l-Proline catalyzed selective synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2006.11.010

l-Proline (10 mol %) was found to be a versatile organocatalyst for the selective synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles from a wide range of substituted o-phenylenediamines and aldehydes in moderate to excellent isolated yields (32-95%) under

Full text of DOI:10.1016/j.tetlet.2006.11.010

Tetrahedron Letters 48 (2007) 69–72
L-Proline catalyzed selective synthesis of
I
2
-aryl-1-arylmethyl-1H-benzimidazoles
*
*
Ravi Varala, Aayesha Nasreen, Ramu Enugala and Srinivas R. Adapa
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 September 2006; revised 23 October 2006; accepted 1 November 2006
Abstract—L-Proline (10 mol %) was found to be a versatile organocatalyst for the selective synthesis of 2-aryl-1-arylmethyl-1H-
benzimidazoles from a wide range of substituted o-phenylenediamines and aldehydes in moderate to excellent isolated yields
(
32–95%) under mild conditions using chloroform as a solvent at ambient temperature.
Ó 2006 Elsevier Ltd. All rights reserved.
Interest in benzimidazole-containing structures stems
from their widespread occurrence in molecules that exhi-
bit significant activity against several viruses such as
HIV, herpes (HSV-1), RNA, influenza and human cyto-
evolved to include the synthesis of benzimidazoles on so-
lid support. Another method for the synthesis of these
compounds is the reaction of o-phenylenediamine with
7
aldehydes in the presence of acidic catalysts under vari-
1
8,9
megalovirus (HCMV). In addition, benzimidazole
ous reaction conditions.
However, many of these
derivatives have been used as topoisomerase inhibitors,
selective neuropeptide YY1 receptor antagonists, angio-
methods have several drawbacks such as low yields,
use of expensive reagents, a special oxidation process
or long reaction times, tedious work-up procedures,
co-occurrence of several side reactions and poor selectiv-
ity. Therefore, the search continues for a better catalyst
for the synthesis of benzimidazoles in terms of opera-
tional simplicity, economic viability and in particular,
with greater selectivity.
tensin II inhibitors, 5-HT antagonists in isolated guinea
3
pig ileum, potential antitumour agents, antimicrobial
agents, smooth muscle cell proliferation inhibitors, a
treatment for interstitial cystitis, as factor Xa inhibitors,
2
and in diverse areas of chemistry. In light of the affinity
they display towards a variety of enzymes and protein
receptors, medicinal chemists would certainly classify
3
them as ‘privileged sub-structures’ for drug design.
Recently, the commercially available and inexpensive
amino acid L-proline has been elegantly used to catalyze
many reactions such as the Mannich reaction and the di-
Therefore, the preparation of benzimidazoles has gained
considerable attention in recent years.
1
0
rect asymmetric aldol reaction. The proline function
has been proposed to act like a ‘microaldolase’ that
facilitates each step of the mechanism, including the for-
mation of the intermediate imine and the carbon–carbon
bond. Very recently, L-proline has also been effectively
used as a versatile organocatalyst in various organic
The traditional synthesis of benzimidazoles involves the
reaction between an o-phenylenediamine and a carb-
oxylic acid or its derivatives (nitriles, amidates, ortho-
4
esters)
under
harsh
dehydrating
conditions.
Benzimidazoles have also been prepared on solid-phase
5
11
to provide a combinatorial approach. The most popu-
transformations. In continuation of our recent efforts
lar strategies for their synthesis utilize o-nitroanilines
to develop novel synthetic routes for carbon–carbon
1
2
as intermediates or resort to direct N-alkylation of an
and carbon–heteroatom bonds and heterocycles, in
the present study, we extend the scope of the L-pro-
line-catalyzed synthesis of 2-aryl-1-arylmethyl-1H-benz-
imidazoles and the results from our study are presented
herein. Obviously the chirality of the catalyst is not nec-
essary for the described procedure, but the cheapness of
L-proline in comparison with the corresponding racemic
amino acid (D,L-proline) makes it the catalyst of choice.
6
unsubstituted benzimidazole. A number of synthetic
protocols that involve intermediate o-nitroanilines have
q
IICT Communication No. 060902.
*
Corresponding authors. Fax: +91 40 27160921; e-mail: rvarala_iict@
yahoo.co.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.010

70
R. Varala et al. / Tetrahedron Letters 48 (2007) 69–72
Initially, we studied the efficacy of proline (20 mol %)
for the model reaction using o-phenylenediamine
Further studies revealed that even 10 mol % of the cata-
lyst was sufficient to carry forward the reaction (95%
yield, 5 h). Using optimized reaction parameters, we
obtained exclusively N-alkylated products 3 and no 2-
substituted products 4 were observed (Scheme 1).
(
o-PD) (1 mmol) and benzaldehyde (2 mmol) in
chloroform with stirring at ambient temperature to
afford the corresponding 1,2-disubstituted benzimid-
azole in 95% yield in 5 h (Table 1, entry 3a).
Chloroform was the best among the solvents tested
This selectivity could be useful in synthesizing a small
library of 2-aryl-1-arylmethyl-1H-benzimidazoles in mod-
erate to excellent yields. To the best of our knowledge,
there are no earlier reports on the preparation of benz-
imidazoles using L-proline as an organocatalyst.
(
THF–H O, acetone, CH CN, MeOH, DMSO and
2 3
chloroform). The optimum yields of the product were
obtained when a ratio of aldehyde to o-PD (2:1) was
used.
Table 1. L-Proline catalyzed selective synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles from o-PDs and various aldehydes
a
Compound (3)
o-PD (1)
Aldehyde (2)
Time (h)
Yield (%)
3a
3b
3c
3d
3e
1a
1b
1c
1d
1e
CHO
5.0
4.5
15
12
4.5
95
82
32
58
72
CHO
3
3
3
3
f
1a
1a
1a
1a
5.0
5.5
7.5
6.0
85
72
80
83
H C
3
CHO
CHO
g
h
i
H CO
3
Me
N
Me
CHO
O N
2
CHO
3j
1a
6.0
78
OCH3
OH
CHO X= F
X= Cl
3
3
k
l
1a
1a
4.5
6.0
80
72
X
CHO
3
3
3
3
m
n
1a
1a
1a
1a
8.5
4.5
6.0
5.0
88
90
92
85
Br
CHO
o
N
O
CHO
CHO
p
NH2
H C
3
H C
NH2
NH2
NH2
Cl
NH2
NH2
Cl
Cl
NH2
NH2
3
o-PD:
:
NH2
H C
3
NH2
1a
1b
1c
1d
1e
a
Yields refer to isolated pure products.

R. Varala et al. / Tetrahedron Letters 48 (2007) 69–72
71
R
NH2
NH2
CHO
R2
R2
+
R
N
L-proline (10 mol%) R
N
N
+
R1
R1
R2
R1
N
H
CHCl , RT
3
R2
1
2
1
1
R, R =H; R=CH , R =H;
4 (not formed)
3
3 (exclusive)
1
1
R=CH , R =CH ; R=Cl, R =H;
3
3
1
R=Cl, R =Cl
Scheme 1.
We studied the scope of the reaction by varying the o-
PDs (1a–e) for condensation with benzaldehyde under
the optimized conditions and the results are shown in
Table 1.
The proposed mechanism for the L-proline-catalyzed
synthesis of 1,2-disubstituted benzimidazoles may tenta-
tively be visualized to occur via a tandem sequence of
reactions as depicted in Scheme 2 involving Path I (i)
formation of dibenzylidene-o-PD via iminium cata-
1
4
Among the various o-PDs tested, the order of reactivity
in terms of yields and reaction times towards benzalde-
hyde was as follows: 1a > 1b > 1e > 1d > 1c. Intrigued
by the results observed, we next studied the scope and
generality of the L-proline catalysis, for the condensa-
tion of electronically divergent aromatic aldehydes with
o-PD to afford the corresponding 1,2-disubstituted benz-
imidazoles selectively. In all cases, the reactions were
clean and complete within 4.5–15 h. All products (en-
lysis, (ii) protonation of the dibenzylidene-o-PD and
ring closure leading to a five-membered ring either in a
sequential or concerted manner, (iii) 1,3-hydride transfer
and (iv) deprotonation or via Path II involving the acti-
vation of the aldehydic carbonyl oxygen by the acid part
of L-proline through intermolecular hydrogen bond-
ing, and subsequent condensation with o-PD to form
dibenzylidene-o-PD, followed by steps (ii)–(iv) as above
to form 1,2-disubstituted benzimidazoles.
1
5
1
tries 3a–p) were characterized by IR, H NMR, MS
1
3
and elemental analyses. The 1,2-disubstituted benz-
imidazoles were the only products obtained and the
remainder of the material was essentially starting
material. The present protocol is equally effective for
aromatic aldehydes bearing either electron-donating or
electron-withdrawing substituents (entries 3f–m).
In conclusion, we have developed a practical and
novel procedure for the selective synthesis of 1,2-
disubstituted benzimidazole derivatives using commer-
cially available, inexpensive L-proline as an organocat-
alyst in chloroform. The present protocol has several
advantages: mild reaction conditions (at room temper-
ature), operational and experimental simplicity. We
believe that this L-proline promoted methodology
will be a valuable addition to the existing processes
in the field of 1,2-disubstituted benzimidazole
synthesis.
In a similar fashion, a-naphthaldehyde (entry 3n) and
heteroaromatic aldehydes (entries 3o,p) also reacted well
with o-PD to furnish the corresponding benzimidazoles
in good yields.
H
N
−
O
C
δ
H O
δ+
O
H
H N
2
Path II-Acid catalysis through
intermolecular H-bonding
2
equiv.
H N
2
H+
Ph
N
H
H
Ph
CO -
O
N
2
N
CO H
N
2
H
H
H
N
Ph
N
2
H O
2
H N
CO2H
2
N
H
2
equiv.
H
N
Ph
2
Ph
H
3
H N
2
1
N
Path I-Iminium catalysis
Ph
H
O2-C
N
Scheme 2. The proposed mechanism for L-proline catalyzed 1,2-disubstituted benzimidazole synthesis.

72
R. Varala et al. / Tetrahedron Letters 48 (2007) 69–72
Otokesh, S.; Baghbanzadeh, M. Tetrahedron Lett. 2006,
Acknowledgements
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Ravi Varala thanks the Council of Scientific Industrial
Research (CSIR, India) and Aayesha Nasreen (WOS-
A) thanks DST (GAP-0128), India, for financial
support.
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2 4
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9