A highly effective sulfamic acid/methanol catalytic system for the synthesis of benzimidazole derivatives at room temperature

Article abstract of DOI:10.1007/s00706-006-0566-1

Sulfamic acid/methanol was found to be an efficient catalytic system for the synthesis of benzimidazole compounds through the condensation of o-phenylenediamine with orthoester in high yields at room temperature.

Full text of DOI:10.1007/s00706-006-0566-1

Monatshefte f€ur Chemie 138, 89–94 (2007)
DOI 10.1007/s00706-006-0566-1
Printed in The Netherlands
Short Communication
A Highly Effective Sulfamic Acid=Methanol
Catalytic System for the Synthesis
of Benzimidazole Derivatives at Room
Temperature
ꢀ
ꢀ
Zhan-Hui Zhang , Tong-Shuang Li , and Jian-Jiong Li
The College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang, China
Received October 13, 2006; accepted (revised) October 21, 2006
Published online December 8, 2006 # Springer-Verlag 2006
Summary. Sulfamic acid=methanol was found to be an efficient catalytic system for the synthesis of
benzimidazole compounds through the condensation of o-phenylenediamine with orthoester in high
yields at room temperature.
Keywords. Benzimidazole; o-Phenylenediamines; Orthoesters; Sulfamic acid=methanol system;
Synthesis.
Introduction
The synthesis of benzimidazole compounds has received significant attention be-
cause of the broad spectrum of their biological and pharmaceutical properties. This
class of molecules has found commercial applications in several therapeutic areas
such as antiparasitic [1], antitumor [2], antimicrobial [3], and anti-inflammatory [4]
agents as well as antihelminthic agents in veterinarian medicine [5]. Furthermore,
these compounds can act as ligands to transition metals for modeling biological
systems [6].
Due to their great importance, many synthesis strategies have been developed.
The most popular synthesis approaches generally involve the condensation of an
arylenediamine with a carboxylic acid or its derivative under harsh dehydrating
reaction conditions [7]. Another method is the condensation of an aldehyde with
arylenediamine [8]. Some methods using transition metal catalyzed coupling re-
actions to construct the benzimidazole nucleus have also been reported. Those
ꢀ
Corresponding authors. E-mail: zhanhui@126.com

90
Z.-H. Zhang et al.
Scheme 1
involved a palladium-catalyzed intramolecular N-arylation of (o-bromophenyl)-
amidine [9]. A method starting from arylenediamine and orthoester in the presence
of Yb(OTf)3 [10], Zeolite [11], or KSF clay [12] at high temperature was also used
for the synthesis of benzimidazole derivatives. However, many of these method-
ologies suffer from one or more disadvantages, such as low yields, lack of easy
availability of the starting materials, prolonged reaction time, high temperature,
requirement of excess of catalysts, special apparatus, and harsh reaction conditions.
Thus, there is a need for simple and efficient processes for the synthesis of benzi-
midazole derivatives.
Recently, sulfamic acid (SA) has been introduced as a promising solid-acid
catalyst for various organic transformations [13]. It is a nonvolatile, non-hygro-
scopic, odorless, uncorrodible, crystalline solid with outstanding physical stability
and is a commercially available, cheap material [14]. The use of SA as a catalyst
makes the process convenient, economic, and environmentally benign, its further
exploration for other organic transformations will be quite useful. During the
course of our recent studies directed at the development of practical, safe, and
environmentally friendly procedures for important transformations [15], we wish
to report an efficient, convenient, and facile method for the condensation of o-
phenylenediamine with orthoester to the corresponding benzimidazole derivatives
using a catalytic amount of SA at room temperature (Scheme 1).
Results and Discussion
Initially, the condensation of o-phenylenediamine as a model substrate was in-
vestigated by using triethyl orthoformate at room temperature in the presence of
SA. For the typical experiment, first o-phenylenediamine (1 mmol) and then SA
(0.05 mmol) were added to a solution of triethyl orthoformate (1.2 mmol) in MeOH
at room temperature. The condensation was completed after 1 h (Table 1, entry 3).
The effect of the relative amounts of SA on the outcome of the reaction was also
studied. It should be pointed out that in the absence of SA the reactions did not
Table 1. SA-catalyzed synthesis of benzimidazole at room temperature
Entry
SA (mol%)
Time=h
Solvent
Yield=%
1
2
3
4
5
6
7
20
10
5
1
1
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
96
95
95
75
0
1
1
1
0
10
1
10
10
89
36
2
CH2Cl2

Synthesis of Benzimidazole Derivatives
91
proceed in MeOH even after prolonged reaction times thus confirming the effec-
tiveness of SA as catalyst. A catalytic amount of SA (5 mol%) is sufficient to obtain
the desired product in high yields. No significant improvement in the yields was
observed on increasing the catalyst loading further. The reaction was also carried
out in some other organic solvents. Methanol was found to give the best yield of
product in comparison with ethanol and dichloromethane. The remarkable effi-
ciency of the SA=MeOH system can be explained by a better synergetic effect of
SA in its zwitterionic form with MeOH. In the light of this, subsequent studies
were carried out under following optimized conditions, that is, with 5 mol% SA at
room temperature in MeOH.
Having established the optimized experimental conditions, various arylenedia-
mines 1 were subjected to react with orthoesters 2 in order to investigate the
reaction scope and several representative results are summarized in Table 2. As
shown in Table 2, various types of o-diaminobenzene derivatives (1a–1t) with
electron-donating and -withdrawing substituents on the aromatic ring were readily
and rapidly converted to the corresponding substituted benzimidazoles in the pre-
sence of 5 mol% of SA. The electronic nature of the substituents on the aromatic
ring of o-diaminobenzene was relevant to the yield of 3. In general, when R
represented electron-withdrawing groups such as chloro (Table 2, entries q and r)
and nitro (Table 2, entries s and t), the yields and purities of the products were
obviously worse, and long reaction times were required. The substituent R2 in the
orthoester has no influence on the reaction course (Table 2, entries a and b). Many
Table 2. SA=MeOH-catalyzed synthesis of benzimidazoles at room temperature
Entry
Arylenediamine 1
Orthoesters 2
Time=h
Yield=% of 3a
a
b
c
d
e
f
o-phenylenediamine
o-phenylenediamine
HC(OMe)3
HC(OEt)3
1.0
1.0
0.8
0.8
0.9
0.5
0.5
0.6
0.6
0.8
0.8
0.9
1.0
0.7
0.7
0.8
2.0
2.0
5.0
4.0
96
98
95
92
95
93
92
92
91
88
86
85
94
93
95
92
89
87
85
86
o-phenylenediamine
CH3C(OMe)3
CH3CH2C(OEt)3
CH3(CH2)3C(OMe)3
HC(OEt)3
o-phenylenediamine
o-phenylenediamine
4-methylbenzene-1,2-diamine
4-methylbenzene-1,2-diamine
4-methylbenzene-1,2-diamine
4-methylbenzene-1,2-diamine
3-methylbenzene-1,2-diamine
3-methylbenzene-1,2-diamine
3-methylbenzene-1,2-diamine
4,5-dimethylbenzene-1,2-diamine
4,5-dimethylbenzene-1,2-diamine
4,5-dimethylbenzene-1,2-diamine
4,5-dimethylbenzene-1,2-diamine
4-chlorobenzene-1,2-diamine
4-chlorobenzene-1,2-diamine
4-nitrobenzene-1,2-diamine
4-nitrobenzene-1,2-diamine
g
h
i
CH3C(OMe)3
CH3CH2C(OEt)3
CH3(CH2)3C(OMe)3
HC(OEt)3
j
k
l
CH3C(OMe)3
CH3(CH2)3C(OMe)3
HC(OEt)3
m
n
o
p
q
r
s
CH3C(OMe)3
CH3CH2C(OEt)3
CH3(CH2)3C(OMe)3
HC(OEt)3
CH3CH2C(OMe)3
HC(OEt)3
t
CH3CH(OMe)3
a
Isolated yield

92
Z.-H. Zhang et al.
of the pharmacologically relevant substitution patterns on the aromatic ring could
be introduced by using this procedure. In all cases, the reaction proceeded effi-
ciently at room temperature without the formation of any by-products. All of the
products were characterized by IR, NMR, and mass spectral analysis and also by
comparison with authentic samples [10].
In conclusion, sulfamic acid=MeOH is introduced as an excellent catalytic
system for the synthesis of benzimidazole compounds. In comparison with the
previously reported methods, this novel and practical method has the advantages
of mild reaction conditions, short reaction times, excellent yields of products,
simple workup procedure, and low cost of catalyst.
Experimental
Melting points were recorded on a X-4 apparatus. IR spectra were obtained using a Bruker-TENSOR
27 spectrometer instrument. NMR spectra were taken with a varain Mercury Plus 400 spectrometer.
Mass spectra were performed on a ThermoFinnigan LCQ Advantage instrument with an ESI source
(4.5keV). Elemental analyses were carried out on an elementar vario EL analyzer. Their results agreed
favourably with the calculated values.
General Procedure for the Synthesis of Benzimidazoles 3
A mixture of 1.0 mmol o-phenylenediamine, 1.2mmol triethyl orthoformate, and 2 cm3 MeOH was
stirred at room temperature in the presence of a catalytic amount of sulfamic acid (0.05 mmol). The
reaction was monitored by TLC. At completion of the reaction, the mixture was distilled under vacuum
to remove the solvent and then diluted with 5 cm3 H2O. After extraction with 3ꢁ10cm3 ethyl acetate,
the combined organic layers were washed with brine and dried (MgSO4). The residue was concentrated
to afford the crude product. The crude product was purified by recrystallization from diethyl ether or by
silica gel column chromatography (20% ethyl acetate in n-hexane as eluent).
The compounds 3a [10], 3c [10], 3d [10], 3e [16], 3f [10], 3g [10], 3h [10], 3j [17], 3k [17], 3m
[18], 3n [18], 3p [19], 3q [10], 3r [11], 3s [10], and 3t [10] are known, their identity was proven by
means of IR, NMR, and mass spectra. Herein we give melting points and spectral data for 3i, 3l, and
3o, which could not be found in literature.
2-Butyl-5-methylbenzimidazole (3i, C12H16N2)
Pale yellow solid, mp 94–95ꢂC; IR (KBr): ꢀꢀ¼ 3413, 2955, 1634, 1548, 1425, 1325, 1281, 1090,
858 cmꢃ1; 1H NMR (400 MHz, CDCl3): ꢁ ¼ 0.90 (t, J ¼ 7.2 Hz, 3H), 1.39 (sext, J ¼ 7.2 Hz, 2H), 1.82
(quin, J ¼ 7.2Hz, 2H), 2.44 (s, 3H), 2.91 (t, J ¼ 7.2 Hz, 2H), 7.02 (d, J ¼ 8.0 Hz, 1H), 7.31 (s, 1H), 7.43
(d, J ¼ 8.0 Hz, 1H), 8.76 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 13.90, 21.80, 22.63, 29.25,
30.75, 114.40, 114.66, 123.60, 131.96, 137.32, 138.76, 155.78 ppm; ESI-MS: m=z ¼ 189 (Mþ 1)þ.
2-Butyl-4-methylbenzimidazole (3l, C12H16N2)
Pale yellow solid, mp 130–131ꢂC; IR (KBr): ꢀꢀ¼ 3414, 2957, 2934, 1619, 1545, 1440, 1278, 1232,
1104, 880 cmꢃ1; 1H NMR (400MHz, CDCl3): ꢁ ¼ 0.86 (t, J ¼ 7.2 Hz, 3H), 1.37 (sext, J ¼ 7.2 Hz, 2H),
1.82 (quin, J ¼ 7.2 Hz, 2H), 2.57 (s, 3H), 2.96 (t, J ¼ 7.2 Hz, 2H), 7.03 (d, J ¼ 7.6 Hz, 1H), 7.12
(t, J ¼ 7.6Hz, 1H), 7.38 (d, J ¼ 7.6Hz, 1H), 9.86 (s, 1H) ppm; 13C NMR (100MHz, CDCl3):
ꢁ ¼ 13.90, 17.38, 22.66, 29.04, 30.76, 112.10, 122.70, 123.30, 124.86, 137.52, 154.85 ppm; ESI-
MS: m=z ¼ 189 (Mþ 1)þ.
2-Ethyl-5,6-dimethylbenzimidazole (3o, C11H14N2)
Pale yellow solid, mp 229–231ꢂC; IR (KBr): ꢀꢀ¼ 3405, 1636, 1540, 1449, 1308, 1216, 1104, 1025,
860 cmꢃ1
;
1H NMR (400MHz, acetone-d6): ꢁ ¼ 1.35 (t, J ¼ 7.6 Hz, 3H), 2.28 (s, 6H), 2.92 (q,

Synthesis of Benzimidazole Derivatives
93
J ¼ 7.6 Hz, 2H), 7.30 (s, 2H), 9.71 (s, 1H) ppm; 13C NMR (100MHz, acetone-d6): ꢁ ¼ 11.90, 19.63,
21.84, 114.69, 130.86, 136.35, 155.45 ppm; ESI-MS: m=z ¼ 175 (M þ 1)þ.
Acknowledgement
We thank the Science Foundation from Hebei Normal University, the Nature Science Foundation of
Hebei Province (B2005000151), and the Natural Science Foundation of Hebei Education Department
(2006318) for financial support.
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