Efficient (bromodimethyl)sulfonium bromide mediated synthesis of benzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2006.11.018

Benzimidazoles have been efficiently synthesized in high yields by treatment of 1,2-phenylenediamine with aldehydes using (bromodimethyl)sulfonium bromide at room temperature.

Full text of DOI:10.1016/j.tetlet.2006.11.018

Tetrahedron Letters 48 (2007) 61–64
Efficient (bromodimethyl)sulfonium bromide mediated
synthesis of benzimidazolesI
Biswanath Das,* Harish Holla and Yallamalla Srinivas
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 18 September 2006; revised 20 October 2006; accepted 2 November 2006
Available online 21 November 2006
Abstract—Benzimidazoles have been efficiently synthesized in high yields by treatment of 1,2-phenylenediamine with aldehydes
using (bromodimethyl)sulfonium bromide at room temperature.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Several aldehydes (aromatic, heteroaromatic and ali-
phatic) underwent the above conversion to form a series
of benzimidazoles (Table 1). Aromatic aldehydes con-
taining both electron-donating and electron-withdrawing
groups worked well. Aliphatic a,b-unsaturated aldehydes
(Table 1, entry 3m) also afforded the desired products in
high yields. The method is suitable for the preparation of
benzimidazoles from an acid sensitive aldehyde such as
furfuraldehyde (entry 3n) and the sterically hindered
aldehyde 2-naphthaldehyde (entry 3o). The reaction
conditions are mild and the experimental procedure is
simple. The products were formed in high yields (72–
91%). The structures of the products were determined
from their spectral (1H NMR, IR and MS) data.
The benzimidazole moiety is found in various bioactive
compounds having antiviral, antiulcer, antihypertension
and anticancer properties.1 General methods for the
synthesis of benzimidazoles involve treatment of 1,2-
phenylenediamines with carboxylic acids or various
derivatives under strongly acidic conditions or with
aldehydes followed by oxidation.2,3
2. Results and discussion
In continuation of our work4 on the development of
useful synthetic methodologies, we have observed that
benzimidazoles can be synthesized efficiently by treat-
ment of 1,2-phenylenediamine with aldehydes using
(bromodimethyl)sulfonium bromide at room tempera-
ture (Scheme 1).
(Bromodimethyl)sulfonium bromide is an inexpensive
reagent. It has been used mainly as a catalyst but its
scope has not been fully explored.5 Here it has been
applied for oxidative dehydrogenation of the cyclic
-
+
O
Me2SBrBr
MeCN
NH2
NH2
N
H
+
r.t., 4-8 h
R
N
H
R
72-91%
1
3
2
Scheme 1.
Keywords: Aldehyde; Diamine; (Bromodimethyl)sulfonium bromide; Benzimidazole.
q Part 119 in the series, ‘Studies on novel synthetic methodologies’. IICT Communication No. 061021.
*
Corresponding author. Tel./fax: +91 40 27160512; e-mail: biswanathdas@yahoo.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.018

62
B. Das et al. / Tetrahedron Letters 48 (2007) 61–64
Table 1. Synthesis of benzimidazoles using (bromodimethyl)sulfonium bromidea
Entry
Aldehyde
Product
Time (h)
5
Isolated yield (%)
85
CHO
N
3a
N
H
CHO
N
CH3
3b
6
6
78
74
N
H
CH3
CHO
N
CH2CH3
3c
N
H
CH2CH3
CHO
N
OMe
3d
6
8
80
72
N
H
OMe
CHO
OMe
N
3e
OMe
MeO
N
H
OMe
CHO
O
N
3f
8
75
O
N
H
O
O
CHO
N
Cl
3g
3h
3i
5
5
4
4
82
84
81
86
N
H
Cl
CHO
Cl
Cl
Cl
N
Cl
N
H
CHO
NO2
N
N
H
O2N
CHO
N
NO2
3j
N
H
NO2

B. Das et al. / Tetrahedron Letters 48 (2007) 61–64
63
Table 1 (continued)
Entry
Aldehyde
Product
Time (h)
Isolated yield (%)
CHO
N
3k
6
84
N
H
N
CHO
3l
8
8
8
6
78
91
72
74
N
H
N
3m
3n
3o
N
H
CHO
N
O
O
CHO
N
H
CHO
N
N
H
O
N
O
O
3p
4
82
N
H
O
CHO
a The structures of the products were determined from their spectral (1H NMR, IR and MS) data.
intermediates formed from the condensation of 1,2-
phenylenediamine and aldehydes.
3.1. Compound 3g
1H NMR (CDCl3 + DMSO-d6): d 12.70 (1H, br s), 8.08
(2H, d, J = 8.0 Hz), 7.59 (1H, m), 7.26–7.20 (3H, m),
In conclusion, (bromodimethyl)sulfonium bromide has
been employed here for the first time as a mild and
efficient reagent for the convenient preparation of benz-
imidazoles in high yields from 1,2-phenylenediamine
and a wide variety of aldehydes.
7.18–7.04 (2H, m); IR (KBr): m 3188, 2981, 1624 cmÀ1
;
FABMS: m/z 231 (37Cl [M+H]+), 229 (35Cl [M+H]+);
Anal. Calcd for C13H9N2Cl: C, 68.27; H, 3.94; N,
12.25. Found: C, 68.42; H, 3.86; N, 12.38.
3.2. Compound 3m
3. General experimental procedure
1H NMR (CDCl3 + DMSO-d6): d 11.82 (1H, br s),
7.62–7.21 (2H, m), 7.18–7.01 (2H, m), 6.42 (1H, t,
J = 7.0 Hz), 2.29–2.22 (2H, m), 2.16 (3H, s), 1.08 (3H,
To a mixture of an aldehyde (0.5 mmol) and 1,2-pheny-
lenediamine (0.6 mmol) in acetonitrile (5 mL) under a
nitrogen atmosphere, (bromodimethyl)sulfonium bro-
mide (0.5 mmol) was added. The mixture was stirred
at room temperature and the reaction was monitored
by TLC. After completion, the solvent was evaporated
and saturated aqueous NaHCO3 (10 mL) was added.
The mixture was extracted with EtOAc (3 · 10 mL)
and the extract was dried and concentrated. The
residue was subjected to column chromatography (sil-
ica gel, hexane–EtOAc) to obtain the pure benzimi-
dazole.
t, J = 7.0 Hz); IR (KBr):
m 3064, 2963, 2923,
1648 cmÀ1; FABMS: m/z 187 [M+H]+; Anal. Calcd
for C12H14N2: C, 77.42; H, 7.53; N, 15.05. Found: C,
77.68; H, 7.64; N, 15.23.
3.3. Compound 3o
1H NMR (CDCl3 + DMSO-d6): d 11.86 (1H, br s), 8.74
(1H, br s), 8.38 (1H, dd, J = 8.0, 2.0 Hz), 8.02–7.90 (3H,
m), 7.69–7.52 (4H, m), 7.26–7.18 (2H, m); IR (KBr): m
3056, 2924, 2853, 1624 cmÀ1
; FABMS: m/z 245
The spectral (1H NMR, IR and MS) data of some
representative benzimidazoles are given below.
[M+H]+; Anal. Calcd for C17H12N2: C, 83.61; H, 4.92;
N, 11.47. Found: C, 83.87; H, 4.88; N, 11.61.

64
B. Das et al. / Tetrahedron Letters 48 (2007) 61–64
Tsumoto, K.; Tasaki, M. Chem. Pharm. Bull. 1982, 30,
3.4. Compound 3p
2996; (c) Fairley, T. A.; Tidwell, R. R.; Donkor, I.;
Naiman, N. A.; Ohemeng, K. A.; Lombardy, R. J.; Bentley,
J. A.; Cory, M. J. Med. Chem. 1993, 36, 1746; (d) Czarny,
A.; Wilson, W. D.; Boykin, D. W. J. Heterocycl. Chem.
1996, 33, 1393.
1H NMR (CDCl3 + DMSO-d6): d 11.79 (1H, br s), 9.28
(1H, s), 8.16 (1H, s), 7.68 (1H, m), 7.58–7.46 (2H, m),
7.24–7.20 (3H, m), 2.56 (3H, s); IR (KBr): m 3308,
3048, 2923, 2854, 1639 cmÀ1
; FABMS: m/z 277
3. (a) Stephens, F. F.; Bower, J. D. J. Chem. Soc. 1949, 2971;
(b) Chikashita, H.; Nishida, S.; Miyazaki, M.; Morita, Y.;
Itoh, K. Bull. Chem. Soc. Jpn. 1987, 60, 737; (c) Kumar, S.;
Kansal, V.; Bhaduri, A. Indian J. Chem. 1991, 20B, 254; (d)
Patzold, F.; Zeuner, F.; Heyer, T. H.; Niclas, H.-J. Synth.
Commun. 1992, 22, 281; (e) Lombardy, R. L.; Tanious, F.
A.; Ramachandran, K.; Tidwell, R. R.; Wilson, W. D. J.
Med. Chem. 1996, 39, 1452; (f) Beaulieu, P. L.; Hache, B.;
von Moos, E. Synthesis 2003, 1683.
[M+H]+; Anal. Calcd for C17H12N2O2: C, 73.91; H,
4.35; N, 10.14. Found: C, 73.98; H, 4.42; N, 10.23.
Acknowledgements
The authors thank UGC and CSIR, New Delhi, for
financial assistance.
4. (a) Das, B.; Reddy, V. S. Catal. Commun. 2006, 7, 997; (b)
Das, B.; Venkateswarlu, K.; Holla, H.; Krishnaiah, M. J.
Mol. Catal. A: Chem. 2006, 253, 107; (c) Das, B.; Reddy, K.
R.; Ramu, R.; Thirupathi, P.; Ravikanth, B. Synlett 2006,
1756; (d) Das, B.; Ravikanth, B.; Ramu, R.; Rao, B. V.
Chem. Pharm. Bull. 2006, 54, 1044; (e) Das, B.; Chowdhury,
N.; Banerjee, J.; Majhi, A.; Mahender, G. Chem. Lett.
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5. (a) Furukawa, N.; Inoue, T.; Aida, T.; Oae, S. J. Chem.
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