Compound

X

Yield (%)

9.61 9.61 9.61 9.62

1

C10, CI

-

99 70' 6Sd 75

9.64 9.64

S Se

78 91

a

m.p. or b.p. [("C)/mm]

195.5-197 170.5-171.5

-c

(128/3) (methiodide : 1 22-1 26) (hydrochloride: 79-86) 157-159.5 185-189

From Ref. 22. Prepared from 5.6-di hydro-4H-imidazd4, 5,l-ij] quinoline and methyl iodide. From the iodide (9.61; X = I) and sodium perchlorate. From benzimidazoline (9.62) and benzoyl chloride. Melting point not recorded.

X = I) (92%)and a trimethyltetrahydroquinoline(9.63; R = Me).22 Physical properties of the derivatives 9.61, 9.62, and 9.64 are listed in Table 9.9. Surprisingly the UV spectrum of the benzimidazoline (9.62) shows more conjugation [h,,,= 223, 268, and 308-310 nm (log E 4.44, 3.67, and 3.60, respectively] than the aromatic benzimidazoles (Table 9.5). Diborane has been employed for the reduction of the side-chain N N diethyl carboxamide function of (9.8; R = R' = H, R2 = (CH,),CONEt,) without concomitant reduction of the imidazole ring."

9.2. TRICYCLIC BENZIMIDAZOLES WITH ONE ADDITIONAL HETEROATOM

'93

0

6 \

N5 1 4

Imidaz~1.5.4-cd]benzimidazole

4H-Imidaz~1,5,4-&]quinoxaline

Imidazo[ 1,5,4-deX1,4]benzothiazine

Imidazo[l,5,4-efXl ,Sbenzodiazepine

9.2. Tricyclic Benzimidazoles with One Additional Heteroatom

523

9.2.1. Synthesb

Cyclization of 5 - Aminoquinoxalines and Other Nonbenzimidazole Heterocycles In its simplest form this type of cyclization is exemplified by the reaction between the dihydrobromide salts of triamines (9.65) and formic acid: the product is either an imidaz~1,5,4-de)quinoxaline (9.66; n = 2 ) or imidazo[ 1,5,4-ef][ 1,5 Jbenzodiazepine (9.66; n = 3).23More ambitious syntheses can be achieved by reacting quinoxalinones (9.67) with carboxylic acids or urea to afford imidazoquinoxalines (9.68) and (9.69) in good yields.” A general alternative synthesis of type (9.68; RZ= H) employs the dinitroanilines (9.70) as starting materials. These cyclize directly to imidazoquinoxalines on catalytic hydrogenation in formic acid. Di- and tricyclic hydroxamic acids (9.71) and (9.72) are intermediates in the latter reaction: one such intermediate (9.71; R = C1, R’ = H) cyclizes with loss of the chloro group.24

(9.65)

n=2or3

(9.68)

(9.69)

524

Condensed Benzimidazoles Bridged Between N-1and C-7

(9.70)

(9.72)

(9.71)

(9.68)

Both reduction and cycluation can be achieved in one step when the aromatic quinoxalines (9.73) are submitted to high-pressure catalytic hydrogenation in acetic acid.25 The nature of the catalytic reducing surface implies a cis arrangement of substituents in the reduced pyrazine ring, and this is c o n h e d by NMR spectroscopy (see section 9.2.2). When hydrogenation of quinoxaline (9.73; R = R2 = H, R’= Me) is conducted in formic acid the product is the 6-formylimidazoquinoxaline(9.75). Physical constants of derivatives of the type (9.66, 9.68, 9.69, 9.74, and 9.75) are collected in Table 9.10).

(9.73)

(9.74)

(9.75)

Cyclizadon of 1,7-Disubstituted Benzimidazoles Benzimidazoles bearing a /3-chloro- or #I-hydroxy-ethyl substituent in the I-position can be induced to cyclize with a nucleophilic group at C-7. Hence, l-(~-chloroethyl)-7-mercaptobenzimidazole (9.76) cyclizes in the presence of potassium hydroxide to yield the sple example of the imida~d1,5,4-&][l,l]benzothiazine ring system (g-fl).’” This reaction can be extended to the


525

TABLE 9.10. IMIDAZo[l,5,4-de]oUINOXALINES AND AN IMIDAZO[1 , 5 , 4 - e f ~ l , 5 ~ E N Z O DPREPARED IP~ FROM 5-AMINOQUINOXALINES AND OTHER AMINO HETEROCYCLES ~

~~

~

Compound

~

R

9.66 9.66 9.68 9.68 9.68 9.68 9.68 9.68 9.68 9.69 9.69 9.74 9.74 9.74 9.74 9.74 9.75

R2

Yield (%)

m.p. (“C)

Ref.

-

n

-

2 3

70 59 83 41 69 84 51 49 16 80 65 93 70 72 75 62 75

162.5- 166 129-132 288 255 300 323 277 288 216 250 270-272 150 178 138 I65 195 175

23 23 24 24 24 24 24 24 24 24 24 25 25 25 25 25 25

-

H

H H Me Me

H

H

CI

H

H H H H H

H

H

9-OMe 7-OMe H

~

R‘

Me Me H Me Me Me Me Me Ph -

H Me

-

Ph Me Ph

-

-

Me Me Me Me -

-

H H

H

-

-

7-aminobenzimidazole substrates (9.78; X = OH or Cl) to achieve a general synthesis of imidazo[ 1,5,4-de]quinoxalines (9.79) (Table 9.1 1). In a minor modification of the method the tri-(P-hydroxyethy1)benzimidazoles (9.80; R = Me or SO,NEt,), formed from substituted 7-aminobenzimidazoles and excess ethylene oxide, can be cyclized in thionyl chloride to yield salts (9.81).30

(9.76)

‘

X

X

R

(9.77)

z

-HX

NHz CH,CH(R’)X (9.78)

X = CI, OH

Ry)---lR2 “UC,, H

(9.79)

Condensed BenzimidazolesBridged Between N- 1 and C-7

526

The sodio derivative of 7-oxobenzimidazole (9.82) when treated with bromoacetophenone followed by ammonium acetate in acetic acid furnishes the tricycle (9.84) probably by way of the intermediate benzimidazole (9.83)." An acid-stable product formed by reacting 1,2,3-triaminobenzene with two mole equivalents of benzoic acid at 180" is claimed to be 2,4diphenylimidaz~1,5,4-~d]benzimidazole (9.86) on the flimsy evidence that it shows no free amino group and can be recovered unchanged from boiling TABLE 9.11. IMIDAZq1,5,4-&~UINOXALINES (9.79) FORMED BY CYCLIZATION OF 7AMINO- 1-(SUBSTITUTED)-BENZIMIDAZOLES (9.78) Starting benzimidazole (9.78)

X

Cyclization

Product (9.79)

Yield m.p.

(%I

method"

R

R'

R2

H C1 H OH Me OH

A

B B

H

H H

H H H

H 63 H 76 Me -b

H

CH2NEt2 Me OH

B

H

CH,NEt2

Me 80

c1

H H H

H OH Me OH Me Cl

B

c1

H

A

CI Me

H

H

H -b Me -b Me 77

Me C1

-

S02NEt2 H

Me 80

R

R'

R2

H H H

H H H

c1 Me

S02NEt2 H

B

A = In refluxing ethanol; B = Polyphosphoric acid at 185". Yield not recorded. 6-Nitroso derivative. 6-Acetyl derivative. 6-Allylthiocarbamoyl derivative. Methiodide. 6-(&HydroxyethyI) derivative. 6-(@-Chloroethyl)derivative. Hydrochloride of 6-(P-chloroethyl) derivative.

'

PC)

Ref.

162.5-166 158 79-8W 175-176' 175-176.5' 257-259' 89-9 1 95-98' 208-210 199-200 203-204 78-79 188-189' 114-11Sh 223-224 181d 197' 225'

23 26 26 26 26 26 27 27 26 26 28 28 28 28 29 29 29 29


Me

' N,L,~~

Me

I

-;

BrCHZCOPh,

Me-

CH,CO;N& C H3C W3*

0 (9.82)

527

CHzCOPh (9.83)

Me

Ph (9.84)

(9.86)

(9.85)

15% hydrochloric (9.85).

A plausible intermediate could be benzimidazole

9.2.2. Wysicocbemical Studies and Reactions

The carbonyl absorptions in 2-substituted imidazoquinoxalin-5(6H)-ones

(9.68) occur in the range 1680-1696 cm-', whereas the diones (9.69) show a

TABLE 9.12. 'H NMR SPECTRA (6 VALUES) OF IMIDAZ0[1,5,4-de]QUINOXALINES ( J IN Hz)" Compound R 9.74 9.74 9.74 9.74 9.74 9.75 a

H H H 7-OMe 9-OMe

-

R'

RZ

Me Me Ph Me

H Me Me Me Me

Me

-

-

H-2 (IH, s)" 8.08

-

-

8.30

From Ref. 25.

" s = singlet.

' d = doublet.

Doublet ( J = 3 Hz) of quartet ( J Doublet ( J = 4 Hz).

= 7 Hz).

H-4

H-5

4.53d 3 . 5 9 4.50d 3 S l d 5.77' 4.99' 4.484 3.454 4.42d 3.4Sd 4.984 4.484

4-Me 2-Me (3H, d, (1H.s)" (3H. s ) ~ J=7Y H-6

5.98 5.86 6.49 5.23 5.49

-

-

2.45 2.21 2.42 2.42

-

1.18 1.08

-

1.09 1.06 0.86

5-Me (3H. d, J=7Y 1.23 1.26

-

1.28 1.20 1.64

528

Condensed Benzimidazoles Bridged Between N-1and C-7

broadened carbonyl band between 1650-1700 ~ m - ' The . ~ ~'H NMR spectra of imidazoquinoxalines (9.74) corroborate the cis arrangement of substituents at C-4 and C-5.25In the 4,5-dimethyl derivatives (Table 9.12) each methine proton appears as double quartet due to coupling with methyl (J = 7 Hz) and vicinal ( J = 3 Hz) protons. The coupling is simplified in (9.74; R = H, R' = Ph, R2 = Me) with the protons showing as the expected doublet: the magnitude of the coupling constant indicates a dihedral angle of -60". No systematic study of the chemical properties of these tricyclic benzimidazoles has been attempted. The imidazoquinoxalines of type (9.79) are readily derivatized with a range of electrophilic reactants at the secondary amine function (N-6).2"29 The 6-formamido substituent of (9.75) can be removed in 10% hydrochloric

REFERENCES 1. A. Richardson and E. D. Amstutz, J. Ore. Chem., 25. 1138 (1960). 2. U.S. Patent, 3,200 123 (1965). 3. V. G. Poludnenko and A. M. Simonov, Khim. Geterotsikf. Soedin., 1970, 1410;Chem. Abstr., 74,53657d (1971). 4. L. M. Werbe.1, J. Battaglia, and M. L. Zamora, J. Heterocycf. Chem., 5, 371 (1968). 5. A. M. Simonov and V. G. Poludnenko, Khim. Geterotsikl. Soedin., 1972, 242; Chem. Abstr., 76, 140645h (1972). 6. V. G.Poludnenko. A. M. Simonov, and L. G. Kogutnitskaya, Khim. Geterotsikl. Soedin., 1971,967;Chem. Abstr.., 76, 34175v (1972). 7. H.Suschitzky and M. E. Sutton, J. Chem. Soc. (C), 1968, 3058. 8. J.-M. Karnenka and M. N. Alam, 1. Heremycl. Chem. 10. 459 (1973). 9. D. S. Chothia, S. Y.Dike, A. B. Engineer, and J. R. Merchant, rd,J. Chem. 14B, 323 ( 1976). 10. F. I. Carroll, J. T. Blackwell, A. Philip, and C. E. Twine, J. Medicin. Chem., 19. 11 1 1 (1976). 11. A. Richardson, J. 0%.Chem., 28, 2581 (1963). 12. I. G. Il'ina, N. B. Kazennova, V. G. Bakhmutskaya, and A. P. Terent'ev, Khim. Geterotsikl. Soedin., 1973, 1112; Chem. Abstr., 79, 126396h (1973). 13. M.Harnana and S. Kumadaki, Chem. Pharm. Buff. (Tokyo), 22, 1506 (1974). 14. 0.Meth-Cohn and H. Suschitzky, I . Chem. Soc., 1964,2609. 15. 0.Meth-Cohn and H. Suschitzky, Adu. Heterocycf. Chem., 14. 211 (1972). 16. R. Garner and H.Suschitzky, J. Chem. SOC. (C),1966, 1572. 17. E.Ziegler, H.Junek, E. Noelken, K. Gelfert, and R. Salvador, Monatsh. Chem., 92,814 (1961). 18. R. T. C. Brownlee, A. R. Katritzky, and R. D. Topsom, J. Chem. Soc. ( B ) , 1966, 726. 19. G. H. Beaven, E. R. Holiday, and E. A. Johnson, Spectrochim. Acta, 4, 338 (1951). 20. A. M. Simonov and V. G. Poludnenko, Khim. Geterotsikl. Soedin., 1968, 567; Chem. Abstr., 71, 124323t (1969). 21. USSR. Patent, 384,854 (1973);through Chem. Abstr., 80, F'21317a (1974). 22. A. V. El'tsov and V. N. Khokhlov, Zh. Org. Khim.. 6,2618 (1970);Chem. Abstr., 74, 64223k (1971). 23. W.Knoblock and G. Lietz, J. Rakt. Chem.,308, 113 (1967). 24. H.Otomasu, S. Ohmiya, H. Takahashi, K. Yoshida, and S. Sato, Chem. Pharm. Bull. (Tokyo), 21, 353 (1973).

References 25. 26. 27. 28. 29. 30. 31. 32.

529

H.Otomasu, H. Takahashi, and K. Yoshida, Chem. Pharm. Bull. (Toyko), 21,492 (1973).

I. M o l n f , Chimia (Switz.), 14. 364 (1960); Chem. Abstr., 55, 9400g (1961). I. Molnh, Pharm. Acra Heiu., 39. 288 (1964); Chem. Abstr., 62, 1662d (1965). A. Dikciuviene, V. Bieksa, and J. Degutis, Liet. TSR Mokslu Akad. Darb., Ser. B. 1974 (No. 3), 81; through Chem. Abstr., 83, 43243n (1975). A. Dikciuviene, V. Bieksa. and J. Degutis, Lier. TSR Mokslu Akad. Darb., Ser. B, 1974 (No. 4), 83; through Chem. Abstr., 85. 21292s (1976). A. Dikciuviene, V. Bieksa, and J. Degutis, Liet. TSR Mokslu Akad. Darb., Ser. B, 1973 (No. 2), 105; through Chem. Abstr.. 79, 115497r (1973). V. I. Shvedov, L. B. Altukhova, and A. N. Grinev, Khim. Geferotsikl. Soedin., 1972. 131; Chem. Abstr., 76, 153710a (1972). L. S. Efros, Zh. Obshchei Khim. 23, 957 (1953); Chem. Abstr., 48. 8223c (1954).


CHAPTER 10

Commercial Applications of Benzimidazoles P. N. PRESTON 10.1 10.2 10.3 10.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . pharmaceuticals, Veterinary Anthelmintics, and Fungicides . . . . . . . . . Polybenzimidazoles-Outlook ..................... Miscellaneous Areas of Potential Commercial Interest . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

531 531 532 541 541

10.1. INTRODUCFION In planning the layout of this book it was decided at the outset to include as a final chapter a compilation of commercially marketed benzimidazoles and congeneric tricyclic compounds. Derivatives of the latter type are extensively described in the patent literature, but there are no commercially marketed products in this category. The compounds described in this chapter thus relate to Chapters 1 and 3 only. Benzimidazoles have been marketed extensively as pharmaceuticals, insecticides, and fungicides (section 10.2); the commercial outlook for polybenzimidazoles is considered (section 10.3), and other areas of potential commercial interest are summarized (section 10.4).

10.2. PHARMACEUTICALS, VETERINARY ANTHELMINTIC AGENTS, AND FUNGICIDES The most widely used compounds in this group have been 2-(4-thiazolyl) derivatives and methyl benzimidazol-2-yl carbamates (see Tables 10.1 and 10.3). The successful commercial utilization of these compounds has stimulated great interest in the synthesis of closely related derivatives, and in Table 10.2 is compiled a list of patented products; it should be noted, however, that derivatives of the latter type are not yet in industrial production. 531

532

Commercial Applications of Benzimidazoles

Benzimidazoles or their precursors have been used extensively as fungicides, and, although three such compounds are no longer commercially available [viz. Cypendazole' (lO.l),Fenzaflor' (10.2),and Fungilon3 (1031, a number remain in industrial production (see Table 10.3). The most important commercial product is methyl 1-(butylcarbamoyl)benzimidazol-2ylcarbamate (Benomyl): which was introduced in 1967 by E. I. du Pont de Nemours and Co. This material is a protective and eradicant fungicide with systemic activity, effective against a wide range of fungi affecting fruits, nuts, vegetables, and field crops; it is effective against mites, primarily as an ovicide. It is also used as pre- or post-harvest sprays or dips for the control of storage rots of fruits and vegetables.

aa.x

a

I a x N H CONH(CH2)'CN C 0 2 M e

(10.1)

I

a

3

CO2Ph

(10.2)

(10.3) There has recently been a decline in activity in the use of benzimidazoles as pesticides, primarily because there have been many reports of pathogenic fungi acquiring resistance to benzimidazole fungicides.

10.3. POLYBENZIMIDAZOLES-OUTLOOK The synthesis of polybenzimidazoles was pioneered by C. S. Marvel's group' and a number of reviews have appeared on this interesting class of heterocyclic poIymers.6" Early studies in the 1920s were focused on the synthesis of polymers in which the benzimidazole moiety was attached as a side chain to the backbone and involved the use of 1-, 2-, and 5-vinylbenzimidazoles. Of more current interest are polymers in which the heterocyclic system forms part of the backbone, and these (cf. 10.4) are readily prepared in the benzimidazole series by allowing tetramine monomers to react with dicarboxylic acids or their derivatives. Polymers of the latter type exhibit a high

W W

wl

COT.

Smith Kline and French Laboratories Hydro-Chemie

Nerninil

Helmatac

Parbendazole

Johnson & Johnson Janssen Andromaco Andrornaco Crown Chemicals Biosintetica Janssen

Cambendazole

Pantelmin Mebenvet Mebutor Sirben Ovitelmin Vermirax Nemasole

Ortho Pharmaceutical

Merck Sharpe and Dohme

Mebendazole

By whom marketed

Merck Sharpe and Dohme Thibenzole Merck Sharpe and Dohme Telmin Crown Chemicals Equiverm plus Crown Chemicals Vermox Janssen

Thiabendazole Mintezol

Proprietary Approved name name

Veterinary anthelmintic

Human anthelmintic

USe

West Germany'

Brazil' Argentina'



Veterinary and human U.K., Ireland anthelmintic U.K. Ireland" U.K.b West Germany' U.S.A.d Brazil' West Germany' Argentina* Brazilh

U.K.'

Where marketed

Bu

I

- .

I

H

NHC0,Me

I

H

NHC0,Me

mq=

H

m k

A

i -PrOCONH

PhCO

Structure

TABLE 10.1. COMMERCIALLY AVAILABLE PHARMACEUTICALS AND VETERINARY ANTHELMINTICS

P

m w

Hoechst

Panacur

Loditac

Fenbendazole

Oxibendazole



Antineoplastic agent Microtubule inhibitor

Syntex

Janssen

Oxfendazole

Nocodazoie


US?

Smith Kline and French Laboratories

Ireland”

Where marketed

Albendazole

Silke Pharmaceuticals Ltd. (for Smith, Kline and French)

By whom marketed


TABLE 10.1 (Conrinued)

I

I

H

H

P o - f J \- ~

0-

n-PrS

H

NHC0,Me

I

H

NHC0,Me

NHC0,Me

q,

n- P a

Structure

VI

cn w

Bellocillin

Clem&le penicillin

Megafillin

Cytostasan

Imet 3393

Laboratories Roger Bellon Griinenthal

Janssen

Bezitramide

Burgodin

Janssen

Flubendazole

Germany

France

Germany

Bactericide

An ticancer

Analgesic

Antineoplastic agent Microtubule inhibitor

F

I

H

NHCOZMe

Benperidol

Glianirnon

Frthactil

Trornast5dan

Diabazole

Diabazol

AIlercur Htrol Histacur Histacuran Reactrol

Clemizole


TABLE 10.1 ( C o n d d )

Jaboratoires ClinComar-Byla Troponwerke Dinklage

Laboratoires Millot

Schering Chemicals

By whom marketed

Germany

France

France

Where marketed

Pyschopharmacological agent

Vasodilator spasrnolytic hypotensive

Antihistamine

USC

b

ELOH

Q

Combination of benzylpenicillin and

StrUCtUR

Janssen

McNeil

Inapsine

'

a

us.

France

Laboratoires Cassenne

Opiran

Droleptan

U.K.

Janssen

&P

Irish Pharmacy Journal, 52, 307 (1974). Chemisr and Druggist. 28th August, 248 (1976). Inpharma, 5th March, 14 (1977). Scrip, 22nd February, (144), 15 (1975). Unlisted Drugs, 25, 46i (1973). Tieraerztliche Umschau, 29,603 (1974)[Advert]. a Unlisted Drugs, 27, 8e (1975). Unlisted Drugs, 27, 75j. (1975). British Farmer and Stockbreeder, 20th March, 35 (1976). Unlisted Drugs. 28, 77m (1976). Inpharma, 2nd October, 18 (1976). Tieraerztliche Umschay 28, 242 (1973). Deutsche Tieraerztliche Wochenschrifr, 81, 177 (1974). "Irish Pharmacy Journal, 55, 295 (1977) [Advert].

Droperidol

Pimozide

Pyschopharrnacological agent

Pyschopharmacological agent

By whom patented Hoechst

Meji Seika Kiosha Ltd.

Fisons

Squibb

Squibb

Potential use

An thelmintic

An thelmintic

Anthelmintic

Anthelmintic

An thelmintic

I Y

H

R3

H

qANHC02MeI

/

R

R

R

R', R2, R' = halogeno

PhSO,

Structure"

DT 2446-259

US 3,864,350

NL 74 02438

JA 40285 11

DT2541-752

Patent number or Denvent Abstract reference

TABLE 10.2. PATENTED BENZIMIDAZOLES OF INTEREST AS POTENTIAL PHARMACEUTICALS AND VETERINARY ANTHELMINTICS (NOT COMMERCIALLY AVAILABLE)

Lilly

Roche

An tiviral

Active vs poultry blackhead

R and AI denote dkyl and aryl, respectively.

Roche

Anthelmintic

a

Smith Kline and French

Anthelmi nt ic

CI

ArX

H

I

x=o.s

H

NHCOzR

R' = 2-pyridyl

='NHCO2h4e

n=&4

iOzR Z = 0 or NOR

R'CO

x=o,s

H R' = furyl, thienyl

DT 2606 531

BE 845641

BE 844949

540


TABLE 10.3. COMMERCIALLY AVAILABLE BENZIMIDAZOLE FUNGICIDES By whom marketed

Approved name

Proprietary name

Thiophanate methyl"

Cercobin methyl or Tospsin methyl

Nippon Soda

Thiophan atea

Cercobin or Tospsin

Nippon Soda

Benomyl

Benlate

Dupont

Structure NHCSNHC0,Me NHCSNHC0,Me

q'NHC02Me dONHn-Bu Fuberidazole

Voronit

Bayer

Thiabendazole

Mertect (TBZ)

Merck Sharpe and Dohme

"These compounds are converted in oivo (and also under some in vim conditions) to benzimidazole-2-carbamates(cf. H. Buchenauer, L. V. Edgington, and F. Grossman, Pesric. Sci., 4, 343 (1973).

degree of thermal and chemical stability: if the X group is aliphatic, the polymer degrades above 350"C, but all-aromatic polymers are stable beyond ca. 500°C in an atmosphere of nitrogen. The material of greatest potential in the series has been prepared by condensation of 3,3',4,4'-tetraminobiphenyl with diphenyli~ophthalate.~ This polymer (PBI) has a variety of valuable characteristics, including the following: high thermal stability, good adhesive properties, useful cryogenic properties, and high moisture regain. PBI has been used by Celanese Corporation' to prepare textile fibers and these have been used in the space program by U.S.Air Force Materials Laboratory, NASA. Among the valuable properties of this fiber are high moisture regain and nonflammability.

(10.4)

References

541

In summary, it appears that PBI has commercial potential, the most likely outlet being in the field of synthetic fiber production.

10.4. MISCELLANEOUS AREAS OF POTENTIAL COMMERCIAL INTEREST Benzimidazole derivatives have been evaluated for use in the following areas, but to the knowledge of the author there are no materials on the market: corrosion inhibitors for copper?-" b r a ~ s ' ~ * ' and ~ ' ' ~a l u m i n ~ m ; ' ~ photosensitive compounds for use in ph~tothermography'~"' and for the preparation of silver-free photographic films;'8719 polymer additives as stabilizing20 and shrinkin8' agents; and as fluorescent brighteners2* One benzimidazole-substituted azo compound (10.5) is cited in the Coiour

and tri-sulfonated)

NHPh (10.5) Colour Index 14150 [Chrome Fast Yellow G W I

Index,23 but this chrome mordant dye is now obsolete. The most likely commercial outlets for benzimidazoles in this field are as merocyanine derivatives for use as sensitizing dyes.24

REFERENCES 1. Marketed until recently by Bayer A. G. Leverkusen as Folcidin (cf. U.S. Patent, 3,673,210). 2. Marketed until recently by Fisons Pest Control as Lovazal (cf. D. T. Saggen and M. L. Clark, Nature, 215, 275 (1967). 3. Marketed until recently by Farbenfabriken Bayer A.G. under code number Bayer 32394 as Fungilon (cf. Fr. Patent, 1,248,412). 4. See C. J. Delp and H.L. Klopping, PI. Dis. Reptr.. 52.95 (1968); also Netherlands Parent, 6,706,331 and US.Patent, 3,631,176. 5. C. S . Marvel, S.P.E. J , 20, 220 (March 1964). 6. V. V. Korshak and M. M. Teplyakov, 3. Macmrnol. Sci. Rev. Macromol. Chern., 5,409 ( 1971). 7. J. R. Leal, Modem Plastics, (August), 60 (1975) and review articles cited therein. 8. Celanese Research Company, Summit, N.J.,U.S.A. (A division of Celanese Corporation).

542


9. A. B. Patel, N. K. Patel, and J. C. Vora, Labdeu, Part A, 1 2 4 86 (1974);Chem. Abstr., 85. 3706%. 10. N. K. Patel. J. Franco, and S. H. Mehta, Chem. Era, 11, 9 (1975);Chem. Abstr., 85, 11 1793k. 11. G. Trabanelli, F. Zucchi, G. Brunoro, and V. Carassiti, Proc. Iw. Congr. Met. h o s . Srh, 565 (1974);Chem. Abstr., 84, 81514e. 12. H. Tobe, N. Morito, K. Monma, and W. Suetaka, Nippon Kinzoku Gakkaishi, 38, 770 (1974);Chem. Abstr., 82, 20777e. 13. N. K. Patel, J. Inst. Chem. Calcuna, 46, 137 (1974);Chem. Abstr.. 82, 1283733. 14. N. K. Patel, S.C. Makwana, and M. M. Patel, Corms. Sci., 14, 91 (1974);Chem. Abstr., 81, 159232. 15. R. K. Shah, B. B. Patel, and N. K. Patel, J . Electrochem. Soc. India, 24, 139 (1975); Chem. Abstr.. 84, 109924q. 16. M. Sasaki, T.Kazami, A. Noguchi, Y. Tsujimoto, T.Yamamuro, and T.Saito, Jap. Patent, 76 01,114(1976);Chem. Abstr.. 85, 151783~. 17. M. Sasaki, T. Kazami, A. Nosuchi, Y. Tsujimoto, T.Yamamuro. and T. Saito, Jap. Patent, 76 01,113(1976);Chem. Abstr., 85. 70696k. 18. M.Sasaki, T. Kazami, A. Noguchi, Y. Tsujimoto, T.Yamamuro, and T. Saito, Jap. Patent, 76 01,112 (1976);Chem. Abstr., 85, 151784q. 19. G. L. Eian, Ger. Patent, 2,433,831 (1975);Chem. Abstr., 84. 67887~. 20. S. I. Sadykh-Zade, R. M. Mamedov, P. K. Mamedova, A. I. Elchueva. A. P. Dzhafarov, and M. F. Ganieva, USSR Patent, 515,765 (1976);Chem. Abstr., 85, 64149t. 21. L.B. Palmer and R.P. Conger, U.S. Patent, 3,849,158(1974);Chem. Abstr., 82,9993Of. 22. D. Guenther, G. Hitschfel, H. J. Nestler, and G. Riesch, Ger. Patem, 2,320,528(1974); Chem. Abstr., 83,61739h. 23. Colour Index (3rd 4.) Vol. . 4.Society of Dyers and Colourists, Bradford, U.K. 24 (a) D. M. Stunner and D. W.Heseltine in The Theory of the Photographic Process, 4th ed. (T. H. James, Ed.), Mamillan, New York, 1977, Chap. 8. (b) H. Meier, Spectral Sensitization, Focal Press, New York, p. 61. (c) G.F. Duffin. in Dye Senzitization (W. F. Berg, V. Mauucato, H. Meier, and G. Semerano, Eds.), Focal Press, New York, 1970,p. 282.


Author Index Numbers in italics indicate pages where reference appear. Abbot, P. J., 19(26), 21(26), 42(26), 43 (26),47(26),246,260(2,3), 261(2,3), 29321, 297(2, 3), 298(2), 300(2), 302 (21, 307(2), 311(2, 3). 313(2), 314(2, 3),321(2), 327(2), 337(2), 339(2), 455,472(25), 47X2.5). 478(25), 479 (25),481(25), 502 Abe, N., 269(19), 272(19), 273(19), 304 (191, 311(19), 314(19), 336(19),455 Abou-State,A., 186(231), 187(231). 205 (231),209(231), 211(231), 253 Abramovitch, R. A., 278(36), 281(36), 456 Acheson, R. M.,19(25,26, 27,28,29). 21(25,26,27,28,29), 39(25,29),42 (26,27), 43(25, 26, 27,29),47(26, 27),48(25, 27,28,29), 180(229), 182 (229),246,253,260(lb, 2,3,4,5), 261(lb, 2,3,4,5,6), 262(6), 264(6), 294(6), 295(2), 297(2, 3,6), 298(2,5, 6), 300(2,6), 301(5,6), 302(2,4,5, 6), 307(2). 309(6), 311(2, 3,4,6), 313 (2,4,5), 314(2,3,6), 320(5,6), 321 (21, 327(2), 337(2), 339(2),455,472 (25),473(26, 27, 28, 29), 474(28. 30, 31, 32, 33), 475425, 32,33), 478(25. 32). 479(25, 32,33),480(33), 481(25, 28, 29, 32, 33), 482(28, 32.38). 502, 503 Adams, R., 29(48), 32(48), 43(48), 56 (481,246, 284(45), 285(45), 286(45), 287(45), 303(45), 320(45), 381(45), 383(45), 394(45), 411(45), 456,464 (2), 465(2). 478(2), 502 Afridi, A. S., 268(18), 27x18). 295(18), 299(18), 305(18), 321(18), 322(18),455 A&, B., 500(57), 501(57), 502(57), 503 Aida, M.,126(179), 132(179),251 Ainsworth, D.P., 29(50), 32601, 34(66), 246, 247,284(47,49), 281(47,49), 289 (651, 294(65), 303(65), 315(49), 316 (491, 327(49), 328(49), 329(49), 330 (49,651, 333(49), 334(49), 339(49), 381(47), 383(47), 394(47), 399(49), 417(49), 420(49), 456,465(5,8), 487 (8), 502

Aka, T..126(179), 132(179), 251 Akasaki, Y.,97(116), 113(142), 146 (142),161(142), 190(142), 21 1(142), 249.250 Akimov, A. V., 432(177),460 Alam, M. N.,509(8), 515(8), 528 Albini, A., 47334, 35,36),476(34, 35, 36),477(36), 478(34,35,36), 479(34, 35, 36),481(34,35), 482(34), 490 (34,35), 502 Alburn, H. E., 217(245), 253 Alcalde, E., 244(278), 245(278), 255 Alekseeva, L.M.,45(72,77), 46(72), 47 (72),49(72), 56(72,77), 57(72,77), 58(72, 77), 59(77), 147(212), 152(212), 160(222), 161(222), 163(212), 164 (212), 168(222), 169(212,222), 179 (222), 182(222), 247, 252, 253 Ali, M. I., 186(231), 187(231), 205(231). 209(231), 211(231), 253 Allen,C. F. H., 355(112), 356(112),458 Alper, A. E., 88(103), 89(103, 108), 90 (103),91(103), 96(103,108), 97(103), 98(103), 103(103), 104(103, loti), 105 (103, 108), 108(103,108), 109(103, 108), 145(103), 146(103), 147(103, 108). 148(103), 152(103, 108), 155 (103). 156(1031, 157(103), 160(103), 161(103), 163(103), 165(103), 168 (103). 169(103, 108). 182(103), 186 (1031, 187(103), 190(103), 215(103), 216(103), 248 Alper, H.,89(108), 96(108). 104(108), 105(108), 108(108), 109(108), 147 ( 108). 152( 108), 169(108), 221(257), 222(257,258), 230(258), 234(258), 242(258), 248,254,255,367(137), 368(137), 370(137), 393(137), 397 (137), 398(137), 41 1(137). 459 Alpermann, H.C.,341(76), 457 Altukhova, L. B., 375(146), 376(146), 459,526(31), 529 Ambrus, A., 461(204) Ananeva, K. V., 352(107), 458 Andersag, H.,88(104), 90( 104),96( 104),248

543

544

Author Index

Anisimova, 0. S., 55(78), 56(78), 171 (229, 173(225), 176(78), 177(78), 247.253 Anisimova, V. A., 117(157), 118(157), 119(162b, 165,166),120(157,162a, 163, 164), 121(157, 162a. 162b), 123 (173), 124(173), 125(175), 126(173, 180), 129(157,162a, 162b, 163,164, 166). 130(166), 131(173), 132(173, 175,180), 149(157, 166, 173, 175, 213),150(163,164, 165,173, 214), 151(173,180), 152(163,164,165, 166,173, 175,180,213,214). 154 (166), 157(165), 158(164,214). 167 (166, 180), 170(166), 171(180), 179 (157,163,227), 181(163), 183(157, 162a, 163,165,166,227),184(157, 162a, 165,227), 185(166), 186(166),

193(157,164,165,173,175.213,214,

238), 194(164,165,173,175,214), 195(164,165,175,180,213,214),

196(180). 197(165,175,180,214), 201(157,162a, 163,164, 166, 180), 202(157.175,180,227), 203(175, 227), 204(175,214), 206(227), 207 (157,227), 208(162a, 162b, 164,165, 173, 180.227), 209(162a, 165, 227), 210(162a, 165). 211(165, 166). 212 (162a. 163, 165, 214, 227), 213(164, 214). 214(214,227), 215(157, 164, 165,166, 180), 216(165, 166,175, 243). 218(166,175), 219(164,214), 250,251,252,253 Antaki, H.,360(121), 361(121), 362(121, 363(121), 365(121), 366(121),458 Aoki, K., 427( 170). 460 Aotani, Y., 140(201), 143(201),252 Aplin, R. T.,482(38), 503 Arai, A., 219(256), 254 Ariyan, Z. S., 96(114), 248 Arya, P., 88(99), 91(99), 92(99), 117 (159), 120(159), 169(99), 219(99), 248,250 Aryuzina, V. M., 137(189, 190, 191, 192, 193). 138(189, 190, 191, 192, 193). 152(192, 1931, 154 (192, 193). 158(190, 191, 192, 193, 221), 159(192, 193, 221), 168(192, 193, 224). 171(224), 178(224), 179(224), 182(190, 191, 224). 197(192, 193, 221, 224), 198(192, 193), 199(221), 202(192,221), 204(192), 205(192),

206(193,221), 207(192, 193.221), 208(193), 211(190, 1911, 212(221), 215(221), 216(193,224), 251,252, 253 Aten, W.C., 22(33), 23(33), 25(33), 246 Atkinson, J, C., 346(87), 347(87), 390 (87). 399(87),457 Aubagnac, J. C., 25(38), 26(38). 27(38). 28(38), 29(38), 38(38), 40(38), 41 (38), 43(38), 53(38), 54(38), 82(38), 246 A u d W h , N. I., 120(164), 129(164), 149(164,213), lSO(164, 214). 152 (164, 213, 214, 215,216), 154(215), 158(164,214, 2151, 159(215), 178 (2151, 193(164, 213, 214, 238), 194 (164,214, 195(164,213, 214), 197 (214,2151, 198(215), 199(215), 201 (164). 2W214,215), 205(215), 208 (1w), 209(215), 212(214), 213(164, 2l4), 214(214), 215(164), 219(164, 2141,251, 252 Augustin, M.,438(187), 439(187), 440( 187),442( 187), 444(187), 447( 187), 448( 187), 460 Awaya, H.,272(17),455 Baba, S.,427(170), 460 Babichev, F. S., 7(12, 13, 14), 10(12, 13, 141, ll(12, 13). 12(12), 13(21), 14(21), 16(12, 13, 14). 17(21), 38(70), 39(12, 13,21),40(21), 41(12, 13).44 (12,13,21,70), 45(14, 74),46(13, 21), 47(13,21,70),48(14), 49(14,70.74), 50(74), 56(12,14,79), 57(12,80), 58 (14), 59(70,74),60(74,81), 57(12,80), 58(14), 59(70,74), 60(74,81), 57(12, 80), 58(14), 59(70,74), 60(74,81), 64 (12, 13, 74, 81), 65(12, 13,74.81), 66 (12),67(70), 68(70), 69(70), 71(70), 7313, 81). 80(70), 84(12), 245, 246, 24 7 Babicheva, A. F., 7(12), 10(12), 11(12), 12(12), 16(12), 39(12),41(12),44 (12), 56(12), 57(12), 64(12), 65(12), 66(12), 84(12). 245 Baboulene. M.,94(113). 96(113), 248 Bacon, R. G.R.,468(15),481(15).482 ( 1 9 , 502 Bagovant, C., 101(124), 102(124), 103 (124),249.348(95), 351(95),457 Bagrii, A. K., 348(99), 349(99), 351(96. 97), 426(96),457

Author Index Bakhrnutskaya, V. C., 507(12), 511(12), 515(12), 528 Balasubramanian, K. K., 90(120a, 120b), 91(120a, 120b), 100(12Oa, 120b), 211 (120a, 120b), 249,348(90), 350(90), 457 Barinotti, A., 475(36), 476(36), 477(36), 478(36), 479(36), 502 Barnett, K. G., 381(153), 383(153), 459 Basaglia, L.,355(117), 356(117), 412 (1 17), 413(117), 458 Basselier, J. J., 279(41), 282(41), 283 (41h 299(41). 304(40, 320(41),456 Battaglia, J., 506(4), 507(4), 508(4), 510 (4). 511(4), 517(4), 518(4), 528 J3axter.C. A. R., 180(229), 182(229),253 Baxter, I., 288(66), 294(66), 303(66), 316 (661, 336(66), 456 Bayer, A. G.,532(1,3), 541 Beard, C.C., 223(259), 244(259), 255, 444(196), 454(196), 461 Beaven,G. H.,478(37), 503,515(19), 528 Bednyagina, H.P., 225(267,268), 226 (267,268),227(267,268), 231(267), 240(267), 242(267), 244(267), 2S5 Behrenz, W., 441(202), 445(202), 448 (202), 454(202), 461 Beilfuss, H. R., 355(112), 356(112),458 Beilis, Y.I., 430(174), 454(174), 460 Bell, S. C., 88(102), 89(102,109), 94(102), 96(102,109), 105(102,109), 106(102, 109h 108(102, log), 109(102), 111 (1411, 113(141), 114(141), 152(102, 1091, 169(102, log), 211(141), 217 (102),219(109,141), 248,249,349 (108). 352(108), 391(108), 458 Bellinger,G. C. A., 110(147), 112(147), 114(147), 178(147), 186(147), 188 (1471,250 Bells, W. S., 381(154), 383(154,155), 384(154,155), 417(154), 423(154), 426(154, US), 459 Belous, A. A., 119(162b), 121(162b), 129 (162b). 212(162b), 219(I62b). 250 Bdgni, F., 86(91,92), 87(91,92), 144 (91,92).145(91,92), 158(91,92), 159 (91,92), 207(91), 217(91,92), 248 Berg, S. S.,387(158), 459 Berg, W.F., 541(24c), 542 Bergel, F., 90(110), 96(110), 248 Bergthaller, P., 219(256), 254

545

Betrabet, M. V., 25(39), 26(39), 27(39), 28(39), 246 Bettinetti, G. F.,475(34,35,36), 476 (34,35,36),477(36), 478(34,35,36), 479(34,35,36), 481(34,35), 482(34), 490(34,35), 502 Bhaduri, A. P., 388(160), 389(160), 409 (160), 459 Bieksa, V.,525(30), 526(28,29), 528(28, 29), 529 Bindler, I., 436(183), 439(183), 442(183), 460 Bird, C. W.,126(182), 127(182,183,184), 132(182), 134(182,183,184), 135(183, 184), 151(182,184), 152(182), 208 (182),251,387(159), 393(159), 459 Bistrzycki, A., 3(1), 5(1), 22(34), 25(34), 73(1), 245,246 Blad~,R. M., 126(177), 132(177), 219 (177), 251 Blackwell, J. T.,507(10), 510(10), 515 (10),522(10), 528 Bobkova, T. V., 157(218). 219(253), 252,254 Boedtly, E., 219(256), 254 Bohme, H., 360(126), 361(126,128a), 363(126,128a), 392(126), 458 Boie, I., 219(256), 254 Boris0va.T. A., 119(166), 123(173), 124 (1731, 126(173,180), 129(166), 130 (166), 131(173), 132(173, l80), 149 (166.173), 150(173), 151(173,180), 152(166,173,180), 154(166), 167 (166,180), 170(166), 171(180), 183 (166), 185(166), 186(166), 193(173), 194(173), 195(180), 196(180), 197 (180), 201(166, 180), 202(180), 208 (173,180), 211(166), 215(166,180), 216(166), 217(166), 218(166), 251 Bortnidt, N. N., 7(9), 8(9), 72(9), 74 (851, 79(87), 84(85), 245,248 Bose, E. A., 445(203), 454(203), 461 Both. S., 23(36),25(36), 27(36), 82 (361,246 Bower, J . D.,225(266), 226(266), 227 (266),244(278), 245(278), 255 Brad, A., 219(254), 254 Brandes, W.,441(202), 445(202), 448 (202),454(202), 461 Brooker, L.C. S., 62(82), 67(82), 247 Brown, R., 3(3), 5(3), 84(3), 245 Brownlee, R. T. C., 514(18),515(18), 528

546

Author Index

Brunoro, G., 541 (1l), 542 Budikova, M.,453 (208). 461 Buechel. K.H.,22 (33), 23 (33). 25 (33). 246 Burness, D.M.. 355 (112,113), 356 (112,113).458 Butler, R. N.,244 (279), 255 Cadogan, J. I. C.,468 (14), 502 Calmon, J. P., 454 (205), 461 Cameron, D.W.,288 (66), 294 (66), 303 (66), 316 (66), 336 (66), 456 Campbell, N.. 278 (37), 282 (37). 303 (37), 336 (37), 456 Campbell, R. H.,91 (115a), 97 (115a), 98 (115a), 145 (115a), 146 (115a). 147 (115a). 207 (115a), 209 (115a). 216 (1 lSa), 249 Capuno, L.,438 (186,189), 439 (186), 440(186), 442(186. 189). 444(186), 460

Carassiti,V., 541 (1 I), 542 Carroll, F. I., 507 (10). 510 (lo), 515 (lo), 522 (10),528

Carruthers, J. R.,260 (3), 261 (3). 297 (3), 31 1 (3), 314 (3), 455 Castellanos, M. L., 230 (272). 231 (272), 235 (272). 240 (272), 241 (272), 242 (272). 243 (272), 244 (272), 255 Cauquis, C., 279 (40,41), 282 (40,41), 283 (41). 299 (40.41). 304 (40,41), 320 (40,41), 456 Celanese Research Company, 540 (8), 541

Chadha,V. K., 88 (96,98,101), 90 (101). 92 (96,98), 93 (101). 96 (96,98),97 (101), 98 (101), 110 (98.101). 113 (98, 101), 114 (98), 145 (98, IOl), 148 (98,101), 161 (96,981,165 (98). 169 (96,98), 170 (98), 186 (101), 187 (101). 188 (101). 197 (101),200 (101), 217 (101), 219 (101.247), 248, 253, 349 (105,106). 351 (105, 106), 391 (105,106),400 (105,106), 458

Chakravarti,G. C.,25 (39), 26 (39), 27 (39), 28 (39), 246 Chapman, D. D., 262(1la, llb), 265 (lla. llb), 266(11a, llb), 295(11a), 297 (lla), 304 (lla), 305 (lla), 307 (lla), 317 (lla), 321 (llb), 330 (lla), 331 (Ila), 332 (lla), 333 (lla), 341

(llb,79),455,457 Chaudhary, H.S.. 88 (101),90 (101). 93(101), 97(101), 98(101), 110(101), 113 (101). 145 (101), 148 (101). 186 (101), 187 (101). 188 (101), 197 (101). 200 (101). 217 (101), 219 (101.247), 248,253, 349 (104), 351 (1041,391 (104). 458 Checchi, S., 355 (116). 356 (1161,360 (124), 361 (116,1241,362 (1241, 363 (124). 365 (116,124). 371 (116). 372 (116), 420 (116),458 Chekrii, G.S., 140 (197), 229 (271). 252,255 Chemyshkova. L.A., 375 (146). 376 (146). 459 Chizevskaya, I. I., 26 (41). 27 (41),28 (41). 40 (41). 110 (131, 132, 133, 137). 112 (132). 113 (131,132,133, 137). 114 (132,133). 115 (132). 145 (133,211). 148 (133,137), 152 (21 11, 157 (21 l), 186 (131), 187 (1 33). 188 (133), 189 (131). 190 (131,132), 197 (133). 200 (133), 205 (131,132,211), 219 (133), 246,249,252, 349 (102, 103), 351 (102.103), 354 (103), 355 (103). 390(103), 391(103), 415 (1021,457 Chothia, D.S., 509 (9). 528 Chow, A. W.,359(120), 360(120), 361 (120), 362(120), 363(120), 365(120), 366(120), 368(120), 369(120), 370 (120). 392(120), 393(120), 396(120), 397(120), 398(120), 401(120). 402 (120), 403(120), 404(120), 405(120), 406(120), 408(120), 412(120), 418 (120), 419(120), 420(120), 421(120), 458 Chuiguk, V. A.. 268 (16), 271 (16). 305 (16), 321 (16), 322 (16). 355 (114), 356 (114), 357 (114). 396 (114),401 (114),411 (114),455,458 Claramunt, R.M., 244 (278). 245 (278), 255 Clark, M.L..532 (2). 541 Clark, R. H.,440 (197). 444 (197), 455 (197). 461 Clark--, J. W., 37(69), 38(69), 41(69), 56(69), 247, 289(62), 292(62), 317(62), 321(62). 322 (62). 338(62), 339(62), 385(62), 399(62), 456 Conger, R. P.. 541 (211,542

Author Index Crippa,G., B., 360(123), 361(123), 362 (123). 417(123), 458 Critchley, S. R., 474(30,31), 502 Cros, J. L., 279(40,41), 282(40,41), 283 (41). 299(40,41), 304(40,41), 320(40. 4 1). 456 Curry, A., 355(111), 356(111). 360(111), 362(111). 365(111), 392(111), 401(111), 402(1 ll), 4O4(11 l), 420(11 l), 421(111), 424( 11 1). 426(111), 458 Czerny. H., 279(39), 282(39), 321(39), 324(39), 456

D’Amiao, J. J.,91(115a, 115b),97(115a. llSb), 98(115a, 115b). 145(115a, llSb), 146(115a, 11Sb). 147(115a, IlSb), 207 (115a. 115b), 209(115a. 115b), 216(115a, 115b). 219(115b). 249 Daneshtalab, M., 269(21), 270(21). 275 (21). 294(21). 297(21), 309(21), 317 (21), 455 Daniel, H., 227(269), 255 Darchen. A., 287(57), 456 Dashkevich, L. B., 365(133), 366(133), 415(133), 416(133), 459 h u m , W., 441(201, 202), 445(201, 202), 448(201,202), 454(201, 202), 461 Davidson, A.,94(121), 100(121), 101(121), 110(147), 112(147), 114(147). 115(121), 178(147), 182(121), 186(147), 188(147), 249, 250,348(91), 350(91), 352(91), 354(91). 390(91). 391(91), 41 l(91). 457

Davies, H. J.. 374(144), 375(144), 389 (144), 394(144), 412(144).459 Day, A. R., 22(32), 23(32), 24(32), 27(32), 69(32), 72(32), 73(32), 76(32), 78(32), 79(32), 82(32), 83(32), 126(176), 132 (176), 151(176), 154(176), 158(176), 167(116), 171(176). 178(176). 185(176), 186(176). 1%(176), 217(176), 218(176), 228(270), 230(270). 239(270), 2420701, 244(270). 246,251,255,277(26), 332 (26), 377(26), 378(150), 379(26,150). 380(150), 395(150), 409(150), 414(150). 416(150), 423(150), 425(26,150). 426 (26, UO),429(172a), 430(172a),446 (172a). 455,459,460 De Benneville, P. L., 84(90), 248 De Cat, A., 357(119), 359(119), 360(119, 122), 361(119,122), 362(122), 363(119, 122). 365(119.122), 458

547

Degutis, J., 525(30), 526(28, 29), 528 (28, 291,529 Dehnert, J., 268(15), 271(15), 329(71). 330(15), 331(15), 332(15), 341(15,71), 455,456 Deichmeister, M. V., 427(170), 460 Delp, C. J., 532(4), 541 De Mendoza, J., 178(226), 225(263), 226 (263). 227(263), 230(263,272), 231 (263,272), 232(226,263,272,273), 233(226,263,273), 234(273,274), 235(263,274), 238(273,274), 239(226, 273), 240(263), 242(263,273), 253, 255 Denzel, T., 363(131), 365(131), 412 (131). 413(131), 418(131), 419(131), 420(131), 421(131), 422(131), 427 1 3 1). 458 Depoorter. H., 29(58). 32(58), 33(58), 60 (58). 62(58), 63(58), 67(58), 69(58), 71(58), 72(58), 73(58), 76(58). 78(58), 79(58), 82(58), 83(58), 84(58), 247, 286(60), 287(60), 288(60), 291(60), 317 (60), 321(60), 322(60), 323(60). 327(60), 328(60), 329(60), 333(60), 334(60). 338 (60),339(60), 341(60), 383(60), 384 (60), 412(60). 417(60). 420(60), 423 (60). 426(60). 427(60), 456 De Selms, K. C.. 22(32), 24(31), 56(31). 246,277(25), 455,471(22). 478(22), 482(22). 502 de Stevens,G., 93(111), 96(111), 181(111), 182(111), 248 Dhal, P. N., llO(135). 113(135), 186(135), 189(135), 219(135), 249 Dickens, J. P., 381(153), 383(153). 459 Dickerson, C. H., 374(144), 375(144), 389(144). 394(144). 412(144), 459 Dighe, V. S.. lOl(124). 102(124), 103 (124), 249,348(95), 351(95),457 Dikciuviene, A., 525(30). 526(28,29), 528 (28,29), 529 Dike, S. Y., 509(9), 528 Dittmar, G., 207(240), 219(240), 253 Dittrich, G., 440(200), 445(200), 461 Doleschall, G., SOO(S7). 501(57), 502 (57),503 Dorofeenko, C . N., 356(118), 357(118), 359( 118). 458 Doyle. F. P., 225(266), 226(266), 227(266), 244(278), 245(278), 255

548

Author Index

Drager, M., 91(122), 92(122), 101(122), 161(122), 169(122), 178(122), 180 (122), 197(122), 200(122). 249 Druhinina, A. A., 375(147), 376(147), 418(147). 425(147), 426(147), 459 Druta, I., 18(24), 20(24), 26(24), 29 (45). 39(24,45), 40(45), 47(24), 54 ( 4 9 , 246,264(9), 455 Druzhinina, A. A., 7(17), 11(17), 12(17), 13(20), 16(17,20), 44(17), 45(17,77), 46(17), 54(75), 56(77), 57(77), 58(77), 59(77), 81(17), 82(75), 246,247 Duewel, D., 444(193,194), 454(193,194), 460 Duffm,G. F., 110(129), 111(129), 113 (129), 156(129), 157(129), 186(129), 187(129), 188(129), 189(129), 190 (129). 208(129), 219(129,251), 249, 254,541(24c), 542 Dunwell, D. W., 363(130), 365(130), 366 (130). 368( 130), 391( 130), 392(130), 397(130), 398(130), 401(130), 403(130), 404(130), 405(130), 412(130), 413(130), 415(130), 416(130), 418(130), 419(130), 458 Dvoryantseva. G. G.,45(72,77),46(72), 47(72), 49(72), 56(72,77), 57(72,77). 58(72,77). 59(77), 160(222), 161(222), 168(222,224). 169(222), 171(224), 178 (224), 179(222.224), 182(222,224), 197(224), 216(224), 247.253 Dyadyusha,G. G., 7(14), 10(14), 16(14). 45(14), 48(14), 49(14), 56(14). 58(14), 245 Dzhafarov, A. P., 541(20), 542 Dziornko, V. M., 141(210), 149(210), 152 (210), 157(210,220), 158(210,220), 252 Eckhard, T., 421(166), 427(166), 459 Edwards. J . A., 444(196), 454(196), 461 Edwards, W. B., 378(150), 379(150), 380 (150), 395(150), 409(150), 414(150). 416(150), 423(150), 425(150), 426 (150), 459 Effenberger, F., 141(209), 252 Efros, L. S., 527(32), 529 Ehrlichmann, W., 438(195), 444(195), 449(195), 450(195), 461 Eian, G. L., 541(19), 542 Eisner, U., 260(3), 261(3), 297(3), 311 (3), 314(3), 455 Elchueva, A. I., 541(20), 542

Elguero, J., 25(38), 26(38), 27(38), 28(38), 29(38). 38(38), 40(38), 41(38), 43(38), 53(38), 54(38), 82(38), 140(207), 142 (207),157(207), 166(207,223), 170 (207,223), 178(226), 211(207), 225 (263). 226(263), 227(263), 230(263), 231(263), 232(226,263,273), 233 (226,263,273),234(273), 235(263), 239(226,273), 240(263), 242(263,

273),246,252,253,255.482(39), 503 Elrnore, N. F., 260(lb), 261(lb), 311(lb), 313(lb), 455,473(29), 481(29), 502 Elslager. E. F., 355(111), 356(111), 360 (lll), 362(111), 365(111), 392(111), 401 (11 1),402(1ll), 4O4(111), 420(111), 421(111), 424(11 l),426(111). 458 El’tsov, A. V., 521(22), 522(22), 528 Elwood, J. K., 262(11a, llb), 265(11a, llb), 266(11a, llb), 295(11a), 297(11a), 304(lla), 305(1 la), 307(1 la), 317(1 la), 321(11b), 330(11a), 331(11a), 332(11a), 333(11a), 341(11b, 79),455,457 Endo, T., 219(256), 254 Engineer, A. B., 509(9), 528 Esayan, Z. V., 7(7,8), 8(7,8), 245 Evans,D., 363(130), 365(130), 366(130), 368(130). 391(130), 392(130), 397 (130), 398(130), 401(130), 403(130), 404(130), 405(130), 412(130), 413 (1 30), 415( 130), 416( 130), 418( 130), 419(130), 458 Fassler, K., 3(1), 5(1), 73(1). 245 Faure, R., 232(273), 233(273), 234(273), 238(273), 239(273), 242(273), 255 Fayet, J. P., 178(226), 232(226), 233(226), 239(226), 253 Fegley, M. F., 7(9). 8(9), 72(9). 74(85), 79 (87), 84(85), 245,248 Fenichel, R. L., 217(245), 253 Ficken, C. E., 180(228), 182(228), 190 (228), 217(228), 253 Fielden, R., 33(62), 34(62), 52(73), 53 (62), 60(62), 75(73), 76(73), 78(73), 247,286(55), 288(55), 291(55), 315 (55). 333(74), 383(55), 384(55), 399 (55), 456,457,469(16, 17,18), 471 (16,17,18), 480(17), 482(16,17), 484 (41,42,43), 486(42), 487(41,42), 488 (42). 489(43), 502,503

Author Index Finch, N., 261(7). 262(7), 264(7), 294 (7), 297(7), 298(7), 301(7), 311(7), 321(7), 322(7), 324(7), 434(7), 435 (7), 436(7), 447(7), 449(7), 451(7), 453(7), 455 Fischer, J., 137(188), 139(188,194), 140 (188,194),152(194), 171(188), 209 (188),251,252,378(151), 380(151), 395(151), 420(151), 459 Foxton, M. W.,19(26), 21(26),42(26), 43(26), 47(26), 246,260(2), 261(2), 295(2), 297(2), 298(2), 300(2), 302 (2). 307(2), 311(2), 313(2), 314(2), 321(2), 327(2), 337(2), 339(2), 455, 472(25). 473(26), 475(25), 478(25), 479(25), 481(25), 502 Franco, J., 541(10). 542 Freddi,S., 86(91), 87(91), 144(91), 145(91), 158(91), 159(91), 207(91), 217(91), 248 Freedman, A. R., 22(32), 23(32), 24(32), 27(32), 69(32), 72(32), 73(32), 76(32), 78(32), 79(32). 82(32), 83(32), 246 Fried, J. H.,444(196),454(196),461 Frohberger, P. E.,441(201), 445(201), 448(201), 454(201), 461 Fruchier, A., 166(223). 170(223), 253 Fry, D. J., 180(228), 182(228), 190(228), 217(228), 219(251), 253,254 Fu Ho,R. I., 228(270), 230(270), 239(270), 242(270), 244(270), 255, 429(172a), 430(172a), 446 (172a), 460 Fuchsgruber, A., 375(145),459 Fueller, F., 421(166), 427(166), 459 Fujihara, M., 219(256). 254 Fujiwara, M.,140(205), 143(205), 207 (205), 211(205), 219(205), 252 Fukuyama, M., 113(142), 146(142), 161 (142). 190(142), 211(142), 250 Furutachi. N., 219(256), 254 Fyong, N. T.N.,45(74), 49(74), 50(74), 59(74), 60(74,81), 64(74,81), 65(74, 81),75(81), 247 Galenko, G. F.,348(99), 349(99), 351 (97). 457 Ganieva, M. F., 541(20), 542 Gapanovich, C.I., 110(131,132), 112 (132), 113(131,132), 114(132), 115 (132), 186(131,132,232), 188(131), 189(131), 190(131,132,232), 205 (131,132). 219(232),249.253,349 (102), 351(102), 415(102), 457

549

Garner, G. V.,286(58), 287(58), 289 (58),291(58), 317(58), 336(58), 338 (58),339(58), 383(58), 384(58), 388 (58), 389(58), 423(58), 456,468(12), 502 Garner, R., 29(5 11, 3 2 0 l), 69(5 I), 76 (51), 79(51), 246,284(48), 286(58), 287(58), 288(48), 289(58), 291(58), 317(58), 329(48), 330(48), 333(48), 336(58), 338(58), 339(48, 58), 381 (48), 383(48,58), 384(58), 388(58), 389(58), 417(48), 420(48), 423(58), 456,465(4), 468(12), 485(4), 489(4), 502,512(16), 513(16), 515(16),528 Gelfert, K., 514(17), 528 Cellen, A., 225(262), 255 Gemenden. C. W.,261(7), 262(7), 264 (7). 294(7), 297(7), 298(7), 301(7), 311(7), 321(7), 322(7), 324(7), 434 (7), 435(7), 436(7), 447(7), 449(7), 451(7), 453(7), 455 Genies, M.,279(41), 282(41), 283(41), 299(41), 304(41), 320(41), 456 Gerloff. J., 29(54), 32(54), 37(54), 38 (541,247, 286(52), 289(52), 290(52), 317(52), 326(52), 327(52), 383(52), 456 Getsova, I. N., 225(267), 226(267), 227 (267),231(267), 240(267), 242(267), 244(267), 255 Gewald, K., 268(13), 271(13), 314(13), 455 Girard, Y.,346(87), 347(87), 390(87), 399(87), 457 Glos, M., 341(79), 457 Glover, E. E., 329(72), 457 Gofman, S. M., 120(164), 129(164), 149 (164), 150(164,214), 152(164,214), 158(164,214), 193(164,214), 194 (164.214),195(164,214), 197(214), 201(164), 204(214), 208(164), 212 (214),213(164,214), 214(214), 215 (164),219(164,214,250),251,252,254

Golubushina,G. M.,355(114). 356(114), 357(114), 396(114), 401(114), 411 (114),458 Gompper, R., 141(209),252 Gougoutas, Z.. 224(261a), 225(261a), 243(261a), 244(261a), 255 Grabovskaya, Z. M.,26(41), 27(41), 28 (41),40(41), 110(137), 113(137), 148 (137),249,349(103). 351(103). 354 (103). 355(103),390(103), 391(103),457

550

Author Index

Grantham, R. K.,29(59), 33(65), 34(65), 35(68), 36(68), 37(59,68), 38(59,68), 40(59), 52(65), 53(65,68), 54(59,68, 76). 60(59,68), 62(68), 66(65), 73(59), 80(68), 82(59,68), 247,288(56,61,63), 291(56), 292(61,63), 294(61), 303(63), 317(56,63), 320(63), 38366). 384(56), 385(63), 399(56,63), 456,466(9, lo), 467(9), 469(20), 471(20), 478(20), 480 (9). 481(20), 502 Greer,A. T.,432(176). 446(176), 460 Gregory, F. J., 217(245), 253 Grin,V. A., 157(217),252 Grinblat, E. I., 115(150), 178(150). 211 (150), 250 Grinev, A. N.,375(146,147), 376(146, 147). 418(147), 425(147), 426(147), 459.526(31), 529 Griill, F., 493(51), 495(51), 497(51), 503 Grushina, L.E., 119(165), 150(165), 152 (165). 157(165), 183(165). 184(165). 193(165), 194(165), 195(165), 197 (165), 208(165), 209(165), 210(165), 211(165), 212(165), 214(165), 215 (165), 216(165), 251 Guenther, D.,541(22). 542 Guinn, E. C., 91(115a), 97(115a), 98 (llsa), 145(115a). 146(115a), 147 (llSa), 207(11Sa), 209(115a). 216 (115a), 249 Haddadin, M. J., 346(86), 347(86), 390 (86). 457 Haertel, K.,438(190), 444(190,191, 192,193), 448(190), 454(190,191, 192,193,194,209),460,461

Hajos, G.. 101(125), 102(125), 103 (125), 163(125). 190(125), 249,348 (98), 349(98), 351(98), 400(98), 426 (981,457 Halamandark, A., 93(111), 96(111), 181 (11l), 182(1111,248 W . N . M.,359(120), 360(120), 361 (120), 362(120). 363(120), 365( 120), 366(120), 368(120), 369(120), 370 (120), 392(120), 393(120), 3%(120), 397(120), 398(120), 401(120), 402 (120), 403(120), 404(120), 405(120), 406(120), 408(120), 412(120), 418 (120). 419(120), 420(120), 421(120), 458 Hamana, M., 507(13). 511(13), 528

Hamilton, S. D.,468(15), 481(15), 482 (15). 502 Hammann, I., 127(187), 136(187), 219 (248),251,254,441(202), 445(202), 448(202), 454(202), 461 Hammouda, H. A., 26(44), 28(44), 246 Hankovszky. H. O., 349(100), 351(100), 367(138), 368(138), 370(138), 376 (148), 377(148), 394(148). 408(148). 426(138.168), 457,459,460 Hankovszky, O., lOl(125). 102(125), 103(125), 163(125), 190(125),249, 348(98), 349(98), 351(98), 400(98), 426(98), 457 Hanzawa, T.,219(256), 254 Hargitai, E., 461(204) Harlow, R. L.. 482(39), 503 Harrison, D.R., 482(38). 503 Hasegawa. G., llO(144). 114(144), 208 (241). 250,253 Hassner, A., 346(86), 347(86), 390(86),457 Hatano, M.. 113(142). 146(142), 161 (142),190(142), 21 1(142),250 Haugwitz, R. D.,116(152,153), 152 (153). 157(15 3). 170( 153), 190(152), 191(152), 208(152,153), 219(152), 224(261a, 261b). 225(261a, 261b), 243(261a, 261b). 244(261a, 261b). 250,255 Hayakawa, Y., 219(256), 254 Hayashi, H., 117(154). 166(154), 170 (154), 250 Hayward, R. J., 88(93). 101(93).248, 345(83), 346(83). 348(83), 351(83), 457,471(24), 472(24), 478(24), 502 Heimbach, N.,440(197), 444(197), 455 (197). 461 Held, P., 440(200). 445(200). 461 Hemmerling, H. J., 29(55), 247,286(53), 290(53), 456 Herdan, J.. 18(24). 20(24), 26(24), 29 (45),39(24,45), 40(45), 47(24), 54 (45).246,264(9), 455 Heseltine, D.W., 262(11a, llb), 265 (lla, llb), 266(11a, llb), 295(11a), 297(11a), 304(11a). 305(11a), 307 (lla). 317(11a), 321(11b), 330(11a), 331(11a), 332(11a), 333(11a), 341 (llb. 79),455,457,541(24a),542 Hess,C. A., 355(111), 356(111), 360 (1 ll),362(11l),365(111), 392(111), 401(111), 402(111), 404(111). 420 (lll),424( 11l), 426(111), 458

Author Index Hess, H.M., 262(11a), 265(11a). 266(11a), 295(11a), 297(1 la), 304(11a), 305(11a), 307(11a), 317(11a), 330(11a), 331(11a), 332(11a), 333(11a), 455 Hey, D.H.,278(36), 281(36), 456 Hideg, K., 101(125), 102(125), 103(125), 163(125), 190(125),249,348(98), 349 (98, 100). 351(98, loo), 367(138), 368 (138), 370(138), 376(148), 377(148), 394(148), 400(98), 408(148), 426(98, 138,168), 457,459,460 Hiller, C. L.,&1(88), 248 Himmelmann, W., 219(256), 254 Hinata, M., 157(219), 183(219), 192(219), 193(219), 219(219.256), 2.52.254 Hiraoka, T.,90(119), 100(119), 168(119), 249 Hitschfel, G., 541(22), 542 Hoehn, H., 363(131), 365(131), 412(131), 413(131), 418(131), 419(131), 420(131), 421(131), 422(131), 427(131), 458 Hoffman, K.,126(178), 132(178), 251 Holiday, E. R.,478(37),503,515(19), 528 HolIies, J. I., 287(64), 29464). 456 Hoovey. J. R. E., 359(120), 360(120), 361(120), 362(120), 363(120), 365(120), 366(120), 368(120), 369(120), 370(120), 392(120), 393(120), 396(120), 397(120), 398(120). 401(120), 402(120), 403(120), 404( 120), 405(120), 406(120). 408( 120), 4 12( 120), 4 18(120), 4 19(120). 420( 120), 42 1(120), 458 Hornyak, Gy., SOO(57). 501(57), 502673, 503

Hubert, A. J., 140(195), 145(195), 146 (195). 155(195), 157(195). 160(195), 168(195),252,278(30), 280(30), 295 (30), 299(30), 304(30), 385(156). 386 (156). 396(156), 456,459 Huisgen. R.. 285(50), 286(50), 303(50), 326(50), 327(50), 456 Hung, Teljes, 493(52), 503 Hunger, A., 126(178), 132(178),251 Hutt, M. P.,355(111), 356(111), 360(111), 362(1l l ) , 365(11l), 3920 1l),401(11l), 402(111), 404(111), 42O(111), 421(11l), 424(111). 426(11 l), 458 Htay, M.,88(93), 101(93),248,345(82, 83), 346(82,83), 348(83), 351(83), 457,492(44), 503

55 1

lkeda, M.,117(154), 166(154). 170 (1541,250 Ilina, 1. G.,507(12), 511(12), 515(12), 528 Imamura, H., 219(256), 254 Inoue, I., 219(256), 254 Isenbruck,C., 3(2), 5(2), 6(2), 38(2), 40 (2), 41(2). 45(2), 53(2), 63(2),73(2), 78(2), 82(2), 245 Ishiwata, S.,499(55), SOl(SS), 503 Ismail, E..26(44), 28(44), 246 Itoh, I., 88(94), 89(94,107), 90(94), 91 (W), 92(107), 96(94,107), 101(94), 102 (94). 103(94), 104(94), 105(107), 108 (94,107),110(94), 113(94), 121(160), 129(160), 155(94,107), 156(94,107), 157(94,107), 160(107), 161(107), 163 (94), 164(107), 165(94), 168(94,107), 169(94,107), 171(107), 173(107), 174 (107), 175(107), 183(160), 184(160), 211(160), 215(94), 219(160), 248,250, 360(127), 361(127), 362(127), 363(127), 365(127), 366(127), 368(127), 392(127), 397(127), 403(127), 404(127), 405(127), 4 10(127), 4 11(127),4 12(127),413(127). 458 Ivanovskaya, S. V., 119(162b), 121(162b), 129(162b), 212(162b), 219(162b. 249, Z O ) , 250, 254 Ivashchenko, A. V., 141(210), 149(210), 152(210), 157(210,220), 158(210.220), 252 Iwai, I., 90(119), lOO(119). 168(119), 249 Iwama, M.,219(256), 254 Jaeschke, M.A., 438(186), 439(186), 440 (186), 442(186), 444(186),460 Jakas, D. R., 359(120), 360(120), 361 (120), 362(120), 363(120), 365(120), 366(120), 368(120), 369(120), 370(120), 392( 120), 393(120),396( 120). 397(120), 398(120), 401(120), 402(120), 403(120), 404(120), 405(120), 406(120), 408(120), 412(120), 418(120), 419(120). 420(120), 421(120), 458 James, T. H., 541(24a), 542 Johnson. E. A., 478(37),503,515(19), 528 Joshi, K.C.,88(99), 91(99), 92(99), 169 (99),219(99). 248 Joullie, M.M.,429(172b), 430(172b), 449 (172b),460

552

Author Index

Junek, H., 326(70). 456.5 14(17). 528 Kaczmar, M. W.. 127(184). 134(184), 135 (184). 151(184), 251 Kadyvov, C. S.. 22(30), 24(30), 52(30), 56(30). 84(30), 246,370(139). 371(139), 372(139), 393(139), 406(139), 408(139), 411(139).459 Kajihara, S., 278(38), 282(38),456 Kalinowski, J., 278(31,33,34,35), 280 (31,33,34,35),295(31,35). 299(31), 304(31,35). 321(33), 322(33),456 Kamenka, J. -M.,509(8), 5 15(8), 528 Kamioka,T., 117(155), 119(155), 121 (155). 129(155), 149(155), 154(155), 167(155), 170(155), 183(155), 184(155), 219(1SS), 250 Kamoshita, K., 117(155). 119(155), 121 (155), 129(155), 149(155), 154(155), 167(155), 170(155), 183(155), 184(155), 219(155), 250 Kano, S., 197(239), 244(275,276),253, 255 Kasyanenko, N. G., 117(158), 118(158), 120(158), 129(158), 157(158), 250 Kato, K., 244(276), 255 Kato, T.. 269(21), 270(21), 275(21), 294 (21), 297(21), 309(21), 317(21),455 Kato, Y., 244(275), 255 Katritzky, A. R., 75(86).248,268(18), 272(18), 295(18), 299(18), 305(18), 321(18), 322(18),455,482(39). 503, 5 14(18), 515(18), 528 Kaufmann, H., 284(44a), 287(44a), 291 (44a), 327(44a). 456 Kawamoto, H., 34(67), 43(67), 52(67), 24 7 Kawano, M., 360(127), 361(127), 362 (127), 363(127), 365(127), 366(127), 368(127), 392(127), 397(127), 403 (1 27), 404( 127), 405 (127), 4 lO(127). 411(127). 412(127), 413(127), 458 Kazami, T., 541(16,17,18), 542 Kazennova, N. B.,507(12),511(12),515 (1 2). 528 Kebrle, J., 126(178), 132(178). 251 Kempter, G., 438(195), 444(195). 449 (195),450(195),461 Kendall, J. D., 110(129), 111(129), 113 (129). 156(129), 157(129), 186(129), 187(129). 188(129), 189(129), 190 (129). 208(129), 219(129,251),249. 254

KeMk, L. E. J., 345(81), 346(81), 457 Keung,E.C. H.,89(108),%(108), 104 (108). 105(108), 108(108), 109(108), 147(108). 152(108), 169(108), 248 Khan, M. A., 141(208), 143(208), 152 (208), 166(208). 170(208), 208(208), 252 Kharchenko, R. S., 186(232), 190(232), 219(232), 253 Khokhlov, V. N., 521(22), 522(22), 528 Khovratovich. N. N., 26(41), 27(41), 28 (41). 40(41), 110(137), 113(137), 148 (137). 165(133), 169(133), 170(133), 186(131,132,133,232), 187(133), 188 (133), 189(131), 190(131,132,232), 197(133), 200(123), 205(131,132), 219(133,132), 246.249,2.53,349(103), 351(103). 354(103), 355(103). 390(103), 391 (103). 45 7 Kikuchi. K., 18(23), 20(23). 21(23), 39 (23), 42(23). 43(23), 45(23), 47(23), 48 (23). 55(23), 89(107), 92(107), 96(107), 105(107), 108(107), 155(107). 156(107), 157(107), 160(107), 161(107), 164(107), 168(107), 169(107), 171(107). 173(107). 174( 107). 175(107), 207(240), 2 19(240. 256). 246, 248, 253. 254, 264(8), 455

KUgore, W. W., 445(198). 461 Kimbrough. R. D., 346(84), 457 Xing,T. J.,94(121), lOO(121). 101(121), 110(147), 112(147). 114(147), 115(121), 178(147), 182(121), 186(147), 188(147), 249.250,348(91), 350(91), 352(91). 354(91), 390(91), 391(91), 411(91), 45 7 Kirsch, K.,444(193,194),454(193,194). 460 Klauke, E., 219(248), 254 Klause, E., 127(187), 136(187), 251 Klopping, H. L., 532(4), 541 Knoblock, W., 523(23). 524)23), 525(23), 526(23), 528 Knorr, H.. 5(4), 6(4), 40(4), 245 Knutsson, L., 166(223), 170(223), 253 Knysh, E. G., 91(118a), 92(118a), 93(118a). 97(118a), 100(118a), 117(118a), 118 (118a). 120(118a), 179(118a),249 Kobayashi, G., 272(17), 455 Kobayashi,S., 117(155), 119(155), 121 (155), 129(155), 149(155), 154(155). 167(155), 170(155), 183(155), 184 (155), 219(155),250

Author Index Kochergin,P. M.,7(11,15, 16,17.18, 19). 10(11,15,19), 11(11,15, 16, 17), 12 (11, 15,17).13(18.19,20),16(11, 15, 16, 17,19), 39(19),42(15),44(17),45 (17,72,77), 46(17,72), 47(72), 49(72), 54(75), 55(78), 56(72,78), 57(72,77), 58(72,77), 81(17), 82(75), 88(100), 89 (105,106). 90(100,106), 91(100, 118a, 118b). 92(100, 118a, 118b), 93(100, 118a, 118b),94(100),96(100, 105, 106), 97(100, 117, 118),98(100, 117),99 (117),100(118), 101(123), 102(123), 103(123), 110(134), 117(118a, 158). 118(118a, 158),119(161), 120(118a, 158.161). 121(161), 126(161), 129 (158, 161). 132(161), 145(117, 134). 146(117), 147(117, 212), 148(134), 152(212), 157(158), 160(222), 161 (222). 163(212). 164(212), 168(222). 169(212,222). 171(225), 173(225), 179(118, 222), 181(123), 182(123, 134,222), 186(134). 187(134), 188 (1 34). 189(134), 190(134). 205(134), 21 1(161), 245,246,247,248,249, 250,252,253, 348(99), 349(99), 351 (97,99),430(173, 174, 175),432(173, 175, 177, 178),449( 178), 454( 1741, 45 7,460 Kogutnitskaya,L. G., 506(6). 508(6), 509 (6),516(6), 520(6), 521(6),528 Kojima, Y., 140(205), 143(205), 207(205), 211(205), 219(205,256).252,254 Kollrnann, K., 375( 145). 459 Konopski, L., 378(152), 381(152), 395 ( 152). 459 Korbelainen, E. S., 365(133), 366(133). 4 15(133). 41 6( 133). 459 Kornilov, M. Y., 7(13, 14). lO(13, 14). 11(13), 16(13, 14). 38(70),39(13),41 (13). 44(13,70), 45(14, 74), 46(13), 47(13,70), 48(14).49(14.70, 74). 50 (74), 56(14,79), 58(14), 59(70,74), 60(74), 64(13. 74). 65(13, 74), 67(70), 68(70), 69(70). 70(70), 71(70). 75(13), 80(70),245.247 Korshak, v. V.,532(6), 541 Koshchienko,Y. V., 119(171). 120(171), 123(171), 127(185). 130(171), 131(171), 132(171), 135(185), 150(171), 151(185), 152(171, 185), 154(185), 167(171), 170(171). 193(171), l94(171), 208 (171, 185),212(185), 213(185), 216 (243), 217(185), 218(185),251,253

553

Kostyuchenko, N. P., 435(182), 447(182), 449(182).450(182),451(182),453(182),

454(182), 460 KotaN, A., 110(144), 114(144), 208(241), 250,253 Kovalev. C. V., 120(164), 129(164), 149 (164), 150(164,214), 152(164,214), 158(164,214), 193(164,214), 194(164, 214), 195(164, 214), 197(214), 201 (164). 204(214), 208(164), 212(214), 213(164,214), 214(214), 215(164), 219(164,214,249,250),251,252,254 Kovpak, D. V., 351(96,97), 426(96),457 Kovtunenko. V. A., 13(21). 14(21), 17(21), 39(21), 40(21), 44(21), 46(21), 47(21), 57(80), 246,247 Kozlovskaya, T. E., 97( 117), 98( 117), 99( 117), 145(117), 146(117), 147(117), 249 Krasnitskaya, T. A., 140(197),252 Krasovskii. A. N.. 88(100), 89(105,106), 90(100.106),91(100,118a, 118b), 92 (100, 118a, 118b),93(100, 118a, 118b). 94(100), 96(100,105, 106), 97(100, 117), 98(100. 117),99(117), 100(118a. 118b). 101(123), 102(123), 103(106, 123). 104(106), 105(106), 106(108), 108(106), 109(106), 110(106, 134), 113(134), 117(118a), 118(118a), 120 (118a), 145(117,134). 146(117), 147 (106. 117,212), 148(134), 152(106, 134,212). 160(222), 171(225), 173 (225), 179(118a, 118b. 222). 180(106), 181(123), 182(106, 123,134,222), 186 (134), 187(134), 188(134), 189( 134), 190(134), 205(134), 248,249,252, 253 Krasyanenko, N. G., 157(217),252 Kreiskott, H., 192(236), 193(236), 219 (236). 253 Kreutzberger,A., 439(184,185), 442(184, 185),448(185), 460 Krohnke, F., 130(168), 251 Kruglenko, V. P., 432(177), 460 Kubodera, S., 219(256), 254 Kuhla, D. B., 180(229), 182(229), 217 (244). 253 Kuhn. W., 5 ( 5 ) , 6(5), 38(5), 40(5), 245 Kukota, S. N.,96(112),248 Kumadaki, S., 507(13). 511(13),528 Kurnar, G., 388(160), 389(160), 409(160), 459

5 54

Author Index

Kunzle, F., 377(149), 379(149), 388 (149),389(149), 398(149), 411(149), 414(149), 418(149).425(149),426 ( 149). 459 Kuppe, K. R.,438(187), 439(187), 440 (187). 442(187), 444(187), 447(187). 448(187), 460 Kurata, K.. 272(17),455 Kurtz,D. W., 262(11a, llb),265(11a, llb), 266(11a, llb), 295(11a), 297(11a), 304(11a), 305(1la), 307(11a), 317(1la), 321(11b), 330(1 la), 331(1la). 332(11a), 333(11a), 341(11b, 79),455,457 Kutr0v.G. F., 7(13), 10(13), 11(13), 16 (13), 39(13), 41(13), 44(13), 46(13), 47( 13), 64( 13). 65(13), 75( 13). 245 Kutrov, G. P., 38(70), 44(70), 47(70), 49(70), 56(79). 59(70), 67(70), 68 (70). 69(70). 70(70), 71(70), 80(70), 24 7 Kuwabara, Y.,427(170),460 Kuzmenko, T.A., 125(174), 152(174), 179(174),193(174,238), 194(174). 206(174), 207(174), 251, 253 Kumetsova, E. A., 103(128). 108(128), 145(128), 147(128), 189(128), 190 (128), 216(128), 249 Kvitko, I. Y.,189(234), 190(234), 253 Lacova, M., 111(148), 112(148), 114 (1481, 115(148), 208(148),250 Lagowaski, J. M.,75(86),248 Larnm,G., 268(14,15), 271(14,15), 324 (14),325(14), 329(71), 330(14,15), 331(14, 15). 332(15), 341(15,71), 455,456 Landberg, B. E., 29(46), 39(46), 246 Langdorf, W.P., 371(142), 372(142), 426( 169),427( 142), 459,460 Lantzbch, R., 7(10), 8(10). 41(10), 42 (101,245 Latham, D. W. S.,492(46,47), 496(47), 499(46.47), 501(47),503 Lazaro, R., 140(207), 142(207), 157 (207),166(207,223), 170(207,223), 211(207), 252,253 Leal, J. R., 532(7), 541 LeCount, D. J., 432(176),446(176), 460 Lee, L. C., 348(93), 350(93), 391(93), 395(93), 400(93), 401(93),457

Lemahieu, R. G., 286(60), 287(60), 288 (60). 291(60), 317(60), 321(60), 322 (60), 323(60), 327(60), 328(60), 329 (60), 333(60), 334(60), 338(60), 339 (60), 341(60), 383(60), 384(60), 412 (60),417(60), 420(60), 423(60), 426 (60), 427(60), 456 Lempert. K., 500(57), 501(57), 502(57). 503 L’Eplattenier, F. A., 326(70), 341(77), 456.45 7 Letsch, G.. 499(56). 501(56). 503 Lettau, H., 137(188), 139(188). 140 (1881, 171(188), 209(188),251,378 (151). 380(151), 395(151), 420(151), 459 Libber, M.J., 29(58), 32(58), 33(58), 60 (58),62(58), 63(58), 67(58), 69(58), 71(58), 72(58), 73(58), 76(58), 78(58), 79(58), 82(58). 83(58), 84(58), 247, 286(60), 287(60), 288(60), 291(60). 317(60), 321(60), 322(60), 323(60), 327(60), 328(60), 329(60), 333(60), 334(60), 338(60), 339(60), 341(60), 383(60), 384(60), 412(60), 417(60), 420(60), 423(60). 426(60), 427(60), 456 Lietz, G., 523(23), 524(23), 525(23), 526(23), 528 Linclon, L. L., 62(82), 67(82). 247 Linke, S., 269(20), 273(20), 275(20), 294(20), 297(20), 307(20),455 Lintschinger, W.B., 375(145),459 Liu, K. C., 112(145), 114(145), 115(145). 148(145), 156(145), 250,348(93), 350 (93). 391(93). 395(93), 400(93), 401 (931,457 Loeffler, K., 140(202, 204), 142(202,204), 143(202), 211(202). 219(204), 252 Logachev, E. V., 430(173,174,175).432 (173, 175, 177, 178),449(178),454 (174), 460 Loudon, J. D., 34(64). 247 Lown, J. W., 29(46), 39(46),246 Lozinskii, M.O., 96(112), 112(151), 115 (151). 127(151, 186). 136(151, 186), 145(151), 148(151), 151(151), 152 (151),154(151), 158(151),248, 250, 251 Luders, H., 25(37), 27(37), 28(37), 56(37), 246 Lymar, 0.F., lll(149). 114(146,149), 157(149). 208(146,149), 219(149),250

Author Index M c Call, E. B., 278(37), 282(37), 303 (37), 336(37),456 McKillop, A., 110(147), 112(147), 114 ( 147),178(147), 186(147), 188(147),250 Maekawa, K., 270(23), 275(23), 317(23), 332(23),455 Makwana, S. C., 541( 14),542 Malichenko, N. A., 270(22), 275(22),455 Malysheva,E.N., 127(185), 135(185),151 (185). 152(185), 154(185),208(185),212 (185). 213( 185),217(185). 218(185),25l Mamedov, R. M.. 541(20), 542 Mamedova, P. K., 541(20), 542 Manji, B. T.. 445(198), 461 Manucharova, L. A., 7(7), 8(7), 245 Mariani, B., 355(117), 356(117),412 (117), 413( 117),458 Martin, J., 30(60), 67(84), 247, 287(67), 381(67), 383(67), 456, 465(6), 502 Marvel, C. S.. 532(5), 540(5), 541 Masukawa, T., 219(256), 254 Matrick, H.,277(26), 332(26), 337(26), 379(26), 425(26), 426(26), 455 Matsuda, Y.,272(17), 455 Matsuo, T., 34(67), 43(67), 52(67), 247 Maurer, B. V.,116(152, 153), 152(153), 157(153), 170(153), 190(152), 191 (152), 208(152, 153), 219(152),250 Mauret, P., 178(226), 232(226), 233 (226). 239(226),253 Maynard, J. A., 389(162), 409(162),459, 496(54), 497(54), 498(54), 503 Mazur, 1. A., 91(118a), 92(118a), 93(118a), 97( 118a). 100( 118a). 117(118a), 118 (118a), 120(118a), 179( 118a),249 Mazzucato, V., 541(24c), 542 Medvedev, Y.V., 14(22). 17(22), 18(22), 38(22), 56(22), 60(22), 246 Mehta, S. H.,541(10), 542 Meier, E., 219(256), 254 Meier, H.,541(24b, 24c). 542 Mencke, B., 267(12). 268(12), 271(12), 299(12), 330(12), 331(12),455 Menzel, K. H.,140(198, 199, 200, 202, 203,204), 142(198, 199,202,203,204), 143(198, 199, 200, 202),157(200), 182 (2301, 190(198), 192(198,200,236), 193(200, 2361, 197(203), 202(199, 200). 207(198, 199, 230, 2401, 208(200, 242), 209(199,200, 242), 210(199,200,242), 211(202,203). 216(199,200), 217(199, 200), 219(198,199,204,230.236,240, 242, 255. 2561,252, 253, 254

555

Merchant, J. R.. 509(9), 528 Merenyi, R., 366(134), 368(134), 403 (1 34). 459 Merkel, W.,91(122), 92(122), 101(122), 161(122), 169(122), 178(122), 180(122). 197(122). 200( 122). 249 Mersch, R., 219(254), 254 Messmer, A., 225(262), 255 MethCohn, O., 29(47,49,52,56,57,59), 30(47,60), 32(47,49,52,57), 33(62, 651, 34(47,66), 35(68), 36(68), 37(57, 59.68):38(57,59,68), 40(59), 52(65, 73), 53(62,65,68), 54(59,68,76), 60 (59.62.68). 62(68), 66(56,65), 67(56, 84),73(56,59), 75(73), 76(73). 78(73), 80(57,68), 82U9.68). 88(93), 101(93), 246,247.248,264(10), 284(42,43, 46).285(42), 286(43,55), 287(43), 288(55,56,59,61,63), 289(65), 290 (43), 291(55,56,59), 292(61,63), 294 (61,651, 303(65), 315(55), 317(63), 320(63), 326(42,43), 327(43), 330(43, 65), 333(74), 345(82,83), 346(82,83), 381(42,46), 383(46,55,56.59), 384 (55,56,59). 385(63). 399(55,56,63), 414(42), 415(69), 423(58), 456,464 (l), 465(6, 7.8),466(9. lo), 467(9), 469(16, 17, 18,20),471(16, 17. 18,20, 24), 472(24), 478(20, 24). 480(9, 17), 481(20),482(16, 17), 484(41.42,43), 486(42), 487(8,41,42), 488(42), 489 (43),492(1,44, 46, 47). 496(47), 501(47),502,503,512(14. 15),513 (14), 515(14), 516(14), 519(14), 520 (14),528 Meyer, R., 25(37), 27(37), 28(37), 56(37), 246 Mignonac-Mondon, S., 140(207), 142(207), 157(207), 166(207), 170(207), 211(207), 252 Miller, G. R., 473(26), 502 Mills,K. R., 19(26), 21(26), 42(26), 43(26), 47(26). 246,260(2), 261(2), 295(2), 297 (2), 298(2), 300(2), 302(2), 307(2), 311 (2), 313(2), 314(2), 321(2), 327(2), 337 (2), 339(2), 455,472(25), 475(25), 478 (25),479(25), 481(25), 502 Minailova, 0.N., 54(75), 82(75), 247 Misra, A. L., 110(130), 113(130), 186(130), 187(130), 188(130), 209(130). 249,349 (101). 351(101), 354(101), 355(101). 388(161), 389(161), 391(101),457, 459

556

Author Index

Miyano, S., 269(19), 272(19), 273(19), 304(19), 311(19), 314(19). 336(19), 455 Miyazawa, K.,363(129), 371(140,141), 372(129,140,141), 393(129,141), 458.459 Mohan, J., 88(97,98), 90(97), 92(97,98), 96(97,98), 110(97,98), 113(97,98), 114(97,98). 145(97,98). 148(97,98), 161(98), 165(97,98), 168(97), 169 (97,98), 170(97,98), 219(247), 248. 253,349(105,106). 351(105,106). 391(105,106). 400(105,106), 458 Mohapatra, L. N., 219(247), 253 Mohrle, H.,29(54.55), 32(54). 37(54). 38(54), 247,286C52.53). 289(52), 290 (52.53). 317(52), 326(52), 327(52). 383(52), 456 Molnar, 1.. 526(26,27). 528(26,27).529 Monma, K., 541(12),542 Moody, K.,37(69), 38(69), 41(69), 56 (691,247, 289(62). 292(62), 317(62), 321(62),322(62), 338(62). 33%621, 385(62), 399(62), 456 Morgan,G.,277(27,28), 278(27,28), 280(27.28), 320(27), 329(27,28), 334(27), 337(27,28), 339(27,28). 455 Morishita, T.,113(142). 146(142), 161 (142). 190(142), 211(142),250 Morito, N., 541(12),542 Moriuchi, S., 219(256), 254 Morosawa, S.. 34(67). 43(67), 52(67), 24 7 Morozov, 1. S., 219(249), 254 Mosby, W.L.,258(1a), 261(la). 276(24), 30Y24),343(80). 429( 171). 455.457, 460 Moser, R. E., 96(114), 248 Moshkovskii, Y.S., 427(170).460 Mueller, W., 341(78), 355(115), 356(115), 362( 1 15),45 7,458 Muenz, F., 219(254), 254 Mukherjee, S. L., 101(124), 102(124), 103(124), 249,348(95), 351(95),457 Mulley. R. D.,278(36), 28i(36),456 Mullock, E.B., 67(83).248,327(69),415 (69). 456 Murobushi, K., 427(170),660 Murray, I. E. P.,94(121), lOO(121). 101 (121). 115(121), 182(121),249,348 (91),350(91), 352(91), 354(91). 390 (91),391(91), 411(91),457

Mustafa, A., 186(231), 187(231), 205 (231), 209(231), 211(231), 253 Nachinennaya, L.G.. 125(174), 152(174), 179(174), 193(174), 194(174). 206 (174). 207(174). 251 Nagarajan. K., 373(143), 374(143), 416 (143),418(143), 420(143),438(143), 443(143),459 Nagarajan, R., 90(120a), 91(120a), 100 (120a), 211(120a),249, 348(90), 350 (901,457

Naik, H. A., 26(42), 27(42). 28(42), 73 (42), 246 Nab. M. D., 29048). 32(48), 43(48), 56 (48h 246,284(45). 285(45), 286(45), 287(45). 303(45). 320(45), 381(45). 383(45), 394(45). 411(45). 456,464 (2), 465(2), 478(2), 502 Nakamura. K.,219(256), 254 Nantka-Namirski, P.,278(31,33,34,35), 280631. 33, 34, 35). 295(31, 35). 299 (31h 30401, 351, 321(33). 322(33), 456 Naqui, M. A.. 35(68), 36(68), 37(68), 38 (68),53(68), 54(68). 60(68), 62(68), 80 (68). 82(68). 247.288(61). 292(61), 294 (61).456,466(10),502 Narang, K. S., 88(95), 91(95), 108(95), 145(95), 161(95), 163(95), 169(95), 248,354(109),458 Narayanan, V. L., 116(152, 153). 152 (153). 157(153), 170(153), 190(152), 191(152), 208(152, 153), 219(152), 224(261b), 225(261b), 243(261b), 244(261b),250,255 Nay&, A., 110(135), 113(135), 186(135). 189(135). 219(135), 249 Neadle. D. J.. 33(63), 34(63), 247 Neiderhauwer, W. D.,84(90). 248 Nestler. H. J., 541(22), 542 Neugebauer, W., 341(79), 457 Noelken, E.,514(17), 528 Noguchi. A.. 541(16,17, 18).542 Noguchi. T.,197(239), 253 Noken, E., 365(132), 366(132),458 North, R. J., 126(176), I32(176). 151 (176). 154(176), 158(176), 167(176), 171(176), 178(176), 185(176), 186 (1 76), 196(176). 217(176), 218( 176), 251 Ochiai, E.,387(157).459

Author Index Ogawa, J. M.. 445(198),461 Ogura, H.,18(23), 20(23), 21(23), 39(23), 42(23), 43(23). 45(23), 47(23). 48(23), 55(23), 88(94), 89(94,107), 90(94). 91 (94), 92(107), %(94, 107). 101(94), 102 (94), 103(94), 104(94), 105(107), 108 (94, 107), 110(94), 113(94), 117(155. 156), 119(155,156). 120(156), 121(155, 156, l60), 129(155.156,160), 149(155, 156), 154(155,156), 155(94,107), 156 (94, 107). 157(94, 107). 160(107), 161 (107), 163(94). 164(107). 165(94), 167 (155), 168(94. 107), 169(94,107), 170 (155), 171(107). 173(107), 174(107), 175 (107). 183(155,160), 184(155, 156, 160). 211(160), 215(94), 219(155, 156, 160). 246,248,250,264(8), 360(127), 361 (127), 362(127), 363(127), 365(127), 366(127). 368(127), 392(127), 397(127), 403( 127), 404( 127),40% 127). 4 10(127), 4 11(127). 4 12(127), 413(127), 455, 458 Ohki, S., 7(6), 127(6). 208(6), 245,360 (125), 361(125), 365(125), 392(125), 404(125),458 Ohmiya, S., 523(24), 525(24), 528(24), 528 Ohno. A.,97(116), 113(142), 146(142), 161(142), 190(142), 211(142), 249, 250 Ohtani, J., 270(23), 275(23), 317(23). 332 (23). 455 Oka, S., 113(142). 146(142), 161(142), 190(142), 211(142), 250 Oki, R., 219(256), 254 Okumura. A., 140(101). 143(101), 252 Ollis, W.D.,114(143), 250 Ost, W.,440(199), 441(199). 445(199), 452(199). 453(199), 454(199).46Z O’Sullivan, D. G., 346(88). 347(88), 426 (167),457,459 Otornasu, H.,29(53), 32(53), 247,28S(Sl), 286(51),456, 523(24), 524(25), 525(24. 25). 527(25), 528(24,25),528 Palei, R.M.,7(11,15,16, 17, 18, 19), 10 (11, 15, 19). ll(11, 15, 16, 17), 12(11, 15. 17), 13(18, 19, 20). 16(11, 15, 16, 17, 19), 39(19), 42(15), 44(17), 45(17, 72,77), 46(17,72), 47(72), 49(72). 54 (75). 55(78), 56(72,78), 57(72), 58(72), 81(17), 82(75), 176(78), 117(78), 231 (1 I), 245,246. 247

557

Palles, C. J., 180(228), 182(228), 190(228), 217(228), 253 Palmer, L. B.,541(21). 542 Palosi. E., lOl(125). 102(125), 103(125), 163(125), 190(125), 249,348(98), 349 (98), 35 1(98), 400(98), 426(98), 457 Panda,C. S., 110(133), 113(33), 114(33), 145(133). 148(133), 165(133), 169(133), 170(133). 186(133), 187(133), 188(133), 197(133), 200(133). 219(133), 249.349 (104), 351(104), 391(104).458 Pandey, B. R., 110(136). 113(136), 114 (136), 145(136), 148(136), 186(136), 187(136), 219(136), 249 Pankina, 2. A.. 432(179), 433(179). 434 (179), 435(181,182), 436( 181), 447 (181,207). 449(179, 182,207),450 (179,182,207),451(181,182.207),

453(179, 182),454(182),460,461 Panshina, M. V., 219(250), 254 Pantic, D.. 426(167),459 Papmi,P., 355(116), 356(116), 361(116), 365(116), 366(116), 371(116), 372(116), 420(116), 458 Pardo, M. C., 234(274), 235(274), 238 (274). 255 Park, S.W.,91(122), 92(122). 101(122), 161(122), 169(122), 178(122), 180(122), 197(122), 20q122). 249 Parmar,S. S., 110(136), 113(136), 114(136), 145(136). 148(136), 186(136). 187(136). 219(136). 249 Partis, R. H.,89(108),96(108), 104(108), 105(108), 108(108). 109(108), 147 (108). 152(108), 169(108), 248 Patel. A. B., 541(9), 542 Patel, B. B.. 541(15),542 Patel. M. M.,541(14),542 Patel. N. K.,541(19, 10, 12. 14, 15), 542 Pathak, V.N.,88(99), 91(99), 92(99), 169(99), 219(99). 248 Paudler, W.W.,26(43). 27(43), 246 Payne, D. S.. 22(32), 23(32), 24(32), 27 (32). 69(32), 72(32), 73(32), 76(32), 78(32). 79(32), 88(32), 83(32), 246 Peiren, M. A., 366(134), 368(134), 403 ( 1341,459 Pelkis.P. S.,96(112), 112(151), 115(151), 127(151, 186). 136(151, 186). 145(151), 148(151), I S l ( l S l ) , 152(151). 154(151), 158(15I), 248,250,251 Peltier, D.,287(57), 456

558

Author Index

Pelz. W., 140(198,204), 142(198,204), 143(198), 190(198), 192(198),207(198), 219(198,204),252 Pepper, L., 367(137), 368(137), 370(137), 393(137), 397(137), 398(137), 41 1(137), 459 Perera, R. C.. 40(71), 52(71).69(71), 71 (71),72(71), 73(71), 76(71), 79(71), 247,284(49), 287(49), 315(49). 316 (49), 327(49), 328(49), 329(49), 330 (49), 333(49), 339(49), 341(75), 399 (49). 417(49), 420(49), 456,465(3), 484(3,40), 485(3.40), 486(40), 487 (40), 489(40), 490(3), 502,503 Peresleni, E. M.. 147(212), 152(212), 163 (212), 164(212), 169(212),252 Perroncito, G., 360(123), 361(123), 362 (123),417(123),458 . Petrov, V. l., 219(250), 254.360(121), 361(121), 362(121). 363(121), 365(121), 366(121), 387(158),459 Philip, A., 507(10), SlO(lO), 515(10),522 (lo), 528 Pietra, S.,475(34.35,36). 476(34,35,36), 477(36).478(34,35,36), 479(34,35, 36). 481(34,35), 482(34), 490(34.35), 502 Pollitt, R. J., 33(63), 34(63),247 Poludnenko. V.G., 506(3,5,6), SW(3.5, 6), 509(6),511(3),512(3),515(3),516 (3,5,6),517(3), 518(3,5.20), 519(3,5, 20), 520(6). 521(6), 528 Ponomar, V. S., 55(78), 56(78). 91(118a), 92(118a), 93(118a), 97(118a), lOO(118a). 117(118a, 158). 118(118a. 158), 120 (118a, 158), 129(158), 157(158), 176 (78), 177(78), 179(11&),247, 249,250 Popov, 1. I., 14(22). 17(22), 18(22), 38(22), 56(22), 60(22), 119(169, 170), 13q169, 170). 149(170), 246,251,366(136), 367 (136), 368(136), 371(136), 372(136), 393(136),459 Poppe, E. J.. 190(233), 219(252),253, 254 Porai-Koshits, B. A., 189(234), 190(234). 253 Porschen, H.,438(186), 439(186), 440 (186). 442(186), 444(186), 460 Postovskii, I. Y.,115(150), 178(150), 21 1 (150). 250 Poustyanoi, M. V.,91( 118a), 92( 118a). 93 ( 118a). 97( 118a). 100(118a), 117(118a). 118( 118a), 120( 118a). 179( 118a), 249

430(173,174, 175).432(173, 175, 177,178). 449(178). 454(174), 460 Powers, L. J., %(114), 248 Pozharskii. A. F., 117(157), 118(157), 120(157), 121(157). 129(157). 149 (157), 179(157), 183(157). 184(157), 193(157). 201(157), 202(157), 207 (157), 215(157),250 Poznyak,L.V., 110(131,132), 112(132). 113(131,132), 114(132), 115(132), 186(131, 132), 188(131), 189(131). 190(131,132), 205(131,132),249. 349(102), 351(102). 415(102),457 Prasad, R., 388(160), 389(160). 409 (160). 459 Preston, P. N.,34(64), 94(121), 100(121), 101(121), 110(147), 112(147), 114(147), 115(121), 178(147), 182(121), 186(147), 188(147),247,249,250,348(91), 350 (91), 352(91), 354(91), 390(91), 391 (91),411(91), 457 Price, D.,287(64). 294(64), 456 Priimenko, E. A., 91( 118a), 92( 118a), 93(118a), 97(118a). lOO(118a). 117 ( 118a). 120(118a). 179(118a),249 Procter, G.. 473(28), 474(28,30, 31). 481(28), 482(28). 502 Pueschel, W.,140(200,204), 142(204). 143(200). 157(200), 192(200), 193 (200), 202(200), 208(200). 209(200), 210(200). 216(200), 217(200), 219 (204). 252 Puetter, R., 140(203), 142(203), 182(230), 197(203), 207(230). 211(203), 219 (230). 252,253 Pugin, S., 341(77),457 Pujari,H.K..88(%, 97.98,101), 90(97, 101). 92(96,97.98). 93(101), %(96, 97,98), 97( 101). 98( 101). 110(97,98, 101, 133). 113(97,98, 101, 133). 114 (97,98,133), 145(97,98,101, 1331, 148(97,98,101, 133). 161(96,98), 165(97,98,133), 168(97), 169(96,97, 98,133), 170(97,98,133), 186(101. 133), 187(101, 1331, 188(101, 1331, 197(101,133), 200(101,133), 217 (101). 219(101,133,247),248,249, 253,349(104,105,106), 351(104, 105,106), 391(104,105,106), 400 (105, 1061,458 Purnaprajna, V., 26(42), 27(42). 28(42), 73(42), 246

Author I n d e x Rae, I. D., 389( 162), 409( 162), 459,496 (54), 497(54), 498(54), 503 Ramsden,C. A., 114(143).250,268(18), 272(18), 295(18), 299(18), 305(18), 321(18), 322(18),455 Rash, D., 389(162), 409(162),459, 496(54), 497(54), 498(54), 503 Rasp, C., 23(36), 25(36), 27(36), 82(36), 246 Reid, W., 493(51), 495(5 l), 497(5 l),

503

Reimlinger, H.. 366(134), 368(134), 385 (156), 386(156), 396(156), 403(134), 459 Reppe, W., 22(35), 25(35), 246 Reynolds, G. A., 225(265), 226(265). 227(265), 232(265). 255,355(112), 356( 11 2), 458 Ribeiro, V. L.T.,141(208), 143(208). 152(208), 166(208), 170(208), 208 (208), 252 Richardson, A., 506(1), 507(1, l l ) , 508 (l), 509(1), 5 1 l(1, 11). 514( 1, 1 l), 5 15( I), 517(1), 518( l), 528 Ridi,M., 355(116), 356(116), 360(124), 361(116,124), 362(124), 363(124), 365(116,124), 366(116, 124). 368 (124), 371(116), 372(116), 420(116), 458 Ried, W., 3(2), 5(2,4,5), 6(2,4, 5 ) , 7(10), 8(7), 38(2,5), 40(2,4,5), 4U2.10). 42(10), 45(2), 53(2), 63(2), 73(2), 78 (2), 82(2), 91(122), 92(122). lOl(122). 161(122), 169(122), 178(122), 180(122), 197(122), 200(122), 245,249,355(1IS), 356(115), 362(115),458 Riesch, G., 541(22), 542 Rist, H., 285(50), 286(50), 303(50), 326 (SO), 327(50), 456 Robert, R., 25(38), 26(38), 27(38), 28(38), 29(38), 38(38), 40(38), 41(38), 43(38), 53(38), 54(38), 82(38), 246 Roechling, A., 438(190), 444(190), 448 (190), 454(190),460 Roechling, H.,444(191,992,193, 194), 454(191,192,193,194,209),460,461 Rogerson. L. G.,40(71), 52(71),69(71), 71(71), 72(71), 73(71). 76(71), 79(71), 247,284(49), 287(49), 315(49), 316 (49), 327(49), 328(49), 329(49), 330 (49), 333(49), 334(49), 339(49), 399(49), 417(49), 420(49). 456.484(40), 485(40). 487(40), 489(40). 503

559

Rokach, J., 346(87), 347(87), 390(87), 399(87), 457 R0man.A. B., 110(134), 113(134), 145 (134), 148(134), 152(134), 186(134), 187(134), 188(134), 189(134), 190 (134),205(134),249 R o d , A., 126(178), 132(178),251 Roueche, A., 329(71), 341(71),457 Rowbottom, K. T., 329(72), 333(72), 45 7 Rozhkova, N. K., 348(92), 350(92), 352 (107), 391(92), 395(92),457,458 Rudner, B., 140(196), 252,336(73),457 Rull, P., 230(272), 231(272), 232(273), 233(273), 234(273), 235(272), 238 (273). 239(273), 240(272), 241(272), 242(272, 273), 243(272), 244(272), 255 Sachse, B., 454(209), 461 Sadykh-Zade, S. I., 541(20), 542 Saggers, D. T., 532(2), 541 Sakamoto, M., 363(129), 371(140, 141), 372(129,140, 141),393(129,141), 458,459 Salvador, R., 514(17),528 Samoilenko. L. V., 91(118b), 92( 1 Mb), 93(118b), 97(118b), 100(118b), 179 (1 18b), 249 Sandstrom, J., 166(223), 170(223),

253

Sasaki,M., 541(16, 17, 18),542 Sato, A., 157(219), 183(219), 192(219), 193(219), 219(219).252 Sato, S., 29(53), 32(53), 247, 285(51), 286(51).456,523(24), 525(24), 528 (24), 528 Sauertag. W., 219(256), 254 Saunders, K. H., 277(29), 278(29), 280 (29),286(29), 287(29), 291(29), 321 (29), 322(29), 324(29), 326(29), 327 (29),328(29), 329(29), 330(29), 332 (29), 333(29), 337(29), 338(29), 339 (29),383(29), 384(29), 388(29), 389 (29), 412(29), 417(29),455,468(11), 482(11),484(11), 485(11),502 Savranskii, L. I., 57(80), 247 Sayag, D. R., 454(205),461 Schaefer, H., 268(13), 271(13), 314(13),455 Schauer, P., 219(246), 253 Schaum, G.,219(255), 254 Schefczik, E., 325(68), 456 Scheinpflug, H.. 441(202), 445(202), 448 (202). 454(202), 461

560

Author Index

Schellenberger, H.,140(204), 142(204), 219(204), 252 Schlaepfer, H..436( 183). 439(183), 442 (1831,460 Schleigh. W. R., 84(89), 248 Schmid, L., 279(39), 282(39), 321(39), 324( 39), 456 Schmidt, A. H.,5 ( 5 ) , 6(5), 38(5), 40(5), 245 Schmidt, M. P.,341(79),457 Schmitt,K., 267(12), 268(12), 271(12), 299(12), 330(12), 331(12),455 Schmutz, W.. 22(34), 21(34), 246,377 (149), 379(149), 388(149). 389(149). 398(149),411(149),414(149),418

(149). 425(149), 426(149).459 Scholl. H.J., 127(187), 136(187), 207 (240). 219(240,248),251,253 Schrepfer. H.J., 438(186, 189), 439(186), 440(186), 442(186, 189), 444(186), 460 Schroeder, L.,440(199),441(199), 445 (199),452(199), 453(199),454(199). 461 Schubert. H., 137(188), 139(188,194), 14q188.194). 152(194). 171(188), 209(188),251,252,378(151), 380 (151),395(151), 420(151),459 Schuckmann. W.. 91(122), 92(122). 101 (122). 161(122), 169(122), 178(122), 180(122), 197(122), 200(122), 249 Schulze. W.. 499(56). SOl(56). 503 Schwerdtk, F.. 454(209), 461 Searby, R.. 67(83), 248,327(69), 415(69), 456 Seitanidi, K.L., 348(92), 350(92), 391 (92), 395(92). 457 Semerano, G.,541(24c),542 Serafin, B., 378(152). 381(152). 395(152). 459 Seshadri. S., 26(42), 27(42), 28(42). 73 (42). 246 Sgarbi, R., 438(188),442(188),452(188), 453(188). 460 Shah, R. K., 541(15),452 Sharma, K . S., 88(96), 92(96), 96(%), 161(%), 169(96). 219(247), 248, 253, 349(106), 351(106). 391(106), 400(106), 458 Shazhenov, A. A., 370(139), 371(139). 372(139), 393(139),406(139), 408 (139). 411(139), 459 Shchukina,M. N., 137(189.190, 191,192,

193), 138(189,190,191, 192,193), 152(192,193.215,216), 154(192. 193,215). 158(190,191,192,193, 215,221), 159(192,193,215.221), 168(192.193,224), 171(224). 178 (215,224). 179(224), 182(190. 191), 197(192,193,215,216,221,224),

198(192.193.215,216), 199(215, 221). 202(192,221), 204(192,215). 205(192.215), 206(193,221).207 (192,193,216,221). 208(193.216), 209(215,216), 211(190.191). 212 (221). 215(221), 216(193.224),251, 252, 253, 432(179), 433(179), 434 (179). 435(181, 182), 436(181). 447 (181, 182, 207), 449(179, 182, 207). 450(179.182,207),451(181, 182,207). 453(179, 182),454(182),460,461 Sheinker,Y.N.,7(17), 11(17), 12(17), 16(17). 44(17). 45(17,77). 46(17), 55 (78). 56(77,78), 57(77). 58(77), 59 (77), 81(17), 147(212), 152(212), 160 (222). 161(222). 163(212), 164(212), 168(222,224), 169(212.222), 171 (224,223, 173(225), 176(78), 177(78), 178(224), 179(222.224), 182(222,224), 197(224),216(224), 246,247,252,253, 435(182), 447(182), 449(182). 450(182), 451(182), 453(182), 454(182), 460 Shen, K. K.W., 381(154), 383(154,155). 384(154.155), 417(154), 423(154), 426(154,155),459 Shiba, K., 157(219), 183(219). 192(219). 193(219),219(219,256), 252,254 Shih, B. J., 112(145). 114(145), 115(145), 148(145), 156(145),250 Shikarev, A. V.,430(174), 454(174), 460 Shimada, Y.. 88(94), 89(94). 90(94), 91 (94).%(94), 101(94), 102(94), 103 (94),104(94), 10804). llO(94). 113 (94),155(94), 156(94), 157(94), 163 (94). 165(94), 168(94), 169(94), 215 (94). 248 Shin, B. J., 348(93), 350(93), 391(93), 395(93), 400(93), 401(93), 457 Shiokawa, Y.,7(6), 127(6), 208(6), 245, 360(125), 361(125), 365(125). 392(125), 404(125). 458, 499(55), 501(55), 503 Shishido, T.,219(256), 254 Shivanyuk, A. F., 112(151), 115(151), 127 (151, 186). 136(151), 145(151), 148(151), lSl(lSl), 152(151), 154(151), 158(151), 250,251

Author Index Shub, N. K., 179(227). 183(227), 184(227), 202(227), 203(227), 206(227), 207(227), 208(227), 209(227), 212(227), 214(227). 253 Shuedov, V. I.. 375( 146), 376(146), 459, 526(31), 529 Shutkova, E. A.. 189(234). 190(234), 253 Simonov, A.M., 14(22), 17(22), 18(22), 38(22), 56(22), 60(22), 117(157), 118 (157), 119(162b), 165,166,169, 170. 171), 120(157,162a, 163.164), 121 (157, 162a. 162b, 163), 123(171,172. 173), 125(174, 175), 126(180), 127(185), 129(157,162a, 162b. 166), 130(166, 169, 170, 171), 131(171, 172. 173), 132(171, 173, 175,180), 135(185), 149(157,164, 166,170,173,175,213), 150(163,164, 165, 171,172,173,214). 151(173, 180, 185), 152(163,164,165.166.171,172, 173, 174,175, 180,185,214), 154(166, 185), 157(165), 158(164,214), 167(166, 171,180), 170(166,171), 171(180). 179 (157,163,174,227),181(163), 183(157, 162a, 163, 165,166), 184(157,162a, 165). 185(166). 186(166), 193f157.164 165, 171,172,173,174.175,214,238). 194(164, 165. 171, 172. 173, 174, 175, 214). 195(164, 165. 175, 180, 214), 196 (180). 197(165,175,180,214), 201(157, 162, 163, 164, 166,180).202(157,175, 180), 203(163,175), 204(163.175,214), 206(174), 207(157,174), 208(162a, 164, 165, 171,172,173,180,185), 209(162a, 1651, 210(162a, 165). 211(166), 212 (162a, 162b. 163, 165, 185, 214), 213 (164, 185,214), 214(165,214), 215(157. 164,165,166,180), 216(165,166,243), 217(166,185), 218(166, 185),219(162a, 162b, 164,214,250),246,250.251,252. 253, 254,356(118), 357(118), 359(118), 366(136), 367(136), 368(136), 371(136), 372(136), 393(136),459,506(3,5,6), 508(3,5,6), 509(6), 511(3). 512(3), 515 (3), 516(3,5,6), 517(3), 518(3,5,20), 519(3,5,20), 520(6), 521(6),528 Simonsen,S. H.. 482(39), 503 Singh, H.,88(95), 91(95), 108(95), 145 (95),161(95), 163(95), 169(95),248, 348(89), 350(89), 354(109), 457.458, 492(45), 503 Singh, J. M., 113(139), 189(235), 190(135), 205(235), 211(139), 216(235), 219(139, 235), 249,253 Singh, M.,88(95), 91(95), 108(95), 145

56 1

(95). 161(95), 163(95), 169(95), 248, 354(109), 458 Singh, S., 88(95). 91(95). 108(95), 110(136), 113(136), 114(136), 145(95,136), 148 (136). 161(136), 163(95), 169(95), 186 (136). 187(136), 219(136), 248,249,348 (89). 350(89), 354(109),457.458.492 (45). 503 Slouka, J.,434(180),435(180),436(180), 446(206), 449(206), 451(206), 453(206, 208). 460,461 Smalley, R. K., 29(57), 32(57), 37(57), 38 (57), 40(71), 52(71), 69(71), 71(71), 72 (71), 73(71), 76(71), 79(71), 80(57), 247, 284(49). 287(49), 288(59), 291 (59), 315(49), 316(49), 327(49), 328 (49),329(49), 330(49), 333(49), 339 (49), 341(75), 383(59), 384(59), 399 (49). 417(49), 420(49), 456,457,465 (3,7), 484(3,40), 485(3,40). 487(40), 489(40), 490(3), 502,503 Smith, R. H.,468(13),482(13),502 Smolanka, I. V.,140(197). 229(271),252, 255 Sohngen, B., 219(254), 254 Soloveva. 1. A., 157(218), 219(253). 252. 254 Somasekhara, S., 101(124), 102(124), 103 (124),249,348(95). 351(95).457 Sorokina, 1. K., 375(147), 376(147), 418 ( 147), 425( 147), 426(147). 459 Spiegel, L., 284(44a), 287(44a), 291(44a), 327(44a),456 Stanek, J., 26(40), 27(40), 28(40), 246 Stanovnik, B., 102(126), 219(246), 224 (260), 234(260). 249,253,255 Stepanova,T. N.. 103(128), 108(128), 145(128), 147(128), 189(128), 190 (128),216(128),249 Stephen, H.W., 110(140), 113(140), 211 (140). 249 Stephenson, L., 278(32), 280(32), 281 (32), 28332). 295(32), 299(32), 303 (32). 304(32), 321(32), 324(32), 336 (32), 337(32), 339(32), 456 Stewart, J., 277(27,28), 278(27,28), 280 (27,28),320(27). 329(27,28), 334(27), 337(27,28). 339(27,28),455 Stubbs, J. K., 180(229), 182(229),253 Sturmer, D.M., 541(24a),542 Sturtz, C., 94(113), 96(113), 248 Suerbaev, K. A., 22(30), 24(30), 52(30), 56(30), 84(30), 246 Suetaka, W., 541(12), 542

562

Author Index

Sugita, H., 219(256),254 Sumoto, K., 269(19), 272(19), 273(19),

304(19). 311(19), 314(19), 336(19), 455 Sus, O.,341(79), 457 Suschitzky, H., 29(47,49,50,51,57). 30 (47,60),32(47,49,50,51,57).33(61, 62), 34(47,66), 37(57), 38(57), 52(73), 53(62), 60(62), 67(83.84), 69(51), 75 (73). 76(51,73), 78(73), 7%51),80(57), 246.247,284(42,44b,46,47,48), 285 (42,46),286(44b,46,54,55,58),287 (44b,47,54,58,64,67). 288(54,55,59). 289(58,65), 290(54), 291(44b,55.58, 59), 294(67), 315(55), 317(58), 326(42), 327(69), 330(48,65), 333(48,74). 336 (58), 338(58), 339(48,58). 381(42,46, 47,48,67),383(46,48,55,58,59,67), 384(58), 388(58), 389(58), 394(47), 399 (55), 414(42), 415(69), 417(48), 423(58), 456,464(1).465(4.5,6, 7.8), 468( 12, 13),469(16, 17,18,19),471(16, 17,18, 19), 480(17), 482(13,16,17),483(19), 484(41, 42,43), 485(4), 486(42), 487 (8,41,42),488(42), 489(4, 43), 492 (1,46,47),496(47), 499(46, 47), 501 (47), 502,503,509(7), 512(14, 15, 16), 513(14, 16),515(14,16),516(14),519 (14). 520(14), 528 Sutton, M . E., 33(61), 34(61), 247,284 (44b), 286(44b,54),287(44b,541,288 (54),290(54), 291(44b), 456,509(7), 528 Suvorova,G. M., 119(171), 120(171), 123 (171). 127(185), 130(171), 131(171), 132(17I), 1 35( 185), 1 SO( 17l), 15 1( 185). 152(171,185), 154(185), 167(171), 170 (171),193(171), 194(171), 208(171, 185), 212(185), 213(185), 217(185), 218 (185),251 Swan, J. M., 389(162),409(162),459, 496(54), 497(54), 498(54), 503 Sycheva, T. P., 168(224), 171(224), 178 (224),179(224), 182(224), 197(224), 216(224), 253 Syrova,G. P., 168(224), 171(224), 178 (224),179(224), 182(224), 197(224), 216(224), 253 Szporny, L.. 101(125), 102(125), 103(125). 163(125), 190(125), 249, 348(98), 349 (98). 35 1(98), 400(98), 426(98), 457 Takabe, K., 21%256),254

Takagi, H., 117(155), 119(155), 121

(155,160), 129(155,160),149(155), 154(155), 167(155), 170(155), 183 (155,160), 184(155,160), 211(160), 219(155,160), 250 Takahashi, H., 29(53), 32(53), 247,285 (Sl), 286(51), 456,523(24),524(25), 525(24,25), 527(25), 528(24,25),528 Takahashi, S., 469(21), 502 Takai, Y.,219(256),254 Takayanagi, H.,117(155), 119(155), 121 (155,150),129(155,160), 149(155). 154(155), 167(155),170(155), 183(155, 160),184(155,160),211(160), 219 (155,160).250 Takeda, K., 269(19), 272(19), 273(19), 304(19), 311(19), 314(19), 336(19), 455 Tamura, Y., 117(154), 166(154), 170 (154),250 Tantawy, A,, 439(184), 442(184),460 Tatevosyan, G.T.. 7(7,8), 8(7,8), 245 Taurins, A., 88(103), 89(103, 108). 90 (103),91(103), 96(103, 108). 97(103), 98(103), 103(103), 104(103,108), 105 (103.108), 108(103, 1081,109(103, 108),145(103), 146(103), 147(103,108), 148(103), 152(103,108), 155(103), 156 (103),157(103). 169(103, 1081,182 (103).186(103), 187( 1031, 190(103). 215(103), 216(103), 248 Taylor, G . A., 346(85), 347(85), 457 Tennant, C., 34(64), 247 Tenor, E.,421(166), 427(166),459 Teplyakov, M.M.,532(6), 541 Terent’ev,A.P.,507(12).511(12),515 ( 121,528 Tertov, B. A., 127(185), 135(185), 151 (185),152(185), 154(185),208(185), 212(185), 213(185), 217(185), 218 (185). 251 Thomann, R.,438(195), 444(195), 449 (195),450(195),461 Thomas, K.,440(199), 441(199), 445 (199),452(199),453(199). 454(199), 461 Thompson, M. J., 37(69), 38(69), 41(69), 56(69), 247,289(62), 292(62), 317(62), 321(62), 322(62), 338(62), 339(62), 385(62), 399(62). 456 Tinker, J. F., 355(112), 356(112),458 Tkler, M., 102(126), 219(246), 224(260), 234(260), 249,253,255

Author Index Tiwari, S. S., 388(161), 389(161),459 Tkachenko, A. A., 91(118a), 92(11&), 93 ( 1Ma), 97( 118a), loo( 118a), 117(11la), 118(118a). 120(118a), 179(118a), 249 Tkachenko, P.V., 14(22), 17(22), 18(22), 38(22), 56(22), 60(22), 119(169, 170). 130(169,170), 149(170),246,251,366 (136), 367(136), 368(136), 371(136), 372(136), 393(136),459 Tobe, H., 541(12),542 Todd, A. R., 90(110), 96(110),248 Toeplitz, B., 224(261a), 225(261a), 243 (26 la), 244(26 la), 255 Tomimatsu, Y.,363(129), 371(140,141), 372(129, 140, 141), 393(129,141), 458,459 Tominaga, Y.,272(17),455 Topsom, R. D.,514(18), 515(18),528 Trabanelli. G., 541(11),542 Trevisan, L.,86(91,92), 87(91,92), 144 (91,92), 145(91,92), 158(91.92), 159 (91,92), 207(91), 217(91,92),248 Troitskaya, V. S., 103(128), 108(128), 145(128), 147(128), 189(128). 190 (128), 216(128), 249 Trotter, B. P., 359(120), 360(120), 361 (120). 362(120), 363(120), 365(120), 366(120), 368(120), 369(120), 370 (120), 392(120). 393(120), 396(120), 397(120), 398(120), 401(120), 402 (120), 403(120), 404(120), 405(120), 406(120), 408(120), 412(120), 418 (120), 419( 120). 420( 120), 421(120), 458 Troxler, F., 126(181), 132(181), 151(181), 152(181),251,366(135), 368(135), 371 (135), 392(135), 393(135), 397(135), 403(135), 406(135), 407(135), 411(163), 4 13(135),418( 135). 4 19(135), 420(135), 421(135), 422(135), 424(135), 426(135), 459 Tsujimoto,Y.,541(16, 17, 18),542 Tuan, J. Y.,112(145), 114(145), 115(145), 148(145), 156(145),250,348(93), 350 (93), 391(93), 395(93), 400(93). 401 (931,457 Tully, W. R., 19(27), 21(27),42(27), 43 (27). 47(27), 48(27), 246,260(5), 261 (5),298(5), 301(5), 302(5), 313(5), 320(5), 455,474(33), 475(33), 479(33), 480(33), 481(33), 502 Turkevich,N.M., 111(149), 114(146,149), 157(149), 208(146, 149), 219(149),250

563

Twibell, J . D., 127(183), 134(183), 135 (183). 251 Twine, C. E., 507(10), 510(10), 515(10), 5 22( lo), 528 Tyutenkov, I. N., 219(250),254 Tyurenkova,G. N., 225(268), 226(268), 227(268), 255 Ulrich, H., 219(256), 254 Ulyanova, T. N., 160(222), 161(222), 168 (222, 224). 169(222), 171(224), 178 (224), 179(222,224), 182(222,224). 197(224), 216(224), 253 Usui, T., 219(256), 254 Vais, A. L., 140(197), 252 van Allan, J. A., 110(138), 113(138), 115 138), 186(138), 187(138), 208( 138), 211(138), 225(264,265), 226(264,265), 227(264,265), 232(265), 244(264), 249,255,355(112), 356(112),458 Van Den Berk, J. B., 345(81), 346(81), 45 7 Van Der Au, M. J. M. C., 345(81), 346(81), 45 7 Van Domael, A., 357(119), 359(119), 360(119,122), 361(119.122), 362 (122). 363(119, 122), 365(119. 1221, 458 Van Heertum, A. A. M. T.. 345(81), 346 (811,457 Van Mierlo, G. C., 29(58), 32(58), 33(58), 60(58), 62(58), 63(58), 67(58), 69(58), 71(58), 72(58). 73(58), 76(58), 78(58), 79(58), 82(59),83(58), 84(58), 247, 286(60), 287(60), 288(60), 291(60), 317(60), 321(60), 322(60). 323(60), 327(60), 328(60), 329(60), 333(60), 334(60), 338(60), 339(60), 341(60), 383(60), 384(60), 412(60), 417(60), 420(60). 423(60), 426(60), 427(60). 456 Venugopalan, B., 90(12Ob), 91(120b), loo( 120b), 2 1I( 120b).249 Verlander,M. S., 19(25,28,29), 21(25, 28,29), 39(25.29), 43(25,29).48(25, 28.29). 246,260(4), 261(4,6), 262 (6). 264(6), 294(6), 297(6), 298(6), 300(6), 301(6), 302(4,6), 309(6), 311 (4,6), 313(4), 314(6), 320(6), 455, 473(27), 474(32), 475(32), 478(32), 479(32), 480(32). 481(32), 482(32), 502

564

Author Index

Vertut, M. C., 178(226), 232(226), 233

(226),239(226), 253 Vincent, E. J., 232(273), 233(273), 234 (273),238(273), 239(273),242(273), 255 Volna, F., 111(148), 112(148), llql48), 115(148). 208( 1481,250 Volovenko, Y. M., 268(16), 271(16), 305 (16), 321(16). 322(16).455 Vora, J. C.,541(9), 542 Vuitel, L., 326(70), 341(77), 456,457 Waddington, H. R. J., 219(251),254 Wahl, O.,140(198. 199), 142(198, 199).

143(198,199), 190(198), 192(198), 202 (199), 207(198, 199). 209(199), 210 (199), 216(199), 217099). 219(198, 199). 252 Wallis, A. K., 346(88), 347(88). 426( 167). 457.459 Warburton, W. K., 278(32), 280(32), 281

(32), 282(32), 295(32), 299(32), 303 (32),304(32). 321(32). 324(32), 336 (32),337(32), 339(32), 456 Watanabe, Y., 126(179), 132(179), 251 Watkin, J. D.,260(3), 261(3), 297(3), 311(3), 314(3),455 Weber, H. P., 126(181), 132(181), 151 (181), 152(181),251,366(135), 368 (135). 371(135), 392(135), 393(135), 397(135), 403(135), 406(135), 407(135), 411(163), 413(135), 418(135), 419(135), 420(135), 421(135), 422(135), 424(135), 426(135),459 Webrter, F.G..416(165). 459 Wei.P. H.L.. 88(102), 89(102, 109), 94 (102). 96(102,109). 105(102,109), 106 (102,109). 108(102,109), 1@(102), 1 1 1 (141), 113(141). 114(141), 152(102, 109), 169(102, 109). 211(141), 217(102), 219(109, 141), 248, 249,349(108), 352 (108). 391(108), 458 Weisel,K. H., 360(126). 361(126,128a). 363(126,128a), 392(126), 458 Weissberger. A., 258(1a), 261(1a).455 Werbel, L.M., 120(167), 129(167),251, 355(111), 356(111), 360(111), 362(111). 365(11 l), 392(1 ll), 401(111), 402(111). 404(111), 420(111), 421(111). 424(111), 426(111), 458, 506(4), 507(4), 508(4), 510(4), 511(4), 517(4). 518(4), 528 Werchan, H. G., 440(200), 445(200), 461

West, D. E., 381(153). 383(153).459 Westphal, K., 88(104), 90(104), 96(104),

248

White, A. C.. 126(177), 132(177), 219

(177).251

White, E. R., 445(198,203),454(203).

461

Williams, R. L., 3(3), 5(3), 84(3), 245 Willis, R. C., 84(89), 248 Wi1son.F. I., 110(140), 113(140), 211

(140),249

Wirth, W., 192(236), 193(236). 219(236),

253

Wolf, R.. 348(94), 350(94), 457 Wolfbeis, 0. S., 326(70), 456 WOlfNm, G.,182(230), 207(230), 219

(230). 253

W0lin.M. S., 221(257). 222(257,258),

223(258), 230(258), 234(258), 242 (258),254,255 Wollrab, V.. 26(40), 27(40), 28(40), 246 Wong, C. K., 127(184), 135(184), 151 (184), 251 Wunderlich. H.,207(240), 219(240), 253 Wunsche, C., 269(20), 273(20), 275(20), 294(20), 297(20), 307(20). 455 Yagupolskii. L. M., 270(22), 275(22), 455 Yakubovskii, E. A., 432(177.178),449

(1781,460

Yamada, N., 207(240), 219(240.256),

253,254

Yamamoto, K., 371(141), 372(140.141),

393(141),459 Yamamuro,T.,541(16,17,18).542 Yamazaki, Y., 117(155), 119(155), 121 (155, 160),129(155, l60), 149(155), 154(155), 167(155), 170(155), 183(155, 160),184(155,160), 211(160), 219(155, 1601,250 Yanai. M., 387(157), 459 Yates, A. W., 180(228), 182(228), 190 (2281,217(228), 253 Yokoo, A., 34(67), 43(67), 52(67), 247 Yonezawa, S.. 117(155), 119(155), 121 (155), 129(155), 149(155), 154(155), 167(155). 170(155), 183(155), 184 (155), 219(155), 250 Yoshida, K., 523(24), 524(25). 525(24, 251, 527(25), 528(24, Z), 528, 529

565 Yoshida, M., 140(201), 143(201), 252 Yurchenko, M. I., 91(118a), 92(118a), 93 ( 118a). 97( 118a), loo( 118a), 117(118ah 118(1Ma), 120( 118a). 179(118a). 249 Zarn0ra.M. L.,120(167), 129(167),251, 506(4), 507(4), 508(4), 510(4), 511(4). 5 17(4), 5 18(4),528 Zavadskaya, M. 1.. 1451211). 152(211), 157 (211). 186(232), 190(232), 205(21l), 219(232),252,253 Zavyalova, L.V., 348(92), 350(92), 391 (92),395(92). 457 Zeiger, A. V.,429(172b), 430(172b), 449 (172b1.460

Zeiler, A. G.,26(43), 27(43), 246 Zhdanova,M. P.,356(118), 357(118), 359(118),458 Zhuravlev, S.V., 103(128), 108(128), 145(128), 147(128), 189(128), 190 (128), 216(128), 249 Ziegler. E.,348(94), 350(94), 365( 132), 366(132),457,458,514(17),528

Zigeuner, G.,375(145), 459 Zoorob, H. H., 26(44), 28(44), 246 Zucchi, F., 541(1 l),542 Zugravescu, I., 18(24), 20(24), 26(24),29 (45). 39(24,45). 40(45), 47(24), 54 (45),246,264(9), 455 Zvezdina, E. A., 356(118), 357(118), 359 ( 118). 458


Subject Index [ 1,31 Diazepino[1,2Q1benzimidazoles. miticidal and fungicidal activity, 493 [ 1,4] Diazepino[1.2-01 benzimidazoles, synthesis, 493 [ 1,2] DiazocinoI 1,8~]benzimidazoles,493 Diethyl thiazolo[ 3 . 2 ~ 1benzimidazole1,2dicarboxylate. 100 3,4-Dihydro-W-[ 1.31 Oxazino[ 3 , 2 ~ ] benzimidazole, ring systems, 341 2,3-Dihydro-oxazolo[3,2v 1 benzimidazole, ring system, 84 2.3-Dihydro-lH-pyrrolo[ 1,2Q]benzimidazole, ring system, 3 ] 3 p-Dihydro[ 1,4 1 thiazino[ 4 , 3 ~benzimidazole, ring system, 341 lO,l(b-Dihydro[ 1,4] thiazino[4,3u] benzimidazole,ring system, 341 2,3-Dihydrothiazolo[3,2a] benzimidazole, ring system, 84

Axpino[ 1,2u]benzimidazole(s):

2-azido-7,8,9,lO-tetrahydrodH-

derivatives, thermolysis, 489 6cyano derivatives: synthesis, 474 tautomerism, 477 N-oxide derivatives, 484,489

7,8,9,10-tetrahydrodHderivatives, quaternary .salts,482

mass spectra, 482 nitration, 484 N M R spectra 481 NMR spectra (' H),480 reactions: with electrophiles, 484 with nucleophiles, 484 spectroscopic properties, 417 synthesis, 464 6H- and 1OH- tautomers, 468 Azepino[ 1 , 21~benzimidazolium salts, ultraviolet spectra of, 478

(*a,

-

Fungicides, benzimidazole derivatives,as, 531

Benzimidazole: 2-aminomethyl derivatives, 493 azo derivative, as dyestuff, 541 2-benzyl derivatives, reaction with DMAD, 473 2-benzyl-1-methyl derivatives, reaction with DMAD, 474 2carbamate derivatives, commercialuse, 531 commercial applications, 531 2-cyanomethyl derivatives, reaction with DMAD, 474 1.2dimethyl derivatives, reaction with D U D , 472 lethyl, reaction with DMAD, 472 2-methyl derivatives, reaction with DMAD,473 vinyl derivatives, polymerisation, 5 32

Imidazo [4,4,1-jk ] benzazepines: oxidation, 519 synthesis, 5 12 Imidazo[4,5,lkl] [ 11benzazocines, 5 15 lmidazo[ 1,2ia]benzimidazole(s): 3-bromo derivatives, synthesis, 201 2,3dihydro-2,3-bis imino derivatives, synthesis, 136 2,3dihydro derivatives, bromination, 201 N(l),/V(9)dimethyl. quaternary salts, 183 mas spectra, 176 N(l)-methyl, methylation, 183 N(9)methyl. methylation, 183 9-methyl-3-Ntro. alkylation, 183 synthesis, 117 C( 3)-unsubstitutcd derivatives, bromination, 201 lH-Imidazoll.2-uI benzimidazole(s): ._ N(l)aikyl:2;3dihydro derivatives, synthesis, 183 l-benzyl, NMR spectrum(' H), 171 biological activity, 219 2.3dihydro derivatives: hydrobromides, 179 hydrochlorides. 179

Cyclobu~4J]pynolo[l,2u]benzimidazole:

NMR spectrum("C), 473 synthesis, 473

[ 1.21 Diaze.pino[ 1 . 7 ~ benzimidazoles: 1 spectral properties, 496 synthesis, 492

567

568

Subject Index

I H-Zmi&zo/l,2aJbenzimidazole(s) (Cont 'd) ionization constants, 178 picrates, 179 synthesis, 132 ultraviolet spectra, 158 N(l),Zdimethyl, synthesis, 183 electrophilic substitution, 179 hydrobromides. 179 hydrochlorides, 179 m.o. studies, 179 pinates. 179 ring system, 84 N( 1)-substituted 2-alkyl derivatives, synthesis, 129 N( 1)-substituted 2-aryl derivatives, synthesis, 129 N( 1)-substituted 2Jdihydro derivatives, synthesis, 133 synthesis, 117 tautomerism, 178 1(4)H-Imidazo[1,2u]benzimidazolc, NMR spectra H), 170 1(9)H-Imidazo[ 1,2u] benzimidazole: 3acyl derivatives, ultraviolet spectra, 158 alkenyl derivatives, ultraviolet spectra, 158 alkylderi~tives,ultravioletspectra.ll7.157 2-aryl derivatives, alkylation, 183 cyanine dyes from, ultraviolet spectra, 158 2.3dihydro derivatives: alkylation, 154,183 infrared spectra, 154 infrared spectra, 154 2-methy1, methylation, 183 phenyl derivatives, ultraviolet spectra, 157 styryl derivatives, ultraviolet spectra, 157 transition metal complexes, ultraviolet spectra, 158 N-unsubstituted derivatives, infrared spectra, 153 4H-Imidazo[ 1,2* j benzimidazoles(s): acylation, 186 biological activity, 219 N(rl)-methyl derivatives, NMR spectra ('HI, 170 4H-Imidazo[ 1,h] benzimidazole(s): acetylation, 197 1-acetyl derivatives, synthesis, 197 3-acetyl derivatives, synthesis, 197 acyl derivatives, ultraviolet spectra, 158 alkyl derivatives, ultraviolet spectra, 158 aminoalkylation, 197 aminoalkyl derivatives, synthesis, 197 1-arylazoderivatives, synthesis, 207

3arylazo derivatives, synthesis, 207 aryl derivatives, ultraviolet spectra, 158 basicity, 182 bromination, 202 l-bromo derivatives, synthesis, 202 3-brOmO derivatives, synthesis, 202 l-bromo4-methyl-3-phenyl, nitrodebromination, 212 carbonyl derivatives, infrared spectra, 154 lerboxaldehyde derivatives,synthesis,197 3-carboxaldehydes,synthesis, 197 carboxaldoximes, dehydration, 207 cyano derivatives: conversion into thioamides, 209 infrared spectra, 154 synthesis, 207 cyanoethylation. 197 diazonium coupling, 207 2.3dihydro derivatives. synthesis, 135 3.4dimethy1, ionization constants, 178 electrophilic substitution, 179 formylation, 197 hydrochlorides: alkylation, 182 m.o. studies, 182 hydrolysis, 208 1hydroxymethylderivatives.synthesis.197 ionization constants, 178 I-mercapto, synthesis, 137 4-methyl, NMR spectrum ( I H), 171 4-methyl-3-phenyl,ionization~,178 Mannich reactions, 197 m.o. studies, 179, 182 nitro derivatives, ultraviolet spectra, 158 l-nitro4-methyl-3-phenyl. synthesis, 21 2 nitrosation, 204 nitroso derivatives, ultraviolet spectra, 158 l-nitroso derivatives, synthesis, 204 3-nitroso derivativcs, synthesis, 204 NMR spectrum ('H),171 oxidation, 216 picrates, 182 protonation, 182 reactions with formaldehyde, 197 N(1)substituted 2,3dihydro derivatives, infrared spectra, 154 synthesis, 137 thiomides, synthesis, 209 ultraviolet spectra, 158 Vilsmeier-Haack reactions, 197 9H-Imidazo[1.2aI benzimidazole(e): 2-acetyl. synthesis, 193 3acety1, synthesis, 193

Subject Index

9H-Imiciazo~l,2~Jbenzimidazole(s) (Cont’d) 3rcetyl derivatives: aldol condensations of, 197, 212 reaction with Grignard reagents, 212 synthesis, 131 Vilsmeier-Haack reactions, 193 acylation, 186, 193 acyl derivatives, hydrolysis, 208 2-acyl derivatives, synthesis, 131 3-acyl derivatives, synthesis, 130 3-alkoxy carbonyl derivatives, synthesis, 131 9-alkyl-2-aryl derivatives, nitrosation, 202 9-alkyl-2-aryl-3-nitrosoderivatives, synthesis, 202 N(9)-alkyL2,3dihydro derivatives, synthesis, 133, 183 amino derivatives, diazotisation, 202 amino hydrochlorides, 179 2amino-3-arylazoderivatives,synthesis,207 24mino derivatives: acetylation, 193 coupling with aryldiazonium salts, 207 synthesis, 132 3 r h o derivatives: acetylation, 193 Schiff base formation, 197 synthesis, 132,209 7-amino-2.3dihydro derivatives, synthesis, 21 7 3-amino-2,9dimethyl, infrared spectrum, 153 a d s . synthesis. 209 2-aryl-3-arylazoderivatives, synthcsis, 207 2-aryl derivatives, coupling with aryl diazonium salts, 207 N49)-aryl-2,3dihydro derivatives, synthesis, 133 3-arylimino derivatives, synthesis, 197 azo derivatives, synthesis, 209 azomethines. synthesis, 21 2 9-benzyl, NMR spectrum (I H), 171

9-benzyl-2,3diethyl-2,3dihydroxy-2,3-

dihydro, synthesis, 21 2 9-benzyl-2,3dihydro. ionization constants, 178 9-benzyl-2-methy1: debenzylation, 216 synthesis, 130 9-benzyl-2-pheny1,debentylation, 21 7 biological activity, 219 3-bromo derivatives: amination, 209

569

nitrodebromination, 21 2 2+-bromophenyl)-9-methyl. nitration, 204 2+-bromophenyl)-9-me thyl-3-nitr0, synthesis, 204 carbonyl derivatives, infrared spectra, 153 carboxylic acids, synthesis, 193 carboxylic esters, hydrolysis, 208 2.3dihydro derivatives: hydrobromides. 179 hydrochlorides, 179 oxidation with KMnO,, 215 oxidation with MnO,, 215 picrates, 179 synthesis, 132 2,3dihydroxy-2,3dihydro derivatives, synthesis, 217 N(9),2dimethyl, synthesis, 183 2.9dimethyl: nitration, 204 nitrosation, 202 2,9dimethyl-3-nitro, synthesis, 204 electrophilic substitution, 179 3ethynyl derivatives: infrared spectra, 153 synthesis, 193 formylation, 193 formyl derivatives: aldol condensation of, 21 2 reaction with Grignard reagents, 21 2 synthesis, 193 hydrobromides, 179 hydrochlorides, 179 hydroxyalkyl derivatives, hydrolysis, 208 3-hydroxyalkyl derivatives, synthesis, 193 hydroxymethyl derivatives, synthesis, 212 lithiation, 193 2-methyl: condensation with aromatic aldehydes, 197 oxidation with S O , , 215 synthesis, 130,216 9-methyl-2-phenyl. nitration, 204 m.o. studies, 179 nitration, 204 3-nitro derivatives: infrared spectra, 153 synthesis, 212 3-nitro derivatives (hydrochlorides), hydrolysis, 179 7-nitro-2.3dihydro derivatives, reduction, 217

570

Subject Index

3-nitro derivatives (Cont'd) nitroso derivatives: condensation with arylamines, 209 hydrolysis, 208 3-nitroso derivatives, condensation with phenylacetonitrile, 212 3-nitroso derivatives (hydrochlorides), hydrolysis, 179 oxidation with KMnO, , 215 2-pheny1, synthesis, 21 7 2-phenyl-2,3dihydro, synthesis, 21 7 picrates, 179 propargyl alcohols, oxidation, 215 ring system, 84 2styryl derivatives, synthesis, 197 9-substituted-2-methyl derivativcs, synthesis, 130 synthesis, 117, 129, 130, 141,215 tautomerism, 178 Vilsmeier-Haack reaction, 193 1(9)H-lmidazo[1,241 benzimidazolc-2,3dione: 3-arylhydrazono-2,3dihydroderivatives, infrared spectra, 154

3-N-phenylimino-2,3dihylimino-2.3dihydro, 135

N(l)substituted-2.3dihydro derivatives,

infrared spectra, 154 9H-lmidazoI 1.2~71benzimidazole-2.3dione: 9-benzyl-2,3dihydro, reaction with ethylmagnesium bromide, 212 2,3dihydro derivatives: hydrolysis, 208 reduction with LiAIH, ,217 synthesis, 135 N(9)substituted 2,3dihydro derivatives, infrared spectra, 154 1H-lmidazo[1,24 1 benzimidazol-2-one: 3-arylidene-2.3dihydro derivatives, synthesis, 197 2,3dihydro derivatives: condensation with aromatic aldehydes, 197 infrared spectra, 153 NMR spectra ( I H), 170 N(1)substituted 2,3dihydro, synthesis, 133 lH,3H-lmidazo[ 1,541benzimidazol-l-one, synthesis, 140 1(9)H-Imidazo[1,24 1 benzimidazol-2-one, 3-ar ylhydrazono derivatives, ultraviolet spectra, 158 1(9)H-lmidazo[1,241benzimidazol-3-one, 2,3dihydro derivatives, infrared spectra, 153

9H-lmidazo[ 1.24 ] benzimidazol-l-one: 3-arylidene2.3dihydro derivatives, synthesis, 197 2.3dihydro derivatives: condensation with aromatic aldehydes, 197 hydrolysis, 208 infrared spectra, 153 9-methyl-2,3dihydro, nitrosation, 202 N(9)substituted 2.3dihydro derivatives, synthesis, 133 9H-lmidazoI1,241 benzimidazol-3-one, 2,3dihydro derivatives, synthesis, 133 Imidazo[ l,5,4.de 1 [ 1,4 1 benzothiazine. synthesis, 524 Imidazo[4,4,1 i j ] quinoline: alkylation, 516 Chichibabin reaction, 519 nitration, 516 oxidation, 521 pKa data, 516 reactions with elcctrophiles, 516 reduction, 521 spectroscopic properties, 514,515 synthesis, 506 Imidazo( 1,5,4de] quinoxalines: catalytic hydrogenation. 523 reaction with electrophiles, 528 synthesis, 523,525 lmidazoquinoxalin-5(6H)-ones. spectroscopic properties, 527 [ 1,3,6 1 OxadiazepinoI3,4* 1 benzimidazoles, synthesis, 499 [ 1.43 1Oxadiazepino[4,3* 1 benzimidazoles, synthesis. 499 Oxadiazolopyrido[ 1,241benzimidazoie, synthesis, 339 [ 1,3] OxazepinoI 3.24 1 benzimidazoles, synthesis, 492 lH[ 1,31 Oxazino[ 3,241 benzimidazole, ring systems, 341 1H[ 1.31 Oxazino[ 3 , 4 4 benzimidazole, 3,4,4,5-tetrahydro derivatives: infrared spectra, 390 synthesis, 346 1H[1,41Oxazino(4,3~]benzimidazole: acetamido-3.4dihydro derivatives, hydrolysis, 417 synthesis. 1acetoxy-8-nitro-3,4dihydro, 384 amino-3.4dihydro derivatives: diazotization, 417

Subject Index amino-3,ldihydro derivatives (Cont U)

synthesis, 4 17 8amino-3,4dihydro, acylation, 415

azido-3,4dihydroderivatives,synthesis,420

chloro-3,4dihydro derivatives, synthesis, 4 20 3,4dihydro derivatives: alkylation, 412 basicity, 41 1 benzoylation, 414 biological activity, 426 chlorination, 417 cyanine dyes from, 427 hydrolysis. 418 infrared spectra, 389 nitration, 417 NMR spectra ( I H). 398 protonation, 411 synthesis, 347,381,423 ultraviolet spectra, 394,398 3,4dihydro,N-oxides, catalytic reduction, 4 26 nitro-3.4dihydr0, catalytic reduction, 426 8-nitro-3,4-dihydro,lO-N-oxides, synthesis, 384 1-phenyl-3,4dihydro, synthesis, 347 ring systems, 341 1,2,3,4-tetrahydro, dehydrogenation, 423 3,4,10,1Oa-tctrahydro derivatives, synthesis, 384 W [1,3]Oxazino[ 3,2u] benzimidazole, 3,4dihydro derivatives, 345 4H[ 1.31 Oxazino[3,2u]benzimidazole, ring systems, 341 1H[ 1,4]Oxazino[4,h] benzimidazolium iodides, l&alkyl-3,4-dihydro, synthesis, 41 2 Oxazolo[3,2u] benzimidazole: 2.3-dihydro. carboxylic acids, 207 2,3dihydro carboxamides, hydrolysis, 207 2,3-dihydro derivatives: biological activity, 21 7 infrared spectra, 144 NMR spectra ('H), 158 synthesis, 86 Oxazolopyrido[ 1,2u] benzimidazoles, synthesis, 339 Pharmawu ticals,benzimidazole dcrivatives as. 531 Phenazined-oxide. photolysis, 475 Phenazine-1O-oxide: 2-nitro, deoxygenation, 477

571

2-substituted derivatives, photolysis, 475 Polybenzimidazoles,532 Pyrazino(4.3uj benzimidazole(s): N(Z)-acetyl-l,2,3,4-tetrahydroderivatives, hydrolysis, 418 2-alkyl-1,2,3,4-tetrahydroderivatives, synthesis, 412 amino-l,2,3,4-tetrahydro,synthesis, 426 N(2)-benzyl-l.2,3,4-tetrahydro, catalytic hydrogenolysis, 426 2-benzyl-l,2.3,4,10,1 DII-hexahydro, NMR spectrum ('H), 410 carboxylic esters, infrared spectra, 394 3ethoxycarbonyl dcrivatives, hydrolysis, 418 lethoxycarbonyl-2-pheny1, catalytic reduction, 426

lethoxycarbonyl-2-phenyl-l,2,3,4-

tetrahydro, synthesis, 426 1,2,3,4,10,lOa-hexahydro, reaction with isothiocyanates, 416 1,2,3,4,1O,lOa-hcxahydroderivatives, synthesis, 389,426 2-hydroxy, synthesis, 385 2-methyl-1,2,3,4-tctrahydro, methylation, 412 nitro-l,2,3,4-tetrahydro,catalytic reduction, 426 1.2.3.4-tetrahydro. alkylation, 41 2 1,2,3,4-tetrahydro derivative(s): ionization constants, 41 1 NMR spectrum ('H),410 synthesis, 379,389 ultraviolet spectra, 398 1,2.3,4-tetrahydro 10-N-oxides, synthesis, 389 Pyrazino[4,3u] be.nzimidazole-l,3(2H,4H)dione: NMR spectrum (' H),412 synthesis, 380 Pryrazino[4,3u] bcnzimidazolium chlorides. 2,2dialkyl-1,2,3,4-tetrahydro. 379 Pyrazino[4,3-o] benzimidazolium iodide,

2,2dimethyl-l,2,3,4-tetrahydro,

414

Pyrazino[4,3u 1benzimidazol-l(Ur)+ne.

3,4dihydro derivatives: reduction with LiAlH, ,426 synthesis, 379 Pyrazino[4,3u] benzimidazol-3(4H)-one: 1,2dihydro, synthesis. 380 l-imino-l,2dihydro. synthesis, 381

572

Subject Index

Pyrazino[4,3-a] benzimidazol4(3f/)-one, 1,2dihydro derivatives, infrared spectra, 394 Pyrazino[4,3*] benzimidazol4( 10H)-ones: N-acetyl, NMR spectra(' H),408 infrared spectra, 394 synthesis, 376 Pyrazolo[ 2,3*] benzimidazoles, electrophillc substitution, 179 1H-Pyrazolo[2,3*] benzimidazole(s): 2-methyl, dipole moment. 178 ring system, 84 2,3,3a,4-tetrahydro derivatives: N M R spectra('H), 170 synthesis, 117 3H-Pyrazolo[2,3a 1 benzimidazole(s): 3-alkylidene derivatives: methylation, 183 quaternary salts from, 183 3-arylidene derivatives, synthesis, 190 3-arylimino derivatives, synthesis, 193 cyanine dyes from, 190 3,3diamino derivatives, synthesis, 209 4H-Pyrazolo(2 , 3 - ~benzimidazole: ] acylamino derivatives, hydrolysis, 208 3-acylaminoderivatives, oxidative amination, 209 alkyl derivatives: aminoalkenyiation, 190 synthesis, 140 amino drivatives: acylation, 193 synthesis, 140 3-amino derivatives, synthesis, 216 3-arylaw derivatives, synthesis, 205 aryl derivatives, synthesis, 140 azo dyes, 205-219 azomethine dyes, 209,219 biological activity, 219 wboxamides, synthesis, 209 carboxylic acid derivatives, synthesis, 140 carboxylic esters. amination, 209 diazonium coupling, 205 halogenation, 197 3-heterylazo derivatives, synthesis, 205 metal complex dyes, 219 2-methyl: dipole moment, 178 NMR spectrum(' H), 170 N-methyl, 182 nitrosation, 202 3-nitroso derivatives: reduction, 216

synthesis, 202

N M R spectrum(' H), 170

photographic developers, 219 photosensitizing agents, 219 reactions: with aromatic aldehydes, 190 with arylamines, 193 ring system, 84 Vilsmeier-Haack reaction, 190 Pyrido[ 1,2111benzimidazole(s): acetamido derivatives: hydrolysis, 330 synthesis, 321 acetamido-l,2dihydro derivatives, hydrolysis, 330 acetamido-1,2,3,4-tetrahydroderivatives, hydrolysis, 330 acetoxy derivatives, synthesis, 321 4-acetoxy-l,2,3,4-tetrahydro derivatives, synthesis, 291 alkylation, 321 alkyl derivatives, synthesis. 282 N-amination, 329 amino derivatives: acetylation, 321 diazotuation. 329 6-amino-8-nitro derivatives, synthesis, 339 amino-l,2,3.4-tetrahydro derivatives: acylation, 326 dinzotization, 329 synthesis. 339 azido-l,2,3,4-tetrahydro: synthesis, 333 thermolysis, 339 azo dyes from, 341 azomethine dyes from, 341 basicity, 320 carboxylic esters, hydrolysis, 330 catalytic reduction, 339 cyanine dyes from, 341 cyan0 derivatives, hydrolysis, 330 cyano-l,2dihydro derivatives, hydrolysis, 330 4-cyano-1Sdihydro. infrared spectra, 294 cyano-1.2.3.4-tetrahydro derivatives: hydrolysis, 330 synthesis. 333 diazonium salts: reaction with azide ion, 333 reduction, 339 1,2dihydro o l r b o x y l i c e s t e r s , h , 330 1Sdihydro olrboxylic ester derivatives, infrared spectra, 294

Subject Index diazonium salts (Cont ‘d)

1,2dihydro derivatives, dehydrogenation, 333 1,5dihydro derivatives: infrared spectra, 294 NMR spectra(DC), 314 oxidation, 333,336 protonation, 298 synthesis, 260.264 tautomerism, 294 ultraviolet spectra, 298 3,Sdihydro: infrared spectra, 294 tautomerism, 294 &,S-dihydro derivatives: bromination, 327 NMR spectra(”C), 314 protonation, 298 synthesis, 260 ultraviolet spectra, 298 6,8dinitro. reduction with sodium polysulfide, 339 1,3diphenyl, synthesis, 272 electrophilic substitution, 327 hexahydro derivatives, synthesis, 292 1.2,3.4,40,5-hexahydro derivatives: oxidation, 336 synthesis, 290,291,292,339 hydroxy, N-amination, 330 hydroxy derivatives: acetylation, 321 synthesis, 282 l-hydroxy-1,2,3,4-tetrahydroderivatives: NMR spectra(’ H), 314 ring-chain tautomerism, 314 4-hydroxy-l,2,3,4-tetrahydroderivatives, synthesis, 291 infrared spectra, 294 mass spectra, 320 methyl derivatives, NMR spectra(*H),314 NWmethyl-1 Sdihydro, NMR spectrum (‘HI,314 nitration, 327 nitro derivatives, synthesis, 271 nitro, 1,5dihydro derivatives, reduction, 336 nitro-l,2,3,4-tetrahydroderivatives, catalytic reduction, 339 NMR spectra(’ H). 299 photographic sensitizing agents from,341 protonation, 320 N(5)quatcmary salts, synthesis, 321 ring system, 259

573

synthesis, 260,266,280,281, 336 1.2,3,4-tetrahydro: carboxylic esters, hydrolysis, 330 diazodum salts, reaction with cyanide ion, 333 5-N-imine, synthesis, 294 4-N-oxide derivatives, synthesis, 290 5-N-oxides, NMR spectra(’ H), 314 quaternary salts, 330 1,2.3,4-tetrahydro derivatives: acylative ring-opening, 327 alkylation, 321 basicity, 320 benzoylation, 327 dehydrogenation, 333 mass spectra, 320 nitration, 327 oxidation, 336 protonation, 320 reduction with W,,339 reduction with NaBH, ,339 synthesis, 275,276,284,290,291, 294,336,339 ultraviolet spectra, 298 6,7,8,9-tetrahydro derivatives: dehydrogenation, 336 synthesis, 281 ultraviolet spectra, 298 Pyrido(l,2w] benzimidazolium perchlorates: 5-alkyl-l.2dihydro derivatives. synthesis, 265 4-cyano-S-methy1,synthesis, 271 Pyrido[ 1,2w 1benzimidazolium salts: Namino, oxidative dimerisation, 333 methyl: acylation, 321 conversion into cyanine dyes, 321 synthesis, 271, 281 1,2,3,4-tetrahydro derivatives, synthesis, 292 Pyrido[ 1 . 2 ~ benziniidazolium 1 tosylate, 5-amino, synthcsis, 329 Pyrido[ 1,2w]benzinUdazol-l(2ff)-one, 3,4dihydro derivatives, synthesis, 275 Pyrido[ 1,2771benziniidazol-l(4H)-one: infrared spectra, 294 synthesis, 273 Pyrido[ 1.2771 benziniidazol-l(SH)-one: N(S)-acetyl derivatives. synthesis, 321

574

Subject Index

~rido[l,2~]benzimidarol-(SH) m e (Cont'd) Zcarboxaldehyde&rivatives,synthesis,325 carboxamides, synthesis, 330 carboxylic acids, synthesis, 330 carboxylic esters, hydrolysis, 330 chlorosulfonation, 330 cyanine dyes from. 325 cyano derivatives, hydrolysis, 330 4-cyan0, infrared spectra, 294 diazo coupling, 329 mass spectra, 320 N(5)-methyl, synthesis, 321 NMR spectra(' H), 314 sulphonation, 330 synthesis, 264,275 ultraviolet spectra, 298 N(5)-unsubstituted derivatives, 321 Pyrido[ 1 . 2 ~benzimidazol-3(5H)-one(s): ) 4cyan0, infrared spectra, 294 mass spectra, 320 synthesis, 264,298 ultraviolet spectra, 298 Pyrido(l.2~1benzimidazol-l,3(W, 4H)diones, 4u,Sdihydro derivatives, synthesis, 275 Pyrimido[ 1,2111benzimidazole(s): alkyl derivatives, synthesis, 355 1O-aByl-2,3,4,1O-tetrahydro derivatives, 368 2-amino, synthesis, 420 4-amino, synthesis, 360 amino derivatives, synthesis, 366 4-amino-3-cyan0, synthesis, 360 &amino derivatives, synthesis, 420 4-amino-3ethoxycarbonyl hydrolysis, 418 aryl derivatives, synthesis, 355 azo dyes, synthesis, 427 chloro derivatives, hydrogenolysis, 426 4cNoro derivatives: amination, 420 synthesis, 420 2,4dimethyl, NMR spectrum(' H),401 ethylation, 412 3-hydroxy-l,2,3,4-tetrahydroderivatives: mass spectra, 41 1 synthesis, 367 2-methyl: NMR spectrum(' H),401 synthesis, 355 2-methyl,3-carboxylic acid ethyl ester, synthesis, 359 2-methyla-phenyl, synthesis, 355

4-methyl, synthesis, 355 4-methyl,3-carboxylic acid, ethyl ester, synthesis, 359 7Qdinitr0, synthesis, 387 NMR spectra ( I H), 401 2-phenyl derivatives, synthesis, 355 photographic emulsion, stabilizers from, 427 protonation, 411 ring systems, 343 synthesis, 355,386 Pyrimido[ 1,2111bendmidazole-2,4(1H, 3Hdiones), synthesis, 372

Pyrimido(1,2~]benzimidazole-3,4( lH,

3H)diones, biological activity, 427 Pyrimido[ I,2u 1 benzimidazole-2,4(3H, 1OH)dione: aminomethylenation, 416 p-nitrobenzoy lation, 4 15 2-p-nitrobenzoyloxy, synthesis, 4 15 Pyrimido[3,4u ] benzimidazole-l,3(W , 4H)dione, alkylation. 41 2 Pyrimidol 1 , 2 1~benximidazole-2(1H)thione: amination, 420 synthesis, 418 Pyrimido[ 3,4111 benzimidazole-1,3(W , 4H)dione, synthesis, 389 Pyrimido[ 3,4u] benzimidazole-l(2H)thione, 3.4dihydro. reaction with amina, 420 Pyrimido[ 3.4111 benzimidazole-l(2H)thione: 3.4dihydro derivatives: reaction with hydrazines, 420 synthesis, 373 3.4,&.5-tetrahydro, synthesis, 375 PyrimidoI 1 , 2 1~benzimidazolium perchlorate(s): lOalkyl derivatives, synthesis. 355 8-methyl, NMR spectrum(' H),401 PyrimidoI1,2u 1 benzimidazolium salts, ultraviolet spectra, 394 Pyrimido[ 1,2u]benzimidazol-2(1H)-ones: alkylation, 412 carboxamides, synthesis, 420 carboxylic esters: aminolysis,420 hydrolysis, 4 18 catalytic reduction, 426 3.4dihydro carboxamides, synthesis, 420 3,4dihydro carboxylic esters, aminolysis, 420

Subject Index Pyrimido[l,24 benrimidazol-2(1H).ones: (Cont 'd) 3,4dihydro derivatives: hydrolysis, 418 mass spectra. 4 10 NMR spectra(' H), 401 synthesis, 369,426 x-ray analysis, 4 11 mass spectra, 410 4-methoxycarbonyl derivatives, reduction with NaBH, ,426 N(l0)methyl derivatives, synthesis, 412 NMR spectra(' H), 401 reaction with Pas,,418 N(l)-substituted-3,4dihydro derivatives, infrared spectra, 391 N(1O)-substitu ted-3,rldihydro derivatives, infrared spectra, 391 synthesis, 366 ultraviolet spectra, 394,398 Pyrimido( 1 , 2 r ] benzirnidazol-2(lOH)one(s): 3,4dihydro derivatives: infrared spectra, 391 synthesis, 372 NMR spectra(' H),401 synthesis, 367 Pyrimido( 1 , 2 r J benzimidazol-4-one(s): N(l)-methyl, infrared spectra, 391 N(lO)-methyl, infrared spectra, 391 ultraviolet spectra, 398 tautomerism, 398 Pyrimido[1,2u] benzimidazol4(lH)one(s) : biological activity, 427 3-carboxylic esters, hydrolysis, 41 8 3-cyano derivatives, hydrolysis, 41 8 2,3dihydro derivatives, synthesis, 387 1-methyl derivatives, synthesis, 365 Pyrimido[l,2a] benzimidazol-4 (1OH)one (s): N(lO)-acetyC3ethoxycarbonyl, synthesis, 415 3-acyl derivatives, synthesis, 365 carboxamides, synthesis, 420 carboxylic esters, 420 3-carboxylicesters, hydrolysis, 41 8 chlorination, 420 3cyano derivatives, hydrolysis, 41 8 3cyano-2-methy1, synthesis, 365 2,3dihydro derivatives: infrared spectra, 394 synthesis, 372

575

3ethoxycarbony1, acetylation, 415 2-hydroxy derivatives, synthesis, 369 mass spectra, 410 2-methyl, bromination, 416 1-methyl derivatives, synthesis, 365 NMR spectra( H) , 4 01 synthesis, 360 ultraviolet spectra, 398 Pyrimido(2,3r] benzimidazol-l(2H)-one, 3,4dihydro, alkylation, 412 Pyrimido[3,4r J benzimidazol-l(2H)-one. 3,ddihydro derivatives. synthesis, 375 Pyrrolo[ 1,2r J benzimidazoles(s): 6-chloro-2.3dihydro derivatives, synthesis, 27 cyanine dyes from, 84 4-methyl-2-phenyl.ionization constants,57 oxidation, 79 ring systems, 3 tautomerism of, 44 hrrolo[ 1,2,3-cd] benzimidazole, synthesis, 407 ~ H - P Y ~ O1I .O2[~ benzimidazole(s): 1 acetamido-2,3dihydro derivatives, hydrolysis, 72 3acetox~-2,3dihydro,synthesis, 34 a w l 2.3dihydro derivatives, hydrolysis, 72 4-acyl-2,3,3~,4-tetrahydro, oxidative deacylation, 80 4-acyl-2,3,30,4-tetrahydroderivatives, synthesis, 38 alkylation, 60 amino 2,3dihydro: acylation, 67 diazotization, 69 nitration, 69 Sandmeyer reactions, 78 synthesis, 82 5a111hIOd-NtrO-2,3dihydrO, synthesis, 75 azido-2,3dihydro derivatives: infrared spectra, 40 synthesis, 79 basicity, 56 4-benzoyl-2,3,3a,4-tetrahydro, synthesis, 38 S-chloro, synthesis, 78 8-chloro. synthesis, 78 7-chloro-2,3dihydro, synthesis, 16 5 -chloro~-Ntr0-2,3dihydro, amination, 75 cyano-2,3dihydro derivatives,synthesis,78 6,7dichloro-2,3dihydro, synthesis, 76 2.3dihydro: acylation, 66 aldol type condensation. 67

576

Subject Index

IH-&rro&/l ,Zu/benrimi&mle(sJ(Cont 'd/ benzoylation, 66 bioogid activity, 84 chlorination, 67 dyestuffs from, 67 nitration, 68 oxidation. 79 polymers from, 84 reduction, 28 synthesis. 22,29,30.38,81,96 2,3-dihydro,4-N-oxides, 34,75 ethoxycarbonyl-2,3dihydroderivatives, hydrolysis, 72 halogeno-3,hIihydro drivatives: nitration, 69 reaction with cyanide ion, 78 synthesis, 78 3-hYdr0~~1-2,3dihydro, 34 methoxy-2,3dihydro derivatives, demethylation, 72 nitro-2,3dihydro derivatives: catalytic hydrogenation, 82 N M R spectra ('HI,55 synthesis, 69 quaternary salts, synthesis, 60 ring system, 3 synthesis, 7 2.3,30.4-tetrahydro derivatives, 28,29, 35, 80, a2 ultraviolet spectra, 41 3H-Pyrrolo[1,2~]benzimidazole(s): basicity, 56 hydrolysis, 72 infrared spectra, 41 1-methyl, synthesis, 7 NMR spectra ( I H),44 polymers from, 84 ring system, 3 synthesis, 7,81 1,2,3,3-tetraaryl, synthesis, 7 1,3,3-trimethyl, hydrolytic ring-opening, 72 ultraviolet spectra, 41 4ff-PYrrolo[1,2Q]benzimidazole(s): acetyl derivatives: hydrolysis, 72 nitration. 69 3-acetyl derivatives, synthesis, 64 acylation, 64 acyl derivatives, 17 alkylation, 60 alkyl derivatives: nitration, 69 synthesis, 7

a r y k o derivatives, synthesis, 6 9 aryl derivatives: nitration, 69 synthesis, 7 basicity, 56 bcnzoyl derivatives, synthesis, 64 bcnzyl, reductive debenzylation, 81 carbonyl derivatives, infrared spectra, 41 carboxaldehyde derivatives, synthesis, 64 carboxamide derivatives, synthesis, 64 3carboxylic acid derivatives, synthesis, 16 3-cyano,16 cyan0 derivatives, infrared spectra, 40 ldiazoaryl derivatives, reduction, 80 diazonium coupling, 69 2.3-dihydr0, nitration, 67 dyestuffs from, 64 electrophilic substitution, 57 3ethoxycarbonyl. 16 formylation, 64 ionization constants, 57 mass spectra, 55 2-methyl derivativcs, 17 2-methyl-3-pheny1,18 4-methyl-2-pheny1, 16 S-methyl thiomidate derivatives, ammation, 75 m.0. studies, 57 nitro derivatives, synthesis, 69 nitrosation. 69 nitroso derivatives, synthesis, 69 1-nitroso derivatives, infrared spectra. 38 NMR spectra (*H),44 protonation, 45,58 quaternary salts, synthesis, 60 reactions: with acyl isocyanates, 64 with aryl isocyanates, 64 ring system, 3 synthesis, 7 ultraviolet spectra, 44 lH-Pynolo[ 1 . 2 ~ benzimidazolium 1 salts: N(4)-alkyE2,3-dihydro, acylation, 67 N(4)-benzyl-2,3,30-4-tetrahydro, 82 2.3,hA-tetrahydro. hydrolytic ringopening, 74 4ff-P~rrol0~1,24] benzimidazolium salts, 64 Pyrrolo[ 1,2u] bensrjmidazol-l+nes, sYn thesis, 3

Subject Index lH-Pyrrolo[ 1,2u]benzimidazol-l-one(s): 2-aryl-l-hydroxy, synthesis, 6 2.3dlihydro derivatives: ring-opening, 82 synthesis, 27 hydrolytic ring-opening, 73 3-hydroxyl-2-pheny1,reduction, 82 infrared spectra, 41 synthesis, 6 2,3,30.4-tetrahydro derivatives: infrared spectra, 38,41 synthesis, 29, 38 3H-PyrroloI 1,2~1] benzimidazol-3-ones, l-aryl-2-bromo-l,2dihydro. 28

[ 1,4]Thiazepino[4,3~1] benzimidazoles,

3-Sila-W-imidazo[1,2-0]benzimidazoles: acylation, 242 infrared spectra, 230 NMR spectra ( I H), 234 ring system, 220 synthesis, 223 2-Sila-3H-thiarolo[3 . 2 ~ bcnzimidazole: 1 ring system, 220 synthcsis, 221

-

3,4,4a,S-Tetrahydro-Y[ 1,3] oxazino[3,4u] benzimidazole, ring systems, 341 2,3,30,4-Tetrahydropyrazolo[2,3* 1 benimidazole, ring system, 84 2,3,30,4-Tetrahydro-lH-pyrrolo[ 1,2u] benzimidazole, ring system, 3 Tetrazolo[ 1,5u] benzimidazoles, synthesis, 244 1,24-Thiadiazolo [ 2 . 3 ~ 1benzimidazoles: biological activity, 244 thiomethyl, Soxides, synthesis, 244 thiomethyl derivatives, oxidation, 244 1,2,4-Thladiazol0[4.3~1 benzimidazoles, biological activity, 244 1,2,4-Thiadiazolo[4,5~1] benzimidazole: biological activity, 244 3-( 1-imidazolyl): nitration, 242 reduction with LiAIH, ,244 sulfones: NMR spectrum ( I H), 234 synthesis, 224 synthesis, 224 1,3,4-Thiadiazolo[3.2~1)benzimidazole: 4a,5,6,7,8& hexahydro derivatives, synthesis, 229 ring system, 220 1,3,6-Thiazepino[3.2~1]benzimidazoles, 501

-

-

577

synthesis, 492 1H[ 1,4]Thiazino[4,3u] benzimidazole: 3,4dihydro, cyanine dyes from, 427 ring systems, 341 synthesis, 354 2H-[ 1,3]Thiazino[3,2u] benzimidazole(s): 3.4dihydro derivatives: NMR spectra ( I H), 398 synthesis, 351 3-hydroxy-3.4dlihydro derivatives: biological activity, 427 synthesis, 35 1 3-pheny1, synthesis, 350 4-phenyl-3,4dihydro derivatives, synthesis, 351 ring systems, 341 synthesis, 350 4H-[ 1.3J Thiazino[3.2*] benzimidazoles, synthesis, 350 1OH-[ 1,4]Thiazino [ 4,3u] benzimidazole: cyano derivatives, infrared spectra, 390 dchydro derivative, synthesis, 352 X-ray analysis, 411 [ 1,3]Thiazino[4,3~1] benzimidazol4one(s): 2-hydroxy. synthesis, 350 infrared spectra, 290 ultraviolet spectra, 394 1H[1,4]Thiazino[4,3~1]benzimidazol4( 3H)-one(s): acylation, 415 arylidene derivativcs, synthesis, 415 cyanine dyes from, 415 infrared spectra, 390 reaction with aromatic aldehydes, 415 synthesis, 354 W[ 1,3]ThiazinoI 3,2u] benzimidazol4(3H)snes, synthesis, 350,35 1 W[ 1,3)Thiazino[4,3~1] benzimidazol4(3H)-ones, NMR spectra ( I H). 401 4H-[ 1.31 Thiazino(4.3~11benzimidazol4(3H)-one, acylation, 415 J benzimidazole(s): Thiazolo[3,2~1 acetyl derivatives, ultraviolet spectra, 157 2-acetyl, synthesis, 97 2-acetyl derivatives, synthesis, 186 acyl derivatives, synthesis, 97 2-acyl derivatives: NMR spectra (IH),169 reduction with NaBH,, 216 aldehyde derivatives, infrared spectra, 145

578

Subject Index

Thiazolo[3,2+z]benzimidazole(s) (Cont U) 2alkanoy1, synthesis, 97 akyl derivatives, synthesis, 88 2-alkyl derivatives, synthesis, 76 3-alkyl derivatives, synthesis, 100 amide derivatives, infrared spectra, 145 amino-2,3dihydro derivatives: acetylation, 190 reaction with aryl isothiocyanates, 190 synthesis, 216 3-amin0, synthesis, 216 2-aroyl, synthesis, 97 aryl derivatives: infrared spectra, 145 synthesis, 88 2-aryl derivatives: NMR spectra ( I H), 168 synthesis, 97 3-aryld-chlor0, synthesis, 96 3-aryl derivatives, NMR spectra (' H), 168 3-aryl-3-hydroxy-2,3dihydro derivatives, synthesis, 108 3-aryl-6-methoxy,synthesis, 96 2-benzoyl-3-phenyl,synthesis, 97 biological activity, 217 bromination, 197 2-bromo derivatives, synthesis, 197 carbinols, synthesis, 216 carbonyl chlorides, amination, 209 carboxamides, synthesis, 209 carboxylic acid derivatives, infrared spectra, 145 2-carboxylic acids, synthesis, 207 2-carboxylic esters, hydrolysis. 207 cyanine dyes from, 219 2,3dihydro derivatives: alkylation, 182 biological activity, 217 NMR spectra ( I H), 169 oxidation, 109 protonation, 179 synthesis, 101 ultraviolet spectra, 157 electrophilic substitution, 179 ester derivatives, infrared spectra, 145 ethoxycarbonyl derivatives, ultraviolet spectra, 157 2ethoxycarbony1, synthesis, 97 3ethoxy-2,3-dihydro derivatives, synthesis, 109 hydrochlorides, 179 hydroxy derivatives, synthesis, 140

3-hydroxy-2.3dihydro derivatives: acetylation, 186, 190 dehydration, 88 Oethylation, 182 infrared spectra, 152 NMR spectra ( I H), 169 oxidation, 215 ring-chain tautomerism, 169 kctone derivatives infrared spectra, 145 m.o. studies, 179 mass spectra, 171 mesoionic derivatives, ultraviolet spectra, 157 methyl derivatives, ultraviolet spectra, 154 2-methyl, mass spectrum, 171 2-methyl derivatives, NMR spectra ( l HI, 168 3-methyl: mass spectrum, 171 NMR spectra ( l H), 168 synthesis, 88,97 nitro-2,3dihydro, reduction with Raney nickel-hydrazine, 216 3-nitro, reduction, 216 NMR spectrum (' H), 168 oximes, 209 perhydro derivatives, synthesis, 140 phenyl derivatives, ultraviolet spectra, 157 2-phenyl, mass spectrum, 171 3-phenyl: mass spectrum, 171 synthesis, 101 2-phenylhydrazono-2,3dihydro, reduction, 216 piaates, 179 protonation, 179 synthesis, 140 ultraviolet spectra, 154 1H,3H-Thiazolo[3,4u 1bedmidazole(s): 3-arylidene-l-imino, synthesis, 190 biological activity, 219 1-imino: acylation, 190 condensation with aromatic aldehydes, 190 infrared spectra. 153 reaction with isocyanate, 190 synthee, 116 tautomerism, 190 ultraviolet spectrum, 157 NMR spectra (' H). 170

Subject Index

I H , 3 H - ~ & z o l o / 3 , 4 fbenzimidazole(s) f) : (Cont 'd)

synthesis, 115 Thiazolo[ 3 . 2 ~ benzimidazole-2,3dione: 1 arylhydrazono-2.3dihydr0, 1 15 arylimino-2.3dihydr0, 115 Thiazolo[ 3,2a] benzimidazole-3-one(s): 2-alkylidene-2,3dihydro : synthesis, 114 ultraviolet spectra, 157 2-aminoalkenyl-2,3-dihydro derivatives, synthesis, 190 2-arylhydrazono-2,3dihydroderivatives: synthesis, 204 ultraviolet spectra, 157 2-arylidene-2,3dihydro derivatives: bromination, 197 reaction with diazomethane, 21 1 reaction with Grignard reagents, 21 1 synthesis, 114, 186 ultraviolet spectra, 157 2-suylimino-2,3dihydro, synthesis, 190 2diaikylaminome thyl-2,3dihydro derivatives, 182 2,3dihydro derivatives: amination, 209 biological activity, 219 condensation with aromatic aldehydes, 114,186 coupling with aryldiazonium salts, 204 cyanine dyes from, 219 dyestuffs from, 186 infrared spectra, 145 NMR spectra (' H), 169 photographic sensitizing agents from, 219 quaternary salts from,182 reactions, 190,209 synthesis, 96,109,208.215 ultraviolet spectra, 157 Vilsmeier-Haack reaction, 190 2ethoxymethylene-2,3dihydro,synthesis, 190 3-hydroxy-2-inino-2,3dihydro derivatives, synthesis, 211 2-imino-2,3dihydro derivatives, 211 1H,3H-Thiazolo[3,4d] benzimidazol-l-one, synthesis, 116 lH,3H-Thiazolo[ 3,4a] benzimidazole-2-ones, synthesis. 208 1,3,5-Triazepino[3.2*) benzimidazoles, 499 1,2,4-Tria&O[ 2,3a] benzimidazoks, 429 1,2,4-T1iazho[4.3-a 1 benzimidazole(s): 1,4dihydro derivatives:

579

electrochemical oxidation, 454 synthesis, 430 1,2,3,4-tetrahydro', synthesis, 432 tetrahydro derivatives, infrared spectra, 445 1,2,4-Triazino[4 , 5 4 bcnzimidazole(s): alkyl derivatives, synthesis, 432 aryl derivatives, synthesis, 432 hydrolytic ring-opening, 453 4-methoxy, synthesis, 451 N M R spectra (*H),449 ring systems, 427 ultraviolet spectra, 447 1,3,5-Triazino[1,2*) benzimidazole(s): 2-ammo. synthesis, 442 4-amino-2-ary1, synthesis, 442 2-amino4-pheny1, synthesis, 442 2-aryH-phenoxy derivatives, synthesis, 442 biological activity, 454 2,4diamino, synthesis, 442 1,2dihydro derivatives: dehydrogenation, 454 synthesis, 442 3,4dihydro derivatives, synthesis, 443 hydrolytic ring-opening, 454 ring systems, 427 synthesis, 436,454 1,2,3,4-tetrahydro derivatives, synthesis, 444 1,3,5-Trhzino[ 1 . 2 ~ benzimidazole-2,4( ~1 lH, 3H)diimine, 3ir-butyJ. synthesis, 444 1,3,5-Triazino[1,2*] benzimidazole-2, 4( lH.3H)dione: N-alkyl derivatives, synthesis, 453 photographic emulsion stabilizer from, 45 5 synthesis, 444 1,3,S-Triazino[1,2a]benzimidazole-2, 4(1H,3H) dione &mines: infrared spectra, 446 synthesis, 444 1,3,5-Triazino[ 1,2u]benzimidazole4(3H)-imines, 1,2dihydro derivatives, synthesis, 444 1,3,5-Triazino[1,2a] benzimidazole-l( 1H)thione, ethylation, 451 1,2,4-Triazino[2,3a] benzimidazol-2(1H)ones: infrared spectra, 445 synthesis, 430,445 1,2,4-Triazino[ 2,3*] benimidazol-3(4H)-one: 2-carboxylic acid, synthesis. 453

5 80

Subject Index

2syano: hydrolysis, 453 ionization constant, 45 1 1,2,4-Triazin0[4,3-a]benzimidazoll(W)-one, synthesis, 433 1,2,4-Triazino[4,311]benzimidazol3(W)-one, 1,4dihydro, synthesis, 432 1,2,4-Triazin0[4,3~~] benzimidazol-hne, 446 1,2,4-Triazino[4,3111benzirnidazoM(1OH)ones, synthesis, 430 1,2,4-Triazino(4,5111 benzimidazol-l(W)one(s) : alkylation, 451 N(2)alkyl derivatives, synthesis, 447, 451 N(5)alkyl derivatives: acylation, 453 ultraviolet spectra, 447 hydrolytic ring opening, 453 infrared spectra, 446 1,2,4-Triazino[4,5u ] benzimidazoLl(5H)ones, infrared spectra, 446 1,2,4-Triazin0[4,5~]benzimidazol-4(3H)one: alkylation, 451 N(3)alkyl derivatives, synthesis. 45 1 cyanoethylation, 451 N(3)-hydroxymethyl, synthesis, 453 methylation, 451 nitration, 453 8-nitro, synthesis, 453 NMR spectra (I H). 449 synthesis, 436 1,2,4,5-tetrahydro derivatives, N M R spectra ( I H),449 ultraviolet spectra, 447 1,2,4-Triazino[4,5u ] benzimidazol4(10H)-one, synthesis, 436 1,3.5-Triazino( 1,211)benzimidazol4(3H)one, 2-amino, synthesis, 443 1,3,5-Tr&o~l.2~) benzimidazol-2(lH)thione, 4-phenyl, synthesis, 442 1,2,4-Triazolo[1,511)benzimidazoles, synthesis, 225 1,2,4-Triazolo[4,3~1]benzimidazoles. biological activity, 244 lH-l,2,4-Triazolo[ 1,5111benzimidazole, ring system, 220 lH-l,2,4-Triazolo [ 2,3111 benzimidazoles: 1-acyl, NMR spectra ( I H),239

N-acyl: hydrolysis, 244 infrared spectra, 230 N(l)-benzyl-2-phenyl, synthesis, 242 2-phenyl, benzylation, 242 ring system, 220 lH-l,2,4-Triazol0[4,3u] benzimidazole(s) : N(l)-alkyl derivatives, ultraviolet spectra, 233 9,Ldihydro derivatives, synthesis, 227 1.3dimethyl: dipole moment, 239 synthesis, 225 N( 1),3dimethyl: synthesis, 242 ultraviolet spectrum, 233 N(1)-methyl, NMR spectrum ( I H), 234 NMR spectra (nC),238 protonation, 239,242 quaternisation, 242 ring system, 220 synthesis, 225 1(9)H-1,2,4-Triazolo [4,3111benzimidazole(s) : acetylation, 242 N(9)acetyl derivatives, synthesis. 242 N-acyl, hydrolysis, 244 1,34methyl, protonation, 242 N(9),3dimethyl, protonation, 242 dipole moments, 239 3-methyl: dipole moment, 239 methylation, 242 NMR spectrum ( ' C ) , 238 NMR spectrum (I H),234 protonation, 233,242 tautomerism, 233, 238 ultraviolet spectrum, 233 photographic antifogging agents from, 244 protonation, 242 tautomerism. 239 ultraviolet spectra, 233 9H-1,2,4-Triazolo[4,3u] benzimidazole(s): N(9)alkyl derivatives, ultraviolet spectra, 233 2,3dihydro derivatives, aminoalkylation, 24 2 3,9dimethyl, dipole moment, 239 N(9),3dimethyl: protonation, 234 synthesis, 242 infrared spectra, 230 N(9)methyl. NMR spectrum ( I H),238

Subject Index 9-methyl-3-thiomethy1, synthesis, 242 NMR spectra ("C),239 protonation, 239 quaternization, 242 ring system, 220 synthesis, 225

1(9W1(9)H-1,2,4-Triazolo[4J.cr 1benzimidazole: 6-amino-3-methyl,24 3, 244 3-methyl, 243

581

9H-1.2,4-Triazolo[4,377 1benzimidazole3-thione: N(2)-aminoalkyl-2,3dihydroderivatives, synthesis, 242 2,3dihydro derivatives: infrared spectra, 230 synthesis, 221 9H-1,2,4-Triazolo~4.3.cr] benzimidazolium salts. N(l)-alkyl-3,9dhethyl, ultraviolet spcctra, 234 1,2,4-Triazolo(4,~~ 1benzimidazol-4(3H)ones, infrared spectra, 446

Benzimidazoles and Cogeneric Tricyclic Compounds, Part 2 (The Chemistry of Heterocyclic Compounds, Volume 40)

Indoles. Part 2 (Chemistry of Heterocyclic Compounds, Volume 25b)

Isoquinolines, Part 1 (The Chemistry of Heterocyclic Compounds, Volume 38)

Indoles. Part 1 (Chemistry of Heterocyclic Compounds, Volume 25a)

Indoles. Part 3 (Chemistry of Heterocyclic Compounds, Volume 25c)

The Chemistry of Heterocyclic Compounds, Isoquinolines (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Part 1, Volume 38)

Heterocyclic Compounds With Three- And Four-Membered Rings (The Chemistry of Heterocyclic Compounds, Volume 19)

The Chemistry of Heterocyclic Compounds, The Naphthyridines

The Chemistry of Heterocyclic Compounds, Acridines

Chemistry of Heterocyclic Compounds The Pyrazines 2C

The Chemistry of Heterocyclic Compounds, The Chemistry of 1,2,3-Thiadiazoles (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 62)

Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications

Quinazolines, Supplement I (The Chemistry of Heterocyclic Compounds, Volume 55)

The Chemistry of Heterocyclic Compounds, Supplement I (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 58)

Triazoles: 1,2,3 (The Chemistry of Heterocyclic Compounds, Volume 39)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

Aza-Crown Macrocycles (The Chemistry of Heterocyclic Compounds, Volume 51)

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The Chemistry of Heterocyclic Compounds, Imidazole and Its Derivatives

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Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

The Chemistry of Organolithium Compounds

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The Chemistry of Heterocyclic Compounds, Small Ring Heterocycles (Part 3, Volume 42)

Benzimidazoles and Cogeneric Tricyclic Compounds, Part 2 (The Chemistry of Heterocyclic Compounds, Volume 40)

Indoles. Part 2 (Chemistry of Heterocyclic Compounds, Volume 25b)

Isoquinolines, Part 1 (The Chemistry of Heterocyclic Compounds, Volume 38)

Indoles. Part 1 (Chemistry of Heterocyclic Compounds, Volume 25a)

Indoles. Part 3 (Chemistry of Heterocyclic Compounds, Volume 25c)

The Chemistry of Heterocyclic Compounds, Isoquinolines (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Part 1, Volume 38)

Heterocyclic Compounds With Three- And Four-Membered Rings (The Chemistry of Heterocyclic Compounds, Volume 19)

The Chemistry of Heterocyclic Compounds, The Naphthyridines

The Chemistry of Heterocyclic Compounds, Acridines

Chemistry of Heterocyclic Compounds The Pyrazines 2C

The Chemistry of Heterocyclic Compounds, The Chemistry of 1,2,3-Thiadiazoles (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 62)

Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications

Quinazolines, Supplement I (The Chemistry of Heterocyclic Compounds, Volume 55)

The Chemistry of Heterocyclic Compounds, Supplement I (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 58)

Triazoles: 1,2,3 (The Chemistry of Heterocyclic Compounds, Volume 39)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

Aza-Crown Macrocycles (The Chemistry of Heterocyclic Compounds, Volume 51)

The Chemistry of Heterocyclic Compounds, Quinoxalines: Supplement II (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 61)

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The Chemistry of Heterocyclic Compounds, Imidazole and Its Derivatives

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The Chemistry of Heterocyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy, Part A (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 60)

The Chemistry of Organolithium Compounds

The Chemistry of Pincer Compounds

The chemistry of Organomagnesium Compounds

Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

The Chemistry of Organolithium Compounds

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