Simple and convenient one-pot synthesis of benzimidazoles and benzoxazoles using N,N-dimethylchlorosulfitemethaniminium chloride as condensing agent

Article abstract of DOI:10.1080/00397910701459423

N,N-Dimethylchlorosulfitemethaniminium chloride (SOCl2-DMF) has been found to be an efficient reagent for the one-pot synthesis of benzimidazoles and benzoxazoles in excellent yield by condensation of carboxylic acids with o-phenylenediamine/2-amino-phenol. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701459423

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Simple and Convenient One‐Pot Synthesis
of Benzimidazoles and Benzoxazoles using
N,N‐Dimethylchlorosulfitemethaniminium
Chloride as Condensing Agent
Savita Kaul a , Ajay Kumar b , Bir Sain a & A. K. Bhatnagar a
a Chemical and Biotechnology Division, Indian Institute of Petroleum,
Dehradun, India
b IOC, Research and Development Centre, Faridabad, Haryana, India
Published online: 09 Aug 2007.
To cite this article: Savita Kaul , Ajay Kumar , Bir Sain & A. K. Bhatnagar (2007): Simple and Convenient
One‐Pot Synthesis of Benzimidazoles and Benzoxazoles using N,N‐Dimethylchlorosulfitemethaniminium
Chloride as Condensing Agent, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 37:15, 2457-2460
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Synthetic Communicationsw, 37: 2457–2460, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701459423
Simple and Convenient One-Pot Synthesis of
Benzimidazoles and Benzoxazoles using
N,N-Dimethylchlorosulfitemethaniminium
Chloride as Condensing Agent
Savita Kaul
Chemical and Biotechnology Division, Indian Institute of Petroleum,
Dehradun, India
Ajay Kumar
IOC, Research and Development Centre, Faridabad, Haryana, India
Bir Sain and A. K. Bhatnagar
Chemical and Biotechnology Division, Indian Institute of Petroleum,
Dehradun, India
Abstract: N,N-Dimethylchlorosulfitemethaniminium chloride (SOCl2-DMF) has been
found to be an efficient reagent for the one-pot synthesis of benzimidazoles and
benzoxazoles in excellent yield by condensation of carboxylic acids with o-phenylene-
diamine/2-amino-phenol.
Keywords: benzimidazole, benzoxozole, carboxylic acid, condensation, o-phenylene-
diamine/2-amino-phenol
INTRODUCTION
Benzimidazoles constitute an important class of heterocyclic compounds that
possess a wide spectrum of biological properties[1] and find wide applications
as antifungal, antibacterial, antihelminthic, and 5-HT receptor antagonist
Received December 26, 2006
Address correspondence to Savita Kaul, Chemical and Biotechnology Division,
Indian Institute of Petroleum, Dehradun 248 005, India. E-mail: skaul@iip.res.in
2457

2458
S. Kaul et al.
agents. There are also literature reports on the use of benzimidazoles as
corrosion inhibitors in oilfields.[2,3] The classical method for the synthesis
of benzimidazoles is the Phillips reaction, which involves condensation of
o-phenylenediamine with carboxylic acid or its derivatives in the presence
of dilute mineral acid at elevated temperature. Although this method of con-
densation works well for the preparation of 2-alkyl-substituted derivatives, it
frequently fails or gives low yields in the preparation of 2-aryl-substituted
benzimidazoles. Polyphosphoric acid has been reported to be a highly
effective, convenient reagent for promoting this type of condensation.[4] The
other important methods for the synthesis of benzimidazoles involve the use
of 2-nitroarylamines or 1,2-dinitroarenes. Similarly, benzoxazoles are also
an important class of biologically active heterocycles, and the classical
method for their synthesis involves condensation of 2-aminophenols with car-
boxylic acids and their derivatives at elevated temperature in the presence of a
condensing agent such as polyphosphoric acid.[4] The other synthetic methods
for benzoxazoles involve reaction of o-hydroxyphenylketoximes with PCl5 or
P2O5[2–4] and reaction of 2-amino phenols with allenic and acetylenic nitriles.
RESULTS AND DISCUSSION
In continuation to our earlier studies,[5–7] herein we report for the first time a
simple and convenient one-pot synthesis of benzimidazoles (3,X55NH) and
benzoxazoles (3,X55O) from carboxylic acids (1) and o-phenylenediamine/
2-amino-phenol (2) using N,N-dimethyl chlorosulfitemethaniminium
chloride (Meþ2 N CHOSOCl) Cl2 as the condensing agent (Scheme 1).
A variety of carboxylic acids, both aliphatic and aromatic, smoothly
reacted with o-phenylenediamine in the presence of N,N-dimethylchlorosulfite-
methaniminium chloride to yield benzimidazoles in almost quantitative yields
(Table 1, entries 1–8). Similarly, 2-aminophenol smoothly reacted with car-
boxylic acids in the presence of N,N-dimethylchlorosulfitemethaniminium
chloride to yield benzoxazoles in excellent yields (Table 1, entries 9 and 10).
The protocol consisted of adding two molar quantities of N,N-dimethyl-
chlorosulfitemethaniminium chloride to a suspension of one molar carboxylic
acid in dichloromethane, stirring the mixture for about 15 min, adding
Scheme 1.

Benzimidazole and Benzoxazole Synthesis
2459
Table 1. Synthesis of benzimidazoles/benzoxazoles from car-
boxylic acid and o-phenylene diamine/2-amino-phenol using N,N-
dimethylchlorosulfite-methaniminium chloride
Entry
Benzimidazoles/benzoxazoles (3)
Yield (%)a
1
2
X55NH, R55C6H5
95
97
91
94
89
97
96
93
90
89
X55NH, R553-CH3-C6H4
X55NH, R552-Cl-C6H4
X55NH, R553,4-Cl2-C6H4
X55NH, R55C6H5CH2
X55NH, R55CH3CH2
X55NH, R 55n-C5H11
X55NH, R55n-C4H9
X55O, R55C6H5
3
4
5
6
7
8
9
10
X55O, R553-CH3-C6H4
aIsolated yield.
one molar quantity of o-phenylene diamine/2-amino-phenol, followed by
adding excess of pyridine, stirring the mixture at room temperature for 6 h,
and using the usual workup.
The reactions proceeded through the formation of activated carboxylic
acid species (4), which react with o-phenylenediamine/2-amino-phenol to
yield acylated product (5), which cyclizes to benzimidazol/benzoxazole (3)
in the presence of acid (Scheme 2).
In conclusion, N,N-dimethylchlorosulfitemethaniminium chloride has
been found to be a novel reagent for the synthesis of benzimidazoles/benzox-
azoles from carboxyl acid and 2-phenylenediamine/2-amino-phenol.
Scheme 2.

2460
S. Kaul et al.
EXPERIMENTAL
A typical procedure for the preparation of benzimidazole from carboxylic acid
and 0-phenylenediamine follows. Freshly prepared N,N-dimethylchlorosulfite
methaniminium chloride (7.68 g, 40 mmol) to a solution of benzoic acid
(2.44 g, 20 mmol) in anhydrous dichloromethane (40 ml) was added at 08C.
After stirring for 15 min, 0-phenylenediamine (2.16 g, 20 mmol) was added,
followed by the dropwise addition of anhydrous pyridine (9.7 ml, 0.12 mol)
in dichloromethane (25 ml). The resulting mixture was stirred at room temp-
erature for 6 h and washed with water (3ꢀ50 ml); the organic layer was
separated and dried over anhydrous sodium sulphate. Evaporation of the
solvent and recrystallization gave pure 2-phenylbenzimidazole (3.69 g, 95%).
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