Microwave irradiation synthesis of 2-substituted benzimidazoles using PPA as a catalyst under solvent-free conditions

Article abstract of DOI:10.1081/SCC-120015381

An efficient microwave irradiation synthesis of 2-substituted benzimidazoles using polyphosphoric acid (PPA) as a catalyst from organic acid and o-phenylenediamine under solvent-free conditions is described. This method is a good option to obtain the title compounds in a simple and an inexpensive way.

Full text of DOI:10.1081/SCC-120015381

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MICROWAVE IRRADIATION SYNTHESIS OF 2-SUBSTITUTED
BENZIMIDAZOLES USING PPA AS A CATALYST UNDER
SOLVENT-FREE CONDITIONS
Jun Lu a , Bingqin Yang a & Yinjuan Bai a
a Department of Chemistry, Northwest University, Xi’an, 710069, P.R. China
Version of record first published: 23 Aug 2006.
To cite this article: Jun Lu, Bingqin Yang & Yinjuan Bai (2002): MICROWAVE IRRADIATION SYNTHESIS OF 2-SUBSTITUTED
BENZIMIDAZOLES USING PPA AS A CATALYST UNDER SOLVENT-FREE CONDITIONS, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:24, 3703-3709
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 24, pp. 3703–3709, 2002
MICROWAVE IRRADIATION SYNTHESIS
OF 2-SUBSTITUTED BENZIMIDAZOLES
USING PPA AS A CATALYST UNDER
SOLVENT-FREE CONDITIONS
*
Jun Lu, Bingqin Yang, and Yinjuan Bai
Department of Chemistry, Northwest University,
Xi’an 710069, P.R. China
ABSTRACT
An efficient microwave irradiation synthesis of 2-substituted
benzimidazoles using polyphosphoric acid (PPA) as a cata-
lyst from organic acid and o-phenylenediamine under
solvent-free conditions is described. This method is a good
option to obtain the title compounds in a simple and an
inexpensive way.
Key Words: Microwave irradiation; 2-Substituted benzimi-
dazoles; Synthesis
Benzimidazole is a versatile core contained in several substances pos-
sessing a broad spectrum of pharmacological activity, e.g., as anticancer,
antimicrobial, pesticide and anthelmintic.[1] In addition, benzimidazole and
its derivatives are also very important intermediates in organic reactions.[2]
Therefore, preparation of benzimidazoles has attracted considerable
attention in recent years.
*Corresponding author. Fax: þ86-29-8303798; E-mail: lujunyue@hotmail.com
3703
DOI: 10.1081/SCC-120015381
Copyright & 2002 by Marcel Dekker, Inc.
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LU, YANG, AND BAI
Benzimidazoles are generally prepared by the condensation of
o-phenylenediamine with organic acids employing hydrochloric acid,[3]
polyphosphoric acid,[4] boric acid[5] or p-toluenesulphonic acid[6] as
catalyst. In addition, the title compounds also can be obtained either by
reduction of o-nitroaniline derivatives, or by reaction of organic acids
derivatives with o-phenylenediamine.[7] Yet these reactions are often carried
out under high pressure and require for long reaction times. Therefore, the
discovery of mild and practical routes for the synthesis of benzimidazoles
continues to attract the attention of researchers. Several improved
procedures for the preparation of benzimidazoles have been reported,
either by fusion of 2-aminobenzamide and organic acid,[8] or by reaction
of o-phenylenediamine and organic acid using FeCl3/O2 as a catalytic
Fe3þ/Fe2þ redox cycling approach.[9] Recently, Villemin et al.[10] and
Loupy et al.[11] reported a fast and convenient synthesis of benzimidazoles
by condensation of orthoesters with o-phenylenediamine in dry medium and
using KSF clay under mono-mode microwave irradiation. Guillermo
Penieres et al.[12] also obtained 2-alkylbenzimidazoles using natural clay
under infrared irradiation in solvent-free conditions. In addition, the devel-
opment of novel, but more complex solid phase routes to benzimidazoles
had been advanced.[13]
Microwave irradiation of organic reactions has rapidly gained
in popularity as it accelerates a variety of synthetic transformations.[14]
The application of microwave irradiation with the use of catalysts or
mineral supported reagents, under solvent-free conditions, provides unique
chemical processes with special attributes such as enhanced reaction rates,
higher yields, greater selectivity and ease of manipulation. Therefore, micro-
wave irradiation in organic synthesis has been the focus of considerable
attention in recent years and is becoming an increasingly popular tech-
nology.[11,15] Reactions in ‘‘dry media’’ or under solvent-free conditions are
especially appealing as they provide an opportunity to work with open
vessels, thus avoiding the risk of high pressure development and with the
possibility of upscaling the reactions to larger scale. Solventless procedures
without the use of supporting reagents are particularly eco-friendly.
Here we would like to report our preliminary investigation concerning
the direct synthesis of 2-substituted benzimidazoles and 2-benzimidazol-
2-one or thione. In this paper, we describe an efficient and practical route
for the benzimidazoles under microwave irradiation using polyphosphoric
acid as the catalyst. All reactions were carried out under solvent-free
conditions in an open Pyrex test tube. Compared with the conventional
reaction, the conditions of this reaction were mild, easy to be executed
and the isolated yields of the benzimidazoles and 2-benzimidazol-2-one or
thione were comparable.

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2-SUBSTITUTED BENZIMIDAZOLES
3705
Scheme 1.
Scheme 2.
In the presence of the PPA(5 mL), the mixture of organic acid
(15 mmol) and o-phenylenediamine (10 mmol) was stirred and irradiated
in a household microwave oven (Type: Galanz 2450 Hz, 900 W) for 6 or
8 min at 162 W (18% of full output power), it can be controlled by the
switches of the microwave oven. After the reaction was completed, the
mixture was allowed to cool to room temperature and then poured into
cold water. Stirring was continued for several minutes and the mixture
was neutralized with aq. NaOH, then the solid products were filtered off.
The crude products 3a–l obtained were purified by recrystallization. It was
found that 2-substituted benzimidazoles 3a–b can be obtained even in the
absence of PPA. However, 2-substituted benzimidazoles 3c–l only can be
achieved in the presence of PPA. On the other hand, when urea and thiourea
were used as substituent for the acid 2, 2-benzimidazol-2-one 5a and thione 5b
were obtained. The results are summarized in Schs. 1 & 2 and Tables 1 & 2.
In conclusion, a rapid and practical procedure for the synthesis of
2-substituted benzimidazoles, 2-benzimidazol-2-one and thione from
organic acids (or urea, or thiourea) and o-phenylenediamine under micro-
wave irradiation conditions was developed. Moreover, the new procedure is
simple, inexpensive, solvent-free, environmentally friendly and give good
yields which makes it a useful alternative to existing methods.
EXPERIMENTAL
1
Melting points are uncorrected. H NMR spectra were recorded at
300 MHz in DMSO-d6 using TMS as internal standard. IR spectra were

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LU, YANG, AND BAI
Table 1. Microwave-Assisted 2-Substituted Benzimidazoles Synthesized Using
PPAas Catalyst
Time
(min)
M.P.
(ꢀC)
M.P. Lit.
(ꢀC)
Yielda
(%)
Entry
R
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
CH3
CH2Cl
CH2CH3
CH2CH2CH3
CH2CH2CH2CH3
CH2CH2CH2CH2CH3
C6H5
4-Cl C6H4
4-CH3C6H4
6
6
6
6
8
8
8
8
8
8
8
8
172–173
174–176
161–162
173–174
156–158
153–155
162–163
292–293
289–291
268–270
224–225
225–227
172–173[16]
175–177[16]
161–163[12]
173–175[16]
157–157.5[16]
155–155.5[16]
163–163.5[16]
293[8]
64
75
88
70
52
49
56
78
72
69
53
39
290[8]
3j
270[8]
3k
3l
4-CH3OC6H4
2-HOC6H4
225[8]
226[8]
aAll yields refer to isolated pure products.
Table 2. Microwave-Assisted 2-Benzimidazol-2-one and Thione Synthesized Using
PPAas Catalyst
Time
(min)
M.P.
(ꢀC)
M.P. Lit.
(ꢀC)
Yielda
(%)
Entry
X
5a
5b
O
S
8
8
304–306
307–308
304–307[12]
308–310[12]
86
71
aAll yields refer to isolated pure products.
measured on EQUINOX55 spectrophotometer as KBr pellets. The output
power of microwave oven could be controlled by the switches of microwave
oven. All the products are known compounds which were characterized by
1
IR and H NMR spectral data and their melting points compared with
literature reported melting points.
2-Methylbenzimidazole (3b). A Typical Procedure
In the presence of the PPA(5 mL), the mixture of acetic acid
(15 mmol) and o-phenylenediamine (10 mmol) was stirred and irradiated

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2-SUBSTITUTED BENZIMIDAZOLES
3707
in the MW oven three times at the 18% full output power (162 W) for 6 min
with 2 min cooling period after the 1st and 2nd irradiation cycle, respect-
ively. After cooling, the reaction mixture was poured into 50 mL of cold
H2O and neutralized with aq. NaHCO3, and the solid products were filtered
off. The crude products obtained were purified by recrystallization from
H2O and dried to give crystalline product 3b in 75% yield (0.99 g); m.p.
174–176ꢀC (lit.[16] m.p. 175–177ꢀC).
Synthesis of Compounds 5a–b
In to a round-bottomed flask were place 1.08 g (10 mmol) of o-phenyl-
enediamine, an equimolar concentration of urea or thiourea to form 5a or
5b, respectively, and PPA(5 mL). Then, the mixture was treated as above.
ACKNOWLEDGMENTS
We thank the natural science foundation of Shaan’xi Province
(2000H03) for financial support.
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Received in the USANovember 25, 2001

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