A simple and efficient synthesis of 2-aryl-substituted benzimidazoles

Article abstract of DOI:10.1134/S1070428008060146

Sodium hydrogen sulfite was used to promote condensation of o-phenylenediamine with aromatic aldehydes in dimethylformamide to obtain the corresponding 2-arylbenzimidazoles. The procedure is simple and convenient, and it implies inexpensive promoter and is characterized by short reaction time and easy purification of the final products.

Full text of DOI:10.1134/S1070428008060146

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 6, pp. 863–865. © Pleiades Publishing, Ltd., 2008.
Published in Russian in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 6, pp. 872–874.
A Simple and Efficient Synthesis of 2-Aryl-Substituted
Benzimidazoles*
a,
b
Xiangming Han , Huiqiang Mab, and Yulu Wanga
a College of Chemistry and Environmental Science, Henan Normal University, Xinxiang, Henan, 453007 China
e-mail: wyl@henannu.edu.cn
b Department of Chemistry and Environmental Engineering, Pingyuan University, Xinxiang, Henan, 453003 China
Received January 26, 2007
Abstract—Sodium hydrogen sulfite was used to promote condensation of o-phenylenediamine with aromatic
aldehydes in dimethylformamide to obtain the corresponding 2-arylbenzimidazoles. The procedure is simple
and convenient, and it implies inexpensive promoter and is characterized by short reaction time and easy
purification of the final products.
DOI: 10.1134/S1070428008060146
Benzimidazoles are very useful intermediates for
the synthesis of compounds of pharmaceutical or
biological interest. Benzimidazole derivatives exhibit
significant activity against several viruses such as HIV
[1], herpes (HSV-1) [2], RNA [3]. influenza [4], and
human cytomegalovirus (HCMV) [1]. Strong interest
in benzimidazole-containing structures has promoted
extensive studies on their synthesis. Although many
strategies are available for the synthesis of benzimid-
azole derivatives [7–16], there are only two general
methods for the preparation of 2-substituted benzimid-
azoles. One of these is based on coupling of o-phenyl-
enediamines with carboxylic acids [4] or their deriv-
atives (nitriles, imidates, or ortho esters) [5], and it
often requires strongly acidic conditions in combina-
tion with very high temperatures or the use of micro-
wave irradiation [6]. The other method is a two-step
procedure including oxidative cyclodehydrogenation
of Schiff bases prepared in turn by condensation of
o-phenylenediamines with aldehydes. Various oxidants
and catalysts, such as sulfamic acid [7], molecular
iodine [8], 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ) [9], atmospheric air [10], Oxone [11], FeCl3·
6H2O [12], In(OTf)3 [13], Yb(OTf)3 [14], Sc(OTf)3
[15], KHSO4 [16], and SO2 [17], were used. Despite
efficiency of some published methods, some of these
suffer from one or more disadvantages such as high
reaction temperature, prolonged reaction time, toxic
solvents, etc. Therefore, development of mild and
practical synthetic routes to 2-substituted benzimid-
azoles continues to attract researchers’ attention.
The goal of the present work was to develop
a simple and ecologically friendly procedure for the
synthesis of benzimidazoles. It is known that the sys-
tem urea–hydrogen peroxide is a stable, ecologically
safe, and easy-to-handle reagent in organic synthesis.
Table 1. Variation of promoter in the condensation of
o-phenylenediamine with 4-chlorobenzaldehyde
Promoter (mol %)
Urea–H2O2 (100)
Time, min Yield,a %
20
20
20
20
20
20
20
20
20
20
20
Traces
Traces
Traces
82
Urea–H2O2 (200)
Urea–H2O2 (500)
Urea–H2O2 +NaHSO3 (100+30)
NaHSO3 (30)
82
Scheme 1.
NaH2PO4 (30)
Traces
Traces
Traces
Traces
Traces
Traces
NaHSO3
DMF, 80°C
NH2
N
NaH2PO4 (100)
KH2PO4 (100)
+ RCHO
R
N
NH2
H
Na2HPO4 (100)
NaHCO3 (100)
None
For R, see Table 3.
* The text was submitted by the authors in English.
863

XIANGMING HAN et al.
864
We tried to synthesize benzimidazoles using urea–
hydrogen peroxide as oxidant, but failed. On the other
hand, we found that sodium hydrogen sulfite is an ef-
fective promoter in the synthesis of 2-aryl-substituted
benzimidazoles via condensation of aromatic alde-
hydes or cinnamaldehyde with o-phenylenediamine
(Scheme 1). In order to find optimal conditions, vari-
ous promoters and solvents were examined in the reac-
tion of o-phenylenediamine with 4-chlorobenzalde-
hyde as model process. The reactions were carried out
in dimethylformamide at 80°C, and the results are col-
lected in Table 1. It is seen that addition of 30 mol %
of NaHSO3 ensures the best yield of the product. When
the amount of NaHSO3 was smaller than 30 mol %, the
reaction took longer time, while larger amount of the
promoter favored increased fraction of by-products.
Next we examined the effect of solvent (Table 2). The
yield of 2-(4-chlorophenyl)benzimidazole increased in
parallel with the boiling point of the solvent, except for
xylene. Good results were obtained in alcohols (metha-
nol and ethanol) and DMSO. Clearly, the best solvent
was DMF: it ensured fast conversion and high yield
and is less toxic.
The scope and versatility of the proposed procedure
were determined using differently substituted benzal-
dehydes. In all cases the corresponding 2-arylbenz-
imidazoles were isolated in good to high yields. How-
ever, reactions of o-phenylenediamine with aliphatic
aldehydes (butanal and heptanal) gave only traces of
the corresponding 2-substituted benzimidazoles. The
results are summarized in Table 3.
Thus we have developed a simple one-pot proce-
dure for the synthesis of 2-arylbenzimidazoles by
condensation of o-phenylenediamine with the corre-
sponding substituted aromatic aldehyde in the presence
of NaHSO3. The procedure is advantageous due to
mild conditions, simple manipulations, the use of inex-
pensive promoter, easy purification, and short reaction
time.
Table 2. Solvent effect on the condensation of o-phenylene-
diamine with 4-chlorobenzaldehyde (reaction time 20 min)
EXPERIMENTAL
Solvent
Temperature, °C Yield,a %
The melting points were determined on a Kofler
micro melting point apparatus and were uncorrected.
The H NMR spectra were measured on a Bruker
DPX-400M spectrometer using tetramethylsilane as
internal standard and CDCl3 as solvent.
Methylene chloride
Tetrahydrofuran
Methanol
Reflux
Reflux
Reflux
Reflux
80
20
35
58
60
55
78
26
82
1
Ethanol
Typical procedure for the synthesis of benzimid-
azoles. Equimolar amounts (0.5 mmol) of o-phen-
ylenediamine and the corresponding aromatic aldehyde
(0.5 mmol) were thoroughly mixed in 2 ml of DMF,
0.15 mmol of sodium hydrogen sulfite was added, and
the mixture was stirred at 80°C until the reaction was
complete according to the TLC data. The mixture was
cooled to room temperature and added dropwise to
20 ml of water under vigorous stirring. If the product
separated as a free flowing solid, it was collected by
filtration, washed with water, and dried. If a gummy
material separated, it was extracted into ethyl acetate,
the extract was washed with water and a solution of
sodium chloride, dried over sodium sulfate, and evapo-
rated, and the residue was purified by column chroma-
tography on silica gel using cyclohexane–ethyl acetate
(3:1) as eluent.
Water
Dimethyl sulfoxide
Xylene
80
80
Dimethylformamide
80
Table 3. Synthesis of benzimidazoles in dimethylformamide
in the presence of NaHSO3 (temperature 80°C)
R
Time, min Yield,a % mp, °C [17]
4-ClC6H4
Ph
20
20
30
45
40
35
20
20
45
60
60
82
84
284–286
289–290
264–265
234–236
203–204
223–225
285–287
199–202
264–266 [7]
–
4-MeC6H4
2-HOC6H4
3-O2NC6H4
4-MeOC6H4
2-Furyl
80
75
81
75
78
1
2-(4-Chlorophenyl)-1H-benzimidazole. H NMR
PhCH=CH
4-Me2NC6H4
MeCH2CH2
Me(CH2)5
70
spectrum, δ, ppm: 12.98 br.s (1H), 8.18 d (2H, J =
8 Hz), 7.63 d (2H, J = 8.4 Hz), 7.22–7.55 m (4H).
72
Traces
Traces
1
2-Phenyl-1H-benzimidazole. H NMR spectrum,
–
δ, ppm: 8.05–8.10 m (2H), 7.65 m (2H), 7.46–7.51 m
(3H), 7.28 m (2H).
a
Isolated product.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 6 2008

A SIMPLE AND EFFICIENT SYNTHESIS
865
1
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