A facile one-pot synthesis of benzimidazoles from 2-nitroanilines by reductive cyclization

Article abstract of DOI:10.3987/COM-08-11384

A facile one-pot process to prepare benzimidazole derivatives is described. Reductive cyclization of a serial of 2-nitroanilines with orthoesters in the presence of Pd/C in methanol at room temperature, which is promoted by a catalytic amount of acetic acid, affords the corresponding benzimidazole derivatives in high yields.

Full text of DOI:10.3987/COM-08-11384

HETEROCYCLES, Vol. 75, No. 8, 2008, pp. 1907 - 1911. © The Japan Institute of Heterocyclic Chemistry
Received, 9th March, 2008, Accepted, 15th April, 2008, Published online, 17th April, 2008. COM-08-11384
A FACILE ONE-POT SYNTHESIS OF BENZIMIDAZOLES FROM
2-NITROANILINES BY REDUCTIVE CYCLIZATION
Zheng Liu,1 Haihong Li,2 Qingjie Zhao,1 and Jingshan Shen1,2*
1
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555,
Zuchongzhi Road, Zhangjiang High-Tech Park, Shanghai 201203, P. R. China
2
Topharman Shanghai Co., Ltd, 1088, Chuansha Road, Shanghai 201209, P. R.
China, email: jsshen@mail.shcnc.ac.cn
Abstract – A facile one-pot process to prepare benzimidazole derivatives is
described. Reductive cyclization of a serial of 2-nitroanilines with orthoesters in
the presence of Pd/C in methanol at room temperature, which is promoted by a
catalytic amount of acetic acid, affords the corresponding benzimidazole
derivatives in high yields.
Benzimidazole derivatives are the useful building blocks for Nonpeptide angiotensin II receptor
antagonist.1-3 A number of methods have been developed for preparation of benzimidazoles. For example,
benzimidazole derivatives were obtained by microwave-enhanced reaction of o-phenylenediamine with
carboxylic acids, urea or thiourea, using polyphosphoric acid as a catalyst.4 2-Alkylbenzimidazoles were
prepared by condensation of o-phenylenediamine with aldehydes catalyzed by iodine5 and Lewis acid6-8
or oxidized by H2O2 in acidic water.9 Using traditional method, 2-alkyloxybenzimidazole was obtained by
catalytic reduction of 2-nitroaniline and subsequently by reaction of the resulting phenylenediamine with
orthoester in the hot acidic solution.10 Microwave-heated one-pot reaction of 2-nitroaniline with
carboxylic acid in the presence of reductive agent was reported for synthesis of 2-alkylbenzimidazoles.11
Though these above methods are very effective to synthesize benzimidazoles, either an excess of acid or
heating is required to promote the reactions. In this paper, we report an efficient one-pot synthesis of
benzimidazole derivatives under mild conditions. Reductive cyclization of 2-nitroanilines with orthoesters
in methanol at room temperature, which is promoted by a catalytic amount of acetic acid, affords the
corresponding benzimidazoles in high yields. The facile procedure avoids isolation and purification of the
unstable o-phenylenediamine and expands application to 2-nitroaniline substrates involving heat or
acid-sensitive substituents.

CH(OEt)3
NO2
NH2
NH2
NH2
N
H2, Pd/C
H2, Pd/C
3a
H
no reaction
3a
MeOH, rt
N
H
4a
2
1a
Scheme 1
Initially, synthesis of the benzimidazole 4a was carried out in two separated steps. Firstly, the
o-phenylenediamine 2 was readily obtained from the corresponding nitroaniline 1a by catalytic
hydrogenation with 10% Pd/C in high yields. In the second step, we found that no reactions were
observed upon treatment of the resulting diamine 2 with orthoesters 3a in methanol at rt either with or
without Pd/C. However, it was noteworthy that cyclization was achieved in the presence of orthoesters
during the catalytic hydrogenation of the nitroanilines (Scheme 1).
Table 1. Investigation of reaction conditions a
NO2
N
3a
H2, Pd/C
N
H
NH2
4a
1a
Entry 3a/1a Catalyst/1a(C/S, w/w) b Time (h) Yield (%) c
d
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
1
1:10
1:4
1:3
Ra-Ni
1:10e
1:10f
1:4
24
12
9
24
8
-
94
93
d
-
95
70
40g
92
30
7
12
11
8
4
1:4
1:4
>10h
a
b
All reactions were performed at room temperature and 1 atm. 10% Pd/C was used as the catalyst
c
d
unless otherwise stated. Isolated yield. Only the diamine 2 was observed after 24 h based on TLC
analysis. e A drop of HOAc (ca. 20mg) was added. f HOAc was used as solvent. g Partially unreacted 1a
was recovered. h No solvent was used.
We investigated the conditions of the one-pot synthesis of the benzimidazole 4a. Experiments were
carried out by stirring a mixture of 2-nitroaniline 1a, triethyl orthoformate 3a and the catalyst in MeOH
under a hydrogen atmosphere at rt. Investigation of reaction conditions is summarized in Table 1. The
reaction time depends on the complete conversion of 1a. According to Table 1, the catalytic amount of
10% Pd/C (C/S =1:10 w/w) in reaction system resulted in the only diamine 2 (entry 1). However, when
more 10% Pd/C (C/S =1:4 w/w) was used as the catalyst, reductive cyclization occurred at rt (entry 2). In
addition, increasing the amount of catalyst could reduce the reaction time (entry 3). No desired product 4a
was observed when Ra-Ni was used as the catalyst (entry 4). A catalytic amount of acid could promote
the one-pot reaction. Both the reaction time and the amount of Pd/C were reduced. When a drop of HOAc

was added to the reaction of entry 1, the desired product 4a was obtained in high yield after 8 h (entry 5).
However, when HOAc was used as solvent, a few minor impurities were detected (entry 6). Only one
equivalent of 3a in the reaction system resulted in incomplete reaction (entry 7) while 4 equivalents of 3a
did not affect the reaction time and product yield (entry 8). In contrast, using triethyl orthoformate as
solvent led to low yield of product (entry 9).
Once the proper conditions were set up, the same procedure12 was applied to synthesis of various
benzimidazoles 4a-k’’ from the nitroanilines 1a-l to investigate the scope and limitations of the one-pot
synthetic methodology. Under the optimized reaction conditions, most of the corresponding
benzimidazoles were obtained in moderate to good yields (Table 2).
Table 2. Synthesis of benzimidazole derivatives a
R3C(OEt)3
3a-c
NO2
N
R3
H2, Pd/C, rt
NHR2
N
R1
R1
R2
1a-l
4a-k"
Entry Substrates R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Boc
Boc
Boc
H
R3
H
OEt
Me
H
OEt
Me
H
OEt
Me
H
OEt
Me
H
OEt
Me
H
OEt
Me
H
OEt
Me
H
OEt
Me
H
OEt
Me
H
OEt
Me
Product Yield (%)b
1
1a+3a
1a+3b
1a+3c
1b+3a
1b+3b
1b+3c
1c+3a
1c+3b
1c+3c
1d+3a
1d+3b
1d+3c
1e+3a
1e+3b
1e+3c
1f+3a
1f+3b
1f+3c
1g+3a
1g+3b
1g+3c
1h+3a
1h+3b
1h+3c
1i+3a
1i+3b
1i+3c
1j+3a
1j+3b
1j+3c
4-Me
4a
95
93
94
95
93
93
90
88
87
93
91
95
78
75
80
52
55
45
2
3
4
5
6
7
8
9
4-Me
4-Me
6-CO2Et
6-CO2Et
6-CO2Et
6-CO2H
6-CO2H
6-CO2H
H
4a’
4a”
4b
4b’
4b”
4c
4c’
4c”
4d
4d’
4d”
4e
4e’
4e”
4bc
4b’c
4b”c
4f
4f’
4f”
4g
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
H
H
H
H
H
6-CO2Et
6-CO2Et
6-CO2Et
4-Cl
4-Cl
4-Cl
5-CF3
5-CF3
5-CF3
4,5-dimethyl
4,5-dimethyl
4,5-dimethyl
4-CN
d
-
-
-
d
H
H
H
H
d
96
96
94
94
94
92
88
90
90
4g’
4g”
4h
H
H
H
H
H
H
H
4h’
4h”
4i
4-CN
4-CN
4i’
4i”

Entry Substrates R1
R2
H
H
H
H
H
H
R3
H
OEt
Me
H
OEt
Me
Product Yield (%)b
31
32
33
34
35
36
1k+3a
1k+3b
1k+3c
1l+3a
1l+3b
1l+3c
5-F
5-F
5-F
4-OH
4-OH
4-OH
4j
93
94
94
75
78
75
4j’
4j”
4k
4k’
4k”
a All reactions were performed overnight by catalytic hydrogenation using 10% Pd/C (C/S =1:10 w/w) as
catalyst at room temperature and 1 atm with a 1: 3 molar ratio = 1:2 and a drop of HOAc inMeOH.
b Isolated via recrystallization or column chromatography. c The reaction was complete after 24 h and the
Boc group was removed. d The reaction was messy after 12 h.
The substituents on the aromatic ring have shown effects on the formation of the target product. The
aromatic ring bearing methyl, ester, carboxyl group, hydrogen, trifluoromethyl, dimethyl, nitrile and
fluoro groups with no substituent on the amino group (1a-d, 1h-k) proceeded in high yields of 87-96%
(entries 1-12, 22-33). Whether orthoester 3a, 3b or 3c was chosen as reactive reagent did not affect the
product yields. Nitroaniline 1e with substituents on amino group led to lower yield than N-unsubstituted
nitroanilines (entries 13-15). The reaction of the chloro-substituted nitroanilines 1g became messy. The
dechloro products and a minor amount of products were detected (entries 19-21). The benzimidazoles
4k-k” were obtained from nitroaniline 1l possessing hydroxyl group in moderate yields (entries 22-24).
Comparing to the unprotected aniline 1b, the presence of Boc group on aromatic amine 1f resulted in the
long reaction time and low yields (entries 16-18). It was suggested that the steric hinderance and low
basicity of carbamate inhibited cyclization. Though the Boc group can be removed at high temperature13
or under acidic conditions,14 we found the Boc group on the nitroaniline 1f was partially removed. The
deprotected diamine derived from 1f was also detected in the reaction mixture during the reductive
cyclization.
In conclusion, we described a facile one-pot process to produce benzimidazoles from 2-nitroanilines and
orthoesters by reductive cyclization in methanol at rt. The attractive features of this process are facile
procedure, mild reaction conditions, expansion of application to heat and acid-sensitive 2-nitroanilines
and high yield of product. Further efforts to optimize the process of candesartan cilexetil 52,15,16 using this
efficient one-pot method are now in progress (Scheme 2) and will be reported in near future.
N
NO2
NH
OEt
N N
NH
N
O
Me
N N
NH
O
Me
N
H2, Pd/C
MeOH, rt
N
O
O
O
O
O
O
O
O
5
Scheme 2

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