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

Condensed Benzimidazoles of Type 6-5-5

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

Reaction conditions"

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,

Reaction conditions" Product

(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

Solvent of crystallisation

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

Solvent of crystallisation

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

Reaction conditions" Product

(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

Condensed Benzimidazoles of Type 6-5-5

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)

6.1. Fused Benzimidazoles with No Additional Heteroatoms

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

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-5

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

6.1. Fused Benzimidazoles with No Additional Heteroatoms

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.

Solvent of crystallization

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

Solvent of crystallization

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

6.1. Fused Benzimidazoleswith No Additional Heteroatoms

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

6.1. Fused Benzimidazoles with No Additional Heteroatoms

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)]

Condensed Benzimidazoles of Type 6-5-5

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

~~

Reaction conditions"

~

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

Solvent of crystallization

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

-

-

-<

3)

R'= H, R2= SO,N

(6.74; R' = H, R2= C0,Et) (6.74; R' = R2= H)' (6.74; R' = C1, R2= C0,Et) (6.74; R' = Br, R2= C0,Et) (6.74; R' = R2= H) (6.74; R' = H, R2= CF,) (6.77; R' = R, = H)' (6.77; R' = R2= H)' (6.77; R' = H, R2= Cl) (6.77; R' = H, R2= Cl) (6.77; R' = H, R2= NO,)' (6.77; R' = H, R2= NO,)k

(6.74;

212 180 (decomp.) 255-260 196-198 190 148

182

-

-

224

148

134 96 138 114 115

239

Ethyl acetate Ethyl acetatelight petroleum (b. p. 60-80")

-b -b

-b -b -b

-b

62 62 65 65

58 61 61 62 62 62 62 62 63

58 58 58

58

Solvent of crystallization not specified. Colorless needles. Purified by sublimation. Yield not quoted. 6-Chloro derivative. 8-Chloro derivative. ' 6-Ethoxycarbonyl derivative. ' 8-Ethoxycarbonyl derivative. Hydrochloride. ' Buff needles.

(I

A = CF,CO,H, 30% H,O,, CH,Cl,/(reflwr)(l5-30 min); B = 9856 HCO,H, 30% H,0,/(100")(10-15 mid; C = CH,CO,H, 30% H,O, (conditions not specified); D = 2 M HCl/(reflux)(lSrnin); E = Sn, HCO,H/(reflux)(3hr); F = HgO, EDTA, EtOH-H,O (1 : l)/(room temp.)(few min); G = PhN0,/(170")(0.5 hr); H = TiCI,, conc. HC1/(800)(1hr); I = conc. HCl/(reflux)(1-20hr); J = hv, 1 M HCI, MeOH, H,O/(room temp.)(4&54 hr); K = kv, AcOH, H,O/(room temp.)(several hr); L = ZnCI,, Ac,O/(reflux)(3-4 hr).

~

(6.75: R' = H, RZ= C0,H) (6.75; R' = H, R2= CF,) (6.75; R' = R2= H) (6.75; R' = H, RZ= NO,)

(6.72; R' = H, R2= C0,EO (6.72; R' = R2= H)h (6.72; R' = CI, R2= C0,Et) (6.72; R' = Br, R2= C0,Et) (6.75; R' = R2= H) (6.75; R' = H. R2= CF,) (6.75; R'= R2= H) (6.75; R' = R2= H) (6.75; R' = H, R2= Cl) (6.75; R' = H, RZ= Cl) (6.75; R' = H, RZ= NO,) (6.75; R' = H, RZ= NO,)

(6.72;

34

Condensed Benzimidazoles of Type 6-5-5

(6.75) --* (6.74)] promoted by titanous chloride in acidic solution has perhaps the greatest synthetic potential. At least in the cases reported4'"' these reactions afford the corresponding 2,3-dihydro-lH-pyrrolo[ 1,2-a]benzimidazoles in essentially quantitative yield (Table 6.8) and are believed61 to owe their efficiency to the intermediacy of an organometallic complex, in which the metal plays the dual role of reducing and chelating agent. The first-formed products in such cyclizations are probably the corresponding 2,3-dihydro-lH-pyrrolo[ 1,2-a]benzimidazole 4-N-oxides, which undergo subsequent deoxygenation to the parent 2,3-dihydro-1 Hpyrrolo[l,2-a]benzimidazoles isolated. In accord with this view, 2,3dihydro-lH-pyrrolo[ 1,2-a]benzimidazole N-oxides are formed, admittedly in variable yield (Table 6.8), in the absence of titanous chloride, when N-(2nitropheny1)pyrrolidines are heated with concentrated hydrochloric acid [Scheme 6.15; (6.75) + (6.77)].47*622,3-Dihydro-lH-pyrrolo[1,2-a]benzimidazole 4-N-oxides (6.77) are also the end-products (Table 6.8) of the photolysis of N-(2-nitrophenyl)pyrrolidines (6.75) in acetic acidd3 or methanolic hydrochloric The mechanistic details of the acidcatalyzed cyclizations of N-(2-nitrophenyl)pyrrolidines to 2,3-dihydro- 1Hpyrrolo[ 1,2-a]benzimidazole 4-N-oxides have not been established, though for the purely thermal processes involvement of an aci-nitro intermediate has been p r ~ p o s e d . ~ However, ~."~ it is conceivable that, as in the case of other acid-catalyzed aromatic nitro group ortho side-chain interactions,& cyclization is the end result of direct aldol-type condensation between the nitro group and an a-methylene center in the pyrrolidine ring activated by protonation of the adjacent nitrogen atom. 2,3-Dihydro-1 H-pyrrolo[ 1,2-a]benzimidazole 4-N-oxides are also plausible intermediates in the zinc chloride-acetic anhydride mediated ring-closure of N-(2-nitrophenyl)pyrrolidines (6.75), which leads, depending on the nature of the workup, to 3- hydroxy- or 3-acetoxy- 2,3-dihydro- lH-pyrrolo[ 1,2-a]benzimidazoles [Scheme 6.15; (6.78; R3= H or AC)]~'."~in good yield (Table 6.8). Isolated instances of ring-closure reactions leading to 2,3-dihydro- 1Hpyrrolo[ 1,2-a]benzimidazoles include the transformation (Scheme 6. 19)Mof the azo-sulfonate (6.89) into the interesting betaine structure (6.90) and the transannular cyclization (Scheme 6.15) via Schmidt rearrangement of the diazepinone (6.76; R' = R2 = H, T = toluene-p-sulfonyl) to 2,3-dihydro1H-pyrrolo[ 1,2-a]benzimidazole (6.74; R' = RZ= H)."'

6.1. Fused Benzimidazoles with No Additional Heteroatoms

I

/ a + N Q r* RH I CHpR (6.95)

CH2R

-H4

T

0;XJ I

(6.94)

35

(6.93)

aD I H CHzR

(6.96)

CqD I H COR

2,3,3a,4-Tetrahydro- IH-pyrrolo[ 1,2-a]benzimidazole derivatives are readily accessible'" by the acid-catalyzed cyclization of N-(2-alkylideneamino or 2-arylideneamino)pyrrolidineseither preformed or prepared in situ by the condensation of N-(2-aminophenyl)pyrolidine with aliphatic, aromatic, or heteroaromatic aldehydes [Scheme 6.20; (6.91) --* (6.94) -+ -+ (6.%)]. Ring-closure reactions of this type proceed in high yield (Table 6.9) and on

m

A A

B

(6.94; R = 2-CI. S-O*NC,HJ

D

D

D D

(6.91)

(6.91)

(6.91) (6.91) (6.91)

D

D D D D

(631) (6.91) (6.91) (6.91) (6.91) (6.91)

c c

B

B B

(636; R=2-CI, 5-0,NC,HJb (6%; R = 4-pyridyl) (6.96;R = 2-thienyl) (6.97; R = Me)' (6.97; R = Ph)' (6.97; R = p-HOC,H,)' (6.97; R=3,4(MeO),C6H3)' (6.97; R = 3-HO, 4-MeOC6H,)' (6.97; R = 2-CI, 502NC6H,)' (6.97; R = CH=CHPh) (6.97; R = 2-pyridyl) (6.97; R = 3-pyridyl)

(6.96; R = Ph) 89 (6.96; R = O - O ~ N C ~ H , 89 )~ (696; R = o-OZNC,H,) 86 (6.96; R = m-O,NC,H,) 82 (696; R = P-O~NC~H,) 85 (6.96; R = 3,4-C12C,H,)b 84 (6.96; R = m-HOC,HJb 81

A

B

(6.94; R = Ph) (6.91)b (6.94; R = o - O ~ N C ~ H ~ ) (6.94; R = m-O,NC,H,) (634; R = P-O~NC~H,) (6.9Ub (6.91)b

86 75 75

84

81

87 85 79 86 80 82

96

89

(6.96; R = Ph)b

A

(6.9lIb

Yield

(% 1

Product

Reaction conditions'

Starting material

J

140 219-220 252 240 (decomp.) 240 (decomp.) 290 (decomp.) 258-260 163 169 (decomp.)

68 68 68 68 68

J J --I -I

J J 1 '

68 68 68 68 68 68

68

68 68 68 68 68 68 68

68

Ref.

J

2 J -J

-f

J

-

Yellow prisms Red prisms Red prisms Red prisms J CoIorIess needles Red-brown prisms

-e

Colorless needles

Crystal form

J

J

-d

d

-

Ethanol

-h

-6

125

Ethanol Ethanol Light petroleum Light petroleum Ethanol Ethanol

-d

-c 155 64 92 91 125- 130 156

Ethanol-ether

Solvent of crystallization

135

m.p. ("C)

BY RING-CLOSURE REACTIONS OF TABLE 6.9. SYNTHESIS OF ~,~,~Q,~-TETRAHYDRO-~H-PYRROLO[~,~-Q]BENZIMIDAZOLES N-(2-AMINOPHENYL)PYRROLIDINEDERIVATIVES

3

(6.92)'

E

F

(6.91)

(6.91)

(6.68)

G

I

(6.87)

96

a4 41

30

32

-

52

-n

88-89.5 122-124

90

(decomp.) >360 (decomp.) 145-150 (decomp.) 85-86

>300

-

Ethanol-water Carbon tetrachloride

J

-1

J

Water

Acetic acid-water

Colorless needles -

J

Colorless prisms Colorless prisms

J

Colorless prisms

J

59

54 59

57

51

68

69

68

'

'

a A = RCHO, EtOH/(roorn temp.)(14 hr); B = conc. HCI, EtOH/(roorn ternp.)(l4 hr); C = RCHO, conc. HCI, EtOH/(room temp.)(l4 hr); D = RCHO, CF,CO,H, CCl,/(reflux)(l hr); E = Alloxan, conc. HCl, EtOH/(room temp.)(l4 hr or 3 days); F = Ac,O or (EtCO),O/heat. G = HgO, EDTA, EtOH-H,O (1 : l)/(room temp.)(few min); H = PhNO,/(reflux)(3 hr); I = Diethyleneglycol dimethyl ether/(reflux)(3hr). Hydrochloride. b.p. 160"/0.6 mm Hg. Purified by distillation. Yellow liquid. f Crystal form not specified. 8 b.p. 165-170°/1 mm Hg. b.p. 160-165"/1 mm Hg. ' Hydrate. I Solvent of crystallization not specified. Dihydrate. Hemihydrate. Acetic acid solvate. " Yield not quoted.

(6.98; R = Ph) (6.88)

H

(6.91; NHCOPh for NH,) (6.67)

(6.98; R = Ph)

F

R' = R2= H)

(6.72;

(6.98; R = Me)

F

R' = R2 = H)

(6.72;

(6.93)

(6.92)"'

E

(6.91)

38

Condensed Benzimidazoles of Type 6-5-5

the basis of deuterium labeling studies6' are suggested to follow a course (Scheme 6.20) initiated by intramolecular proton transfer [(6.94) +(6.95) 4 (6.%)]. In contrast, the condensation of the amine (6.91) with aliphatic or aromatic aldehydes in carbon tetrachloride in the presence of trifluoroacetic acid leads to high yields (Table 6.9) of the corresponding 2,3-dihydro-lHpyrrolo[ 1,2-a]benzimidazoIium salts [Scheme 6.20; (6.97)] as a result of oxidation of the first-formed tetrahydro compounds (6.96) by the solvent. The formation (Scheme 6.20 and Table 6.9) of the betaine (6.92)av6g bY condensation of the amine (6.91) in ethanolic hydrochloric acid can likewise be r a t i o n a l i ~ e d in ~ . terms ~ ~ of initial anil formation followed by cyclization to and in situ oxidation of a tetrahydro- 1H-pyrrolo[1,2-a]benzimidazole intermediate [cf. Scheme 6.20; (6.91) --.* (6.94) -+ -+ (6.96) +(6.97)]. In the similar condensation6' of the amine (6.91) with N-methylisatin, the tetrahydro intermediate (6.93) is stable enough to be isolated (Table 6.9). The isolation in moderate yield (Table 6.9) of 4-acyl-2,3,3a,4-tetrahydro-lHpyrrolo[ 1,2-a]benzimidazoles [Scheme 6.20; (6.98)] when N-(Z-azidopheny1)pyrrolidine [Scheme 6.15; (6.72; R' = RZ= H)] is thermolyzed" in carboxylic anhydrides and the high yield thermolysis (Table 6.9) of N-(2azidophenyl)pyrrolidin-2-one to 2,3,344-tetrahydro- 1H-pyrrolo[ 1.243benzimidazol- l-one [Scheme 6.18; (6.&7)4(6.88)p9provide evidence for the intermediacy of 2,3,3a,4-tetrahydro-l H-pyrrolo[ 1,2-a]benzimidazoles in the presumed nitrene-initiated cyclizations of N-(2-azidophenyl)pyrroIidines leading to 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole derivatives (see before). 4-Benzoyl-2,3,3a,4-tetrahydro-1H-pyrrolo[l,2-a]benzimidazole (6.98; R = Ph) is also formed in high yield (Table 6.9) by the oxidative cyclization of N-(2-benzamidophenyl)pyrrolidine [Scheme 6.20; (6.91; NHCOPh for NHz)].54 6.1.2. Wysicochemid Properties

Spectroscopic Studies INFRAREDSPECTRA. N(4)-Unsubstituted 4H-pyrrolo[ 1,2-a]benzimidazoles exhibit22IR N H absorption at ca. 3500cm-', whereas the NH group in N(4)-unsubstituted 2,3,3a,4-tetrahydro- 1H-pyrrolo[ 1,2-a]benzimidazol-1ones [Table 6.11; (6.103; R = H or Ph)] gives rise to IR absorption at somewhat lower frequencies (3390-3280 ~ r n - ' ) . ' * * ~ Broad ~ absorption at of 3-hydroxy-1H-pyrrolo[ 1,2-a]benz3 100-2200 cm-' in the IR imidazol-1-ones [Table 6.1 1; (6.101; R' = OH)] demonstrates the strongly chelated nature of the hydroxyl group in such molecules. The presence of a band at 3400cm-' (OH) and the absence of absorption at 1470cm-' (N=O) in the IR spectra"' of the acid salts of l-nitroso-4H-pyrrolo[1,2-a]benzimidazoles show that these compounds exist in the oximino tautomeric form [Scheme 6.21; (6.105)] rather than the nitroso form (6.104).

H H H H H H H H H H H H H H H H H H H H Me Me COPh CN

H H H H H H H H H

H H H H H H H H H H Me Me Me CH,Ph

H

R?

R'

Medium not specified. KBr.

Compound

R4

Nujol. CHCI,-.

Me Me COMe Me Me C02Et Me C0,Et C02Et Et C0,Et Et C02Et CH2Ph C02Et Me C0,Et Et Me COMe Me COMe Me C02Me CH,Ph C0,Me Me C02Me Me CO,Et Et C02Me CH=CHCO,Me CH2C02Me CH2COMe H p-BrC,H,COCH, H P - N O ~ C ~ H ~ C O C HH~ CH,COPh H CH2COPh Ph COPh COPh H C0,Et

R3

(6.99)

-

-

-

COMe Me COPh p-BrC,H,CO COPh p-BrC,H,CO COPh C0,Me C0,Me C0,Et CN COPh COPh C02Me C0,Me C0,Me H H H H H H Me Me H H H H H H H H H C0,Me C02Me C0,Me C0,Me C0,Me C02Me Me p- BrC,H, p-N02C6H4 Ph Ph

-

(6.100)

R"

.

R'

~

-c -A -

-

-

-0

-b

-

-b

-2'

-h

-*

-a -b -h

-'

-h

-'

-b

0

-

-*

1640-1 620 1640-1620 1690, 1620 1685,1610 1695, 1620 1680,1610 1702,1630 1705,1650 1675,1650 1680,1640 2200,1640 1735,1685 1722,1695,1618 1742,1690,1655 1740,1726,1694 1740.1710.1690 1735.1706, 1691 1740 1710 1692 1696 1688 1680 2140,1745

46 45

19

12,13 12,13 23 23 23 23 24 23 23 21 21 23 24 23 29 23 25 19 19 19 19

Ref.

TABLE 6.10. INFRARED SPECTRA OF CARBONYL DERIVATIVES OF 4H-PYRROLO[ 1.2-a]BENZIMIDAZOLES (6.99) AND 2,3,3a,4TETRAHYDRO-1H-PYRROLqI ,2-a]BENZIMIDAZOLES (6.100)

40

Condensed Benzimidazolesof Type 6-5-5

TABLE 6.11. LNFRARED SPECTRA OF ~H-PYRROLO(~.~-Q]BENZMIDAZOL-~ONES (6.101). 25DIHYDRO- lH-PYRROLq1,2-a]BENZIMIDAZOL1-ONE (6.102)AND 2,3,3&4TET'RAHYDRO-lH-PYRROLq1,2QJBENZMDAZOL-1-ONES (6.103)

(6.101)

Compound

(6.101) (6.101) (6.101) (6.102) (6.102) (6.102) (6.103) (6.103)

(6.102)

R

R'

-

Ph OH OH

-

-

-

H Ph

-

Medium

RZ

-

(6.103) u,,(cm-')

Ref.

1745 3 100-2200' 3100-2200, 1740 1760 1755 1755 3280, 1690 3390, 1705

4 2 5 41 38 38 59 38

Medium not specified. KBr. 'C=O absorption not quoted. CHQ. Nujol.

The IR spectra" of 6- and 7-azido-2,3-dihydro- 1H-pyrrolo[ 1,Zalbenzimidazoles contain orthodox IR azide absorption at 2120 cm-',which serves to characterize these otherwise relatively unstable molecules. The similar IR stretching frequencies (Table 6.10) for the cyano groups in the molecules (6.99; R' = R2 = R5 = H, R3 = Me, R4 = Ac, R6= CN)" and (6.100; R' = CH2Ph, R2=CN, R 3 = H , R4=C02Et)45 implies a surprising lack of sensitivity to conjugate effects on the part of the cyano substituent in the former case. In contrast, the marked variation in carbonyl stretching frequency (Table 6.10) with the site of substitution, observed for carbonyl derivatives of 4H-pyrrolo[ 1,2-a]benzimidazoles is directly attributable to the presence

N=O

R (6.104)

R

X[X= a of ao41 !wluoe 6.21

(6.105)

X-

6.1. Fused Benzimidazoleswith

No Additional Heteroatoms

41

COR

J"

(6.107)

(6.106)

sebcgc 6.22

z

0-

(6.108)

or absence of conjugative interaction with the bridgehead nitrogen atom. 12*13 Thus, in accord with their vinylogous amide character [Scheme 6.22; (6.106) t* (6.107) f+ (6.108)] ester and ketonic substituents at the C(1) and C(3) positions in 4H-pyrrolo[ 1,2-a]benzimidazoles absorb at significantly lower frequencies (cf. Table 6.10) than their C(2) counterparts. Conversely, the much higher carbonyl frequencies (Table 6.11) observed for IH-pyrrolo[1,2-afienzimidazol- 1-ones (6.101) and their 2,3-dihydro analogs (6.102) compared with normal amides may be attributed38 to the absence of the usual nitrogen-carbonyl interaction in the latter as a result of preferential conjugation between the bridgehead nitrogen atom in (6.101) and (6.102) with the other nitrogen center and the benzene ring. In accord with this interpretation are the markedly lower carbonyl frequencies (Table 6.11) found for 2,3,3a,4-tetrahydro-1 H-pyrrolo[1,2-a]benzimidazol-1-ones (6.103). The IR spectra" of simple 3H-pyrrolo[ 172-a]benzimidazoles contain characteristic bands at 1630-1625 cm-'.

ULTRAVIOLET SPECTRA.The U V spectra (Table 6.12) of 2,3-dihydro-lHpyrrolo[ 1,2-a]benzimidazoles (6.111), not unexpectedly in view of the saturated nature of the fused five-membered ring present, resemble that of 1methylbenzimidazole. Correspondingly, the U V absorption69 of the 2,3dihydro- lH-pyrrolo[ 1,2-a]benzimidazolium betaine [Scheme 6.20; (6.92)] is akin to that of the benzimidazolium cation. The essential lack of conjugation involving the C(1)-C(2) double bond in 3H-pyrrolo[ 1,2-a]benzimidazoles [Table 6.12; (6.109)], and the carbonyl group in 2,3-dihydro-lHpyrrolo[ 1,2-a]benzimidazol-l-one[Table 6.12; (6.112)] likewise results in U V spectra (Table 6.12) not too far removed from those of simple benzene derivatives. In contrast, the U V spectra2 of the 1H-pyrrolo[ 1,2-a]benzimidazole derivatives [Scheme 6.23; (6.113) and (6.114)] exhibit the marked bathochromic shift in U V maxima anticipated from the extensive conjugation present.

P

h)

R' R2

-

-

-

-

-

-

(6.110) (6.110) (6.110)

(6.110)

(6.110) (6.110) (6.110)

(6.110)

-

-

(6.109 (6.109) (6.110)

Compound R

(6.109)

R'

Me

Me Et Me

Et

Me Me Me

Ph Ph Me

R'

C0,Me

C02Et C02Et C0,Me

C0,Et

Ph C0,Et

H

Ph P-'m6H4 H

(6.110)

a,-R2

H

C0,Me

H C0,Me

C0,Me

p-BrC6HaCO p-BrC6HdCO C0,Me

C02Me

H

H

Me H C0,Me

rn -N02C6H,

A

B

B B

B

B B

B

B

H

p-MeC6H, p -PhC6H4

A A

-

-

-

(6.111)

272(4.26), 310(3.8) 272(4.43), 310(3.94) 263(4.20), 283(4.20), 330(3.80) 25q4.22). 36q4.60) 268(4.35) 246(4.73), 313(4.07), 32q4.02) 2W4.63). 294(4.18), 313(4.10), 327(4.17) 227(4.41), 333(3.77) 228(4.42), 332 (3.81) 247(4.49), 292(4.29), 331(4.22) 214(4.39), 247(4.45), 291(4.36), 332(4.27)

26, 27

23 23 23

23

15 15 23

15

10 10

TABLE 6.12. ULTRAVIOLET SPECTRA OF 3H-PYRROLq1,2-a]BENZIMIDAZOLES (6.109), 4H-PYRROLO[ 1,2-a]BENUMIDAZOLES (6.110), AND 2.3-DIHYDRO- lH-PYRROL0[1.2-a]BENZIMIDAZOLES (6.111) AND (6.112)

’ B B

-

-

-

-

Me CHkHC0,Et

CH*HCO,Et

-

(6.110) (6.110)

(6.110)

-

-

(6.112)

-

-

C0,Me

C0,Me C0,Me

C0,Me

C0,Me

-

-

H

COPh H

C0,Me

C0,Me

C0,Et

B

D

B

C

B

A

B

A

C

A = methanol; B =ethanol; C = methanol+3 drops of 72% HCl0,aq; D = phosphate buffer (pH 8).

-

-

(6.111)

a

-

-

C0,Me CH,CO,Me

C02Me

C0,Et

(6.111)

(6.111)

_.

-

-

Et

(6.110)

(6.111)

CH,CO,Me

Me

C0,Et

A

(6.110)

C0,Et

C0,Et

Me

C0,Et

C

(6.110)

C0,Et

C0,Me

Me

C0,Me

(6.110)

C0,Me

Me

(6.110) 214(4.39), 247(4.45), 291(4.36), 332(4.27) 214(4.66), 247(4.74), 291(4.64), 332(4.56) 214(4.65), 247(4.71), 291(4.63), 332(4.54) 216(4.45), 24N4.51). 292(4.41), 332.5(4.31) 215(4.43), 247(4.48), 292(4.38), 331(4.31) 234(4.51), 330(3.83) 215(4.29), 240(4.50), 262inf (4.35). 315(4.41) 21 l(4.29). 238(4.46), 260 inf (4.23) 255(3.69), 284(3.66), 292(3.65) 243(3.72). 248(2.95), 266(3.58), 271(3.7 1). 278(3.72) 255(3.69), 284(3.66), 292(3.65) 255(3.69), 284(3.66), 292(3.65) 233(4.22), 275 inf (3.20)

38

48

48

67

48

25

23 25

23

29

27

27

26, 27

44

Condensed Benzimidazolesof Type 6-5-5

R (6.113)

OMe (6.114) 6.23

The UV spectra (Table 6.12) of 4H-pyrrolo[ 1,2-a]benzimidazoles (6.110) are typified by the presence of two or more intense absorption bands at relatively long wavelength consistent with the high degree of delocalization and aromatic character (see later) associated with these molecules. These spectral properties have been put to practical use in the formulation of cyanine dyes based on 4H-pyrrolo[ 1,2-u]benzimidazole frameworks which absorb strongly in the visible region at 520-680 nm.” The somewhat longer wavelength absorption of l-acyl-4H-pyrrolo[ 1,2-u]benzimidazoles in comparison with the less extensively conjugated 3-acyl isomers has been used as a criterion for assigning the position of acylation in 4H-pyrrolo[l,2-a]benzimidazoles (see later).”*” The low basicity of polyacylated 4H-pyrrolo[ 1,2ulbenzimidazoles is demonstrated by the invariability of their UV absorption (Table 6.12) in changing from neutral to acidic solution. NUCLEAR MAGNETIC RESONANCE SPEW. Representative examples of the ‘HN M R spectra of pyrrolo[ 1,2-a]benzimidazole derivatives of the different

structural types are collected in Tables 6.13-6.16. The C(1) protons in the 3H-pyrrolo[ 1,2-u]benzimidazole derivatives [Table 6.13; (6.115)] absorb in the range 6 6.80-8.00, whereas the protons at C(3) give rise to signals at higher field (6 5.15-5.38).” The relatively high-field position for the latter in comparison with the low-field absorption of the C(3) proton in 4H-pyrrolo[l,2-u]benzimidazolesprovides a clear cut distinction between the 3 H and 4 H tautomeric forms of pyrrolo[l,2-a]benzimidazoles of utility in assigning the structures of the debenzylation products of 4-benzyl-4H-pyrrolo[ 1,2-a]benzimidazoles.l7 ‘H NMR signals associated with protons at the C(1) position in 4Hpyrrolo[ 1,2-a]benzimidazoles [Table 6.14; (6.116)] appear at significantly lower field (6 6.45-6.55) than those of their C(3)H counterparts (6 4.955.83) with which they are weakly coupled (J = 1 hz) (Table 6.14).13*’7Additional splitting (J = 1 Hz)of the C(1) proton resonances, which arises as a result of coupling with C(2)alkyl substituents, is absent in the signals due to the C(3) protons. The ready differentiation of unoccupied C(1) and C(3) positions in 4H-pyrrolo[ 1,2-~]benzimidazoleson the basis of these differing ‘HNMR characteristics of the C(1) and C(3) protons allows the determination of the site of electrophilic substitution in such molecules (see ~ater).‘~,’’”~

6.1. Fused Benzimidazoles with No Additional Heteroatoms

45

TABLE 6.13. 'H NMR SPECTRA"*bOF lH-PYRROLq1,2-a]BENZIMIDAZOLE AND 3H-PYRROLqI ,2-a]BENZIMIDAZOLE DERIVATIVES

(6.114)-(6.115)

Et

P

R

OMe

H

(6.114) Compound

R

(6.114) (6.115) (6.115)

-

Ph p-MeOC6H,

H

(6.115)

Solvent'

H(1)

H(3)

ArH

Ref.

A B

0.40td, 2.200ct' 6.80-8.00m1 6.80-8.00mp

4.30' 5.15 5.38

7.10-7.90m

2

B

6.80-8.00mR 6.80-8.00mo

17 17

S values in ppm measured from TMS. Signals are sharp singlets unless otherwise specified as t = triplet; oct =octet; m = multiplet. A = CDCI,; B = Me,SO. Me of Et. CH, of Et. f MeO. ArH t H(1).

Comparison of the 'H NMR spectra of 4H-pyrrolo[ 1,2-a]benzirnidazoles in neutral (carbon tetrachloride) and acidic (trifluoroacetic acid) solution (Table 6.14) demonstrates preferential protonation at C(1) in the absence of a C(1) substituent and competing protonation at C(1) and C(3)when a C(1) alkyl substituent is present.'4*72s74.77 A feature of the 'H NMR absorption (Table 6.14) of the resulting 4H-pyrrolo[ 1,2-a]benzirnidazolium cations (6.117)and (6.118)is the predictable downfield shift (compared with the parent bases) in the resonances of protons at the alternative C(3) and C(1) vinyl sites and in attached alkyl s u b s t i t u e n t ~ . Additionally '~~~~ the protons of N(4) alkyl substituents show a shift to lower field roughly double that experienced by a C(3) methyl substituent (Table 6.14) implying considerable delocalization of the positive charge in the 4H-pyrrolo[ 1,2-a]benzimidazolium cations (6.117)and (6.118)to the N(4) and N(9) centers.72A further feature of the 'H NMR absorption (Table 6.14) of cations of the types (6.117) and (6.118)is homoallyl coupling ( J = 1.5-2.5 Hz) between C(1) and C(3)vinyl methyl groups and protons at the alternative C(3) and C(1) of the effect of structure on the 'H NMR absorption of 4H-pyrrolo[ 1,Za]benzimidazoles in trifluoroacetic acid also provide useful information on the equilibration and relative stability of 4H-pyrrolo[ 1,2-a]benzimidazolium cations. C(1) Acyl substituents in 4H-pyrrolo[ 1,2-a&enzimidazoles exert a paramagnetic anisotropic effect at C(8), resulting in the specific deshielding of H(8), which resonates in the range 6 8.139.80.23This effect permits the

P

u?

3.79" 2.38' 2.808

2.36'

5.53dk 5.69

5.59

-

R' = p-MeOC,H,) (6.116;R' = R2 = Me, R3 = p-BrC,H,, R4 = H) (6.116;R' = R4= Me, R2 = H, R3 = p-PhC,H,) (6.116;R' = CH2Ph, R2 = R' = Ph, R4 = H) (6.116;R ' = R2 = Me, R' = Ph. R4 = H)

R3= Ph) (6.116;R' = CH,Ph, R2 = R4 = H,

R3 = Ph)

(6.116;R' = CH2Ph, R2= R4=H,

-

5.55 5.57d' 5.83

(6.116;R' = Me, R2 = R4 = H, R3 = Ph) (6.116;R' = Me, R2 = R4 = H, R' = Ph) (6.116;R' = CH2Ph, R2 = R4 = H,

1.Y7dd.' 2.23' 2.30R 1.96' 1.95de.h 1.99' -

Me

-

H(3)

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

H(2) 4.95dd 5.15 4.94

Solvent' H(1)

3.69

5.04

3.60

3.72

5.24

5.05

3.44 3.51 5.25

_f

J

3.5 1

J

N(4)CH

~~

6.50-7.00111

7 .OO-7 .60m1

72

17, 72

17

-n

17

72

17 72 17

13

13 21 13

Ref.

17

Others

-

7.08-n.001

6.50-7.001

6.90-8.00111' 6 SO-7 .OOm 7.00-8 .OOm'

6.77

6.75 6.95-7.3511 6.82

ArH

DERIVATIVES (6.116b(6.119) 'H NMR SPECTRA".h OF 4H-PYRROLql,2-a]BENZIMIDAZOLE

(6.116; R' = R" = Me, R2 = R4 = H ) (6.116; R' = R3 = Me, R2 = R4 = H) (6.116; R' = R3 = R4 = Me, R2 = H)

Compound

TABLE 6.14.

5

(6.116;R' = Me, R2= R3= R4= C0,Me)

R4= COPh) (6.116;R' = CH2Ph, R2= R3= C02Me, R4= COPh) (6.116;R' = Me, R2= R3= R4= C02Me)

(6.116;R' =Me, R 2 =R'= C02Me.

R3= Ph. R4= C02Et) (6.116;R' = R3= Me, R2 = COMe, R4= CN) (6.116;R' = CH,Ph, R2 = C02E1, R3= H, R4= COPh)

(6.116;R' = Me, R2 = COPh,

R4= COPh) (6.116;R' = R3= Me , R' = H, R4= N=NPh) (6.116;R' = R' = Me, R2= COMe, R4= C02Et)

(6.116;R' = R3= Me, R2 = H, R4= COMe) (6.116;R' = R3= Me. R2 = H.

R4= CHO)

(6.116;R' = R4= Me, R2= R' = Ph) (6.116;R' = R' = Me. R2= H.

R3= Ph) (6.116;R' = R2 = R4= Me, R3= Ph)

(6.116;R' = R4 = Me, R2= H, 2.578 2.25' 2.65" 2.15'

C

2.33' 2.59" 1.42tP.' 0.97tks

B

C

C

C

C

C

G

3.76"' 3.83"' 3.30"' 3.72"' 3.86"' 3.93" 4.00" 3.93" 3.87" 3.80"

2.28' 2.46" 1.27tP

3.20'

F

B

-

-"

A

4.12

4.23

5.72

2.90

6.10

3.87

3.91

4.0 1

4.20

0

-n

2.13'

3.46

-

3.70

3.50

A

A

C

2.69a

C

7.00-7.40111 8.64'

26.27

23

24

23

24

7.22-8.00m 7.23111 7.73 6.86-7.63111 8.08-8.36m' 7.36111 8.40'

21

21

21

70

13

13

72 13

72

72

6.95-7.55111

6.75-7.45m

7.05-7.25m

7.60-8.50m

6.98

6.89

6.50-7 .OOm 6.88

6.50-7.00m

6.50-7.00111

OC

P

(Continued)

5

R2

(6.116)

RI

R'

6\

& R 7 $4-

(6.116; R' = CH&CHCO,Me, RZ= CH,CO,Me, R' = CO,Me, R4 = H) (6.117;R1= R2= R' = Me, R4 = H, X=Cl)

(6.116; R' = Me02CCPCHC02Me, R2 = R3 = R4 = C0,Me)

I

(6.116;R1= CH&CHCO,Me, R2 = R3 = R4 = C0,Me)

(6.116;R' = Me, R2 = CO,Et, R3= R4 = C0,Me)

(6.116;R' =Me, R2 = R3= R4 = C02Et)

(6.116;R' = Et, R2 = R3 = R4 = C0,Me)

Campound

6

8

RI

R2

R' X-

4.72

G

-

-

-

-

-

-

-

H(3)

67 \ @

-

-

-

7.74

-

-

-

-

H(2)

-

C

C

C

-

-

C C

-

H(1)

C

Solvent'

(6.117)

7q..pR4

TABLE 6.14

q

3.90" 3.95" 4.02" 1.41tp 1.36tp 1.34tp 3.93" 3.99" 1.36Pq 3.90" 3.94" 3.96" 4.00" 3.82" 3.79" 3.76" 3.60" 3.53" 3.90" 3.85" 3.75" 2.25' 2.19'

Me

(6.118)

e

*

M ~ H R

M

7.45 8.87m'

8.YOm'

7.80m 7.30-7.60m

7.20-7.60m 8.80m'

7.00-7.40m 8.70m'

7.33m 8.40'

ArH

3.95

7.40m

7.98dvSw 7.05-7.60m 5.36dX."

6.75"

9.62dU," 6.37dx3"

4.22'

4.18

1.43tP 4.76q'

N(4)CH

phCF,CO;

-

4.93y

-

-

4.33q'.q

4.01-4.56m'

-

Others

Me R) ' (6.119

:c&&c:2 8

14

25

28

28

29

27

23

Ref.

x-

P \o

(6.118;R = Ph) (6.119; R' = H, R2 = Me, Y = NNHPh, X = CF3C0,) (6.119; R' = H,R2 = Me, Y =NOH, x = CIO,) (6.117;R' = R3 = R4 = Me, R2 = CONHCOPh. X = CF,C02) (6.117;R' = R2= R4 = Me, R2 = CSNHCOPh, X = CF3C02) (6.119;R' = H,RZ= Me, Y = C(0H)NHCOPh. X = CF,C02) (6.119;R' = H, R2 = Me, Y = C(SH)NHCOPh, X = CF3C0,)

(6.117; R' = Me, R2 = R4 = H, R3= Ph, X = CF3C02) (6.117;R' = CH2Ph, R2= R4 = H, R' = Ph, X = CF3C02) (6.117;R' = R2= Me, R3= Ph, R4 = H, X = CF,CO,) (6.117;R' = CH,Ph, R2 = R3 = Ph, R4 = H, X = CF3C02) (6.117; R' = R4= Me, R2 = H, R3 = Ph, X = CF,C02) (6.117;R' = R2 = R4= Me, R3= Ph, X=CF,C02) (6.117;R' = R4 = Me, R2 = R'= Ph, X = CF,C02) (6.118;R = H) (6.118; R = Me)

(6.117;R' = R3 = R4= Me, R ~ = H X=CI) , (6.117;R' = R2 = R3 = R4 = Me, X = Cl)

6.76qd

-

6.46 6.39

-

-

4.93qq 4.96qq

-

G

G G

G G

5.68q""

6.80q"

4.38q"" 4.68q"'

G G

-

-

-

G

G

-

5.82qq

G

-

-

1.98'

1.52dg*q 2.18' 1.53d8*q 2.02' 1.98'

2.15d'.d

2.87dg."" 2.84g.a" 1.64dI.q 2.92ds*" 2.73d'.d

1.72dg.q 2.63'."" 1.89dg4

3.57

3.57

3.7 1

3.70

3.77

3.90 3.92

4.20 4.25

3.57

4.25

-

-"

G

1.90d8.q

4.15

7.31

-

5.93qq

G

5.67

5.69

5.38

G

-

4.17

4.05

3.85

-

5.33q""

G

7.31

-

-

2.19' 2.31' 1.688.q

1.608

2.22d'*d

4.28

5.54

G

7.38

-

-

6.60q'

-

-

5.57

4.95qq

G G

5.ooqq

G

74

-

74

74

74

-n

70

72 70

72 72

72

72

72

7.35

6.50-7.00m 7.30-7.70m

6.50-7.00m 6.50-7.00m

6.50-7.00m

6.50-7.00m

6.50-7.00m

72

72

6.50-7.00m 6.50-7.00m

72

72

14

14

6.50-7.00111

6.50-7.00m

7.50

7.45m

t~,

(Continued)

-

-

-

-

G

G G G

-

-

-

6.53

-

-

G

6.38

-

H(3)

-

H(2)

G

Solvent' H(1)

2.10'

2.05' 2.05' 2.06' 2.13' 2.15'

-

-

Me

3.93

3.92

3.95

3.82

3.73

3.82

N(4)CH

Signals are sharp singlets unless otherwise specified as: d = doublet; t = triplet; q = quartet; m = multiplet. A = tetrahydrofurane; B = CCI,; C = CDCI,; D = Me2SO; E = CHCI,; F = CS,; G = CF,CO,H. dJMe(Zt-H(3)= 1.0-1.5Hz. 'Me(2). Me(4) not quoted. Me(1). Jhfe,,,,,,,= 1.0 HzMe(3).

6 in ppm measured from TMS.

(6.119;R' = H, R' = Ph, Y = C(OH)NHCOPh, X = CF,CO,) (6.119;R' = H,R2= Ph, Y = C(SH)NHCOPh, X = CF,C02) (6.119;R' = R2= Me, Y = C(0H)NHCOPh. X = CF,CO,) (6.119;R' = R2 = Me, Y = C(SH)NHCOPh,X = CF,C02) (6.119;R' = Me, R2 = Ph, Y = C(OH)NHCOPh, X = CF,C02) (6.119;R' = Me R' = Ph, Y = C(SH)NHCOPh,X = CF-CO,)

Compound

TABLE 6.14

-

-n

-

-

-

-

-

-

Others

-

ArH

14

14

74

74

74

74

Ref.

H(1) masked by ArH.

COMe. Me of Et group.

J = 13.614.5 Hz. Vinyl H(2). CH,.

" ?his signal may be interchanged with M a . " Vinyl H(1).

' H(8).

4

J = 7.0-7.5 Hz. ' CH, of Et group. ' H(5).

P

" not quoted.

MeO.

' ArH+H(l).

'I H ( I k H ( J ) = l.o Hz'

J

N

VI

= RZ= R' = R4 = R5 = H) = R2 = R' = R4 = = H) = R3 = R4 = R5 = H, R2 = Cl) = R2 = R3 = RS= H,

R4 = 1-pyrrolidinyl) (6.120; R' = R4 = Rs = H, RZ= R' = Cl) (6.130; R' = R4 = Rs = H, R2 = NHAc, R' = NO,) (6.120; R' = R4 = RS= H, R2 = NH,, R3 = NO,) (6.120;R' = R4 = Rs = H, R2 = N,, R3 = NO,) (6.120;R' = R2 = Rs = H, R3 = NO,, R4 = a) (6.120; R' = R2 = RS= H R' = NO,, R4 = 1-pyrrolidinyl) (6.120;R' = R2 = RS= H, R' = NO,, R4 = 1-piperidinyl) (6.120;R' = R2 = R' = H, R3 = NO,, R4 = 1-perhydroazepinyl) (6.120;R' = R2 = R' = R4 = H, RS= OH) (6.120;R' = R2= R4 = H, R3 = NO,, R5 = OAc)

(6.120;R' (6.120; R' (6.120; R' (6.120;R'

Compound

-

-

-

7.80m

6.28q" 8.60d"

4.57q" 2.503.60111

4.12t' 4.03t' 3.80-4.60m 4.37m

B B

B

B

2.64-3.27n1 +

c 2.48-3.21m

c

4

c 2.543.18m -+

4.08t'

B

--+

-

c 2.64-3.32m

4.22tr

B

c 2.90-3.85rn

-

-

8.53

4.55-4.93t"

B

7.55df

8.19df

7.10-7.40m

6.79dl

6.55df

7.23df

7.77

7.97

8.88

7.36

7.26dh 6.64dd'

7.48df

6.70df

73

-

2.17q

65

65

73

73

73

71

71

-

71

73

30 67 73 73

Ref.

n

2.55"

-

3.79te.k 1.82-2.13m'

-

-

Others

(6.124)

R'

3.79te.' 1.81-2.1 lm' 3.38-3.60111' 1.63-1.86m' 3.42-3.69m' 1.48-1.93m' 7.8brP

R

H(8)

-

7.68dr

7.73df

7.80d'

-

-

2.90-3.85m + 8.91

--+

-

7.12tJ

-

-

-7.10m 7.18ddg 6.32dd'

9.13

2.90-3.Wm

4.55-4.80t" t

H(7)

-

7.78

-

7.60m 7.62df

B

+-

H(6)

c----- 7.00-7.70m

H(5)

(6.123)

CH,R

-

2.53-3.27m +

t

t

4 --*

c 2.48-3.22m

2.44-3.21m

-+

2.75td

+ 2.00-3.10m

2.25m

H(3)

4.58-4.84t"

4.061'

3.60td 3.91t' 4.01t' 4.00t'

H(2)

(6.122)

0-

B

B

B B B

A

H(l)

'OCOM~

Solvent'

(6.121)

Me'

8

'H NMR SPECTRA4b OF 2,3-DIHYDRO-lH-PYRROLO[ 1,2-a]BENZIMIDAZOLE DERIVATIVES (6.120)-(6.124)

(6.120)

TABLE 6.15.

cn w

D

(6.123; R = CH=CHF'h)"

-

-

4.55tl

4.40ti

4.40ti

4.34tJ

4. 13tC 4.26t' 4.58t' 4.49t'

4.03t'

4.26d

+

4

7.90d' 8.69dh

7.00-7.70m

6.90-7.80m

7.40-7.70m

7.20-7.5Om-

7.20-7.90 7.80m 7.10-7.90m

-

8.20m

7.27-7.36m 8.45ddg 7.92df 7.00-7.50m

c----- 7.14-7.38m

7.80m -7.00-7.45m

- - - --

5.2Od(brb-

3.50tJ

3.40tJ

3.431'

3.35tJ

3.18t' 3.37t' 3.601' 3.54t1

-

c-3.50-4.00-

-3.17-

3.00m

.2.60m

2.88m

2.85quin.'

2.62quin. 2.85q' 2.80q' 2.90quin.I

3.17m

6.40(br)P

-

1.57tJ 4.47q' 5.25" 7.40" 6.88dW*' 7.31d"*' 5.43" 6.20" 6.25" 5.42" 5.85-6.60mY 4.88"

-

2.18q 2.58'.k

a

6 in pprn measured from TMS. Signals are sharp singlets unless otherwise specified as: d =doublet; t = triplet; q = quartet; quin. =quintet; dd = double doublet; m = multiplet. A = pyridine; B = CdCI,; C = CF,CO,D; D = D,O; E = (CD,),SO; F = CF,CO,H; G = CDCI,-(CD,),SO. J = 6.7 Hz. 'J=7Hz. fJ=9Hz. K J = 2and 9Hz. OCOMe. J = 2 Hz. ' CH,DC. ' J = 7 . 5 and 1.5 Hz. ' Hydrochloride. ' J = 7.5 Hz. ' J = 2.5 Hz. ' N(CH,), of C(5) substituent. " Chemical shift in ppm relative to HOD. (CH,), of C(5) substituent. + J value not quoted. " =NCH,-. " COMe. ArH. " J = 7 and 4%. MeO. OH. Y -CH?cH-.

G

D

(6.123;R = 3.4-(MeO),C6H,)"

E F

D

(6.123;R = p-HOC6H.J"

(6.124;R' = R2= H) (6.124: R' = R2= H) (6.124;R' = OH, R2= Ph)

D

D

D

C

B

B

(6.123;R = Ph)"

(6.122;R = H)' (6.122;R = Cl) (6.122; R = NO,)' (6.123;R = Me)"

(6.121)

38 38 2

68

68

68

68

62 62 62 68

65

~

A

B C

B

B

4.30-5.20111

-

4.WP

2.80-3.80m

-3.32-

-1.50-3.OOm--. -2.30-2.80m -2.60m-2.36-2.84m-

2.20-2.40111

1.70111

-

2.91-3.20qh

- -

2.20

-

6.15br 5.83t"'

5.40-5.49dh

5.03m

4.92

6.25-8.20m6.50-7.101117.42 c- 6.50-7.10m-7.25-7.60 6.60111 c 6.85m+7.55m t

-

-6.86-

6.10-7.50111-

'

-a

--

" 8 values in ppm measured from T M S . * Signals are sharp singlets unless otherwise specifiecl as: d = doublet; t =triplet; q = quartet; m = multiplet. A = CCI,; B = CDCI,; C = (CD,),SO. Not quoted. ' NMe. CH,Ph. 8 Ph. kH,Ph. h J value not quoted. ' J = 13 Hz. CH, of Et. " 5 = 7 Hz. Me of Et. NH.

(6.W (6.127; R = H) (6.127;R = Ph) (6.127: R = Ph)

R2= R4 = H, R3= Ph) (6.m;R' = CH2Ph, B RZ=R3=R4=H) (6.125;R'=CH2Ph, B R2 = CN, R3 = H, R4= C0,Et)

(6.125;R' =Me,

4.22' 7.23O 7.521~~ 4.61' 4.30qLh 1.34t'eh 3.78' 4.50bf 7.25-7.60mg 7.25-7.45mg

2.69'

76 59 38 38

45

68

75

TABLE 6.16. 'HNMR SPECTRA"*bOF 2.3,3a,4-TETRAHYDRO-lH-PYRR0~1,2-a]BENZIMIDAZOLE DERIVATIVES (6.125)-(6.UT

6.1. Fused Benzimidazoles with No Additional Heteroatoms

55

orientation of the 4H-pyrrolo[ 1,2-a]benzimidazole products formed in the cycloaddition reactions of benzimidazolium ylides with acetylenic esters.23 The protons at C( 1) in 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole derivatives [Table 6.15; (6.120)] resonate as a triplet in the range 6 3.64.6 clearly distinguishable from the C(2) and C(3) protons, which collectively give rise to a multiplet at S 2.0-3.9. The effect of a quaternary center at N(4), as in the salts (6.123) and the N-oxides (6.122), is to produce an overall downfield shift in the pyrrolidine ring proton resonances with specific deshielding of the protons at C(3).As a result, the signals due to the protons at each of the sites in the pyrrolidine ring become clearly discernable (Table 6.15). The deshielding effect of a quaternary nitrogen center is also seen in the comparatively low-field position of the C( 1) proton resonances in the salt [Table 6.16; (6.126)]. In general, however, the pyrrolidine ring protons in 2,3,3~,4-tetrahydro-1H-pyrrolo[ 1,2-a]benzimidazoles [Table 6.16; (6.125)] absorb at higher field than their counterparts in 2,3-dihydro- 1Hpyrrolo[ 1,2-u]benzimidazoles [Table 6.15; (6.120)]. In contrast, protons at the bridgehead [C(3a)] position in 2,3,3~,4-tetrahydro-1H-pyrrolo[ 1,2-a]benzimidazoles absorb uniformly at relatively low field in the range 6 4.96.2 (Table 6.16) making them clearly distinguishable from protons at the other ring positions. The relative deshielding of the C(8) proton in 2,3dihydro-1 H-pyrrolo[ 1,2-a]benzimidazol- 1-ones [Table 6.15; (6.124)] and their 2,3,3~,4-tetrahydroanalogs [Tables 6.16; (6.127)] may be attributed to the paramagnetic anisotropic effect at the C(8) position, of the C(1) carbony1 group in these molecules. MASSSPECTRA. Relatively little information is available concerning the mass spectral fragmentation pathways available to pynolo[ 1,2-a]benzimidazoles of the various structural types. The most comprehensive study to date who have examined in appears to be that of Anisimova and his colleague~,~" detail the mass spectral fragmentation undergone by 4H-pyrrolo[ 1,2-a]benzimidazoles [Table 6.17; (6.128)]. Apart from the primary loss of HCN observed in all cases, the electron-impact induced fragmentation (Scheme 6.24) of 4H-pyrrolo[ 1,2-a]benzimidazoles lacking a C(3) methyl substituent (6.128;R2#Me) is initiated by loss of the N(4) substituent from the molecular ion, the driving force being the formation of stabilized cations of the type (6.129). Subsequent breakdown of the latter can then be rationalized'" in terms of scission of the pyrrole ring with loss of C(2) and C(3) and the attached substituents as a discrete unit (i.e., an alkyne) and concomitant formation of the common ion (6.131), which fragments further in orthodox fashion by loss of HCN [Scheme 6.24; (6.131)+ (6.132) +etc]. This fragmentation pattern is akin to that observed for thiazolo[3,2-a]benzimidazoles and imidazo[ 1,2-a]benzimidazoles (see later). In the case of 3methyl-substituted 4H-pyrrolo[ 1,2-a]benzimidazoles, mass spectral fragmentation occurs by initial hydrogen atom loss from the molecular ion to give cations of the type (6.130) (Scheme 6-24).''

Condensed Benzimidazoles of Type 6-5-5

56

TABLE 6.17. MASS

SPEaRA".b OF DERIVATIVES (6.128)78

4H-PYRROLq1,2-a]BENZIMIDAZOL.E

(6.128)

R'

R2

R'

Me

H

Ph

Me

Me

Ph

CH,Ph

H

Ph

a

m/e (rel. abundance, %)

248(2.1),247(20.9),246(100), 245(7.5),244(2.4),232(5.5), 231(14.9), 230(3.7),229(3.6),204(1.3), 203(1.3),202(1.5), 200(l), 149(1.1). 129(7.3),128(1.7),127(1.2), 122(1.2), 118(1.2),115(2.1), 103(2.7),102(6.6),91(1.3), 81(1),78(3.4), 77(4.5), 71(1),57(2.1),56(8.1),55(2.1),51(1.4),43(7.6), 42(3.6),41(6.7), 40(5.1). 262(2.2),261(20), 260(100), 259(49.4),258(5.8),257(2.5), 246(3.3),245(15.6), 244(6.8),243(8.9),242(3), 218(1.2), 183(2.4),169(1.2),168(1.3), 157(1.1), 149(1.3), 140(1), 117(2.4), 116(2), 115(3.2), 109(1), 103(1), 102(2.3),92(1). 91(1),89(1),77(3.5),76(2.4),75(1.1),74(1),64(1). 62(1), 50(1.2),49(1). 324(3.2).323(21.2),322(76.3),321(18.2),233(3.4).232(28.8). 231(100), 204(1.0), 129(6.3),128(1.2), 115(1), 103(1.9), 102(2.8), 92(2),91(1),77(1.4),65(1.4).

Measured at 50 e V and an emission current of 75 mA at 125". Only peaks with m/e > 39 are indicated; peaks with intensities <1%

are not shown.

Primary loss of the N(4)-pyrimidyl substituent is also a feature of the mass spectral fragmentati~n~~ of the 2,3-dihydro-lHi-pyrrolo[l,2-a]benzimidazole betaine (6.92) (cf. Scheme 6.20), while the most intense peaks in the mass spectraM of simple 2,3-dihydro- lH-pyrrolo[1,2-aJbenzimidazoles correspond to the formation of cations of the type (6.133) (cf. Scheme 6.24).

General Studies The typically basic character of 3H and 4H-pyrrolo[1,2-a]benzimidazoles, 2,3-dihydro-lH-pyrrolo[1,2-aJbenzimidazoles, and 2,3,3a,4-tetrahydro- lH-pyrrolo[l,2-a Jbenzimidazoles is qualitatively demons~ated12. 14.2231.37.48.79 by the tendency for such molecules to form well-defined, stable, acid salts (e.g., hydrochlorides, perchlorates, and picrates, cf. Tables 6.3, 6.4, and 6.7-6.9). Surprisingly, however, only a few quantitative of the basicity of pyrrolo[1,2-a]benzimidazoles of the various structural types appear to have been carried out. Basicity

6.1. Fused Benzimidazoles with No Additional Heteroatoms

57

(6.128)

R'+ / ;M

R3

CH, (6.130)

(6.129)

I

R3

-R2ChCR3

(6.131)

(mle 129)

\ (6.132)

(m/e

102)

Scheme 6.24

constants for 4H-pyrrolo[ 1,2-a]benzimidazoles (measured in nitromethane relative to diphenylguanidine) fall in the range 0.6-3.8,72~77while 2-phenyl4-methylpyrrolo[ 1,2-a]benzimidazole has a pK, value in 80% ethanol of 6.86. These data demonstrate 4H-pyrrolo[ 1,2-a]benzimidazoles to be more basic than pyrrolo[l,2-a]pyridines (indolizines) (pK, = 3.5 to 5.2 in 60% ethanol) but less basic than pyrrolo[l,2-a]imidazoles (pK, ca. 8.6 in 80% The introduction of a substituent into the C(1) position in 4Hpyrrolo[ 1,2-a]benzimidazoles leads to a considerable decrease in basicity.72

6.1.3. Reactions Reactions with Electrophiles Molecular orbital calculations" imply a high degree of aromatic character12 for 4H-pyrrolo[ 1,2-a]benzirnidazoles and also their susceptibility to

58

Condensed Benzimidazoles of Type 6-5-5

electrophilic attack at the C(1) and C(3) positions [Scheme 6.25; (6.134)c, (6.135)c,(6.136)] with the former site being more reactive than the latter in this respect. These predictions are fully vindicated in practice by the propensity of 4H-pyrrolo[ 1,2-a]benzimidazole derivatives to undergo substitution at the C(1)and C(3)positions by a variety of electrophilic reagents.

I R

R (6.135)

I

R

scbcc# 6.25

(6.136)

PROTONATION. The simplest manifestation of the susceptibility of 4Hpyrrolo[ 1,2-a]benzimidazoIes to electrophilic attack is provided by their ready protonation at the C(1) and C(3) positions in acidic media. Thus, in accord with theoretical predictions (see before), solutions of C(1)-unsubstituted 4H-pyrrolo[ 1,2-~]benzimidazolesor their acid salts in trifluoroacetic acid exhibit ‘H NMR splitting patterns consistent only with exclusive protonation at C(1) to give monocations of the type (6.137; R4 = H) (Scheme 6.26).’4.72*77 In general however, the site of predominant protonation in 4H-pyrrolo[ 1,2-a]benzimidazoles is controlled by the nature and position of the substituents present.72 Broadly, the presence of C(1) alkyl groups tends to suppress C(1) protonation in favor of the predominating formation of C(3) protonated monocations [Scheme 6.26; (6.138; R4 = alkyl)], whereas the reverse is true for C(3) alkyl groups. For example,’* protonation of l-methyl-4H-pyrrolo[ 1,2-a]benzimidazoles affords a mixture of the C(1) and C(3) monocations (6.137;R4=Me) and (6.138;R4=Me) with the latter predominating, whereas the C(1)-protonated species is largely in excess in the mixture of monocations (6.137;R2= R4 = Me) and (6.138;R2= R4 = Me) produced from 1,3-dimethy1-4H-pyrrolo[1,2-a]benzimidazoles. On the other hand, a C(3) phenyl substituent has a facilitating ~ ~ temperature and acid strength of the effect on C(3) p r o t o n a t i ~ n .The medium also play an important role as d e m ~ n s t r a t e dby ~ ~the fact that at fixed acidity lowering of the temperature results in a decrease in protonation at C(1) in favor of increased formation of the C(3) monocation. This effect has been interpreted7’ in terms of initial kinetic control of monocation

6.1. Fused Benzimidazoles with No Additional Heteroatoms

59

formation and a low rate of attainment of the equilibrium [Scheme 6.26; (6.137)S (6.138)]and hence predominance of the thermodynamically more stable C(1) monocation at low temperature. This interpretation has the consequence that, under conditions of kinetic control, protonation of 4Hpyrrolo[ 1 . 2 4 Jbenzimidazoles occurs fastest at the less basic C(3) center.77 The electrophilic deuterium exchange (in CDCl-JCD,OD) observed for the C(1) and C(3) positions in 4H-pyrrolo[ 1,2-a]benzimidazoles has been to follow first-order kinetics.

(6.138)

(6.139)

(6.140)

(X= CI or CIO,)

XH

Scheme 6.26

4H-Pyrrolo[l,2-a]benzirnidazoles with heteroatom substituents tend to protonate on the side chain rather than the pyrrole ring. This situation is exemplified'" by the protonation of C(1) and C(3) arylazo and nitroso derivatives of 4H-pyrrolo[ 1,2-a]benzimidazoles to give stable salts (hydrochlorides and perchlorates), whose spectral properties are consistent with the hydrazone and oxime structures (6.139;Y = NHAr or OH) and (6.140) (Scheme 6.26). The formation7" of cations of the type (6.141;X = 0 or S ) (Scheme 6.26) on dissolution of the parent C(1) acyl or thioacyI4H-pyrrolo[ 1,2-~]benzimidazolesin trifluoroacetic acid contrasts with the more orthodox C(1) protonation undergone by the corresponding C(3) acyl and

Condensed Benzimidazoles of Type 6-5-5

60

thioacyl 4H-pyrrolo[ 1,2-a~enzimidazolesand is r a t i o n a l i ~ e din~ ~terms of conjugative stabilization of the structures (6.141; X = 0 or S) as opposed to the alternative C(1)-protonated forms. ALKYLATION. The reactions of 4H-pyrrolo[ 1,2-a]benzimidazoles with alkylating agents are less well documented than their reactions with acylating agents (see later). N(4)-Unsubstituted 4H-pyrrolo[l,2-a]benzimidazoles react with alkyl halides under alkaline conditions in orthodox fashion to afford good yields (Table 6.18) of the corresponding N(4)-alkyl derivatives, e.g. [Scheme 6.27; (6.142) 4(6.143)].22In reactions (Table 6.18) akin to those of related substrates with protic acids (see before), N(4)-methyl-4Hpyrrolo[ l72-a-Jbenzirnidazoles containing thioamide substituents at C(1) or C(3) react with methyl iodide under neutral ("sealed tube") conditions to give quaternary salts formed by alkylation of the side chain at sulfur [Scheme 6.27; (6.144) + (6.145) and (6.146) +(6.147)]." TABLE 6.18. ALKYLATION REACTIONS OF 4H-PYRROLOf1,2-a]BENZIMIDAZOLE DERIVATIVES (6.142), (6.144). AND (6.146). Starting materials (6.142) (6.144) (6.144) (6.144) (6.144) (6.146)

Reaction

R'

Rz conditions" Product R'

R2

Yield (%)

m.p. ("C)

Ref.

-

-

-

Me Ph Me Ph

68 48 62 45 43 62

-b

H H Me Me

22 81 81 81 81 81

H H Me Me

-

A Me B Ph B Me B Ph B - B

(6.143) (6.14S)c (6.145)' (6.145)' (6.145)c (6.147)c

-

-

172 169 196 198 173-174

A =MeI, KOH, EtOH/(room temp.)(l hr); B = MeI/(100", sealed tube)(l.5 hr).

Picrate has m.p. 132-133'. Crystallized from nitromethane.

2,3-Dihydro-1H-pyrrolo[l,2-a]benzimidazolesare alkylated preferentially at N(4) [as opposed to the bridgehead center N(9)] under effectively neutral conditions by a wide variety of reagents including ~ h l o r i d e s , ~ ~ * ~ ~ bromides,sB iodides,58 and tosylates,s8*62to afford moderate to high yields (Table 6.19) of quaternary salts [Scheme 6.28; (6.148)] of utility as starting N(4)-Arylmethyl-2,3,3u74materials for the synthesis of cyanine tetrahydro- 1H-pyrrolo[ 1,2-a]benzimidazoles7 on the other hand, are reported76 to undergo benzylation at the bridgehead position to give quaternary salts of the type (6.149) (Scheme 6.28) in unspecified yield. C(3)Hydroxy substituents in 1H-pyrrolo[ 1,2-a]benzimidazoles behave in an orthodox manner toward methylation by diazomethane in tetrahydrofurane giving moderate to good yields (Table 6.19) of enol ethers of the types (6.150) and (6.151) (Scheme 6.28).

0; A

'

Me - a T @ M e

Ph (6.142)

Me Ph (6.143)

(6.145)

(6.144)

he

$+s

Me

Me

NHPh (6.146)

Scheme 6.27

(6.147)

I-

1-

w

o\

C B C

F

C

F

C

B

B

B B

C C C C C

c

E F

D

B C

A

Alkylating agent'

100

110

-c

110 100 100 105 110 105-1 10 110 110 110 110 100 125 90 90 105 125 110 105 100

-c

2 0.5 15 36 0.25 6 15 3.5 5.5 16 15 15 15 16 3 3.5 16 15 8 3 8 0.25 16

~

Reaction temp. ("C)

Reaction time (hr)

~~~

(6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148) (6.148)

Solvent Product

~~

Me Me Et Et CH2Ph (CHz),OH Et Et Et Et Et Et Me Me Me Me Et (CH2)2OH Et (CH2)ZOH Et Me Et

R'

H H

Me

H C02Et H CN CN H H

Br COzH

H

H H H H H H CI H H F

R2

NH2 NHAc

H

CN CN

H

H

H

H

H

H H H H H H H H CI H F H H

R3

H H H H H H H COzH H C0,Et H H H H H H H

H

H H H H H

R4

I 1 I

Br I Br

I 1 I I

I

1 1

I

1

CI I I TSO: CI Br I CI

X

Yield (70)

180 242 238 238 237 210 250 304 265 238 190 >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

Condensed Benzimidazoles of Type 6-5-5

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)

Solvent of crystallization

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

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-5

(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)

6.1. Fused Benzimidazoleswith No Additional Heteroatoms

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,

Condensed Benzimidazoles of Type 6-5-5

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

Reaction conditions"

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

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-5

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

Solvent of crystallization

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.”

6.1. Fused Benzimidazoles with No Additional Heteroatoms

75

nuB H N
(6.188)

(6.187)

A

c & P h

Me Me Me 1(6.189)

NPh

(76%)

I

Me

Me Me (6.190)

(m.p. 108-109")

(i) PhNH,/(130-140°, sealed tube) (30 min), then NH, Meme 6.39

The failure of C(1)and C(3) aldehydic and ketonic substituents in 4Hpyrrolo[ 1,2-a]benzimidazoles to undergo the usual condensation reactions with amino reagents (amines, hydrazines, hydroxylamine) is attributed" to the amide-like character imparted by resonance interaction with the bridgehead nitrogen atom [Scheme 6.39; (6.187) f* (6.188)]. S-Methylthioimidate salts of the 4H-pyrrolo[l,2-a]benzimidazole series undergo orthodox aminative replacement reactions as illustrated by the transformation" [(6.189) +(6.190)] (Scheme 6.39). 1HThe activation of the chlorine atom in 5-chloro-6-n~tro-2,3-dihydropyrrolo[ 1,2-a]benzimidazole to nucleophilic attack is demonstrated by its smooth replacement by cyclic secondary amines to give the corresponding 5amino-6-nitro-2,3-dihydro- 1H-pyrrolo[ 1,2-albenzimidazoles in excellent yield (Table 6.23).73

HALOGENATION. As in the case of electrophilic halogenation (see before) the nucleophilic halogenation of pyrrolo[ 1,2-a]benzimidazoles is only rarely observed. Noteworthy examples are essentially confined to the 2,3-dihydro1H-pyrrolo[ 1,2-a]benzimidazole ring system and in particular to 2,3dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole 4-N-oxides [Scheme 6.40; (6.191)]. Analogy with simpler a!-alkylated heterocyclic N-oxidese6 suggests

76

Condensed Benzimidazoles of Type 6-5-5

TABLE 6.23.

NUCLEOPHILIC DISPLACEMENT REACTIONS OF 29-DIHYDRO1H-PYRROLO[1,2-a]BENWMIDAZOLEDERIVATIVES

Reaction conditions'

2.3-Dihydro- lH-py~rol~l.2-a~nzimidazole Yield Substrate Product (%I

A

5-Chloro-6-nitro

5-( 1-Pyrrolidiny1)-

6-Nitro5-( 1-Piperidiny1)6-nitro5-( 1-Perhydroazepinyl)-6-nitro7-chloro6.7-Dichloro5-Chloro-6-nitro-

A

5-Chloro-6-nitro-

A

5-Chloro-6-nitro

B B

4-N-Oxide 6-Chloro 4-N-oxide

B

6-Nitro 4-N-oxide

C D E

H I

6-Nitro 4-N-oxide 6-Amino 7-Amino 7-Amino 6-Bromo7-Amino7-Amino-6-bromo7-Amino-6-chloro7-Amino-6-fluoro7-Amino-

8-Chloro-6-nitro5-Chloro-6-nitro6-Chloro'I-ChlOro7-Huoro6-Cyano7-Cyano6-Bromo-7-cyano6-Chloro-7-cyanob~uoro-7-cyanoJ 7-Azido-

I I

6-Amino7-Amino-6-nitro-

6-Azido7-Azido-6-nitroJ

I

6-Amino-7-nitro-

6-Azido-7-nitro-

F

G H H

H

m.p.

("0

Ref.

95-100

lSb

73

95-100

193'

73

95-100

131b

73

100 100 32

136 211

73 73

68 78 30 21 19 -d

-

d

48

d

_.

-d -d

-

d

-d

-d

1843 162 133-134 136' 124' 190b 155 224 215 210 150 (d-mp.) 136 190 (decomp.) 186 (decomp.)

73 73 32 58 58 58 58 58 58 58 51 51 71

71

'A = amine, EtOH/(reflux)(l2 hr); B = POCI,, CHClJ(reflux)(4 hr); C = conc. HCV(1lOO) (144 hr); D = NaNO,, HCI/(Oo), then CuCI, conc. HCl/(room temp.); E = NaNO,, HCY(O"), then CuCI, conc. HCl/(50-6Oo); F = NaNO,, H13FJ(Oo), then tetralin/(reflux); G = CuCN, PhNO,/(reRux 1.5 h). then NaCN, H20/(100")/(few min);H = NaNO,, HCY(0O). then C u m , KCN/(room temp.)(0.5 hr), then 50-60" 15 min); I = NaNO,, HCl/(O"), then NaN,, NaOAc, H,O. Crystallized from ethanol. Crystallized from benzene. Yield not specified. Boiling point 166"/3m m Hg. f Crystallized from benzene-hexane.

that these molecules should be susceptible to nucleophilic halogenation at the C(3) position. In practice, reaction of 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole 4-N-oxide and its 6-chloro derivative (6.191;R = H or Cl) with phosphorus oxychloride in refluxing chloroform results in specific chlorination at the C(7) position in the benzene ring giving 7-chloro- and 6,7-dichloro-2,3-dihydro1H-pyrrolo[ 1,2-u]benzimidazoles (6.193; R = H

R

i 0(6.191)

ax

(6.192)

l3;m 1

c1 R

(6.193)

C1

(6.195)

78

Condensed Benzimidazoles of Type 6-5-5

or Cl) in essentially quantitative yield (Table 6.23).73The analogous reaction of 6-nitro-2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazoIe 4-N-oxide (6.191; R = NO,), on the other hand, leads to competing attack at C(5)and C(8), affording a mixture of 5- and 8-chloro-2,3-dihydro-1H-pyrrolo[ 1,2-a]benzimidazoles (6.195)and (6.194)again in good overall yield (Table 6.23) with the latter product ~ r e d o m i n a t i n gThe . ~ ~ exclusive formation of the 5-chloro product (6.195) in high yield (Table 6.23) by simply heating the nitro is indicative N-oxide (6.191;R = NO2) in concentrated hydrochloric of the enhanced reactivity of this substrate to halogenation of this type. The chlorination reactions of 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole 4-Noxides may be rationalized mechanistically (Scheme 6.40) in terms of the initial coordination of the chlorinating agent at the N-oxide oxygen atom. The resulting species (6.192; X = H or POCI,) produced would then be susceptible to attack by chloride ion at all three available sites in the benzene ring (cf. Scheme 6.40) and hence is a plausible common intermediate for the subsequent alternative C ( 3 , C(7), and C(8) chlorination observed. However, this mechanistic rationale does not readily account for the contrasting chlorination reactions of the parent and 6-chloro N-oxides (6.191; R = H or Cl), o n the one hand, and the nitro N-oxide (6.191; R=NO,), on the other, in terms of the site of substitution. Nor does it explain the apparent dichotomy in the behavior of the nitro N-oxide (6.191; R = NO,) toward chlorination by phosphorus oxychloride as opposed to chlorination in concentrated hydrochloric acid. Substitution reactions of this type obviously warrant further study in order to clarify these details. Halogen substituents are also introduced into the benzene nucleus of 2,3dihydro- 1H-pyrrolo[ 1,2-~]benzimidazolesvia Sandmeyer reactions of the corresponding amines. Halogenation of this proceeds in moderate yield (Table 6.23) and, though not strictly nucleophilic in a mechanistic sense, is included for convenience under the present heading. MISCELLANEOUS REACTIONS. The transformation2 [(6.1%) + (6.197)] (Scheme 6.41) exemplifies what appears to be the sole reported example of carbanion attack on a pyrrolo[ 1,2-u]benzimidazole derivative. On the other hand, the behavior of pyrrolo[ 1,Zu]benzimidazoles toward nucleophilic attack by cyanide ion has been reported in a number of instances, as

OH

(6.1%)

(6.197) (i) EtMgBr, ether/(reflux)/(8 hr)

Scheme 6.41

6.1. Fused Benzimidazoles with No Additional Heteroatoms

79

(Ref. 87)

Q--(Zi) 0;CH2Ph

CH2Ph

+I

I

’

\

I

CH2Ph

i CN CH2Ph

c1-

(Ref. 76) (i) HCN liq./SoO (ii) NaCN, H,O/room temp.

sebcme 6.42

illustrated by the reaction^'^*^^ shown in Scheme 6.42. 2,3-Dihydro-1Npyrrolo[ 1,2-a]benzimidazolescontaining cyano substituents in the benzene nucleus are synthesized in orthodox fashion by reaction of the corresponding halogeno compounds under forcing conditions with cuprous cyanide” (Table 6.23) or by the Sandmeyer reaction^^^*^' of appropriate amines (Table 6.23). reaction^^'-^^ related to the latter type also allow synthetic access to azido-substituted 2,3-dihydro-1H-pyrrolo[ 1,2-u]benzimidazoles (Table 6.23).

Oxidation Relatively little information is available regarding the behavior of pyrrolo[ 1,2-a]benzimidazoles toward oxidizing agents. However, the relative stability of the 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole ring system to oxidation is indicated by the successful chromic acid oxidation3*of the hydroquinone (6.198)to the quinone (6.199)(Scheme 6.43) in moderate yield,

0 (45% 1

0

OH

(6.198)

(i) Cr0,,H20/600 scheme 6.43

(6.199)

Condensed Benzimidazoles of Type 6-5-5

80

and by the peracid-mediated deacylation of 4-acyl-2,3,3a14-tetrahydro1Hpyrrolo[ 1,2-a]benzirnidazoles to 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimida ~ o l e . ~The ’ not-unanticipated ease of oxidation of the 2,3,3a,4-tetrahydro1H-pyrrolo[ 1,2-a]benzimidazole ring system is illustrated (Scheme 6.44) by the conversion of the derivatives (6.200) into the salts (6.201) with concomitant formation of chloroform, simply by heating under reflux in carbon tetrachloride.68 Similar oxidation is effected by heating the hydrochlorides of the tetrahydro- 1H-pyrrolo[ 1,2-a]benzimidazoles (6.200) in acetone, which is coreduced to 2-propanol in the process.68

AI

Ph

Yield (%) 86

m.p. (“c) 2 1e220

Reduction The zinc and acetic acid reduction (Scheme 6.45) of readily available 1diazoaryldH-pyrrolo[ 1,2-a]benzimidazoles (6.202) which provides synthetic access (albeit in low yield)” to the unstable 1-amino derivatives (6.203) is dependent on the stability of the 4H-pyrroio[ 1,2-a]benzimidazole ring

Me

(6.202) (i) Zn, AcOH

R

Me picrate (6.203) Yield (Yo) m.p. W)

Ph 13 Me not quoted Schane 6.45

221 249

6.1.Fused Benzimidazoleswith No Additional Heteroatoms

81

system to metal-proton donor reduction of this type. The debenzylation of the 4-benzyl-4H-pyrrolo[ 1,2-a]benzimidazoIes (6.204) and (6.205) (Scheme 6.46) using sodium in liquid a m m ~ n i a , 'is~ accompanied by an unprecedented hydrogen shift, the products, formed in good yield, being the corresponding 3H-pyrrolo[ 1,2-a]benzimidazoles (6.209). However, the stability of the 4W- and 3H-pyrrolo[ 1,2-a]benzimidazole ring systems toward metal-proton donor reduction under basic conditions, implicit in these transformations, is not extended to the diphenyl derivative (6.206). The debenzylation and hydrogen shift induced in this substrate by treatmentI7 with sodium in liquid ammonia is accompanied by further reduction, the product being the 2,3-dihydro- 1W-pyrrolo[ 1,2-a]benzimidazole derivative

R'

R'

R3

CH2ph H Ph CHzPh H p-MeoC,H4 Ph (6.2@6) CH2Ph Ph (6.207) Me H Ph (6.204) (6205)

Ph

Me (6.210)

(6.208) (58%) (m.p. 93-94")

(36%) (m.p. 104-106")

H' 'H

(6.209)

Ar Yield(%) m.p.CC) Ph 60 217-218 p-MeOC,H4 87 226-228 (i) Na,NH, liq./lO min (ii) Na,EtOH/(reflux)/(30 min)

sebcme 6.46

82

Condensed Benzimidazoles of Type 6-5-5

(6.208). Sodium and ethanol r e d ~ c t i o n ’o~f the N-methylpyrrolobenzimidazole (6.207) (Scheme 6.46) proceeds a stage further and affords the 2,3,3a,4-tetrahydro- 1H-pyrrolo[ 1,2-a]benzimidazole (6.210). Zinc in acetic acid effects the specific reduction [Scheme 6.47; (6.211)+ (6.212)12 of the carbon-carbon double bond in the enone (6.211) which somewhat surprisingly is reported2 to be inert to complex metal hydride reduction under a variety of conditions. This inertness contrasts with the ready reductive ring-opening induced in 2,3-dihydro- 1H-pyrrolo[ 1,243benzimidazol- 1-one by treatment” with lithium aluminum hydride [Scheme 6.47; (6.213) --* (6.214)]. N(9)-Quaternary salts derived from 2,3,3q4-tetrahydro- 1H-pyrrolo[ 1,2-a]benzimidazoles are also susceptible to sodium borohydride-promoted ring-opening [Scheme 6.48; (6.215) +(6.216)],’“ whereas in the analogous reduction of N(4)-benzyl-2,3-dihydro-1Hpyrrolo[ 1,2-a]benzirnidazolium salts the ring system remains intact, the product being the corresponding N(4)-benzyI-2,3,3~,4-tetrahydro-lHpyrrolo[ 1,2-a]benzimidazole, e.g. [Scheme 6.48; (6.217) +(6.218)].68 Debenzylation of compounds of the latter type can be accomplished by catalytic hydr~genation.~’However, the products are not the anticipated parent 2,3,3~,4-tetrahydro-1H-pyrrolo[ 1,2-a]benzirnidazoles, but the 2,3dihydro- 1H-pyrrolo[ 1,2-a]benzimidazoles produced by their ready in situ oxidation, e.g. [Scheme 6.48; (6.218) +(6.219)--+ (6.220)].59 The catalytic hydrogenation of nitro-substituted 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazoles proceeds in standard fashion to give the corresponding amines (Table 6.24).32.36.58

OH

HO’ ‘H (6.212)

(6.211)

[m.p. 19P (decamp.)]

(6.213)

H (6.214)

(i) Zn.AcOH/(refluxNshort time) (ii) LiAlH,, ether/(reflux)l(15 hr) Scheme 6.47

CH2Ph

qy-5

CH2Ph

\

CH,Ar (6.215)

I H CH2Ar (6.216)

(6.217)

(6.218)

(6.219)

(i) NaBH,,H,O/(room temp.)(short time) (ii) NaBH,.H20/(O")(short time) (iii) 10%. Pd-C, EtOH/atm. press., room temp. S c k m 6.48

TABLE 6.24. CATALYTIC HYDROGENATION OF NITRO-2,3-DIHYDRO-I HPY RROLOC1.2-aIBENZIMIDAZOLES 2.3-Dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole Hydrogenation conditions" Substrate Product

Yield

(%I

m.p. ("C)

A

6-Nitro-

6-Amin0-~

quant.

294-297

B B B

6-Bromo-7-nitro6-Chloro-7-nitro6-Ruoro-7-nitro-

7-Amino-6-bromo7-Amino-6-chloro7-Amino-6-fluoro-

75 -c

264 264 230

-c

Solvent of crystallization Ref. Ethanol- 32 hexane Ethanol 58 -d 58

-d

58

" A =H2, no2.EtOH/room temp., atm. press; B = H,, Raney-Ni, methyl glycol/room temp., atm. press. * Dihydrochloride. Yield not quoted. Solvent of crystallization not specified. 83

84

Condensed Benzimidazolesof Type 6-5-5

6.1.4. Practical Applications

Biological Properties The pharmacological properties of 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzimidazoles have attracted attention3’ because of their structural similarity to alkaloids such as deoxypeganine. 2,3-Dihydro- 1H-pyrrolo[ 1,2-a]benzimidazole derivatives have also been patented as fungicides.”

Dyes tuffs Various pyrrolo[ 1,2-a]benzimidazole derivatives have found application in the formulation of cyanine dye^'^^^'^'' and also as photographic sensitizing” and nucleatings9 agents.

Polymers

Two patents describe the use of 3H-pyrrolo[ 1,2-a]benzimidazoles3 and 2,3-dihydro- 1H-pyrrolo[ 1,2-a]benzirnidazole~~~ as monomers in polymer synthesis.

FUSED BENZIMIDAZOLES WITH ONE ADDITIONAL HETEROATOM

6.2. TRICYCLIC 6 - 5 5

Six ring systems having a tricyclic 6-5-5 fused benzimidazole structure with one additional heteroatom (oxygen, sulfur, or nitrogen) have been documented to date (6.Scheme 6.49 and Table 6.25). Of these, the oxazolo[3,2-a]benzimidazole ring system, so far described only in the 2,3dihydro form (6.221), represents the sole example of an oxygen-containing framework of this type. Sulfur-containing 6-5-5 fused benzimidazoles with one additional heteroatom include the lH,3H-thiazolo[3,4-a]benzimidazole (6.224) and thiazolo[3,2-a]benzimidazole (6.222) ring systems, the latter also being encountered in the 2,3-dihydro form (6.223). Fully nitrogen-containing structures of the type under consideration are represented by the pyrazolo[2,3-a]benzimidazole framework, known in 1H(6.225), 4H- (6.226), and tetrahydro (6.227) forms, the 1H- and 9Himidazo[ 1,2-aIbenzimidazole ring systems (6.228) and (6.229) and their 2,3-dihydro derivatives (6.230) and (6.231), and the respective 4H-imidazo[3,4-a&enzimidazole and lH,3H-imidazo[l,S-a]benzirnidazole isosteres (6.232) and (6.233).

R

(6.225)

(6.226)

(6.233) !kbaue 6.49

85

Condensed Benzimidazoles of Type 6-5-5

86

TABLE 6.25 TRICYCLIC 6-5-5 FUSED BENZlMlDAZOLE RING SYSTEMS WITH ONE ADDITIONAL HETEROATOM Structure”

Nameb

(6.221) (6.222) (6.223) (6.224) (6.225) (6.226) (6.227) (6.228) (6.229) (6.230) (6.231) (6.232) (6.233)

2,3-Dihydro-oxazolo[3,2-a]benzimidazole Thiazolo[3,2-a]benzimidazole 2,3-Dihydrothiazolo[3,2-a]benzimidazole 1 H.3H-Thiazolo[3.4- a]benzimidazole 1H-F‘yrazolo[ 2,3-a ~enzirnidazole 4H-Pyrazolo[2,3-aJbenzimidazole 2,3,30,4-Tetrahydro-1 H-pyrazolo[2,3-a]benzimidazole 1H- Imidazo[ 1,2-a]benzimidazole 9H- Imidazo[ 1,2-a]benzimidazole 2.3-Dihydro-1 H- imidazo[ 1,2-a]benzimidazole 2.3-Dihydro-9H- imidazo[ 1,2-a]benzimidazole 4H-Imidazo[3,4-a ]benzimidazole 1 H,3H-Imidazo[l,S-albenzimidazole

Cf. Scheme 6.49. Based on the Ring Index.

6.2.1. Synthesis

Ring-closure Reactions of Benzimidazole Derivatives

2-Chloro-l-(2-hydroxyethyl)benzimidazoles undergo smooth basecatalyzed cyclization by the intramolecular nucleophilic displacement of the 2-chloro group by the hydroxy substituent in the side chain, affording high yields (Table 6.26)of the corresponding 2,3-dihydrooxazolo[3,2-a]benzimidazoles [Scheme 6.50;(6.236) +(6.237)].y1*9* The convenience and flexibility of this useful general synthetic method are enhanced by the fact that the requisite 2-chloro-l-(2-hydroxyethyl)benzimidazolesare readily synthesized by the condensation of the sodium salts of 2-chlorobenzimidazoles with variously substituted epoxides under conditions that also tend to promote spontaneous cyclization to the 2,3-dihydrooxazolo[3,2-a]benzimidazole [Scheme 6.50;(6.234) + (6.235) +(6.236) +-(6.237)] (Table 6.26).91*92 However, the nature of these ring-closures is such that the use of unsymmetrically substituted epoxides with marginal electronic bias in the direction of ring-opening will tend to lead to mixtures of products, or structural ambiguity when a single product is formed. Information on these possible synthetic limitations is not available as yet. Moreover such “in situ” condensation reactions suffer from the inherent disadvantage of lack of control over the two directions of ring-closure possible when 2-chlorobenzimidazoles substituted in the benzene ring (6.234; R’ # H) are used as substrates. This situation is demonstrated by the reaction” of 2,5(6)-dichlorobenzimidazole

4

00

+

+

R' = CH,CI)

+

+

I

LJ

I I l

C

w

R' = CH,NAO)

(6.237; R' = CH,CI, R3 = 6(7)-C1)

(6337; R' = C0,Et. R2 = M e )

(6.237;

(6.237; R ' = CH20Ph)

66

-

64

70

52

-

(6.237; R ' = CH,CI)

(6.237; R' = CH,OH)

75

(6.237; R' = Et) (6.237; R'=CONH,)

-

(Yo)

Yield

127-128

147-148

147-148

160-161

192-193

136-138

105-107 236-237

104-105

m.p. ("C)

Benzene

Benzene

Benzene

Ethanol

Ethanol

Benzene

Benzene Benzene MeOH

Solvent of crystallization

Ref.

91

92

91. 92

91

91, 92

91.92

92 92 91

A = NaOH, H,O, EtOH/(reflux)(5-14 hr); B = NaOMe. MeOH/(reflux)(B hr); C = no solvent/(room temp.)( 14-72 hr); D = benzene/(room temp.)( 14 hr); E = benzene/(reflux)(4-16 hr); F = benzenekoom temp.)(3 days). Yield not specified.

(6.235; R' = CH,CI)

c D E

Ic

(6.235; RZ= Me, R3 = C02Et) (6.234; R3 = 5(6)-C1)

(6.234)

(6.234)

(6.235; R' = CH,OPh)

+

(6.235; R' = CH,OH) (6.234)

(6.235; (6.234)

B

(6.237)

A A

(6.236) (6.236; R' = Et) (6.236; R'=CONH,) (6.234)

~

Product Reaction conditions" (R'+R7 unspecified = H)

~

SYNTHESIS OF 2,3-DIHYDRO-OXAZOLO[3,2-a]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF 2CHLORO- 1-(2-HY DR0XYETHYL)BENZIMIDAZOLEDERIVAIXVES.

Starting materials (R' -+ R3 unspecified = H)

~~~~~

TABLE 6.26.

88

Condensed Benzimidazoles of Type 6-5-5

(6.234)

(6.235)

(6.236)

1

(6.237) Sehenm 650

sodium salt (6.234; R3= 5-chloro) with epichlorohydrin (6.235; R' = CH,CI, R2 = H) to give an apparently single 2,3-dihydrooxazolo[3,2-albenzimidazole product (6.237; R' = CH2Cl, R2 = H,R3= Cl) in good yield (Table 6.26) whose 6- or 7-chloro orientation was not established. The synthesis of 2,3-dihydrooxazolo[3,2-a]benzimidazole (6.237; R' --* R3 = H) by the sodium hydride catalyzed condensation of 2-benzimidazolone with 1,2dibromoethane has recently been reported93 but without experimental details. Thiazolo[3,2-a~enzimidazolescontaining alkyl or aryl substituents in the C(2) and/or C(3) positions [Scheme 6.51; (6.242; R', R2 = alkyl or aryl)] are generally accessible, usually in high yield (Table 6.27) by the dehydrative cyclization of 2-(~-oxoalkylthio)benzimidazoles (6.240) or the related acetals [6.240; CH(OR)2 for COR'] using a variety of acid catalysts, the most though hydrochloric acid,'m102 common of which is polyphosphoric acid?hydrobromic a ~ i d , ' ~ . phosphoric '~~ acid,'00 sulfuric acid,'00 and even acetic acid, 'M)~'04 have also been employed successfully. The acid-catalyzed nature of the ring-closures [(6.240) +(6.242)] is demonstrated'00 by the fact that 2-(2-benzimidazolylthio)propanone (6.240; R' = Me, R2 --* R6 = H) is unaffected by heating in ethanol, whereas its hydrochloride on similar treatment is efficiently converted (Table 6.27) into 3-methylthiazolo[3,2-aJbenzimidazole (6.242; R' = Me, R2 + R6 = H). Cyclization reactions of the type [(6.240) + (6.242)] probably involve the intermediate formation of the corresponding 3-hydro~y-2~3-dihydrothia-

6.2. Fused Benzimidazoles with One Additional Heteroatom

89

X

+

&-w I COR'

(6.238)

\

(6.239)

c0r2

(6.242)

/

(6.243)

zolo[3,2-a]benzimidazoles (6.241) isolable in certain instances (see later) as in the ring-chain equilibria the stable tautomeric forms r(6.240) g (6.241)P4.102.103,10S-109 and convertible in high yield (Table 6.27) into thiazolo[3,2-a]benzimidazoles (6.242) by dehydration with reagents such as phosphorus oxychloride in combination with pyridine,'03*'0' polyphosphoric hydrochloric acid,Io2or sulfuric acid."' The 2-(@ oxoalky1thio)benzimidazoles (6.240) or tautomeric 3-hydroxy-2,3-dihydrothiazol~3,2-a]benzimidazoles(6.241) required as substrates for the synthesis of thiazolo[3,2-a]benzimidazoles (6.242) are readily available by the uncatalyzed condensation of 2-benzimidazolethiones [Scheme 6.5 1; (6.238)] with free a-chloro- or a-bromoaldehydes (6.239; R' = H, R2= alkyl or aryl,

\o

+

X = Cl)

(6.239;

R' =Me, X = C1)

+

(6.239; R' =Me, X = Cl) (6.247; R2 = R3 = Me) (6.247; R' = Q) (6.238; R4 = R5 = Me)

+

(6.239; R' =Me, X = Cl) (6.241; R' = Me) (6.241; R'=Me)' (6.241; R' = Me) (6.238) (6.247) (6.247)m (6338; R5 = MeO)

+

(6.239; R' =Me, (6.238)

1

I

1 145

D

K

K

75 80 98

(6.249; R2= R3 = Me) (6.249; R2 or R3 = (6.242; R' = R4 = RS = Me)h

205-206 Ethanol-water

206-207 Benzene 138-139 Benzene

Ethanol

I00

120 120

97

100

66

Hexane Ethanol Benzene Ethanol

-

(6.242; R' = Me, R4 = MeO)

=Me)

-

103 101 120 119

104

110

160-161 162-163 165-166 161-162

Methanol

Ethanol

100

164-165

100

103 103

94 106

103

Ref.

161-162 Ethanol-water

D

L

I J K

Benzene Hexane

Methanol-water Ethanol-water

Hexane

161-162 Ethanol-water

135.5136.5 140 141.5 142.5 164-165 134-135

Solvent of crystallization

78-46 95 quant. 35 68 78

= Me) = Me) = Me)

(6.242; (6.242; (6.242; (6.242; (6.249) (6349)

G R' R' R' R'

(6.242; R' = Me)

H

89

73

78 93

-

94

77

("C)

m.p.

165

R' = Me)

Yield (%)

-'

(6.242;

F

E

(6.242; R' = Me)d

D

(6.239; R' = Me, (6338)

I

(6.242; (6.242;

A A

(6.241; R4 = RS = Me) (6.241; R3 = R6 = Me) (6.238)

X = Cl)

(6.242) (6342)b

B C

(6.241) (6.240; CH(OEt), for COR')

+

(6.242)

A

(6.241)

R4= R5 = Me) R' = R6 = Me)

Product (R' -+ R6 unspecified = H)

Reaction conditions"

Starting materials (R'+R6 unspecified = H)

TABLE 6.27. SYNTHESIS OF ALKYL AND ARYLTHIAZOL0[3,2-a]BENZIMlDAZOLESBY RING-CLOSURE REACTIONS OF BENZIMIDAZOLE DERIVATIVES

2

1

}

R3= CI)

(6.240; R' = p-MeC,H,) (6.240; R' = p-MeOC,H,) (6.240; R' = m-NO,C,H,)

(6.239; R' = Ph, X = Br) (6.240; R' = Ph) (6.240; R' = Ph) (6.240; R' = Ph) (6.240; R' = Ph) (6.238) (6.240: R' = p-CIC,H,) (6.240; R' = p-CICeH,) (6.240; R' = p-BrC,H,) (6.240; R' = p-BrC,H,) (6.240: R' = p-BrC,H,) (6.240; R' = p-FC,H,)

+

(6.247; R' = Ph. (6338)

RZ= R3= Me)

(6.239; R' = Pr". X = Br) (6.245; R = Bu') (6.247; R' = Ph) (6.247; R = H. R' = Ph,

+

(6.239; R' = Et, X = Br) (6.247; R = Me) (6338)

+

(6.241; RZ= Me) (6.241; RZ= Me) (6.245; R = Me) (6.247) (6.238)

99 80 82

(6.246; R = Bu') (6.249; R' = Ph) (6.249; R' = Ph, RZ= R3

M

P

B B

B

P

B B B B

R

B

0 B

P

0

L

94 43 48 85 50-60 77 45 72 46 97 44 46 44 87

(6342; R' = Ph)" (6.242; R' = Ph) (6.242; R' = Ph) (6.242; R' = Ph) (6342; R' = Ph) (6342; R' = p-CIC,H,) (6.242; R' = p-ClC,H,) (6.242; R' = p-BrC,H,) (6.242; R' = p-BrC,H,) (6.242: R' = p-BrC,H,)" (6.242; R' = p-FC,H,) (6.242; R' = p-MeC,H,) (6.242; R' = p-MeOC,H,) (6.242; R' = m-NO,C,H,)P

85

40

R' = Ph, RZ or R3 = CIp

(6.242; R' = Ph)

(6.249;

= Me)

65

R' = Pr")"

(6.242;

D L L

_.

R = Me)

(6.250;

N

72

(6.242; R' = Et)'

93 90 78 -c

D

RZ= Me) R2= Me) R = Me)

(6.242; (6.242; (6.246; (6350)

A

B M N

_.

Dioxane-water

Methanol

Ethanol-water Methanol Methanol

Ethanol-whter

Ethanol Ethanol Ethanol Benzene-hexane Ethanol Ethanol-water Ethanol Ethanol-water I-Butanol Chloroform-light petroleum 150 Ethanol-water 155 Ethanol-water 196.5-197 Dimethylformamidewater

140-142 I40 140 139 203 200 197 200 200.5-201 274

_.

139.5 140.5

124-12.5

131-132 80-8 1 201-202

76-77

103-10s

-'

-i

161-162

157-158

Hexane Hexane Ethanol-water

158-159

158-159

9.5 95 100

100 99

94 95

95

100 103 9.5 94 122 94

100

120

118 120 120

100

120

100

103 1 I5 118 120

h)

R5 = Cl)

B

P

P

R4 = R5 = Me)

(6.240; R' = p-BrC,H,,

(6.240; R' = m-BrC6H4, R4 = R5 = Me)

(6.240; R' = m-N0,C6H4, R4 = R5 = Me)

M

s

R

(6.241; R2 = Ph) (6245; R = Ph)

B

0

B

(6.239; R' = Ph, X = Br) (6.240; R' = Ph, R4 = RS = Me) (6338; R4 = RS= Me)

-4.

(6.238; R4 = R5 = Me

(6.240; R' = p-MeC6H4, R6 = Me)

= p-BrC6H4, R5 = Me)

= p-PhC,H,,

= p-MeC6Hd, RS= Cl) = p-BrC6H4, RS = C1)

= Ph, RS = Cl)

= Ph, Rs = MeO) = p-MeC,H,, Rs = MeO) = p-PhC6H4; Rs = MeO) = p-BrC6H4, RS = MeO)

= 3-CI. 4-FC6H.J

B B B

P

= p-N0&6H4) = 4-F, 3-MeC6H3)

(6.240; (6.240; (6.240; (6.240; (6340; (6.240; (6.240; (6.240; (6.240; (6.240; (6.240; (6.240;

R' R' R' R' R' R' R' R' R' R' R' R'

Reaction conditions"

Starting materials (R'+R6 unspecified = H)

TABLE 6.27 (Continued)

90 95

60

98

168- 170 166-167

305-306

265-266

276 71

(6.242; R' = p-BrC,H,, R4 = R5 = Me) (6.242; R' = m-BrC6H4, R4 = R5 = Me) (6.242; R' = m-NO,C,H,, R4 = R5 = Me) (6.242; RZ= Ph) (6.246; R = Ph)

189-190 192 66 72

(6.242; R' = Ph, R4 = Rs = Me) (6.242; R' = Ph, R4 = R5= Me)

192-1 93

231-232

230-23 1 170 230-234 155 140 185 175 212 184 210 150 240

m.p. ("C)

40

53

-c 64

C

-

89 42 54 52 56 46 42 51

Yield

(%I

(6.242; R' = Ph, R4 = R5 = Me)'

(6.242; R' = p-BrC@,, R3 or R" = Me)*

R4 or R5 = Me)*

(6.242; R' = p-NO&&)' (6.242; R' = 4-F, 3-MeC6H3) (6.242; R' = 3-CI, 4-FC6H4) (6.242; R' = Ph, R4 = MeO) (6342; R' = p-MeC,H,, R4 = MeO) (6.242; R' = p-PhC6k4; R4= MeO) (6342; R' = p-BrC,H4, R4 = MeO) (6.242; R' = Ph, R4 = CI) (6.242; R' = P-MeC6H4, R4 = Cl) (6.242; R' = BrC6H4, R4 = (3) (6.242; R' = p-Phc6H4. R4 = CI) (6.242; R' = p-BrC6H4,

Product (R'+R" unspecified = H)

Ethanol-water Ethanol

Dimethylformamide

Ethanol Acetone-light petroleum (b.p. 40-80') Chloroform-light petroleum (b.p. 40-60') Dimethylformamide

Ethanol-water

Ethanol

Ethanol

1

-

Ethanol

Ethanol

-i -

-,

1-Butanol Chloroform-light petroleum Chloroform-light petroleum

Solvent of crystallisation

107 118

100

100

96

96 122

100

96

100 99 99 97 97 97 97 98 98 98 98 96

Ref.

I

1

I

(6.239; R' = Ph, R2 = Me, X = Br)

+

(6.239: R' = Me, R2 = Pr", X =Cl) (6.241; R' = Me, R2 = CH,Ph) (6.240; R' = Me, R2 = Ph) (6.238)

+

(6.239; R' = Me, R2= Et. X = Br) (6.238)

+

(6.239; R' = R6 = Me, X = Br) (6.241; R' = Et, K2 = Me) (6.238)

+

(6.239; R' = R2 = Me, X = Br) (6.241; R1 = R2 = Me) (6.241; R' = R2 = Me) (6.241; R' = R2 = Me) (6341; R' = R2= Me) (6.238; R4 = R5= Me)

+

(6.239; R' = R2 = Me, X = Br) (6.238)

+

(6.245; R = Ph) (6.245; R = Ph) (6.245; R = p-CIC,HJ (6.245; R = p-BrC6H4) (6.245; R = p-MeC6H4) (6.245; R = p-MeOC6H4) (6.245; R = p-PhCeH4) (6.245; R = 2-naphthyl) (6.245; R = 2-thienyl) (6338)

88 93 93

(6.242; R1= R2 = R4 = R* = Me)' (6.242; R' = Et, R2= Me)" (6342; R' = Me, R2 = Et)"

D P D

79 91

(6.242; R' = Me, R2 = CH,Ph) (6.242; R' = Me, R2 = Ph)Y (6.242; R' = Ph, R2 = Me)

P P

W

20

76

(6.242; R' = Me, R2 = PI")'"

D

1

89 99 97 95

= R2 = Me) = R2 = Me) = R2 = Me) = R2 = Me)

(6.242; R' (6.242; R' (6.242; R' (6.242; R'

42

64

(6.242; R' = R2 = Me)' (6.242; R' = R2 = Me)$

58 99 93 98 99 89 99 93 97

(6.246; R = Ph) (6.246; R = Ph) (6346; R = p-CIC6HJ (6.246; R = p-BrC,H,) (6.246; R = p-MeC6H4) (6.246; R = p-MeOC6H4) (6.246; R = p-PhCeH4) (6.246; R = 2-naphthyl) (6346; R = 2-thienyi)

U V

T

D

D

M

0 M M M M M M

1

-

179-180

122-123 131-132

107-108

127-1 28

162-164

151-152

273-275

Ethanol-water

Ethanol-water Ethanol-water

Ethanol-water

Ethanol-water

Ethanol-water

Ethanol

-

Ethanol-water

225-226 Ethanol 222-223 Ethanol 178-179 Ethanol 162- 163 Ethanol 205-206 Ethanol 228-229 Ethanol 150-1 5 1 Ethanol

c

-

100

100 100

100

100

100

100

100 100 100 101

100

111

118 118 118 118 I18 118 118 118 118

]

l 30

(6.242; R' = R2= C02Me)

B 85

= CH,

23

(OEt),)'

(6.242; R'

R2 = CH2C02H)

51

(6.242; R' = R2 = Ph, R4 = Rs= Me) (6.242; R' = p-CIC,,H.,,

92 98

(6342; R' = Ph, R2 = Me) (6342; R' = R2 = Ph)'

Yield (Oh)

Product (R'+R" unspecified = H)

166-167

134

242-243

121

113

Benzene-hexane

102

100

100 100

Ref.

Dimethylformamide

Methanol

1-Butanol

225-226

-

193-194

Solvent of crystallization

-

m.p. ("C)

'

'

MeO,CbCCO,Me, tetrahydrofurane/(reRux)(30 hr). Forms a hydrochloride, m.p. 193-194" (decomp.) (from ethanol), and a picrate. yellow needles, m.p. 235-236" (decomp.) (from ethanol). ' Yield not quoted. Forms a picrate, m.p. 241-242". Hydrochloride. Hydrobromide. 8 Single isomer formed; C(6) or C(7) orientation for the substituent not determined. Forms a picrate, m.p. 285-286", and a hydrochloride, m.p. 263-266". ' Solvent of crystallization not specified. Forms a hydrochloride, m.p. 221-222". ' Oil, b.p. 227-228/760 m m Hg. Purified by tlc. Forms a picrate, m.p. 248-250", and a hydrochloride, m.p. 226-228".

" A = POCI,, pyridine/(room temp.)(I hr); B = polyphosphoric acid/(150-170")(2-4 hr): C = conc. H,S04/(30")(15 min, then 18-20")(3 hr): D = EtOH/(reflux)(3-6 hr); E = melt/3-5 min; F = NaOEt, EtOH/(50-6O0)(1 hr, then AcOH)(reflux)(4 hr); G = conc. HCI, EtOH/(reflux)(4 hr); H = H,O/reflux (reaction time not specified); I = 4-6'10 HCll(reflux)(rllS hr); J = acetone, 1,428 hr)(reIlux); K = Hg(OAc),, AcOH, conc. H,SO,/(reflux)(S hr); L = NaOEt. EtOH/(reflux)(3 hr); M = POCIJ(reflux)(O.S-l hr); N = HMPT/(reflux)(lS-40 min): 0 = hexanol/(reflux)( 1-22 hr): P = POC13/(reflux)(l-22 hr); 0 = conc. HBr/(reEux)(2-5 hr); R = Hg(OCPh),, PhN=(===S, pyridine/(reflux)(6 hr); S = 4 M HCl/(reflux)(l3-20 hr); T = conc. H,S0,/(18-22")(32 hr); U = 8 5 4 9 % H,P0,/(95-100")(1 hr); V = AcOH/(reflux)(4 hr); W = Dimethylformamide/(reflux)(5hr); X =

+ 9

(6.239; R' = RZ= Ph, X = Cl) (6.241; R' = p-CIC,H,, R2=CHZC02H) S (6338) D (6.239; R' = CH,P(OEt),) (6.240; CN for COR') X

o

P P

(6.241; R' = Ph, R2 = Me) (6.241; R' = R2= Ph) (6.238; RJ = R5 = Me)

+

Reaction conditions"

Starting materials (R'+ R6 unspecified = H)

TABLE 6.27 (Continued)

Forms a picrate, m.p. 264-266". Forms a picrate, m.p. 244-245'. q Forms a picrate, m.p. 268-270". ' Forms a picrate, m.p. 263-264". ' Forms a picrate, m.p. 233-234". and a hydrochloride, m.p. 267-268". ' Forms a picrate. m.p. 259-260". and a hydrochloride, m.p. 308-309". " Forms a picrate. m.p. 127-128". ' Forms a picrate, m.p. 224-226". and a hydrochloride, m.p. 227-229". Forms a picrate, m.p. 212-213". Oil, b.p. 237-238"/760 m m Hg. Forms a picrate, m.p. 232-232". ' Forms a picrate. m.p. 215-216".

" Forms a picrate. m.p. 242-243".

96

Condensed Benzimidazoles of Type 6-5-5

X = C l or Br)'03*106 or their acetals [6.239; R2 = alkyl or aryl, X = C1 or Br, or a-chloro or a-bromo alkyl or aryl CH(OA1k)2 for COR']W~'03*10s-'07 in ketones (6.239; R', R2= alkyl or aryl, X = C1 or Br),'00~'02.103~108.109 or in aqueous (or in the case of acetals, aqueous acidic) media'02*105~'06~109 solvents such as alcohols (methanol, ethanol, hexanol)100~105*'06~'09 2b u t a n ~ n e , ' ~ ~dimethoxyethane,lw "~ dimethylf~rmamide,'~~~'~~ or acetic acid,Iw with or without the application of heat. Preferential condensation of the a-halogeno carbonyl compound at sulfur rather than at nitrogen in the benzimidazolethione to give the S-alkyl derivative (6.240) and not an N-alkylated isomer is demonstrated by the structures of the derived thiazolo[3,2-a]benzimidazoles whose orientation is established unequivocally by mass s p e c t r o ~ c o p y . 'It ~ ~follows that ring-closure reactions of the types [(6.240)--* (6.241) or (6.242)] are unambiguous in relation to the position of substituents in the thiazole ring of the products. However, this is not the case for substituents in the benzene ring. Cyclization of a 2-(p-oxoalky1thio)benzimidazole (6.240) unsymmetrically substituted in the benzene nucleus can, depending on which of the nonequivalent benzimidazole nitrogen atoms is involved in the ring-closure, lead to two possible isomeric products. In all such cycli~ations%*~~ reported to date one isomer tends to predominate to the virtual exclusion of the other. However, there has been no systematic study of the orientational preference shown by substituents in cyclizations of this type, largely because of the difficulty of establishing with certainty the site of substituents in the cyclic product. More success in this Jbenzimidazoldirection has been achieved with 2,3-dihydrothiazolo[3,2-a 3-one derivatives (see later) and the orientation of similarly unsymmetrically substituted thiazolo[3,2-a]benzimidazoles has tended to be assigned, someWithin this limitation, it has been what unwisely, by that 5(6)-chloro- or methoxy-substituted 2'-(2-benzimidazolylthio)acetophenones (6.240; R' = aryl, R2 = R3 = R6= H, R4,R5= C1 or MeO) tend to ring-close preferentially at the benzimidazole nitrogen atom meta (rather than para) to the substituent, the products being the corresponding 3-aryl-6chloro- or methoxythiazolo[3,2-a]benzimidazoles (6.242; R' = aryl, R2 = R3= R5= R6= H, R4= C1 or MeO). This orientational preference is the opposite to that observed in closely analogous alkylative ring-closures leading to 2,3-dihydro- 1H-pyrrolo[ 1,2-albenzimidazoles and if correct has the surprising consequence that the acylative ring-closure involved takes place at the predictably less basic of the two available benzimidazole nitrogen centers. In view of these apparent anomalies, the orientational preference involved in cyclizations of the type [Scheme 6.51; (6.240)4 (6.241)4 (6.242)] warrants more detailed scrutiny. In some instances, thiazolo[3,2-a]benzimidazoles are reported to be formed in high yield (Table 6.27) without the need to isolate intermediates of the types (6.240) and (6.241)by the direct condensation of a 2-benzimidazolethione (6.238) with an a-halogeno carbonyl compound (6.239) in the . ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ melt"' or in hot ethanolic ~ ~ l u t i o nThiazolo[3,2-aJbenzimidazole formation can be achieved even more directly (albeit in only moderate

6.2. Fused Benzimidazoles with One Additional Heteroatom

97

yield, cf. Table 6.27) by condensation of a 2-benzimidazolethione with an a-iodo ketone generated in situ by reaction of the corresponding alkyl ketone with iodine (the Ortoleva-King reaction).'" In this way 2-benzimidazolethione (6.238; R3 + R6 = H) reacts with acetone in the presence of iodine to give 3-methylthiazolo[3,2-a Jbenzimidazole (6.242; R'=Me, R2+R'=H) in 35% yield."' The use of 0-dicarbonyl compounds (e.g., ethyl acetoacetate) in this modified procedure provides synthetic access to thiazolo[3,2-a]benzimidazoles having an acyl substituent at C(2) [e.g. (6.242;R2 = C02Et)] though again only in low yield (Table 6.28).'"' On the other hand, 2-acetyl and 2-ethoxycarbonylthiaolo[3,2-a]benzimidazoles (6.242;R2 = COMe or C0,Et) are formed in high yield (Table 6.28) by the more orthodox cyclization of 3-(2-benzimidazolylor ethyl thio)pentane-2,4-diones (6.240;R' = Me, R2 = COMe)'00~'0'~103~1's 2-(2-benzimidazolylthio)acetoacetates (6.240; R' = Me, R2 = C02Et)"S catalysed by hydrochloric acid or acetic anhydride in the presence of pyridine. The facility of this type of cyclization is highlighted by the observation"' that 2-(2-benzimidazolylthio)-l-phenylbutane-1,3-dione (6.240;R' = Me, R2 = COPh) is partly converted into the isomeric 2-acyl-, thiazolo[3,2-a]benzimidazoles (6.242; R' = Me, R2 = COPh) and (6.242; R' = Ph, R2 = COMe) merely on standing in chloroform. However, undoubtedly the most convenient general method for the synthesis of 2-acylated thiazolo[3,2-a]benzimidazoles is provided by the thermal cyclization of N(1)-acyl-2-(@-oxoalky1thio)benzimidazoles either preformed or generated in situ by the reaction of suitable 2-(/3-oxoalkylthio)benzimidazoles with the sodium salts of carboxylic acids (formic, acetic, propionic) in the presence of acetic or propionic anhydride [Scheme 6.5 1; (6.240;R2 = R3 = R' = H)+(6.243)+(6.244)I.ll7 Ring-closure of this type gives uniformly high yields (Table 6.28) of both 2-alkanoyl and 2-aroylthiazolo[3,2-a]benzimidazoles and is made flexible by the ready availability of the 2-(P-oxoalkylthio)benzimidazoles (6.240; R2 = R3 = R6 = H) required as starting materials. The conversion1l6 of 2'-(2-benzimidazolylthio)acetophenone (6.240; R' = Ph, R2+ R6 = H) into 2-benzoyl-3-phenylthiazolo[3,2-a]benzimidazole (6.244; R' = R2 = Ph, R3 = H) is explicable in terms of the intermediate formation and dehydrative cyclization of the N-benzoyl intermediate (6.243; R 1 = R 2 = P h , R 3 = H ) and hence exemplifies a further version of ring-closure of the general type [Scheme 6.52; (6.243)+ (6.244)]. An alternative synthetic route to thiazolo[3,2-a]benzimidazoles, which (see before) in complements that through 2-(~-oxoalkylthio)benzimidazoles giving high yields (Table 6.27) of 2-alkyl and most notably 2-aryl derivatives, involves the ring-closure of N( 1)-(/3-oxoalkyl)-2-benzimidazolethiones [Scheme 6.52; (6.245)- (6.246)]."' Cyclization of this type is readily effected by heating with phosphorus oxychloride, or with hydrobromic or sulfuric acids, and derives its synthetic utility from the fact that it provides synthetic access to 2-arylthiazolo[3,2-a Jbenzimidazoles, products not readily available through 2-(~-oxoalkylthio)benzimidazolesbecause of the relatively inaccessible nature of a-halogeno arylacetaldehydes. On the other

4'3; R'=Ph) 4'0; R' = p-BrC6H4) 483; R' = p-B&&) 46;R' = p-NOZC6H4) 43;R' = p-NO2C6Hd) 46;R'=Ph, R 4 = R s = M e ) 4'3; R' = Ph, R3 = Me) 40 ; R' = p-B&&, 4 = RS = Me) 4'3;R' = p-BrC6H4, R3 = Me) 46;R' = p-NOzC&, 4 = RS = Me)

46;R' =Me, R2 = C02Et) 388) 40 ; R' = Me, R2 = COMe) 40 ; R' = Me, R2 = COMe) 46;R' =Me, R2 = COMe) 46;R' = Me, R2 = COMe) 4'0; R' =Me, R2 = COMe) 4Q ; R ' = Ph)

Starting material (R'+R6 unspecified = H)

G E

G E

E

G

E

G

E, F

C C D E, F G

A A

B

A

Reaction conditionso

(6.244; R' = p-N02C6&,

R' =Me)

(6.244;R' = p-BrC6H4, R3 = Me)

(6.244; R' = OEt, R2 =Me) (6344; R' = OEt, R2 =Me) (6.244; R' = R2 = Me) (6.244; R' = R2 = Me) (6.244; R' = R2 = Me) (6344; R' = R2 = Me) (6.244; R' = R2 = Me) (6344; R' = Ph) (6.244; R' = Ph) (6344; R' = p-BrC&) (6.244; R 1= p-BrC6H4) (6.244; R' = p-NOzCeH4) (6.244; R' = p-NO,C&) (6.244; R' = Ph, R3 = Me) (6344; R' = Ph, R3 = Me) (6.244; R' = p - B G H 4 , R3= Me)

Product (R'+R3 unspecified = H)

122-123

97 15 99 quant. 89 95 95 90-93 90-93 93-98 93-98 90-96 90-96 90 90 91-97 91-97 91

277-278

Dioxane

I-Butmol

-

-

279-280

1-Butanol

-

Ethanol

255-256

-

186-187

-

-

-

Dioxane-water

-

-

227-228

-

Ethanol Ethanol Ethanol-water

Ethanol Ethanol Ethanol Ethanol

Solvent of crystallization

165-166 163-164 163-164

-

167-168 163-165

123

m.p. ("C)

(YO)

Yield

117 117

115 101 115 103 103 101 100 117 117 117 117 117 117 117 117 117

Ref.

BY RING-CLOSURE REACTIONS OF BENZIMIDAZOLE TABLE 6.28. SYNTHESIS OF ACYLTHIAZOL~[~,~-U]BENZIMIDAZOLES DERIVATIVES

G

H

G H G

H

G H G H G H G H G

H

G 91

81 81 96 96 86 86 85 85 83-85 83-85 73 73 80 80 90 90

(6344;R ' = p-N0,C6H4, R3 = Me) (6.244; R2 = Me)b (6344,R Z = M e ) (6.244; R' = R2 = Me) (6.244;R' = R2= Me) (6344;R' = p-BrC6H,, R2=Me) (6344;R' = p-BrC6H4, R2= Me) (6.244;R ' = R2 = R3= Me) (6344;R' = R2= R3 = Me) (6344;R' = P - C ~ H R2 ~ , Et) (6.244;R' = p-BrC6H4, R2 = Et) (6.244;R ' = R3 = Me, R2 = Et) (6.244;R' = R3 = Me, R2 = Et) (6.244;R' = Bu', R2 = Et, R3= Me) (6.244;R' = Bu'. R2= Et, R3= Me) (6344;R ' = Ph, R2= Et, R3 = Me) (6.244;R' = Ph, R2= Et, R3 = Me)

Ethanol 187-188

-

Ethanol

-

-

161-162

-

-

Meth a noI

-

Ethanol Methanol

-

Ethanol-1 -butanol

-

Ethanol Ethanol-water

160-161 132-133

-

163-164 2 17-2 18 229-230

227-228

-

-

117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117

117

A = Ac,O, pyridine/(90-100")(3 hr); B = CH,COCH,CO,Et, I,/(reflux)(28 hr); C = 5-6% HCl/(reflux)(3-5 hr); D = POClJreflux (time not specified); E = HCO,Na, 85% HCO,H, Ac,O/(reflux)(l-2 hr); F = 85% HCO,H, Ac,O with or without dimethylformamide/(150-155", autoclave)(2-6 hr); G =sodium salt of the corresponding acid, Ac,O or (EtCO),O/(reflux)(O.5-2 hr); H = NaOAc or NaOCOEt, Ac,O or (EtCO),O/(reflux or 120160")(0.5-2 hr). Forms a p-nitrophenylhydrazone, m.p. 250-251" (decomp.) (from acetic acid).

(6343;R ' = P-NOZC~H~, R' = R3= Me) (6.240) (6.243; R2 = Me) (6.240;R' = Me) (6.243;R' = R2 = Me) (6.240;R ' = p-BrC,H,) (6.243;R' = p-BrC,H4, R2 = Me) (6.240; R' = R ' = R5 = Me) (6.243; R' = R2= R3= Me) (6340;R ' = p-BrC6H4) (6343;R' = p-BrC,H,, R2 = Et) (6.240;R' = R4= R5 = Me) (6343;R' = R3=Me, R Z= Et) (6340;R' = Bu', R4= RS= M e) (6.243;R' = But, R2= Et, R3 = Me) (6.240;R' = Ph, R4 = Rs = Me) (6343;R' = Ph, R2 = Et, R3 =Me)

100

Condensed Benzimidazoles of Type 6-5-5

hand, the N(1)-(j?-oxoalkyl)-2-benzimidazolethiones required as substrates for ring-closure of the type [(6.245) +(6.246)] are readily prepared from 2chlorobenzimidazoles by N-alkylation with an a -halogeno carbonyl compound followed by treatment with thiourea."'

(6.245)

scbew 652

(6.246)

2- and 3-Alkylthiazolo[3,2-~]benzimidazoles are also the end-products of cyclization reactions undergone by 2-(2-propynylthio)benzimidazoles (Scheme 6.53). Thiazolo[3,2-u]benzimidazole formation of this type proceeds in uniformly high yield (Table 6.27) and is accomplished catalytically using ethanolic sodium e t h o ~ i d e " ~or *'~ mercuric ~ acetate in acetic acid,12" or purely thermally by heating under reflux in hexamethylphosphoric triamide (HMPT).12' However, the course followed in the purely thermal process differs markedly from that involved in the catalytically mediated ring-closures. In the latter, cyclization is the result of direct interaction between a benzimidazole nitrogen atom and the triple bond in the propynylthio side chain, the product being the corresponding 3-alkylthiazolo[3,2a]benzimidazole [Scheme 6.53; (6.247; R = H) +(6.249)].119*120a In the thermally induced process, on the other hand, ring formation is preceded by [3,3] sigmatropic shift, the resulting N(l)-allenyl-2-benzimidazolethioneintermediate then cyclizing to a 2-alkylthiazolo[3,2-u~enzimidazole [Scheme 6.53; (6.247; R ' = R 2 = R 3 = H , R = H or Me)-,(6.248; R = H or Me)+ (6.250; R = H or Me)).lZob The thiazolo[3,2-a]benzimidazole diester (6.242; R'=RZ=C02Me, R3-R6=H) is the product formed in low yield

(6.247)

(6.248)

(6.249)

(6.250) [R=H or Me]

I

sebcw 6.53

6.2. Fused Benzimidazoleswith One Additional Heteroatom

101

(Table 6.27) by the somewhat unusual reaction of (2-benzimidazolylthi0)acetonitrile (6.241; R2+ R6 = H, CN for COR') with dimethyl acetylenedicarboxylate.'2' The course followed in this transformation is not clear. 3-Phenylthiazolo[3,2-a~emimidazolesare also formed in unorthodox, but nonetheless efficient, fashion (Table 6.27) by the reaction of 2-benzimidazolethiones with mercury bisphenylacetylide in the presence of phenylisothiocyanate.'22 These deep-seated transformations are accounted for'*' by a course (Scheme 6.54) involving the formation of, and extrusion of mercury from an eight-membered cyclic intermediate (6.251) followed by ring-contraction of the fused dithiazepine (6.252) produced.

R

m K

R

H

Y

H

,CSNHPh

R

SHgbCPh

(6.251)

I

[ R = H or Me]

(6.252) Scheme 6.54

2,3-Dihydrothiazolo[3,2-a]benzimidazole derivatives are most simply constructed by the thermal or base-catalyzed dehydrohalogenative cyclization of 2-(~-halogenoalkylthio)benzimidazoles [Scheme 6.55; (6.254; X = CI or Br)-,(6.256)], which can either be pref~rmed''~or prepared in sifu by reaction of a 2-benzimidazolethione with a lY2-dihalogenoalkanesuch as or brom~chloroethane,'~~ and cyclized withd i c h l o r 0 - , 9 ~ * ' ~dibrorn0-,9~ ~.'~~ out isolation. To judge from the limited amount of information available,'23 ring-closure of this type proceeds in good yield (Table 6.29) only with the preformed 2-(/3-halogenoalkylthio)benzimidazole and in conjunction with

102

Condensed Benzimidazoles of Type 6-5-5

H

A

(6.253)

H

(6.254)

I (6.255)

(6.256) !3cbame 6.55

catalysis by a relatively strong base, such as an alkali metal h y d r ~ x i d e ~ ~ * * ~ * ~ ~ or sodium hydride? or with heating under reflux in a suitable solvent such as toluene.'23 In the context of the base-promoted process it is noteworthy that the reportedly'26 successful condensation of 2-benzimidazolethione with 1,2-dibromoethane in the presence of potassium carbonate to give 2,3-dihydrothiazolo[3,2-u]benzimidazole has been ~ u g g e s t e d to '~~ be in error. The melting point associated with the latter compound (cf. Table 6.29) is also a source of some confusion, having been assigned values as widely differing as 108-1090,'23 l10°?4 141-142°,124and last but not least, 239-240°.'25 A value of ca. 110" may be assumed on statistical grounds if nothing else! As in the case of related cyclizations leading to thiazolo[3,2-a]benzimidazole derivatives (see before), ring formation of the type [(6.254) +(6.256)] using substrates unsymmetrically substituted in the benzene ring can lead to two possible, isomeric products, depending on which of the benzimidazole nitrogen atoms is involved in the ring-closure step. The single 2,3-dihydrothiazolo[3,2-a]benzimidazole products obtained in the cyclization of the C5(7)-chloro- and nitro-2-(~-halogenoalkylthio)benzimidazoles[Scheme 6.55; (6.254; R ' = R Z = H , R3 or R4=C1 or NO,, X=Cl)] have been assigned the C(7) orientation (6.256; R' = RZ= R3 = H, R4= CI or NO,) but without compelling evidence to exclude the alternative C(6) formulations (6.256; R' = R2= R4 = H, R3 = CI or NO2). If correct, the orientation assigned to the nitro product in particular requires, contrary to expectation, that alkylative cyclization of the type [(6.254) +(6.256)] occurs preferentially through ring-closure at the less basic of the two benzimidazole nitrogen atoms. For this reason firmer evidence for the orientation of the

+

X = Cl)

I I I I

+

X = CI)

(6.239: X = Br. CH(OEt), for COR')

(6.239; (6.238)

+

(6.239; X = CI) (6.238)

+

(6.239; X = CI) (6.238)

+

(6.239; (6.238)

R4 = CI) R4 = NO,) R' = NO,) R'= NHAc) R 3 = R4 = Me) R3 = R4 = Me)

X = CI) X = Cl)

J

1

H (6.241)

(6.241)

(6.241)

I

J

(6.241)'

(6.241)'

H

G

D E

F

B B F

F

E

C D

B

A A

(6.253) (6.253) (6.253) (6.253) (6.254; (6.254: (6.255) (6.253; (6.253; (6.255; (6.255: (6354; (6354; (6.238)

(6.256)b (6.256) (6.256)' (6.256), (6.256) (6.256) (6.256) (6356; R'= C1)8 (6.256: R4 = NO# (6.256; R4 = NO,) (6.256; R4 = N H A c ) ~ (6.256; R' = R4 = Me) (6.256; R3 = R' = Me)

Reaction Product conditions" (R'-D R6 unspecified = H)

-

71

89-93

89-93

95

quant.

90 82 81 92

-c -c

-

-

-

194-196 (decomp.)

I 80- 180.5

-

176-178 180-1 82 229-230 > 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

Solvent of crystallization

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)

+

Reaction conditions"

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

Acetonitrile, acetone, or ethanol-water

Diethyl ether

Tetrah ydrofurane

Ethanol

Tetrahydrofurane

Methanol

-

200-202

Solvent of crystallization

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

Acetonitrile, acetone or ethanol-water

Acetonitrile, acetone or ethanol-water

Acetonitrile, acetone or ethanol-water

Acetonitrile, acetone or ethanol-water

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

Solvent of crystallization

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)

TABLE 6.29 (Continued)

-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

Condensed Benzimidazoles of Type 6-5-5

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

Product (R'+R6 unspecified = H)

Reaction conditions"

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-

Solvent of crystallization

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)

Product (R'+R6 unspecified = H)

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

Solvent of crystallization

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

Reaction conditions'

(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)

TABLE 6.30 (Continued)

6.2. Fused Benzimidazoles with One Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-5

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

6.2. Fused Benzimidazoles with One Additional Heteroatom

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

Solvent of crystallization

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;

'

6.2. Fused Benzimidazoles with One Additional Heteroatom

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)

Solvent of crystallization

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

Solvent of crystallization

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

Reaction conditions"

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

TABLE 6.33 (Continued)

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)

Reaction conditions" Product

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.) -

Solvent of crystallization

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-CI<;H.,)' (6376;R = H , R ' = (CH,),NEt,, R2= p-CIC6HJb (6376;R = H, R' = (CH,),NEt,, R2 = p-BrC,H,)* (6376;R = H , R ' = (CH,),NEt,, R2 = p-BrC6H,)b (6376;R - H , R ' = (CH,),NMe,, R2 = P-CIC,H,)~ (6376;R = H, R' = (CH2),NMe2, R2 = p-BrC6H,)b 160

155, 160 155, 160

162b

Ethanol Ethanol

Ethanol-water

190-192 218-219

80-82

78 70 65

95

(Footnotes overleaf)

160 155, 160

155, 160

Ethanol

162b

-

187-189

155, 156

-

78

239-240

98

155,156

c

-

-

321-323

97

157

Ethanol-water

-

265

quant.

155, 156

-

68

268-269

96

162a

Methanol

Ethanol

141

93

163

Ethanol

197-199

163

68

161

Ethanol

15

156-157

98

161

Ethanol

-'

2 12-2 13

77

161

Ethanol

95

112-113

84

-

J

K = NH,/(160-180". autoclave)(6 hr); L =

dimethylformamide/(reflux)(lO min); A4 = 48% HBr/(reflux)(6 hr); N = POCI,. O*NAsLCOCH2Br, conc. HCl/(reflux)(8-20 hr); 0 = 85% HCO,H/(reflux)(S hr); P = no solvent/(190-210")(10 min). Hydrobromide. Solvent of crystallization not specified. Hydrochloride; free base has m.p. 94" (from ethanol); hydrates o n standing. ' Picrate. Yield not quoted. * Forms a hydrate, m.p. 80'. Forms a dihydrochloride, m.p. 256258" (from ethanol), and a dipicrate, m.p. 160-lh2" (from ethanol). ' oil. Forms a picrate, yellow prisms, m.p. 178-179" (from ethanol). Ir Decomposes on storage at room temp. Forms a hydrochloride, m.p. 262" (decomp.) (from ethanol-water), and a picrate, m.p. 248" (decomp.) from ethanol-dimethylformamide). Forms a picrate, m.p. 238-240' (decomp.) (from ethanol). " Forms a picrate, m.p. 228-230". O Forms a picrate, m.p. 224-226'. Forms a picrate, m.p. 238-240'. Hydrobromide; free base has m.p. 218" (from ethanol). ' Hydrobromide; free base has m.p. 207-208" (from ethanol-water). a Hydrobromide; free base has m.p. 218-219" (from ethanol). ' Hydrobromide; free base has m.p. 240-242'. " Forms a dihydrochloride, m.p. 247" (decomp,) (from ethanol) and a dipicrate. m.p. 205-206" (from ethanol). ' Forms a dihydrochloride, m.p. 269" (decomp.) (from ethanoMiethy1 ether) and a dipicrate, m.p. 225" (Irom acetic acid).

A = 2M HCl/(room temp.)(l4 hr); B = MeCOCH,Br, B~"OH/(130-135~)(30 min); C = NaOEt, EtOH/(reflux)(l-5 hr); D = conc. HCI/ (reflux)(2-7 hr); E = KOH, tetrahydrofurane/(rom temp.)(2-24 hr); F = 10% HCl/(reflux)(l hr); G = POCl,/(reflux)(4-12 hr); H = I,, MeCOMel (reflux)(l hr, then conc. HCl)(reflux)(lS hr); I = 10% NaOH, MeOH/(room temp.)(few min); J = EtOH or MeOH/(reflux)(lO-24 hr);

(Foomotes to Table 6.33)

D

(6.282; R = H, R' = Me,

R'= Ph)

Ethanol Benzene Ethanol-water

176 156 138

96 48

H

G

F

89

Ethanol

170

R2 = Me)c (6.286; R = R2= Me. R' = Et)d (6.286; R = H, R' = Me, R2 = Ph) (6386; R = H. R' = Me, R2 = OMe)

Ph for Me)

95

R2 = CH,COMe)b (6.282; R = Me, R' = Et, R2 = CH,COMe)h (6.284; R = H, R' = Me, R2 = Ph)' (6.282; R = H, R' = Me. R2 = Ch2C02Me)'

F

(6.286; R = H, R' = CH2Ph,

(6382; R = H, R' = CH,Ph,

Ethanol

I Ethanol

212

56

(6.286; R = H, R' = R2 = Me,

CH2COPh)

178

42

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

F

(6.282; R = H. R' = Me, RZ=

Ethanol

178 100

Ethanol-water

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

178

Octane

F

SO

156

=

R' = R' = Me)

61

Octane

-

(6.286;

R = H,

(6.285: R = H, R' = R2 = Ph)

152

-

32 50 58

140-142

40

(6.284; R ' = R' = Me)

Acetone

Acetone

177

Yield

(6.284; R' = Ph, RZ= Me) (6.285; R' = Ph, R2 = Me) (6.285; R = H, R ' = Me,

Solvent of crystallization

m.p. ("C)

(Yo)

Product

E

R2 = COPh) (6.282; R = H, R' = Me, R' = CH2C02H) (6.282; R = H, R' = Me, R' CH,COMe)'

= COPh)

B

(6.283; R' = Ph. R2 = Me) (6.282; R = H, R' = Me,

R'

A

(6.274; R' = Ph, R' = H)

C

Reaction conditions"

Starting material

173

172

I72

172

172

172

173

171

171 171

171

Ref.

TABLE 6.34 SYNTHESIS OF ACYL-9H-IMIDAZO[ 1,2-a]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF 2-AMINOBENZIMIDAZOLE DERIVATIVES

85

76

(%)

Yield

112

79-80

m.p. ("C)

173

173

Light petroleum Light petroleum

Ref.

Solvent of crystallhation

Hydrobromide. Forms a dinitrophenylhydrazone, m.p. 218" (from ethanol4imethylformamide). Forms a dinitrophenylhydrazone, m.p. 216" (from ethanol). ' Hydrochloride.

A = Ac,O, NaOAc/(room temp.)(few min); B = dimethylformamide/(80-90")(20 hr); C = MeCOCKBr. dimethylformamide/(80") (20 hr); D = PhCOCH,Br, dimethylfonnamide/(8OO)(l6 hr); E = A%O/(reflw)(3 hr); F = A%O, NaOAC/(reflw)(U)-60 mh); G = Et,N, dimethylformamide/(reflux)(S hr); H = AGO, NaOAc/(reflux)(S hr).

H

R 2 = OC,H,,) (6.286; R = H, R ' = CH,Ph, R2 = OMe)

(6.286; R = H, R' =Me,

H

(6.282; R = H, R' = Me,

R2 = CH2C0,C,H,,)' (6.282; R = H, R' = CH2Ph. R2 = CH,CO,MeY

Product

Reaction conditions"

Starting material

TABLE 6.34 (Continued)

C D

B

A

A

A

A

A

(6.289)’

P-CIC,H,NH)~ (6.276; R = H, R’ = Me, R2 = p-EtO,CC,H,NH) (6388; R = Me,Ar = p O2NC,H,)’ (6.288; R = Ar = Ph)’

(6.276; R = H, R’ =Me, R2 = NHPh)b (6.276; R = H, R’ =Me, R2 = N(Me)Ph)* (6.276; R = H, R’ =Me, R2 = p-02NC6H,NH)b (6.276; R = H, R’ = Me, R2 =

Reaction conditions” Product

Acetic acid

162 189 234

90-95 90-95 90-95

175 175 175

Ethanol 137-138 Ethanol 235 Ethanol (decornp.) 97 91

174 232

Dimethylformarnide

174

174

174

174

Ref.

-d

90-95

230

Ethanoi-dimethylforrnarnide Ethanol

226

90-95

Dimethylforrnarnide

Solvent of crystallization

m.p. (“0

Yield (%)

‘

I,

@

Picrate; free bases and their hydrochlorides are unstable. Orange needles. Yield not quoted. Colorless plates.

A = POCl,/(reflux)(3 hr); B = p-02NC,H4CH0, EtOH/reflux (reaction time not specified); C = PhCH0/(130°, rnelt)(5-7 rnin); D = Ac,O/reflux (reaction time not specified).

(6.287; R = Ph) (6.287; R = Ph)

(6.273; R = H, R2 = Me, R2 = NHPh) (6.273; R = H, R’ =Me, R2 = N(Me)Ph) (6.273; R = H, R’ = Me, R2 = P-O~NC~H~NH) (6.273; R = H, R’= Me, R2 = P-CIC~H~NH) (6.273; R = H, R’ = Me, R2 = p-EtO*CC,H,NH) (6.287; R = Me)

Starting material

TABLE 6.35 SYNTHESIS OF AMINO-9H-IMIDAZO[ 1,2-a]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF 2-AMINOBENZIMIDAZOLE DERIVATIVES

h ) OI

c.L

A

(6.290; R = NO,) (6.292) (6.292; R2 = NO,) (6392; R' = Et)

1

I1

(6.299; R2 = CI)

(6.302) (6.299; R' = CI)

= Br)

F F I

(6.297; R = Me) (6.297; R=CH,Ph) (6.299; R' = C I )

R'

H

(6.294; R = CH,CO,H)

(6.299;

G

E

I

F

C

(6.292; R' = CH,Ph)R (6.271; R' = Ph) (6.292; R' = Ph) (6.292; R ' = p-CIC,H,, R2 = a) (6.294; R' = NH,) (6.295)

C D

-d

B B

A

(6.290)

Me

80 55

18

(6.301; R2 = Cl) (6.301; R' = CI) (6.301; R3 = Br)

85 90 78 42

60

22 23

u

296-298 272-276

Nitromethane Xylene

-

1 -1

Xylene

Dimethylformamide Ethanol Xylene Xylene

Acetone

Ethanol -

-

Acetone -

Diethylether-light petroleum Ethanol Dioxane Ethanol Acetic acid

Solvent of crystallization

335-337

-

265-266 198 268-270 291-293

227-229

y23

214

78

(6.301); R4 = CI) (6.301; R3 = Cl)

I i

(6.298; R = Me) (6.298; R = CH,Ph) (6.301; R'=CI) (6.301; R2 = CI)

6.296; R=CH,CON

(

-k

225-228 -

2

37

14

(decomp.)

22

(6.293; R' = CH,Ph)h (6.293; R ' = Ph)' (6.293; R' = Ph)' (6.293; R' = p-CIC6H4, R2 = Cl) (6.296) (6.296)

-'

161-163 204-206 262-263 267-268

92 68 75

(6.291)b (6.293) (6.293; R2 = NO,)' (6.293; R' = Et)'

-'

97.5-98

m.p. ("C)

17

(YO)

Yield

(6.291)

Reaction Product conditions" (R, R'-+R4 unspecified = H)

{

Starting material (R, R2+Rs unspecified = H)

182 182

182

182

173 173 182

181

180 180

176 177 177 177

178 176 176 161

179

Ref.

TABLE 6.36 SYNTHESIS OF 2.3-DIHYDRO- 1 H-AND OH-IMIDAZO[ 1.2-a]BENZIMIDAZOLES BY RING-CLOSURE REACTIONS OF 2-AMINOBENZIMIDAZOLE DERIVATIVES

+

4

N

Y

(6.306)

(6.306: R' = CH,Ph) (6.306;R' = CH,Ph. R2 = COC0,Me) (6.306) (6.306)

R2 = COC0,Me)

(6306;R 1= Et) (6.306;R 1 = E t ,

R2= COC0,Me)

R

Q R

P

M

M P

0

M M

N

(6.306;R2 = C0,Et)

(6.306) (6.306: R' = Me) (6.306;R' =Me.

N

M N

L

K

I' I I I I J I

(6306;RZ= C0,Me)

(6.299; R3 = NO,) (6.299;R3 = CN) (6.299;R' = F) (6.299;R3 = COPh) (6.299;R L= R' = CI) (6399;R' = Rs= CI) (6399;R' = R4 = CI) (6.299;R ' = R' = R - Br) (6.303) (6.306;R 1 = CH,Ph) (6306)

Y = O-CIC~H~NHN)

(6.308;X = 0

p-CICbHaNHN)

49

22.5-227

2 18-2 19 180- 182 69 56

(6.308;X = 0,Y = NPh) (6.308;X = 0,Y =

269 -

280-283 255-259 265-267 239-24 1 285-287 326-330 300-304 237-238 110 175 (decomp.) 152-153 (decomp.) 108 (decomp.) 324-325 295 -

172-173 -

67 27

66 90 25

76

74

17 80 20 94 58 70

80

-1

-I

f

52

_.

(6.308;R = CH,Ph, X = Y = 0) 66 (6.308;R = CH,Ph, X = Y = 0) 20

(6.308;R = Et. X = Y = 0) (6.308;R = Et, X = Y = 0)

(6.308;X = Y = 0) (6.308;R = Me, X = Y = 0) (6.308;R = M e , X = Y = O )

(6.307;R = CO,Me, X = NCF,) (6.307;R = C0,Et. X = NCF,)

(6.301;R' = NO,) (6.301;R3 = CN) (6.301;R'= F) (6.301;R3 = COPh) (6.301;R' = R~ = CI) (6.301;R' = R4 = CI) (6.301;R' = R4 = CI) (6.301;R' = R3 = R4= Br) (6.305) (6.307;R = CH,Ph, X = 0) (6.307;X = NCF,)

Ethanol

Ethanol Ethanol

Ethanol

-

Ethanol-water -

Acetic acid Ethanol -

Ace tone

Xylenc Benzene-acetone Octane -m

-

-m Xylene Nitrobenzene

-m

Xylene -m

151, 186

151 151. 186

185 185

185 185

185

185 185

187

187

187

185

182 183 183 183 182 184 184 184 6

OC

h)

c

hr); H = SOCl,/(reflux)(lO min) then treatment with

n

NMe U

HN

(room

'

(temp.)(30 min); I = xylene/(reflux)(15 min); J = bromobenzene/(reflux)(S min); K = xylene/(reflux)(45 min); L = Ph,-O, dioxanel (room temp.)(l4 hr); M = (COCl),, dioxane/(l5-20")(1 hr, then Et,N)(reflux)(30 min); N = (FC=NCF,),, NaF, M e w / ( - 3 0 " then 0°)(2 hr); 0 =melt (240-250")/8 hr; P = melt (180-200")/5 hr; Q = PhN=C(Cl)COCl, Et,N, benzene-dioxane/(reRux)(3 hr); R = ArNH"E(Cl)COCl. Et,N, benzene-dioxane/( 100")(3hr). * Forms a hydrochloride, m.p. 245-248". ' Forms a hydrochloride, m.p. 262-263'. Reaction conditions unspecified. Picrate. f Yield not quoted. Hydrochloride. Forms a picrate, m.p. 204-206" (ethanol). ' Yellow oil, b.p. 192-194"/0.15 mm Hg. Hydrobromide. Oil. Time of reflux, 2 hr. W v e n t ofcrystallization unspecified.

J

AcO/(reflux)(5-20 min); G = ClCH,CO,Me/(reflux)(l

A = 160-190" (no solvent)/(2 hr); B = SOCI,, dimethylformamide/(O-2")(1 hr, then reflux 3-8 hr); C = SOCI,, CHClJ(reflux)(2-3 hr, then NaOH or KOH, H,O, MeOH/(reflux)(24 hr); D = Br(CH,),Br, toluene/(reflux)(24 hr); E = SOCI,, CHCl,/(reflux)(Z hr); F =

(Foomotes 10 Table 6.36)

6.2. Fused Benzimidazoles with One Additional Heteroatom

R

R

RE

X

T

O NH R I

I

(6.272)

R

'

I

(6.275)

R2

I I Me R2 (6.274)

R'

(6.273)

nJ;J

R

Nl

Rq A N : o R 2

R'

R1

I

R

129

I R1 (6.276)

Scbeme 6.61

I

R2

R 1 - H or Ac

a;l$R I Me (6.277)

diethylacetal in the presence of hydrochloric acid"' affords the parent 9 H imidazo[ 1,2-a]benzimidazole (6.276; R = R' = R2 = H) in excellent yield (Table 6.33). General synthetic access to 2-alkyl and 2-aryl N ( 1)-substituted lH-imidazo[l,2-a]benzimidazoles(6.275; R' = alkyl or aryl, R2 # H) (Table 6.32) is provided by the ring-closure of 2-(suhstituted amino)-N(l)-(poxoalky1)benzimidazoles (6.272; R' = alkyl or aryl, R' # H) catalyzed by hydrochloric or promoted spontaneously in the course of the reactions of 2-chloro-N( l)-(j3-0xoalkyl)benzimidazoles (6.270) with aliphatic and aromatic amines.1'7.'5" Conversely, 2-alkyl and 2-aryl N(9)-substituted 9H-imidazo[1,2-a]benzimidazoles (6.276; R # H, R2= alkyl or aryl) are synthesized usually in excellent yield (Table 6.33) by the cyclization of preformed N(3)-substituted N(1)-(~-oxoalkyl)-2-iminobenzimidazolines (6.273; R ' f H, R2=alkyl or aryl) or their hydrobromides, made readily available by the N ( 1)-alkylation of N(3)-substituted 2-aminobenzimidazoles with a-halogeno carbonyl compounds. Ring-closure of this type can be induced in a purely thermal fashion in the p r e ~ e n c e " ~ - ' ~or~ -ab'~~ Sence155.360 of an alcoholic solvent or under the influence of a variety of acidic catalysts including phosphorus o x y ~ h l o r i d e , ~ * ~hydrochloric -'~~ acid, 157,162,166 hydrobromic acid,167and formic acid.16' A potentially useful,

Condensed Benzimidazoles of Type 6-5-5

130

yet little exploited "one pot" version of such 9H-imidazo[ 1,2-a]benzimidazole synthesis is based on the in sifu formation of the N ( l)-(P-oxoalkyl)-2iminobenzimidazoline precursor by N-p-oxoalkylation of N(1)-substituted 2-aminobenzimidazoles with acetone in the presence of iodine (the Ortoleva-King reaction'""). This modification is exemplified'66 by the reaction of 2-amino- 1-benzylbenzimidazole with acetone and iodine to give, via the presumed intermediacy of the iminobenzimidazoline (6.273; R = H, R' = CH,Ph, R2= Me), Y-benzyl-2-methyl-9H-imidazo[ 1,2-a]benzimidazole (6.276; R = H, R' = CH,Ph, R2= Me) in high yield (Table 6.33). 9Substituted-2-methyl-9H-imidazo[ 1,2-a]benzimidazoles are also the endproducts (Table 6.33) of the sodium ethoxide or potassium hydroxide mediated ring-closure of N(3)-substituted N(I)-(Z-propynyl)-2-iminobenzimidazolines or of their vinyl bromide precursors [Scheme 6.62; (6.278; R' or R2= Br) +(6.279) + -+(6.281)].169*170 A course for these reactions involving base-catalyzed rearrangement [Scheme 6.62; (6.279) -+(6.280)] prior to cyclization is dern~nstrated'~'by the isolation of allene intermediates of the type (6.280) and their smooth transformation into the (6.281) on treatcorresponding 2-methyl-9H-imidazo[1,2-a]benzimidazoles ment with base. Derivatives of the 9H-imidazoE1,2-a]benzimidazole ring system are also accessible in high yield (Table 6.33) by the hydrochloric acid-catalyzed ring-closure of N(1)-substituted 2-(/3-oxoalkylamino) benzimidazoles [Scheme 6.6 1; (6.274) +(6.277)I.l" Cyclization of this type complements that through N(l)-(~-oxoalkyl)-2-iminobenzimidazolines [e.g. (6.273)] in providing synthetic access to 3-substituted (as opposed to 2substituted) 9H-imidazo[1,2-a]benzimidazoles.

/ eJzl- CL...XMe (6.278)

(6.279)

I

k

(6.280)

sebeme 6.62

R (6.281)

Ring-closure in N(1)-(~-oxoalkyl)-2-iminobenzimidazolinederivatives also provides the basis for the efficient synthesis (Scheme 6.63) of 9Himidazo[ 1,2-a]benzimidazoles containing an ester or ketonic substituent at

6.2. Fused Benzimidazoles with One Additional Heteroatom

131

the C(3) position. For example, reaction with acetic anhydride in the presence of sodium acetate affords acetylimino intermediates (6.284; R’ = alkyl, aryl, or 0-alkyl), which undergo spontaneous intramolecular aldoltype condensation, affording the corresponding 3-acyl- or 3-alkoxycarbonyl9H-imidazo[ 1,2-a]benzimidazoles (6.286; R2= alkyl, aryl, or 0-alkyl) in moderate yield (Table 6.34).’72*’73 One disadvantaget7’ of this approach is the tendency for “acyl scrambling” to occur giving mixtures of the 3-acyl and 3-acetyl derivatives, the latter as a result of deacylation of the former and reacetylation in Friedel-Crafts fashion (see later). However, this difficulty can be circumvented by cyclization of the preformed acetyliminobenzimidazoline (6.284) using triethylamine as catalyst.I7’ 2-Acyl-9H-imidazo[ 1,2-~]benzimidazolesare synthesizedt7’ in moderate yield (Table 6.34) by the in situ formation and dehydrative cyclization of N(l)-acyl-2-(poxoalky1imino)benzimidazolines [Scheme 6.63; (6.283) +(6.285)].”’ This otherwise convenient synthetic method is complicated by the tendency for the N(l)-acyl-2-iminobenzimidazoline(6.282; RZ= acyl) used as starting

, /

R’ = yU

R’ (6.282)

RICwH

R‘= COR

2x

\

2COR2

R COR’

I

R

N--

COMe

I

R’ (6.284)

Me (6.283)

COR’

R2

CL~XCORl “nJ\X Me I

R

(6.285)

R’ I

(6.286) Scheme 6.63

Me

Condensed Benzimidazoles of Type 6-5-5

132

material to undergo initial thermal rearrangement to the corresponding 2acylaminobenzimidazole with consequent ultimate contamination of the 2acyl-9H-imidazo[ 1,2-a]benzimidazole product by the 3-acyl isomer. However, the thermal cyclization of the preformed N ( l)-acyl-2-(P-oxoalkylimino)benzimidazoline (6.283) (as the hydrobromide) in dimethylformamide gets round this difficulty and affords the required 2-acyl-9H-imidazo[ 1,2-a]benzimidazole in reasonable yield (Table 6.34)."' The alternative app r o a ~ h ' ~to ' 2-acyl-9H-imidazo[l,2-a]benzimidazoles, of in situ acylationcyclization of 2-(~-oxoalkylamino)benzimidazoles[Scheme 6.6 1; (6.274; R2=H)] is only moderately successful and also tends to result in acyl scrambling as a consequence of deacylation of the initial product followed by reacylation by the reagent. of N ( 1)-(0-carbamoylThe phosphorus oxychloride-catalyzed~yclization'~~ methyl)-2-iminobenzidazolines [Scheme 6.63; (6.282; R2 = CH2CONHR)] provides a high yield (Table 6.35) route to the otherwise difficultly accessible and highly unstable 2-amino derivatives of 9H-imidazo[ 1,2-a]benzirnidazoles. The equally elusive 3-amino-9H-imidazo[ 1,2-a]benzimidazoles can be isolated'75 in the form of acetyl and benzylidene derivatives produced by the reaction of their open-chain 2-(a-cyanoalkyl)benzimidazole tautomers with acetic anhydride and aromatic aldehydes, respectively [Scheme 6.64; (6.287)+= (6.2881, or (6.289)].

/

(6.287)

N==CHAr

I Me (6.288)

R

\

q,-,;<" h

Me (6.289)

Schcmc 6.64

The importance of suitably functionalized 2-aminobenzimidazoles as key intermediates for the synthesis of 1H- and 9H-imidazo[l,2-a]benzimidazole derivatives (see before) is equally apparent in synthetic routes leading to their 2,3-dihydro counterparts. A simple example is the dehydrochlorinative ring-closure of N ( 1)-(~-chloroalkyl)-2-aminobenzimidazoles [prepared by the in situ reaction of the corresponding (p-hydroxyalky1)benzimidazoles with

6.2. Fused Benzimidazoles with One Additional Heteroatom

(6.290)

(6.291)

133

Et

T J -E /

RZ

1

R' (6.292)

N H OH

Mame 6.65

Rz

I

R' (6.293)

thionyl chloride] which provides an efficient (Table 6.36) and potentially general method for the synthesis of tautomeric 2,3-dihydro- l(9)Himidazo[ 1,2-a]benzimidazole derivatives [Scheme 6.65; (6.292; R' = H)+ +(6.293; R' = H)].'76 E ~ t e n s i o n ' ~ ' * ' ~ of~ this . ' ~ ~methodology to N(3)(6.292;R' # H) substituted N( I)-(/3-hydroxyalkyl)-2-iminobenzimidazolines affords high yield (Table 6.36) synthetic access to N(9)-alkyl- and aryl-2,3dihydro-9H-imidazo[1,2-a]benzimidazoles (6.293;R' = alkyl or aryl). Products of the latter type are also formed, though in poor yield (Table 6.36) by the direct annelation of N( l)-substituted-2-aminobenzimidazoleswith 1,2dibr~moethane.'~'The corresponding chlorinative-dehydrochlorinative cyclization of 2-(N-substituted amino)-N(1)-(P-hydroxya1kyl)benzimidazoles does not appear to have been reported, the anticipated N ( 1)-substituted 2,3-dihydro- 1H-imidazo[ 1,2-a]benzimidazole products of such ring-closure being available, though in variable yield (Table 6.36) by the alternative dealkylative thermal cyclization of N ( l)-(/3-dialkylaminoalkyl)-2-chlorobenzimidazoles, e.g. [Scheme 6.65; (6.290)+ (6.291)J. 178*179 The dehydrative cyclization (Scheme 6.66) of [2-(N-substituted amino)-1benzimidazolyl]acetic acid derivatives, e.g. (6.294;R' = OH, OMe, or NH2), which can be induced thermally'80 or by heating with acetic anhydride"" or thionyl chloride,'*' represents a simple and potentially general method for the synthesis of N( 1)-substituted 2,3-dihydro- 1H-imidazo[1,2-a]benzimidazol-2-ones, e.g. (6.296). N(9)-Substituted 2,3-dihydro-9Himidazo[ 1,2-a]benzimidazol-2-onesare formed in excellent yield (Table 6.36) by the analogous, acetic anhydride-catalyzed cyclization of N(3)substituted N ( 1)-(2-iminobenzimidazolyl)acetic acids [Scheme 6.67; (6.297)-*(6.298)].'73 (2-Benzimidazolyl) aminoacetic esters, on the other hand, cyclize thermally to 2,3-dihydro-1(9)H-imidazo[l,2-a]benzimidazol3-ones only in low yield (Table 6.36)."* Moreover, the efficiency of 2,3dihydro- 1(9)H-imidazo[1,2-a Jbenzimidazole synthesis of this type is further

134

a.

Condensed Benzimidazoles of Type 6-5-5

Me I

Q L 1 3 0 : 1

HI

(6.294)

NHMe

(6.295)

Me

(6.296)

Scheme 6.66

I R (6.297)

C02H

Scbemc 6.67

I R

(6.298)

diminished by the tendency for substrates unsymmetrically substituted in the benzene ring to give rise to isomer mixtures as a result of alternative ring-closure at the nonequivalent benzimidazole nitrogen atoms, e.g. [Scheme 6.68; (6.302)+(6.301; R' = R3= R4= H, R2= Cl) + (6.301;

R'

= R2 = R4= H,R ' = Cl)].182 2,3-Dihydro-1(9)H-imidazo[l,2-a]benzimid-

azol-3-ones are also formed less orthodoxly, but nonetheless in high yield (Table 6.36) by the smooth thermal rearrangement of adducts (l-cyano-2aryl-4,4-diphenylazetidin-3-ones) derived by the cycloaddition of diphenylketene to arenediazo cyanides [Scheme 6.68; (6.299)+ --* (&301)].'82-'" Applied to diazetidinones (6.299) containing orrho- or para -substituted phenyl groups, transformations of this type allow the unambiguous synthesis of 5- and 7-substituted 2,3-dihydro-1(9)H-imidazo[l,2-a]benzimidazol-3ones (6.301)in high yield (Table 6.36).'82*'83 On the other hand, mixtures of 6- and %substituted products (6.301)result from the thermolysis'82 of 2(rneta-substituted pheny1)diazetidinones (6.299), and the rearrangement of substrates (6.299),in which both of the ortho positions of the phenyl ring are occupied by halogen substitutents, leads to nuclear substituted

6.2. Fused Benzimidazoleswith One Additional Heteroatom

135

dihydroimidazo[l,2-a]benzimidazol-3-ones (6.301) derived by unprecedented halogen migration. '84 The activation parameters observed'83 for the deep-seated thermal transformations of 1-cyano-2-aryldiazetidinones (6.299)into 2J-dihydro- 1(9)H-imidazo[ 1,2-u]benzimidazol-3-ones(6.301) are consistent with a course (Scheme 6.68) initiated by Cope rearrangement and concluded by transannular cyclization in the eight-membered carbodiimide (6.300)formed. This course is further substantiated by the results of "N-labeling studiesLR4which demonstrate, in accordance with initial Cope rearrangement, that N(l) in the substrate (6.299)becomes N(1) in the final product (6.301).A mechanism (Scheme 6.69) involving the initial formation and subsequent cyclization of a zwitterionic intermediate (6.304) has been proposed6 to account for the reaction of 2-azido- 1 -methylbenzimidazole (6.305) with diphenylketene to give the 2,3-dihydro-9H-imidazo[ 1,2-u]benzimidazol-3-one(6.305)in high yield (Table 6.36). Cyclization of intermediate N-chlorooxalyl derivatives accounts for the smooth reaction'" (Scheme 6.70) of 2-(N-substituted amino)benzimidazoles (6.306; R' = H, R2# H) and N(1)-substituted 2-aminobenzimidazoles (6306;R' f H, R2 = H) with oxalyl chloride followed by triethylamine, to afford high yields (Table 6.36) of 2,3-dihydro-1 H- and 9H-imidazo[ 1,2a]benzimidazole-2,3-diones (6.307; X = 0),and (6.308; X = 0),rethough spectively. Products of the latter type are also obtained,"' less efficiently by the thermal ring-closure of N(1)-alkyl 2 - ( N methoxalylamino)benzimidazoles [Scheme 6.70; (6.306; R' = alkyl, R2 = COC02Me)--,(6.308; R = alkyl, X = O)].The products, obtained in good

136

Condensed Benzimidazoles of Type 6-5-5

(6.303)

L c;l$;h-

I Me (6.305)

Ph

I

111 N

0

QJ$@ '

Me Scheme 6.69

c1 N2

Ph

(6.304)

yield (Table 6.36) by the triethylamine-catalyzed condensation of 2arninobenzirnidazole with the mono-N-phenylimine and mono-Narylhydrazones of oxalyl chloride are f ~ r r n u l a t e d ' " ~ ' ~as ~ the 3-Nphenylirnine and 3-N-arylhydrazones of 2,3-dihydro- 1(9)H-imidazo[ 1,2a]benzimidazole-2,3-dione [Scheme 6.70; (6.308; X = 0,X = NPh or NNHAr)] but without any compelling evidence to exclude the alternative 2irnino-3-0x0 formulations (6.308; X = NPh or NNHPh, Y = 0). Further investigation of the orientation of these products would therefore be desirable. 2,3-Dihydro-lH-irnidazo[l,2-a]benzirnidazole-2,3-di(t~fluoromethyl)irnines (6.308; X = Y = NCF,) are the somewhat unusual end-products (Table 6.36) of the annelation reactions of 2-aminobenzimidazole derivatives with perAuoro-2,5-diazahexa-2,4-diene[F3CN=C(F)C(F)=NCF,].'87

w;AXx 1

R (6.307)

R

!kknw 6.70

(6.308)

6.2. Fused Benzimidazoles with One Additional Heteroatom

137

Until recently imidazo[ l15-a]benzimidazoles of the different structural types (cf. Scheme 6.49) were unknown due to the lack of suitable methods for their synthesis. However, such 6-5-5 fused benzimidazoles are now generally accessible in high yield (Tables 6.37 and 6.38) by a variety of procedures sharing the common feature of ring-closure in suitable 2-(aaminoalky1)benzimidazole derivatives (Scheme 6.7 1).A simple example188is provided by the condensation of the amine (6.309;R = R3= H, R’ = R2= Ph) with ethyl orthoformate under reflux to afford the imidazo[ 1 3 a]benzimidazole derivative (6.310) in good yield. The closely related cyclodehydration of 2-(a-acylaminoalkyl)benzimidazoles (6309;R’ = acyl), promoted by heating with phosphorus oxychloride, proceeds in excellent yield (Table 6.37) and permits flexible synthetic access to 4H-imidazo[1,5apenzimidazoles (6.311)unsubstituted at C(1)and C(3) or containing alkyl or aryl substituents at one or both of these position^.'^^-'^^ The thermal transformation of the thiourea derivative (6.309; R = Me, R’ = 4-pyridyl, R2=H, R3=CSNHPh), in moderate yield (Table 6.37), into the 1mercapto-4H-imidazo[1,5-a]benzimidazole (6.311;R = Me, R’ = 4-pyridyl, R2=SH) illustrates a further synthetic aspect of cyclization of this type.189

R’= R’= Ph

”=/

I \

(6.313)

R=”\

\

I

(6.311,

Scheme 6.71

(6.312)

R3

L

00

w

H

H H H H H H H H H H

R2

CSNHPh

CHO CHO CHO CHO COMe COMe Me Ph Ph CSNHPh

R3

F

E

D

A

B C

A

C C

A

B

Reaction conditions"

Me

CH,Ph Me Me Me Me Me Me Me CH2Ph Me

R

4-Pyridyl

H Me Ph 4-Pyridyl H Me Ph H H 4-Pyridyl

R'

Product (6.311)

SH

Me' Me Ph' Ph SH"

Hb Hd H Hf

R2

Yield

49-51

42 55 89 94 62 75 99 41 93 49-51

(Yo)

-

107-108 99-101.5 130.5-13 1 204.5-206 92-94 119-121.5 133-135 117-118.5 147.5-150 215.5-216

m.p. ("C)

Benzene-hexane Ethyl acetate -I Ethanol Dimethylformamidewater

-

~~

189

189 189 191 190 189 192 193 189

190

191

-

-e Benzene Ethanol-water

Ref.

Solvent of crystallization

~

~

A = POCl,, tolueneheflux-until evolution of HCI ceases; B = POCl, benzeneheflux-until evolution of HCI ceases, C = POCl,, benzene/(reflux)(4hr); D = POCl,, benzenel(reflux)(35hr); E = phenetole/(reflux)(5min); F = melt (175-185O)/5-7 min. Forms a picrate, yellow crystals m.p. 189-190.5" (from ethanol). Purified by distillation, b.p. 207-208"/0.3 mm Hg. Deliquesces in air, turning green in color; forms a picrate, yellow crystals, mp. 197.5-199.5" (from acetone). Purified by distillation. Forms a picrate, yellow crystals, m.p. 264-264.5" (decomp.). * Unstable in air, turning violet in color. Forms a picrate, yellow crystals, m.p. 214" (decomp.) (from acetone). ' Purified by distillation, b.p. 135-136"/0.25 mm Hg. ' Forms a picrate, yellow needles, m.p. 220-221.5" (decomp.) (from ethanol). Purified by distillation, b.p. 219-221"/0.25 mm Hg. Forms a picrate, red crystals, m.p. 235.5-237 (decomp.).

4-Pyridyl

H Me Ph 4-Pyridyl H Me Ph H H 4-Pyridyl

CH,Ph Me Me Me Me Me Me Me CH2Ph Me

Me

R'

R

Starting material (6.309)

(a-AMIN0ALKYL)BENZIMIDAZOLES(6309)

DERIVATIVES (6311)BY RING-CLOSURE REACTIONS OF 3TABLE 6.37. SYNTHESIS O F 4H-IMIDAZO[1,5-A]BENZIMIDAZOLE

\o

w

L

A

(6.309; (6.309; (6.309; (6.309 (6.309

R' R' R' R' R'

= Ph. R3 = p-MeC,H,)

= Ph, R3 = p-CIC&) = RZ= Ph) = R 2 = Ph, R3= C,H, = R2 = Ph, R3 = p-CIC6H4)

(6.313; Ar = p-MeC,H,)

(6.312; R' = R2= Ph, R" = p-O,NC6H,CO) (6313; Ar= p-MeOC,H,)

(6312; (6.312 (6.312; (6.312 (6.312;

(6.312; R' = Ph, R3 = CH2Ph) (6.312; R' = Ph. R3 = p-MeOC,H,)

(6312 R' = Ph, R3 = C6Hll)

87

83

89

81 86 41

203-205

169-1 7 1

193-195

195-196 2 18-220 195-196 222-224 274-276 74

-b

128-130 167-170

125-126

m.p. ("C)

56 78

72

Yield

(Yo)

Yield not quoted. Solvent of crystallization not specified.

A = 30% HCHO aq., ethanol or dioxane (reflux/4 hr); B = COCI,, Et,N, tetrahydrofurane/(140°)(30 min).

B

(6309; R' = Ph, R3 = p-MeC,H,)

a

B

A

A

A A A

(6.W: R ' = R 2 = P h , R3= P-OZNC~H~CO) (6.309 R ' = Ph, R3 = p-MeOC6H4)

R' = Ph, R3 = p-MeC,H,) R' = Ph, R" = p-CIC,H,) R' = R2 = Ph) R ' = R 2 = P h , R3=C6Hl,) R ' = R 2 = P h , R3=p-CIC6H4)

A

(6.309; R' = Ph, R3 = CH,Ph) (6.309; R' = Ph, R3 = p-MeOC6HJ A

A

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

(6.309; R' = Ph, R3 = C6Hl

~~

Starting material (R.R' + R3 unspecified = H)

Toluene-light petroleum Acetone Acetone-benzene -light petroleum Ethanol Benzene-hexane Ethanol Dimethylfonnamide -water Toluene-light petroleum Ethanol-water or acetone-cyclohexane Ethanol

Solvent of crystallization

188

188

188 194 188 188 188

188 188

188

Ref.

188 -

TABLE 6.38. SYNTHESIS OF 1H,~H-IMIDAZ~~,~-CI]BENZIMIDAZOLE DERIVATIVES (6.312) AND (6313) BY RING-CLOSURE REACTIONS OF 2-(a-AMINOALKYL)BENZIMIDAZOLES(6.309).

140

Condensed Benzimidazolesof Type 6-5-5

Mannich-like condensation reactions of 2-(or -aminoalkyl)benzimidazoles (6.309) with formaldehyde provide the principal method for the synthesis of derivatives (6312) of the lH,3H-imidazo[ 1,5-a]benzimidazole ring systern. 188.194 This mode of ring-closure generally occurs in good yield (Table 6.38), though not unexpectedly it fails completely for substrates (6.309) containing electron-withdrawing amino substituents (e.g., p-nitrophenyl). A further synthetic limitation is revealed by the reported188 failure of aldehydes (other than formaldehyde) and ketones, to participate in 1H,3Himidazo[l,5-a]benzimidazole formation [(6.309)-+(6.312)]. In contrast, treatment with phosgene in the presence of triethylamine effects the smooth ring-closure of 2-(a-aminoalkyl)benzimidazoles (6309) to 1H,3Himidazo[ 1,5-a]benzimidazol- 1-ones (6.313) in high yield (Table 6.38).

Ring-closure Reactions of Other Heterocycles In addition to their more commonplace synthesis by cyclization of 2benzimidazolethione derivatives (see before), thiazolo[3,2-a]benzimidazoles of various structural types are also the end-products of a miscellany of transformations undergone by thiazole derivatives (Scheme 6.72). These include the photolysis of N(1)-(2-thiazolyl)benzo- 1,2,3-triazoIe (6.314) which represents a convenient, if low yield method for the synthesis of the parent thiazol0[3,2-~]benzimidazole (6317),195 and the condensation of 1,4-benzoquinones with 2-aminothiazole to afford nuclear hydroxythiazolo[3,2-a]benzimidaoles of unestablished orientation, in unspecified yield [e.g. (6.315) + (6.316)+ (6.318)].lY6 Correspondingly, access to perhydrothiazolo[3,2-a]benzimidazoles [e.g. (6.320) and (6.322)] in variable yield (Scheme 6.72) is provided by the condensation of 2-chlorocyclohexanone (6.319) with 2-aminothiazole (6.316),lo3 and by the brominative cyclization of substrates of the type (6.321).19’ Derivatives of the 4H-pyrazolo[2,3-a]benzimidazolering system [Scheme 6.73; (6325)] are generally accessible in moderate to excellent yield (Table 6.39) by the dehydrative or deaminative ring-closure of N(1)-(2-aminoaryl)5-pyrazolones (6323) or N(1)-(2-aminoaryl)-5-aminopyrazoles (6324; R4 = NH3. Cyclizations of these types are variously effected by heating with a high-boiling amine (e.g., aniline or m-toluidine) in the absence or presence of the amine h y d r o ~ h l o r i d e , ’ ~ ~or- *with ~ hydrochloric,201~ ~ l f ~ ror i ~ , ~ acetic205206 acids, and afford 4H-pyrazolo[2,3-a]benzimidazoleswith a wide aryl, 198-200 amino,201.205.206 choice of substituents (e.g., alky1,198*199.202-204 ~ a r b o x y 1 ’ ~ ” at ~ ~ the ~ ) C(2) position. C(2)- and C(3)-substituted 4Hpyrazolo[2,3-a]benzimidazoles are also formed in moderate yield (Table 6.39) by means of intramolecular nucleophilic displacement of the orthochloro group by the aminopyrazole substituent in N(1)-(2-chlorophenyl)-5aminopyrazoles (6324; R2 = R3 = H, R4 = Cl). These ring-closure reactions are promoted by treatment with potassium in liquid ammonia207 or by

6.2. Fused Benzimidazoles with One Additional Heteroatom

'NAS (6.314)

0

(6316)

(6.315)

/

\

(ii)

0 0 % ) (i)

(6.317) (6.318)

H OH

140

> 1.50

(6.320)

L 1

(6319)

141

(m.p. 72-13")

H (6.321)

(6.322)

I

(i) hv (Ammx 360 nm), benzene or ethanol (ii) AcOH, 90-100" (iii) reflux, 15 min (iv) Br,, CCI,

(m.p. 59-60")

Scbeme 6.72

heating with Cu(I1) oxide in dimethylformamide,2"8 and, under the former conditions at least, may follow a benzyne pathway. The annelation of ortho-phenylenediamine by 2-chlorooxazoles [Scheme 6.74; (6.326)+ (6.327)- (6.328) or (6.329)]209*2*0 exemplifies a little used alternative to ring-closure in 2-aminobenzimidazole derivatives (see before) as a means for the construction of the 9H-imidazo[l,2-a&enzimidazole ring system.

R4 = NH,) (6.324;R = n-CI7H35, R2=C02H, R4 = NH,) (6.323;R = n-C,,H,,, R2 = S0,H) (6.324, R = n-C,,H,, R2=S03H, R4 = NH,) (6.324:R = n-C,,H,,, R2 = SO,NMe,, R‘ = NH,) (6.324,R = ~I-C,,H,~,R2= CF,, R4 = NH,)

(6.323;R = Me) (6.324;R=Me, R4=C1) (6.324;R = n-C,,H,,, R4 = NH,) (6.323;R = n-C,,H,,, R’ = Cl) (6.324; R = n-C,,H,,, R3 = Cl, R4 = NH,) (6.323;R = n-C,,H,,, R3= Br) (6.323;R = n-C,,H,,, R3 = F) (6.323;R = n-C,,H3,, R3= OEt) (6.323;R = n-C,,H,,, R3=C02H) (6.323;R = n-C,,H,,, R 3 = C 0 2 W ) (6.3233;R=n-Cl,H,,, R2=R3=CI) (6.324,R = n-C,,H,,, R2 = Me, R4 = NH,) (6.323;R = n-C,,H,,, R2= CF,) (6.324;R=n-C,,H,,, R2=CF3, R4=NH2) (6.324;R = n-C,,H,,, R2 = OMe,

Starting material (R, R1+R3 unspecified = H)”

~

R2=C02H) R~=SO,H) R2=S03H) R2 = SO,NMe,) R2=CF3)

(R=n-CI,H,,,

( R = ~-c,,H,,, (R=n-C,,H,,, (R= n-C,,H,,, (R=n-C,,H,,,

C D C C C

C C C C

C C

C C C C C C C

R’=CI) R’=CI) R3=Br) R3=F) R’ = OEt) R=CO,H) R3 = C0,Pr‘) R2 = R’ = Cl) R2 = Me) R2=CF-,) R2=CF3) R2 = OMe)

~

Product (6.325) (R’+R3 unspecified= H)” (R=Me) (R=Me) (R= n-C,,H,,) (R=n-C17H3,, (R=n-C,,H3,, (R=n-C,,H,,, (R=n-C1,H3,, (R = n-C,,H,,, ( R = n-C,,H,,, ( R = fl-C,,H,,, ( R = n-C,,H,,, ( R = n-C,,H,,, (R=n-C,,H,,, ( R = n-C17H3,, (R = n-C,,H,,,

B

A

Reaction conditions‘

-d

83

-d

76

-d

-d

74 62

-d -d

-d

-d -d

-d

-d -d

75

-d

40 60

(90)

Yield

172-1 73

(decomp.) 182-183

> 260

J

(decomp.)

> 260

246248 240 119-120 147 140-146 150 72 99-100 125 115 144 123-125 152-154 158-159 114-1 16

m.p. (“C)

-c

-d.r

Methanol

-

Methanol

-

Ethyl acetate

-c -e

Ethyl acetate

Methanol

-c

Solvent of crystallization

202

202

198 202

202

199 207 202 203 202 203 203 203 203 203 203 202 204 202 202

Ref.

TABLE 6.39. SYNTHESIS OF ~H-PYRAZOL~[~,~-UIBENZIMIDAZOLES (6.325)BY RING-CLOSURE REACTIONS OF PYRAZOLE DERIVATIVES

w

c P

D F F

(6.323;R = C0,H) (6323;R = CO,H) (6.323;R = R2= CO,H)

(R = NHCOMe) (R' = C0,Et) (R' = CN)

(R = CO,H, R2 = SO,H)

(R= NHPhY (R= P-OZNC~H~NH)

(R = C0,H) (R = C0,H) (R = R2 = C0,H)

( R = Ph, R2 = S0,H)

(R = Ph, R2 = CF,) (R= Ph, R2 = S0,H)

(R = n-C,,H,,, R2= CF,) ( R = n-C,,H,,. R2=CF3) (R=Ph) (R = Ph)

60 quant. 46 80 15 42

82

50

45

88

91

-d

-d

71

-d -d

-

171-172 281-282

-c -<

Methanol

-

Methanol -e

-

-

-

-

-

19y

199 20 1 20 1 205 208 208

198 199 199

200

202 198,

202 202 Acetone-water 198 202

-c

-

270 > 270 (decornp.) > 320 232-235 > 260 J

J

244-247 >310 (decornp.) 2 80 (decomp.)

(decamp.)

165-167 156-158 260 > 260

a

n-C,,H,, =stearyl. A = HCI, AcOH, H,O/(reflux)(6 hr); B = K, NH, liq./30 min; C = 20% H,SO4/(10Cb12Oo)(2 hr); D = PhNH,/(140-1700)(2-3 hr); E = mtoluidine/(160")(2-3 hr); F = PhNH,, PhNH,Cl-/(140-170°)(l-2 hr); G = conc. HCI, Pr"OH/(reflux)(time not specified); H = AcOH/(reflux) (2 hr); I = Cu(II)O, dimethylformamide/heat (precise conditions not specified). Purified by sublimation. Yield not quoted. Solvent of crystallization not specified. Melting point not quoted. Hydrochloride.

(6.323;R = C0,H. R2= S03H) (6.323;R = NHPh) (6.323;R = p-0,NC,H4NH) (6.323;R = NHCOMe) (6.324;R' = C0,Et. R4 = Cl) (6.324,R' = CN, R4 = Cl)

F

E

C

C C D C

(6.323;R = Ph, R2= S0,H)

(6.324;R = Ph. R2= CF,, R4= NH,) (6.323;R = Ph, R2= SO,H)

(6.324;R = n-C,,H,,, R2= CF,, R4 = NH,) (6.324;R=n-C,,H,,. R2=CFj, R4=NH2) (6.323;R = Ph) (6.324;R = Ph, R4 = NH,)

144

Condensed Benzimidazoles of Type 6 - 5 5

(6.325)

R

R'

!kbtmt 6.73

EN"' NH2 (6.326)

+

I

J-fR c1 N ' R (6.327)

H

R Yield (X) m.p. ("C) Solvent of crystallization 297-298 Ethyl acetate 65 (6.328) Ph (6.329) PI'

30

212-273

Benzene

sehcmt 6.74

6.22. Wysicoehdcal Properties

Spectroscopic Studies

INFRARED SPECTRA. The infrared spectra of derivatives of several of the 6-

5-5 fused benzimidazole ring systems with one additional heteroatom (cf.

Tables 6.40-6.45) display a number of structurally revealing and diagnostically useful features. The I.R. spe~tra''*~~ of 2,3-dihydrooxazolo[3,2-

6.2. Fused Benzimidazoles with One Additional Heteroatom

145

TABLE 6.40. INFRARED SPEmRA" OF 2,3-D1HYDROOXAZOLq3,2-a]BENZIMlDAZOLES (6336)

(6.330) Substituents R'

R2

H H H H H H

H

v,,

OH, NH

c=o

Others

Ref.

H Et CH,CI CH,OH CH,OAc CH,OPh

1635,1590 1635,1590 1635,1585,1550 1630,1590, 1550 1640,1590,1560 1630,1600,1590,1550

92 92 91.92 91,92 91 91

CH,Nrb

1630.1590, 1550

91,92

w

H H Me

cm-'

CONH, C0,Et

-

1770. 1720

1635,1610,1590, 1560

91

3300,3150

1685 1755

1640,1590, 1565 1635,1590

91 91

-

Measured for suspensions in Nujol.

a]benzimidazole derivatives (Table 6.40) in particular are typified by a series of bands at 1640-1630, 1590-1585, and 1560-1550 cm-', which appear to be characteristic of this particular ring system. An IR band in the range 1490-1460cm-' is likewise a feature of the spectra of simple thiazolo[3,2-a]benzimidazoles (Table 6.41),'03~''5~'28~'95while 3arylthiazolo[3,2-a]benzimidazoles are specifically associated95 with IR absorption in the ranges 1620-1610 and 1585-1580 cm-'. Resonance interaction with the N(4) bridgehead nitrogen atom [Scheme 6.75; (6.339)c* (6.340)] imparts "vinylogous amide" character to C(2) carbonyl derivatives (esters, aldehydes, ketones, carboxylic acids, amides) of thiazolo[3,2a]benzimidazoles thus accounting for the exceptionally low IR carbonyl l7 stretching frequencies observed for such compounds (Table 6.41).'03*115*1 On the other hand, the adjacent bridgehead nitrogen atom appears to have minimal effect on the C(3) carbonyl substitutent in 2,3-dihydrothiazolo[3,2a]benzimidazol-3-ones, which absorbs uniformly at high frequencies (17401730 cm-l) (Table 6.42)97.98.101,103.133.134,136.1S1 diminished only by conjugation with arylidene 101.133.134.136.15 1 or imine134.151,21 1 unsaturation at the C(2)

Q,

P

L

R'

H

H H H Me Ph H H Me Me Me Me Me H Me Me Me Me OC0,Et Me Et Et H H H H

Compound

(6.331)

(6.331) (6.331) (6331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6331) (6.331) (6.331) H" Hb Me H H CHOHMe CH(0Ac)Me CH,OH CHOHMe CO,Et C0,Et CHO COMe COMe COMe COMe C(Me)=NOH COMe COMe COMe" COBu'" COPh COPh"

H

R2

R3

(6331)

KBr KBr KBr KBr KBr KBr KBr KBr Nujol KBr CHCI, Nujol KBr CHCI, KBr Nujol Nujol KBr Nujol Nujol Nujol Nujol Nujol Nujol Nuiol

KBr

Medium

. (6332)

OH, NH

vmU

1770,1680 1658 1650 1660 1635 1630 1657 1640

-

1711 1708 1678 1660 1674 1646 1650

-

-

1734

-

-

-

-

-

-

1490

-

1490 1483

-

-

1490

-

1490

-

-

1462 1471 1461 1463 1479

-

1459

Others

-

c-0

(cm-7

U,&AR3

& N -

103, 195 103 103 103 103 103 103 103 103 115 103 115 117 103 115 103 117 115 142 117 117 117 117 117 117 117

Ref.

DERIVATIVES (6.331) AND (6.332) TABLE 6.41. INFRARED SPECTRA OF THIAZOLO[~,~-Q]BENZIMIDAZOLE

OH OH OH

(6332) (6.332) (6.332)

OAc

OH

OH OH OH OH

6.7-Dimethyl derivative. 5.8-Dimethyl derivative. 7-Nitro derivative. 7-Acetamido derivative.

(6.332) (6.332)

(6.332) (6.332) (6.332) (6.332)

OH OH

OAc

OH OH OAc

H

(6.332)

(6.332) (6.332) (6.332) (6.332) (6.332) (6332)

H H Me Et Et H H H

(6.331) (6.331) (6.331) (6.331) (6.331) (6.331) (6331) (6.332)

H H

H H

Et

Pr'

H H H H Me Me

H H H

H

-

Me

Me Me

Me

H H

H H H H

Ha Hb

H H H

Hd

H'

-

-

-

-

Free OH. Free NH. Bonded NH.

' Bonded OH.

p-BrC,H,CO" p-0,NC6H,CO" p-BrC,H,CO COPh" p-BrC6H4C0 CO,H CONHPh H

Nujol KBr

KBr KBr KBr CHCI,

KBr KBr KBr CHCl, KBr CHCI,

KBr Nujol CHCI,, MeCN, or dimethyl sulfoxide

Nujol or KRr

Nujol Nujol Nujol Nujol Nujol Nujol CHCI, Nujol or KBr

-

3200-2W 365@ 3554' 344V 3250h 3200-27W 3300-27OW 3200-2600 b f 3605' 3448' 3060-2680 b f

-

3200-2500 b f 3060-2680 b f 3670-3660' 3561-3545' 3480-3420' 3320-3 150' 3200-2600 b f 3200-2600 b f -

3245, 3198

-

2353 3300

-

1748

-

1710

-

1715

-

1732 1750

-

17201685

-

1698

-

1648 1651 1623 1639 1648 1675 1670

106 103

108 108 103 212

103 103 103 103 103 103

103 106 108

128

117 117 117 117 117 115 115 128

TABLE 6.42. INFRARED CARBONYL STRETCHING FREQUENCIES OF 2,3-DIHYDROTHIAZ OL0[3,2-alBENZIMIDAZOL-3-ONEDERIVATIVES (6.333)

Substituent (X)

Medium

u-(C==O)

H, H H, H H, H H, Ha H, Hb H, H' H, Hd H, He

KBr KBr KBr KCI KC1 KBr Nujol Nujol KCI

1742 1728 1748 1745 1750 1734 1745 1740 1735 1736 1735 1704 1738 1725 1680 1730 1713 1726 1708 1735 1725 1685 1770-1710 1735 1732 1730 1740

H, H,' H, Hf

-=

KCI H, Hh Nujol H, Me -I H, M d Nujol CHPh KBr CHPh' CHPY Nujol p-MeOC6H,CH Nujol p-NO,C&CH Nujol P - M ~ N C ~ H ~ C HKBr p-MeOC6H,CHe Nujol p-CIC6H4CH' Nujol CHC0,H KBr -I PhN Nujol p-M+NC6H4N p-MeOC6H,NHN Nujol o-MeOC6H4NHN KBr Nujol p-BKbH4NHN 6-Methyl derivative. &Methyl derivative. 6-Methoxy derivative. 6-Chloro derivative. ' &Nitro derivative, 6,7-Dimethyl derivative. 0 Medium not specified. 5,s-Dimethyl derivative.

a

f

148

(cm-')

Ref. 103 101 137 133 133

97 98

136 133 134 133 101 134 134 133 136 134 134 101 136 136 145 151 134 134 151 134

Me

Me Me CH,Ph

(6335) (6.335) (6.335)

Me Me H H H CH=C==CH2 H H H H H H Me Me Me Me CH2Ph Me

(6.335)

(6.334) (6334) (6.335) c. (6.335) $ (6.335) (6.335) (6.335) (6.335) (6.335) (6.335) (6.335) (6.335) (6.335) (6.335) (6.335) (6.335) (6.335) (6.335)

Compound R'

R3

Me Me Me

Ph

CH(0H)b C P h

Ph Ph H H H Me H Me Me H Pi ff Ph H Ph H Ph H P - C I C ~ H ~H H P-BG& Me NH, NeCHPh Ph GCH Me ChCH Ph C-=CH Me CH(OH)C=CPh Me

R2

(6334)

b

Nujol or CHCI, Nujol or CHCI, CHCI, Nujol CHCI,

C

-c -

-

3595, 3300-3200 3595, 3300-3200

-

-

-

3487,3380

b

Nujol Nujol -c

-b

c

-

C

-

3225 3435

-b

3485

-

3480

-

-b

OH,NH

Nujol CHCI,

-<

CHCI, CHCI, KBr -c CHCI, CHCI, CHCI,

Medium

vm..

-

2240 w

2210 2210 2210 2240 w

-

2143'

-

-

-

1980d

-

-

-

-

CkC

(6335)

c=o

(m-')

-

-

-

1619 1683 1643 1611 1622 1643' 1632

-

1643 1638 1613 1660 1650

C=N

Others

DERIVATIVES (6.334) AND (6.335) TABLE 6.43. INFRARED SPECTRA OF 1H-AND ~H-IMIDAZ@~,~-UJBENZIMIDAZOLE

113

173 173

164

166 157 155 156 166 170 210 156 166 166 156 156 175 175 213 213 213 164

Ref.

-

Me

(6.335)

Me NO2

Formyl derivative; orientation not established. (N-H) not quoted. Medium not specified.

*,Y

a

Me

(6.335) COC3CPh

C-Ph

Me

Me

(6.335)

Ph

COCHICHPh

Me Ph Me CHO CHO COMe COMe COMe COMe COMe COPh COPh COCHSHPh

Ph

COMe COMe COPh Me Ph Me Me Ph Me Me Me Ph Me

R'

Me

Me Me Me Me Me Me Me Me Et CH,Ph Me Me Me

R2

(6334)

(6335)

(6.335)

(6.335) (6.335) (6.335) (6.335) (6.335)

(6.335)

(6.335) (6.335)

(6335)

(6.335) (6.335) (6335)

Compound R'

TABLE 6.43 (Continued)

OH,NH

C=C

Y , , , ~(&N)

,Y

-

C=N

-

-

163

164

1575-1570

1526,1345

164

-

1575-1570

2 14

-

171 171 171 165 165 173 172 172 172 172 172 172 214

Ref.

-

-

-

-

-

-

Others

1645-1635

-

-

1624 1619 1710 1640 1638 1630 1640-1620 1640-1620 1640-1620 1640-1620 1640-1620 1640-1620 1645-1635 -

c=o

Y,,,.~ (an-')

(CH=C=CH,). of open-chain tautomer. May be due to NH def.

-c

Nujol CHCI, CHCI, CHCI, CHCI, CHCI, CHCI, Nujol or CHCI, Nujol or CHCI, Nujol or cn CI, Nujol or CHCI,

c

-

-c

Nujol Nujol Nujol

Medium

R'

(6335)

c

VI

c

Me CH,Ph H H

(6.337) (6.337) (6336) (6336)’ (6.337)( (6.336) (6.336) (6.337) (6.337) (6.337) (6.337) (6.337) (6.337) (6.337)

a

H CH,Ph CH,Ph Me CH,Ph CH,Ph Me Me

(6.336) (6.336) (6.337) (6.337) (6.337) (6.337) (6.336) (6.336)

Medium not specified. 7-Chloro derivative.

H

H

Et CH,Ph (CHJzNEt, H

Me

CH,Ph

H H

R

Compound

d

I

H, H H, O H H, OH Et, OH 0 0

H,H H, H

Y

R

5,8-Dichloro derivative. ,v (N-H) not quoted.

0 0 Ph, Phb Ph, Ph Ph, Ph 0 0 0 0 0 0 0 0 NPh 0 P-CIC~H~NHN 0 O-CIC~H~NHN 0

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

CH,coN-NMe

H, H H, OH H, OH Et, OH H. H H,

H, H H,H

X

(6336)

OJx;

KBr KBr

-a

Nujol Nujol Nujol Nujol Nujol Nujol Nujol Nujol Nujol Nujol Nujol

Nujol Nujol Nujol Nujol CH,CI,

a

-

-a

-

Medium

1725-1720 1725-1720 1760 1770 1780 1690 1799, 1764 1748, 1694 1760, 1700 1758, 1705 1767, 1703 1770-1710 1750-1730 1750-1730

1760 1750, 1655-1640

-

* 5.7.8-Tribromo derivative.

3320-3250 3320-3250

-d

-

-

-

3329

-d -d

3100

-

-

3490-3130 3370-3 100 3380-3300

-

-

Co-

(6.337)

OH,NH

I

R

1660 1610-1585 1610-1585

-

1624

-

1632

-

1660 1660 1650

-

-

-

-

1640 1630 1660

C=N

185 185 185 185 185 185 151 151 151

184

173 173 182 184

181

180

176 176 176 185 185 185

Ref.

TABLE 6.44. INFRARED SPECTRA OF 2.3-DIHYDRO-1H-AND 9H-IMIDAZq1,2-a]BENZIMIDAZOLE DERIVATIVES (6.336)AND (633n

Condensed Benzimidazoles of Type 6-5-5

152

TABLE 6.45. INFRARED S P E O X A " OF ~H-IMIDAZO[~,SQ)BENZIMIDAZOL,E DERIVATIVES (6.338)

(6338) Substituents

~,,,(Cm-')

R'

R2

R'

Me Me Me CH,Ph Me Me CH,Ph Me Me CH,Ph

Ph Me Ph CN Ph Ph CHO COMe COMe COMe

CH,OH CN CN Ph CHO COMe Ph Me Ph Ph

,,

OH,NH

C=N

c==

-

2210 2215 2200

-

-

1640 1645 1662, 1650 1634 1642 1640

Ref.

215 216 216 193 215 215 193 192 192 193

Measured for suspensions in Nujol.

position (Table 6.42). Conversely, the conjugative lowering of the C(3) carbonyl frequency in 2,3-dihydrothiazolo[3,2-albenzimidazol-3-ones by a C(2) arylhydrazono s ~ b s t i t u e n t , ' ~together ~ . ' ~ ~ with the presence of IR NH a b ~ o r p t i o n , ' implies ~~ the existence of the latter at least partially in the hydrazone tautomeric form rather than completely in the azo form as inferred from the claimed211absence of N H absorption and the presence of IR azo bands at 1580-1550cm-'. Bands at 3300-2600 cm-' attributable to hydrogen-bonded hydroxyl groups and the lack of carbonyl absorption in the solid state IR spectra (Table 6.41) of certain 2-@oxoalky1thio)benzimidazoles [cf. page 108, Scheme 6.51; (6.240)] demonstrate the existence of these molecules (at least in the solid phase) entirely in the ring tautomeric 3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazole

6.2. Fused Benzimidazoles with One Additional Heteroatorn

153

form~l~Z,l~3.1~6.1~8,109.Z12

On the other hand, IR spectra run in chloroform, acetonitrile, or dimethyl sulfoxide (Table 6.41)'08*2'2contain bands due to both NH and OH groups as well as carbonyl absorption, thereby revealing the existence in solution of the ring-chain tautomeric equilibrium [Scheme 6.5 1; (6.24O)e (6.241)].108The presence of well-defined NH absorption and ~ 1the total absence of bands due to cyano groups in the IR s p e ~ t r a ' ' of imino- lH,3H-thiazol0[3,4-a]benzimidazoles [cf. page 116, Scheme 6.59; (6.267)] excludes the possible open-chain tautomeric 2-(a-thiocyanoa1kyl)benzimidazole structure (6.266) for these molecules. The IR spectrum of 1(4)H-pyrazolo[2,3-a]benzimidazole2""exhibits characteristically broad NH absorption at 3240-2500 cm-', which is shifted to higher frequencies in the range 3485-3225 cm-' and becomes sharper in the IR spectra of N-unsubstituted 1(9)H-imidazo[1,2-a]benzimidazoles (Table 6.43).'66*2'0The presence of IR cyano absorption in addition to the anticipated NH bands at 3487 and 3380cm-' in the spectrum of 3-amino2,9-dimethyl-9H-imidazo[l,2-a]benzimidazole(Table 6.43)17' is indicative of the existence of this molecule to a significant extent in the open-chain 2(a-cyanoalkylamino)benzimidazole form [cf. page 132, Scheme 6.64;

(6*m)I-

A~etylenic"~and nitro'63 substituents at the C(3)-position in 9Himidazo[ 1,2-a]benzimidazoles show the expected IR absorption characteristics. On the other hand, carbonyl substituents at this site and at the C(2) position in 9H-imidazo[1,2-a]benzimidazoles absorb at anomalously low presumably due to "vinylogous frequencies (Table 6.43),'64~'6'~'7'-'74,214 amide" character imparted by resonance interaction with either the N( 1)or N(4) (bridgehead) nitrogen atom, a phenomenon already encountered in the C(2) carbonyl derivatives of thiazolo[3,2-a]benzimidazoles (see before). The lower frequency (1725-1720 cm-') for the carbonyl absorption in N(9)substituted 2,3-dihydro-9H-imidazo[1,2-a]benzimidazol-2-ones (Table 6.44)17' compared with that (1760-1750 cm-') in their N(1)-substituted 2,3-dihydro-1H-imidazo[ 1,2-a]benzimidazol-2-one counterparts (Table 6.44)180.181 is consistent with the conjugated nature of the carbonyl substituent in the former structures and is diagnostic for distinguishing the 1Hand 9H-tautomeric forms of 2,3-dihydroimidazo[1,2-a]benzimidazol-2-one derivatives. High-frequency IR carbonyl absorption at 1780- 1760 cm- ' and bands at 1660-1650 cm-' attributable to the C==N group are characteristic 1,2features of the IR spectra of 2,3-dihydro-1(9)H-imidazo[ a]benzimidazol-3-one derivatives (Table 6.44).'82,'y4Correspondingly, the IR spectra of N(1)-substituted 2,3-dihydro- 1H-imidazo[ 1,2-a]benzimidazole-2,3-diones (Table 6.44)'" contain intense carbonyl absorption at 1799 and 1764cm-' assignable to the C(3) and C(2) carbonyl groups, respectively. The lower frequencies (1770-1740 and 17051690cm-') observed (Table 6.44)'" for the C(3) and C(2) carbonyl substituents in N(9)-substituted 2,3-dihydro-9H-imidazo[1,2-a]benzimidazoIe2,3-diones are consistent with the effect of increased conjugation and again

154

Condensed Benzimidazoles of Type 6-5-5

I

H

H

(6.343)

SeLeme 6.76

serve to distinguish these molecules from their N( 1)-substituted 2,3dihydro- 1H-imidazo[ 1,2-a]benzimidazole-2,3-dioneisomers. Comparison of the IR spectra of both structural types with that of the parent 2,3dihydro- 1(9)H-imidazo[1,2-a]benzimidazole-2,3-dione (Table 6.44)'85 demonstrates the existence of the latter molecule predominantly in the enol form [Scheme 6.76; (6.343)] as opposed to either of the two possible NH tautomeric forms (6.341)or (6.342).Interestingly, the IR absorption of the C(3) arylhydrazones of 2,3-dihydro- 1(9)H-imidazo[1,2-a Jbenzimidazole2,3-dione (Table 6.44)15' is more in accord with fully ketonized structures E(6.341) or (6342);C(3)Oreplaced by ArNHN] rather than the alternative enol formulations [6.343; ArNHN for C(3)Ol. Simple, unfunctionalized, 1(9)H-imidazo[1,2-a]benzimidazoles give rise to characteristic IR C=N absorption in the range 1660-1610cm-' (Table 6.43). 8 55,156.166 The ready differentiation of N(9)- and N( 1)-substituted 2,3dihydro- 1(9)H-imidazo[1,2-a]benzimidazoles on the basis of the conjugated or unconjugated character, respectively, of the IR C==Nabsorption exhibited by such molecules (Table 6.44)'76 permits the demonstration of the preferred site of alkylation in 2,3 -dihydro - 1(9)H-imidazo[ 1,2 albenzimidazole derivatives. carbony1192,193.2 15 (but not cyano)216substituents at the C(1) and C(3) positions in 4H-imidazoC1,5-a]benzimidazoles are associated with excepwhich, as in the tionally low-frequency IR absorption (Table 6.45),'92*'93*21s case of carbonyl substituted 1(9)H-imidazo[1,2-a]benzimidazoles (see before) can be attributed to the effect of resonance interaction with the bridgehead nitrogen atom.

-

ULTRAVIOLET SPECTRA. The UV absorption characteristics of thiazolo[3,2a]benzimidazoles vary significantly with the nature of the substituents in the thiazole ring. The UV spectra of thiazolo[3,2-a]benzimidazole and its C(2) and C(3) methyl derivatives (Table 6.46) are typified by the presence of an intense imidazole band at 240-250 nm and a somewhat less intense T+T*

TABLE 6.46. ULTRAVIOLET SPECTRA" OF THIAZOL0[3,2-a]BENZIMIDAZOLE DERIVATIVES (6.344),(6.345). (6.346).AND (6.347)

Ph

(6.346)

H

H

H

H

H

H

H

H

H

Me

H

Me

Me

H

Me

H

H

Ph

Ph

H

Ph

H

p-CIC,H, F-BGH4 H Me Me

H H COMe COMe C0,Et

-

-

-

-

(6.347)

250 (3.76).286 (3.84), 293 (3.94),306sh (3.75) 215 (4.48),242 (4.18), 247 (4.16),275 (3.99). 283 sh (3.90) 215 (4.59).245 (4.28), 277 (4.05) 221 (4.57), 241 (4.16).277 (4.04) 215 (4.63),242 (4.36). 248 (4.40).275 (4.12), 286 (3.95) 244 (3.89).250 (3.95). 277 (4.09) 213 (4.58),238.5 (4.40), 245.5(4.40).277 (4.15). 288 sh 240 (4.17).247 (4.46), 280 (4.91) 218(4.19),277 (4.14), 311 (4.11) 235 (4.26).248 (4.lo), 268 (4.10),283 (4.01) 235 (4.301,251 (4.13). 270 (4.15).285 sh (4.05) 235 (4.29),275 (4.12) 236 (4.37),275 (4.18) 212 (4.67),271 (4.62) 213 (4.62),273 (4.64) 212 (4.49),266 (4.49) 251 (3.93),286 (4.08). 293 (4.10) 250 (3.96),282 (4.02). 282 (4.06)

94, 107 103, 195 103 103 103 107 103 107 107 103 94, 107 94 94 103 103 103 94 94, 107

TABLE 6.46 (Continued)

(6.344)

(6345)

(6.345)

Me, OH

H, H

(6.345)

H, OH

Me,H

(6.345)

H, OH

Ph, H

(6.345)

0

H, H

(6.345)

0

H, Me

(6.345)

0

H, Et

(6.345)

0

H, Pr"

(6.345)

0

H, Bu"

(6.345) (6.345)

0 0

-

CHC0,Me CHC0,Et -

(6.346)

-

-

(6.346)

-

-

(6.346)

-

-

(6.346)

(6.347)

-

249 (3.99), 284 (4.12), 291 (4.15) 250 (3.98). 284 (4.04), 291 (4.08) 250 (4.08). 284 (4.07). 291 (4.10) 238 (4.28), 282 (4.01). 291 (3.94) 239 (4.49). 283 (3.94). 292 (3.92) 240 (4.10). 283 (4.06), 292 (3.84) 240 (4.62), 283 (4.08), 292 (4.01) 240 (4.46), 283 (3.89), 292 (3.78) 217 (3.43), 257 (3.52)d 214 (2.23). 257 (2.36)d 255 (4.08). 286 (3.90), 293 (3.89). 350 (3.99) 270 (4.06). 287 (3.88), 294 (3.88), 360 (3.88)L 288 (3.90). 295 (3.91), 365.5 (3.84)' 292 (3.83). 352 (4.02)' 213 (4.39, 260 (3.98)

Measured for solutions in ethanol, unless otherwise specified. 6,7-Dimethyl derivative. 5.8-Dimethyl derivative. Spectrum measured in methanol. Spectrum measured in dioxane. Spectrum measured in benzene. Spectrum measured in pyridine-water.

156

107 107 107 129 94 94 94 94 145 145 129 129 129 129 103

6.2. Fused Benzimidazoles with One Additional Heteroatom

157

band at longer wavelength (270-290 nm).94"03"07"95'217 The introduction of a C(3)-phenyl-~ubstituentresults in a hypsochromic shift in both bands,'" whereas the presence of a C(2)-phenyl group causes the disappearance of the imidazole band, an increase in the intensity of the 7 r 4 7 r * band, and the appearance of a charge-transfer band at 308-314 nm?4.103*107 Curiously, other studies2" report the reverse effects for C(2) and C(3) phenyl substituents in thiazolo[3,2- a]benzimidazoles. The UV spect~a'~' of thiazolo[3,2- a]benzimidazoles containing a C(2) carbonyl substituent (acetyl, ethoxycarbonyl) (Table 6.46), while retaining a T--,T* band at ca. 270 nm, also lack imidazole absorption at ca.240 nm. Not unexpectedly, in view of their lesser unsaturation, 2,3-dihydrothiazolo[3,2-a]benzimidazole derivatives exhibit lower intensity imidazole and 7r-* 7 ~ *UV absorption (Table 6.46)'07 in comparison with their thiazolo[3,2-a]benzimidazole parents. Interestingly, the intensity of the lower wavelength imidazole band but not that of the 7r+ 7r* band in 2,3-dihydrothiazolo[3,2-a]benzimidazolesis increased by the introduction of a C(3) carbonyl moiety as evidenced by the UV spectra of 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones (Table 6.46).94,129 The effect of increased conjugation in such structures is demonstrated by the UV absorption (Table 6.46) of the corresponding C(2) arylidene derivatives (6.345; X = 0, Y = CHAr) which consists of three intense bands at 257-273, 281-296, and 319-390 nm, believed149to originate in amido, benzimidazole, and K-band transitions respectively. In contrast, C(2)-alkylidene-2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones of the type (6.345; X = 0, Y = CHC02Me or CHC0,Et) exhibit relatively shortwavelength UV absorption at 210-240 and 260-320 nm (Table 6.46).14' The high intensity and relatively long-wavelength bands in the W spectrum of the mesoionic compound (6.346)(Table 6.46)'29further demonstrate the dramatic effect of increased delocalization on the UV absorption of the thiazolo[3,2-a]benzimidazole ring system. The presence of intense bands at 382 and 400nm in the UV spectra211 of 2-arylhydrazono-2,3dihydrothiazolo[3,2-a]benzimidazol-3-ones (6.345; X = 0, Y = NNHAr) has been cited as evidence for the azo as opposed to hydrazone structures of these molecules. The UV absorption [A, nm (log E ) , 226 (4.36), 275 (3.41), and 285 (3.73)1lS3 of 1-imino-lH.3H-thiazol0[3,4-a]benzimidazole [cf. page 116. Scheme 6.59; (6.267; R' .--* R3= H)] is significantly different from that of the structurally related 2,3-dihydrothiazoIo[3,2-a]benzimidazol-3-one(6345; X = 0, Y = H2)(cf.Table 6.46). The 4H-pyrazolo[2,3-a]benzimidazolenucleus207absorbs strongly in the UV at 229 and 306 nm (log E 4.42 and 4.00) and consequently has been widely used as a chromophoric unit in dyestuffs, which show intense absorption in the visible region at ca. 525-560 nm.200*2'"*2'9 Simple alkyl derivatives of 1(9)H-imidazo[1,2-a]benzimidazoles give rise to intense UV absorption at ca. 240 nm (log E 4.46),"8*210*220 which not unexpectedly is shifted to longer wavelength (ca. 280-300 nm) by phenyl or styryl substitution at the C(2) position,'6' and into the visible region

158

Condensed Benzimidazoles of Type 6-5-5

(370-420 nm) by acyl or alkenyl substitution at C(3).2'4The increased delocalization afforded by metal complexation or incorporation in a cyanine framework is illustrated by the strong absorption in the visible region associated with 1(9)H-imidazo[1,2-a]benzimidazole transition metal complexes210*220 and cyanine dyestuff^,'^^ respectively. The UV spectra''l of compounds formulated as 3-arylhydrazono-1(9)H-imidazo[ 1,2-a]benzimidazol-2-ones are characterized by the presence of three strong absorption bands at 206, 291-301, and 394 nm. The presence of the intact benzimidazole unit in N(1)-substituted 2,3-dihydro- lH-imidazo[ 1,241benzimidazoles confers UV absorption at 242-247 and 278-300 nm'76"93 attributable to imidazole and benzenoid transitions, respectively. Conversely, the absence of a discrete benzimidazole nucleus in N(g)-substituted 2,3-dihydro-9H-imidazo[l,2-~lbenzimidazoles accounts for their lack of imidazole UV absorption at 242-247 nm and allows the clear structural differentiation of N(1)- and N(9)-substituted 2,3-dihydro-1(9)H-imidazo[ 1,2-a]benzimidazole derivative^."^"^^ Moreover, the presence of a band at 242-247 nm in the UV ~ p e c t r a " ~ . 'o~f ~N-unsubstituted 2,3dihydro- l(9)H-imidazo[ 1,2-a]benzimidazoles implies their preferential existence in the 1H as opposed to the 9 H tautomeric form. The UV absorption of 4H-imidazo[ 1,5-a]benzimidazole derivatives is markedly influenced by both the nature and the site of substituents in the imidazole ring, those at the C(3) position having a particularly strong effect on band position and intensity. The UV spectra of simple C(1) and C(3) alkyl derivatives are typified by the presence of three equally intense (log E ca. 3.8) bands at 240-250, 270-280, and 320-330 nm. The introduction of a C(3) aryl substituent results in a marked increase in the intensity of all three bands accompanied by a bathochromic shift of ca. 20-30 nm in the two longer wavelength absorptions at 270-280 and 320-330nm. In contrast, the presence of a C(1) aryl substituent, though resulting in a similar overall intensification of the W absorption (Table 6.47),'92 produces a shift to longer wavelength only in the 320-330 nm band. Interestingly the disparity in their influence on the W absorption of 4H-irnidazo[l,5-aIbenzimidazoles is apparently reversed for C(1) and C(3) acyl, nitroso, and nitro substituents (Table 6.47). Whereas substituents of these types at the C(1) p ~ s i t i o n * ~produce ~ * ~ ~ ' both an intensification and a marked shift to longer wavelength in all three bands, those at the C(3) p ~ s i t i o n , ' ~ while ~ . ' ~ ~causing an increase in the intensity and complexity of the W absorption have little effect on its wavelength.

NUCLEAR MAGNETIC RJZSONANCE SPECTRA. Representative examples of the

'HN.M.R. spectra of 6-5-5 fused benzimidazole derivatives having one

additional heteroatom are collected in Tables 6.48-6.55. In accord with their closer proximity to the oxazole ring oxygen atom, the derivatives absorb C(2) protons in 2,3-dihydrooxazolo[3,2-~]benzimidazole at lower field than those at the C(3) position (Table 6 . 4 8 ) . 9 ' ~ ~ ~

TABLE 6.47. ULTRAVIOLET SPECTRA" OF 4H-IMTDAZO[1,5-aPjENZlMIDAZOLE DERIVATIVES (6.348)

qqR3 D3

(6.348) (6.348)

a

Me

H

Ph

CH,Ph

H

Ph

Me Me Me Me

Ph Ph Ph Ph

CH,OH CHO COMe NO

Me

Ph

NO2

PhCH, Me

CN COMe

Ph Me

Me CH,Ph Me Me

COMe COMe NO NO

Ph Ph Me Ph

R' I R'

" RZ

230 inf. (4.17).250 inf. (4.02), 280(4.00),352(4.16) 230 inf. (4.22),251 inf. (4.02). 281(4.05),351(4.18) 232(4.41). 255(3.90), 300(4.33) 261(4.28),298(4.32),386(4.36) 257(4.22),300(4.29), 382(3.35) 265(4.22),286(4.06),322(3.90), 427(4.27) 218(4.44), 269(4.34), 304(4.11), 452(4.32) 232(4.30), 280(4.34),327(4.12) 214(4.34), 224(4.33), 242(3.95), 303(4.12),332(4.44) 225(4.28), 329(4.54) 225(4.36), 328(4.53) 228(4.04),294(4.21) 238(4.30),259(4.29),283(4.29)

192 192 215 215 215 215 221 193 192 192 193 192 192

Measured for solutions in ethanol.

TABLE 6.48. 'H NMR SPECTRAab OF 2,3-DIHYDROOXAZOLO(3.2-a~ENZIMIDAZOLE DERIVATIVES (6.349)

(6.349)

R

Solvent'

H(2)

Et

A

5.25qd 3.90-

CH,CI

A

CONH,

B

H(3)

H(6) H(7) H(8) Others

-7.101~1 4.25td 5.40q" 3.90- -7.10111 4.241~1~ 5.859' 4.4M -7.10rn-

" 6 in ppm measured from TMS.

'

H(5)

and 7.50m+

l.lOtd'

92

and 7.S0m-r

-

92

7.70h

91

1.9oq"'

8.00h

Signals are sharp singlets unless denoted as: t = triplet; q = quartet; m = multiplet. A = CDCI,; B = (CH,),SO. Coupling constant not quoted. Me of Et group. CH, of Et group. Overlapping NCH, and CH,CI.

NH.

159

Ref.

(6350)

Hi

H H

H

A A A A

A A

Me Me'

H H

Me Me Me Me

A A

Me Me

H H

D

E

D D A D

E

C D

A

-

7.30q" 7.007.80m 7.26q" 7.18q"

7.6odd 8.10dd 7.61dd 7.72dd 8.19dd 8.28dd 8.18dd 8.40dd 7.46dd 8.07dd 8.20dd 8.28dd 7.70dd

H(3)

6.1 lq" 6.11 6.27d" 6. 18dm

-

-

6.70dd 7.07dd 6.73dd 6.83dd 7.52dd 7.57dd 7.51dd 7.68dd 6.63dd 7.42dd 7.52dd 7.61dd 6.68de

A

B

H(2)

Solvent'

A

Hi.' Hi.h

H'.'

Hi

HE Hh

H'

H H H'

H

H

RZ

H k

H H H

H

H H H H

H H H H H

R1

+ 7.40

+

7.51 7.19

-7.15-7.90m-

-

7.79m 7.58 7.70 7.96 8.00 7.98 8.12 7.52' 7.69 7.82 7.85

H(6)

-

-

-

7.72m

7.47

7.13 7.49

-

7.79m 7.70 7.70 7.86 7.89 7.98 7.80 7.26 1.63 7.63 7.52

___)

H(8)

-

H(7)

7.00-7.9Om

-7.23-

-

t -

H(5)

(6.350)

TABLE 6.49. 'H NMR SPECTRAab OF THIAZOL0[3.2-a]BENZIMIDAZOLEDERIVATIVES (6.350)

2.34 2.30 2.35 2.59d" 2.59 2.65 2.25 2.5Od"

2.55 2.64 2.40d" 2.53

c

-

-c

2.30

-

-

-

Me

-

-

-

-

-

-

-

-

-

-

Others

103 107 222 222

222 222

103 107

103 195 222 222 222 222 222 222 103 222 222 222 103

Ref.

A A A A A A

A A A

Me'

H H H H H HY

Hq H' Hh

CH(0H)Me

CH(0AclMe

CH,OH

Me

Ph Ph Ph p-MeC,H, p-BrC,H, Ph

p-BrCbH, p-BrC,H, p-BrC,H,

H

H

Me

H Me

COMe

OC0,Et

A

4

A

C0,Et

Me -

A

4

-

F

COMe COMe

-

4

-

A

c

4

-

A

-

c

-

A

+ 7.61

+

7.077.82m

4

*

4

4

7.36

-

6.60 6.82 6.55 6.5 1 6.64 6.69

c

7.54 7.78 7.92 7.77 7.83

-

6.28d" 6.93d" 7.04" 6.94d" 7.13d"

6.70 6.64 6.76

A

A

D

D

E

D

C

H H' H' H' Hh Me

Me Me Me Me Me Me 7.46

7.47 7.64 7.64 7.69 7.55

-

7.50-8.50m

7.00-7.90m-

7.10-8.00m7.00-7.80111-

-

7.00-7.90111-

7.10-7.90m-

7.00-7.90m

7.02

-

7.00-7.90111 7.10-7.9Om t7.07-7.82m+

7.00-8.10m7.10-7.60111

-

7.18.7.66-

-

-

7.02-7.88m7.08-7.82m -

-

-

-

-

-

-

-

5.50br"

4.55

5.00q"." 5 .70brw 6.13q"

7.65qp

-

7 47-7 .82mP

7.5OP

-

-

-

-

142

103

103 103

103

103

103

96 96 96

103 122 107 95 96 98

222

222 222 222 222 222 222

(Footnotesoverleaf)

2.45' 2.47' 2.95 1.40tY.' 4.38q' 3.00 1.63tY."" 4.70q"" 2.60"

1.67d" 2.08' 2.52

2.50 2.65 2.30 2.39 1S9d"

-

2.49

-

-

2.21" 2.45" 2.24" 2.46" 2.33

-=

-'

-=

-e

-*

c

O

a

6 in ppm measured from TMS. Signals are sharp singlets unless denoted as br = broad: d = doublet; t = triplet; q = quartet; m = mukiplet. 'A = CDCI,; B = CD,OD; C = CH2C12;D = CH2C12-CF3C02H;E = CF,CO,H; F = (CD&SO. J = 4.5-4.8 Hz. 6 values not quoted. Trifluoroacetate. * Hydrochloride. Methiodide. 6.7-Dimethyl derivative. These signal assignments may be interchanged. 5.8-Dimethyl derivative. ' J = 11.1 and 7.5 Hz. 1 = 1.5-2.5 Hz. Me(2). Me(3). Protons of the aryl substituent. 6-Chloro derivative. ' 6(7)-Methyl derivative; orientation not established. ' 5(8)-Methyl derivative; orientation not established. ' H ( 3 ) obscured by ArH absorption. " J = 6.5 Hz. " CHOH. OH. Me of Ac group. Me of Et group. 'J = 7.2 Hz. " J value not quoted.

(Footnotes fo Table 6.49)

(6.351)

3.94q" 3.78dh 3.92d'

Meq C*

D" B Cg

C

HP

Me Me H H

H H H H Me Me

OH

OH

OH

OAc

OH

OH

C'

C P

H"

4.29q' 3.64qh 4.24q' 3.65qh 4.25q' 4.1 20ctq 4.65111' 4.30' 4.75' 4.20q' 4.780ct'

3.70dk

H

OH

-3.97111-3.933.531 3.92qh 6.62q' 3.77qy 4.45q'

B

H

OAc

C'

B

A

-d

H(2)

H

H

OH

H H H H

Solvent'

D

H H H H

H H Me OH

R3 +

-*-

H(5)

-

-

5.82d'.' 5.9fkV' 6.01'.' 6.17'." 6.75' 7.od',"

6.32q)

6.304)

-m

6.38qh

-6.80-

-

-6.95-7.72-

-7.10-7.80111-

-6.90-7.6Om-

7.43"

-

7.00-7.70111-

-

7.60-

-

7.50"

H(6) H(7) H(8)

3.97 sexf -7.20-7.50m-7.30-7.90m-

-e

H(3)

(6.351)

R'

-

1.63 1.69 2.10 1.94 2.32y 1.84 2.3OY

1.54

2.42 2.53 1.40

2.28

2.05

-

1.29df

-

-

Me

4.23y

212

103

103

4.3SY

212

103

103

-

-

103

103

-

212

94 125 95 103

-

-

-

Others Ref.

OF 2,3-DIHYDROTHIAZOLO[3,2-a]BENZIMIDAZOLE DERIVATIVES

H

RZ

R'

(6.351)

TABLE 6.50. 'H NMR

c Q\ P

H

Me

OH

OH

R2

R'

Ph

Me

R3

6.85"

5.95"

-d

-

-

4.26' 4.46'

E

H(3)

H(2)

Solvent'

--'A

--'A

4

H(5)

R'

-e

-

H(6) H(7) H(8)

-

-

107

212

Others Ref. 1.07'." 4.76y 1.13y 1.18'"" 1.31'.' 2.Oy" 2.3lY

Me

6 in ppm measured from TMS. Signals are sharp singlets unless denoted as: d = doublet; q = quartet; sex = sextet; oct = octet; m = multiplet. A = D,O; B = CDCI,; C = (CD,),SO; D = (CD,),NCDO; E = C,D,N. Solvent not specified. 6 values not quoted. Mixture of cidtrans isomers in the ratio 4 : 5. fJ=6.5Hz. 'Trans isomer. * After exchange with CF,CO,H. ' J = 2.0-2.5 Hz. H(2) trans to OH; J = 11.!+12.5 and 1-2.5 Hz. ' Cis isomer. ' H(2) cis to OH; I = 11.9-12.5 and 5.0-6.0 Hz. J = 5.2 Hz. i J = 5.0-6.0 and 1.5-2.5 Hz. " Mixture of cisltrans isomers in ratio 3:4. H(2) cis to OAc; I = 13.5 Hz. "J=7.0-7.5 Hz. H(2) trans to OAc; J = 13.5 and 5.0 Hz. = J = 11.5 and 8.8 Hz. H(3) obscured by ArH. Me and CH, of open-chain tautomer. 6,7-Dimethyl derivative. ' Me (2). These signal assignment may be interchanged. On Me (3). 5.8-Dimethyl derivative.

a

(6.351)

TABLE 6.50 (Continued)

TABLE 6.51. 'H NMR SPECTRA"*bOF 2,3-DIHYDROTHIAZOL~3,2-a]BENZIMIDAZOL-3-ONE DERIVATIVES (6.352)

(6.352)

(6.352)

R

Solvent'

H(2)

H

A

H Me Et

A A

4.5 4.34 4.65qd 4.68qd 4.55qd 4.604 4.66 4.43 4.35 4.33 4.30 4.32

W

Bu" H' Hi H'

H" H"

H"

A A A

B

A A A A A

H(5)

H(6)

4

7.89

7.39

H(7) 7.00-7.00m7.39

4

-=

4

c--

7.47d' 7.92qi.k 7.76 7.66 7.64

-

-

-

-

7.17dP

6.93dP

Me

7.69

-

-

7.05qeh 7.34qh.' 7.18 7.18

7.18

H(8)

7.57dh 7.51qhk 7.48

-

7.34 -

1.85d" 1.12td l.0ltd 1.ootd 3.86 2.47 2.57 2.30 2.52 2.77

Others

Ref.

-

103 133 94

-

-

2.20

-

-

-

94

94 94 97 98 133 133 133 133

" S in ppm measured from TMS.

Signals are sharp singlets unless denoted as: d = doublet; t = triplet; q = quartet.

A = CDCI,; B = (CD,),SO. ' J = 7.0-9.0 Hz. ' 8 values not quoted.

J5,8= 0.6 Hz. 6-Methyl derivative. 8-Methyl derivative. " 6,7-Dimethyl derivative. O 5.8-Dimethyl derivative. J = 8.0 Hz.

6-Methoxy derivative. J5., = 3.0 Hz. 'J7.* = 8.5 Hz. ' 6-Chloro derivative. ' J , , , = 1.8Hz.

TABLE 6.52. 'H NMR SPECTRAa.bOF~H,~H-THIAZOL~~,~-UJBENZIMIDAZOLE DERIVATIVES (6353Y

(6353) (6.353)

R'

R2

H H CI H

H CI H H

X

H(3)

NH

4.70 4.68 4.68 4.82

NH

NH O

H(5)

7.75' 7.718 +

H(6)

H(7)

H(8)

7.30-7.931114 8.00-8.24m 7.38q'.5 8.04d' 7.38q'" 8.04' 7.53-8.00m

-

"6 in ppm measured in (CD,),SO solution from TMS. Signals are sharp singlets unless denoted as: d =doublet; q = quartet; m = multiplet. J,, = 2.0 Hz. From Ref. 153. Jmk, = 8.5 Hz. 'NH.

'

165

Others 9.74d 9.74' 9.71'

-

QI

Me B

Me A Me C Me B - B

- B

H

H H COMe C0,Me

CN

(6.354) (6.354) (6.354) (6.355)

(6.355)

3.163.66m

5.064.025.21~1 4.55m"

5.67 6.28q' 5.73 4.053.185.103.45111 5.21111 4.45111"

-

4

4

8.25

4

7.43f.sh 7.22

7.26I.l.'

-7.10-7.90~1

5.58

-

-6.90-7.50m-

-

5.72dd

7.62dd

H(6)

H(5)

H(3a)

H(3)

H(2)

Signals are sharp singlets unless denoted as: d = doublet; t = triplet; q = quartet; m = multiplet. A = (CD,),SO; B = CDCI,; C = CF,CO,H. J = 2.25 Hz. NH. J = 0.75 Hz. Js.a = 8.08 Hz. Poorly resolved. yJ5.7=1.14Hz. " Overlapping H(3a) and CH, of Et group. J5,8 = 0.62 Hz. Me of Et group. ' = 7.43 Hz. PJ=7.0H~. 'J,.*= 1.26Hz. NMe. Ir J7,R = 8.02 Hz. ' OMe.

" 6 in ppm measured from TMS.

A

(6.354)

H

H

(6.354)

R' Solvent'

R

Compound

6.45-7.40 m

Me

-

-

2.95q

2.7P 4.55~1" 2.874 3.76' 1.37PP 4.02154 2.904 4.45111"

223 223 223 154

207

11.37' 10.39"

208

Ref. 11.30'

Others

1.38t0.P 4.05-

2.37 2.68d' 2.43

7.557.80111 b 2.46

H(8)

7.17'.'," 7.70h.'.' -m b 7.29 7.61 6.45-7.10111-

H(7)

TABLE 6.53. 'H NMR SPECTRA*b OF PYRAZOL0[2.3-a]BENZIMlDAZOLEDERIVATIVES (6.354) AND (6.355)

5

-

H H Me Me Me Me CH,Ph CH,Ph Me Me

H Me Ph Ph Ph

H

H Me H H COMe COPh H,H H,H 0 0

A A

D

D

C B

B B

A A

'H NMR SPECTRA".* OF IMIDAZO[ 1.2-a JDENZIMIDAZOLE DERIVATIVES (6.356)-(6.358)

L_

" 6 in ppm measured from TMS. Signals are sharp singlets unless denoted as: m = multiplet. A = CF,CO,H; B = CCI,; C = CHCI,; D = CDCI,. S values not quoted.

(6.356) (6.356) (6.356) (6.356) (6.356) (6.356) (6.357) (6.358) (6.357) (6.358)

TABLE 6.54.

3.60 3.65 3.77 3.70 4.65 4.93 3.22

-

2.10

-

-

2.05 2.20

-

180

155 166 171 171 171 171 176 176 180

Condensed Benzimidazoles of Type 6-5-5

168

TABLE 6.55. 'H NMR SPECTRA" OF ~H-IMIDAZ~~,~-U]BENZIMIDAZOLE DERIVATIVES (6.359)

(6359) (6.359)

R

R'

RZ

Solventb

CH,Ph Me Me Me Me CH,Ph Me CH,Ph Me

H H H Me Ph Ph CHO Ph Me

H Me Ph H H H Ph CHO COMe

A

Me CH,Ph Me Me

Ph Ph Me

COMe COMe NO NO

B B

Ph

A A A

B B B B B

A

B

H(1)

H(3) N(AlU Me

-

Others

Ref.

4.19

224 224 224 224 192,224 193 224 193 192

4.30 6.13 4.14 4.18

192 193 192 192

d

3.17 3.35 3.04 3.47 5.09 3.78

-d

6 in ppm measured from TMS. A = CD,OD; B = CDCI,. CHO. 6 values not quoted. * Me of Ac group. Me (1). a

'HNMR signals due to the C(2) and C(3) protons in C(2)/C(3)unsubstituted thiazolo[3,2-a]benzimidazoles are found at uniformly low field in the ranges 6 6.6-7.1 and S 7.4-8.1 and appear as doublets, due to H(2)/H(3) spin interaction, with a characteristic coupling constant, 52.3= 4.5-4.8Hz (Table 6.49).94*'03*'95*222 The observed order of shielding for the various protons in thiazolo[3,2-a]benzimidazole, namely H ( 8 )< H(3) = H ( 5 )< H ( 6 ) H ( 7 )< H(2) is in accord with the calculatedz2' T electron densities for the molecule. The latter also account for the greater shielding of the methyl substituent in 2-methylthiazolo[3,2-ulbenzimidazoles compared with that in 3-methylthiazolo[3,2-a]benzimidazoles (Table 6.49).97,103.107.119.222 Shielding by the adjacent methyl groups produces the anticipated upfield shift in the resonances of the thiazole protons in 2- and 3-methylthiazolo[3,2-a]benzimidazoles, which appear as welldefined quartets due to allylic coupling (JMe,"= 1.5 Hz) (Table 6.49).97*'03*222 In contrast, the aryl substituent in 2- and 3-arylthiazolo[3,2-a]-

-

6.2. Fused Benzimidazoles with One Additional Heteroatom

169

benzimidazoles has little effect on the chemical shift of the adjacent thiazole proton (Table 6.49).95.96.98.99,'02.107,122 A C(2)-acyl substituent, on the other hand, has the expected marked deshielding effect on protons and methyl substituents at the C(3)-position in thiazolo[3,2-a]benzimidazoles (Table 6.49).'03 Not unexpectedly, protonation of thiazolo[3,2-a]benzimidazoles results in a shift of all of the ring proton resonances to lower field, H(2) and H(3) being deshielded to the greatest extent (6 0.65-0.69 and 6 0.47, respectively) (Table 6.49).222The enhanced deshielding of H(2) and H(3), which results from the protonation of thiazolo[3,2-a]benzimidazoles,implies extensive delocalization of the positive charge to the heteroatoms of the thiazole ring, in the cation produced. The methylene protons of 2,3-dihydrothiazolo[3,2-a]benzimidazoles give rise to 'H NMR absorption in the range 6 3.5-4.0 (Table 6.50).94*95*125 'H NMR spectroscopy provides a valuable alternative method to IR spec~ ~ ' ~ ~tautomerism - ' ~ ~ ~ ~ ~ ~ troscopy (see before) for the ~ t ~ d y ' ~ ~ ~ 'of~ring-chain derivatives [cf. page in 3-hydroxy-2,3-dihydrothiazolo[3,2-~]benz~midazole 108, Scheme 6.51; (6.241) (6.240)]. For example, the 'H NMR spectra (Table 6.50)103*212 of 3-hydroxy-2,3-dihydrothiazolo[3,2-~~enzimidazole and derivatives substituted in the benzene ring are typified by the presence of discrete signals in the ranges 6 3.66-3.77, 4.24-4.35, and 6.30-6.38. The of these signals, on the basis of splitting pattern and associated coupling constants (Table 6.50) to the C(2) protons trans and cis to the hydroxyl group and the proton at C(3), respectively, is clearly consistent only with cyclic (3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazole) as opposed to open-chain structures. Correspondingly, on the basis of its 'H NMR absorption (Table 6.50),103*2'23-hydroxy-2-methyl-2,3dihydrothiazolo[3,2-a]benzimidazole (6.351; R' = OH, R2 = H, R3 = Me) exists entirely as a mixture of cis and trans isomeric ring-closed forms. On the other hand, the 'H NMR spectrum (Table 6.50)103*212 of the isomeric 3hydroxy-3-methyl-2,3-dihydrothiazolo[3,2-a~enzimidazole (6.351; R' = OH,R2 = Me, R3 = H)contains, in addition to proton resonances due to the cyclic form, signals at 6 2.30-2.32 and 4.23-4.35 which r e ~ e a l ' ~ the ~.~'~ presence of the open-chain keto form and hence the establishment in solution of ring-chain tautomeric equilibrium. The 'H NMR absorption (Table 6.50)2'2 of 2,3-dimethyl-3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazole (6.351; R' = OH, R2 = R3 = Me) likewise demonstrates this molecule to coexist in solution with the corresponding open-chain keto tautomer. The results of a thorough 'HNMR study"' of the effect of structure on the ring-chain tautomerism of 3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazoles indicate that, as the bulk, or ability to participate in conjugation, of the C(3) substituent increases, the greater is the tendency for the molecule to exist in solution in the open-chain form. The deshielding influence of the C(3) carbonyl group is apparent in the lower field resonance of the C(2) methylene protons of 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones (Table 6.5 1)94*97*98*103*133 compared with that of

170

Condensed Benzimidazoles of Type 6-5-5

the C(2) methylene protons in simple 2,3-dihydrothiazolo[3,2-a]benzimidazoles (Table 6.50). The C(5) proton in 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones is readily differentiated from the other benzenoid protons on the basis of its lower field 'H NMR absorption (Table 6.5 1) as a result of the anisotropic effect of the proximate C(3) carbonyl group. This effect (with due allowance for perturbation by the substituent) has been utilized to establish the orientation of nuclear substituted 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones formed in ring-closure reactions (see Analogous deshielding before) of 2-benzimidazolythioacetic (Table 6.52) of the C(8) proton by the C(1) imino substituent in l-iminolH,3H-thiazo10[3,2-a]benzimidazoles(6.353) likewise permits the demon~ t r a t i o n of ' ~ ~the substitution pattern of unsymmetrically substituted derivatives formed by the ring-closure of 2-(a-thiocyanoalkyl)benzimidazoles (see page 116). The 'H NMR signal (Table 6.53) of the C(3) proton in 4H-pyrazolo[2,3albenzimidazole (6354;R = R' = H) appears as a doublet at 6 5.72 due to coupling with H(2) (.Izm3 = 2.25 Hz),which resonates at considerably lower field (6 7.62).208The C(2) methyl substituent in 2-methyl-4H-pyrazolo[2,3a]benzimidazole exerts the expected shielding effect on the C(3) proton (Table 6.53),2°7-223whereas protonation has a more dramatic deshielding effect (Table 6.53).223Application of the LAOCN program in conjunction with the identification of H(8) on the basis of its long-range coupling with the NH proton, allows the assignment of the chemical shifts and associated coupling constants of the benzenoid protons in 2-methyl-4H-pyrazolo[2,3albenzimidazole (6.354;R = H,R' = Me) (Table 6.53).223Conversely, spin interaction between H(8) and the NH group requires the latter to be sited at N(4), thus demonstrating223 the preferential existence of 2-methyl-4Hpyrazolo[2,3-aJbenzimidazolein the 4H as opposed to the alternative 1H-tautomeric form. The 4H-tautomeric structure of 2-methyl-4Hpyrazolo[2,3-aJbenzimidazole is further supported by the lack of allylic coupling between H(3) and the protons of the C(2) methyl s~bstituent.**~ The bridgehead proton in 2,3,3a,4-tetrahydro-lH-pyrazolo[2,3-a]benzimidazole derivatives (6.355) resonates in the range 6 5.06-5.21 (Table 6.53).'54 Despite their accessibility, relatively little information on the 'H NMR absorption (Table 6.54) of the various types of imidazo[ 1,2-a]benzimidazole derivative is available. The resonances of H(2) and H(3) in l(4)H-imidazo[ 1,2-a]benzimidazole are not distinguishable from those of the benzenoid protons (Table 6.54).lSs On the other hand, C(2) and C(3) methyl substituents in 1(4)H-imidazo[1,2-a]benzimidazoles are distinguishable on the basis of the lower field 'HNMR absorption of the latter (Table 6.54).'66*'71 The protons of N(4)-methyl groups in 4H-imidazo[ 1,2-albenzimidazoles absorb uniformly in the range 6 3.60-3.80.'7' The 'HNMR absorption (6 ca. 4.9)Ia6 of the C(3) methylene protons in 2,3-dihydro-lH-imidazo[ 1,2a]benzimidazoles undergoes the expected shift to lower field (Table 6.54) in 2,3-dihydro-lH-imidazo[ 1,2-a]benzimidazol-2-ones[e.g. (6.357; R = Me,

6.2. Fused Benzimidazoles with One Additional Heteroatom

171

X = O)]'" due to the deshielding effect of the adjacent carbonyl group. The isomeric N ( 1)- and N(9)-benzyl derivatives of 2,3-dihydro-l(9)H-imidazo[ 1,2-a]benzimidazole (6.357; R = CH2Ph, X = H2) and (6.358; R = CH2Ph, X = CH2)are readily distinguished by the lower field resonance (Table 6.54) of the benzyl protons in the latter resulting from combined deshielding by the cyclic azomethine group and the benzene ring.'76 Protons at the C(1) position in 4H-imidazo[1,5-a]benzimidazoles (6.359) resonate at consistently lower field in the range 6 7.5-8.0, compared with those at the C(3) position which absorb at 6 5.9-6.5 (Table 6.55).224The enhanced shielding of H(3) in comparison with H(l) in 4H-imidazo[l,5-a]benzimidazoles is in accord with greater electron localization at the C(3) position than at the C(1) position as predicted by molecular orbital calculat i o n ~ The . ~ ~protons ~ of N(4) methyl substituents in LSH-imidazo[ 1,5-a]benzimidazoles are deshielded to a significant extent (Table 6.55) by the presence of electron-withdrawing groups in the imidazole ring, this effect being most marked in the case of C(3) substituents of this type.224In accord with their 1-dialkylaminoethylbenzimidazole-likestructure, 1H,3Himidazo[l,5-a]benzimidazoles give rise to singlet 'H NMR absorption at 6 5.03 attributable to the C(1) methylene protons.'" However, the latter become nonequivalent when an asymmetric center is present at the C(3) position, and then absorb at 6 4.96 as an AB quartet (J,,, = 6 Hz)."' MASSSPECTRA. The mass spectral fragmentation of thiazolo[3,2-a]benzimidazoles (Tables 6.56, 6.57, and 6.58)'07*225 follows several pathways (Schemes 6.77 and 6.78), which are principally initiated by cleavage of one or other of the bonds in the thiazole ring. The (M-SH) fragmentation [(6.360)+ (6.361)] which is a f e a t ~ r e ' ~ 'of' ~2~ ~and 3-methyl and ethyl thiazolo[3,2-a]benzimidazoles is not observed for the 2- and 3-phenyl derivatives, indicating its origin in initial hydrogen abstraction from the alkyl s u b ~ t i t u e n t .Ions ~ ~ ~(6.361) derived by extrusion of sulfur, on the other of hand, figure prominently in the mass spectra (Tables 6.56 and 6.57)107*225 2- and 3-phenylthiazolo[3,2-a]benzimidazoles. (M - 1)' fragment ions derived by hydrogen abstraction from the molecular ions of 2- and 3-methylthiazolo[3,2-a]benzimidazoles have been variously formulated as having or ring-~ontracted"~ structures, intact thiazoI0[3,2-a]benzimidazole~~~ (6.363) and (6.367), or (6.364) and (6.368), respectively. Prior ringcontraction by preferential C-S bond cleavage in the molecular ion is also i n ~ o k e d "to ~ account for the major mass spectral fragmentation pathway of thiazolo[3,2-a]benzimidazoles (Scheme 6.77),107,225 which leads to the ions (6.365) and (6.366), the former subsequently undergoing further cleavage and fragmentation to the species (6.370) and (6.371). Since the sulfurcontaining ions (6.366) are constituted from the C(2) carbon atom of the thiazole ring with its attached substituent their mass numbers are diagnostic of the C(2)lC(3) substitution pattern in the original thiazolo[3,2-a]benzim i d a z ~ l e . ' ~Similar ' * ~ ~ ~structural information is provided by a consideration of the mass numbers of the fragment ions [(R'C%CR2)+]and the thiirenyl

TABLE 6.56. MASS SPECTRA" OF THIAZOL0[3,2-a]BENZIMIDAZOLE DERIVATIVES (6.360)b

R'

R2

m/e (rel. abundance,

H

H

176 (5.6),175 (13.7),174 (loo),173 (2),134 (3),130 (2.4),129 (24.9), 103 (6.1).102 (21.2).90 (63,77 (2.3).76 (8).59 (9).74 (2.7),70 (3.8), 69 (2.3).64 (5.6).63 (7.6).62 (2.7).58 (7.3).57 (3.3),52 (2.3),51 (7.1). 50 (6.7),46 (2.6).45 (6.8).39 (6.5).

H

Me

Me

H

O/O)

190(5.9), 189 (14),188 (100). 187 (13.8), 160 (2), 155 (4.2). 143 (21.6). 134(2.7), 118(2.7), 117(3), 116(2.6), 103(4.6), 102(19), 90(7), 77 (4.2),76 (7.6),75 (8.5),74(2), 73 (6.8),71 (4.3,70(2.8), 69(2.8), 64(4.5),63 (6). 52 (2.7), 51 (7). 50 (5.4). 45 (9),44 (3),40 (5.71, 39 (10.5). 190 (5.9).189 (14).188 (100). 187 (13.8),160 (2). 155 (4.2),143 (21.6), 134 (2.7).118 (2.7),117 (3),116 (2.61,103 (4.6),102 (19).90 (7), 77(4.2),76(7.6),75(8.5), 74(2), 73(6.8),71 (4.7). 70(2.8),69(2.8), 64 (4.9,63 (6),52 (2.7).51 (7),50 (5.4),45 (9),44 (3).40 (5.7).

39 (10.5).

203 (9.7).202 (loo),201 (27),200 (2.5).188 (2.8),187 (19.7),175 (4.9), 169 (5.71,168 (3.7).161 (2).144 (3.4).143 (13.7),134 (7.4),129 (2), 116 (2.3).103 (2.3).102 (13.51,YO (7.71,77 (3.1),76 (4.9).75 (6.3). 71 (2). 69 (2),64 (3.4).63 (4.9),59 (6.3),58 (2),53 (6.3).52 (2.5).51 (6.8), 50(4.3),45(3.4),44(3.4),42(3.1),41 (4),40(7.7),39(7.4).

Me

Me

Et

Me

218 (5.1),217 (13.9).216 (loo),215 (5.6).202 (9.9).201 (54.5).200 (4.5). 188 (2).187 (6.1).168 (2.3).161 (2.1).156 (2.1).143 (13.2),142 (2.1). 134 (4.1),129 (3.3).122 (2).102 (4.3).90 (3.8).59 (2.81,41 (2.5).

Me

Et

H

Ph

218 (5.1).217 (13.9),216 (80.3),215 (4.9),203 (5.7),202 (16.4).201 (loo), 200 (5.7),199 (2.5),187 (3.1).175 (2.5).168 (3). 161 (2),156 (2), 144 (2.6),143 (21.3).142 (3.2),134 (11.5).131 (3),129 (3),116 (3.1). 115 (3.1),108 (3.8),107 (2.1).103 (2.3).102 (13.1),101 (2).90 (7.4). 77 (2).76 (2.6),75 (3),69 (2),63 (2.1).53 (21,51 (2.3),45 (2.1),41 (3.6). 39 (3.7).

Ph

H

252 (7.4),251 (22.3),250 (100).249 (5.5). 248 (7.3),218 (2).217 (1). 212 (2),205 (5.8), 190 (1). 121 (1.7).116 (1.3).102 (3.9).90 (2.1), 77 (3.6).45 (1.5).

Ph

Me

266 (6.3),265 (21.4),264 (loo),263 (16.1).262 (4.81,261 (2),237 (5.2). 231 (2.7),212 (2),205 (3.5),204 (3.4). 187 (2.6).134 (2).116 (2). 115 (5.4).104 (2).103 (3).102 (2).90 (1).77 (2.6).45 (2.1).

252 (6.51,251 (20.5),250 (100).249 (5.1). 248 (3.2).218 (4),217 (2). 190 (2).134 (1).129 (4.11,122 (3.2),121 (14.4),116 (3.6). 102 (4.4), 101 (2).90 (3.6),89 (2.9,86 (lo),58 (2.1),41 (2).

172

6.2. Fused Benzimidazoles with One Additional Heteroatom

173

TABLE 6.56 (Continued)

R'

R2

m/e (rel. abundance, 70)

Ph

Ph

328 (8.1), 327 (27.1). 326 (loo), 325 (2.7), 266 (2), 250 (2.7), 205 (6.3). 190 (2). 179 (2). 178 (8.9). 177 (2), 166 (2.8), 165 (15.3). 163 (4.2). 149 (2.7), 121 (2.7). 103 (2.51, 102 (4.4), 101 (2.8), 91 (2.9), 86 (12.2). 77 (5.5). 58 (3). 53 (2). 44 (2.2). 43 (2.2), 42 (2).

Ph

H'

280 (6.9). 279 (3.1). 278 (loo), 277 (27.9), 264 (3), 263 (14.9). 262 (2.1), 261 (2.2). 176 (2), 139 (3.7), 134 (2.2), 117 (2). 116 (2). 103 (2.2). 102 (2), 91 (2.4). 77 (2.8). 45 (2).

Ph

Ph'

356 (6.1). 355 (29). 354 (100). 353 (21.2), 352 (4.4), 341 (2.1), 340 (7.2), 178 (4.4), 177 (3.41, 165 (3.8), 77 (1.5).

Me

COMe

236 (19), 230 (loo), 216 (lo), 215 (67.5), 202 (1.4), 201 (3.6), 190 (2.7), 189 (13). 188 (14.6). 155 (2.4). 144 (9.4), 143 (65.1). 142 (2.4). 134 (5.2). 129 (2.8). 128 (2). 118 (2.2). 116 (3.3, 107 (2). 103 (4.8), 102 (31.3). 101 (2.2). 91 (2.2), 90(10.4), 89 (2.71, 77 (3.6). 76 (8.6), 75 (9.5). 71(3.6), 70(5.1), 69(4.8), 64(4.9), 63(6.6), 58(3.7), 52(2.9), 51(8), 52(5.1), 45 (7), 43(2.8), 42(2.2), 39(11).

H

COPh

308 (7.31, 307 (20). 306 (100). 305 (20). 304 (3.6), 292 (2.11, 291 (8.8), 277 (2). 229 (2.2). 201 (3.9), 157 (4). 106 (2.5). 105 (27), 78 (2). 77 (18), 44 (2.4).

a

Measured at 50 eV. From Ref. 225. 6.7-Dimethyl derivative.

cations (6.375) formed by the alternative fragmentation modes of thiazolo[3,2-a]benzimidazoles involving cleavage of the S( 1)-C(2) and C(3)-C(4) bonds225or the S( 1)-C(9a) and C(3)-C(4) bonds (Scheme 6.78),'07 respectively, in the thiazole ring. In the case of the methyl-substituted thiirenyl cations (6.375; R' or R2= Me) subsequent rearrangement to the thietenyl ion (6.379) is observed.""' The tendency for thiazolo[3,2-a]benzimidazoles to undergo mass spectral fragmentation with extrusion of neutral sulfur species [Scheme 6.78; (6.360)+(6.373) + (6.376) and (6.360)+(6.374)-* (6.377)] is symptomatic of the controlling influence on the mode of bond cleavage, exerted by charge localization on nitrogen.225Metastable transitions in the mass spectra of thiazolo[3,2-a]benzimidazoles (Table 6.58)"' support the different modes of fragmentation postulated for these molecules.

4 P

c

Ph

H

H

Ph

187 (36.0) 156 (1.4) 155 (4.3)

142 (0.5)

(6.361)

250 (100)

250 (100)

143 (40.0)

129 (14.6)

129 (12.2)

(6.365)

249 (19.2) 218 (3.2) 205 (9.2) 217 (1.5) El29 (0.7)]

249 (17.6) 218 (7.8) 129 (9.3) 217 (4.3) 1205 (2.2)]

188 (100) 187 (13.3) 156 (1.3) 155 (4.3)

From Ref. 107.

H

188 (100)

Me

H

Me

174 (100)

H

H

M+

R2

R’

(6.364)/ (6.368)

72 (2.0)

58 (3.1)

179 (1.1)

103 (5.4)

134 (1.6)

134 (4.3)

117 (2.7) 72 (1.6)

103 (2.7)

102 (3.1)

(6.375)

.

(rel.abundance, YO)

(6.371)

m/e

45 (1.4)

121 (30.2)

45 (7.0)

59 (8.6)

45 (2.8)

(6.366)

TABLE 6.57. MASS SPECTRA OF THIAZOLq3,2-a~ENZIMlDAZOLE DERIVATIVES (6.360)a

102 (9.6)

102 (14.1)

102 (20.0)

90 (4.5)

90 (12.8)

90 (5.9)

90 (6.6)

90 (3.6)

102 (2.3) 102 (14.0)

(6.372)

(6.370)

TABLE 6.58. METASTABLE TRANSITIONS IN THE MASS SPECTRA OF THIAZOL0[3,2-a)BENZIMIDAZOLEDERIVATIVES (6.360)"

R'

RZ

H

Me

Ph

H

Transition

-

188'187'. 188'+ 188' 90+. 188'

250'

+ 249'. 250++

205'

" From Ref. 107.

-+

102'

155', 188++ 1 29'.

129'-

103'.

129'+

134'. 205'+

179'.

205'

+ 72+

218',

250'-

102',

+

103'.

-

R2 Me

*' m/

(6.363) or

(6.367)

(6.365) or

\

(6.366)

4

Q+ N s C.

or

(6.370)

scheme 6.77

175

(m/e 102)

(6.371)

Condensed Benzimidazoles of Type 6-5-5

176

~CLLX:~

\

(6.360)

1

-@-I

+

R'

AR2

(6.373) ( m / e 116)

+

(6.375)

R' or

' R

-

R' ~c

I-

(6.374)

c

AR2

( m / e 134)

@+ (6.377) ( m / e 90)

(6.376)

i

'a*

(6.378)

(6.379)

(6.380)

(m/e 71)

(m/e 45)

Sdmnt 6.78

Charge localization on nitrogen apparently also dictates the course followed in the mass-spectral fragmentation of lH-imidazo[ 1,ZaIbenzimidazoles (Scheme 6.79; Table 6.59)'* which closely resembles that of 4Hpyrrolo[l,2-~]benzimidazoles(cf. page 55) and proceeds by initial loss of the N(l) substituent to give relatively stable cations of the type (6.382). As well as decomposing further in standard fashion by loss of HCN, these eliminate N(l) and C(2) with its attached substituent as an intact unit (i.e., a nitrile) to afford the ion (6.383) also encountered in the fragmentation of 4H-pynolo[ 1,2-a]benzimidazoles (see before). The opportunity for charge localization at the N(l) position accounts for the presence in the mass spectra of lH-imidazo[ 1,2-a]benzimidazoles of relatively intense peaks due to ions of the type [ ( R e N R ) ' ] and [RCkN)+].78 The mass spectra of lH,3H-imidazo[1,5-a]benzimidazoles contain base peaks attributable to ions produced by the fragmentation process [Scheme 6.80; (6.385) +(6386)].

(6.383)

(6334) !ikhane 6.79

TABLE 6.59. MASS SPECTRAQb OF 1H-IMIDAZO[1,~-u]BENZIMIDAZOLE DERIVATIVES (6.381)E

(6.381) m/e (rel. abundance, %)

R'

R2

H

Ph

235 (3). 234 (25.5). 233 (loo), 232 (12.3). 231 (3.6). 230 (1.1). 207 (1.31, 206(2.3), 205 (4.7). 179 (1.7), 130 (1.3), 129 (5.11, 104 (3.8). 103 (10.4), 53 (I), 45 (I), 102 (5.1), 91 (1.2), 90(2.8). 89 (2.3), 77 (3.3, 76 43 (1.1).

Me

Ph

249 (1.9), 248 (19), 247 (100). 246 (6.3), 245 (1.7). 233 (2.5). 232 (12.5). 231 (1.5), 206 (1). 205 (2). 170 (l),130 (1.2). 129 (9.2), 118 (2.7), 117 (1.7). 104 (1.8). 103 (1.2). 102 (4.8), 77 (1.9). 45 (1).

Ph

Me

249 (1.8), 248 (8.9). 247 (100). 246 (63.6). 245 (9.1). 232 (1.1). 220 (1.4). 219 (2.7), 208 (1.2). 207 (2.7), 206 (2.1). 205 (1.8). 179 (IS), 178 (1.1). 171 (1.4), 170 (9.1). 144 (6.4), 143 (5.2). 142 (l.O), 132 (l.l), 130 (2), 129 (3, 128 (1.4). 118 (5.3), 117 (3.1), 116 (2), 115 (2.9, 104 (2.2). 103 (4.3). 102 (4.8), 92 (l.l),91 (l.l), 90 (2.3), 78 (1.2). 77 (9.1). 76 (2), 5 1 (1.2).

Ph

Ph

311 (3.1), 310 (24.2), 309 (loo), 308 (66.3), 307 (18.4), 281 (l), 232 (1.5), 207 (1). 206 (1.8), 205 (4.1). 180 (2.6), 179 (1.3), 178 (1.5), 165 (1.3). 129 (1.8), 103 (2.3), 102 (1.3), 72 (1.8).

a

Measured at 50eV and an emission current of 75 mA at 125". Only peaks with m/e >39 are indicated; peaks with intensities <10/0 are not shown. From Ref. 78.

177

178

Condensed Benzimidazoles of Type 6-5-5

(6.385) Scheme 6.80

General Studies CRYSTALLOGRAPHY. X-ray analysis of the dibromo derivative [Scheme 6.8 1; (6387)l shows122 the thiazolo[3,2-a]benzimidazole ring in this of one of the products of molecule to be nonplanar. A single crystal the reaction of 2-benzimidazolethione with dimethyl acetylenedicarboxylate confirms the structure (6.388) tentatively a ~ s i g n e d ' ~ ' . ' on ~ ~ the basis of chemical evidence.

(6.388) Scheme 6.81

DIPOLE MOMENTS.Comparison of the dipole moments of 2-methyl-Wpyrazolo[2,3-a]benzimidazole ( p = 6.92 D) and 2-methyl-4H-pyrazolo[2,3albenzimidazole ( p= 3.97 D) calculated by CND0/2, with the experimental value ( p = 3.75 D in dioxane at 25"), demonstrates the predominance of the 4H-tautomeric form in dioxane at room temperature.226 IONIZATION CONSTANTS. The measured ionization constants for 2,3dihydro- lH-imidazo[ 1,2- a]benzimidazole (pK, = 6.20-6.23 f 0.03- 0.04) and 9-benzyl-2,3-dihydro-9H-imidazo[ 1,2-a]benzimidazole (pK, = 8.488.49 f 0.03-0.04) have been used to evaluate the equilibrium constant for the tautomeric equilibrium between 2,3-dihydro-lH- and 9H-imidazo[ 1,2~]benzimidazoles.'~~ The value obtained (K,,,,, = 1.87 x lo2) indicates the predominance of the 1H-tautomer at equilibrium. The pK, data for 3,4-dimethyl-4H-imidazo[ 1,5-a]benzimidazole (pK, = 6.01) and 4-methyl-3-phenyl-4H-imidazo[ 1,5-a]benzimidazole (pK, = 4.75) are consistent with preferential protonation of 4H-imidazo[l,5-a]benzimidazoles in general at the N(2)-position as predicted on the basis of molecular orbital calculation^.^^^*^^^

6.2. Fused Benzimidazoles with One Additional Heteroatom

179

6.2.3. Reactions Reactions with Electrophiles The high degree of aromatic character manifest in the spectroscopic properties of the fully unsaturated thiazolo[3,2-a]benzimidazole, pyrazolo[2,3-a]benzimidazole, 9H-imidazo[l,2-a]benzimidazole,and 4H-imidazo[1,5-a]benzimidazolering systems is also readily apparent in the propensity of their derivatives to undergo electrophilic substitution at available sites in the thiazole, pyrazole, and imidazole nuclei, respectively. This reactivity is consistent with the results of molecular orbital calculations which demonstrate the C(2) and C(3) positions in thiazol0[3,2-a]benzimidazoles~~~ and 9H-imidazo[ 1,2-a]ben~imidazoles~~' and the C(1) and C(3) positions in 4H-imidazo[ 1,5-a]benzirnidazole~~~~ to be the sites of highest m-electron localization and hence the most prone to electrophilic attack. Conversely, the significantly lower electron localization ~ a l c u l a t e d 'for ~ ~ the C(2) and C(3) positions in the 1H-imidazo[ 1,2-a]benzimidazole ring system accounts for the lower reactivity of its derivatives toward electrophilic attack (see later).

PROTONATION. The ease of protonation of simple thiazolo[3,2-a]benzimidazoles and 2,3-dihydrothiazolo[3,2-a]benzimidazolesis demonstrated by their ready solubility in dilute mineral acids"* and by their tendency to form

well-defined acid salts (e.g., hydrochlorides and picrates-see Tables 6.27 and 6.29). Changes in the 'H NMR absorption of thiazolo[3,2-a]benzimidazoles produced by dissolution in trifluoroacetic acid (see Table 6.49*") are consistent with monocation formation and, moreover, demonstrate preferential protonation at N(9). Proton uptake at this site is also favored on theoretical grounds, formation of the N(9) cation resulting in a significant overall stabilization of the r-system in thiazolo[3,2-a]benzimidazoles as revealed by molecular orbital calculations.222The involvement of the sulfur atom and the N(4) nitrogen atom in the aromatic vframework of thiazolo[3,2-a]benzimidazoles precludes protonation at these sites. The formation of stable acid salts (hydrochlorides, hydrobromides, picrates-see Tables 6.32-6.34 and 6.36) by 1H- and 9H-imidazo[ 1,241benzimidazoles and their 2,3-dihydro derivatives is illustrative of the generally basic character of such molecules. Paradoxically, the hydrochlorides of 2-amino-9H-imidazo[ 1,2-a]benzimidazoles like the parent bases are too unstable to be is01ated.I~~ The ready h y d r ~ l y s i s ' ~of~ * hydrochlorides ~~~ derived from 3-nitroso- and 3-nitro-9H-imidazo[1,2-a]benzimidazoles demonstrates the base-weakening effect of electron-withdrawing substituents at the C(3) position in the 9H-imidazo[1,2-aJbenzimidazole ring system.

A

A

B B

B B B B B

B B

C

B B B

A A

Reaction conditions"

9-Ph(CH2),-3-Me-, bromide 9-CHz=CHCHz-3-Me-, bromide 9-Me-3-Ph-, iodide 6,7,9-tri-Me-3-Ph-, iodide

9-Me-, iodide 9-Et-, iodide 9-Et-3-Me-, bromide 9-(n-C,,H3,)-3-Me-, bromide 9-PhCH2-3-Me-,bromide 9-PhCH2-3-Me-,bromide 9-(4-CIC,H,CH2)-3-Me-, chloride 9-(4-NCC6H,CH,)-3-Me-, bromide 9-(3-F3CC,H,CH,)-3-Me-, chloride 9-(3-C1C,H4CH,)-3-Me-, bromide 9-(3-FC,H4CH,)-3-Me-, chloride 9-(3-MeC,H,CH2)-3-Me-, chloride 9-(3-NCC,H,CH2)-3-Me-, bromide

Thiazolo[3,2-a]benzimidazole Product

3-Me3-Me3-Ph 6,7-di-Me-3-Ph-

Unsubstituted Unsubstituted 3-Me3-Me3-Me3-Me3-Me3-Me3-Me3-Me3-Me3-Me3-Me-

Substrate

86 86

-

-

-b

-b

-

-

-b

-b

-

-

-

-

(%I

Yield

Solvent of crystallization

197-198 -' 256-257 -' 196 Ethanol 269 Ethanol

237-239 Ethanol-ether 214-216 Ethanol-ether -c 284 160-161 -' 229-231 -' 227-229 -' 227-229 -' 3 14-315 -' 234 -c 243-245 -= 233-235 -' 2 18-219 -' 252 -C

m. p. ("a

TABLE 6.60. ALKYLATION REACTIONS OF THIAZOL0[3,2-a]BENZIMIDAZOLES AND 2.3DIHYDROTHIAZOLO[3,2-a]BENZIMIDAZOLES

229 229 122 122

106 106 229 229 229 228 229 229 229 229 229 229 229

Ref.

2,3-dihydro-3-one

2,3-di-Me2,3-di-Me2.3-Dihydro6,7-di-Me-2,3dihydro2.3-dihydr0-3-one 2.3-dihydro-3-one 2.3-dihydro-3-one 2,3-dihydro-3-one 2,3-dihydro-3-one 2.3-di hydro-3-one 2.3-dihydro-3-one

quant.

-b -b -b

2-( ENCH2)-2.3-dihydro-3*ne

41

40

42 2-(Et2NCH2)-2.3-dihydro-3-one 45 2-(Me,NCH2)-2,3-dihydro-3-one 50 2-Ph2NCH,-2.3-dihydro-3-one 2-[Ph(Et)NCH2]-2,3-dihydro-3-one 40 24 n-Pr2NCH,)-2,3-dihydro-3-one 45 2-(n-Bu2NCH,)-2,3-dihydro-3-one 50 2-(sec-Bu2NCH2)-2,3-dihydro-3-one45

2,3.9-tri-Me-, iodide 2,3-di-Me-9-[HO2C(CH2),]-, iodide 9-Me-2.3-dihydro6,7,9-tri-Me-2,3-dihydro-

Ethanol Ethanol

230

Ethanol Ethanol Ethanol Ethanol Ethanol Ethanol Ethanol

Ethanol-ether Ethanol-ether

-'

-'

215

210 190 175 250 240 250 210

303-304 250-253 239-240 245-246

163

163

163 163 163 163 163 163 163

111 111 123 123

'

A = alkyl halide, acetone/(reflux)(1 hr); B = alkyl halide, dimethylformamide/(100")(20min.); C = alkyl halide, acetonitrile/(room temp.)(l6hr); D = alkyl halide, ethanol/(reflux)(ll hr); E = Et,NH, HCHO. AcOH/(100")(7hr). Yield not quoted. ' Solvent of crystallization not specified. Reaction conditions not specified.

E

E

-d -d

D D

182

Condensed Benzimidazolesof Type 6-5-5

Ready solubility in dilute hydrochloric acid19'.19' and stable hydro~hloride"~ and picrate (Table 6.37)formation are symptomatic of the marked basicity of 4H-imidazo[ 1,5-a]benzimidazole derivatives. The available pK, data as well as the results of molecular orbital calculations pinpoint N(2) as the preferred site of protonation in these rn~lecules.~'~

ALKYLATION. Thiazolo[3,2-a]benzimidazoles are readily alkylated by reaction with alkyl bromides or alkyl iodides in acetonitrile at room temperature'" or in ethanol,"' acetone,'06*122 or dimethylf~rmamide''~at elevated temperature, to afford high yields (Table 6.60) of the corresponding N(9) quaternary salts. Specific alkylation at N ( 9 ) in thiazolo[3,2-a]benzimidazoles is supported by 'HNMR evidence222and is consistent with the high electron localization at this center as indicated by the results of molecular orbital circulations.2'' 2,3-Dihydrothiazolo[3,2-a]benzimidazoles are also rep ~ r t e d " to ~ form quaternary salts, albeit in unspecified yield (Table 6.60), by exclusive alkylation at the N(9) position. The 0-ethylation, which is r e p ~ r t e d ' " ~to occur when 3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazoles are treated with ethanolic hydrochloric acid, can be rationalized by prior ring-opening to the aldehyde tautomer followed by acetal formation and recyclization [Scheme 6.82; (6.389)- (6.390)- (6.391)- (6.39211.The enhanced nucleophilic reactivity of the C(2) methylene group in 2,3dihydrothiazolo[3,2-a]benzimidazol-3-oneis illustrated by its ability to participate in Mannich condensations with formaldehyde and a variety of secondary amines giving moderate yields (Table 6.60) of the corresponding 2-dialkylaminomethyl-2,3-dihydrothiazolo[3,2-u]benzimid~ol-3-ones. 134

(6389)

/ - Q;lLoEt EIOH. HCI

(6390)

@-yJHm2 (6.391)

(R= H or Me)

R

(6392)

Scheme 6.82

Dyestuff intermediates produced by heating 4H-pyrazolo[2,3-a]benzimidazoles with dimethyl sulfate in a high-boiling solvent (e.g., chlorobenzene or 1,2-dichlorobenzene) are f~rmulated'~'as N(1)-methyl derivatives, but without any apparent evidence to exclude the alternative N(4)-alkyl

6.2. Fused Bemimidazoles with One Additional Heteroatom

183

structures. Conversely, the reaction of 3-alkylidene-3H-pyrazolo[2,3-a]benzimidazoles with methylating agents such as methyl tosylate is reported to result in exclusive quaternization at the N(4)-position, e.g. [Scheme 6.83; (6.393)-,(6394)].2’ubut again in the absence of rigorous structure proof for the products.

Me

CHR (6.393)

JQ-y

Me

Me CHR I-

(6.394)

a-,,, R

Yield (YO) m.p. (“c) 51

214

I

Et

(i) p-MeC,H,SO,Me/(heat)(l min). then treat with K1. srbeme6.83

Methylation of the tautomeric 2-methyl- 1(9)H-imidazo[1,2-a]benzimidazole under basic conditions involves the intermediacy of the ambident anion [Scheme 6.84; (6.395)-(6.396), R = Me] and consequently results in the formation of a difficultly separable mixture of the N(1)- and N(9)-methyl derivatives.16hIn contrast, the base-catalyzed alkylation of 2-aryl- l(9)H-

sebeme 6.84

imidazo[ 1,2-a]benzimidazoles occurs specifically at N(9) in high yield (Table 6.61),IS5.160 presumably as a result of conjugative stabilization of the resonance form (6.395) by the C(2)-aryl substituent. Methylation of simple JV( 1)- or N(9)-methylimidazo[1,2-a]benzimidazoles is readily accomplished or by fusion with by heating with methyl iodide in ethano1’s7”h2a”6s”66’227 methyl t o ~ y l a t e ’and ~ ~ produces uniformly good yields (Table 6.6 1) of the corresponding N( I),N(9)-dimethyl quaternary salts. In accord with the base-weakening effect of the nitro- substituent 9-methyl-3-nitroimidazo[ 1,2albenzimidazole is alkylated only with difficulty to give quaternary salts, which are readily dealkylated to the parent bases in alkaline media.’63 The superior conjugative stabilization of the resonance form [Scheme 6.85;

01 P

c

2-(4-C1C,H4)-9H-

2-(4-CIC,H4)-9H2-(4-C1C,H4)-9H-

2-(4-BrC,H4)-9H-

A A

A

68 62

1-Me-9-PhCH2-2-Ph-,iodide

9-PhCH2-2-Ph-

3-Br-9-Me-2-Ph-

3-Br- 1-Me-2-Ph-

2.9-di-Me-3-CHO9-Me-2-Ph-3-CHO-

D

E

E

F

G

60 40

-J

246-247 232-233 (decornp.)

227

1,2.9-tri-Me-, iodide 1,9-di-Me-2-Ph-, iodide

2.9-di-Me9-Me-2-Ph-

D D

96

70

9-PhCOCH2-2-Ph-

3-Br- 1,9-di-Me-2-Ph-, benzenesulfonate 3-Br-1,9-di-Me-2-Ph-, benzenesulfonatec 1,2,9-tn-Me-3-CHO-, iodide 1,9di-Me-2-Ph-3-CHO-, iodide

249 234 (decornp.) 257 (decornp.) 227 78 72

9-[Me,N(CH,),]-2-(4-BrC6H.,)-b

A A

245-248 249-250 268-269

268-270

65 56 80

9-[Et,N(CH,)2]-2-(4-BrC,H,)-”

9-[Me,N(CH2)2]-2-(4-BrC6H4)-b 62

9-[Et,N(CH2)2]-2-(4-C1C~H4)-d

9-[Me2N(CH2),]-2-(4-ClC6H4)-

260-263 268-169 266-267 271-212 (decornp.) 271-272 (decornp.) 258-259 26 1-263

65 70 92 71 55

(“C)

m. p,

(%I

Yield

2-(4-BrC,H4)-9H2-(4-BrC,H4)-9H2-Ph-9H-

C

A

A

B

1(9)H-Imidaz~l.2-a]benzimidazole Product

A A

Substrate

2-Ph-9H2-Ph-9H2-Ph-9H2-(4-CIC,H4)-9H-

Reaction conditions”

165 165

157

Ethanol-ether Ethanol

162a

Ethanol Ethanol-ether

166

Ethanol Ethanol

160

155 155, 160 155,

155 155 155 155, 160 160

Ref.

155 155 155, 156 227 162a

-c -c -

-c

-c

c

-

c

-c -c -

-

Solvent of crystallization

TABLE 6.61. ALKYLATlON REACTIONS OF 1(9)H-IMIDAZO[1,2-a]BENZLMIDAZOLES AND 2,3-DIHYDRO-1(9)H-IMIDAZq1,2a IBENZIMIDAZOLES

7-N02-2,3-dihydro-l(9)H-

I I

A

9-Me-2-Ph-2.3-dihydro-

m D

m

-

D

1-PhCH(Me)-7-N02-2,3-dihydro1-Ph2CH-7-NO,-2,3-dihydro-

1.9-di-Me-2-Ph-2.3-dihydro-

1-[Et2N(CH,)J-7-NO,-2.3dihydro1-Me-2-Ph-2,3-dihydro-'.' 9-PhCH2-2,3-dihydro-' 9-PhCH2-2,3-dihydro-' 9-Me-2-Ph-2.3-dihydro-'

1-PhCH2-7-NO,-2,3-dihydro-

_I

J

100 80 85 95

47

41 71

I-[Et2N(CH2),]-2,3-dihydro-*

1-Et-7-N02-2,3-dihydro-

80 67 85 77 72

1-PhCH2-2-3-dihydro1-Ph,CH-2.3-dihydro-

112 262-264 236 234 (decomp.) -

120-121

159-160 2 17-2 18

171-172 174.5-176

-h

115-116 206.5-207.5

Ethanol Ethanol

-

Ethanol-water

Benzene-hexane Benzene-ligroin Ethanol Dimethylformamidewater Benzene Dimethylformamidewater Benzene-hexane

166

166 176 176 166 166

176

176 176

176 176 176 176 176

' '

A = NaNH,, NH,liq./(l hr), then alkyl chloride, toluene/(9O0)(3hr); B = NaOEt, EtOH then alkyl chloride/(9O0)(3 hr); C = PhCOCH,Br, MeOH/(reflux)(Shr); D = Mel, EtOH/(reflux)(2-12 hr); E = PhSO,Me/(8Oo)(l5-30 min); F = MeI, EtOH/(reflux)(lS-20 hr); G = MeI, EtOH/ (reflux)(35-40hr); H = NaNH,, MI, liqJO.5 hr, then PhCH,CI, ether; I = NaNH,, NH, liq.10.5 hr. then alkyl bromide, ether; J = MeI, NaNH,, NH, liq./20 min; K = PhCH,CI, EtOH/(reflux)(4hr); L = PhCH,CI, dimethylformamide/(reflux)(4 hr). Hydrochloride. ' Solvent of crystallization not specified. Dihydrochloride. * Iodide has m.p. 265" (decomp.)(from ethanol-water). Yield not quoted. Forms a hydrochloride. m.p. 255-257" (from 2-propanol). ' Oil. ' Monohydrate: anhydrous product has m.p. 146'. I Forms a hydrochloride, colorless needles, m.p. 234" (from ethanokther). Hydrochloride; free base is an oil, b.p. 192-194"/0.15 mm Hg. Hydriodide; free base has m.p. 65'; forms a hydrochloride, m.p. 258" (from ethanol-ether).

K L D

J

2-Ph 2,3-dihydro-1(9)H 2.3-dihydro-l(9)H2.3-dihydro- l(9)H2-Ph-2,3-dihydro-l(9)Hl-Me-2-Ph-2.3-dihydro-

-

7-N02-2,3-dihydro-l(9)H7-N02-2,3-dihydro-l(9)H-

H

I

A

I

2.3-dihydro-l(9)H2.3-dihydro-l(9)H2.3-dihydro-1(9)H7-N02-2.3-dihydro-I(9)H7-N02-2,3-dihydro-1(9)H-

H

186

Condensed Benzimidazoles of Type 6-5-5

(6.397)] of the ambident anion r(6.397) t* (6.3S)J provides a rationale for the observed preferential alkylation of 2,3-dihydro-1(9)H-imidazo[ 1,2-a]benzimidazoles at the N ( 1)-position under strongly basic conditions (Table 6.61).''*'76 Conversely, the specific N(9)-alkylation of such substrates in neutral protic or aprotic media (Table 6.61) is a measure of the greater resonance stabilization of the cationic intermediate produced by attack at N(9) as opposed to that derived by substitution at the N ( l ) p ~ s i t i o n . ' ~ ~ * ' ' ~

(6.397)

(6.398) sebeme 6.85

ACYLATION. Despite the enhanced reactivity to electrophilic attack predicted for the C(2) and C(3) positions in the thiazolo[3,2-a]benzimidazole ring system (see before), bona fide examples of Friedel-Crafts and related acylation reactions of thiazolo[3,2-a]benzimidazole derivatives do not appear to have been reported to date. The paucity of such reactions is surprising when compared with the well-documented C-acylation undergone by the structurally and electronically related 9H-imidazo[ 1,2-a]benzimidazole and 4H-imidazo[ 1,5-a]benzimidazole ring systems under a variety of conditions (see later). Dehydration to and acetylation of the corresponding thiazolo[3,2-a]benzimidazole provides an obvious rationale for the conversion (by heating with acetic anhydride in the presence of pyridine) of 3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazoles in good to excellent yield (70-90%) into the corresponding 2-acetylthiazolo[3,2-a]ben~irnidazoles.'~~ However, the of N ( l)-acetyl-2-(P-oxoalkyl)benzimidazole derivatives from such reactions under milder conditions supports an alternative course for 2-acetylthiazolo[3,2-a]benzimidazoleformation involving prior ring-opening to and acetylation of a 2-(P-oxoalkyl)benzimidazole, followed by dehydrative cy~lization.'~~ Activation by the adjacent sulfur and C(3) carbonyl substitutents confers enhanced reactivity toward electrophilic attack on the C(2) methylene group in 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones.As a result such molecules condense smoothly with aromatic aldehydes in the presence of condensation piperidine,'3'-'"4'3s~23'.232 sodium acecatalysts such as trieth~lamine,'~~ tate,101.130.133.136 or dicyclohexylcarbodihide-pyridine,'32 to afford the corin responding 2-arylidene-2,3-dihydrothiazol~3,2-a]benzimidazol-3-ones good to excellent yields (Table 6.62). Reaction of 2,3-dihydrothiazolo[3,2a]benzimidazol-3-one with functionalized aldehydes (e.g., glyoxylic acid'47) and ketones (e.g., 2-pr0panone'~') proceeds similarly (Table 6.62), while the closely related condensations with enethiol and e n a m i d e ~ ' ~ ~ . ' ~ '

?

E

c

E

E E E D

E F

F E E E

E E

E F

r D

C

B

A A

Reaction conditions”

X

Substrate

Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted 6-Me6-NO26.7-di-Me6,7-di-MeUnsubstituted Unsubstituted Unsubstituted Unsubstituted 6-Me6.7-di- Me6-NO26-N02Unsubstituted Unsubstituted Unsubstituted Unsubstituted

(6.399)

Y Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted 6-Me6-NOz6,7-di-Me6,7-di-MeUnsu bstituted Unsubstituted Unsubstituted Unsubstituted 6-Me 6.7-di-Me6-NOZ6-NOZUnsubstituted Unsubstituted Unsubstituted Unsubstituted

(6.399)

H, OAc H,OAc 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

x

Product

Y

H. H H, Me PhCH PhCH PhCH PhCH PhCH PhCH PhCH H, H 2-CIC6H4CH 2-CIC,H,CH 4-CIC6H4CH 4-CIC6H4CH 4-CIC6H,CH 4-ClC6H4CH 4-CIC,H,CH 4-MeC6H,CH 2-HOC6HACH 4-HOC,HACH 2-Me&,H4CH 2-EtOC6HdCH

(6.399)

102-103

-b

m.p. (“C)

219 226 216-217 78 222 221 68 295 85 265-266 82 254-255 80 294 55 74 186 2x0 65 272 80 182 62 73 >320 255 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

-

Solvent of crystallization

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

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-5

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

Solvent of crystallization

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.

-

Solvent of crystallization

-

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 <330 Methanol (decomp.)

Yield

(70)

236 236 200, 236, 237 200, 236 236 198 219 219 200

Ref.

5

a A = Fe, AcOH/95-100", then treat with Ac,O; B = MeCOCI. pyridine/(80-90')(0.5 hr); C AQO, pyridine/(reflux)(30min); D = EtCOCl, pyridinel (80-90°)(1 hr); E = PhCOCI. pyridme/(80-90°)(1 hr); F = 4-Me,NGH4CH0, NaOW(reflux)(3hr); G = POCI,, dimethylformamide/(warm)(l min); H = 4-Et,NC6H,NH,, AgNO,, NaCI, Na2C03, H,O/(room temp.)(30 min). Solvent of crystallization not specified. ' Melting point not quoted. Yield not specified.

H

G G

E F

b

Id

C

B

A

Reaction conditions"

TABLE 6.64. ACYLATION AND RELATED REACTIONS OF 4H-PYRAZOL0[2,3-a]BENZIMIDAZOLE DERIVATIVES

6.2. Fused Benzimidazoles with One Additional Heteroatom

193

oxychloride) (Table 6.64).2'9 The oxidative condensation of 4H-pyrazOlO[2,3-a]benzimidazoles with arylamines also takes place at the C(3) position and provides a viable method (Table 6.64) for the synthesis of 3-arylimino3H-pyrazolo[2,3-a&enzimidazoles (6.403; X = ArN)?OOThe amino subundergoes acylation stituent in 3-amino-4H-pyrazolo[2,3-~lbenzimidazoles in orthodox fashion (Table 6.64).200*236*237 9H-imidazo[ 1,2-a]benzimidazoles are readily acylated at the C(2) and C(3) positions under a variety of conditions (Table 6.65) in Friedel-Craftstype reactions, which substantiate theoretical predictions (see before) of the enhanced reactivity of the imidazole ring in these molecules to electrophilic attack. Acetylation is accomplished simply by heating with acetic anhydride a l ~ n e ' ~or ~ .in' ~the~ presence of sodium and starting with a 2,9- or 3,9-disubstituted 9H-imidazo[ 1,2-a]benzimidazole affords the corresponding 3 - a ~ e t y l ' ~ * -or ' ~ ~2-acety1I7' derivative in high yield (Table 6.65). Acylation with ~ i m p l e ' ~ ' . ' ~and * a@-unsaturated (ethylenic2" or a ~ e t y l e n i c ' ~acid ~ ) chlorides is also readily achieved by heating in the absence of ~ o l v e n t ~or~ in ~ the . ~ 'presence ~ of pyridine as ~ a t a l y s t . ' ~The ~"~~ trichloroacetylation of 2,9-disubstituted 9H-imidazo[l,2-a]benzimidazoles followed by treatment with sodium methoxide provides an efficient method (yields > 90"/0)for the synthesis of the C(3) methoxycarbonyl The corresponding carboxylic acids are more directly accessible (yield > 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

Solvent of crystallization

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)

Solvent of crystallization

~~

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

Reaction conditions"

TABLE 6.65

6.2. Fused Benzimidazoles with One Additional Heteroatom

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

Solvent of crystallization

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

Reaction conditions"

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

6.2. Fused Benzimidazoles with One Additional Heteroatom

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)

Solvent of crystallization

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

Solvent of crystallization

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

Solvent of crystallization

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

Reaction conditions"

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.

Condensed Benzimidazoles of Type 6-5-5

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

6.2. Fused Benzimidazoles with One Additional Heteroatom

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

Solvent of crystallization

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

Solvent of crystallization not specified.

'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

Solvent of crystallization

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

Reaction conditions"

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

6.2. Fused Benzimidazoles with One Additional Heteroatom

~

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

Condensed Benzimidazoles of Type 6-5-5

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-

6.2. Fused Benzimidazoles with One Additional Heteroatom

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

Reaction conditions'

(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

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-5

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

Reaction conditions"

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

Solvent of crystallization

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

Solvent of crystallization

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

Reaction conditions"

TABLE 6.80 (Continued)

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]-

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-5

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);

6.2. Fused Benzimidazoles with One Additional Heteroatom

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)

Solvent of crystallization

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

Solvent of crystallization

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

Reaction conditions"

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

6.3. Fused Benzimidazoles with Two Additional Heteroatoms

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

6.3. Fused Benzimidazoles with Two Additional Heteroatoms

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.

Condensed Benzimidazoles of Type 6-5-5

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

6.3. Fused Benzimidazoles with Two Additional Heteroatoms

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

Solvent of crystallization

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)

Reaction conditions"

(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

6.3. Fused Benzimidazoles with Two Additional Heteroatoms

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

6.3. Fused Benzimidazoles with Two Additional Heteroatoms

,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

Condensed Benzimidazoles of Type 6-5-5

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

6.3. Fused Benzimidazoles with Two Additional Heteroatoms

233

TABLE 6.92 (Continued)

(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,

Condensed Benzimidazoles of Type 6-5-5

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'

Condensed Benzimidazoles of Type 6-5-5

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

-

-

-

Solvent of crystallization

-

-

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

Condensed Benzimidazolesof Type 6-5-5

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

6.3. Fused Benzimidazoles with Two Additional Heteroatoms

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

Condensed Benzimidazoles of Type 6-5-5

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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Condensed Benzimidazoles of Type 6-5-5

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.

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

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

Condensed Benzimidazoles of Type 6-5-6

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

Condensed Benzimidazolesof Type 6-5-6

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;

Reaction conditions"

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

Solvent of crystallization

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

Solvent of crystallization

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)

Product (R + R4 unspecified = H)

Reaction conditions"

Starting material (R + Rs unspecified = H)

TABLE 7.2 (Continued)

/ 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

Condensed Benzimidazoles of Type 6-5-6

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

Condensed Benzimidazoles of Type 6-5-6

(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

Reaction conditions"

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

Dimethylformamidewater

Dimethylformamidewater

12

12 Dimethylformamidewater

Dimethylformamidewater

12

12

Dime t hylformamidewater

Dimethylformamidewater

12

Ref.

Dimethylformamidewater

Solvent of crystallization

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

Reaction conditions'

(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

Solvent of crystallization

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-light petroleum

Benzene (decomp.)

20

Benzene-light petroleum

Benzene-light petroleum

20

20

Benzene-ligh t petroleum

Benzene-light 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

Reaction conditions"

79

10

50

91

Yield (YO)

165

217-219

315

273-275 (decomp.)

m.p. (OC)

Ethyl acetatelight petroleum

Acetone

Ethanol

Acetic acid-water

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-6

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)

7.1. Fused Benzimidazoles with No Additional Heteroatom

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

Condensed Benzimidazolesof Type 6-5-6

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

7.1. Fused Benzimidazoles with No Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

(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

7.1. Fused Benzimidazoles with No Additional Heteroatom

(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

Solvent of crystallization

>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)

Condensed Benzimidazoles of Type 6-5-6

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

7.1. Fused Benzimidazoles with No Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

(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)

Product (R + R4 unspecified = H)

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 (%)

Solvent of crystallization

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)

Reaction conditions'

(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)

TABLE 7.5 (Continued)

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

Solvent of crystallization

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

Condensed Benzimidazolesof Type 6-5-6

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

7.1. Fused Benzimidazoles with No Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

(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)

-

Condensed Benzimidazolesof Type 6-5-6

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

Condensed Benzimidazoles of Type 6-5-6

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.

7.1. Fused Benzimidazoles with No Additional Heteroatom

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

TABLE 7.12 (Continued)

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

TABLE 7.12 (Continued)

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

Condensed Benzimidazoles of Type 6-5-6

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

Condensed Benzimidazoles of Type 6-5-6

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

7.1. Fused Benzimidazoles with No Additional Heteroatom

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

-

Solvent of crystallization

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)

Condensed Benzimidazoles of Type 6-5-6

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

Benzene-light petroleum

-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

7.1. Fused Benzimidazoles with No Additional Heteroatom

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

Solvent of crystallization

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

Reaction conditions"

Table 7.19. N I T R A T I O N REACllONS OF PYRIDOl1.2-alBENZIMIDAZOLEDERIVATIVES

7.1. Fused Benzimidazoles with No Additional Heteroatom

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

Condensed Benzimidazolesof Type 6-5-6

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.

Solvent of crystallization

" 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

Reaction conditions"

TABLE 7.20 (Continued)

7.1. Fused Benzimidazoles with No Additional Heteroatom

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

-

Solvent of crystallization

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,-

Reaction conditions"

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

Solvent of crystallization

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

Reaction conditions'

TABLE 7.22.

336

Condensed Benzimidazolesof Type 6-5-6

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

-

Solvent of crystallization

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

Solvent of crystallization

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

TABLE 2.23 (Continued)

7.1. Fused Benzimidazoles with No Additional Heteroatom

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

7.2. Fused Benzimidazoles with One Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

346

a
I

H

O

X

H

(7.263)

(7.264)

J (7.265) scbane 7.49

(Scheme 7.50) of C(2)-unsubstituted benzimidazoles containing an electronwithdrawing group at N(1) (7.266; R = COMe, COCHPh2, or S0,Me) with diphenylketene, and originally formulatede4 as pyrido[ 1,Zu)benzimidazole derivatives, have been reassigned 3,4,4a,Stetrahydro- 1H-[ 1,3]oxazino[3,4albenzimidazole structures (7.267)" on the basis of their spectroscopic properties. On the other hand, the adducts derived by the analogous TABLE 7.26. SYNTHESIS OF OXAZINOBENZIMIDAZOLES BY RING-CLOSURE REACnONS OF BENZIMIDAZOLE DERIVATIVES Reaction Starting materials conditions" Product

Yield m.p. (XI ("C)

Solvent of crystallization

Ref.

(7.263)

A

(7.265)

-b

(7.264;

B

(7.265)

74

116.5-1 18.5 Toluene

81

(7.266; R=H)

C

(7.267;

83

152-153

84,86

(7.266; R = COCHPh,) (7.266; R = COMe) (7.266; R = S0,Me)

C

(7.267; R = COCHPh,) (7.267; R = COMe) (7.267; R = S0,Me)

86

(7.269) + (7.272) (7.272)

E F

(7.271) (7.273)

2 35

X = OS0,Me)

D D

R = COCHPh,)

73 70

82, 83

Benzene-light petroleum (b.p. 40-60')

84 -d 135-138 (decomp.) 130-135 Ethyl acetate(decomp.) light petroleum (b.p. 60-80") 215-217 -d 161-1 62 Methanol-water

85 85 81 88

A = Br(CH,),Br, NaH, dimethylformamide/20" (reaction time not specified); N = NaOEt, EtOH/(reBux)(Zhr); C = Ph,GC=O (no cosolvent)/(10O0)(1 hr); D = Ph2-0, benzene/(room temp.)(several days); E = dimethylformamide/(l10°)(2 hr); F = 47% HBr/(reflux)(2.5 hr). * Yield not quoted. ' Melting point not quoted. Solvent of crystallization not specified.

7.2. Fused Benzimidazoles with One Additional Heteroatorn

(7.266)

347

(7.267)

Scheme 7.50

reaction of simple P [ l ) alkyl and aryl benzimidazoles (7.266; R=Me, CH,Ph, or Ph) with diphenylketene are variously assigned ring-closed oxazinobenzimidazole [e.g. (7.267; R = Me)JS6and open-chain benzimidazole (7.268)’’ structures. Derivatives of the 3,4-dihydro- 1H-[ 1,4]-oxazino[4,3-a]benzimidazole ring system are most efficiently and conveniently synthesized by ring-closure of 1- (2-substituted phenyl) morpholine derivatives (see later). However, because of the problem of isomer formation, this approach does not lend itself to the unambiguous synthesis of 3,4-dihydrolH[1,4]oxazino[4,3-a Jbenzimidazoles substituted in the morpholine ring. Syntheses, albeit in low yield (Table 7.26) of molecules of the latter type are exemplified (Scheme 7.5 1) by the thermal reaction of ethyl 2-benzimidazolecarboxylate (7.269) with 2-phenyloxirane (7.270) to give the oxazinobenzimidazolone (7.271)87 and the acid-catalyzed ring-closure of the benzimidazole derivative (7.272) to 1-phenyl-3,4-dihydro-1H-[ 1,4Joxazino[4,3albenzimidazole (7.273).88

a x I H

+/“\

C0,Et

Ph (7.270)

(7.269)

a v ’ \

- r .x P h .lr 0

-a+ (7.271)

(CH,),OMe

4%-iPh

I

OH (7.272)

Nrl Ph

(7.273)

srheme 7.51

O0

&

1

(7.283; X = Br) (7.281) + (7.283; R3 = Me, X = Cl)

-+

(7383; X = Cl) (7381; R' = R2 = Me)

+ (7.283; x = a) (7.281; R' = RZ=Me) +

1

(7.281) + (7.283; X = Br) (7.281) + (7.283; X = Br) (7381) + (7.283; X = Br) (7.281; R2 = CI)

(7.275; R' = Ph) (7.275; R' = Ph, R2 = Cl) (7.275; R' = Ph, R2 = R3 = Me) (7.277) (7.279) (7.279) (7.279) (7.279; R = Me) (7.279; R = Cl) (7379; R = NO,) (7379; R=CO,H) (7.279) (7.281) + (7.283; X = Cl) 100

210-211 119-120

99 (7.286; R3=Me)

J

225-226

178-179

-d

147-148 -d

138-139

-d

95

75

-b

-b

63 98

-h

(7.286; R' = R2 = Me)

(7.286; R' = R2 = Me)'

(7.286; R' or R2 = Cl)c.h

(7386)s (7386) (7386)

81

44 32 24 15 25

J

I

I

K

I J

H

F G

F

F

D E F F

C

B

70 61 63 23 48

(7376; R' = Ph) (7.276; R'= Ph, R2 or R" = Cl)c (7.276; R' = Ph, R2 = R3 = Me) (7.278) (7380) (7.280) (7380; R' =Me) (7.280; R = R' =Me)' (7.280; R = CI, R' = Me)' (7.280; R = NO,, R' = Me)' (7380; R=CO,H, R' = Me) (7.280; R' =OH) (7.286)'

B

B

160-161 (decomp.) 148-149 180-181 213-214 350 (decamp.) 207-208 167-170 169- 172 156-158 201-203 297-300

-b

(7376; R' = Me)

A

(7374; R' = Me)

m.p. ("C)

Yield (%)

Product (R-r R3 unspecified = H)

Reaction conditions"

Starting materials (R- R3 unspecified = H)

-c

e

-

-

-

-

Benzene-light petroleum (b.p. 60-809 Ethanol

-

Chloroform Chloroform Chloroform Ethanol Acetic acid Methanol Methanol Methanol Ether-methanol Acetone

Ethan oI

Solvent of crystallization

BY RING-CLOSURE REACTIONS OF 2TABLE 7.27. SYNTHESIS OF [~,~~HIAZIN~[~,~-U]BENZIMIDAZOLES BENZIMIDAZOLETHIONE DERIVATIVES

99

99

98

98

98 99 83

90 90 90 91 92 92 93 93 93 93 93 94 95

89

Ref.

I

l J

Q

L L M N 0 P P P (7.289) (7.289; R = Me) (7.287) (7.287) (7.287) (7.287; R2 = Cl) (7.287; R' =NO,) (7.287; R' = R2 = Me) (7.292)

90 90 76 47 72 67 40 74 92

45

-b

(7.285; R' = R2 = Me) (7.285; R' = R2 = Me)

53

-b

92

(7.285)' (7.285)

( 7 . m ; R' = R2 = R3 = Me)

126-128 248-250 151-152 168 168 175 190 173-174 189-19 1

268-269

266-267

2 14-2 15 214-215

250-25 1

-c

Ethanol Ethanol Ethanol Ethanol

-c

Ethanol-water

Ethanol-water

-

-c

Ethanol

-e

-

-

106 104 108

105

100 100 101 102 103

99

98

99

98

99

a

A = polyphosphoric acid/( 155-16W)(I5 min); B = Hg(OAc),, conc. H2S0,, AcOH/(reflux)(5 hr); C = MeO,CC=CCO,Me, EtOH, H2/(reflux)(4 hr); D = ck-CICH=CHCO,H, EtOH, xylene/(80")(10 hr); E = H D C C O , H , EtOH, xylene/(reflux)( 1 hr); F = CIC(Me)=CHCO,Et. NaOEt, EtOH/(reflux)(4 hr); G = C,02, tetrahydrofurane, ether/-70" then 20" (reaction time not specified); H = 20% KOH, NaHCO,, Pr'OH/(reflux)(4 hr); I = KOH, EtOH/ (reRux)(3 hr); I = K1,NaHCO,, Pr'OH (reaction conditions not specified); K = NaH, dimethyIf0rmamide~20~ (reaction conditions not specified); L = NaOH, H 2 0 , EtOH/(reflux)(l hr); M = Ac20, pyridine/(reflux)( 1 hr); N = Ac20, pyridine (reaction conditions not specified); 0 = dicyclohexylcarbodiimide, pyridine/(5-10")(1012 hr); P = Ac,O, pyridine/( loo")(10-30 min). Yield not quoted. C(7) or C(8) position for the substituent in the benzene ring not established. Melting point not quoted. ' Solvent of crystallization not specified. Forms a picrate, m.p. 242-4" (decomp.). Forms a hydrochloride, m.p. 198-199'. Forms a hydrochloride, m.p. 182-183'. ' Forms a hydrochloride, m.p. 218-220". Forms a hydrochloride, m.p. 21 1-212".

(7.283; R 3 = O H , X = C l ) (7.288) (7.288; R = Me) (7.282) (7.282) (7.282) (7.282; R2 = Cl) (7.282; R2 =NO2) (7.282; R' = R2 = Me) (7.290)

+

(7.283; R3 =Me, X = Cl) (7.281)+ (7.284) I (7.281) + (7.283; R3 = OH, X = C1) I (7.281; R' = R2 = Me) f I (7.284) (7.281; R' = R2 = Me)

+

(7.281; R' = R2 = Me)

350

Condensed Benzimidazolesof Type 6-5-6

The 2H-[ 1,3]thiazin0[3,2-a]benzimidazole ring system has been constructed in a single instance, in unspecified yield (Table 7.27), by the polyphosphoric acid catalyzed acylative ring-closure of a 2-(y-oxoalkylthio)benzimidazole derivative [Scheme 7.52; (7.274; R' = Me, R2 = R3 = H) + (7.276; R' = Me, R2= R3= H)].89 Ring-closure of this type cannot be accomplished, as in related cyclizations (see later), by heating with acetic anhydride in the presence of ~yridine.'~ More general synthetic access to the R'

R'

R3 R2 (7.274)

(7.275)

(7.276) !Scheme 7.52

2H-[ 1,3]thiazino[3,2-a]benzimidazole ring system is provided by the mercuric acetate catalyzed cyclizationgOof 2-(3-phenyl-2-propynylthio)benzimidazoles (7.275), which affords 3-phenyl-2H-[l,3]thiazino[3,2-a]benzimidazoles (7.276; R'=Ph) in good yield (Table 7.27). The uncatalyzed reaction (Scheme 7.53) of 2-benzimidazolylthioacetonitrile (7.277) with dimethyl acetylenedicarboxylate affords a low yield (Table 7.27) of a product tentatively formulatedg1 as the 4H-[1,3]thiazino[3,2-a)benzimidazole derivative (7.278). More orthodox ring-closure to the 4H-[ 1,3]thiazino[3,2-a]benzimidazole ring system is exemplified (Scheme 7.53) by the uncatalyzed or base-catalyzed condensation of 2-benzimidazolethiones (7.279) with 3chloroacrylic acid,Y23-chlorocrotonic acid?3 or propiolic acid,92to give good yields (Table 7.27) of [ 1,3]thiazino[3,2-a]benzimidazol-4-ones(7.280). The use of unsymmetrically substituted 2-benzimidazolethiones in such cyclizations is reported93 to give only one of the two possible thiazinobenzimidazolone products of as yet unestablished orientation. The unstable product obtained in quantitative yield (Table 7.27) by the reaction of 2-benzimidazolethione with carbon suboxide is formulated,Y4without structure proof, as 2-hydroxy-[ 1,3)thiazino[3,2-a&enzimidazol-4-one (7.280; R = H, R' = OH).

7.2. Fused Benzimidazoles with One Additional Heteroatom

351

H SCH,CN (7.277)

(7.278)

H (7.279)

3,4-Dihydro-2H-[ 1,3]thiazino[3,2- a]benzimidazoles are generally accessible in good yield (Table 7.27) by the base-catalyzed condensation of 2benzimidazolethiones with 1,3-dihalogenopropanes [Scheme 7.54; (7.281)+ (7.283; R 3 = H , Me, or OH, X = C I or Br)-*(7.286; R 3 = H , Me, or OH)]-83.95-99 The use of epichlorohydrin as the reagent in annelation reactions of this type provides an alternative method for the synthesis in good yield (Table 7.27) of 3-hydroxy-3,4-dihydro-2H-[l,3]thiazino[3,2-a]benzimidazoles [Scheme 7.54; (7.281)+ (7.284)+ (7.285)].96The base-catalyzed transformation (Scheme 7.55) of readily accessible 2-(y-ch1oropropylthio)benzimidazole derivatives (7.288) in high yield (Table 7.27) into 4-phenyl3,4-dihydro-2H-[ 1,3]thiazino[3,2-a]benzimidazoles (7.289) exemplifies a further synthetic approach"' to the 3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole ring system. 223-[ 1,3~iazino[3,2-a]benzimidazol-4(3H)ones (7.287) are simply prepared (Scheme 7.54), usually in high yield (Table 7.27), by the cyclodehydration of 2-benzimidazolylthioaceticacid derivatives (7.282) available by the condensation of 2-benzimidazolethiones with chloroacetic acid.'"'-''" Ring formation of this type is readily effected by heating with acetic anhydride'0'~'02~'""'w or dicyclohexylcarbodiimide'03 in each case in conjunction with pyridine. The cyclization of 2-benzimidazolylthioacetic acids unsymmetrically substituted in the benzene ring can lead to two possible, isomeric, 2H-[1,3]thiazino[3,2-a]benzimidazol-4(3H)-ones,depending on which of the nonequivalent benzimidazole nitrogen atoms is involved in the ring-closure step. In one of the few instances of this situation'06 reported to date, the orientation established for the single isomer obtained is as would be expected, consistent with cyclization via the more basic of the two available nitrogen centers. Other transformations leading to 2H-[1,3]thiazino[3,2-a]benzimidazol-4(3H)-ones include the

352

Condensed Benzimidazoles of Type 6-5-6

H (7.281)

(7.282)

X

I

(7.285)

(7.286)

(7.287) schaae 7.54

reaction of 2-benzimidazolethione with acryioyl chloride to give 2H-[ 1,31thiazino[3,2-a]benzimidazol-4(3H)-one itself,"' and the ring expansion of a 2,3-dihydrothiazolo[3,2-a]benzimidazole derivative rationalized"* by the ring-opening/ring-closuresequence outlined in Scheme 7.56. The thermal reaction (Scheme 7.57) of 1-methyl-2-benzimidazolylthioacetonitrile (7.293) with dimethyl acetylenedicarboxylate affords two products in low yield (Table 7.28) whose structures have been demonstrated" unambiguously by X-ray analysis to be the 10H-[ 1,4]thiazino[4,3-a]benzimidazole (7.294) and its dihydro derivative (7.295). The novel transposition of the sulfur atom and methylenecyano moiety required to account for these

(7.288)

(7.289) !wIeme 7.55

(7.290)

\ (7391)

(7.292) seherm 7.56

0,Me

Me (7.294)

(7.295) scheme 7.57

353

Condensed Benzimidazoles of Type 6-5-6

354

TABLE 7.28. SYNTHESIS OF [1,4]THIAZINo[4,3-a]BENZlMIDAZOLES BY RING-CLOSURE REACTIONS OF BENZIMIDAZOLE DERIVATIVES (Oh)

("a

Solvent of crystallisation

(7.294)

1

199-200

Ethyl acetate-

(7.295) (7.297)

1 34

165-167 300

-

C

(7.298; R = H ) 50

104-105

D

(7.298; R = H ) 54

104

Light petroleum (b.p. 40-60') Ethanol

103

E

(7.298; R=CI) 75

213

-b

110

Starting material

Reaction conditions" Product

(7.293)

A

(7.2%; R = H , R' = p-tolyl) (7.2%; R = H ,

B

R' =OH) (7.296; R = H , R' = OH) (7.296; R=CI, R' = OH)

{+

Yield

m.p.

Ref.

Ether b

109 101

A = Me02CCwCO&ie, dimethylformamidel( 100")(3 hr); B = polyphosphoric acidl(l60170°)(2 hr); C = Ac,O. pyridine/(reflux)(15 min); D = dicyclohexylcarbodiimide, pyridinel(510")(10-12 hr). Solvent of crystallization not specified.

products is suggested" to involve a thiirane derivative as the crucial intermediate. The polyphosphoric acid catalyzed cyclization (Scheme 7.58) of the 2-(~-oxoalkylthiomethyl)benzimidazole(7.2%; R = H, R' = p-tolyl) to the 1H-[ 1,4]thiazino[4,3-~]benzimidazole derivative (7.297)'09 exemplifies a more obvious, if still relatively inefficient (Table 7.28), method for the construction of a [ 1,4]thiazino[4,3-a]benzimidazole framework. 1 H-[ 1,4]thiazino[4,3-a]benzimidazol-4(3H)-ones are readily accessible in moderate

(7.2%)

\ -

R' OH

(7.297)

(7.298) Wcw 7.58

7.2. Fused Benzimidazoles with One Additional Heteroatom

355

-

to good yield (Table 7.28) by the orthodox cyclodehydration of 2-benzimidazolylmethylthioacetic acids catalyzed by acetic anhydride-pyridine'""'" [Scheme 7.58; (7.296;R' = OH) or dicyclohexylcarbodiimide-pyridine1~3

(7.298)].

Syntheses of the various ring systems containing a pyrimido[ 1,2-a]benzimidazole framework (cf. Scheme 7.48) are largely based on ringclosure reactions of 2-aminobenzimidazole derivatives. Thus, pyrimido[ 1,2a)benzimidazole and its simple alkyl and aryl derivatives are directly accessible in moderate yield (Table 7.29) by the thermal condensation of N(1)unsubstituted 2-aminobenzimidazoles with malondialdehyde diethyl acetal, P-keto aldehydes, and P-diketones [Scheme 7.59; (7.299;R = H) --$ (7.300; R3 = R4 = H, alkyl, or a~yl)]."'-''~The use of unsymmetrical P-dicarbonyl compounds in such annelation reactions can in theory lead to two possible pyrimido[ 1,2-a]benzirnidazole products, though in practice, one isomer is often formed largely in preference to the other. The condensation of 2aminobenzimidazole with acetoacetaldehyde dimethyl acetal gives a single product" '-''' whose 'H NMR spectrum is consistent with its being 2methylpyrimido[ 1,2-a]benzimidazole (7.300; R' = R2 = R' = H, R4 = Me) and not the 4-methyl isomer (7.300;R' = R2 = R4 = H, R3 = Me). However, the former structure is open to question in the light of the report"4 that a methylpyrimido[ 1,2-albenzimidazole having essentially the same m.p. as the acetoacetaldehyde dimethyl acetal derived product is formed in good yield (Table 7.29) in the perchloric acid catalyzed condensation of 2aminobenzimidazole with methyl p -chlorovinyl ketone, as the perchlorate salt, whose 'H NMR absorption requires its formulation as the 4-methyl isomer (7.300; R' = R2 = R4 = H, R' = Me). The 2-phenylpyrimido[l,2-a]benzimidazole' and 2-methyl-4-phenylpyrimido[1,2-a]benzimidazole' I' structures (7.300;R' = R2= R3 = H, R4 = Ph) and (7300; R3 = Ph, R4 = Me) assigned without structure proof to the products of the condensation of 2aminobenzimidazoles with benzoylacetaldehyde and benzoylacetone, respectively, also require verification. N(l)-Alkyl-2-aminobenzimidazole hydrochlorides also condense thermally with p-diketones to give, after treatment with perchloric acid, generally good yields (Table 7.29) of the corresponding 1O-alkylpyrimido[l,2-a]benzimidazolium perchlorates (7.301;R = a l k ~ l ) . "The ~ 'H NMR a b s ~ r p t i o n "o~f the products so-derived from benzoylacetone are consistent with their f~rmulation"~ as lO-alkyl-2methyl-4-phenylpyrimido[ 1,2-a]benzimidazolium perchlorates (7.301; R = alkyl, R 3 = P h , RS=Me). This orientation implies that the reaction of an unsymmetrical p-diketone with an N(l)-alkyl-2-aminobenzimidazolehydrochloride involves preferential initial condensation of the amino substituent in the latter with the more electrophilic of the carbonyl centers in the diketone. Dibenzoylmethane tends to give only low yields (Table 7.29) in annelation reactions of this type, but can be effectively replaced by 2,4,6-triphenylpyrilium perchlorate to afford high yields (Table 7.29) of 10-alkyl2,4-diphenylpyrimido[1,2-a]benzimidazolium perchlorates [Scheme 7.60;

m

L

L

L

M

(7.299)

(7.299;R' = OMe)

(7.299; R' = Cl)

(7.299)

(7.299) (7.299; R = Me)b (7.299;R = Me)b ( 7 m ;R = Me) (7.299;R = Et) (7.299;R=CQH,Q) (7.299; R = CH,Ph) (7.299;R = Ph)'

J

(7.299;R' =Cl)

J

J

K

I J

(7.300;R3= R4 = Ph) (7.301;R = R3 = Me) (7.301;R = R3= RS= Me) (7.301; R = R3 = RS = Me) (7.301; R = Et, R3 = RS = Me) (7.301; R = GH,,.R3 = RS= Me) (7.301;R = CH,Ph, R3 = RS = Me) (7.301; R = Ph. R3= RS = Me)'

RS = R4 = Me)8 (7.300;R' or R2=CI, R 3 = R 4 = Me)8 (7.300;R3 or R4= Me or Ph)h (7.300;R' or RZ= OMe, R3 or R4 = Me or Ph)g.' (7.300;R' or R2 = OMe, R3 or R" = Me or Ph)8*h (7.300;R' = R" = Ph) 16 11 42 88 63 17 48 20

48

-c

(7.300;R"= Ph) 47 32 (7.300;R" = Ph)d -d (7.300;R3= R4= Me) -d (7.300;R3 = R" = Me) (7.300;R3 = R" = Me) 43 (7.300;R' or R2 = R3 or R" = Me)R (7.300;R' or R2=OMe,

G H

(7.299) (7.299)b (7.299) (7.299) (7.299) (7.299; R' =Me) (7.299; R' = OMe)

11 59 94 24 54 61

Yield (YO)

(7.300) (7.300;R" = Me) (7.300;R" = Me) (7.300; R" = Me) (7.300; R3 = Mep (7.300;R" = Ph)

Product (R+RS unspecified = H)

(7.299) (7.299) (7.299) (7.299) (7.299)b (7.299)

Reaction conditions"

311 230-23 1 228-230 228-229 222 138-139 245 164-166

3 12-3 15

195-196

> 245

172- 173

2 10-2 14

Ethanol or ethanol-water Ethanol or ethanol-water Acetic acid Acetic acid Methanol Acetic acid Ethanol or ethanol-water

_f

Dimethylformamidewater

f

J

J f

-r

Ethanol or ethanol-water Water

268-269 230-231 234-235 239-241 230-23 1 188- 190

-

2-Propanol Ethanol Ethanol Ethanol Ethanol or ethanol-water Dimethylformamidewater

Solvent of crystallization

197-200 233-234 233 230-232 210-21 1 287-290

m.p. ("C)

SALTS BY RING-CLOSURE REACTIONS OF 2-AMINOBENZIMIDAZOLE DERIVATIVES

118 114 114 118 118 118 118 114

115

117

117

117

117

115 114 116 117 111 117 117

111 112 113 111 114 115

Ref.

SYNTHESIS OF ALKYL AND ARYL PYRIMIDa1,2-a JBENZIMIDAZOLES AND PYKlMII)O~1,2-a]BENZIMlDAZOLIUM

Starting materials (R-r R2 unspecified = H)

TABLE 7.29.

N

U V N

(7.299; R = R' = R2 = Me)

(7.299; R = Et) (7.299; R = Et) (7399; R = Et) (7.299; R=Pr") (7.299; R=C,H,,) (7.299; R = CH,Ph) (7.310) + (7.311)

R = R3 = R4 = R5= Me) R = R4 = R5 = Me, R3 = Et) R = R5= Me, R3 = Ph) R = Me, R3 = R5= Ph) (7.301;R = R' = R2 = Me, R3=R5=Ph) (7.301; R = R ' = R ? = M e , R3= RS= Ph) (7.301; R = Et. R3 = R5 = Ph) (7.301; R = Et, R3 = R5 = Ph) (7.301; R = Et, R' = Rs= Ph) (7.301; R=Pr", R 3 = R S = P h ) (7.301; R = (aH,,, R3 = Rs = Ph) (7.301; R = CH,Ph, R3 = R5 = Ph)

(7.312)

(7.301; (7.301; (7.301; (7.301; 50

268-270 187 294-295 210-212

Acetic acid Acetic acid Acetic acid Ethanol

Nitromethane

-

118 118 118 118 118 118 119

-

282

114 114 114 118 118

6 13 47 86 84 96 62

Ethanol or ethanol-water Ethanol or ethanol-water Ethanol or ethanol-water Acetic acid Acetic acid 118

181-182 154-155 230-23 1 279-281 270

92

46 13

34 24

PhCOCH,COPh, xylene/(140")(5hr); N =

ClO./dimethylformamide/(reflux)(I hr); 0 = MeCOCH,CHO (no cosolvent)/(l50-l7O0)(3 hr), Ph Ph then treat with HCIO,; P = MeCOCH,COMe (no cosolvent)/(l50-17Oo)(3hr), then treat with HCIO,; Q = MeCOCH,COMe, 70% HCIO,, AcOH/(reflux)(l hr); R = MeCOCH(Me)COMe (no cosolvent)/(l50-170")(3 hr), then treat with HCIO,; S = EtCOCH(Me)COMe (no cosolvent)/(150170°)(3 hi), then treat with HCIO,; T = PhCOCH,COMe (no cosolvent)/(l50-17O0)(3hr), then treat with HCIO,; U = PhCOCH,COPh, 70% HCIO,, dimethylformamide/(reflux)(2hr); V = PhCHSHCOPh, 70% HCIO,, dimethylformamide/(reflux)(3 hr); W = AcOHlreflux (reaction time not specified). Perchlorate. Perchlorate; free base has m.p. 235-237" (from ethanol-water). Perchlorate: free base ha5 m.p. 174176". ' Yield not quoted. f Solvent of crystallization not specified. 8 C(7) or C(8) position for the benzene substituent not established. Respective positions of the pyrimidine ring substituents not established. ' Picrate.

J,&k

A = (MeO),CH,CH(OMe)z, conc. HCI, AcOH/(reflux)(2hr); B = MeCOCH,CH(OMe),, xylenc/heat (reaction time not specified); C = MeCOCH,CH(OMe),, xylene/(reflux)/(Shr); D = MeCOCH,CH(OMe), (no cosolvent)/(13O-14Oo)/(3.5 hr); E = C I C H d H C O M e , 42X HCIO,. EtOH/(room tempJ(3-4 days); F = PhCOCH,CHO, tetrahydrofuranel( 140°)(2hr); G = PhCOCH,COCO,H, xylene/(14O0)(3hr); H = PhCOCH==CHCI, 42% HCIO,, EtOH/reflux till solution is obtained; I = MeCOCH,COMe, H,O/(reflux)(3 hr); J = MeCOCH,COMe/heat (reaction conditions not specified); K = MeCOCHZCOMe/(100")(2hr); then Pr'OH/(reflux)(18 hr); L = PhCOCH,COMe/heat (reaction conditions not specified); M =

W

N N

N

I N

S

U

R

R = Me)b R = Me)b R = MeIh R = Me) R = R' = RZ= Me)

(7.299; (7.299; (7.299; (7399; (7.299;

R' (7.302)

I R

0

0

OH

R'

I

R

OH

R'

scheme 759

R

AN'

(7303)

R2myR3 ' I

R (7.299)

7.2. Fused Benzimidazoles with One Additional Heteroatom

359

(7.304; R = alkyl) + (7.305) + + (7.309; R = alkyl)]."8 The mechanism suggested"* to account for this variant is outlined in Scheme 7.60. Ethyl ethoxymethyleneacetoacetate behaves as a P-keto aldehyde rather than a P-keto ester component in its thermal condensation with 2-aminobenzimidazole in acetic acid solution which affords in good yield (Table 7.29) a product formulated' l9 as ethyl 2-methylpyrimido[ 1,2-a]benzimidazole-3carboxylate. However, this structure probably requires revision to that of ethyl 4-methylpyrimido[ 1,2-a]benzimidazole-3-carboxylate[Scheme 7.61; (7.312)] in the light of more recent studies'20 which demonstrate conclusively that the thermal reaction of a 2-aminobenzimidazole with an ethoxymethylene compound occurs by preferential initial condensation between the primary amino and ethoxymethylene substituents. In particular, the product obtained in moderate yield (Table 7.30) by heating 2-aminobenzimidazole with ethyl ethoxymethylenecyanoacetate has been shown120to be ethyl 4-aminopyrimido[ 1,2-a]benzirnidazole-3-carboxylate (7.315; R' = H, R 2 = C 0 2 E t ) and not, as previously reported"' the 2-amino isomer. It follows that the 2-amino-3-cyanopyrimido[1,2-a]benzimidazolestructure

II

R (7.304)

(30;

(7.305)

360

Condensed Benzimidazoles of Type 6-5-6

H (7310)

(7.312)

I

(7315) R-Me

MeCOCHzCO&t

0

Me (7313) !Scheme 7.61

assigned119to the product (Table 7.30) of the thermal condensation of 2aminobenzimidazole with ethoxymethylenemalononitrile should be revised to that of 4-amino-3-cyanopyrimido[ 1,2-a]benzimidazole (7.315; R' = H, R2 = CN).4-Aminopyrimido[1,2-a]benzirnidazoles (7315) are also generally accessible (Scheme 7.61)'21*'22 in moderate to good yield (Table 7.30) by the thermal reaction of 2-aminobenzimidazole (7.310; R = H) with P-cyanoenamines (7314; X = NH,) in the absence of solvent'22 or in solvents such as ethanol or acetic acid."' In a simple extension of the p -diketone condensations already discussed, the reaction (Scheme 7.59) of 2-aminobenzimidazoles (7.299) with p-keto esters provides a general method for the synthesis, often in good yield (Table 7.31) of pyrimido[1,2-a]benzimidazol-4(10H)-ones (7.301).1'1~120-'27

7.2. Fused Benzimidazoleswith One Additional Heteroatom

361

BY TABLE 7.30. SYNTHESIS O F 4-AMINOPYRIMIDq1,2-a]BENZIMIDAZOLES -

~

RING-CLOSURE REACTIONS O F 2-AMINOBENZIMIDAZOLE

Starting materials

(7.310)

+

(7.314;R' = Me, R2 = H,X = NH,) (7310)

+

(7.314;R' = Ph, R2 = H, X = NH,) (7.310)

+

(7314;R' = Ph, RZ= H, X = NH,) (7.310)

+

(7.314;R' = RZ= Me, X = NH,) (7.310)

+

(7314;R' = H, RZ= CO,Et, X = OEt) (7310)

+

(7314;R ' = H , R2 = CO,Et, X = OEt) (7.310)

Reaction conditions" Product

lA ).

lB

IB I'

1

+

(7314;R' = H, R2 = CN,

X = OEt)

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

Solvent of crystallization

-~

Ref.

(7315;R' = Me, R~ = H)

-b

> 300

Ethanol-acetic acid

121

(7.315; R'=Ph, R, = H)

-b

> 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)

Reaction conditions"

~

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

Solvent of crystallization

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)

7.2. Fused Benzimidazoles with One Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

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)

Solvent of crystallization

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.

7.2. Fused Benzimidazoles with One Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

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)

Reaction conditions'

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

7.2. Fused Benzimidazoles with One Additional Heteroatom

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

-

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-6

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)].

7.2. Fused Benzimidazoles with One Additional Heteroatom

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)

Reaction conditions" Product

(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

Solvent of crystallization

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

7.2. Fused Benzimidazoles with One Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

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

Reaction conditions" Product

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).

Solvent of crystallization not specified.

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)

Reaction conditions"

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

Solvent of crystallization

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

Solvent of crystallization

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

Reaction conditions"

R = p-MeCeHJ

(7356; R = CH,Ph)

(7353) (73%; (7354; (7356; (7356; (7356; (7356; (7.356; (7356;

Starting material

TABLE 7.37 (Continued)

7.2. Fused Benzimidazoles with One Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

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

Reaction conditions" Product

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)

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-6

(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

7.2. Fused Benzimidazoles with One Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

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'

7.2. Fused Benzimidazoles with One Additional Heteroatom

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)

Reaction conditions" Product

(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

Solvent of crystallization

-

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)

7.2. Fused Benzimidazoles with One Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

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

7.2. Fused Benzimidazoles with One Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-6

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

TABLE 7.48 (Continued)

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

Condensed Benzimidazoles of Type 6-5-6

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.

~

7.2. Fused Benzimidazoles with One Additional Heteroatom

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)<4r-H(4)=

J-

CH,OH.

JH(3)nans-H(4)

' OH; JOHXH,= 5 Hz. JH(3ku-H(4) = Hz. ' J ~ c m m ~ - H=w7 HZ. " Jprm = 16 Hz. Piperazine H. "H(3) and H(4). NHMe. NH.

135

Condensed Benzimidazoles of Type 6-5-6

408

carbonyl substituent in these molecules. Despite their adjacency to the carbonyl center, the protons at the C(3) position in 3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-ones (7.441) resonate at higher field (Table 7.55) than those at the C(4) position. The chemical shifts (64.15 and 2.90) (cf. Table 7.55) reported'3g for H(3) and H(4) in 3,4-dihydropyrimido[1,2a]benzimidazol-2(1H)-one (7.441; R' = R2= R3= R4= H) are not in accord with the values (6 3.43 and 4.72) (cf. Table 7.55) obtained in other studies"' and considered in the context of the 'H NMR absorption (Table 7.55) of 3,4-dihydropyrimido[1,2-a]benzimidazol-2(lH)-ones as a whole, appear to be incorrect. The deshielding effect (Table 7.56) of the N(10)-acetyl substituent in the pyrazino[4,3-a]benzimidazol-4( 10H)-one (7.442; R' = COMe, R2= H, TABLE 7.56 'HNMR

OF PYRAZINq4.3-alBENZIMIDAZOL-4(10H)-ONES 0

(7.442)

R'

R2

R'

H(1)

H

H

Ph

7.80

H

Me

H

H

H

Me

H

H

H

Me

COMe H

H(3)

H(6)

H(7) H(8)

4.22" 8.65df -7.10-7.80111'7.10-7.80m' Ph 2.52O 4.2T 8.82df -7.00-7.50m'7.00-7.50111' o-CIGH, 7.10-7.6Od 4.16d 8.628 -7.10-7.60mh7.10-7.60111~ 0-ClC,H, 2.44. 4.18d 8.71df -6.90-7.60m'6.90-7.6Om' I-Naphthyl 7.10-8.40mh 4.42d 8.60d' -7.10-8.40111~7.10-8.40111~ I-Naphthyl 2.40g 4SOd 8.70' -7.10-8.1Om'7.10-8. 1Om' 1-Naphthyl 8.14 4.20d 8.70df c.--' 7.10-7.7Om

" 8 values in ppm measured from TMS in (CD,),SO as solvent. Signals are sharp singlets unless denoted as d = doublet; m = multiplet.

From Ref. 148. CH,.

* H(7). H ( 8 ) . H(9), and ArH. J = 7.2-8.4 Hz.

'

C(Me). H(1). H(7), H(8), H(9). and ArH. 6 values not specified. COMe.

H(9) H(10)

-

-

+ 2.78i

8 \o

C A

A

3.50m"

2.53O -

3.754.50m"

3.49 7.29'

-

2.32* 2.50' 3.66' 7.28111' 3.754.50m" 4.76' 8.58' 2.18m

-

'

~

-

8

-7.20m7.25 7.92 7.28111~-

(7.446)

4

b

3.92' 8.35

-

4

150 162 152 150

160

150

150 I60

H(l0a) Ref.

(7.447)

7.63111 3.90' 8.33 7.70111

7.30-7.79m"-7.25m 5.90 -8.00 2.73m t---6.54m

2.833.171"

2.92th 3.921'-

- -

3 754.5Qm" -3.961114.20

2.86t'

-8

-3.03t'-

(7.445)

"6 values in ppm measured from TMS. Signals are sharp singlets unless denoted as t = triplet; q = quartet; m = multiplet. A = CDCI,; B = (CD,),SO; C = CF,COzH. NH; exchangeable with DZ9. 'J = 5.7 Hz. NMe. "J=6Hz. H ( 6 ) . H ( 7 ) , H ( 8 ) , H(9), and CH,Ph. '6 values not quoted. p SMe. J = 6 Hz. c==. OMe. ' CI1,Ph. ' CHO. * H(1) and NH. H(6). H(7), H(8), and CH,Ph. ' CH,Ph ' J values not quoted. " X part of ABX spin system Jm + JBx = 6 Hz. H(1). H(3), and CH2Ph.

(7.444) (7.445) (7.444) (7.447)

B

A

RZ=CHzPh)

(7.443;R' = CO,Me,

4.00 3.83 3.87

A A A

(7.444)

(7.443;R' = RZ= H) (7.443;R' = CO,Me, R2= Me) (7.443;R' = H, R2= CHzPh)

(7.443)

Solvent' H(1)

~

Compound

~~~

(7.443H7.447) TABLE 7.57. 'H NMR SPECTRA"*bOF TETRAHYDRO- AND HEXAHYDROPYRAZINq4,3-a]BENZIMIDAZOLES

Condensed Benzimidazoles of Type 6-5-6

410

R3= I-naphthyl) is apparent in the low field position (6 8.14) for H(1), which in the N(10)-unsubstituted derivative (7.442; R' = R2= H, R3= Ph) resonates at S 7.80 (Table 7.56). H ( 1) in 1,2,3,4-tetrahydropyrazino[4,3-a]benzimidazole (Table 7.57; (7.443; R' = R2 = H)] absorbs at lower field (Table 7.57) than H(3) or H(4). The deshielding effect of the C(3) carbonyl substituent in pyrazino[4,3-a]benzimidazole-l,3(2H,4H)-dione (7.446) accounts for the low field position (Table 7.57) of the C(4) proton resonance in this molecule. The 'H NMR signal (Table 7.57) of the bridgehead proton at the C(l0a) position in 2-benzyl-1,2,3,4,10,1Oa-hexahydropyrazino[4,3albenzimidazole (7.447) appears as a quartet centered at 6 4.79 due to coupling with the protons of the C(1) methylene group. MASSSPECTRA. PyrimidoC 1,2-aJbenzimidazol-2(1H)-ones and pyrimido[ 1,2-a]benzimidazol-4(10H)-ones are readily distinguished on the basis of their mass spectral fragmentati~n.'~'The mass spectra of both structural

R4 R3

t0

[RtH1 NH2

[alNI /

R' R'-R'-Me =R'- H

--Me

(7.450)

(7.449)

(mle 131)

(mle 133)

- MeCH-CHI?O

M \e a -

*

A

(7.451)

(mle 200)

SeLCmt 7.83

7.2. Fused Benzimidazoles with One Additional Heteroatorn

411

types exhibit base peaks corresponding to the molecular ion, but whereas pyrimido[ ~,2-a]benzimidazol-4(I OH)-ones undergo initial fragmentation by simple loss of the C(4) carbonyl moiety, pyrimido[ 1,2-a]benzimidazol2( lH)-ones give rise to fragment ions resulting from the primary extrusion unit with its attached sub~tituents.'~~ Isomeric of the N(l)-C(2)-C(3) 3-hydroxy-1,2,3,4-tetrahydropyrimido[ 1,2-a]benzimidazoles can also be differentiated on the basis of their mass spectral fragmentati~n.'~'The electron-impact induced breakdown of 3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-ones [Scheme 7.83; (7.448)]'39 typically involves the primary excision of C(2)-C(3)-C(4) and attached substituents as a discrete unit giving fragment ions of the type (7.449) and (7.450). In the case of 4,41H)-ones [e.g. disubstituted 3,4-dihydropyrimido[1,2-a]benzimidazol-2( (7.448; R' = R2 = H,R3 = R4 = Me) major fragmentation is preceded by loss of a C(4) substituent giving stable cations [e.g., Scheme 7.83; (7.451)].13' General Studies

CRYSTALLOGRAPHY. The structures of the 10H-[ 1,4]thiazin~4,3-a]benzimidazole [Scheme 7.81; (7.412)] and its 1,lOa-dihydro derivative, formed" in novel fashion from 2-benzimidazolylthioacetonitrileand dimethyl acetylenedicarboxylate, were established" by X-ray analysis. The determination of the crystal structure of a 3,4-dihydropyrimido[1,2-a]benzimidazol2( lH)-one has revealed the slightly pyramidal configuration of N ( 5 ) in such

molecule^.'"^

IONIZATION CONSTANTS. Quantitative information on the basicity of tricyclic 6-5-6 fused benzimidazole structures with one additional heteroatom appears to be available only in the single instance of the 1,2.3,4tetrahydropyrazino[4,3-~]benzimidazolering system. The strongly basic character of the latter is indicated by the ionization constants (pK, = 2.55 f for 2-methyl- 1,2,3,4-tetrahydro0.05 and pK, = 5.39 f 0.05) pyrazino[4,3-n]benzimidazole. 7.2.3. Reactions Reactions with Electrophiles

PROTONATION.The basicity of 3,4-dihydro- 1H-[ 1,4]oxazino[4,3-a]benzimidazoles is indicated by their ready protonation in mineral acids at N(10) to give stable salts from which the parent bases are liberated unchanged on ba~ification.~'The stable perchlorate salts formed by fully unsaturated pyrimido[ 1,2-a]benzirnidazoles are likewise derived by protonation at the N(10) p~sition."~

Condensed Benzimidazoles of Type 6-5-6

412

TABLE 7.58. ALKYLATION REACTIONS OF 3,4-DIHYDRO-lH-

[1,4]OXAZINq4,3-a]BENZIMIDAZOLE DERIVATIVES

1,2,3,4-Tetrahydro[1,4Joxazino[4,3-a]

benzimidazole Reaction conditionso Substrate Productb

m.p.("C)E

242-244d 8-Cl8-Cl-lO-Me-, iodide 186 8-Cl8-CI-lO-Et-. iodide 8-CN-lO-Et-, iodide 200-210 8-CN202-205 7.8-ClZ7,8-C12-10-Et-, iodide 7-CN-8-CI-lO-Me. iodide 170 7-CN-8-CI7-CN-8-CI7-CN-8-CI-lO-Et-, iodide -' -~ A = MeI1100" (reaction time not specified); B = Et1/(100", sealed (15-16 hr); C = MeU(11O0, sealed tube)(4hr). Yields not quoted. Solvents of crystallization not specified. Crystallized from water. ' Melting point not quoted.

A

B B B C B

Ref. 29 60 60 60 60 60

~

tube)

ALJCYLATION. 3,4 - Dihydro- 1H-[1,4]oxazino[4,3 - a]benzimidazoles react readily with alkyl iodides at elevated temperatures under sealed-tube conditions, giving the corresponding 10-alkyl-3,4-dihydro-1H-[1,4]oxazino[4,3a]benzimidazolium iodides in unspecified yield (Table 7.58),6* The similar ethylation of fully unsaturated pyrimido[ 1,2-a]benzimidazoles using ethyl iodide or ethyl sulfate affords quaternary salts of undetermined structure. I 17,16* In accord with their N ( l)H tautomeric structures, pyrimido[ 1,2albenzimidazol-2( 1H)-ones are methylated by diazomethane'" or methyl iodide in the presence of potassium hydroxide'" or sodium hydride,I3' specifically at N(1) to afford the corresponding methyl derivatives in moderate to good yield (Table 7.59). The outcome of the base-catalyzed alkylation of tautomeric pyrimido[ 172-a]benzimidazol-4(10H)-ones, on the other hand, appears to be markedly dependent on the nature of the catalyst employed as base, Whereas reaction with methyl iodide-potassium hydroxide is rep~rted'~'to give the N(10)-methyl derivative in low yield (Table 7.59), the use of alkyl halides in conjunction with potassium carbonate is variously claimed to yield (Table 7.59) the N(l)-alkyl deri~ative'~'or a mixture of the latter and its N(l0)-alkyl isomer."' The attempted alkylationlU of pyrimido[3,4-a&enzimidazol-l,3(2H,4H)-dione is reported to afford intractable gums. In contrast, 3,4-dihydropyrimido[ 3,4- albenzimidazol1(2H)-one is readily alkylated under basic conditions, though in low yield, at N(2) [Scheme 7.84; (7.452) +(7.453)].'44 1,2,3,4-Tetrahydropyrazino[4,3-a]benzimidazole reacts at the NH substituent with alkyl halides in the presence of triethylamine to give moderate to good yields (Table 7.60) of 2alkyl- 1,2,3,4-tetrahydropyrazino[4,3-a]benzimidazole derivative^.'^^^‘^^ The methylation of 2-methyl-1,2,3,4-tetrahydropyrazino[4,3-a]benzimidazole

3-C02Et-4(1OH)-one

E

3-C02Et-4(10H)-one

3-C02Et-4(10H)-one

3-C02Et-4(10H)-one

2.4-Me23,4-dihydro-2(1H)-one

F

G

F

H I

+

Yield

+

I0-CH2Ph-3-CO,Et-4(10H)-one 1(10)-Et-2.4-Me2-.iodide' IO-(CH,),CO,H-3,4-dihydro-2(10H)-one -- -

-b

I -CH,Ph-3-C02Et-4(1H)-one

1O-(CH,),NMe,-3-CO2Et-4( 10H)-one

188-Iyo 254-25s 260-262

142-143 186-187

123-1 25 125-126

10-(CH2),CHMe,-3-C0,Et-4( 10H)-one 1-(CH,),NMe,-3-C0,Et-4( 1H)-one

+

134-136

-+

10-Pr"-3-C0,Et-4( lOH)-one 1 -(CH,)&HMe2-3-C0,Et-4(lH)-one

155- 158

160-161 158-161

+

1-Et-3-C02Et-4(1H)-one 10-Et-3-C02Et-4(1OH)-one 1-Pr"-3-C0,Et-4( 1H)-one

178-180 222-224 1 70-1 72 21 8-2 19 244 2 33-2 35

m.p. ("C)

172-175 211-213

47 22 70 36

(YO)

I O-Me-3-C02Et-4(10H)-one

1 -Me-2(1H)-one 1-Me-4-Ph-2(IH)-one 1-Me-4-CO2Me-2(1H)-one 2-Ph- 10-Me-4(10H)-one 3-C02Et-10-Me-4(10H)-one I -Me-3-C02Et-4(1H)-one

Product

Acetone Ethanol Water

Acetone Acetone

Acetone Acetone

Acetone Acetone

Acetone Acetone

Acetone Acetone

Methyl chloride-ether Chloroform Acetone

Ethyl acetate

-b

Solvent of crystallization

117 139

131

131

131

131

131

131

120 127 135 127 130

Ref.

A = CH,N,, ether, MeOH, dimethylformamide/(O0)(4.5hr); B = MeI, KOH, EtOH/(rwm tempJ(14 hr); C = NaH, toluene, dimethylformamide/(60"), then MeI/(room temp.)(l hr) and (60")(1 hr); D = MeI, K,CO,, dimethylformamide/(room temp.)(l hr); E = RI,K,CO,, dimethylformamide/(80")(72hr). F = RBr, K,CO,, dimethylformamide/(80")(72hr); G = Me,N(CH,),CI, K,CO,, dimethylformamide/(80°)(72 hr): H = EtI/(loo", sealed tube)(4hr); I = CH,==€HCO,H/(loo")(few min., then room temp.)(4hr). Solvent of crystallization not specified. Purified by chromatography. Yields not quoted. 'N(1) or N(1O) position for the Et group not established.

3-C02Et-4(1OH)-one

U F

2

3-C02Et-4(10H)-one

E

B

A

C B D

Substrate

Pyrimido[ 1,2-a]benzimidazole

2( lH)-one 4-Ph-2( 1H)-one 4-C02Me-2(1H)-one 2-Ph-4(10H)-one 3-C02Et-4(1OH)-one

Reaction conditions"

TABLE 7.59. ALKYLATION REACTIONS OF PYRIMIDO[ 1.2-a]BENZIMIDAZOLE DERIVATIVES

Condensed Benzimidazoles of Type 6-5-6

414

(7.452)

R

C N ? o (i) R(CH,),CI,

u

(7.453) Yield (TO)

m.p.

(Oc)

21

81-84

34

116-119

NaNH,, dioxane/reflux (time not specified) scheme 7.84

also takes place at the N(2) position affording the quaternary salt, 2,2dimethyl-1,2,3,4-tetrahydropyrazino[4,3-a]benzimidazolium iodide, in unspecified yield.‘49

ACYLATION. As also observed with 1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole (cf. section 7.1.3, “Reactions with Electrophiles”), the ben1,4]oxazino[4,3-a]benzimidazole results in zoylation of 3,4-dihydro- 1H-[ both ring-opening to 1-(2-benzamidophenyl)morpholin-2(1H)-one and acylation of the oxazine nucleus to give the enol benzoate [Scheme 7.85; (7.454)].42Analogy with the behavior of 7-amino-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole (cf. section 7.1.3, “Reactions with Electrophiles”) also TABLE 7.60. ALKYLATION REACTIONS OF 1,2.3,4-TETRAHYDROPYRAZINO[4,3-alBENZIMIDAZOLE DERIVATIVES 1,2.3,4-tetrahydropyrazin0[4,3-a] benzimidazole

Reaction conditions“ Substrate A

B

C D E F G

Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted Unsubstituted 2-Me

Product

Yield (X) m.p. (“C)

Solvent of crystallization

2-Me 2-Et 2-pr” 2-CH2CN 2-CH,Ph 2-p-MeOC,H,CH2 2,2-Me,, iodide

32 36 26 70 66 57 -

Acetonwther 149 Cyclohexane 150 Hexane 150 Acetone 150 Cyclohexane 150 Cyclohexane 150 -‘ 149

145-147 107-108 75.5-77 176-176.5 124-125 150-151 212-215 (dewmp.)

Ref.

” A = MeI, acetone/(reflux)(lOmin); B = EtBr. Et,N, acetone/(reflux)(138 hr); C = W B r ,

Et,N, acetone/(reflux)(l38 hr); D = NCCH&I (reflw)(48 hr); E = PhCH,Cl/(reflw)(31 hr); F = p-MeOC,H4CH,Cl/(reflux)(18 hr); G = Me1 (reaction conditions not specified). Yield not quoted. Solvent of crystallization not specified.

7.2. Fused Benzimidazoles with One Additional Heteroatom

Me

(7.454)

415

(7.455)

scheme 7.85

extends to the reaction of S-amino-3,4-dihydro- 1H-[ 1,4]oxazino[4,3-a]benzimidazole with ethyl 2-methylacetoacetate in the presence of ethyl polyphosphate to give the fused pyridinone derivative [Scheme 7.85; (7.455)].69The methylene substituent adjacent to the carbonyl group in 4H[1,3]thiazino[3,2-a]benzimidazol-4(3H)-one unlike that in 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-one(cf. Chapter 6, section 6.2.3, "Reactions with Electrophiles") is insufficiently reactive to undergo acylative condensation with aromatic aldehydes even under forcing In contrast, 1,4]thiazin0[4,3-a]benzimidazolthe C(3) methylene substituent in 1H-[ 4(3H)-one is reactive in this sense and condenses with aromatic aldehydes in hot glacial acetic acid to afford (albeit in low yieid) arylidene derivatives of the type [Scheme 7.86; (7.456)].'03 The related acylative condensation of 1H-[ 1,4]thiazino[4,3-a]benzimidazol-4(3H)-one with heterocyclic enarnines provides the basis for the synthesis of cyanine dyes containing a 123[1,4]thiazino[4,3-a]benzimidazol-4(3H)-one nucleus.""

(7.456) (rn.p. 217-218') §theme 7.86

The acylation of pyrimidor 1,2-a]benzimidazolone derivatives can take place at nitrogen, oxygen, or carbon, depending on the nature of the substrate and the type of acylating agent used. Acetylation of 3-ethoxycarbonylpyrimido[1,2-a]benzimidazol-4( 10H)-one in hot acetic anhydride takes place at nitrogen giving the N(10)-acetyl derivative in moderate yield (Table 7.61).13' On the other hand, the sodium ethoxide catalyzed p-nitrobenzoylation of pyrimido[ 1,2-a]benzimidazol-2,4(3H, lOH)-diones affords ' ~ ~C(2) p-nitrobenzproducts in 60-70°/0 yield (Table 7.6 1) f ~ r r n u l a t e d as oyloxy derivatives on the basis of their IR carbonyl absorption and ready

Condensed Benzimidazoles of Type 6-5-6

416

TABLE 7.61. ACYLATION REACTlONS OF PYRIMID~[~,~-Q]BENZIMIDAZOL4(10H)-ONES

Pyrimido[l,2a]benzimidazol-4(10H)-one Reaction conditions" Substrate Product A

Yield

Solvent of m.p. ("C) crystallization Ref.

(%)

3-C02Et-4(10H)-one 3-CO2Et-10-COMe- 52 4( 10H)-one 2-OH-10-Me2-p-02NC,H4C0,60-70 10-Me-4(lOH)-one 4( 10H)-one 2-OH-10-Et2-p-02NC,H4C0,60-70 10-Et-4(10H)-one 4(1OH)-one 2-OH-10-PI''2-p-O2NC&f4CO2- 60-70 10-Pr"-4(10H)-one 4(1OH)-one 2-OH- 10-Bu" 2-p-0,NC6H4C0,60-70 4( 10H)sne 10-Bun-4(10H)-one 2-OH-4( 10H)-one 3-(=cHNHPh)-2,4- 64 (3H, lOH)-dione

B

B B

-

B C

181 258-260

Toluene-light 130 petroleum Methanol 133

195-196

Methanol

133

177-178

Methanol

133

168-169

Methanol

133

-b

-

165

= Ac,O/(reflux)(2 hr); B = NaOEt, EtOH, then p-O,NC,H,COCI, PhNdHOEt, N-methylpyrrolidone/(heat)(fewmin.). Melting point not quoted. Solvent of crystallization not specified.

aA

c

benzene/(10O0)(2hr); C =

hydrolysis to the starting materials. In further contrast, pyrimido[ 1,241benzimidazol-2,4(3H, l0H)-dione is aminomethyleneated at the C(3) position in good yield (Table 7.61) by heating with ethyl isoformanilide in Nmethylpyrr~lidone.'~~ The N H substituents in 1-(pchloropheny1)- 1,2,3,4tetrahydropyrimido[3,4- a l b e n ~ i m i d a z o l e 'and ~ ~ 1,2,3,4,10, loa-hexahydropyrazin0[4,3-a]benzimidazole'~~react in orthodox fashion with isothiocyanates to give the corresponding thioureas [e.g., Scheme 7.87; (7.457) and (7.458)].

..

I C

(7.457) R Me (CH,),W

Ph

Yield (%)

m.p. ("C)

96

197-200 178-180 154-155

-

SH 'NHPh (7.458) (mp. 137")

7.2. Fused Benzimidazoles with One Additional Heteroatom

417

TABLE 7.62. CHLORINATION AND NITRATION REACTIONS OF 3.4-DIHYDRODERIVATIVES 1H-[~.~]OXAZIN~~,~-Q]BENZIMIDAZOLE Reaction conditions" A

B

c

D D

B

1.2,3,4-tetrahydro[1,4]oxazin44.3-a].benzimidazole Substrate

Product

7-NHZ-8-CF38-CF38-CI7-NHCOMe8-NHCOMe7-CI-8-CF3-

6-CI-7-NHz-8-CF37-NO2-8-CF37-NO2-8-CI7-NHCOMe-%NO,7-NOz-8-NHCOMe6-NOZ-7-Cl-8-CFX-

Yield (Oh)

90 92

-= 65 42 95

m.p. CC) 156-157 186-187 220 262 255 196-197.5

Solvent of crystallization

Ref.

154 154 -b 60 Ethanol 49 Ethanol 49 C h l o r o f o ~ 154 n -hexane -b -b

" A =S02C12, AcOH/(13")(15min); B =W%HNO,. conc. H,SO,/(O") then (room temp.)(2 hr); C = conc. HNO,, cow. H2SO,/O-5" (reaction time not specified); D = KNO,. COIIC. H,SO.J(O-S"), then (room temp.)(1 hr). Solvent of crystallization not specified. Yield not quoted.

ELECTROPHILIC SUBSTITUTION REACTIONS. With the exception of studies of the orthodox ~ h l o r i n a t i o n , ' ~n ~i t r a t i ~ n , ~ ~ , ~and ~ , "d~i a' ~z ~ t i z a t i o n ~ * * " ~ ~ ~ ~ reactions (Table 7.62) of 3,4-dihydro- 1H-[1,4Joxazino[4,3-aJbenzimidazoles, and the isolated report'z3 of the bromination of 2-methylpyrimido[1,2-a Jbenzimidazol-4(10H)-one to give the dibromo derivative [Scheme 7.88; (7.459)],the investigation of the susceptibility of tricyclic 6-5-6 fused benzimidazole ring systems with one additional heteroatom, to electrophilic substitution has been virtually neglected.

(7.459) (m.p. 300")

scheme 7.88

Reactions with Nucleophiles HYDROXYLATION AND RELATED REACTIONS. The 3,4-dihydro- 1H-[1,4]oxazin~4,3-aJbenzimidazole ring system is stable to acidic hydrolysis under conditions applicable to the conversion of acetamido derivatives into the corresponding amines [e.g., Scheme 7.89; (7.460;R' = NH2, R3 = NOz) and (7.460; R' = NO2, R2 = NH2)].08*49However, as in the case of 1,2,3,4-tetrahydropyrido[ 1,2-a]benzimidazole (d.section 7.1.3, "Reactions with Nucleophiles,"

Condensed Benzimidazoles of Type 6-5-6

418

R'

R'

(7.460)

N3 NO2

R2 NO2 NHZ CN NO, N3

m.p. (OC)

262 300 300

163 (decomp.) 145 (decomp.)

Scheme 7.40) coordination at the N(10) position destabilizes 3,4-dihydro1H-[1,4]oxazino[4,3-~lbe~dazole to hydrolytic attack, thus accounting for the ring-opening to 1-(2-benzamidophenyl)rnorpholin-2(lH)-one which occurs on treatment with benzoyl chloride in the presence of Acidic hydrolysis of the ester substituent in 4-amino-3-ethoxycarbonylpyrimido[ 1,2-a]benzimidazole is accompanied by hydrolytic removal of the amino group, the end-product obtained in good yield (Table 7.63) being pyrimido[ 1,2-a]benzimidazol-4( 1OH)-one-3-carboxylic acid.I2" The hydrolytic stability of the pyrimido[ 1,2-a]benzimidazol-4-one framework thereby demonstrated is further substantiated by its survival intact under both a ~ i d i c ' ~and ~ *alkalineI3' '~~ conditions suitable for the hydrolysis (Table 7.63) of C(3) cyano and ester derivatives of pyrimido[ 1,2-a]benzirnidazol4(1H and lOH)-ones to the corresponding carboxylic acids. However, the pyrimidinone ring in pyrimid~1,2-a]benzimidazol-4( 1H and lOH)-ones is cleaved under more forcing alkaline conditions giving benzimidazole derivatives. 123.130 The dihydropyrimidinone ring in 3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-ones is also susceptible to hydrolytic scission under alkaline condition^.'^' The parent pyrimido[ 1,2-a]benzimidazol-2( lH)-one ring system, on the other hand, is stable enough to allow the alkaline hydrolysis of ester to carboxyl substituents (Table 7.63),135and the conversion of pyrimido[ 1,2-a]benzimidazol-2( 1H)-one into pyrimido[ 1,2-a]benzimidazol-2(1H)-thione by heating with phosphorus pentasulfide in pyridine (Table 7.63).lZ0 1-Substituted 1,2,3,4-tetrahydropyrimido[3,4-a]benzimidazole derivatives are decomposed by acids and bases to aldehydes and 2 4 8 aminoethy1)benzimidazole in processes'43 corresponding to the reverse of their formation (cf. section 7.2.1, "Ring-closure Reactions of Benzimidazole Derivatives"). The pyrazino[4,3-a]benzimidazole and 1,2,3,4-tetrahydropyrazino[4,3a]benzimidazole ring systems are stable under acidic conditions, which effect the hydrolytic removal of a C(3) ethoxycarbonyl substituent in the former'47 and an N(2) acetyl group in the latter.149 The success of the sodium methoxide catalyzed Stevens rearrangement [Scheme 7.90; (7.461) + (7.462)]'"' also implies the relative stability of the 1,2,3,4-tetrahydropyrazino[4,3-a Jbenzimidazole ring system to basic solvolysis.

P

L

Product (%)

Yield

1-Me-3-C02Me-2(lH)-one 3-COZEt-4-NH23-C02Et-4(10H)-one 3-CN-4(10H)-one 3-C02Et-10-Me-4(10H)-one

l-Me-3-C02H-2(1H)-one -h 79 3-C02H-4(1OH)-one 3-C02H-4(10H)-one -b 3-C02H-4( 10H)-one -b 3-C02H-lO-Me-4(10H)- 74 one 3-C0,Et-10-Me-4( 10H)-one 3-C02H-10-Me-4(10H)59 one 1-Et-3-C0,Et-4( 1H)-one 1-Et-3-C02H-4(1H)-one 8 1 3-C02Et-10-Et-4(1OH)-one3-C02H-10-Et-4(10H)-one 79 2(1H)-one 2( 1H)-thione -b

Substrate

Pyrimido[l,2-a]benzimidazole

>300

252-253 228-230 310-313 (decomp.)

213-2 16

-

-

207 280-282

m.p. ("C)

Ref.

131 131 131 120

-c Dimethylformamide Dimethylformamide

Water 135 Dimethylformamide 120 130 120 Dimethylformamide 130

Solvent of crystallization

a A = 1 M NaOH/(room temp.)( 1.5 hr); B = dil. HCl/(reflux)(OShr); C = conc. HCl/(reflux)(2hr); D = KOH, EtOH/(room temp.)(l5 hr); E = P,S,, pyridine/(reflux)(l.5hr). Yield not quoted. Not crystallized.

E

D

D

D

C

B

C

A B

Reaction conditions"

TABLE 7.63. HYDROLYTIC AND RELATED REACTIONS OF PYRIMIDO[1,2-a]BENZIMIDAZOLE DERIVATIVES

420

Condensed Benzimidazolesof Type 6-5-6

(7.461)

CHzPh (7.462)

c1-

(i) NaOMe, MeOH/(20°)(40min)

(m.p. 116-117")

AMINATION. 4-Chloropyrimido[1,2-a]benzimidazoles,derived by the orthodox chlorination of pyrimido[ 1,2-a]benzimidazol-4( 1OH)-ones with phosphorus oxychloride," react with amines under mild conditions to afford moderate to good yields (Table 7.64) of 4-aminopyrimido[ 1,241benzimidazole derivatives.' ' 'Jl6 Pyrimido[ 1,2-a]benzimidazol-2( 1H)-thione is reported"' to react with ammonia in diethylene glycol dimethyl ether to give 2-aminopyrimido[l,2-a]benzimidazole,though in unspecified yield. The aminolysis of ester substituents in pyrimido[ 1,2-a]benzimidazol4( l O H ) - ~ n e s ' ~ and ' pyrimido[ 1,2-a]benzimidazol-2( 1H)-0nes'~' proceeds readily to give good yields (Table 7.64) of the corresponding amides. In the reactions of ester substituted pyrimido[ 1,2-a]benzimidazol-2( 123)-ones with amines at elevated temperatures, amide formation is accompanied by addition of the amine across the C(3)-C(4) double bond (Table 7.64).13' 3,4Dihydropynmido[ 1,2-a]benzimidazol-2( lH)-one carboxylic esters can also be converted into amides on brief treatment with amines under mild conditions (Table 7.64).13' However, on prolonged treatment aminolytic scission of the N ( 1)-C(2) bond tends to occur with ring-opening to benzimidazole derivatives. 13' 3,4-DihydropyrimidoC3,4-a]benzimidazol1(2H)-thione is also ringopened at the C(l)-N(2) bond by reaction with amines or hydrazine giving the corresponding N-[2-(2-benzimidazolyl)ethyl]thiourea and thiosemicarbazide derivatives, re~pectively.'~~ Treatment of pyrazino[4,3-a]benzimidazol-3,4-( 1H,2H)-diones with amines, even under mild conditions, results in cleavage of the pyrazinedione ring giving benzimidazole derivatives.' " MISCELLANEOUS REACTIONS. The formally nucleophilic displacement of diazonium substituents in 3,4-dihydro- 1H-oxazino[4,3-a]benzimidazoles under the conditions of the Sandmeyer reaction6' and by reaction with azide iOn48.49 provides synthetic access to chloro- and azido-substituted 3,4dihydro-l H-[ 1,4]oxazino[4,3-a&enzimidazole derivatives (cf. Scheme 7.89). Oxidation Information on the susceptibility of tricyclic 6-5-6 fused benzimidazole structures with one additional heteroatom to oxidation is in general terms

C

2-Me-4(10H)-one 2( 1H)-thione 1-Me-4-C02Me-2(1H)-one

1-Me-4-C02Me-2(lH)-one

1-Me-3-CO2Et-4(lH)-one 1-Et-3-C02Et-4(lH)-one 1-CH2Ph-3-CO,Et-4(1H)-one 1-Me-3-C02Et-4(1H)-one 1-Et-3-C02Et-4(1H)-one 1-Pr"-3-C02Et-4(lH)-one 1-CH2Ph-3-CO,Et-4(1H)-one 1-Et-3-C02Et-4(1H)-one 3-C02Et-10-Me-4(10H)-one 3-C02Et-10-Et-4(10H)-one 3-CO2Et-lO-CH,Ph-4(10H)-one 3-CO,Et- 10-Me-4(10H)-one

F

G

I

J J J

K

L L L

K K K K K

H

2-Me-4-N-0

2-Me-4-C1-

E

96

-c

95

40

50

75 53

60

16

60 45 45 10

Yield (To)

1-Me-3-NHMe-4-CONHMe-3,4-dihydro52 2( lH)-one 65 l-Me-3-CONHMe-4(lH)-one 1-Et-3-CONHMe-4(lH)-one 88 71 1-CH2Ph-3-CONHMe-4(1H)-one 1-Me-3-CONHBun-4(1H)-one 88 l-Et-3-CONHBu"-4(1H)-one 76 1-Pf-3-C0NHBun-4(1H)-one 81 75 1-CH2Ph-3-CONHBu"-4( 1H)-one l-Et-3-CONHCH(Me)Et-4(lH)-one 85 3-CONHMe-10-Me-4(10H)-one 68 3-CONHMe-lO-Et-4(10H)-one 63 70 3-CONHMe-10-CH2Ph-4(10H)-one 3-CONHBu"-lO-Me-4(10H)-one 81

2-Me-4-p-MeC6H,NH2-NHZ1-Me-4-CONHMe-2(1H)-one

U

2-Me-4-N

h)

2-Me-4-CI-

D

3

2-Me-4-NH(CH2),0H2-Me-4-NEt,-

2-Me-4-CI2-Me-4-CI-

- c

P

2-Me-4-NH(CH2),N

2-Me-4-0

C

3

2-Me-4-NH(CH,),NEt2-8-CI-

2-Me-4.8-CI2-

B

A A A

2-Me-4-NH(CH2),NMe,2-Me-4-NH(CH2),NEt,2-Me-4-NH(CH2),NEt,2-Me-4-NH(CH2),NEt,-7-CI-

Product

2-Me-4-C12-Me-4-C12-Me-4-Cl2-Me-4.7-0,-

PyrimidoE 1,2-a]benzimidazole Reaction conditionsa Substrate

TABLE 7.64. AMINATION REACTIONS OF PYRIMIDOE1.2-alBENZIMIDAZOLE DERIVATIVES Solvent of crystallization

166

166

166 166

166

111

111 111 111

Ref.

325-326 Diineth ylformamide 131 270-272 Dimeth y lformamide 131 280-283 Dirneth ylformamide 131 266-267 Dimethylformamide 131 232-234 Dimethylformamide 131 219-221 Dimethylformamide 131 242-243 Dimethylformamide 131 260-261 Dimethylforrnamide 131 180-182 Dimethylforrnamide 131 131 178-180 Acetone 165-167 Dimeth ylformamide 131 175-177 Ethyl acetate 131

166 120 302-303 Dimethylformamide- 135 ether 135 148-149' Methanol

-

Amy1 acetate

-b

Ethanol Light petroleum

Benzene

3 12-3 13 Dimethylformamide

-d

248

188-189

260-262 107-108

155

209-21 1 Ethyl acetate

198-200 Ethyl acetate 100-102 n-Heptane 180-181 Ethyl acetate 158- 160 Ethanol-water

m.p. ("C)

(Conrinued)

3-C02H-10-Et-4(10H)-one

3-C02H-10-Et-4(10H)-one

M

M

3-CO2H-1O-CH,Ph-4(10H)-one

M N

65

68

1-Me-3-CONH(CH2),NMe2-3,4-dihydro-82 2( 1H)-one

LJ

n 3-CON 0-lO-CH,Ph- 4(lOH)-one

3-CONHPh- lO-Et-4(10H)-one

U

NMe-lO-Et-4(1OH)-one

n

3-CON

73

76

A 3-CON O-lO-Et-4(1OIf)-one

u

70

-

63

3 - C O N 3 1O-Et-4(10H)-one

d

3 - C O P N M e -lO-Me-qlOH)-one

72

74 69 77 68 71

Yield

(Yo)

206-207

203-205

241-242

180-182

200-202

145-147

288-290

188-1 90

118-120 211-212 112-1 13 108-1 10 80-82

m.p. ("C) acetate acetate acetate acetate acetate

Methylene chlorideether

Dimethylforrnamide

Ethyl acetate

Ethyl acetate

Ethyl acetate

Ethyl acetate

Dimethylformamide-water Ethyl acetate

Ethyl Ethyl Ethyl Ethyl Ethyl

Solvent of crystallization

135

131

131

131

131

131

131

131

131 131 131 131 131

Ref.

a A = amine, CHCIJroom temp.)(21hr); B = Et,N(CH,),NH,, CHCl,/(roorn temp.)(3 days); C = amine, EtOH/(reflux)(2-3hr); D = Et,NH, Pr"OH/(60")(4hr); E = Morpholine, Bu"OH/(1000)(2hr); F = POCl,/(reflux)(l hr), then p-MeC,H,NH,l(reflux)(l.S hr); G = NH,. diethylene glycol dimethyl ether/(120")(3hr); H = MeNH,, CH,Cl,/(-2O0)(l hr); I = MeNH,, CH,Cl,/(mm temp.)(l hr); J = MeNH,, BunOH/(120", autoclave)(l2hr); K = amine/(reflw)(12hr); L = M e w , EtOH/(lOO", autoclave)(l2hr); M = SOCl,/(reflux) (reaction time not specified), then amine, tolueoe/(room tempJ(6 hr); N = Me,N(CH,),NH,/(room tempJ(l.5 hr). Not crystallized. ' Yield not quoted. Melting point not quoted. Solvent of crystallization not specified. Remelts at 250".

1-Me-3-C02Me-3,4-dihydro-2( lH)-one

3-C02H-10-Et-4(10H)-one

M

3-C02H-10-Et-4(10H)-one

3-C02H-10-Me-4(10H)-one

M

U

3-C02H-10-Me-4(1OH)-one

M

n O-lO-Me-4(10H)-one

3-CONHBun-10-Et-4(1OH)-one 3-CONHBu"-lO-PP-4(10H)-one 10H)-one 3-CO2Et-1O-(CH,),NM~-4(10H)-one3-C0NHBu"- 10-(CH2),NM~-4( 3-CONHCH(Me)Et-10-Et-4(10H)-one 3-C02Et- 10-Et-4(10H)-one 3-CONH(CH2),NMe,- 10-Et-4(10H)-one 3-C02Et- 10-Et-4(10H)-one 3-CON

3-C02Et-10-Et-4(10H)-one 3-CO2Et-10-PP-4(10H)-one

Product

K K K K K

Pyrimidd 1.2-a ]benzimidazole Reaction conditions" Substrate

TABLE 7.64

lacking. However, the relative stability of the 3,4-dihydro- 1H-[ 1,410xazino[4,3-a)benzimidazole ring system to oxidation may be inferred from the dehydrogenation of 3,4,4a&tetrahydro- lH-[l,4~xazin~4,3-~~enzi1nidazole to 3,4-dihydro- 1H-[ 1,4]oxazino[4,3-albenzimidazoleby a variety of oxidizing agents.'* The relative stability of the 172,3,4-tetrahydropyrazino[4,3-a]benzimidazole ring system to oxidizing conditions is also indicated by the successful formation of its derivatives by palladium-charcoal-mediated dehydrogenation of 1,2,3,4,10,10a-hexahydropyrazino[4,3-a]benzimida~oles.''~ 1,410XAZINO TABLE 7.65. CATALYTIC REDUCTION OF 3,4-DIHYDRO-1H-[ [4,3-a]BENZIMIDAZOLE DERIVATIVES Reaction conditions" A

B C

D D D D D

D

D D D D D D D D D

D D

D D D

D D D D D

1,2,3,4-Tetrahydro[1,4Joxazin~4,3-a]benzimidazole Substrate

Product

m.p.("C)

Ref.

7-NO2-8-CF37-N02-8-CI6-N02-7-CI-8-CF3&Me-, N-oxide 8-F"-, N-oxide l-Me-8-Pr'-, N-oxide 3-Me-8-Pr'-, N-oxide 8-Bu'-. N-oxide 8-CF3-,N-oxide 1-Me-8-CF3-, N-oxide 3-Me-8-CF,-, N-oxide 1,3-Me,-8-CF3-,N-oxide' 1,3-Me2-8-CF3-.N-oxide* 4,4-Me2-8-CF,-, N-oxide 1-Et-8-CF3-,N-oxide 3-Et-8-CF3-,N-oxide 4-Et-8-CF,-, N-oxide 8-C1-, N-oxide 8-F-, N-oxide 8-S02Me-,N-oxide 7,8-Me2-,N-oxide 7-CI-8-Me-, N-oxide 7-Cl-8-CF3-,N-oxide 7-OMe-8-CF3-,N-oxide 7-CN-8-CF3-,N-oxide 7,8-C12-,N-oxide 7-CI-8-SO2Me-,N-oxide 7-OMe-8-S02Me-,N-oxide

7-NH,-8-CF,-b 7-NH2-8-C16-NH,-7-C1-8-CF,-d 8-Me8-Pr'l-Me-8-F"3-Me-8-F"8-Bu'8-CF3-' 1-Me-8-CF33-Me-8-CF31,3-Mq-8-CF3-' 1,3-Me2-8-CF,-* 4,4-Me,-8-CF3l-Et-8-CF33-Et-8-CF34-Et-8-CF38-C18-F8-S02Me7,8-Me27-CI-&Me7-CI-8-CF37-OMe-8-CF37-CN-8-CF37,8-C1,7-C1-8-S02Me7-OMe-8-S02Me-

204-205' 264 2 12-2 12.5 165-168 95-97.5 91-93 148-150 127-1 30 129-131 114-1 16 155-156 83-85 95-98 82-84 133-134 122-123 108-109 180-185 126-128 214-215 187.5-188.5 191-193 160-161 118-120 188-190 187-189.5 219-221 209-2 12

154 60 154 154 154 154 154 154 155 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154

" A = H,, 10°/~ PdC, MeOH, ethylene glycol monomethyl etherlroom temp., atm. press; B = H,, Raney Ni, ethylene glycol monomethyl etherlroom temp., atm. press; C = H,, PtO,, MeOH, dimethoxyethane/room temp., atm. press; D = H,, PtO,, MeOH/room temp., atm. press. Yield 97%. ' Yield 88%. Crystallized from chloroform. f Cis isomer. Yield 92%. Trans isomer.

423

5 P

I +

CH20H-3,4-dihydro1(1H)-one

1-(CH,),NM+-4-

-+

1-Me-4-CH20H-3,4dihydro-2(1H)-one 1-(cH,),NM%-4CH,OH-2(1 H)-one

2-Me1-Me-4-C02Me-3,4dihydro-2(lH)-one 1-(CH2),NMe2-4Me-2( lH)-one 1-Me-4-CH20H2(1H)-one

-b

152-154

197-198

b

194-197

28

Methylene chloride-ether

Ethyl acetate

}

} Methanol-et her

287-288

54

Methanol-ether

Methanol-ether

b

152-154

Ethanol Methanol

Solvent of crystallization

-

ec,

230-232 177-179

m.p.

49 94

(YO)

Yield

135

135

135

111 135

Ref.

A =H2, 5% PdC, NaOAc, EtOWrmm temp., am. press; B = H,, PtO,, MeOH/room temp., atm. press; C =H,, PtO,, tartaric acid, H20/(room temp., atm. pressJ(7 hr); D = NaBH,, MeOH/(room temp.)(30 min). Yield not quoted.

D

4-C02Me-2(lH)-one

1-Me-4-C02Me2(1H)-one

D

C

1-(CH,),NM%-

2-Me-4-Cll-Me4-CO2Me2( lH)-one l-(CHd,NMe,4-CH20H-2(IH)-one

B

A

Pyrimido[l,2-a]benzimidazde Reaction conditions" Substrate Product

TABLE 7.66. REDUCllON OF PYRIMI~l.2-alBENZIMIDAZOLEDERIVATIVES

E

P

bromide

2-Me-2-CH,Ph-1,2,3,4-tetrahydro-, 2-Me-1,2,3,4-tetrahydro-'

2-(CHz),NHz-1,2,3,4-tetrahydro-'

1,2,3,4-tetrahydro-

2-CH,Ph-1,2,3,4-tetrhydro-

1,2,3,4-tetrahydro-

2-CH2Ph-1,2,3,4,10,10a-hexahydro-

2-CH2Ph-3,4-dihydro-1(2H)-one

3,4-dihydro-l(2H)-one 2-CH2Ph-3,4-dihydro-1(2H)-one 2-CH2Ph-3,4-dihydro-1(2H)-one 2-CH2CN-1,2,3,4-tetrahydro-

2-Bu"-8-NH2-1,2,3,4-tetrahydro-

l-CO2Et-3-Ph-1.2.3.4-tetrahydro1,2,3,4-tetrahydro-

1-CO,Et-3-Ph-

92

62 60 76 88 40

97 77

55

Yield (%)

2-CHZPh-1,2,3,4-tetrahydro-* 2-Bun-8-N0,-1,2,3,4-tetrahydro-

Product

Substrate

Pyrazino[4,3-a]benzimidazole

82-88 130-132 124-125 130-132 256 (decamp.) 243-245

194-196 130-132 122-124

~

-c

-c

~~~

Benzene Cyclohexane Benzene

-d

Ether-light petroleum (b.p. 30-60")

Ethyl acetate

-'

Solvent of m.p. (T) crystallization

149

150 150 150 150 150

147 150 26

Ref.

-

Raney Ni, EtOH/(70°, 100 atm.)(lO hr); B = H,, 10% PdC, EtOH/(5O0, 50 psi)(7 hr); C = H,, PtO,, EtOH/room temp. atm. press; D = LiAIH,, ether/(reflux)(60hr); E = LiAIH,, tetrahydrofurane/(reflux)(68-70 hr), then 10% PdC, EtOH/(room temp.)(l7 hr); F a LiAIH,, tetrahydrofurane/(reflux)(60 hr), then 1056 PdC, EtOH/(12 hr), then H2.10% PdC, HCl/(55", 5 8 psi)(7 hr); G = LiAIH,, tetrahydrofurane/(reflux)(72 hr), then 10% PdC/(room temp.)(20min), then HCI; H=H,, 10% PdC, MeOH/room temp., a m . press. Hydrochloride. Solvent of crystallization not specified. Unstable. ' Trihydrochloride. Dihydrobromide; free base has m.p. 146-147" (from aceton-ther).

a

A = H,,

H

G

E E F

D

C

A B

Reaction conditions"

TABLE 7.67. REDUCTION OF PYRAZINq4,3-a]BENZIMIDAZOLEDERIVATIVES

426

Condensed Benzimidazoles of Type 6-5-6

Red ucrion Nitr0,6".'~~ and N - ~ x i d e ' ~ ~ substituents .'~~ in 3P-dihydro-lH[ 1,4]oxazin0[4,3-a~enzimidazoles can be reduced catalytically (Table 7.65) without affecting the ring system. The fully unsaturated pyrimido[ 1,2-a]benzimidazole ring system is likewise stable to catalytic reduction under conditions that accomplish the hydrogenolytic removal of a C(4)-chloro substituent (Table 7.66)." ' In contrast, the sodium borohydride reduction of C(4)-methoxycarbonyl substituents in pyrimido[ 1,2-a]benzimidazol-2( 1H)ones is accompanied by reduction of the C(3)-C(4) double bond, but not the lactam carbonyl substituent, giving good yields (Table 7.66) of 3,4dihydropyrimido[1,2-a]benzimidazol-2( 1H)-one derivative^.'^^ The reduction of the C(3)-C(4) double bond in pyrimido[ 1,2-a]benzimidazol-2( 1H)ones can also be achieved catalytically (Table 7.66).13' The Raney nickel catalyzed h y d r ~ g e n a t i o n ' ~of~ l-ethoxycarbonyl-2phenylpyrazino[4,3-a]benzimidazole at elevated temperature and pressure to give the corresponding 1,2,3,4-tetrahydro derivative in moderate yield (Table 7.67) is indicative of the resistance of the 1,2,3,4-tetrahydropyrazino[4,3-a]benzimidazole ring system to reduction of this type. This stability also extends to hydrogenation over platinum and palladium catalysts under conditions (Table 7.67) suitable for the reduction of nitro to amino groupsz6 and for the hydrogenolysis of N(2)-benzyl s u b s t i t ~ e n t s . ' ~In ~ *the ' ~ ~lithium aluminum hydride reduction of 3,4-dihydropyrazino[4,3-a]benzimidazol1(2H)-ones (Table 7.67), on the other hand, reductive removal of the carbonyl substituent is accompanied by hydrogenation of the azomethine double bond giving unstable 1,2,3,4,10,10a-hexahydropyrazin0[4,3-a]benzi m i d a z ~ l e s . ' These ~~ can be isolated or dehydrogenated in siru with palladium charcoal giving the corresponding 1,2,3,4-tetrahydropyrazino[4,3a]benzimidazole derivatives (Table 7.67).'" 7.2.4. Practical Applications

Biological Properties 1-Phenyl-3,4-dihydro- 1H-[ 1,4~xazino[4,3-albenzimidazolehas been reto afford protection against polio virus. Other 3,4-dihydro- 1H[ 1,4]oxazino[4,3-a]benzimidazole derivatives have been patented'" as herbicides. 3-Hydroxy-3,4-dihydro-2H-[ 1,3]thiazino[3,2-a]benzimidazole is useful in the treatment of pulmonary asthma" and has also attracted attention because of its antiviral action.y6s9R The antiviral properties of tetrahydropyrimido[ 1,2-a]benzimidazole derivatives have also been r e p ~ r t e d . ' ~ ~1-Alkoxycarbonyl*'~~ 1,2,3,4-tetrahydropyrimido[1,2-~]benzimidazoles'~~ and pyrimido[ 1,2-a]benzimidazole-

7.3. Fused Benzimidazoleswith Two Additional Heteroatoms

427

2,4(1H , 3 H ) - d i o n e ~ ’ ~ are * . ~associated ~~ with pesticidal and fungicidal properties. Pyrimido[ 1,2-a]benzimidazo1-4( 1H)-ones have been patented”’ as central nervous system depressants and as psychotropic and antiinflammatory agents.

Dyestuffs The 3,4-dihydro- 1H-r 1,4]oxazino[4,3-a]benzimidazole,6° 3,4-dihydro1H- [1,4]thiazin0[4,3-a]benzimidazole,~~~ and pyrimidor 1,2 -a]benzimida ~ o l e ” ~ ring * ’ ~ systems ~ have been employed as chromophoric units in cyanine dyes. PyrimidoE1,2-a]benzimidazole derivatives have also found use as azo and as photographic emulsion stabilizer^.'^"

7.3. TRICYCLIC 6-5-6 FUSED BENZIMIDAZOLES WITH TWO ADDITIONAL HETJ3ROATOMS Only fully nitrogen-containing structures (Scheme 7.9 1 and Table 7.68) having a tricyclic 6-5-6 fused benzimidazole framework with two additional heteroatoms appear to be known. These include the fully unsaturated 1,2,4triazino[2,3-a]benzimidazole (7.463), 1,2,4-triazino[4,5-a]benzimidazole (7.467). and 1,3,5-triazino[ 1,2-aJbenzimidazole (7.470A) ring systems and derived di- and tetrahydro- structures (cf. Scheme 7.91 and Table 7.68). The

R (7.464)

(7.463)

a-4 N-l

(7.465)

R (7.466B)

*me

7.91

(7.4660

R

n 9p A + / R

9

< 4 N 3

7 \ 6

S

4

6

(7.467)

5

4

(7.468A)

(7.470A)

(7.470B)

(7.470C)

(7.470D)

R

R

TABLE 7.68 TRICYCLIC 6-5-6 FUSED BENZIMIDAZOLE RING SYSTEMS WITH TWO ADDITIONAL HETEROATOMS Structure"

Nameb

(7.463) (7.464) (7.465) (7.466A) (7.4668) (7.4660 (7.467) (7.468A) (7.468B) (7.469) (7A7OA) (7.470B) (7.47oc) (7.470D)

1,2,4-TriazinN2,3-a]benzirnidazole 3.4-Dihydro-1,2,4-triazino[2,3-a~emimidazole 1,2,4-Triazino[4,3-a]enzimidazole 1,4-Dihydro-1,2,4-triazino[4,3-a]benzimimidazoIe 4,10-Dihydro-l,2,4-triazin~4,3-a]enzimimidazole 1,2,3,4-Tetrahydro-l,2,4triazino[4,3-a]benzimidazole 1,2,4-Triazino[4,5-a]benzimidazole 1,2-Dihydro-1,2,4-triaziono[4,5-a]benzimidazole 3,4-Dihydro-1,2,4-triazino[4,5-a]benzimidazole 1,2,4-Tnazind1,6-a]benzimidazole 1,3,5-Triazino[ 1,2-a]benzimidazole 1,2-Dihydro-1,3,5-triazino[l,2-a]benzimidazole

3,4-Dihydro-l,3,5-triazino[l,2-a]benzimidazole

1,2,3,4-Tetrahydro-1,3,5-triazino[1,2-albenzimidazole

" Cf. Scheme 7.91.

Based on the Ring Index.

428

7.3. Fused Benzirnidazoles with Two Additional Heteroatorns

429

1,2,4-triazino[4,3-a]benzimidazoleframework, as yet unknown in the fully unsaturated form (7.465) is represented by the 1,4-dihydro- and 4,lOdihydro- 1,2,4-triazino(4,3-a]benzimidazole ring systems (7.466A) and (7.466B) and by the 1,2,3,4-tetrahydro-l,2,4-triazino[4,3-a~enzimidazole ring system ( 7 . m ) . A search of the literature has failed to reveal any compound having a structure based on the 1,2,4-triazin~1,6-afienzimidazole skeleton (7.469). Of the 12 known ring systems (Scheme 7.91 and Table 7.68) to be dealt with under the present heading those having a 1,3,5-triazino structure [Scheme 7.91 ; (7.47OA)-(7.47OD)Jhave been most extensively investigated. The chemistry of 1,3,5-triazino[l,2-a]benzimidazoleswas briefly reviewed in 1961.17’ 7.3.1. Synthesis

Ring -closure Reactions of Benzimidazole Derivatives The condensation of the readily available 1,2-diarninobenzimidazole with a-diketones provides a simple, and potentially general method for the synthesis of alkyl and aryl derivatives of the fully unsaturated lY2,4-triazino[2,3-albenzimidazole ring system [Scheme 7.92; (7.471)+ (7.472)4(7.474; R = alkyl or ary1)].’72Ring-closure of this type proceeds in high yield (Table 7.69) and is usually effected by simply heating the reactants together in alcoholic solvents. However, condensation fails’72” in the case of benzil unless potassium hydroxide is present as The uncatalyzed condensation of 1,2-diaminobenzirnidazole (7.471) with a-keto acids (7.473) is

(7.471)

I

H (7.475)

(7.474) Scheme 7 9 2

Condensed Benzimidazoles of Type 6-5-6

430

TABLE 7.69. SYNTHESIS OF 1.2.4-TRIAZINO[2.3-a]BENZIMIDAZOLES(7.474) AND (7.475) BY RING-CLOSURE OF 1.2-DIAMINOBENZIMIDAZOLE (7.471) WITH a-DICARBONYL COMPOUNDSa Starting materials (7.471)

+

i

(7.472; R=Me) (7.471)

+

(7.472; R = Ph) (7.471)

+

(7.473; R = Me) (7.471)

+

(7.473; R = Ph)

Reaction conditionsb Product

Yield m.p. (Yo) (“C)

Solvent of crystallization

Ref.

A

(7.474; R=Me) 58

236-239

Ethanol

172a

B

(7.474; R=Ph) 94

278-281

-‘

172b

C

(7.475; R = Me) 72

350-355

Dimethylformamide

172a

(7.475; R = Ph)

355-358

Dimethylformamide-water

172a

68

“From Ref. 172. A = MeOH(reflux)(2hr); B = 2M KOH, EtOH/(reRux)(30 min); C = EtOH/(reflux)(2hr). Not crystallized.

reported”2a to afford the corresponding 1,2,4-triazin0[2,3-a]benzimidazol2(1H)-ones (7.475) in good yield (Table 7.69). However, the orientation of these products was not rigorously established, but if correct, is consistent with preferential initial condensation between the more nucleophilic N(1)amino group in 1,2-diaminobenzimidazole and the more electrophilic keto center in the a-keto acid. Syntheses of ring systems containing a 1,2,4-triazino[4,3-a]benzimidazole skeleton (Scheme 7.93 and Table 7.70) are largely based on ring-closure reactions of 2-hydrazinobenzimidazole derivatives. In particular, the triethylamine catalyzed reaction (Scheme 7.93) of 2-hydrazinobenzimidazoles (7.477) with a-bromoketones affords, via presumed hydrazone intermediates (7.476), moderate yields (Table 7.70) of 1,Cdihydro- 1,2,4triazino[4,3-a]benzimidazole derivatives (7.479).’73 Alternative synthetic access (Scheme 7.93) to molecules of the latter type is provided by the reaction of l-(~-oxoalkyl)-2-chlorobenzimidazoles (7.482) with hyd~ a 2 i n e . lThe ~ ~ deceptively simple acylative cyclization of a-keto acid or ester 2-benzimidazolylhydrazones to 1,2,4-triazino[4,3-a]benzimidazol4(10H)-ones [e.g., Scheme 7.93; (7.478)--,(7.480)] is difficult to accomplish in practice. Thus, the cyclization (Scheme 7.93) of a-keto acid 2-benzimidazolylhydrazones (7.478; C02H for C02Me) (prepared in sitw from 2hydrazinobenzimidazole and a-keto acids) though giving 1,2,4-triazino[4,3a]benzimidazol-4( IOW-ones (7.480) in high yield (Table 7.70) requires Nor can cyclization of extreme conditions of temperature and pres~ure.”~ the preformed hydrazone be effectively achieved under milder conditions, as

a

i

43 1

Condensed Benzimidazoles of Type 6-5-6

432

TABLE 7.70. SYNTHESIS OF 1,2.4-TRIAZINq4,3-a]BENZIMIDAZOLES BY RINGCLOSURE REACllONS OF BENZIMIDAZOLE DERIVATIVES Yield

(%I

m.p. ("C)

Solvent of crystallization

(7.479; R = H,

43

293-295

(7.479; R = H , R' = P-OZNC~HJ (7.479; R = Me, R' = p-CIC6H4) (7.480; R=Me) (7.480; R=Ph) (7.480;

51

298-299

45

309-310

Dimethylformamide-water Dimethylformamide-water Dimethylformamide-water

Starting material

Reaction conditions" Product

(7.477; R = H)

A

(7.477; R = H )

A

(7.477; R = Me)

A

(7.477; R = H) (7.477; R = H ) (7.478; R = CH2C02Me) (7.477; R = H)

B B

C

D

(7.482; R = RZ= H, E R' = OEt) (7.483) F (7.484) G

R' = Me)

66-85 -b 66-85 -b 23 286

-c

(7.481)

-*

287-288

(7.481)

84

-

-c Dimethylformamide-water Dimethylformamide-water -

(7.481) (7.485)

84 76

-

-

R = CH,CO,Me)

223-225

(decornp.)

Methanol

Ref.

173 173 173 175 175 176 177 177 177 179

Et,N, EtOH or dimethylformamide/reflux (reaction time not specified); B = RCOCO,H(l 50°, autoclave)(5hr); C = Et,N, MeOH/(reflux)(Z.S hr); D = CICH,CO,Et (reaction conditions not specified); E = N2H4, Et,N or pyridine, dimethylformamide/150-160°(reaction time not specified); F = Et,N or pyridine, dimethylformamide/heat (reaction conditions not specified); G = 85%N2H4/150-1600,sealed tube (reaction time not specified). Melting point not quoted. Solvent of crystallization not specified. * Yield not quoted.

" A = RICOCH,Br,

demonstrated by the low yield (23%) ~ b t a i n e d ' ~ in " the triethylamine catalyzed cyclization (Table 7.70) of the keto ester hydrazone (7.478; R = CH,CO,Me) to the 1,2,4-triazino[4,3-a]benzimidazol-4(10H)-one derivative (7.480; R = CH2C02Me). The condensation (Scheme 7.93) of 2hydrazinobenzimidazole (7.477; R = H) with ethyl chloroacetate affords a routeI7' to 1,4-dihydro- 1,2,4-triazin44,3- a]benzimidazol-3(2H)-one (7.481). This product is also formed (Scheme 7.93) in high yield (Table 7.70), via the presumed intermediacy of the hydrazide (7.483), by the reaction of l-(ethoxycarbonylmethyl)-2-chlorobenzimidazole(7.482; R = R2 = H, R' = OEt) with h ~ d r a 2 i n e . IThe ~ ~ related reaction (Scheme 7.94) of l-(2-chloroethyl)-2-chlorobenzimidazole (7.484) with hydrazine at high temperature and pressure affords 1,2,3,4-tetrahydro- 1,2,4-triazino[4,3-a]benzimidazole (7.485) in good yield (Table 7.70).17* Alkyl and aryl derivatives of the fully unsaturated 1,2,4-triazino[4,5-a]benzimidazole ring system are generally accessible in good yield (Table 7.7 1) by the thermal ring-closure of readily available 2-benzimidazolylketone hydrazones with orthoesters [Scheme 7.95; (7.488; R = R2 = H)+ +

7.3. Fused Benzimidazoles with Two Additional Heteroatoms

(7.484)

433

H scheme 7.94

(7.485)

(7.489)].'7y The imidic ester intermediates in these reactions can be isolated in some instances and cyclize as expected on heating (Table 7.7 1) to give the corresponding 1,2,4-triazino[4,5-a]benzimidazolederivatives [Scheme 7.95; (7.487)- (7.489)].17' Arylhydrazones (7.488; R = H, R' = CN, R2 = aryl), derived by the coupling of arenediazonium salts with Z-cyanomethylbenzimidazole (7.486; R = H, R' = CN), undergo acylative cyclization on heating with ethyl chloroformate in pyridine to afford 1,2,4-triazino[4,3-a]benzimidazol- 1(2H)-ones (7.490; R' = CN, R2= aryl) in excellent yield

R'

I

(7.487)

(7.488)

R2 A N R'

(7.489)

R'

R'

scheme 7.95

(7.490)

P

$

E

(7.486; R = C02Et, R' = CN) (7.488; R = H, R' = CN. R2 = Ph) (7.486; R = C02Et, R' = CN) (7.488;R = H, R' = CN, R2 = p-MeOC,H,)

E

F

R2= p-MeOC,H,)

= CN.R2= p-MeOC,H,)

= CN,

= CN, R2 = Ph) = CN, R2 = Ph)

(7.490; (7.490; (7.490; (7.490;

D D

(7.491; R = H) (7.491; R = Et)

R' R' R' R'

(7.492) (7.493)

C

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

F

(7.489; R' = Ph. R2 = Me)

B

(7.489; R' = Ph, R2 = H)b (7.489; R' = H, R2 = Me)

(7.489; R' = R2= H)

Product

A

A

Reaction conditions"

(7.488; R = R2 = H, R' = Ph) (7.487; R' = H, R2= Me)

(7.488; R = R * = R 2 = H )

~-

Starting material

es

200-201 %

220-221

-

95 96 97

50 3

170-172 (decomp.) 154-155 224-225

(decamp.)

235-236 (decomp.) 205-206 162

m.p.

42

80

-c

65

(yo)

Yield

-

Ethanol

-

Ethanol Dimethyl sulfoxideethanol Ethanol

Ethanol

Benzene Ethanol

Ethanol

Solvent of crystatiization

BY RING-CLOSURE REACTIONS OF BENZIMIDAZOLE TABLE 7.71. SYNTHESIS OF ~,~,~-TRIAZIN~[~,~-U)BENZIMIDAZOLES DERIVATIVES

180 180 1 80 1 80

7 7

179

179 179

179

Ref.

VI

W

P

(7.495; R' = H, R2 = Me) (7.495; R' = H, R Z =Me) (7.495; R' = NO,, R2 = H)

C

H

(7.494; R = R' = H)

(7.494; R = COMe, R' = H) (7.494; R = H, R' =NO,)

-

Dimethylformamide-benzene 305

Dimethylformamide-water Dimethylformamide-water

-

345

47 70 15

336

80

Ethanol

-

181 182

181

181

A = HC(OEt),/(lhO-210")(1.25-2hr); B = 200-21V (no cosolvent)/(l hr); C = MeC(0Et),/(l5O-2lOo)(l.25-3hr); D = Br,, diisopropylamine, CH,Cl,/(room temp.)(lO-15 min); E = ArN,,pyridine/(V)(3-12 hr); F = ClCO,Et,pyridine/(O0)(3 hr), then(room temp.)(15-20 hr),andfinally(reflux)(3 hr); G =melt or heat in ethanol; H = POCI,, benzenel(reflux)(l2 hr); I = HC(OEt),/(reflux)(6 hr). Forms a hydrochloride, m.p. 203-203.5" (from ethanol). Yield not quoted.

I

(7.495; R' = Rz = HI

A

266-268

quant.

-

7

(7.490; R' = C O N 3 7

G

RZ= p-BrC,HJ

F

P=H)

180 180

Ethanol

265-267

99 100

(7.490; R' = CN, R2= p-BK&H,) (7.490: R' = CN, R2 = p-BrC6H.J

E

(7.486; R = CO,Et, R' = CN) (7.488; R = H, R' = CN,

RZ= p-EtOC6H.J

180 180

Ethanol

-

298-299

-

98 97

(7.490; R' = CN, R2 = p-EtOC6H.J (7.490; R' = CN, RZ= p-EtOC,H,)

F

E

(7.486; R = CO,Et, R' = CN) (7.488; R = H, R' = CN,

436

Condensed Benzimidazoles of Type 6-5-6

R

COZEt

9

OEt

C02Et (7.492) Scheme 7.%

(7.493)

(Table 7.71)."' The oxidative ring-closure (Scheme 7.96) of the adduct (7.491; R = H) (obtained by the hetero-ene reaction of ethyl 2-benzimidazolylacetate with diethyl azodicarboxylate) using bromine in the presence of diisopropylamine results in the formation of the 1,2,4-triazino[4,5-a]benzimidazole derivative (7.492) in 50% yield (Table 7.7 l).' The analogous oxidative cyclization of the adduct (7.491; R = Et) affords the 1,2,4-triazino[4,5-a]benzimidazol-4( 10H)-one (7.493), though only in 3% yield (Table 7.7 l).' Readily accessible 2-benzimidazolylhydrazides undergo cyclization on heating with orthoesters affording a simple high yield (Table 7.71) route to 1,2,4-triazino[4,5-a]benzimidazol-4(3H)-ones [Scheme 7.97; (7.494; R = H)+ (7.495)].181.183 The phosphorus oxychloride promoted cyclodehydration (Scheme 7.97) of the N-acetyl hydrazide (7.494; R = COMe, R' = H) to give the 1,2,4-triazino[4,5-a]benzimidazol-4(3H)-one (7.4%; R' = H, R2 = Me) exemplifies an alternative approach to the synthesis of molecules of this type."' R2

(7.494)

(7.495) SchutN? 7.97

Methods for the construction of 1,3,5-triazino[1,2-a]benzimidazole derivatives (Scheme 7.98 and Table 7.72) rely heavily on cyclization reactions of 2-aminobenzimidazoles (7.496) or simple derivatives such as N-(2-benzimidazoly1)guanidines (7.497; X = NR), ureas (7.497; X = 0),or thioureas

&z:2

R

(7.4%)

scheme 7.98

(7.505; R = OPh, R' = Ph)

E

76 85 87 63 83 69

(7.506; R = OPh, R' = p-02NC6H,) (7.506; R = OPh, R' = 2-fu~l) (7.506 R = NH,, R' = p-02NC6H,) (7.506; R = NMe,, R' = Ph) (7506; R=NEt,, R1=p-O2NC6H,) (7.499)

G

R = OPh)

(7.504; (7.504 (7504; (7.505; (7.4%;

(7.504;

R = OPh) R = NH,) R = NMe,) R = NEt,) R = H)

H

G

G

69 73 53

(7.506; R = OPh, R' = Ph) (7.506; R = OPh, R' = diphenylyl) (7.506; R = OPh, R' = p-Me,NC,H,)

G G G

(7.504; R = OPh) (7.504; R = OPh) (7.504; R = OPh)

G G

70

(7.498; R = NH,)'

F

R = OPh) R = OPh) R = OPh) R = NH,) R = NH,) R = NH,) R = H)

Toluene Toluene Toluene Toluene Dioxane-water

Toluene

Toluene Toluene Toluene

Water

Toluene Toluene Toluene Toluene Toluene Toluene -d

27 1-273 268-270 302-305 276-278 281-282 305-306 277 (decomp.) 304-306 (decornp.) 205-206 236238 >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

Solvent of crystallization

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

Reaction conditions" Product

(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

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-6

(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-

7.3. Fused Benzimidazoles with Two Additional Heteroatoms

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

7.3. Fused Benzimidazoles with Two Additional Heteroatoms

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

Condensed Benzimidazoles of Type 6-5-6

!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

7.3. Fused Benzimidazoles with Two Additional Heteroatoms

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

Condensed Benzimidazoles of Type 6-5-6

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

7.3. Fused Benzimidazoles with Two Additional Heteroatoms

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

7.3. Fused Benzimidazoles with Two Additional Heteroatoms

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)

Solvent of crystallization

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

Condensed Benzimidazoles of Type 6-5-6

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

References

455

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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133. L. B. Dashkevich and E. S. Korbelainen, Chem. Heterocycl. Compd, 1966, 457; Khim. Geterotsikl. Soedin., 1966, 602; Chem. Abstr., 66, 37836 (1967). 134. H. Reimlinger, M. A. Peiren, and R. Merenyi, Chem. Ber., 105, 794 (1972). 135. F. Troxler and H. P. Weber, Helu. Chim. Acta, 57, 2356 (1974). 136. P. V.Tkachenko, A. M. Simonov, and I. 1. Popov, Chem. Heterocycl. Compd., 1978,73; Khim. Geterotsikl. Soedin.. 1978. 90;Chem. Abstr.. 88, 190727 (1978). 137. H. Alper and L. Pepper, Can. J. Chem., 53, 894 (1975). 138. H. 0. Hankovszky, K. Hideg, and S. Pacsa, Ger. Patent, 2,420,108; Chem. Abstr., 82, 140203 (1975). 139. A. A. Shazhenov and C. S. Kadyrov, Chem. Heterocycf. Compd., 1977. 1114; Khim. Geterotsikl. &din., 1977, 1389; Chem. Abstr., 88. 50780 (1978). 140. M. Sakamoto, K. Miyazawa, K. Yamamoto, and Y. Tomimatsu, Chem. Pharm. Bull. (Tokyo), 22, 2201 (1974); Chem. Abstr., 82, 16767 (1975). 141. M. Sakamoto. K. Miyazawa, K. Yamamoto, and Y. Tomimatsu. Chem. Phamt. Bull. (Tokyo), 24, 2532 (1976); Chem. Abstr., 86, 89744 (1977). 142. W. P. Langsdorf, Ger. Parent, 2,043,811; Chem. Abstr., 76, 140910 (1972); French Patenr, 2,102,857; Chem. Abstr., 77, 164772 (1972); Brit. Parent, 1,291,312; Chem. Abstr., 78, 43481 (1973); U.S. Patent, 3,804,830; Chem. Abstr., 81, 3942 (1974). 143. K. Nagarajan, V. R. Rao, and A. Venkateswarh, Indian 1. Chem.. 8,126 (1970); Chem. Abstr., 73, 3879 (1970). 144. H. J. Davies and C. H.Dickerson, J. Chem. Soc., 1%5. 5125. 145. G. Zigeuner, W. B. Lintschinger, A. Fuchsgruber, and K. Kollmann, Monauh. Chem., 107. 171 (1976); Chem. Abstr., 85, 5579 (1976). 146. V. I. Shvedov, L. B. Altukhova, L. A. Chernyshkova, and A. N. Grinev, Chem. Pharm. J., 3, 566 (1969); Khim. Farm. Zh., 3, 15 (1969); Chem. Abstr., 72, 66899 (1970). 147. A. N. Grinev, A. A. Druzhinina, and I. K. Sorokina, Chem. H e w y c l . Compd., 1976, 1048; Khim. Geterotsikl. Soedin., 1976, 1266; Chem. Abstr., 86, 29761 (1977). 148. K. Hideg and H. 0. Hankovszky, Synthesis, 1978, 313. !3, 1144 (1956). 149. J. Schmutz and F. Kunzle, Helu. Chim. Ac~I,3 150. W. B. Edwards and A. R. Day, J. Org. Chem., 39, 1519 (1974). 151. H. Schubert, H. Lettau, and J. Fischer, Tetrahedron, 30, 1231 (1974). 152. B. Serafin and L. Konopski, Pol. J. Chem., 52, 51 (1978); Chem. Abstr., 89, 24218 (1978). 153. K. G. Barnett, J. P. Dickens, and D. E. West, Chem. Commun., 1976, 849. 154. K. K. W. Shen and W. S. Belles, U.S. Patent. 4,049,422; Chem. Abs tr... 88, 22937 (1978). 155. K. K. W. Shen and W. S. Belles, U.S. Patent, 4,094,662; Chem. Abstr.. 89, 163584 (1978). 156. A. J. Hubert and H. Reimlinger, Chem. Ber., 103, 2828 (1970). 157. E. Ckhiai and M. Yanai, J. Pharm. Soc. Japan, BQ, 493 (1940); Chem. Abstr., 35, 743 (1941). 158. S. S. Berg and V. Petrow, J. Chem. Soc.. 1952, 784. 159. C.W. Bird, Tetrahedron, 21, 2179 (1965). 160. R. Prasad, G. Kumar, and A. P. Bhaduri. Indian J. Chem., 15B, 652 (1977); Chem. Abstr., 88, 89622 (1978). 161. S. S. Tiwari and S. B. Misra, Indian J. Chem., 14B, 725 (1976); Chem. Abstr., Sa, 121291 (1977). 162. 1. A. Maynard, I. D. Rae, D. Rash, and J. M. Swan, Ausr. J. Chem., 24,1873 (1971). 163. F. Troxler and H. P. Weber, Helu. Chim. Acta, 57, 2364 (1974). 164. Italian Patent, 658,238; through Chem. Abstr., 63, 15026g (1965). 165. F. G. Webster, Fr. Patent. 1,577,440; Chem. Abstr., 73, 20441 (1970). 166. E.Tenor, T.Eckhard, and F. Fueller, East Ger. Patent, 76,515; Chem. Absrr.. 75,63822 (1971). 205, 262 (1%5). 167. D. G. OSullivan, D. Pantic, and A. K. Wallis, NQ~UW,

460

Condensed Benzimidazoles of Type 6-5-6

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).

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

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

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

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)

8.1. Tricyclic Benzimidazoles with No Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

(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

8.1. Tricyclic Benzimidazoles with No Additional Heteroatom

(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

8.1. Tricyclic Benzimidazoles with No Additional Heteroatom

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

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

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)

8.1. Tricyclic Benzimidazoles with No Additional Heteroatom

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 <5

206-207 204-205 253255

25 25

210 105-110

33 33

8.39 8.39 8.46

-

-

-

8.50 8.50

-

-

C0,Me C0,Et

DMAD DEAD

CH,CN CH,CN

8 9

-

8.52 8.52

-

C0,Me C0,Et

DMAD DEAD

CH,CN CH,CN

6 <5

(decomp.)

(decomp.) 157

120

Ref.

32

33 33

DMAD = dimethyl acetylenedicarboxylate; DEAD = diethyl acetylenedicarboxylate.

Photolysis of Phenazine N - Oxides Irradiation of phenazine-5-oxide (8.53; R = H) gives the unsaturated ~~ lactam (8.54) together with the deoxygenated product ~ h e n a z i n e .The yield of lactam is sensitive to solvent changes being a maximum (42%) in oxygen-flushed benzene, and a minimum (3%) in nitrogen-flushed methanol in which phenazine formation (68%) predominates. Irradiation of a series of 2-substituted phenazine-5-oxides (8.53) and their 10-oxide isomers (8.55) gives an insight into the mechanism of the It is claimed that annulenes (8.56) or (8.57) cannot be intermediates, since each oxide

A

aNTJR ENDR

(8.53)

(8.54)

'N

(8.55)

"

(8.57)

(8.56)

TABLE 8.6. AZEPJNO[ 1,~-u]BENZIMIDZOLES(8.54) FORMED BY IRRADIATION" OF PHENAZINE OXIDES IN ACETONITRILE Phenazine oxide Compound

R

8.53 8.53

H' CI

8.53

OMe

8.55

CI

8.55

OMe

8.55

Me

8.55

a

CN

Product(s) [substituent in (8.S4)l

-

Maximum yieldb (%) 42 9.5 12 25 1 1 2 18.5 20 12.5 12 24 48 34.5' 34.5' 34.5' 26.5 27.5 22.5

2-CI 3-CI 7-Cl 2-OMe 3-OMe 7-OMe 2-CI 3-CI 8-CI 2-OMe 3-OMe 8-OMe 2-Me 3-Me 8-Me 2-CN 3-CN 8-CN

Medium-pressure mercury lamp with Pyrex filter. Based on reacted phenazine oxide. In oxygen-flushed benzene. Melting point not recorded. Combined yield. 476

m.p. ("C)

Ref.

176-177 176-177 159-161 138-139 153-154 147-148

34 35 35 35 35 35 35 35 35 35 35 35 35 36 36 36 36 36 36

-d

129-130 146-147

-d

113-116 110-111 238-239 221-223 191- 192

8.1. Tricyclic Benzimidazoles with No Additional Heteroatom

411

should then yield four different azepinobenzimidazoles-namely, the lactams (8.54) substituted in the 2-, 3-, 7-, and 8-positions. In practice only three of the four possible isomers are detected in each case (Table 8.6). 2Nitrophenazine-10-oxide (8.55; R = NOz) is the exception undergoing deoxygenation only.36 The product distribution is compatible with a mechanism involving the sequence phenazine oxide (8.53) -+ oxaziridine (8.58) + oxadiazepine (8.59) 4spiro-benzimidazole (8.60) +azepinobenzimidazole (8.54) (Scheme 8.4).

(8.58)

(8.59)

8.1.2. Physicochemical Studies Infrared Spectra

No systematic study of the IR spectra of azepino[ 1,2-a]benzimidazoles or their larger ring homologs has been conducted: data recorded in the literature have been mainly used to corroborate the presence or absence of a particular functional group. A low-frequency nitrile absorption (2200 cm-') indicates that resonance involving the imidazole ring and the 6-cyano group is important in the 6-cyanoazepinobenzimidazole (8.46) (Scheme 8.5): that

GE Hw;E CN

c?

HE H E

E

478

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

the NH tautomer predominates in the solid state is inferred from a broad band at 3300-3000 ~ r n - ' . ~ * The conjugated lactam (8.54) and its chloro, rnethoxy, methyl, and cyano derivatives show carbonyl absorptions in the range 1650-1682 in the saturated lactarn (8.34) carbonyl absorbs at higher frequency (17151710 cm-').24,34

Ultraviolet Spectra The UV spectra of tricyclic benzirnidazoles with a fully saturated additional ring closely resemble the spectrum of 1,2-dimethylbenzimidazole (Table 8.7);generation of the benzimidazolium cation is marked by a weak TABLE 8.7. ULTRAVIOLET SPECTRA OF 7,8,9,10-TETRAHYDRO-6HAZEPINq 1.2-u1BENZlMIDAZOLES ~~

Compound

Solvent

Amax in nm (loge)

Ref.

8.2

-b -.I

2.50(3.45) 284(3.54) 292(3.53) 252(3.84) 276(3.79) 283(3.85) 241(3.65) 270(3.93) 277(4.00) 216(3.94) 254(3.98) 269(3.86) 27N3.94) 283(3.89) 240(4.58) 307(4.14) 250(3.79) 274(3.78) 280(3.80)

2 22 22 20 20 37

-

240(3.69) 269(3.90) 27X3.97)

37

8.30

8.31 1.2-Dimeth ylbenzimidazole In In In In

-

ethanol. methanol. 0.OlN-HCI. 0.01N-KOH.

hypsochromic shift. Unsaturated linkages in conjugation with the benzimidazole chrornophore shift the absorption into the visible range (Table 8.8). The spectra of cations obtained from azepinobenzimidazoles (8.39) are and the more conjugated than that of the benzimidazolium chromoph~re?~ proton probably adds to C-8 (8.61).In contrast, the spectra of derivatives

'

a

(8.61)

R = Me,Et

E = C0,Me

- N-

/Me p

(8.62) E = CO,Me.CO,Et

h

TABLE 8.8. ULTRAVIOLET AND VISIBLE SPECTRA OF AZEPINw1,2-a]BENZIMIDAZOLES WITH CONJUGATED GROUPS IN THE AZEPINE RING Substit uents Compound

E

Others

8.39

CO,Me

R=Me

Solvent

-h 8.39

CO,Me

8.46

CO,Me

R = Et

-h 8.50

C0,Me

8.50

CO,Er

8.52

C0,Me

8.52

C0,Et

8.54 8.54

2-CI

8.54 8.54

3-CI 7-C1

8.54 8.54

8-CI 2-OMe

8.54

3-OMe

8.54

7-OMe

-d

8.54

8-OMe

-d

8.54 8.54

3-Me 8-Me

8.54 8.54 8.54

2-CN 3-CN 8-CN

-

d

-1

A,

in nm (loge)

21 7(4.27) 253.5(3.95) 296sh(3.62) 431(4.82) 240(4.38) 243.5(4.38) 249(4.36) 326(4.55) 21634.23) 253.5(3.91) 295sh(3.58) 431(4.76) 244(4.06) 249(4.05) 326(4.35) 208(4.23) 224(4.25) 250(4.10) 288sh(3.93) 298(4.01) 305sh(3.99) 308(4.59) 222(4.34) 248sh(4.05) 295(3.73) 370(4.02) 233(4.18) 344(4.44) 216sh(4.25) 274(4.11) 282(4.03) 233(4.35) 345(4.56) 220sh(4.34)274(4.22) 282(4.14) 253(4.43) 279(4.29) 352(4.25) 252(4.43) 278(4.29) 35 l(4.25) 252(4.56) 279(4.40) 352(4.40) 252(4.59) 278(4.44) 350(4.44) 236(4.23) 243(4.24) 272(4.34) 399(3.76) 238(4.26) 245(4.32) 269(4.41) 278(4.43) 378(3.76) 401(3.76) 430(3.49) 245.5(4.40) 263(4.43) 383(3.76) 238(4.27) 244(4.31) 27544.49) 397(3.73) 413(3.70) 444(3.38) 228(4.25) 244(4.34) 272.34.56) 386(3.71 ) 253(4.09) 273.5(4.09)284.5(4.09) 405(3.61) 452(3.50) 242(4.24) 276(4.19) 288(4.20) 410(3.78) 43X3.85) 237.5(4.28) 24X4.32) 275(4.30) 281.5(4.30) 3933.38) 418(3.55) 226(4.18) 242(4.27) 255.5(4.41) 264(4.411 350.5(3.66) 37 1.5(3.71) 393(3.42) 23q4.13) 24fd4.20) 277(4.25) 402(3.73) 237(4.15) 243(4.18) 265(4.22) 274(4.20) 389(3.55) 264(4.49) 274(4.48) 370(3.82) 245(4.47) 259(4.36) 368(3.73) 223(4.32) 239(4.31) 27N4.42) 406(3.61)

' MeOH.

MeOH-72% HCIO,, 2: I v/v. ' MeOH acidified with 3 drops of 72% perchloric acid. Cyclohexane. Acctonitrile. 479

Ref. 25 25 25 25 32 32 33 33 33 33 33 33 33 33 34 35 35 35 35 35

35 35 35 36 36 36 36 36

480

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

(8.50) are changed on acidification to the benzimidazolium cation type33 suggesting protonation at C-6 (8.62). In the case of the 6-cyanoazepinobenzimidazole (8.46)the long-wavelength band is substantially retained in acid,32 implying that protonation may not involve the azepine ring. Finally, the spectra of the fully conjugated azepines (8.52) are unmodified on acidification.33

Nuclear Magnetic Resonance Spectra The bridgehead hydrogen at C-5a in the stable dihydrobenzimidazole (8.12)absorbs at S 5.12: Otherwise the ‘H NMR spectra of benzimidazoles fused to a fully saturated ring (8.28),or their N-oxide precursors (8.27), are as expected.” The chemical shifts of the proton($ attached to C-6 in the azepine (8.23) and the hydroxy- (8.34)) and acetoxyazepines (831)are at 6 3.47, 5.08, and 6.33, respectively (Table 8.9). TABLE 8.9. CHEMICAL SHIFlS (6) AND COUPLING CON!STANTS (I)OF Compound Substituent(s) Solvent

H-1

H-2

H-3

H-4

H-6

-

7.21q

7.5%

3.474

-

7.67m 8.61d

5.08brJ 6.33br 4.455

8.23

-

CDCl,

7.38d

8.30 8.31 8.39

-

CDCI, CDCl, CDCI,

-7.4-6.h 7.46d 8.22dd c-7.2-7.05m

CDCI,

C-

8.39

c

R=Me E = C0,Me R=Et E = C0,Me

-

7.2-7.05m

4.555

7.8-7.2m

*

-

7.35-6.90111

*

-

7.2-6.85m

b

-

8.46

E = C0,Me

(CD,),CO

8.50

E=CO,Me

CDCI,

8.50

E=CO,Et

CDCI,

8.52

E=CO,Me

CDCI,

8.73d

8.52

E=CO,Me

CF,CO,H

c-----7 . 8 6 ~and ~

8.52

E=CO,Et

CDCI,

8.71d

a

*

- 7.36-7.10m

7.50~~

7.28-7.05m

-

-

s =singlet; d =doublet; dd =double doublet; m = multiplet; br = broad absorption; t = triplet;

Apparent singlet. Protonation possibly at C-10. Possibly interchangeable with ester CH,.

8.1. Tricyclic Benzimidazoles with No Additional Heteroatom

48 1

Products formed from 2-substituted benzimidazoles and acetylenic esters, which were originally considered to be azepinobenzimidazoles on the basis of their ’H NMR spectra, are now thought to be cyclobutapyrrolobenzimid a z o l e ~ (see ~ ~ *section ~ ~ 8.1.1, “Cyclization of 1- and 2-Substituted Benzimidazoles”). The “normal” adducts with an azepine ring [e.g., structures (8.39), (8.46), and (8.50)] show a relatively low field AB system for the The unusual azepinoprotons attached at saturated carbons C-9 and Cbenzimidazoles (8.52; E = CO,Me, C02Et) exhibit an exceptionally lowfield aromatic proton at C- 1, which is deshielded by the nearly coplanar 10-ester in trifluoroacetic acid the deshielding effect disappears possibly because of protonation at C-10. The hydrogens in the azepine ring in the conjugated lactams (8.54) absorb in the olefinic region as expe~ted.~~.~’ A I3C NMR spectrum of azepinobenzimidazole (8.39; R = Me, E = C0,Me) distinguishes between C-6, C-9, and C-10; the shifts (in ppm to low field of internal TMS) are 72.6, 46.0, and 58.0, respectively.28

H-7

H-8

H-9

H-10

-

6.03d 7.04d

- 5.66br. t

-

7.05s 7.69s 6.98s

Others

Ref.

1,3(1.8); 3.4(8.3); 15 6,7(6.4); 7,CH,( 1.1); 9,10(9.0) 1.9m 4.6-3.5m 5.32br (OH) 20 2.04br 4.41br,t 2.19s (CH,) 2,4(2.2); 1,2(9.1) 20 5.47d 5.95d 3.41s (NCH,); 3.85, 3.74, 3.69, 9.10(6) 25 3.51 (ester CH,) 5.45d 5.9M 1.32t (NCH,CH,); 3.83, 3.72, 9,10(6) 25 3.68, 3.51 (ester CH, and NCH,CH,) 5.254 6.50d 3.76, 3.67, 3.61, 3.45 9,10(5.8) 32 (ester CH,) 4.50d 5.64d 3.66s (NCH,)d; 3.64, 3.64, 9,10(3.5) 33 3.46. 3.16 (ester CH,) 4.43d 5.54d 3.59s, (NCH,); 1.16, 1.16, 0.85, 9,10(3.5); CH,,CH,(7) 33 0.77 (ester CH,);4.30-3.28m (ester CH,) 3.69s (NCH,); 3.89, 3.86, 3.69 1,203) 33 (ester CH,) 6.48br‘ 3.91s (NCH,); 4.22, 4.07, 4.07 33 (ester CH,) 3.68s (NCH,); 1.35. 1.30, 1.1 1 1,2(8); CH,, CH,(7) 33 (ester CH,); 4.49-3.92rn (ester CH,)

-

q =quartet

1.86d (CH,)

J value5 (Hz)

482

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

Mass Spectra The azepino[ 1,2-~]benzimidazole adducts from 2-substituted benzimidazoles and acetylenic esters can be distinguished from their cyclobutapyrrolo[ 1,2-a]benzimidazoIe isomers by their mass spectra. The adducts with a 7-membered ring primarily lose the ester groups, whereas the latter give an intense peak corresponding to loss of an acrylate residue." For example, the mass spectra of azepines (8.39) display base peaks resulting from loss of one ester group (M-59) followed by losses of MeO., MeOH, and MeOC0.;38 the 6-cyanoazepine (8.46) gives a strong M-MeOH peak probably by sequential loss of MeO- (metastable-confirmed) and an H atom .32 The initial events in the fragmentation of the molecular ion of the 6 H azepinobenzimidazole (8.23) are loss of an H-atom or methyl radical,I5 whereas the conjugated lactam (8.54) loses CO to form the stable pyridino[ 1,2-~]benzimidazoleradical ion (8.63) as base peak.34

(8.63)

General Properties

7,8,9, IO-Tetrahydro-6H-azepino[1,2-a]benzimidazole (8.2) and its derivatives forms salts with hydrochloric" and picric acids' 1 ~ 1 3 * 2 2and quaternary salts with methyl i~dide."~"Some N-oxides of tricyclic benzimidazoles also form hydrochlorides.16*" The pK, values of the aforementioned have not been determined and even the site of protonation has not been explicitly defined: moreover, although the quaternary salts are nominally classified as 1l-methiodides (8.64), methylation of the related bisbenzimidazodiazocine (8.65) with methyl toluene-p-sulfonate yields a quaternary salt (8.66) methylated at the 5,13-p0sitions.~~

(8.64)

substituted NH,

8.1. Tricyclic Benzimidazoles with No Additional Heteroatom

483

Me p-W&SO+tc

2x-

Me (8.66)

(8.65)

X = toluene-p-sulfonate

Reduction of N-( o-nitropheny1)hexahydroazepine with titanous chloridehydrochloric acid to the azepinobenzimidazole (8.2) (see section 8.1.1, “Cyclization of orrho-Substituted N-Aryl Heterocycles”) is facilitated by complex formation between the intermediates and titanous salts (Scheme 8.6). Formation of an initial complex (8.67) is followed by proton transfer and ring-closure (8.68) onto the favorably aligned a-methylene group. The N-oxide (8.70) is envisaged as being formed via a w-complexed intermediate (8.69) formed by overlap of the metal atom with the w-orbital of the benzimidazole N and 0 atoms. Failure of morpholino or N-methylpiperazino derivatives to cyclize may be attributed to the titanous chloride being prevented from forming a complex because of preferential chelation with the other heteroatom (0or N) in the heteroalicyclic ring.Ig

c1-

c1-

Pd

-

(8.67) l+

0-

484

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

8.1.3. Reactions

Reactions with Electrophiles Nitration of 2-substituted azepinobenzimidazoles (83; R = H, R' = CI, NHAc) yields the corresponding 3-nitro derivatives4' and the 3-substituted analogs (83; R = C1, NHAc, C02Et, R' = H) conversely undergo nitration in the Z-p~sition.~.' Reduction of 2- or 3-nitroazepinobenzimidazoles or their derivatives yield the corresponding amines, which can be further transformed by conventional processes into a range of benzimidazoles substituted in the 2- or 3-positions (Table 8.10). 3-Amino-7,8,9,1O-tetrahydro-6H-azepino[ 1,2-a]benzimidazole (8.3; R = NH2, R' = H) condenses to yield the salt with 2-amino-4-chloro-6-methylpyrimidine-l-methiodide (8.71),with 1-hydroxynaphthalene-2-carboxylic acid and adipoyl chloride to yield amides (8.72)and (8.73),respectively, and with phosgene to form the urea (8.74)."

Me' (8.71)

(8.72)

RHN-OC( CHJ4CO-NH R (8.73)

RHN-CO-NHR (8.74)

R = 7,8,9,1O-tetrahydro-6H-azepino[1,2-a&enzimidazol-3-yl

Reactions with Nucleophiles Cyclization of N-(0-nitropheny1)heterocycles (8.24) in acids yields azepinobenzimidazole-5-oxidesor their deoxygenated counterparts'6-'8 (see section 8.1.1, "Cyclization of ortho-Substituted N-Aryl Heterocycles"). Prolonged action in hydrochloric acid gives chlorobenzimidazoles which derive from N-oxide Ring chlorination of the N-oxide (8.27; R = NO2; n = 5 ) is effectively accomplished using acid chlorides: the chlorobenzimidazoles (8.75;R' = Cl) are often accompanied by a range of by-products including deoxygenated benzimidazoles, benzimidazoles substituted in the heteroalicyclic ring (8.76), and unusual 1,3-bridged benzimidazolones (8.77). Varying proportions of 1- and 4-chloro derivatives are

8.1. Tricyclic Benzimidazoles with No Additional Heteroatom

485

TABLE 8.10. PHYSICAL CHARACTERISTICS OF 2- AND 3-SUBSTITUTED AND 2,3-DISUBSTITUTED AZEPINOBENZIMIDAZOLES Compound

8.3 8.3 8.3 8.3

R NH2 N3 NHAc NHC02Et {‘rnethiodide)

8.3 8.3 8.3 8.3 8.3

OH H H H NHAc

8.3

NH2

8.3 8.3 8.3 8.3 8.3 8.3 8.3

co2

8.3

N3

8.3 8.3 8.71 8.72 8.73

C02Et CO,H C02H NO2 NO2 NO2

CI NO2 (Meth iodide. hydrate) -

-

(Dimethiodide)

8.74

(Dirnethiodide)

R’

m.p. (“C)

Ref.

180.5- 181 108 254-255 238-240 270-272 (decornp.) 295-296 196-197 198-199 98 190-1 9 1 183 295-296 273 165

11 4 II II

-u

183 228 178 (decornp.) 140 (decornp.) 171 180 220 335 310-311 345 (decornp.) 345 (decornp.) 335 31G-318 (decornp.)

11

11 11

11 11 4 11 40 11

40 3 3 3 3

40

40 40 40 40 40 11

11

II

11

11 11

11

Melting point not recorded.

formed (Table 8.11). Although C-4 is the position most favored for nucleophilic substitution the large leaving group attached at N-5 (8.78) hinders approach of the nucleophile and substitution predominates at the electronically less-favored c-1 (Scheme 8.7). When a reagent with a good potential leaving group (e.g., tosyl chloride) is combined with a nucleophile stronger than chloride ion (e.g., cyanide,

486

Condensed Benzimidazoles of Type 6-5-7and Higher Homologs

(8.75)

(8.77)

azide, or thiocyanate ions, thiols, and amines) the added nucleophile substitutes in the benzene ring.42With azide ion-tosyl chloride the N-oxide (8.27; R = NO,, n = 5 ) gives two products in a 2 : 1 ratio. The major product, the 1azido-3-nitroazepinobenzimidazole(8.75; R = NO,, R' = l-N3, n = 5 ) is accompanied by the furoxan (8.79). The same furoxan is formed from the chloronitroazepine (8.75); R = NO,, R' = 4-C1, n = 5 ) and sodium azide in TABLE 8.1 1, RING CHLORINATION OF 7,8,9,10-TETRAHYDRO-3-NTTRO-6H-AZEPmq 1,2-aDENZIMIDAZOLE-5-OXIDE (8.27: R = NO,, n = 5)O

Reagent

Product (s) (R= NO,, n = 5 in all cases)

=I,

8.75

SO,CI,

8.75

SOCI,

8.75

AcCl BzCl

8.76 8.75 8.76 4-MeO-C6H,,CoCI 8.75 8.76 TsCl 8.75 POBr, * From Ref. 42.

8.77 8.75

Yield

m.p

R'

(Yo)

("C)

1-c1 4-CI 1-CI 4-CI 1-CI 4-CI Ac 4-CI

65 35 55 27 65 35 100 50 50 10 84 27 19 7

136 162

BZ

4-CI 4-MeO-C,H4C0 1-CI 4-CI

H

Yield not recorded. See Table 8.3: compound (8.19;R = NO,).

-b

-

204 179

155 -

131

-c

8.1. Tricyclic Benzimidazoles with No Additional Heteroatom

487

dimethyl sulfoxide at 55". In contrast the chloro groups in the isomeric chloronitro compounds (8.3; R = Cl,R' = NO,) or (8.3; R = NO2, R' = (3) are insensitive to nucleophilic substitution, despite being activated by the adjacent nitro groups."o With thiocyanate anion as nucleophile the major product from (8.27; R = NO,, n = 5 ) is the expected thiocyanate (8.75; R = NO,, R' = 4-SCN, n = 5) together with a yellow dimeric substance tentatively identified as the disulfide (8.80). With oxidizable anions (e.g., bromide, iodide, and butan-1-thiolate) and tosyloxy as leaving group deoxygenation rather than ring substitution OCCUTS."~

Major products of the coaction of an acid chloride and sodium hydroxide on N-oxides (8.27) are the polymethylene-bridged benzimidazolones (8.77; n = 5-7).41*42The mechanism of this reaction is best explained in terms of attack by hydroxide ion at C-5a of the tosylated N-oxide (8.81) followed by concerted loss of the tosyloxy group and rearrangement (Scheme 8.8). A similar nucleophilic attack at C-5a is probably involved in the alkaline degradation of the benzimidazolium sulfamate (8.8) to N-phenylcaprolactam (40%).' Azepinobenzimidazoles formed by the coaction of an acid chloride and a range of nucleophiles are tabulated in Table 8.12.

scheme 8 8

TABLE 8.12. PRODUCTS OF THE COACTION OF AN ACID CHLORIDE AND NUCLEOPHILE ON THE N-OXIDES (8.27)" Starting N-oxide (8.27)

R

n

Reagents

5

BzCI/CN-

5

5

TsCI/CN TsCVN;

5

TsCI/SCN-

5

TsCI/Bu"SH

5

TsCI/Bu"NH,

5

TsCl/PhNH,

5 5

TsCI/OHTsCI/OHBzCI/OH-

5 6 7

TsCIIOHTsCI/OHTsCl/OH-

5

a

Products Compound R n 5

8.75 8.76 8.75 8.75 8.79 a75 8.80 8.75 8.75 8.75 8.75 8.77 8.75 8.77 8.75 8.75 8.77 8.77 8.76 8.77 8.77 8.77 8.77

5

5

5

5

5

5 5 5

5

5 5 5

5 5 5 5 5 5

6 7

From Ref. 42.

See Table 8.11.

See Table 8.3: compound (8.19; R = NO,).

488

Yield

R'

(Oh)

4-CN BZ 4-CN I-N3 4-SCN

20 43 20 66 33 60 20 27 21

-

4-CI 4-SBu" H 1x1

-

4-NHBu"

-

4-NHPh 2-NHPh

BZ

-

-

6

14 10 60 20 90 10

23 35 36 27 55

85 63

m.p. ("C) 205

-b -

154 218 142 300

-b 71

-c

-b 131 99

-

150 198 81 112 171

-

105

143

8.1. Tricyclic Benzimidazoies with No Additional Heteroatom

489

Photochemical and Thermal Reactions When N-oxides (8.27; R = H, (3) with fewer than five methylene groups are photolyzed in methanol they are generally recovered unchanged.43 N-Oxides with larger rings either undergo deoxygenation or rearrange to yield benzimidazolones (8.77) (Table 8.13). In one case (8.27; R = CI, n = 5 ) ring substitution by the solvent to yield the 2-methoxyazepinobenzimidazole (8.82) was also observed. TABLE 8.13. PRODUCTS FORMED BY PHOTOLYSIS" OF N OXIDES (8.27)b Startine N-oxide 627) Roduct(s) R n Compound R H

5

CI

5

CI

6

CI

7

8.28 8.77 8.28 8.77 8.82 8.28 8.77 8.77

H

n

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

c1 c1 -

5 5 5 5 -

32 25 16 44

CI

6

CI

6 7

22 66

H

CI

15

124 81 -c 112 164 117

105 143

"low"

Hanovia 200 W medium-pressure lamp with a Pyrex cooling jacket; AnalaR methanol under nitrogen as solvent. I, From Ref. 43. See Table 8.3: compound (8.19;R = CI).

The benzofuroxan (8.83) (32%) together with traces of nitroamines are formed when the azidonitro compound (8.3; R = NO,, R' = N,) or its isomer (83; R=N,, R'=NO,) are photolyzed in acetic acid.40 The method is inferior to a thermolysis route (57%) employing hot 2-ethoxyethanol (133135") as solvent. At higher temperatures (boiling ethylene glycol or propionic acid) the benzofurazan (8.84) is formed in 60% yield.40 Benzoxazoles (8.85) and (8.86) result when 2-azido- or 3-azido-7,8,9,10-tetrahydro-6Hazepino[ 1,2-a]benzirnidazoles, respectively, are thermolyzed in an acetic acid-polyphosphoric acid mixture."

0-

(8.82)

(8.83)

490

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

Fragmentation of the diazonium betaine (8.87) at high temperature proceeds via the aryne (8.88), which can be trapped by tetracyclone to give a low yield of the tetracycle (8.89).’

Reduction Catalytic hydrogenation of the conjugated lactam (8.54) affords a tetrahydro derivative (834) which is ring-opened on acidic m e t h a n o l y ~ i sto~ ~ give ester (8.90; R = H).Azepines (8.54) substituted with chloro or methoxy groups in the 2- and 3-positions form two isomeric saturated lactams on reduction. Nucleophilic ring-opening by methanol yields only one benzimidazole (8.90; R = C I or OMe) from each pair of isomers.35 Partial hydrogenation of the 8-methoxyazepine (8.91) affords a dihydro derivative (8.92), which cleaves in acidic methanol to form the ketone (8.93).

8.2. Tricyclic Benzimidazoles with One Additional Heteroatom

49 1

MeOH-HCI

(8.93)

0

(8.91)

OMe

OMe (8.92)

9ab

:a+

8.2. TRICYCLIC BENZIMIDAZOLES WITH ONE ADDITIONAL HETEROATOM

8 \

7

s\

4

2

[1.3]0xazepin~3,2-a]benzimidazole

1 H-[ 1,2]Diazepin~l,7-a]benzirnidazole

7

.qH H

I H,3H-[ 1,4~iazepin~4,3-a]benzimidazole

1H - [ 1,3]Diazepin~1,2-a~nzimidazole

1H-[ 1,4]Diazepino[l,2]a]nzimidazoIe

492

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

8.2.1. Synthesis Interaction of benzimidazolone with sodium hydride in dimethylformamide generates an anion which reacts with a,o-dibromoalkanes. Products are either 1,3-plymethylene-bridgedbenzimidazolones (8.77; n = 10, 12) or the corresponding dimers and trimers when the methylene chain is ~ h o r t e n e d .Reaction ~~ with 1,4-dibromobutane yields mainly trimer and a low yield (5.9%) of the oxazepinobenzimidazole (8.94). Entry to the [ 1,4]thiazepino[4,3-a]enzimidazole system can be achieved by heating S-alkyl derivatives of 2-mercaptomethylbenzimidazole.45Cyclodehydration of 4-(2-mercaptomethylbenzirnidazolyl)propiophenone (8.95a) or the corresponding alcohol (8.9513) in polyphosphoric acid at 100” furnishes thiazepinobenzimidazoles (8.96) and (8.97), respectively: the propionic acid (8.9%) yields thiazepinone (8.98) in refluxing xylene.

(895)

(8.94)

a,R=Bz b, R = CH(0H)Ph C, R = CO,H

Acid catalyzed cyclization of NN-dialkyl-N’-(o-nitropheny1)hydrazines represents an intriguing variant of the 1-amino e f f e ~ t . ” ~ ~ Cyclization .~’ of the parent hydrazine (8.99; R = R ’ = H , n = 4 ) is best achieved in refluxing trifluoroacetic acid or 48% hydrobromic acid, whereas substituted analogs cyclize efficiently in boiling 6N-hydrochloric acid to yield a series of [1,2]diazepino[l,7-a]benzimidazoles and higher ring homologs (8.100; n = 4, 5).

8.2. Tricyclic Benzimidazoles with One Additional Heteroatom

493

TABLE 8.14. FORMATION OF IH-[1,2]DIAZEPINo[l,7-~]BENZIMIDAZOLES AND HIGHER HETEROALICYCLIC HOMOLOGS (8.100) FROM THE ACIDCATALYZED CYCLIZATION OF HYDRAZINES (S.!19)a Starting hydrazine (8.99)

R

R'

n

H

H H

4 4 4 4

H H CF, NO, NO2 H CF, NO, NO,

CI H H

H

CI H H H

4

4 5 5 5 5

Acid (time of heating in hr) TFA

HCI (3)

HCI (4) HCI (5) HCI (8) PPA (4) HCI (2) HCI ( 5 ) HCl ( 5 ) PPA (6)

Product (8.100) R R' n H CI CI H H H CI H H H

4 4 4 4 4 4

5

5 5 5

Yield (O/O)m.p. ("C)

50 63 23 34 6 50

46 22 8 10

226 198-199 189 224-226 203-205 148 222

" From Ref. 47.

Exceptions are the dinitrophenylhydrazines, which give poor yields in hydrochloric acid but improved results in polyphosphoric acid (Table 8.14). The mechanism is believed to be initiated by attack of the 1-amino nitrogen at the electron-deficient nitronic acid group (8.101) which ring-closes to a spiro-benzotriazole N-oxide (8.102).Subsequent rearrangement and cyclization generates N-oxides (8.103)which are deoxygenated under the reaction conditions (Scheme 8.10). The inability of pyrollidinohydrazines (8.99; n =3) to undergo cyclization may stem from steric constraints in the formation of the spiro-benzotriazole. Evidence for a benzimidazole N-oxide intermediate (8.103)can be adduced from the observation that the parent hydrazine (8.99; R = R' = H, n = 4) and the corresponding chloro analog (8.99; R = H, R' = CI) both give the same diazepinobenzimidazole (see section 8.1.3, "Reactions with Nucleophiles"). Methyl 2-benzimidazolylcarbamate (8.104) condenses with succinyl or dimethylsuccinyl chloride in alkali to yield representatives of the [ 1,3]diazepino[ 1,2-a]benzimidazole system (8.10Ja,b),which are claimed to have miticidal and fungicidal activitie~.~'-~' 2-Aminomethylbenzimidazole (8.106) is a convenient substrate for the preparation of [1,4]diazepino[ 1,2-a]benzimidazoles: it reacts with 1,3diketones, a#-unsaturated ketones and difunctional acids to yield diazepinobenzimidazoles (8.107), (8.108), and (8.109), re~pectively,~'in reasonable yields (Table 8.15). Epichlorohydrin can serve as the difunctional cyclizing agent reacting with amine (8.106) to form the diazepinobenzimidazole (8.110). Virucida15*and virustatic activities53 are claimed for this compound.

(8.101)

(8.103)

(8.102)

Scheme 8.10

RLCoIMe H (8.104)

(8.105)

O, R

= H (3050) b, R = Me (54%)

RCH-CHBZ

H< Me

(8.107)

(8.109)

R = Me.Ph

clq

R

NH

I

H

R

m.

5 7

Ph

(8.108)

R = Ph,Z-ThienyI

H

(8.110)

OH

R = H,Me

TABLE 8.15. [ 1.4]DIAZEPINO[ 1,~-u]BENZIMIDAZOLE!SFROM 2-AMINOMETHYLBENZIMIDAZOLE (8.106) AND CARBONYL COMPOUNDS" R

8.107

Me Acetylacetone 4N-HCI; reflux (Picrate) Benzoylacetone Ph 160"; 4 hr Benzylidene acetophenone DMF: reflux; Ph 1-2 hr 2-Thienyl Thien-2-ylidene DMF: reflux; 1-2 hr acetophenone Crotonic acid 120-130"; 4 hr 3-Chlorobutyric acid DMF; reflux; I hr -

8.107 8.108 8.108 8.109 8.109

Reagent

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

Product

From Ref. 5 1. Yield not recorded. 495

81 64

222 258 (decomp.) 176 (dihydrate) 243

58

256 (decomp.)

67 56

194 (hydrate) 234 (decomp.) (hydrochloride)

4%

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

An unusual synthesis of [ 1,4]diazepino[ 1,2-a]benzimidazoles starts with the bromopropylbenzimidale (8.111). Above 100" this compound cyclizes to the thiazolium salt (8.112):alternatively, the salt can be prepared by interaction of the anthelmintic thiabendazole (8.113) and 1,3-dibromop r ~ p a n e . 'The ~ unstable thiazolium ring can be cleaved in aqueous alkali to form a thiol which probably has the Z-configuration (8.114a).The thiol is not isolable but is readily transformed to a crystalline S-methyl derivative (8.114b) with methyl iodide. The N-methylbenzimidazolium dibromide (8.115)in aqueous alkali forms the stable vinylogous amide (8.116).

Br-

(8.112)

(8.111)

45%

(8.113)

N-

(8.114)

a, R = S H b, R = SMe c, R = NHCH,Ph

(8.115) 8.2.2. Physicochemicrrl Studies and Reactions The UV spectrum of the 1H-[ 1,2]diazepinobenzimidazole (8.100;R =

R'= H, n = 4) shows characteristic benzimidazole peaks at 282 and 288 nm

and the IR spectrum an NH absorption at 3200cm-'. 'H NMR spectra of compounds (8.100;n = 4, 5 ) exhibit a characteristic feature in that the NH proton appears as a triplet (in some cases), or broadened, because of coupling to the adjacent methylene group.47

8.2. Tricyclic Benzimidazoles with One Additional Heteroatom

4w

Ring-opening of the [ 1,4]diazepine ring in the lactarn (8.109)is effected in boiling 6N-hydrochloric acid;" the product is the 1,2-disubstituted benzirnidazole (8.117). The thiol (8.114a) can be converted to a series of products with physical characteristics recorded in Table 8.16. Oxidation of the anion of (8.114a) 'TABLE 8.16. PHYSICAL CHARACTERISTICS OF [1,4]DIAZEPINq1,2- a]BENZIMIDAZOLEY Compound R

Yield (%)

m.p. PC)

Chemical shifts (ti)b;J (Hz) 2.3br quintet (2H. CH,. J = 7); 2.48s (3H. SCH,); 3.901 (2H, CH,NCHO, I=7); 4.2Om (2H, CH,N); 7.2-7.4m (3H. arom.); 7.7m (lH, arom.); 7.70s (lH, =CHSCH,); 8.38s (lH, NCHO) 2.1-2.5111 (2H, CH,); 3.87t (2H, CH,NHCHO, I = 7); 4.0-4.2111 (2H, CH,N); 4.48d (2H, PhCH,, J = 7); 6.66d' (1H. =CHN, I =12.5); 7.1-7.25m (3H. arom.); 7.33s (5H, arom.); 7.6m (1H. arom.): 8.27s (1H. NCHO); 9.OObr sd (123, NH)

8.114

SMe

Y2

150-151

8.114

NHCH,Ph

52

121-122

8.116

-

91

8.118

-

90

259-260 (decomp.) 268 (decomp.)

8.119

CHO

65f

127- 128

8.119

Me

3s

146

8.119

H

XI

152

-L

2.3Sbr quintet (2H, CH,, I = 7); 3.91t (2H, CH,NCHO, J = 7); 4.2m (2H. CH,N); 7.2-7.4111 (3H, arom.); 7.7m (lH, arom.); 7.7m (1H. =CHS); 8.40s (lH, NCHO) 1.698 and 1.83hdd (3H. CH,CH. J = 7); 5.2Sh and 6.05'qq (IH, CHCH,, J = 7); 8.15* and 8.3Shss (IH, NCHO) 1.70d (3H. CH,CH, J = 7); 2.15s (3H. CH,N); 1.82111(2H. CH,); 3.2-3.45111 (2H, CH,NCH,); 4.0-4.5m (3H. CH,N and CHNCH,); 7.2-7.3m (3H. arom.); 7.75m (1H. arom.) 1.73d (3H, CH,CH, I = 7); 1.8m (2H, CH,); 3.85-4.6Sm (3H. CH,N and CHCH,); 4.101 (2H, CH,NH, J = 7 ) ; 7.15-7.3m (3H, arom.);7.73111(1H.arom.) ~~

~~~~~

From Ref. 54. In CDCI,. s = singlet; t = triplet; m = multiplet; dd = double doublet; qq = double quartet; br = broad absorption. Collapses to a singlet with D,O Removed by D,O. Insoluble in CDCI, and DMSO. Mixture (2: 1) of E- and Z-geometrical isomers. Z-isomer E-isomer.

498

Condensed Benzimidazolesof Type 6-5-7 and Higher Hornologs

with hydrogen peroxide affords the sulfide (8.118):the sulfide reacts with Two geometribenzylamine at 120" under nitrogen to form amine (8.114~). cal isomers of the N-formyldiazepinobenzimidazole (8.11%) are formed in 2: 1 ratio when the anion of (8.114a) is treated with Raney nickel: a minor product of desulfuration is the r-amine (8.11%). The corresponding secamine (8.119~)is liberated when the N-formyldiazepinobenzimidazoleis refluxed in 2N-hydrochloric acid.'4

n

CH2NHz CH(Me)CH2C02H

I

O H C- J (

(8.117)

(8.118)

(8.119)

a, R=CHO

b, R=Me c,

R=H

8.3. TRICYCLIC BENZIMIDAZOLES WITH TWO

ADDXTXONAL HETEROATOMS

4

1H,5H-[1,4,5]0xadiazepin~4,3-a]benzirnidazole

[1,3,6~iadiazepin~3,2-a]benzimidazole

1H,3H-[ 1.3,6]0xadiazepin~3,4-aJbenzimidazole

1H-[ 1,3.5JTriazepin~3,2-a]benzimidazole

8.3. Tricyclic Benzimidazoles with Two Additional Heteroatoms

499

4

1 H-[1,3,5JTriazepino[l,2-a]benzimidazole

8.3.1. Synthesis and Reactions Unlike cyclizations of the corresponding piperido- or hexahydroazepinohydrazines (see section 8.2.1) the morpholinohydrazine (8.120) forms a tricycle, the [1,4,5]oxadiazepin0[4,3-~]benzimidazole (8.121), only with Unstable [1,3,6]oxadiazepino[3,4-a]benzimidazoles (8.123) can be prepared from substituted 2-aminomethylbenzimidazoles (8.122):the products revert to starting materials in 4N-hydrochloric acid at room t e m p e r a t ~ r e The . ~ ~ 'H NMR spectrum of derivative (8.123;R = Me) shows singlets for the methylene groups at S 5.59, 4.79, and 4.31.

-a

NO2

6N-HCI

q

a N H W d o C1

C1

(8.120)

H

I

N

~

O

(8.121)

37% HCHO 4N-HCI

H

CHzNHR

(8.122) R = Me,Et,Pf.Bu"

0 (8.123)

Bis-(P-chloroethy1)carbamoyl chloride (BCC) reacts with the anion of 2mercaptobenzimidazole, at -5 to - 10" to yield the S-carbamoylated product (8.124). If the reaction mixture is warmed to 5-10' the thiadiazepinobenzimidazole (8.125) is formed.56 2-Amino- or 2-anilinobenzimidazoles (8.126), on the other hand, must initially undergo carbamoylation at N- 1, since the products are [ 1,3,5]triazepino[3,2-~]benzimidazoles(8.127).These derivatives are worthy of examination as potential antitumor agents.

500

Condensed Benzimidazoles of Type 6-5-7 and Higher Homologs

2-Amino- 1-aminoethylbenzimidazoles (8.128) cyclize with a range of conventional "1-carbon'' reagents5' to form [1,3,5]triazepino[ 1,2-a]benzimidazoles (8.129) or (8.130). Reaction of diamines (8.m;R = H, R' = H, Bu") with carbon disulfide are the exceptions stopping at the inner salt stage (8.131). The salt (8.131; R = R' = H) loses hydrogen suifide in boiling dimethylformamide to afford a thione (8.129; R = R' = H, X = S), which undergoes S-methylation in methyl iodide.

R

R.

NH2

ax,,

CNk

I (CH2)*NHR1

(8.128)

x = 0.s.NTs

(8.130)

(8.131)

X = H,NH,,SMe

(8129)

R = H,CI R' = H,Bu"

CI CI CI H H

8.128

8.128 8.128 8.131 8.129

- 8.129 - 8.129

Bu" Bu" H H

S

8.130 8.130 8.129 8.130

Bu" - 8.129

H Bun

H

-

-

-

Compound

8.121 - 8.123 - 8.123 - 8.123 - 8.123 - 8.125 - 8.127 - 8.127 - 8.129

-

X

Methyl iodide in methanol

" Bis-(0-ch1oroethyl)carbamoyl chloride.

H CI

H Ph H

-

Bu"

-

-

-

Pr"

_

Me Et

R'

-

8.128 8.128

8.126 8.128

8.126

8.120 8.122 8.122 8.122 8.122 8.124

Starting materials Compound R

C1 CI H H

CI

H CI

H Ph H

-

Me Et p r Bu"

-

-

-

-

-

X

H

Bu" Bu" H

Bun

H Bu"

H NH, S SMe

S

NTs 0

H 0

-

-

-

-

-

-

Products R R'

-b

6N-HCI 37% HCHO 37% HCHO 37% HCHO 37% HCHO NaH in DMF BCC"-NaH BCC-NaH 1.1'-carbonyl diimidazole (MeS),C=NTs 1.1'-Carbonyldiimidazole 1.1'-Thiocarbonyldiimidazole HC(OEt), BrCN DMF

Cyclizing reagent

67 52 73 90

46

51 53

36 77 71 75 77 30 30 60 35

(Oh)

Yield

260-261 267-268 258-260 308-9 275 (hydroiodide)

264-266

334-335 291-294

215-217 227.5-228.5 202-203 151.5-152.5 141.5-142.5 171-173 152-154 171-172 298-300

m.p. ("C)

TABLE 8.17. SYNTHESIS AND PHYSICAL CHARACTERISTICS OF OXADIAZEPINO-, THIADIAZEPINO-, AND TRIAZEPINOBENZIMIDAZOLES

57 57 57 57

57

57 57

47 55 55 55 55 56 56 56 57

Ref.

502

Condensed Benzirnidazoles of T y p e 6-5-7a n d Higher Hornologs

Cleavage of the triazepine ring of the hydroiodide salt of the S-methyl derivative (8.130;R = R’= H, X = SMe) can be effected with aqueous 48% hydrobromic acid: the starting diamine (8.128;R = R’= H)is regenerated in 88% yield.” The close similarity in the UV spectra of the triazepinobenzimidazoles (8.130; X = H , NH2, SMe) implies that they exist in their 3-H-tautomeric forms. Data on the synthesis and physical constants of tricyclic compounds with two additional hetero atoms is collected in Table 8.17.

1. 2. 3. 4. 5.

6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

36. 31.

0. Meth-Cohn and H. Suschitzky, Adu. Heterocycl. Chem., 14, 211 (1972). M. D. Nair and R. Adams, 1. Am. Chem. Soc., 83, 3518 (1961). R. C. Perera and R. K. Smalley, Chem. Commun., 1970, 1458. R. Garner and H. Suschitzky, J. Chem. Soc. (C),1967, 74. D. P. Ainsworth and H. Suschitzky, J. Chem. Soc. ( C ) . 1966, 111. J. Martin, 0. Meth-Cohn, and H. Suschitzky, Tetrahedron Len. 1973,4495. 0.Meth-Cohn, R. K. Smalley, and H. Suschitzky, J. Chem. Soc., 1963, 1666. D. P. Ainsworth, 0. Meth-Cohn, and H. Suschitzky, 1. Chem. Soc. ( C ) , 1968, 923. R. K. Grantharn and 0. Meth-Cohn, J. Chem. Soc. ( C ) . 1969, 1444. R. K. Grantham, 0. Meth-Cohn, and M. A. Nagui, J . Chem. SOC. (C), 1969, 1438. K. H.Saunden. J . Chem. Soc., 1955, 3275. R. Garner, G. V. Garner, and H. Suschitzky, J . Chem. Soc. (C),1970, 825. R. H.Smith and H. Suschitzky, Tetrahedron, 16, 80 (1961). J. I. G. Cadogan, Quart. Reu., 22, 222 (1968). R. G. R. Bacon and S. D. Hamilton, J. Chem. SOC. Perkin Trans. I, 1974, 1975. R.Fielden, 0. Meth-Cohn, D. Price, and H.Suschitzky, Chem. Commun., 1969, 772. R. Fielden, 0. Meth-Cohn, and H.Suschitzky, J. Chem.Soc. Perkin Trans. I, 1973,696. R. Fielden, 0.Meth-Cohn, and H. Suschitzky, Tetrahedron Lett., 1970, 1229. H. Suschitzky and M. E. Sutton, Tetrahedron, 24, 4581 (1968). R. K. Grantharn and 0. Meth-Cohn, J. Chem. Soc. ( C ) , 1969, 70. S. Takahashi and H. Kano, Chem. Pharm. Bull. (Tokyo), 14, 1219 (1966). R. C. DeSelms, J. Org. Chem.,27, 2165 (1962). Ger. men., 2,435.406 (1976); Chem.Abstr.., 84, 164782s (1976). R. J. Hayward and 0. Meth-Cohn, J. Chem. Soc. Perkin Trans. I, 1975, 212. R. M. Acheson, M. W. Foxton, P. J. Abbot, and K. R. Mills, 1. Chem. Soc. (C),1967. 882. R. M. Acheson, M. W. Foxton, and G. R. Miller. 1. Chem. Soc., 1965, 3200. R. M. Acheson and M. S. Verlander, J. Chem. Soc. Perkin Trans. I, 1974, 430. R. M. Acheson and G. Procter, J. Chem. SOC.Perkin Trans. I, 1977, 1924. R. M. Acheson and N. F. Elmore, Adu. Heterocycl. Chem., 23, 265 (1978). R. M. Acheson, G. Procter, and S. R. Critchley, J . Chem. Soc. Chem. Commun. 1976, 692. R. M. Acheson, G. Procter, and S. R. Critchley, Acta. Cryst., B33, 916 (1977). R. M. Acheson and M. S. Verlander, J. Chem.Soc. Perkin Trans. 1, 1972, 1577. R. M. Acheson and W. R. Tully, J. Chem. Soc. (C),1968, 1623. A. Albini, G. F. Bettinetti, and S. Pietra, Tetrahedron Len., 1972, 3657. A. Albini, G. F. Bettinetti, and S. Pietra, Gazz. Chim. Ital., 105, 15 (1975). A. Albini, A Barinotti, G. F. Bettinetti, and S. Pietra. J. Chem. Soc. Perkin Trans. 11, 1977, 238. G. H.Beaven, E. R. Holiday, and E. A. Johnson, Spectrochim. Acta, 4, 338 (1951).

Ref erences

503

38. R. M. Acheson, R. T. Aplin. and D. R. Harrison, J. Chem. Soc. (C), 1968, 383. 39. J. Elguero, A. R. Katritzky, B. S. El-Osta, R. L. Harlow, and S. H. Simonsen, J. Chem. SOC. Perkin Trans. I, 1976, 312. 40. R. C. Perera, R. K. Smalley, and L. G. Rogerson, J. Chem. Soc. (C), 1971, 1348. 41. R. Fielden, 0. Meth-Cohn, and H. Suschitzky, Chem. Commun., 1970, 1658. 42. R. Fielden, 0. Meth-Cohn, and H. Suschitzky, J. Chem. Soc. Perkin Trans. I, 1973.705. 43. R. Fielden, 0. Meth-Cohn. and H.Suschitzky. J. Chem. Soc. Perkin Trans. I, 1973,702. 44. M. M. Htay and 0. Meth-Cohn, Tetrahedron Lett., 1976, 79. 45. H. Singh and S. Singh, lnd. J. Chem., 13,323 (1975); Chem. Abstr., 83, 164142n (1975). 46. D. W. S. Latham, 0. Meth-Cohn, and H.Susfhitzky, J . Chem. Soc. Chem. Commun., 1973, 41. 47. D. W.S. Latham, 0. Meth-Cohn, and H. Suschitzky, J. Chem. Soc. Perkin Trans. 1, 1977, 478. 48. Brit. Parenr, 1,291,312 (1972); Chem. Absrr., 78, 43481k (1973). 49. FR. Parenf, 2,102,857 (1972); through Chem. Absrr., 77,164772 (1972). 50. U.S. Patent. 3,804,830 (1974); Chem. Abstr., 81, 3942s (1974). 51. W.Reid and F. Griill, Chem. Ber.. %. 130 (1963). 52. Hung. Teljes, 10,396 (1975); through Chem. Abstr., 84, 135623k (1976). 53. Ger. Offen., 2,420,108 (1974); through Chem. Abstr., 82, 140203111 (1975). 54. J. A. Maynard, I. D. Rae, D. Rash, and J. M. Swan, Ausrr. 1. Chem., 24.1873 (1971). 5 5 . S. Ishiwata and Y. Shiokawa, Chem. Pharm. Bull. (Tokyo),18, 1245 (1970); Chem. Abstr., 73, 56076d (1970). 56. W. Schulze and G. Letsch, Pharmazie, 28,367 (1973); Chem. Abstr., 79,78753~(1973). 57. B. Agai, G. Doleschall, Gy. Hornyhk, K. Lempert, and Gy. Simig, Tetrahedron, 32, 839 (1976).

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

CHAPTER 9

Condensed Benzimidazoles Bridged Between N-1 and C=7 .

M F. G. STEVENS

9.1 Tricyclic Benzimidazoleswith No Additional Heteroatom . . . . . . . . . . 9.1.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cyclization of 8-Aminoquinolines . . . . . . . . . . . . . . . . Cyclization of N-(+Acylamino)phenylHeterocycles . . . . . . . . Cyclization of 2-Methylbenzimidazole . . . . . . . . . . . . . . 9.1.2 F'hysicochemical Studies . . . . . . . . . . . . . . . . . . . . . 9.1.3 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions with Electrophiles . . . . . . . . . . . . . . . . . . Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2 Tricyclic Benzimidazoles with One Additional Heteroatom . . . . . . . . . 9.2.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cyclization of 5-Aminoquinoxalines and Other Nonbenzimidazole Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . Cyclization of 1,7-Disubstituted Benzimidazoles . . . . . . . . . . 9.2.2 F'hysicochemical Studies and Reactions . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

505 506 506 511 514 514 516 516 517 519 521 522 523

523 524 527

528

9.1. TRICYCLIC BENZIMIDAZOLES WITH NO ADDITIONAL HETEROATOM

Pyrrolo[l.2. 3.cdJbenzimidazole

4H.Imidazo[4.5. 1.ijlquinoline 505

Imidazo[4.5. l.jkIl]benzazepine

Condensed Benzimidazoles Bridged Between N-1 and C-7

506

9.1.1. Synthesis

Cyclisation of 8-aminoquinolines Ring-closure of 8-amino-1,2,3,4-tetrahydroquinolines(9.1) with carboxylic acids, acid amides, anhydrides, or chlorides, continues to be the most general route to imidazo[4,5,l-ij]quinolines (9.3), and earlier work on this versatile synthesis has been summarized.' When a carboxylic acid is the reactant cyclization may often be achieved simply by heating the acid with the aminoquinoline alone, or in 4N-hydrochloric acid: alternatively (dihydrochloride) salts of the amine may be combined with the acid.l4 Decarboxylation of the acid is sometimes an interfering side reaction and the method, in general, fails with aromatic, heterocyclic, or unsaturated aliphatic acids; with the aromatic or heterocyclic derivatives the appropriate acid chloride is an effective substitute for the acid.' Occasionally the intermediate amides

R

S

:

,

+

aNH

R2COX

R

yJH R'

(9.1)

X = OH,CI,NH,,0COR2

RCqH

HCI-

AJ

0

c&L

0

(9.4) R=Me,Et

(9.6)

(9.5)

R

9.1. Tricyclic Benzimidazoles with No Additional Heteroatom

507

(9.2)can be isolated and separately cyclized with a range of dehydrating (9.4) to agents.' Cyclization of 8-amino-1,2,3,4-tetrahydroquinolin-4-ones imidazoquinolines (9.5) with acetic or propionic acids proceeds in only moderate yields, but reaction between 8-amino-1,2,3,4-tetrahydroquinoline

and dibasic acids or their derivatives occasionally gives satisfactory yields of bisbenzimidazoles (9.6).Derivatives of imidazo[4,5,1-ij]quinoline prepared by the aforementioned methods are listed in Table 9.1. A series of amides of 8-amino-6-methoxyquinoline (9.7)can be transformed to reduced tricyclic benzimidazoles (9.8)by catalytic hydrogenation at high pressure in acetic the formamide group surprisingly de. ~ bridged creases the propensity of the pyridine ring toward r e d ~ c t i o n The derivative (9.9) can similarly be prepared by the reduction-cyclization approach (Table 9.2). Representative 8-methoxybenzimidazoles show no antimalarial activity against mice infected with Plasmodium berghei." Me0

Me4 2n2 CHKOzH - Hz0

'

8-Amino- 1,2,3,4-tetrahydroquinolinescyclize with cyanogen bromide to afford 2-aminobenzimidazoles (9.10).'*2.4.11 Either or urea4 can act as the 1-carbon donor in t h e formation of benzimidazolin-2-one (9.11; X = 0).Alternatively, synthesis of the 8-methoxybenzimidazolin-2-one (9.11; R=8-OMe, X = O ) can be effected by catalytic reduction of the urethan (9.12)in acetic acid, or hydrolytic cleavage of the urea (9.13)in 4N-hydrochloric acid." Cyclization of the quinolone (9.14)to tricycle (9.15) proceeds smoothly at l9Oo.l3 Benzimidazolin-2-thiones (9.11;X = S) are formed from 8-amino- 1,2,3,4-tetrahydroquinolines and carbon disulfide.'*2*12Cyclization of 5,7-diamino-2,3-dihydro-2-methylindole(9.16) with carbon disulfide furnishes a representative of the pyrrolo[ 1,2,3-cd]benzimidazole ring system (9.17).12

H

H H 7-OMe 8-OMe 9-Me 9-OPh 9-NEt2 8-OMe 8-Me 8-Me

9.3

9.3 9.3 9.3 9.3 9.3 9.3 9.3 9.3 9.3 9.3

H H H H H H

A

B G H

2-HO2CC6H4 H H H H H H H CH,OH

H

H H H H H H Me Me Me

F

H

D

B F

3-Indol ylmeth yl

H

H

C

D E

H H H H

H

B

H H H

H H H H H H

9.3 9.3 9.3 ln 9.3 0 m 9.3 9.3 9.3 9.3

B

74 39

B B

CH,OH CH$H

H

H H

9.3 9.3

H

50 35

A A

H Me

H H

H H

Yield

10 30 80 48 96 89 98 86 92 98

51

83 63 67 100 43 100 53 62

(Yo)

9.3 9.3

Cyclization method"

RZ

R'

R

Compound X

_.

-

-

m.p. of picrate

58-60 225 128 237-238 (methiodide: 249-250) 185 216 160-161 215-216 (decomp.) 103-104 Oil 190 93-95 (hydrate) 183-184 80-82 196-197 179-180 214-215 181-182 208-210 92-94 169 142.5 183-185 (hydrochloride: 256-25 8) 206-207 221-222 (hydrochloride: 250) 232-233 211-213 314-315 127-128 89-91.5 102-103 110-112 88-89 115-116 106-107 167-168 -

m.p. of base ("C)

Ref.

TABLE 9.1. 5,6-DIHYDRO-4H-IMIDAZ~4,5,l-ij~UINOLINES (9.3). (9.9, AND (9.6) FROM 8-AMINO-1,2.3,4-THYDROQUINOLINES AND CARBOXYLIC ACIDS OR THEIR DERIVATIVES

%

cn

~

~~~~~~

B K B

-

-

-

~~~

B

B B

B B

J A' Ad

I I

H

H

H

H

-

-

-

-

-

8-OMe 9-Me 8-Me 9-Me 9-Piperidino Me Et

14

65

47

61

70 11

11 11 73 61

b

-

80 99 80 76 100 45

225-225.5 (hydrate)

194 (hydrate) 139.5- 140

179-180 183-184 154-155 150-151 157-158 154-155 125- 127 26 1-262 262-263 256-258 198 (dihydrate) 217-218 318-320 (dihydrate) 171-172 254 (decamp.) 247 (decornp.) 228 (decornp.) >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%

9.1. Tricyclic Benzimidazoles with No Additional Heteroatom

(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

Condensed Benzimidazoles Bridged Between N-1 and C-7

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.

9.1. Tricyclic Benzimidazoles with No Additional Heteroatom

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

Condensed Benzimidazoles Bridged Between N-1 and C-7

(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

Condensed Benzimidazoles Bridged Between N-1 and C-7

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

9.2. Tricyclic Benzimidazoles with One Additional Heteroatom

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

9.2. Tricyclic Benzimidazoles with One Additional Heteroatom

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).

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

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 anthelmintic

Veterinary anthelmintic

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

Veterinary anthelmintic

Veterinary anthelmintic

Antineoplastic agent Microtubule inhibitor

Syntex

Janssen

Oxfendazole

Nocodazoie

Veterinary anthelmintic

US?

Smith Kline and French Laboratories

Ireland”

Where marketed

Albendazole

Silke Pharmaceuticals Ltd. (for Smith, Kline and French)

By whom marketed

Proprietary Approved name name

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

Proprietary Approved name name

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

Commercial Applications of Benzimidazoles

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

Commercial Applications of Benzimidazoles

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.

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

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

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

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

Indoles. Part 2 (Chemistry of Heterocyclic Compounds, Volume 25b)

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 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)

The Chemistry of Heterocyclic Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy, Part A (Chemistry of Heterocyclic Compounds: A Series Of Monographs) (Volume 60)

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)

Aromaticity in heterocyclic compounds

The Chemistry of Heterocyclic Compounds, Imidazole and Its Derivatives

The Chemistry of Heterocyclic Compounds, Thiazole and Its Derivatives

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 Pincer Compounds

The Chemistry of Organolithium Compounds

The Chemistry of Organozinc Compounds

The chemistry of organomagnesium compounds

New Types of Persistent Halogenated Compounds (Handbook of Environmental Chemistry, Volume 3 Anthropogenic Compounds, Part K)

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)

Aromaticity in heterocyclic compounds

The Chemistry of Heterocyclic Compounds, Imidazole and Its Derivatives

The Chemistry of Heterocyclic Compounds, Thiazole and Its Derivatives

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 Pincer Compounds

The Chemistry of Organolithium Compounds

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