A simple and convenient one-pot synthesis of benzimidazole derivatives using cobalt(II) chloride hexahydrate as catalyst

Article abstract of DOI:10.1080/00397910802654815

A simple and efficient method for the convenient synthesis of 2-arylbenzimidazole has been described on reaction with o-phenylenediamine and various aromatic aldehydes using cobalt(II) chloride hexahydrate as a catalyst. The method is cost-effective, high

Full text of DOI:10.1080/00397910802654815

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A Simple and Convenient One-
Pot Synthesis of Benzimidazole
Derivatives Using Cobalt(II)
Chloride Hexahydrate as
Catalyst
a
a
Abu T. Khan , Tasneem Parvin & Lokman H.
b
Choudhury
a
Department of Chemistry, Indian Institute of
Technology Guwahati, Guwahati, India
b
Department of Basic Sciences and Social Sciences,
Northeastern Hill University, Shillong, India
Available online: 01 Jun 2009
To cite this article: Abu T. Khan, Tasneem Parvin & Lokman H. Choudhury (2009):
A Simple and Convenient One-Pot Synthesis of Benzimidazole Derivatives Using
Cobalt(II) Chloride Hexahydrate as Catalyst, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:13,
2339-2346
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1
Synthetic Communications , 39: 2339–2346, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802654815
A Simple and Convenient One-Pot Synthesis
of Benzimidazole Derivatives Using Cobalt(II)
Chloride Hexahydrate as Catalyst
1
Abu T. Khan, Tasneem Parvin, and Lokman H. Choudhury
Department of Chemistry, Indian Institute of Technology Guwahati,
Guwahati, India
1
2
1
2
Department of Basic Sciences and Social Sciences, Northeastern Hill
University, Shillong, India
Abstract: A simple and efficient method for the convenient synthesis of 2-arylben-
zimidazole has been described on reaction with o-phenylenediamine and various
aromatic aldehydes using cobalt(II) chloride hexahydrate as a catalyst. The
method is cost-effective, high-yielding, clean, and selective.
Keywords: Aldehydes, benzimidazole, catalysis, cobalt(II) chloride hexahydrate,
o-phenylene diamine
INTRODUCTION
Benzimidazole and its derivatives have some significant importance in
[1]
medicinal chemistry. The synthesis of benzimidazole is carried out by
the reaction of o-phenylenediamine and carboxylic acid or its derivatives
[
2–4]
(
nitriles, amides, orthoesters) under harsh dehydrating conditions.
Another alternate approach is the condensation of o-phenylenediamine
and aldehyde in the presence of oxidative reagents such as sodium
[
5]
[6]
metabisulfite,
[
irradiation,
I =KI=K CO =H O,
3
Na S O under microwave
2 2 5
2
2
2
7]
[8]
[9]
silica sulfuric acid,
iodobenzene diacetate (IBD),
Received September 12, 2008.
Address correspondence to Abu T. Khan, Department of Chemistry, Indian
Institute of Technology Guwahati, Guwahati 781 039, India. E-mail: atk@iitg.
ernet.in
2
339

2340
A. T. Khan, T. Parvin, and L. H. Choudhury
Scheme 1. Synthesis of 2-aryl benzimidazoles using cobalt(II) chloride hexahydrate
as catalyst.
[
10]
[11]
HCl=H O ,
2
air in dioxane,
and CAN=H O .
2 2
bromodimethylsulfonium bromide
In continuation of our endeavor to
2
12]
[
[13]
(BDMS),
[14]
develop new synthetic methodologies,
herein we report a simple and
efficient method for the preparation of 2-arylbenzimidazole using
cobalt(II) chloride hexahydrate as an effective catalyst (Scheme 1).
RESULTS AND DISCUSSION
Initially, the reaction of 3,4,5-trimethoxybenzaldehyde with o-phenylene-
diamine was chosen as a model reaction to find a suitable catalyst and
solvent for the preparation of 2-arylbenzimidazole derivatives. In the
course of the study, several solvents including acetonitrile, dichloro-
methane, ethanol, and 1,4-dioxane were examined to obtain better yields.
The best results with 88% yield and selectivity were obtained in
acetonitrile. In the absence of catalyst, it gives only 38% yield of the
desired product after 12 h.
A wide variety of aromatic aldehydes were treated with o-phenylene-
diamine in the presence of cobalt(II) chloride hexahydrate under similar
experimental conditions. Notably, various aromatic aldehydes containing
both electron-withdrawing and electron-donating groups underwent oxi-
dative cyclization at room temperature in good yields. From the results of
Table 1, it is quite clear that aromatic aldehydes with electron-donating
groups such as hydroxyl and methoxy (entries e–j) provided the corre-
sponding 2-arylbenzimidazole in good yields in less time than aldehydes
tethered with withdrawing groups (entries c, d, k, and l). Similarly,
terephthalaldehyde (entry m) reacts with two molecules of o-phenylene-
diamine and afforded the corresponding bis-2-arylbenzimidazole in good
yields under the same experimental conditions.
EXPERIMENTAL
Melting points were recorded on a B u¨ chi B-545 melting-point apparatus.
Infrared (IR) spectra were recorded in KBr on a Nicolet Impact 410

One-Pot Synthesis of Benzimidazole Derivatives
2341
Table 1. Cobalt(II) chloride hexahydrate–catalyzed synthesis of 2-aryl
benzimidazole
a
Product (2)
b
Entry Aldehydes (1) Time (h)
Yield (%) [ref.]
[
11]
a
b
c
4
3
6
81
83
[
12]
9]
80
[
d
e
f
6
3
3
81
82
83
[
9]
g
3
3
85
h
86
84
i
j
2
6
88
k
l
5
4
78
79
(
Continued )

2342
A. T. Khan, T. Parvin, and L. H. Choudhury
Table 1. Continued
a
Product (2)
b
Entry Aldehydes (1) Time (h)
Yield (%) [ref.]
80
m
2
a
1
Products were characterized by recording IR, H NMR, and C NMR spec-
13
tra and elemental analysis.
b
Isolated yield.
1
13
spectrophotometer. H NMR spectra and C NMR spectra were
recorded on a Varian 400-MHz spectrometer in dimethyl sulfoxide
(DMSO-d ) using tetramethylsilane (TMS) as internal standard. Elemen-
6
tal analyses were carried out in a Perkin-Elmer 2400 automatic carbon,
hydrogen, nitrogen, and sulfur analyzer.
Typical Experimental Procedure for Synthesis of 2-Aryl Benzimidazoles
Cobalt(II) chloride hexahydrate (0.1 mmol) was added to a mixture of an
aldehyde (1.1 mmol) and o-phenylenediamine (1 mmol) in acetonitrile
(5 mL). The mixture was stirred at room temperature, and the progress
of the reaction was monitored by thin-layer chromatography (TLC).
After completion, the solvent was evaporated, and the crude product
was dissolved in 5 mL of hot ethanol and then treated with 0.2 mL of
NH OH, followed by 5 ml of water. The mixture was heated, and after
4
cooling, the solid was filtered and washed with a cold solvent mixture
(
ethanol þ hexane) to get the pure benzimidazole derivative. All the pro-
ducts were fully characterized by the usual spectroscopic techniques.
Data
2
-(4-Methylphenyl)benzimidazole (2b)
ꢀ
[6]
Mp 275 C (lit. mp 277 C). IR (KBr): 1622 (C¼N), 3446 (NH) cm . H
ꢀ
ꢁ1 1
NMR (400 MHz, DMSO-d ): d 2.38 (s, 3 H), 7.18 (d, J ¼ 7.2 Hz, 2 H),
6
7
.34–7.37 (m, 2 H), 7.47–7.51 (m, 1 H), 7.60–7.63 (m, 1 H), 8.06 (d,
1
3
J ¼ 8.0 Hz, 2 H), 12.80 (bs, 1 H). C NMR (100 MHz, DMSO-d ): d
6
21.0, 111.1, 118.7, 121.6, 122.3, 126.4, 127.4, 129.5, 139.6, 143.8, 151.4.
Anal. calcd. for C H N (208.26): C, 80.74; H, 5.81; N, 13.45. Found:
C, 80.60; H, 5.85; N, 13.59.
1
4
12
2

One-Pot Synthesis of Benzimidazole Derivatives
2343
2
-(4-Hydroxyphenyl)benzimidazole (2e)
ꢀ
[7]
Mp 256 C (lit. mp 254–256 C). IR (KBr): 1612 (C¼N), 3360 (NH), 3570
ꢀ
ꢁ
1 1
OH) cm . H NMR (400 MHz, DMSO-d ): d 6.90 (d, J ¼ 8.4 Hz, 2 H),
(
7
(
6
.12–7.16 (m, 2 H), 7.46 (d, J ¼ 6.8 Hz, 1 H), 7.59 (d, J ¼ 7.6 Hz, 1 H), 7.99
1
3
d, J ¼ 8.8 Hz, 2 H), 9.94 (bs, 1 H), 12.63 (bs, 1 H). C NMR (100 MHz,
DMSO-d ): d 114.2, 115.4, 120.5, 121.4, 128.0, 138.8, 145.0, 158.9. Anal.
6
calcd. for C H N O (210.23): C, 74.27; H, 4.79; N, 13.33. Found: C,
7
1
3
10
2
4.17; H, 4.82; N, 13.51.
2
-(3-Hydroxyphenyl)benzimidazole (2f)
ꢀ
ꢁ1
1
Mp 277 C. IR (KBr): 1618 (C¼N), 3447 (NH), 3565 (OH) cm . H
NMR (400 MHz, DMSO-d ): d 6.89 (d, J ¼ 7.6 Hz, 1 H), 7.17–7.20 (m,
6
2
7
H), 7.33 (t, J ¼ 7.2 Hz, 1 H), 7.48–7.51 (m, 1 H), 7.57–7.59 (m, 2 H),
1
.62–7.66 (m, 1 H), 9.74 (s, 1 H), 12.81 (s, 1 H). C NMR (100 MHz,
3
DMSO-d ): d 114.1, 115.5, 117.6, 118.0, 122.6, 130.4, 131.7, 139.6,
6
1
52.2, 158.3. Anal. calcd. for C H N O (210.23): C, 74.27; H, 4.79; N,
13 10 2
1
3.33. Found: C, 74.19; H, 4.83; N, 13.49.
2
-(3,4-Dimethoxyphenyl)benzimidazole (2h)
ꢀ
ꢁ1 1
Mp 282 C. IR (KBr): 1609 (C¼N), 3445 (NH) cm . H NMR (400 MHz,
DMSO-d ): d 3.80 (s, 3 H), 3.85 (s, 3 H), 7.09 (d, J ¼ 8.4 Hz, 1 H),
6
7
1
5
1
5
.14–7.17 (m, 2 H), 7.49 (bs, 1 H), 7.59 (bs, 1 H), 7.70 (d, J ¼ 8.4 Hz,
1
3
H), 7.73 (s, 1 H), 12.81 (bs, 1H). C NMR (100 MHz, DMSO-d ): d
6
6.3, 110.5, 111.7, 112.5, 119.1, 119.9, 122.1, 122.8, 123.4, 135.7, 144.5,
49.6, 150.9, 152.2. Anal. calcd. for C H N O (254.29): C, 70.85; H,
.55; N, 11.02. Found: C, 70.72; H, 5.59; N, 11.13.
1
5
14
2
2
2
-(2,4-Dimethoxyphenyl)benzimidazole (2i)
ꢀ
ꢁ1
1
Mp 176 C. IR (KBr): 1619 (C¼N), 3446 (NH) cm
.
H NMR
(
(
400 MHz, DMSO-d ): d 3.86 (s, 3 H), 4.02 (s, 3 H), 6.72 (s, 1 H), 6.75
6
d, J ¼ 8.8 Hz, 1 H), 7.15–7.18 (m, 2 H), 7.57–7.60 (m, 2 H), 8.24 (d,
1
3
J ¼ 8.0 Hz, 1 H), 12.00 (bs, 1 H). C NMR (100 MHz, DMSO-d ): d
6
5
1
1
6.1, 56.6, 99.1, 103.4, 107.5, 113.8, 125.7, 131.1, 131.4, 146.4, 159.8,
65.2. Anal. calcd. for C H N O (254.29): C, 70.85; H, 5.55; N,
1.02. Found: C, 70.70; H, 5.59; N, 11.12.
1
5
14
2
2

2344
A. T. Khan, T. Parvin, and L. H. Choudhury
2
-(3,4,5-Trimethoxyphenyl)benzimidazole (2j)
ꢀ
ꢁ1
1
Mp 262 C. IR (KBr): 1620 (C¼N), 3447 (NH) cm
.
400 MHz, DMSO-d ): 3.74 (s, 3 H), 3.91 (s, 6 H), 7.19–7.21 (m, 2 H),
H NMR
(
6
1
.51–7.54 (m, 3 H), 7.63–7.66 (m, 1 H), 12.85 (bs, 1 H). C NMR
3
7
(100 MHz, DMSO-d ): 56.0, 60.2, 103.8, 111.2, 118.7, 121.7, 122.4,
6
125.5, 135.0, 138.9, 151.2, 153.2. Anal. calcd. for C H N O (284.31):
16 16 2 3
C, 67.59; H, 5.67; N, 9.85. Found: C, 67. 44; H, 5. 63; N. 9.99.
2
-(4-Nitroyphenyl)benzimidazole (2k)
ꢀ
[15]
Mp 317 C (lit. mp 316 C). IR (KBr): 1347, 1554 (NO ), 1615 (C¼N),
ꢀ
2
ꢁ
1 1
446 (NH) cm . H NMR (400 MHz, DMSO-d ): 7.19–7.22 (m, 2 H),
3
6
7
.54–7.56 (m, 1 H), 7.65–7.67 (m, 1 H), 8.32 (d, J ¼ 8.0 Hz, 2 H), 8.37
1
3
(d, J ¼ 8.8 Hz, 2 H), 13.20 (bs, 1 H). C NMR (100 MHz, DMSO-d ):
6
1
C H N O (239.23): C, 65.27; H, 3.79; N, 17.56. Found: C, 65.40; H,
20.0, 123.1, 124.4, 127.5, 129.6, 136.1, 147.9, 149.1. Anal. calcd. for
1
3
9
3
2
3
2
.83; N, 17.42.
-(3-Nitrophenyl)benzimidazole (2l)
ꢀ
ꢁ1
.
Mp 144 C. IR (KBr): 1345, 1552 (NO ), 1617 (C ¼ N), 3346 (NH) cm
2
1
H NMR (400 MHz, DMSO-d ): 7.25–7.27 (m, 2 H), 7.58–7.60 (m, 1 H),
6
7
1
1
.69–7.72 (m, 1 H), 7.84–7.88 (m, 1 H), 8.32–8.35 (m, 1 H), 8.60–8.64 (m,
1
3
H), 9.02 (s, 1 H), 13.31 (bs, 1 H). C NMR (100 MHz, DMSO-d6):
21.0, 123.0, 124.4, 131.0, 131.7, 132.6, 148.5, 149.2. Anal. calcd. for
C H N O (239.23): C, 65.27; H, 3.79; N, 17.56. Found: C, 65.41; H,
2
1
3
9
3
3
.82; N, 17.44.
0
0
1
,4 -Di-(2-Phenylbenzimidazole)benzene (2m)
ꢁ
1 1
IR (KBr): 1623 (C¼N) 3304 (NH) cm . H NMR (400 MHz, DMSO-d6):
.19–7.26 (m, 4 H), 7.57 (d, J ¼ 7.6 Hz, 2 H), 7.70 (d, J ¼ 7.6 Hz, 2 H), 8.35
7
(
1
s, 4 H), 13.05 (s, 2 H). C NMR (100 MHz, DMSO-d ): 111.5, 119.0,
3
6
1
21.9, 122.9, 126.9, 131.2, 143.9, 150.6. Anal. calcd. for C H N
20 14 4
(310.36): C, 77.40; H, 4.55; N, 18.05. Found: C, 77.28; H, 4.52; N, 18.16.
CONCLUSION
In summary, we have devised a simple and efficient method for the facile
synthesis of benzimidazole derivatives using a readily available and

One-Pot Synthesis of Benzimidazole Derivatives
2345
cost-effective catalyst. The significant features of this method are good
selectivity, good yields, and clean reactions, as well as avoidance of column
chromatographic purifications. We believe this method is a useful contribu-
tion to the existing methodologies and a new addition of the catalytic activity
of cobalt(II) chloride hexahydrate in the arsenal of organic synthesis.
ACKNOWLEDGMENTS
T. P. is thankful to the Indian Institute of Technology Guwahati (IITG)
for her research fellowship. Authors are also grateful to the director,
IITG, for providing the general facilities to carry out the work.
REFERENCES
1
. Bhattacharya, S.; Chaudhuri, P. Medical implications of benzimidazole deri-
vatives as drugs designed for targeting DNA and DNA associated processes.
Curr. Med. Chem. 2008, 15, 1762–1777, and references cited therein.
2
. Chi, Y.-C.; Sun, C.-M. Soluble polymer-supported synthesis of a
benz-imidazole library. Synlett 2000, 591–594.
3
. Huang, W.; Scarborough, R. M. A new ‘‘traceless’’ solid-phase synthesis
strategy: Synthesis of a benzimidazole library. Tetrahedron Lett. 1999, 40,
2665–2668.
4
. Dudd, L. M.; Venardou, E.; Garcia-Verdugo, E.; Licence, P.; Blake, A. J.;
Wilson, C.; Poliakoff, M. Synthesis of benzimidazoles in high-temperature
water. Green Chem. 2003, 5, 187–192.
5
. Goker, H.; Ku, C.; Boykin, D. W.; Yildiz, S.; Altanar, N. Synthesis of
some new 2-substituted-phenyl-1H-benzimidazole-5-carbonitriles and their
potent activity against Candida species. Bioorg. Med. Chem. 2002, 10,
2589–2596.
6
. Gogoi, P.; Konwar, D. An efficient and one-pot synthesis of imidazolines and
benzimidazoles via anaerobic oxidation of carbon–nitrogen bonds in water.
Tetrahedron Lett. 2006, 47, 79–82.
7
. Navarrete-Vazquez, G.; Moreno-Diaz, H.; Aguirre-Crespo, F.; Leon-Rivera, I.;
Villalobs-Molina, R.; Munoz-Munizd, O.; Estrada-Soto, S. Design, microwave-
assisted synthesis, and spasmolytic activity of 2-(alkyloxyaryl)-1H-benzimidazole
derivatives as constrained stilbene bioisosteres. Bioorg. Med. Chem. Lett. 2006,
16, 4169–4173.
8
. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Otokesh, S.; Baghbanzadeh, M.
Selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles in water at
ambient temperature. Tetrahedron Lett. 2006, 47, 2557–2560.
9
. Du, L.-H.; Wang, Y.-G. A rapid and efficient synthesis of benzimidazoles
using hypervalent iodine as oxidant. Synthesis 2007, 675–678.
0. Bahrami, K.; Khodaei, M. M.; Kavianinia, I. A simple and efficient one-pot
1
synthesis of 2-substituted benzimidazoles. Synthesis 2007, 547–550.

2346
A. T. Khan, T. Parvin, and L. H. Choudhury
1
1. Lin, S.; Yang, L. A simple and efficient procedure for the synthesis of benzi-
midazoles using air as the oxidant. Tetrahedron Lett. 2005, 46, 4315–4319.
2. Das, B.; Holla, H.; Srinivas, Y. Efficient (bromodimethyl)sulfonium
bromide–mediated synthesis of benzimidazoles. Tetrahedron Lett. 2007, 48,
1
61–64.
1
1
1
3. Bahrami, K.; Khodaei, M. M.; Naali, F. Mild and highly efficient method for
the synthesis of 2-arylbenzimidazoles and 2-arylbenzothiazoles. J. Org. Chem.
2008, 73, 6835–6837.
4. Khan, A. T.; Parvin, T.; Choudhury, L. H. Iron(III) chloride–catalyzed con-
venient one-pot synthesis of b-acetamido carbonyl compounds. Tetrahedron
2007, 63, 5593–5601, and references cited therein.
5. Alloum, A. B.; Bougrin, K.; Soufiaoui, M. Synth e` se chimios e´ lective des
benzimida zoles sur silice trait e´ e par le chlorure du thionyle. Tetrahedron Lett.
2003, 44, 5935–5937.