Practical, ecofriendly, and chemoselective method for the synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles using amberlite IR-120 as a reusable heterogeneous catalyst in aqueous media

Article abstract of DOI:10.1080/00397910802448440

A simple, efficient, and environmentally benign method has been developed for the exclusive formation of biologically significant 2-aryl-1-arylmethyl-1H- benzimidazoles under the heterogeneous catalysis of Amberlite IR-120 in aqueous media in excellent yi

Full text of DOI:10.1080/00397910802448440

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Practical, Ecofriendly, and
Chemoselective Method for
the Synthesis of 2-Aryl-1-
arylmethyl-1H-benzimidazoles
Using Amberlite IR-120 as
a Reusable Heterogeneous
Catalyst in Aqueous Media
Saikat Das Sharma a & Dilip Konwar a
a Synthetic Organic Chemistry Division, Northeast
Institute of Science and Technology, Jorhat, Assam,
India
Available online: 25 Feb 2009
To cite this article: Saikat Das Sharma & Dilip Konwar (2009): Practical, Ecofriendly,
and Chemoselective Method for the Synthesis of 2-Aryl-1-arylmethyl-1H-
benzimidazoles Using Amberlite IR-120 as a Reusable Heterogeneous Catalyst in
Aqueous Media, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:6, 980-991
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Synthetic Communications1, 39: 980–991, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802448440
Practical, Ecofriendly, and Chemoselective
Method for the Synthesis of 2-Aryl-1-arylmethyl-
1H-benzimidazoles Using Amberlite IR-120
as a Reusable Heterogeneous Catalyst in
Aqueous Media
Saikat Das Sharma and Dilip Konwar
Synthetic Organic Chemistry Division, Northeast Institute of Science and
Technology, Jorhat, Assam, India
Abstract: A simple, efficient, and environmentally benign method has been
developed for the exclusive formation of biologically significant 2-aryl-1-
arylmethyl-1H-benzimidazoles under the heterogeneous catalysis of Amberlite
IR-120 in aqueous media in excellent yields. The catalyst is recyclable without loss
of activity.
Keywords: Amberlite IR-120, aqueous media, chemoselective, 1,2-disubstituted
benzimidazole, heterogeneous catalysis
1,2-Disubstituted benzimidazoles are endowed with an extensive range of
biological activities. They have emerged as potent nonnucleoside inhibi-
tors of HIV-1 reverse transcriptase[1a,1b] and specific inhibitors of the
NS5B polymerase of the hepatitis C virus (HCV).[1c] Appropriately
functionalized 1,2-disubstituted benzimidazoles are used as agonists
against c-butyric acid A receptor (GABAA).[1d] Moreover, they display
potent thrombin inhibitory activity[2a] and antibacterial activity against
gram-positive bacteria.[2b]
Received May 26, 2008.
Address correspondence to Dilip Konwar, Synthetic Organic Chemistry Divi-
sion, Northeast Institute of Science and Technology (Formerly Regional Research
Laboratory), Jorhat 785006, Assam, India. E-mail: dkonwar@yahoo.co.uk
980

Synthesis of 2-Aryl-1-arylmethyl-1H-benzimidazoles
981
A number of improved methods have been developed for the synthesis
of 1,2-disubstituted benzimidazoles, which include N-alkylation of
2-substituted benzimidazole in the presence of a strong base,[3a,3b] N-
alkylation of o-nitroanilides followed by reductive cyclization,[1a,1b]
cyclocondensation of N-substituted o-aminoanilides,[2a] reductive cycliza-
tion of o-nitroanilides followed by N-alkylation in the presence of a strong
base,[1b] and condensation of N-substituted phenylenediamine with
sodium salt of a-hydroxybenzylsulphonic acid.[2b] In addition, 1,2-
disubstituted benzimidazoles can also be accessed by direct one-step
condensation of o-phenylenediamines with aldehydes under the influence
of different acid catalysts.[4] But one of the major limitations of these
methodologies is that they show poor selectivity in terms of N-1 substitu-
tion, which results in the formation of two compounds (i.e., the formation
of 2-substituted benzimidazole along with 1,2-disubstituted benzimida-
zole as a mixture[4a–c,4e]). We report the synthesis of 1,2-disubstituted
benzimidazoles by the reaction of o-phenylenediamines and aldehydes in
the presence of Amberlite IR-120 resin (Scheme 1).
At the beginning of this work, to evaluate the catalytic efficiency of
Amberlite IR-120, the reaction of o-phenylenediamine and benzaldehyde
was studied by employing 0.100 g of the catalyst in water at room tem-
perature. The resulting yield was not very good (entry 1, Table 1).
Optimization of the reaction condition was carried out next to increase
the yield of the product, employing different catalyst loadings in a wide
variety of solvents. The results are listed in Table 1. The conversion
was dramatically increased to 95% within a much shorter time by adding
0.100 g of the catalyst in an ethanol=water (2:1) mixture (entry 3). It was
found that a higher amount of the catalyst did not improve the yield at all
(entries 6 and 7), whereas the yield was substantially reduced by decreas-
ing the amount of Amberlite IR-120 in an ethanol=water (2:1) mixture
(entries 4 and 5). Methanol=water (2:1) mixture was also found to be
Scheme 1. Synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles.

982
S. Das Sharma and D. Konwar
Table 1. Optimization of the reaction conditionsb
Catalyst
load (g)
Time
(h)
Yield
(%)a
Entry
Catalyst
Solvents
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Amberlite IR-120
Silica gel
0.100
0.100
0.100
0.050
0.075
0.125
0.150
0.100
0.100
0.100
0.100
0.100
0.100
0.100
0.100
0.100
0.100
0.100
0.100
0.100
H2O
EtOH
3.00
1.45
1.45
7.00
3.00
2.00
2.00
2.50
2.10
1.45
6.30
7.00
22.00
10.00
10.00
10.00
9.00
9.00
3.00
3.00
66
90
95
80
86
95
95
83
90
92
84
85
59
47
37
51
62
53
80
81
EtOH þ H2O (2:1)
EtOH þ H2O (2:1)
EtOH þ H2O (2:1)
EtOH þ H2O (2:1)
EtOH þ H2O (2:1)
EtOH þ H2O (1:2)
EtOH þ H2O (1:1)
EtOH þ H2O (3:1)
MeOH
MeOH þ H2O (2:1)
MeCN
CHCl3
CH2Cl2
Toluene
THF
Dioxane
EtOH þ H2O (2:1)
Alumina
EtOH þ H2O (2:1)
aIsolated yield.
Stirring at 25–30 C.
b
ꢀ
an effective reaction medium for this transformation (entry 12). Other
solvents, such as CH3CN, CHCl3, CH2Cl2, toluene, tetrohydrofuran
(THF), and dioxane (entries 13–18), rendered unfavorable results for
this reaction. Otherwise, silica gel and alumina (entries 19 and 20) as
heterogeneous catalysts also furnished high yield of products. Evidently,
the reaction conditions in entry 3 of Table 1 were found to be the most
optimal.
To test the generality of this reaction, a series of aromatic aldehydes and
o-phenylenediamines was subjected to the optimal reaction conditions.

Synthesis of 2-Aryl-1-arylmethyl-1H-benzimidazoles
983
Table 2. Synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoleb
Time Yield
(%)a
Entry
1
Diamines
Aldehydes
Products
(h)
1.45
95
2
3
2.30
2.55
89
86
4
4.0
83
5
4.3
84
(Continued )

984
S. Das Sharma and D. Konwar
Table 2. Continued
Time Yield
(%)a
Entry
6
Diamines
Aldehydes
Products
(h)
5.4
92
7
4.4
79
8
6.5
87
9
6.4
88
10
4.0
80
(Continued )

Synthesis of 2-Aryl-1-arylmethyl-1H-benzimidazoles
Table 2. Continued
985
Time Yield
(%)a
Entry
11
Diamines
Aldehydes
Products
(h)
6.3
86
12
6.4
81
13
14
6.5
6.0
70
75
15
5.4
76
aIsolated yield.
Stirring at 25–30 C.
b
ꢀ

986
S. Das Sharma and D. Konwar
Scheme 2. Synthesis of 2-(2,4-dichlorophenyl)-1H-benzimidazole.
Almost all substrates could give their corresponding 1,2-disubstituted
benzimidazoles exclusively as a single product (i.e., without the formation
of 2-substituted benzimidazoles). The results are documented in Table 2.
It is noteworthy that 2,4-dichlorobenzaldehyde represents as a single
exceptional example by furnishing 2-substituted benzimidazole exclu-
sively instead of 1,2-disubstituted benzimidazole (Scheme 2).
In conclusion, the synthetic protocol described herein allows the for-
mation of biologically significant 2-aryl-1-arylmethyl-1H-benzimidazoles
exclusively under the heterogeneous catalysis of Amberlite IR-120 in
aqueous media in excellent yields.
EXPERIMENTAL
General Experimental Procedure for the Synthesis of 2-Aryl-1-
arylmethyl-1H-benzimidazoles
In a 50-ml, round-bottom flask, o-phenylenediamine (1 mmol) and alde-
hyde (2 mmol) were stirred in the presence of Amberlite IR-120 (0.100 g)
in an EtOH=H2 O (2:1) mixture (10 ml) at room temperature for the
stipulated time. The progress of the reaction was monitored by thin-
layer-chromatography (TLC). After completion of the reaction, the
solution was filtered to remove the catalyst. The filtrate was concentrated
under reduced pressure to furnish the crude product, which was recrystal-
lized from methanol to afford the pure product. The catalyst could be
reused for fresh reactions without any loss of activity.
Characterization Data of the 2-Aryl-1-arylmethyl-1H-benzimidazoles
1-Benzyl-2-phenyl-1H-1,3-benzimidazole (1)
Mp 132 ꢀC; 1H NMR (CDCl3, 300 MHz): d 5.34 (s, 2H), 7.01–7.28 (m, 8H),
7.34–7.40 (m, 3H), 7.62–7.64 (m, 2H), 7.83 (d, J ¼ 8 Hz, 1H); FT-IR

Synthesis of 2-Aryl-1-arylmethyl-1H-benzimidazoles
987
(KBr, cm–1): 1613.9; ESI-MS (m=z): 285.2 (Mþ þ 1). Anal. calcd. for
C20H16N2: C, 84.48; H, 5.67; N, 9.85. Found: C, 84.41; H, 5.63; N, 9.89.
1-(4-Methylbenzyl)-2-(4-methylphenyl)-1H-1,3-benzimidazole (2)
1
ꢀ
Mp 128–130 C; H NMR (CDCl3, 300 MHz): d 2.47 (s, 3H), 2.53 (s,
3H), 5.54 (s, 2H), 7.11 (d, J ¼ 7.9 Hz, 2H), 7.25 (d, J ¼ 7.9 Hz, 2H),
7.33–7.37 (m, 2H), 7.35 (d, J ¼ 8 Hz, 2H), 7.39 (m, 1H), 7.70 (d, J ¼ 8.1
Hz, 2H), 7.97 (d, J ¼ 8.1 Hz, 1H); FT-IR (KBr, cm–1): 1621.7; ESI-MS
(m=z): 313.2 (Mþ þ 1). Anal. calcd. for C22H20N2: C, 84.58; H, 6.45; N,
8.97. Found: C, 84.50; H, 6.41; N, 8.90.
1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-1H-1,3-benzimidazole (3)
1
ꢀ
Mp 130 C; H NMR (CDCl3, 300 MHz): d 3.84 (s, 3H), 3.78 (s, 3H),
5.38 (s, 2H), 6.83 (d, J ¼ 8.4 Hz, 2H), 6.95 (d, J ¼ 8.5 Hz, 2H), 7.01 (d,
J ¼ 8.01 Hz, 2H), 7.20–7.30 (m, 3H), 7.61 (d, J ¼ 8.6 Hz, 2H), 7.84 (d,
J ¼ 7.7 Hz, 1H); FT-IR (KBr, cm–1): 1619.3; ESI-MS (m=z): 345.3
(Mþ þ 1). Anal. calcd. for C22H20N2O2 : C, 76.72; H, 5.85; N, 9.29.
Found: C, 76.77; H, 5.80; N, 9.22.
1-(4-Chlorobenzyl)-2-(4-chlorophenyl)-1H-1,3-benzimidazole (4)
Mp 135–136 ꢀC; 1H NMR (CDCl3, 300 MHz): d 5.35 (s, 2H), 7.14
(d, J ¼ 7.1 Hz, 2H), 7.23 (d, J ¼ 8.7 Hz, 1H), 7.27–7.56 (m, 8H), 7.81
(d, J ¼ 7.2 Hz, 1H); FT-IR (KBr, cm–1): 1619.8; ESI-MS (m=z): 354.2
(Mþ þ 1). Anal. calcd. for C20H14 N2Cl2: C, 68.00; H, 3.99; N, 7.93.
Found: C, 68.07; H, 3.91; N, 7.98.
1-(4-Bromobenzyl)-2-(4-bromophenyl)-1H-1,3-benzimidazole (5)
Mp 157–158 ꢀC; 1H NMR (CDCl3, 300 MHz): d 5.38 (s, 2H), 6.95 (d, J ¼ 8.4
Hz, 2H), 7.20–7.59 (m, 9H), 7.86 (d, J ¼ 7.2 Hz, 1H); FT-IR (KBr, cm–1):
1622.0; ESI-MS (m=z): 443.1 (Mþ þ 1). Anal. calcd. for C20H14N2Br2: C,
54.33; H, 3.19; N, 6.34. Found: C, 54.29; H, 3.12; N, 6.40.
1-(3,4-Dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)-1H-
1,3-benzimidazole (6)
1
ꢀ
Mp 171–173 C; H NMR (DMSO-d6, 300 MHz): d 3.76 (s, 3H), 3.78
(s, 3H), 3.84 (s, 3H), 3.93 (s, 3H), 5.44 (s, 2H), 6.61–6.68 (m, 2H), 6.80

988
S. Das Sharma and D. Konwar
(d, J ¼ 8.2 Hz, 1H), 6.95 (d, J ¼ 8.2 Hz, 1H), 7.22–7.32 (m, 4H), 7.55 (m,
1H), 7.79–7.91 (m, 1H); FT-IR (KBr, cm–1): 1613.1; ESI-MS (m=z): 405.1
(Mþ þ 1). Anal. calcd. for C24H24N2O4: C, 71.27; H, 5.98; N, 6.93.
Found: C, 71.20; H, 5.93; N, 6.99.
1-(2-Chlorobenzyl)-2-(2-chlorophenyl)-1H-1,3-benzimidazole (7)
Mp 157–159 ꢀC; 1H NMR (CDCl3, 300 MHz): d 5.35 (s, 2H), 6.59
(dd, J ¼ 8.6 and 1.3 Hz, 1H), 7.27–7.01 (m, 1H), 7.10–7.53 (m, 9H),
6.86 (d, J ¼ 8.8 Hz, 1H); FT-IR (KBr, cm–1): 1615.9; ESI-MS (m=z):
354.2 (Mþ þ 1). Anal. calcd. for C20H14N2Cl2: C, 68.00; H, 3.99; N,
7.93. Found: C, 68.09; H, 4.03; N, 7.98.
1-(4-Hydroxy-3-methoxybenzyl)-2-(4-hydroxy-3-methoxyphenyl)-1H-
1,3-benzimidazole (8)
1
ꢀ
Mp 184–186 C; H NMR (DMSO-d6, 300 MHz): d 3.72 (s, 3H), 3.76
(s, 3H), 5.41 (s, 2H), 6.48 (d, J ¼ 8.1 Hz, 1H), 7.76 (d, J ¼ 8.0 Hz,
1H), 6.94 (d, J ¼ 8.1 Hz, 1H), 7.13–7.45 (m, 5H), 7.73 (d, J ¼ 8.0 Hz,
1H), 7.77–7.89 (m, 1H), 9.25 (s, 1H), 9.32 (s, 1H); FT-IR (KBr, cmꢁ1):
1623.3, 3447.2; ESI-MS (m=z): 377.2 (Mþ þ 1). Anal. calcd. for
C22H20N2O4: C, 70.20; H, 5.36; N, 7.44. Found: C, 70.16; H, 5.31;
N, 7.49.
1-(3-Hydroxy-4-Methoxybenzyl)-2-(3-Hydroxy-4-Methoxyphenyl)-1H-
1,3-benzimidazole (9)
1
ꢀ
Mp 229–231 C; H NMR (DMSO-d6, 300 MHz): d 3.82 (s, 3H), 3.90
(s, 3H), 5.35 (s, 2H), 6.77 (d, J ¼ 8.1 Hz, 1H), 6.90 (d, J ¼ 8.2 Hz, 1H),
7.11–7.27 (m, 5H), 7.62–7.73 (m, 3H), 8.60 (s, 1H), 8.82 (s, 1H); FT-IR
(KBr, cm–1): 1621.8, 3436.9; ESI-MS (m=z): 377.2 (Mþ þ 1). Anal. calcd.
for C22H20N2O4: C, 70.20; H, 5.36; N, 7.44. Found: C, 70.24; H, 5.39; N,
7.47.
1-(2-Methoxybenzyl)-2-(2-methoxyphenyl)-1H-1,3-benzimidazole (10)
1
ꢀ
Mp 151–153 C; H NMR (CDCl3, 300 MHz): d 3.72 (s, 3H), 3.76 (s,
3H), 5.31 (s, 2H), 6.71 (dd, J ¼ 7.2 and 1.3 Hz, 1H), 6.76 (m, 1H),
6.84 (d, J ¼ 8.3 Hz, 1H), 6.97 (d, J ¼ 8.9 Hz, 1H), 7.05–7.48 (m,
6H), 7.53 (dd, J ¼ 8.6 and 2.4 Hz, 1H), 7.91 (d, J ¼ 8.6 Hz, 1H);
FT-IR (KBr, cm–1): 1618.6; ESI-MS (m=z): 345.3 (Mþ þ 1). Anal.

Synthesis of 2-Aryl-1-arylmethyl-1H-benzimidazoles
989
calcd. for C22H20N2O2: C, 76.72; H, 5.85; N, 9.29. Found: C, 76.79;
H, 5.82; N, 9.28.
1-(4-Hydroxybenzyl)-2-(4-hydroxyphenyl)-1H-1,3-benzimidazole (11)
1
ꢀ
Mp 222 C; H NMR (DMSO-d6, 300 MHz): d 5.50 (s, 2H), 6.82–7.82
(m, 12H), 9.44 (s, 1H), 9.95 (s, 1H); FT-IR (KBr, cm–1): 1618.7, 3445.0;
ESI-MS (m=z): 317.1 (Mþ þ 1). Anal. calcd. for C20H16N2O2: C, 75.93;
H, 5.10; N, 8.86. Found: C, 75.99; H, 5.08; N, 8.82.
1-(3-Hydroxybenzyl)-2-(3-hydroxyphenyl)-1H-1,3-benzimidazole (12)
1
ꢀ
Mp 253 C; H NMR (DMSO-d6, 300 MHz): d 5.22 (s, 2H), 6.69–7.34
(m, 12H), 8.35 (s, 1H), 8.70 (s, 1H); FT-IR (KBr, cm–1): 1618.3, 3438.7;
ESI-MS (m=z): 317.1 (Mþ þ 1). Anal. calcd. for C20H16N2O2: C, 75.93;
H, 5.10; N, 8.86. Found: C, 75.97; H, 5.15; N, 8.90.
1-(2-Furylmethyl)-2-(2-furyl)-1H-1,3-benzimidazole (13)
Mp 94–96 ꢀC; 1H NMR (DMSO-d6, 300 MHz): d 5.58 (s, 2H), 6.19
(m, 1H), 6.25 (m, 1H), 6.62 (m, 1H), 7.17 (m, 1H), 7.24–7.29 (m, 3H),
7.46–7.53 (m, 1H), 7.62–7.82 (m, 2H); FT-IR (KBr, cm–1): 1622.0; ESI-
MS (m=z): 265.1 (Mþ þ 1). Anal. calcd. for C16H12N2O2: C, 72.72; H,
4.58; N, 10.60. Found: C, 72.78; H, 4.52; N, 10.55.
5,6-Dimethyl-1-(4-methylbenzyl)-2-(4-methylphenyl)-
1H-benzimidazole (14)
1
ꢀ
Mp 177–178 C; H NMR (CDCl3, 300 MHz): d 2.32 (s, 3H), 2.36 (s,
3H), 2.41 (s, 3H), 2.43 (s, 3H), 5.39 (s, 2H), 7.01–7.70 (m, 10H); FT-IR
(KBr, cm–1): 1621.3; ESI-MS (m=z): 341.4 (Mþ þ 1). Anal. calcd. for
C24H24N2: C, 84.67; H, 7.11; N, 8.23. Found: C, 84.62; H, 7.18; N, 8.19.
1-(4-chlorobenzyl)-2-(4-chlorophenyl)-5,6-dimethyl-
1H-benzimidazole (15)
Mp 190–191 ꢀC; 1H NMR (CDCl3, 300 MHz): d 2.34 (s, 3H), 2.37 (s, 3H),
5.42 (s, 2H), 7.04–7.81 (m, 10H); FT-IR (KBr, cm–1): 1618.8; ESI-MS

990
S. Das Sharma and D. Konwar
(m=z): 382.4 (Mþ þ 1). Anal. calcd. for C22H18N2Cl2: C, 69.30; H, 4.76;
N, 7.35. Found: C, 69.26; H, 4.71; N, 7.38.
2-(2,4-Dichlorophenyl)-1H-benzimidazole (Scheme 2)
1
ꢀ
Mp 227 C; H NMR (DMSO-d6, 300 MHz): d 7.27–7.78 (m, 6H), 8.00
(d, J ¼ 8.4 Hz, 1H), 12.67 (s, 1H); FT-IR (KBr, cm–1): 1655.3, 3378.0;
ESI-MS (m=z): 263.9 (Mþ þ 1). Anal. calcd. for C13H8N2Cl2: C, 59.34;
H, 3.06; N, 10.65. Found: C, 59.39; H, 3.10; N, 10.60.
ACKNOWLEDGMENT
The authors acknowledge the director of the Northeast Institute of
Science and Technology, Jorhat, for his help. Also, S. D. S. is grateful
to Council of Scientific and Industrial Research (CSIR), New Delhi,
for the senior research fellowship.
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