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 G. TENNANT DEPARTMENT OF PHARMACY,

UNIVERSITY OF ASTON.

DEPARTMENT OF CHEMISTRY.

UNIVERSITY OF EDINBURGH.

BIRMINGHAM. EDINBURGH.

ENGLAND S C O n A N D

AN IMFRSCIENCE @ PUBLICATION

JOHN WILEY & SONS

New York . Chichater . Brisbane . Toronto

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 COMPO-

A 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 G. TENNANT DEPARTMENT OF PHARMACY,

UNIVERSITY OF ASTON.

DEPARTMENT OF CHEMISTRY.

UNIVERSITY OF EDINBURGH.

BIRMINGHAM. EDINBURGH.

ENGLAND S C O n A N D

AN IMFRSCIENCE @ PUBLICATION

JOHN WILEY & SONS

New York . 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;

“An Interscience publication.” Includes index 1. Benzimidazoles. I. Preston, P. N.

-v. 40, pt. 1 ISSN 0069-3154)

QD401.BM 547.593 80-17383 ISBN 0-471-03792-3 (v. 1) ISBN 0-471-08189-2 (v. 2)

The Chemistry of Heterocyclic Compounds

The chemistry of heterocyclic compounds 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 specific interests of the authors.

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

ARNOLD WEISSBERGER Research Laboratories Eosmtan Kodak Company Rochester, New York

EDWARD C. TAYLOR Princeion University Princeton, New Jersey

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 de- scribed in chapter 10 bears witness to the large commitment to ben- zimidazole chemistry. I hope that this book will stimulate further research, particularly on the synthesis of new tricyclic derivatives and related con- densed analogs.

I am indebted to a number of friends and colleagues who have contrib- uted 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 pro- ducts 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

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.

... V l l l

P. N. PRESTON

Edinburgh, Scotland January 1981

Contents

PART TWO

1 6. Condensed Bemimidazoles of Type 6 - 5 5

G . TENNANT

7. Condensed Benzimidazdes of Type 6-5-6

G. TENNANT

257

8. C~adeased Beazinddozdes 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

531 10. commereirrl Applications of Benzimidazdles

P. N. PRESTON

AptborIndex 543

567 Subject I d e x

PART ONE

1. Benzimidazoles

P. N. PRESTON

1

X

2. Benzimidazde N-Oxides

D. M. SMITH

Co-ntents

287

3. Mhydrobenzimidazoles, Benzimidazdones, Benzimidazdethiones and Related Compounds

D. M. SMITH

4. Condensed Benzimidazdes of Type 5-6-5

G. TENNANT

5. Condensed Benzimidazoles of Type 6-6-5

P. N. PRESTON AND G. TENNANT

Autbor Index

Subject Index

331

391

483

645

675

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 . . . . . . . . . . . . . . . . . . Hydrox ylation . . . . . . . . . . . . . . . . . . . . . . . . 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 . . . . . . . . . . . . . . . . . . . . . . 154 Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . 158 Massspectra . . . . . . . . . . . . . . . . . . . . . . . . 171

General Studies . . . . . . . . . . . . . . . . . . . . . . . . 178 Crystallography . . . . . . . . . . . . . . . . . . . . . . . 178 Dipole Moments . . . . . . . . . . . . . . . . . . . . . . . 178 Ionization Constants . . . . . . . . . . . . . . . . . . . . . 178

6.2.3 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Reactions with Electrophiles . . . . . . . . . . . . . . . . . . 179

Protonation . . . . . . . . . . . . . . . . . . . . . . . . . 179 Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . 182 Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Halogenation . . . . . . . . . . . . . . . . . . . . . . . . 197 Nitrosation and Nitration . . . . . . . . . . . . . . . . . . . 202 Diazo Coupling . . . . . . . . . . . . . . . . . . . . . . 204

Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . 207 Deprotonation . . . . . . . . . . . . . . . . . . . . . . . 207 Hydroxylation and Related Reactions . . . . . . . . . . . . . 207 Amination . . . . . . . . . . . . . . . . . . . . . . . . . 209 Reactions with Anionic Reagents . . . . . . . . . . . . . . . 211

Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . 216

6.2.4 Practical Applications . . . . . . . . . . . . . . . . . . . . . . 217 Biological Properties . . . . . . . . . . . . . . . . . . . . . . 217 Dyestuffs . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

6.3 Tricyclic 6-5-5 Fused Benzimidazoles with Two Additional Heteroatoms . . . 219 6.3.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Ring-closure Reactionsof Benzimidazole Derivatives . . . . . . . . 221 Ring-closure Reactions of Other Heterocycles . . . . . . . . . . . 229

6.3.2 Physicochemical Properties . . . . . . . . . . . . . . . . . . . . 230 Spectroscopic Studies . . . . . . . . . . . . . . . . . . . . . . 230

Infrared Spectra . . . . . . . . . . . . . . . . . . . . . . . 233 Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . . 234 Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . 239

General Studies . . . . . . . . . . . . . . . . . . . . . . . . 239 Dipole Moments . . . . . . . . . . . . . . . . . . . . . . . 242

6.3.3 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . 242 Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . 244 Oxidation and Reduction . . . . . . . . . . . . . . . . . . . . 244

6.3.4 Practical Applications . . . . . . . . . . . . . . . . . . . . . . . 244 6.4 Tricyclic 6-5-5 Fused Benzimidazoles with Three Additional Heteroatoms . . . 244

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 ben- zimidazole 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 4H (6.3) tautomeric forms as well as in the guise of 1H-2,3- dihydro (6.4) and 1 H-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) 1 H-Pyrrolo[ 1.2-a]benzimidazole (6.2) 3H-Pyrrolo[ I ,2-a]benzimidazole (6.3) JH-Pyrrolo[ 1.2-a]benzimidazole (6.4) 2,3-Dihydro- 1 H-pyrrolo[ 1.2-albenzimidazole (6.5) 2.3.3a.4-Tetrahydro- 1 H-pyrrolo[ 1,2-a]benzirnidazole

Cf. Scheme 6.1. ' Based on the Ring Index.

6.1.1. Synthesis

Ring -closure Reactions of Benzimidazole Deriuatiues

The c~ndensation'-~ of ortho-phenylenediamine (6.6) and its derivatives 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

TA

BL

E 6

.2.

SYN

TH

ESI

S O

F lH-PYRROL0[1,2-a]BENZIMIDAZOLES BY

RIN

G-C

LO

SU

RE

RE

AC

TIO

NS

OF

BE

NZ

IMID

AZ

OL

E

DE

RIV

AT

IVE

S A

ND

RE

LA

TE

D P

RO

CE

SSE

S.

Rea

ctio

n Y

ield

m

.p.

Solv

ent o

f C

ryst

al

Star

ting

mat

eria

ls

cond

ition

s"

Prod

uct

(YO)

("C

) cr

ysta

lliza

tion

form

R

ef.

(6.6

) + (6

.7; R

' = R

2 = P

h)

A

(6.1

0; R

' = R

2 = P

h)

-b

186

-

Bro

wn

1

(6.8

; R' =

R2 =

Ph)

B

(6

.10;

R' =

R2 =

Ph)

-*

-

-

-

(6.6

) + (6

.7; R

' = R

2 = H

) -

(6.1

0; R

' = R

2 =

Me)

-b

-

-

J

3

(6.6

) + (6

.14;

R =

H, R

' = P

h)

E

(6.1

0; R

' = R

2 = P

h)

2 184

Eth

anol

R

ed s

olid

4

need

les

1 1 (6

.9; R'

= R

2 =

Ph)

C

(6

.10;

R' =

R2 =

Ph)

85

(6.6

)+(6

.7;R

1=O

Me.

D

(6

.10;

R' =

OM

e,

7 16

9 A

ceto

ne-

Ora

nge-

red

2

-

-

-

d c

R2 =

Ph)

R2 =

Ph)

chlo

rofo

rm

crys

tals

(6.6

) + (6

.14;

R =

H. R

' = O

Me)

F

(6

.10;

R'

= O

H,

76

258

Dim

ethy

lfor

- R

ed n

eedl

es

2

Dim

ethy

lfor

- R

ed p

owde

r 5

(6.6

) + (6

.14;

R =

NO

,, R' =

OH

) G

(6

.10;

R' =

OH

, 57

3 16

R

2 = P

h)

(dec

omp.

) m

amid

e-w

ater

VI

R2

= P

-NO

~C

~H

,)

(dec

omp.

) m

amid

e-

acet

ic a

cid

a A =

heat

in

the

mel

t; B

=he

at i

n a

high

b.p

. so

lven

t or

in

the

mel

t; C =

hea

t at

250

"; D

=h

eat

at 1

80-1

90"/

0.5

hr; E =

AcO

H/(r

eflw

)(40

min

) F

= A

cOH

/(ro

om t

emp)

(l2

hr);

G =

AcO

H/(

room

tem

p)(2

hr)

. Y

ield

not

qu

ote

d.

Solv

ent

not

spec

ifie

d.

Rea

ctio

n co

ndit

ions

not

spe

cifi

ed.

Mel

ting

poin

t no

t quote

d.

Cry

stal

for

m n

ot s

peci

fied

.

6 Condensed Benzimidazoles of Type 6-5-5

formation and thermal cyclization of 2-benzimidazolylacrylic acid inter- mediates (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 inter- mediates, 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]benz- imidazol-1-one (6.10; R' = R' = Ph) in high yield (Table 6.2). Information on the general scope and efficiency of 1 H-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)maleimide is 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-l- ones. In the only extant example' of this situation the condensation of ortho- phenylenediamine (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 prefe- rential 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, RZ=Ph)+ (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 con- densations 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). 1 H-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 con- traction 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 Benzimidazoles with No Additional Heteroatoms 7

(6.16) (6.17) SeLemO 6.3

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 CIS structure. 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 im- idazole 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-benzimi- dazolylethyl 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 reac- tions are readily explained'" in terms of initial condensation to give ben- zimidazole 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 4H- pyrrolo[ 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

TA

BL

E 6

.3.

SYN

TH

ESl

S O

F 3

H-P

YR

RO

LO

[ I,~

-u]B

EN

ZIM

~D

AZ

OL

ES

B

Y R

ING

CL

OS

UR

E R

EA

CT

ION

S O

F O

RT

HO

PHE

NY

LE

NE

- D

IAM

INE

Star

ting

mat

eria

ls

Rea

ctio

n co

nditi

ons"

Pr

oduc

t Y

ield

(96)

m.p

. ("C

) R

ef.

(6.6

) + (6.

18;

R' =

Me,

(6.6

) + (

6.18

; R

' = R

3 =

Me,

(6.6

) + (6

.18;

R' =

Me,

R2 =

R4 =

H,

(6.6

) + (6

.18;

R'

= M

e, R

2 =

R4

= H

,

(6.6

) + (6

.18;

R' =

Me.

R2 =

R4 =

H,

(6.6

) + (6

.18;

R' =

R3 =

R4 =

Me,

(6.6

) + (6

.23;

Ar =

Ph)

(6

.6) + (

6.2

3; A

r = p

-MeO

C,H

,)

R2 =

R3 =

R4 =

H)

R2 =

R4

= H

)

R3 =

Et)

R' =

Pr"

)

R3 =

Bu"

)

R2 =

H, C

N fo

r C02

H)

00

A

A

A

A

A

B C

C

(6.2

0; R'

= M

e,

(6.2

0; R

' = R

3 =

Me,

(6.2

0; R

' =

Me,

R2 =

R4 = H

.

(6.2

0; R

' = M

e, R

2 = R

4 = H

,

(63

0; R

' = M

e, R

2 = R

4 = H

,

(6.2

0; R

' = R

3 =

R4 =

Me,

(6.2

0; R

' = R

2 =

R3

= R

4 =

Ph)

(6

.20;

R' =

R3 =

p-M

eOC

6H4,

R2

= R

3= R

4 =

H)b

R2 =

R4 =

H)'

R3 =

Et)

"

R3 =

Pr"

)'

R3 =

Bu

")~

R~ =

H)

R2 =

R4 =

Ph)

88

87

73

71

80

80

205-

207

210-

212

154-

156

116-

1 18

110-

111

180-

189

206'

24

6'

7,8

7.8

7.8

7.8

7.8

9 10

10

*A

= 80

-200

";

B =

HC

llref

lux;

C =

AcO

H,

MeO

H/(

refl

ux)/

(2 hr

).

Form

s a

hydr

ochl

orid

e, m

.p. 2

81-2

83'.

Form

s a

hydr

ochl

orid

e, m

.p. 2

60-2

63".

dF

orm

s a h

ydro

chlo

ride

, m.p

. 14

7".

' Yie

ld n

ot q

uote

d.

f Fo

rms

a hy

droc

hlor

ide,

m.p

. 20

4-20

6".

ZFo

rms

a hy

droc

hlor

ide,

m.p

. 210

-213

".

Cry

stal

lized

fro

m m

etha

nol-

acet

ic a

cid.

COR' H ~ H R * I - a,ql /

R aNH2 / + R4CR3 R3 R4 I

C02H NH2

(6.6) (6.1%) (6.19)

R' /

RZ R3 R4

(6.27) srkmc 6.5

(6.26)

9

TA

BL

E 6

.4.

SYN

TH

ESI

S O

F 4

H-P

YR

RO

LO

[ 1,

2-a J

BE

NZ

IMID

AZ

OL

ES

BY

RIN

G-C

LO

SU

RE

RE

AC

TIO

NS

OF

BE

NZ

IMID

AZ

OL

E

DE

RIV

AT

IVE

S

Rea

ctio

n Y

ield

m

.p.

Solv

ent

of

Cry

stal

St

artin

g m

ater

ial

cond

ition

s"

Prod

uct

(Yo)

("C

) cr

ysta

llisa

tion

form

R

ef.

(6.2

5; R

' = R

3 = M

e, R

2 = R

4 =

H)

(6.2

5; R

' = R

2 =

R3 =

Me,

R4 =

H)

(6.2

5; R

' = R

3 =

R4 =

Me,

R2 =

H)

(6.2

5; R

' = R

3 =

R4

= M

e, R

2 = H)

(6.2

5; R

' = R

' =

R4 =

Me,

R2 =

H)

(6.2

5; R

' = R2 =

R'

= R

4 = M

e)

(6.2

5; R

' = R

3 =

Me.

R2 =

H,

(6.2

5; R

' =

R'

= M

e, R

2 =

Ph,

(63

5; R

' = E

t, R

2 = R

4 = H,

(6.2

5; R

' =

Et,

R2 =

H,

(6.2

5; R

' = E

t, R

2 = H

, R3 =

Me,

(63

5; R

' = R

3 =

Me,

+

0

R4

= Pr

")

R4 =

H)

R' =

Me)

R3 =

R4 =

Me)

R4 =

Ph)

R2

=R

4=

H)'

(6.2

5; R

' = C

H,A

c, R2 = R

4 = H

,

(63

5; R

' = M

e, R

2 =

R4 =

H,

R' =

Me)

R3 =

Ph)

A

B C

D

E F

E E E

E

E

E

E

E

(6.2

7; R

' =

R3 =

Me,

(6.2

7; R

' =

R2 =

R'

=M

e,

(63

7; R

' = R

3 =

R4 =

Me,

(6.2

7; R

' = R

3 = R

4 =

Me,

46

50

69

65

74

39

R2 =

R4

=H

)b

R4 =

H)'

R~ =

H)'

R~

= H)

(6.2

7; R

' = R'

= R

4 =

Me,

R

2 = HY

(6.2

7; R

' = R

2 =

R3 =

R4 =

Me)

'

(63

7 ; R

' = R

3 =

M e,

R

2 = H

, R4 =

Pr"

) (6

.27;

R' =

R3 =

Me,

R

2 = P

h, R

4= H)'

R3 =

Me)

'

70

86 k

(6.2

7; R

' = E

t, R

2 =

R4 =

H,

(63

7; R

' = E

t, R

2 = H

,

(6.2

7; R

' = E

t, R

2 = H

,

-

78

82

90

R3 =

R4 =

Me)

'

R3 =

Me,

R4 =

Et)

' (6

37

; R' =

R3 =

Me,

R

2 =

R4

= H)'."

(6.2

7; R

' = C

H2A

c,

74

R2 =

R4

= H

. R'

= M

e)

R3 =

Ph)

" (6

.27;

R'

= M

e, R

2 =

R4 =

H,

95

90

99

96

96

114-

116

165-

166

136-

138

152-

153

177-

178

138-

140

139-

140

207-

208

1 69-

1 7

1

Eth

anol

Met

hano

l

Met

hano

l

Isop

ropa

nol

Eth

ano

kth

er

Eth

anol

Ace

tone

Eth

anol

Eth

anol

Wat

er

Ace

tone

-wat

er

Dim

ethy

lfor

- m

amid

e-

wat

er

Eth

anol

Col

orle

ss

plat

es

Col

orle

ss

plat

esd

Col

orle

ss

plat

esf

Col

orle

ss

plat

esf

- h

Col

orle

ss

crys

tals

h

- h

-

- h h

- h

- h

- h

-

12

12

12

13

15

14

15

15

11

15

15

15

19

(dec

omp.

) 10

9-1

11

Eth

anol

C

olor

less

11

so

lid

(6.2

5; R

' =

Me,

R2

= R

4 =

H,

(6.2

5; R

' = E

t, R

2 =

R4

= H

,

(63

5; R

' =

CH

,Ph,

R2 =

R4 =

H,

(6.2

5; R

' = M

e, R

2 =

R4 =

H,

(6.2

5; R

' =

Me,

R2 =

R4 =

H,

R'

= P

h)

R3 =

Ph)

R3 =

Ph)

R3

= p

-BrC

6H4)

R'

= p

-N02

C,H

4)

(6.2

6; R

' =

Me,

R2 =

R4 =

H,

(6.2

5; R

' = M

e, R

2 =

R4 =

H,

(6.2

6; R

' =

Me,

R2 =

R4 =

H,

(6.2

5; R

' = M

e, R

2 =

R4 =

H,

(6.2

5; R

' =

Me,

R2 =

R4 =

H,

(6.2

5; R

' =

Et,

R2

= R

4 =

H,

(6.2

5; R

' =

Et,

R2

= R

4 =

H,

(6.2

5; R

' = E

t, R

2 =

R4

= H

,

(6.2

5; R'

= M

e, R

2 =

R4 =

H,

(6.2

5; R

' =M

e, R

2 =

R4 =

H,

(6.2

5; R

' = C

H2P

h, R

2 =

R4 =

H,

R3 =

p-N

O2C

6H4)

R'

= m

-N02

C,H

4)

R3 =

m-N

O,C

,H,)

R3 =

p-M

eC,H

4)

R'

= p

-MeO

C,H

,)

R3 =

p-B

rC,H

,)

w -

R3

= p

-NO

ZC

bH4)

R3 = 2

-thi

enyl

)

R3 =

Ph)

'

R'

= p

-BrC

,H,)

'

R3 =

p-M

eOC

,H,)

A

E

E

E

E

G

E

G

E

E

E E E

E

E

E

(62

7; R

' = M

e, R

2 =

R4

= H

,

(6.2

7; R

' = E

t, R

2 =

R4 =

H,

(6.2

7; R

' = C

H2P

h,

(6.2

7; R

' =M

e. R

2=

R4 =

H,

(6.2

7; R

' =M

e, R

Z = R

4 =

H.

R3

= P

h)"

R3 =

Ph)

P

R2

= R

4=

H.

R3 =

Ph)

R3 =

P-B

~C

~H

,)~

R'

= p

-N02

C,H

4)

(6.2

7; R

' =

Me,

R2 =

R"

= H

.

(6.2

7; R

' = M

e, R

2 =

R4

= H

.

(6.2

7; R

' =

Me,

R2 =

R4

= H

,

(6.2

7; R

' =

Me,

R2 =

R4 =

H,

(6.2

7; R

' = M

e, R

2 =

R4 =

H,

(6.2

7; R

' = E

t, R2 =

R4 =

H.

(6.2

7;R

'=E

t,R

2=

R4

=H

,

(6.2

7; R

' =

Et,

R2 =

R4

= H

,

(6.2

7; R

' =

Me,

R2

= R

4=

H,

(6.2

7; R

' =

Me,

R2 =

R4 =

H.

(6.2

7; R

' = C

H,P

h,

R3 =

p-N

02C

6H4)

R' =

m -N

02C

6H4)

R3 =

m -

N0,

C6H

4)

R3 =

p-M

eC,H

,)

R'

= p

-MeO

C,H

,)

R3

= p

-BrC

,H,)

'

RJ =

p-B

rC,H

,&'

R3 =

2-t

hien

yl)'

R3 =

Ph)

"

R" =

p-B

rC&

)"

R2

=R

4=

H,

R3 =

p-M

eOC

,H4)

k 11

4 -

97

119-

120

92

123-

124

(dec

omp.

) 8

6

155-

156

90

180-

182

96-9

8 -

92

17

0.5-

17

1.5

96-9

8 -

67

13

1-13

2

84

14

1-14

2

95

123-

124

118-

121

81

79

178-

1 79

98

14

9- 1

SO

82

20

3-20

4

95

159-

160

(dec

omp.

)

Eth

anol

Eth

anol

Eth

anol

Eth

anol

Eth

anol

- di

met

hyl-

fo

rmam

ide

-

Dim

ethy

l-

form

arni

de

-

Eth

anol

Eth

anol

Eth

anol

Ace

tone

-lig

ht

petr

oleu

m

Wat

er

Dim

ethy

l-

Dim

e thy

l-

Dim

ethy

l-

form

amid

e

form

amid

e

form

amid

e

Col

orle

ss

need

les

Col

orle

ss

solid

h

-

Col

orle

ss

solid

R

ed c

ryst

als

-

Red

cry

stal

s

- h

- h

-

Col

orle

ss

solid

R

ed c

ryst

als

h - h

- h

- h

-

12

11

17

11

I1

16

11

16

13

15

11

11

1s

15

15

17

TA

BL

E 6

.4

(Co

nti

nu

ed)

Star

ting

mat

eria

ls

Rea

ctio

n co

nditi

ons"

Pr

oduc

t Y

ield

m

.p.

Solv

ent of

Cry

stal

("

C)

crys

talli

satio

n form

Ref

.

(6.2

5; R

' = M

e, R

' =

R3 =

Ph,

(6.2

5; R

' = C

H,P

h, R

' =

R3 =

Ph,

R

4 = H

)

R4

= H

)

(6.2

5; R

' = M

e, R

' =

Ph,

R

' =

p-B

rC6H

4, R

4 = H

)

(6.2

5; R

' =M

e, R

2 =

Ph,

R'

=

p-N

02C

6H4,

R4 =

H)

(6.2

5; R' =

Me,

R'

= P

h,

R'= m

-NO

,C,H

,, R

4 = H

) (6

.225

; R' =

RZ

= M

e, R3 = P

h,

R4

= H

) (6

.25;

R' =

R2 =

Me,

R3 =

Ph,

R

4=

H)

(6.2

5; R'

= R

2 = M

e, R' =

p-B

rC6H

4,

R4 =

H)

(6.2

5; R' =

R' =

Me,

R'

= p

-NO

,C,H

,, R

4 =

H)

(6.2

5; R

' = R

4 = M

e, R

' =

H,

R3

= P

h)

(6.2

5; R

' = R

4 = M

e, R

2 =

H,

R3 =

Ph)

(6

.25;

R' =

R4 =

Me,

R2 =

H,

(6.2

5; R'

= R

' =

R4 =

Me,

R3 =

p-Ph

C6H

4)

R'

= P

h)

E

E

E E

E

D

E E

E H

E

E E

(63

7; R

' =M

e, R

2 =

R3 =

Ph,

(6.2

7; R

' = C

H,P

h,

R4 =

H)

R'

= R3 =

Ph,

R4 =

H)

(6.2

7; R'

=M

e, R

' =

Ph,

R

3 = p

-BrC

,H,,

R4 =

H)

(6.2

7; R'

=M

e, R

' =

Ph,

R

' =

p-N

02C

6H4,

R

4 = H

) (6

.27;

R' =

Me,

R'

= P

h,

R' =

m -

N02

C6H

4, R

4 = H

) (6

.27;

R' =

R'

= M

e, R

3 =

Ph,

R

4= H

) (6

.27

R' =

R2 =

Me,

R3 =

Ph.

R4 =

H)'

(6.2

7; R

' = R

' =

Me,

R

3 = p

-BrC

,H,,

R4 =

H)

(6.2

7; R

' =

R'

=M

e,

R3 =

p-N

02C

6H4,

R4 =

H)

(6.2

7; R' =

R4 =

Me,

R2 =

H,

R3 =

Ph)

" (6

.27;

R' =

R4 =

Me,

R2 =

H.

R' =

Ph)

(6

.27;

R' =

R4 =

Me,

R'

= H

,

(6.2

7; R

' = R

' =

R4 =

Me,

R

3 =

p-P

hChH

4)

R' =

Ph)

'

96

94

99

92

97

66

97

91

83

85

84

91

87

157-

159

157-

158

156-

158

184-

185

170-

172

36'

136-

137

162-

163

143-

144

145-

146

141-

142

191-

192

1 72-

17 3

Dim

ethy

l-

Eth

anol

- fo

rmam

ide

dim

ethy

l-

form

amid

e

dim

ethy

l-

form

amid

e

dim

ethy

l-

form

amid

e

form

amid

e

Eth

anol

-

Eth

anol

-

Dim

ethy

l-

Eth

anol

Dir

neth

yl-

Dim

ethy

l-

Dim

ethy

l-

Met

hano

l

form

amid

e

form

amid

e

form

amid

e

Eth

anol

Dim

ethy

l-

form

amid

e A

ce to

ne-w

ate

r

Col

orle

ss

solid

h

-

Col

orle

ss

solid

Red

cry

stal

s

h - h

- h

- h

- h

-

Yel

low

pla

tes

k - h

-

11

17

11

15

12

15

15

15

12

15

15

15

(6.2

5; R'

= C

H,C

OP

h, R

2 = R

4 = H

,

(6.2

5; R'

= C

H'C

OPh

, R'

= R

4 =

H,

R3 =

Ph)

R3 =

Ph)

'

(6.2

5; R'

= p

-BrC

6H4C

OC

H2,

R

2 = R

4 = H

. R3 = p

-BrC

6H4)

(6.2

5; R'

= p

-NO

2C6H

4CO

CH

2,

(6.2

5; R'

= p

-BrC

,H,C

OC

H,,

R2 =

R4 =

H, R3 =

p-N

02C

6H4)

R2 =

Ph,

R3 =

p-B

rC6H

4, R

4 = H

)

(6.2

5; R'

= C

H,C

OPh

, R

2 = R3 =

Ph,

R4 = H

)'

E

E

(6.2

7; R'

= C

H,C

OP

h,

(6.2

7; R'

= C

H2C

OP

h,

R2= R

4= H

, R3 =

Ph)

R'=

R4 =

H, R3= ph

)"

k

-

47

160-

161

164-

166

(dec

omp.

) E

than

o I

h

- h

-

18

19

Met

hano

l-

dim

ethy

l-

form

amid

e

dim

ethy

l-

form

amid

e

form

amid

e

dim

ethy

l-

form

amid

e

dim

ethy

l-

form

amid

e

dim

ethy

l fo

rmam

ide

Eth

andl

-

Dim

ethy

l-

Eth

anol

-

Met

hano

l-

Eth

anol

-

Eth

anol

E

(6.2

7; R'

= p

-BrC

6H4C

OC

H2,

R'

= R4 =

H, R3 =

p-B

rC6H

4)

68

180-

181

h

-

19

h

- h

-

E

E

98 k

-

238-

240

196-

197

19

18

E

67

188-

189

h

-

19

F

(6.2

5; R'

= p

-BrC

6H4C

OC

H2,

w

R'

= M

e, R3 =

p-B

rC,H

4, R4 =

H)

(6.2

4; R'

= M

e, R

2 =

C0,

Et)

(6.2

4; R'

= M

e, R

2 = C

N)

E

(6.2

7; R'

= p

-BrC

,H,C

OC

H,,

R2 =

Me,

R3 =

p-B

rC6H

4,

R4 =

H)

(6.2

7; R'

= M

e, R'

= C

0,E

t.

R3 =

Ph, R4= H

) (6

37

; R'

= M

e, R

2 = C

N,

R3 =

Ph,

R4 =

H)

(6.2

9; R'

= R3 =

Me,

(6.2

9; R'

= M

e, R

2 = C

0,E

t.

(6.2

9; R' =

Me,

R2 =

C0

2E

t,

(6.2

9; R'

= E

t, R'

= C

O,E

t,

(6.2

9; R'

= R3 =

Me,

R2 =

CN)

(6.2

9; R' =

Me,

R2 =

CN

,

R' =

C0

2E

t)

R3 =

Et)

R3 = P

h)

R3 =

Me)

R3 =

Et)

k -

167-

169

h

-

18

1 J

41

45

94-9

5

160-

161

h

- h

-

20

20

Met

hano

l-

dim

ethy

l-

form

amid

e Is

opro

pano

l (6

.28;

R'

= M

e, R2 =

C0,

Et)

(6.2

8; R'

=M

e, R'

= C

0,E

t)

(6.2

8; R'

= M

e, R'

= C

0,E

t)

(6.2

8; R'

= E

t, R2

= C

0,E

t)

(6.2

8; R' =

Me,

R2 =

CN

) (6

.28;

R'

=M

e, R

2 =

CN

)

K K

67

153-

154

h -

21

40

110-

111

h -

Eth

anol

21

K K

32

63

156

162-

163

Eth

anol

k

-

21

21

Eth

anol

h

- h h

-

-

K

K

74

58

259

158-

1 59

E

than

ol

lsop

ropa

nol

21

21

TA

BL

E 6

.4

(Co

nti

nu

ed)

Star

ting

mat

eria

ls

Rea

ctio

n co

nditi

ons"

Pr

oduc

t Y

ield

m

.p.

Solv

ent of

Cry

stal

(Yo)

("C

) cr

ysta

llisa

tion

form

R

ef.

(6.2

8; R

' = E

t, R

2 =

CN

)

(6.2

8; R

' = M

e, R

2 =

Ph)

(6

.28

; R' =

Me,

R2 =

Ph)

(6.3

0; R

' = M

e, R

2 =

H)

(6.3

0; R

' = E

t, R2 =

H)

(6.3

0; R

' = R

2 = M

e)

(6.3

0; R

' =

Me,

R2 =

Ph)

(6

.30

; R' =

Et,

R2 =

Ph)

P

K K K

L

L

L M M

(6.2

9; R

' =

Et,

R2 =

CN

,

(6.2

9; R'

= R

3 =

Me,

R2 =

Ph)

(6

.29;

R' =

Me,

R2 =

Ph,

(6.3

4; R

' = M

e, R

2 =

H)

70

55

41

32

30

R3 =

Me)

R3 =

Et)

(6.3

4; R

' = E

t, R

Z = H

)

(6.3

4; R

' =

R2

= M

e)

41

76

73

(6

.34; R

' = M

e, R

Z = P

h)'

(6.3

4; R'

= E

t, R

2 =

Ph)

'

187-

188

246

207-

208

88-8

9 90

-100

(d

ecom

p.)

(dec

omp.

) 17

8-1

79

151-

152

132-

133

(dec

omp.

)

Eth

anol

- h

lsop

ropa

nol

-h

Isop

ropa

nol

-h

21

21

21

22

22

22

22

22

(6-3

5)

M

(6.3

4: R

' = H

. R

2 =

Ph)

" 8

1

64-6

5 E

than

ol-w

ater

Y

ello

w p

rism

s 22

a A

= 0

.7%

N

a,C

O,,

Na,

SO,,

H20

/(80

-90'

)(2

hr);

B

= 0

.7%

N

a,C

O,,

Na,

SO,,

H20

/(90

-95'

)(40

m

in);

C

- 0

.7%

N

a,C

O,,

H20

/(80

0)(1

.5 h

r);

D =

NaO

Et,

N

a,SO

,, E

tOH

/(re

flux

)(Z

O m

in);

E

= N

aHC

O,,

H20

/(re

flux

)(2-

8 hr

);

F=

Na,

CO

,, N

a,SO

,, H

20/(

100'

)(2.

5 hr); G

HzO

/ (r

eflu

x)(1

5-30

min

); H =

0.8

%

Na2

C0,

, H

20/(

9O0)

(1 hr

);

I =

PhC

OC

H,B

r,

acet

one/

(ref

lux)

(96

hr);

J

= P

hCO

CH

,Br,

ac

eton

e/(r

eflu

x)(4

hr)

; K

= (R

3CO

)20,

Et,N

/(13

0-14

O0)

(1 h

r); L

= N

aHC

O,,

NaH

SO,,

HzO

/(re

flux

)(4

hr);

M =

KO

H,

TH

F/r

oom

tem

p.)(

4-14

hr)

. Fo

rms

a pe

rchl

orat

e, c

olor

less

nee

dles

, m

.p.

199-

200'

. Fo

rms

a pi

crat

e, y

ello

w p

late

s, m

.p.

164"

(fro

m e

than

ol)

and

a pe

rchl

orat

e, m

.p.

212"

(fr

om w

ater

).

Tur

n gr

een

in a

ir.

' Fo

rms

a pe

rchl

orat

e, c

olor

less

nee

dles

, m

.p.

178'

(fr

om e

than

ol).

f

Tur

n re

d in

air

. R

Form

s a

picr

ate,

m.p

. 15

1-15

3" (

from

wat

er).

C

ryst

al f

orm

not

spe

cifi

ed.

' H

ydro

chlo

ride

; fr

ee b

ase forms

colo

rles

s cr

ysta

ls w

hich

rap

idly

tur

n re

d in

air

; for

ms

a pe

rchl

orat

e, c

olor

less

cry

stal

s, m

.p.

194-

195"

(from

acet

ic a

cid

then

eth

anol

).

Picr

ate.

Yie

ld n

ot q

uote

d.

5,6-

Dim

ethy

l de

riva

tive.

6,

7-D

imet

hyl

deri

vativ

e.

Form

s a

picr

ate,

m.p

. 20

2" (

from

ace

tone

).

Form

s a

hydr

ochl

orid

e, m

.p.

273"

(fr

om w

ater

) an

d a

hydr

iodi

de.

yello

w n

eedl

es,

m.p

. 27

6".

Form

s a

picr

ate,

m.p

. 19

2-19

4".

For

ms

a pi

crat

e, m

.p.

200-

201"

(f

rom

ace

tic a

cid)

. Fo

rms

a pi

crat

e, m

.p.

205-

207"

(fr

om a

cetic

aci

d).

Form

s a

picr

ate,

m.p

. 18

5-18

6" (

from

ace

tone

).

Thi

s m

.p. differs widely

from

tha

t ci

ted

in R

ef.

15.

Forms

a pi

crat

e, m

.p.

155-

156"

(de

com

p.)

(fro

m w

ater

).

Form

s a

picr

ate,

yel

low

nee

dles

, m

.p.

185"

(fro

m e

than

ol),

a p

erch

lora

te,

yello

w c

ryst

als,

m.p

. 20

8" (

from

aqu

eous

hyd

roch

lori

c ac

idha

nd a

hyd

riod

ide,

ye

llow

nee

dles

, m

.p.

245"

(fr

om a

queo

us h

ydri

odic

aci

d).

Form

s a

picr

ate,

yel

low

pri

sms,

m.p

. 25

1-25

3" (

from

eth

anol

).

Condensed Benzimidazoles of Type 6-5-5

THE EFFECT OF VARYING THE BASIC CATALYST ON THE

PHENACYLBENZIMIDAZOLIUM 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)

EFFICIENCY OF THE CYCLIZATION OF I,2-DIMETHYL-3-

16

TABLE 6.5.

Basic catalyst' Yield (YO) Basic catalyst" Yield (YO)

Sodium ethoxide 93 Sodium methoxide 86 Sodium hydroxide 91

Potassium carbonate 86 Sodium carbonate 91

Ammonium carbonate 35

Calcium hydroxide 95

Sodium hydrogen carbonate 95

Reaction conditions: H20 or EtOH/(reflux)(S hr). Reaction conditions: H20 or EtOH/(reflux)(20 hr).

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

18 70 7 50 91 36 70 19

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]benzirnid- azoles (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-4H- pyrrolo[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; R2=C02Et 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 17

n T q R 2 R3

I R’ R1 COR~

(6.28) (6.29) Scheme 6.6

[Scheme 6.6; (6.28; R2 = Ph, C02Et, or CN)] have been shown” to con- dense 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, ethoxy- carbonyl, 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)].z2 These transformations are reported22 to proceed in moderate to excellent yield (Table 6.4) and are

(6.32) (6.33)

Me

(6.35) (6.34)

Scheme 6.7

18 Condensed Benzimidazoles of Type 6 - 5 5

rationalized by a course (Scheme 6.7) involving the formation and cycliza- tion 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 consis- tent 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)benz- imidazole (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-acylmethyl- benzimidazolium bromides (6.36) with acetylenic esters under basic condi- t 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]benz- imidazoles convertible by oxidation in the reaction medium into the ob- served 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

CH2COR2 CHCOR~

3% aj’ pJj’ / N I I

(6.39) S&eme 6.8