Synthesis of 2-arylbenzimidazoles catalyzed by transition metal nitrates

Article abstract of DOI:10.1007/s11164-012-0825-1

A simple and practical procedure for synthesis of 2-arylbenzimidazoles by a one-pot condensation of o-phenylenediamine with aromatic aldehydes in the presence of a catalytic amount of M(NO₃)₂·6H ₂O (M = Mn, Fe, Co, Ni, Cu)

Full text of DOI:10.1007/s11164-012-0825-1

Res Chem Intermed
DOI 10.1007/s11164-012-0825-1
Synthesis of 2-arylbenzimidazoles catalyzed
by transition metal nitrates
Mehdi Kalhor
Javad Jamshidi
•
Akbar Mobinikhaledi
•
Received: 11 August 2012 / Accepted: 19 September 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract A simple and practical procedure for synthesis of 2-arylbenzimidazoles
by a one-pot condensation of o-phenylenediamine with aromatic aldehydes in the
presence of a catalytic amount of M(NO ) Á6H O (M = Mn, Fe, Co, Ni, Cu) in
3
2
2
ethanol at room temperature is described. Major advantages of this practical pro-
cedure are use of a readily available catalyst, high yields, short reaction times, and
simplicity of the reaction and workup.
Keywords Benzimidazole Á Catalyst Á o-Phenylenediamine Á Aryl aldehyde Á
Transition metal
Introduction
Benzimidazoles are useful intermediates or subunits in the development of
molecules with pharmaceutical and biological activity [1–7]. Benzimidazoles have
several commercial applications in veterinarian medicine, for example as anti-
helminth agents, in diverse human therapy, treatment of ulcers and as anti-
histamines [5–8]. They have also been used as intermediates in organic and
inorganic synthesis [9, 10]. Because of their importance, the synthesis of substituted
benzimidazoles is of special interest to organic chemists. Several methods have
reported for the synthesis of these compounds, including reaction of carboxylic
acids or their derivatives (nitriles, orthoesters, and imidates) with o-phenylenedi-
amines and reaction of o-phenylenediamines with aldehydes in the presence of an
acid catalyst under a variety of reaction conditions [11–17]. However, the most of
M. Kalhor (&)
Chemistry Department, Payame Noor University, P.O. Box 19395-4697, Tehran, Iran
e-mail: mekalhor@gmail.com
A. Mobinikhaledi Á J. Jamshidi
Department of Chemistry, University of Arak, P.O. Box 14335-186, Arak, Iran
123

M. Kalhor et al.
these methods have limitations, including harsh reaction conditions, low yields, long
reaction times, high temperature, use of not readily available catalyst, and tedious
workup procedure. Consequently, the introduction of new methods and/or further
work on technical improvements to overcome these limitations is still needed.
Recently, synthesis of organic compounds in the presence of heterogeneous or
homogeneous catalysts has attracted special interest because they have many
advantages, for example availability, ease of handling, and easy workup.
For these reasons, and as a part of our interest in research on the development of
new methods for synthesis of heterocyclic compounds [18], benzimidazole
derivatives in particular [19–21], we report a clean and facile synthetic procedure
for preparation of 2-substituted benzimidazoles using transition metal nitrates as
efficient catalysts.
Results and discussion
First, a convenient synthetic method for synthesis of 2-arylbenzimidazoles at room
temperature was sought. Then, to evaluate the catalytic efficiency of metal nitrates,
reaction of o-phenylenediamine and p-nitrobenzaldehyde was performed in the
presence of 10 mol%, Cu(NO ) Á6H O in ethanol as catalyst (Table 1: entry 1). For
3
2
2
optimization the type and amount of catalyst, this reaction was used as a model
under the same conditions (Scheme 1). On the basis of the experimental results
(
metal nitrates.
Table 1), we found that Mn(NO ) Á6H O is more efficient catalyst than the other
3
2
2
Amounts of catalyst less than 6 mol% could catalyze the reaction, but it needed a
longer reaction time. The optimum amount of Mn(NO ) Á6H O catalyst for 12 min
3
2
2
reaction time was 10 mol%. Amounts of catalyst in excess of 10 mol% did not
improve the yield of the product.
Table 1 Benzimidazoles
derived from reaction of o-
phenylenediamine and
4-nitrobenzaldehyde using
a
Entry
Catalyst
Catalyst
load (mol%)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
Cu(NO
3
)
2
Á6H
Á6H
Á6H
Á6H
Á6H
Á6H
2
O
10
10
10
10
10
10
10
10
6
EtOH
EtOH
EtOH
EtOH
EtOH
82
84
87
84
92
58
71
94
65
70
87
87
different catalysts and solvents
for 12 min
3
Ni(NO )
2
2
O
Co(NO
3
)
2
2
O
Fe(NO
Mn(NO
Ni(NO
3
)
2
2
O
3
)
2
2
O
3
)
2
2
O
3
CH CN
Mn(NO
Mn(NO
Mn(NO
Mn(NO
Mn(NO
Mn(NO
3
3
3
3
3
3
)
)
)
)
)
)
2
2
2
2
2
2
Á6H
Á6H
Á6H
Á6H
Á6H
Á6H
2
2
2
2
2
2
O
DMSO
MeOH
EtOH
EtOH
EtOH
EtOH
O
O
O
O
O
1
1
1
0
1
2
8
12
15
a
Isolated yields
1
23

Transition metal nitrates catalyzed synthesis of 2-arylbenzimidazoles
CHO
H
N
NH2
Cu(NO ) .6H O, 10mol%
3
2
2
NO2
NH2
rt, C H OH
2
5
N
NO2
1
3h
Scheme 1 The model reaction for optimization of reaction conditions
To examine the effect of solvent, the reaction was conducted in different organic
solvents at room temperature with 10 mol% catalyst for 12 min. The results are
summarized in Table 1. Although the yield of the reaction was higher when CH OH
3
was used as solvent, we used C H OH as solvent for our procedure because of its
2
5
lower toxicity.
To study the development and generality of this simple method, the optimized
procedure was extended to preparation of several benzimidazoles. The reaction was
performed at room temperature by taking a 1:1 mol ratio mixture of o-phenylene-
diamine 1 and the corresponding aromatic aldehyde 2 in the presence of
Mn(NO ) Á6H O (10 mol %) in ethanol to give 2-arylbenzimidazoles 3a–n
3
2
2
(
Scheme 2).
The results are summarized in Table 2. The yields of reactions using this
practical procedure for preparation of a variety of benzimidazoles are quite good,
the workup is very simple, and reaction times are short.
Aliphatic aldehydes or ketones, for example formaldehyde, acetaldehyde, and
acetophenone, were also examined under the same conditions, but the correspond-
ing products were isolated in trace amounts. All synthesized compounds were
identified by use of IR and NMR spectroscopy and elemental analysis, and by
1
comparison with authentic samples. In the H NMR spectrum of new compound
3
m, a singlet at 3.79 ppm, multiple signals at 6.24–7.99 ppm, and a broad singlet at
3.19 ppm were observed because of the resonance of the methoxy group, aromatic
1
protons, and –NH and OH groups, respectively. The C NMR of novel product 3n
contained 11 peaks for aliphatic and aromatic carbons in the expected regions of the
1
3
NH2
NH2
H
N
M(NO ) .6H O
3
2
2
+
Ar CHO
rt, C
2
H
5
OH
N
R
1
2
3a-n
3
a: R=H
3h: R=4-NO2
3
3
3
3
3
3
b: R=4-Br
c: R=2-Cl
d: R=3-Cl
e: R=4-Cl
f: R=2-NO
3i: R=4-Me
3j: R=4-OMe
3k: R=2-OH
3l: R=2-OH, 5-Br
3m: R=2-OH, 4-OMe
3n: R= 4-OCH -4-C H -
2
2
g: R=3-NO
2
6 4
4
-CH O-4-C H -4-CHO
2 6 4
Scheme 2 Synthetic method for compounds 3a–n
123

M. Kalhor et al.
Table 2 Benzimidazoles derived from reaction of o-phenylenediamine and aromatic aldehydes in the
)
presence of 10 mol% Mn(NO
3
2
Á6H
2
O in ethanol at room temperature (t = 12 min)
b
Compound
R
M.p. (8C)
Yield (%)
a
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
a
b
c
d
e
f
H
293–294 (288–290)
284–286 (283–284)
230–232 (232–234)
233–235 (234–236)
292–294 (291–293)
269–271 (264–266)
205–207 (203–204)
314–316 (312–314)
278–279 (268–270)
231–232 (225–226)
241–243 (240–242)
257 (256–257)
70
86
73
75
77
87
89
92
54
50
77
82
79
74
4-Br
2-Cl
3-Cl
4-Cl
2-NO
3-NO
4-NO
4-Me
2
2
2
g
h
i
j
4-OMe
k
l
2-OH
2-OH–5-Br
m
n
2-OH–4-OMe
4-OCH –4-C
224–226
2
6
H
4
–4-CH
2
O–4-C
6
H
4
–4-CHO
280
Melting points of 3a–k reported in the literature [12, 14–16]
b
Isolated yields
spectrum, which is in support of the symmetrical structure. Other physicochemical
data also confirmed the structures of the target products.
Experimental
NMR spectra were recorded on a Brucker 300 MHz spectrometer. Infrared spectra
were recorded on a Galaxy FT-IR 5000 spectrophotometer. Microanalysis was
performed with an Elemental Vario EL III elemental analyzer at Arak University.
Results were in agreement with calculated values. Reaction progress was routinely
monitored by thin layer chromatography using silica gel F254 aluminum sheets
(
Merck). All chemicals were used as obtained without further purification.
Typical procedure for preparation of 2-arylbenzimidazoles
To a solution of o-phenylenediamine (0.1 g, 1 mmol) and the corresponding
aromatic aldehyde (1 mmol) in ethanol (10 ml) was added Mn(NO ) Á6H O
3
2
2
(
10 mol%). The reaction mixture was stirred at room temperature for the desired
time (12 min). After completion of reaction, cold water (15–20 ml) was added to
precipitate the product, which was then isolated by filtration, washed with water–
ethanol (70:30), and dried in air.
1
23

Transition metal nitrates catalyzed synthesis of 2-arylbenzimidazoles
Spectroscopic data for selected compounds
2
-Phenyl-1H-benzimidazole (3a)
-
1
;
1
IR (KBr) (mmax): 3,348 (N–H), 3,047 (C–H), 1,462 (C=C) cm
H NMR
(
300 MHz, DMSO-d ): dH 7.21–7.66 (m, 7H, H–Ar), 8.16–8.20 (m, 2H, H–Ar),
6
12.94 (br, 1H, NH) ppm. Anal. Calcd. For C H N : C, 80.39; H, 5.19; N, 14.42 %.
13 10 2
Found: C, 80.45; H, 5.21; N, 14.46 %.
2
-(2-Chlorophenyl)-1H-benzimidazole (3c)
-
1 1
IR (KBr) (mmax): 3,377 (N–H), 3,061 (C–H), 1,599 (C=N), 1,440 (C=C) cm ; H
NMR (300 MHz, DMSO-d ): dH 7.22 (q, J = 2.6 Hz, 2H, H–Ar), 7.51–7.55 (m,
6
3
H, H–Ar), 7.65 (q, J = 3.8 Hz, 2H, H–Ar) 7.89 (t, 1H, J = 9.4 Hz, H–Ar), 12.73
br, 1H, NH) ppm. Anal. Calcd. For C H N Cl: C, 68.28; H, 3.97; N, 12.25 %.
(
Found: C, 68.07; H, 4.10; N, 12.35 %.
1
3 9 2
2
-(4-Nitrophenyl)-1H-benzimidazole (3h)
-
1 1
IR (KBr) (mmax): 3,367 (N–H), 3,061 (C–H), 1,597 (C=N), 1,516 (C=C) cm ; H
NMR (300 MHz, DMSO-d ): d 7.24–7.74 (m, 4H, H–Ar), 8.40–8.70 (m, 4H, H–
Ar), 13.30 (br, 1H, NH) ppm. Anal. Calcd. For C H N O : C, 65.27; H, 3.79; N,
6
H
13 9 3 2
1
7.56 %. Found: C, 65.46; H, 3.70; N, 17.37 %.
2
-(4-Methylphenyl)-1H-benzimidazole (3i)
-
1 1
IR (KBr) (mmax): 3,323 (N–H), 3,059 (C–H), 1,622 (C=N), 1,448 (C=C) cm ; H
NMR (300 MHz, DMSO-d ) d : 2.37 (s, 3H, CH ), 7.17–7.57 (m, 6H, H–Ar),
6
H
3
8
.06–8.11 (m, 2H, H–Ar), 12.83 (br, 1H, NH) ppm. Anal. Calcd. For C H N : C,
14 12 2
8
0.74; H, 5.81; N, 13.45 %. Found: C, 80.51; H, 5.78; N, 13.53 %.
2
-(4-Methoxyphenyl)-1H-benzimidazole (3j)
IR (KBr) (mmax): 3,481 (NH), 3,032 (C–H), 1,622- (C=N), 1,502–1,437 (C=C),
-
1
1
1
,158 (C–O) cm ; H NMR (300 MHz, DMSO-d ) d : 3.83 (s, 3H, OCH ),
6
H
3
7
H–Ar), 8.14 (t, J = 8.9 Hz, 2H, H–Ar) 12.78 (br, 1H, NH) ppm; C NMR
.10–7.17 (m, 2H, H–Ar), 7.2 (q, J = 3.2 Hz, 2H, H–Ar), 7.56 (t, J = 3.0 Hz, 2H,
1
3
(
(DMSO-d , 75 MHz) d : 55.8 (OCH ), 114.0, 116.8, 122.2, 123.0, 128.3, 134.7,
6
c
3
1
1
51.9, 161.6 (C–O) ppm. Anal. Calcd. For C H N O: C, 74.98; H, 5.39; N,
2.49 %. Found: C, 74.71; H, 5.51; N, 12.73 %.
1
4 12 2
2
-(2-Hydroxyphenyl)-1H-benzimidazole (3k)
IR (KBr) (mmax): 3,329, 3,236 (OH, –NH), 3,057 (C–H), 1,627 (C=N), 1,489 (C=C),
-
1 1
1
,261 (C–O) cm ; H NMR (300 MHz, DMSO-d ) d : 6.99–7.07 (q, 2H, H–Ar),
6
H
7
.29–7.38 (m, 3H, H–Ar), 7.68–8.08 (m, 3H, H–Ar), 13.25 (br, 2H, –NH, –OH)
123

M. Kalhor et al.
1
3
ppm; C NMR ((DMSO-d , 75 MHz) d : 112.2, 113.8, 117.8, 119.1, 123.0, 123.6,
6
c
1
26.9, 132.7, 152.9, 158.1 (C–O) ppm. Anal. Calcd. For C H N O: C, 74.27; H,
13 10 2
4
.79; N, 13.33 %. Found: C, 74.41; H, 4.77; N, 13.43 %.
2
-(2-Hydroxy-4-methoxyphenyl)-1H-benzimidazole (3m)
IR (KBr) (mmax): 3,336 (OH, –NH), 3,085, 2,931 (C–H), 1,639, 1,606 (C=N), 1,546,
-
1 1
1
,492, 1,454, 1,396 (C=C), 1,269 (C–O), 1,203 (O–CH ), 1,033, 819, 723 cm ; H
2
NMR (300 MHz, DMSO-d ) d : 3.79 (s, 3H, OCH ), 6.24–6.62 (m, 2H, H–Ar),
6
H
3
6
.98–7.62 (m, 4H, H–Ar), 7.99 (s, 1H, H–Ar), 13.19 (br, 2H, OH, NH) ppm, the OH
1
3
and NH protons disappeared on D O addition; C NMR ((DMSO-d , 75 MHz) d :
2
6
c
5
5.7 (OCH ), 101.9, 106.2, 106.9, 114.3, 122.9, 127.7, 138.2, 152.6, 160.5, 162.7
3
(C–O) ppm. Anal. Calcd. For C H N O : C, 69.99; H, 5.03; N, 11.66 %. Found:
14 12 2 2
C, 69.78; H, 5.02; N, 11.74 %.
1
,4-Bis((4-(1H-benzimidazol-2-yl)phenoxy)methyl)benzene (3n)
IR (KBr) (mmax): 3,400 (N–H), 3,118, 2,905 (C–H), 1,687, 1,610 (C=N), 1,548,
1
7
1
,516, 1,371, 1,300 (C=C), 1,250 (C-O), 1,145 (O–CH ), 1,024, 912, 810,
-
2
1 1
60 cm ; H NMR (300 MHz, DMSO-d ) d : 5.25 (s, 4H, 2OCH ), 7.27–7.69 (m,
6
H
2
1
6H, H–Ar), 8.25 (d, J = 6.9 Hz, 4H, H–Ar), 12.96 (br, 2H, NH) ppm; C NMR
3
(
(DMSO-d , 75 MHz) d : 69.7 (O–CH –), 114.6, 116.1, 119.1, 124.4, 128.5, 129.7,
6
c
2
1
35.5, 136.8, 150.2, 161.5 (C–O) ppm. Anal. Calcd. For C H N O : C, 78.14; H,
34 26 4 2
5
.01; N, 10.72 %. Found: C, 77.73; H, 4.98; N, 10.63 %.
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