Rapid one-pot preparation of 2-substituted benzimidazoles from 2-nitroanilines using microwave conditions

Article abstract of DOI:10.1016/j.tetlet.2005.07.130

A high yielding one-pot procedure for the generation of 2-substituted benzimidazoles directly from 2-nitroanilines by in situ reduction and cyclization using a microwave procedure is described.

Full text of DOI:10.1016/j.tetlet.2005.07.130

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6741–6743
Rapid one-pot preparation of 2-substituted benzimidazoles
from 2-nitroanilines using microwave conditions
David S. VanVliet,a,ꢀ Paul Gillespieb and Jan J. Scicinskia,*
aNuada Pharmaceuticals, 4324 S. Alston Avenue, Durham, NC 27713, USA
bHoffmann-La Roche, Inc., Roche Research Center, 340 Kingsland Street, Nutley, NJ 07110, USA
Received 28 March 2005;revised 20 July 2005;accepted 25 July 2005
Available online 10 August 2005
Abstract—A high yielding one-pot procedure for the generation of 2-substituted benzimidazoles directly from 2-nitroanilines by
in situ reduction and cyclization using a microwave procedure is described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The condensation/cyclization with the carboxylic acid is
frequently done thermally,15 while the closure with an
aldehyde is an oxidative process.16
The benzimidazole scaffold is a useful structural motif
for displaying chemical functionality in biologically
active molecules. Optimization of benzimidazole-based
structures has resulted in marketed medicines such as
Omeprazole1 and Pimobendan2 and lead compounds
in a wide range of therapeutic areas (e.g., casein kinase
2,3 factor Xa,4 hepatitis C virus5). From a combinatorial
chemistry perspective, the benzimidazole scaffold allows
the stepwise incorporation of diverse functionality with
control of regiochemistry, making it a suitable target
for library synthesis. Library synthesis has been
reported using solid6 and solution7,8 phase approaches
as well as parallel polymer-assisted synthesis.9,10
Early preparations of 2-substituted benzimidazoles from
phenylenediamines and carboxylic acids or carboxylic
acid derivatives were carried out under vigorous dehy-
drating conditions.17 Performing the reaction under
milder conditions by the addition of Lewis acids,15 inor-
ganic clays,18,19 mineral acids,12 or PyBOP,11 has im-
proved both the yield and purity of this reaction. Long
reaction times for this condensation4 have been miti-
gated by the use of microwave heating,20,21 both with
and without polyphosphoric acid.22 Many of these pro-
cedures require chromatographic purification of the
intermediate phenylenediamine, decreasing both the use-
fulness and throughput of these approaches. Herein, we
report a one-pot, high-yield synthesis of 2-substituted
benzimidazoles directly from 2-nitroanilines.
Synthetic approaches to 2-substituted benzimidazoles
from o-halonitroaromatics or from 2-nitroanilines have
been described;however, these procedures require a
multistep process resulting in compromised yields and
purity. The conversion of 2-nitroanilines to benzimid-
azoles is a two-step process. In the first step, the nitro
group is reduced using one of many possible reagents
(e.g., zinc,11 iron,12 tin(II) chloride,13 hydrogen,10 or
Raney nickel14). The second step is the ring closure
performed with either a carboxylic acid or an aldehyde.
2. Results and discussion
The reduction of nitro aromatics is readily achieved by
treatment with tin(II) chloride.13 Although this reaction
can be carried out effectively in a variety of solvents,
such as DMF or alcohols, the rate of reaction is greatly
enhanced in the presence of mineral acids.12 During the
course of our studies, we optimized a simple, micro-
wave-based procedure for the formation of benzimidaz-
oles by cyclization of phenylenediamines with carboxylic
acids, greatly reducing the reaction time required and
enhancing the yield of the process.23 We hypothesized
Keywords: Microwave;Benzimidazole formation;Cyclization.
*
Corresponding author at present address: ALZA Corporation, 1010
Joaquin Road, Mountain View, CA 94043, USA. Tel.: +1 650 564
2595;fax: +1 650 564 5398;e-mail: jscicins@alzus.jnj.com
ꢀ Current address: Nanosyn, Inc., 3760 Haven Avenue, Menlo Park,
CA 94025, USA.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.130

6742
D. S. VanVliet et al. / Tetrahedron Letters 46 (2005) 6741–6743
that the formation of the 2-substituted benzimidazoles
could be achieved directly from the 2-nitroanilines by
substituting the carboxylic acid from the second step
for the mineral acid during the tin(II) chloride reduc-
tion. Thus treatment of o-nitroaniline with tin(II) chlo-
ride using formic acid as solvent under microwave
conditions resulted in clean conversion to 2-H benzimid-
azole (Scheme 1). The reactions were carried out in a
CEM24 focused microwave heating to 130 ꢁC for 5 min.
of benzimidazoles 5, 13, and 21 with none of the dimeric
derivative being observed.25 For all reactions, the con-
version to the heterocycle as well as the residual quantity
of the starting nitroaniline and the N-acylphenylene-
diamine (IP in Table 1) were first determined by LC–
MS using chemiluminescent nitrogen detection
(CLND). The benzimidazole was then obtained by
extraction and chromatography. None of the corre-
sponding unsubstituted phenylenediamines were seen
by LC–MS in any of the reactions.
With the initial success of this reaction, we set out to
determine the scope and variability of the procedure.
Using a variety of substituted nitroanilines and three
different acids, we used a standard set of conditions to
test this new method. For all combinations of nitroani-
line and acid, the desired benzimidazole was observed as
the major product with complete conversion in 16 of 24
reactions. The N-acylphenylenediamine was observed as
the side product where complete conversion was not
obtained. A large variety of functionality was tolerated
on the nitroaniline, including phenol, carboxylic acid,
halogen, and nitrile (see Table 1). Interestingly, the
carboxylic acid substituent on the nitroaniline did not
participate in the reaction resulting in clean formation
Although all of the acids used (formic, acetic, and tri-
fluoroacetic) resulted in acceptable yields, the use of
trifluoroacetic acid resulted in lower overall yields,
particularly for 4-carboxy-2-nitroaniline. For all of the
reactions which resulted in incomplete conversion, fur-
ther microwave irradiation at 130 ꢁC (5–10 min) was
sufficient to effect full conversion. Reaction of phenylene-
diamine with acetic acid under the same conditions,
either in the presence or absence of tin(II) chloride
resulted in complete conversion to 2-methylbenzimid-
azole, suggesting that once the reduction of the nitro
group is complete, acylation and cyclization occur
rapidly.
3
NH2
O
NO2
NH2
SnCl2•2H2O
R2CO2H
N
R2
2
N
H
R2
N
R1
R1
1
R1
H
IP
Scheme 1. SnCl2Æ2H2O (3 equiv), RCO2H (0.35 M), 130 ꢁC, 5 min.
Table 1. Conversion and isolated yield for the formation of substituted benzimidazoles
Entry #
R1
R2
Conversiona
%IP
%SM
Isolated yieldb
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
100
92.3
98.0
100
83.2
90.7
100
100
99
87
95
99
60
86
98
99
4,5-Dimethyl
5-OH
5-OCH3
5-CO2H
5-CN
6.2
1.5
2.0
16.8
9.3
5-CF3
4,6-Dichloro
9
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
100
100
93.7
100
100
100
100
100
100
100
86
98
86
100
96
99
10
11
12
13
14
15
16
4,5-Dimethyl
5-OH
5-OCH3
5-CO2H
5-CN
6.3
5-CF3
4,6-Dichloro
17
18
19
20
21
22
23
24
H
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
100
100
100
78.7
58.3
100
64.7
100
100
100
89
72
45
100
45
96
4,5-Dimethyl
5-OH
5-OCH3
5-CO2H
5-CN
21.3
40.5
1.2
5-CF3
4,6-Dichloro
35.3
a Determined by HPLC/MS/CLND.
b Isolated via column chromatography. Determined by CLND. All compounds gave satisfactory HPLC, MS, and 1H NMR data.26

D. S. VanVliet et al. / Tetrahedron Letters 46 (2005) 6741–6743
6743
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In summary, we have described a simple, rapid, one-pot
procedure for the generation of 2-substituted benzimid-
azoles directly from 2-nitroanilines using a microwave
procedure. An advantage of this approach is that the
intermediate phenylenediamines or N-acyl derivatives
are not isolated. Additionally, although it is possible
that N,N-diacylphenylenediamines may form post-
reduction of the nitro functionality due to the presence
of excess acid, none of the corresponding 2,4-disubsti-
tuted-3,1,5-benzoxadiazepines, derived by cyclization
of the diacyl compounds were formed, thus leading to
simple isolation of the desired benzimidazole. Work
aimed at investigating further the scope of the reaction
is currently being pursued and will be reported when
complete.
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In a CEM microwave vial with a stir-bar (optional), the
nitroaniline (0.36 mmol), carboxylic acid (1.03 mL,
0.35 M), and SnCl2Æ2H2O (3.0 equiv) were combined
and heated at 130 ꢁC (125 W, 1.0 min ramp time) for
5 min. After cooling, the reaction mixture was diluted
with water (4 mL) and neutralized with 50% aq NaOH
(pH = 7.0 0.5). It was extracted with ethyl acetate
(3 · 4 mL) and the combined organic phases were dried
(Na2SO4), filtered and evaporated under reduced pres-
sure. The crude product was analyzed by HPLC/MS/
CLND and purified by passing through a plug of silica
gel (500 mg prepacked columns) using 30 mL of ethyl
acetate. Compounds with purity below 95% were further
purified using the ISCO CombiFlash 16sqx with a gradi-
ent of either 5–100% EtOAc–hexanes or 0–20% DCM–
MeOH (5, 13, and 21).
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Supplementary data
23. Unpublished Results.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.07.130.
24. CEM Corporation, PO Box 200, Matthews, NC 28106.
25. For reactions of 5-carboxy-2-nitroaniline, none of the
dimeric derivative, potentially formed from participation
of the carboxylic acid substituent, was detected:
N
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N
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26. NMR data for all the benzimidazoles can be found in
Supplementary data.