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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