A simple, mild and efficient one-pot synthesis of 2-substituted benzimidazoles in the presence of H2O2/HCl under microwave irradiation

Article abstract of DOI:10.1002/jccs.201100591

Asimple, fast and efficient method for the preparation of several 2-substituted benzimidazole derivatives is reported. Compounds were synthesized through a rapid one-pot synthesis via microwave irradiation, starting from aldehydes and o-phenylenediamine,

Full text of DOI:10.1002/jccs.201100591

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
A Simple, Mild and Efficient One-Pot Synthesis of 2-Substituted Benzimidazoles in the
Presence of H O /HCl under Microwave Irradiation
2
2
Hossein Naeimi* and Nasrin Alishahi
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, 87317, I.R. Iran
(Received: Oct. 5, 2011; Accepted: Mar. 9, 2012; Published Online: ??; DOI: 10.1002/jccs.201100591)
A simple, fast and efficient method for the preparation of several 2-substituted benzimidazole derivatives
is reported. Compounds were synthesized through a rapid one-pot synthesis via microwave irradiation,
2 2
starting from aldehydes and o-phenylenediamine, in the presence of H O /HCl system in acetonitrile. The
significant features of this method are short reaction times, high yields, easy and quick isolation of the
products.
Keywords: O-Phenylenediamine; Synthesis; Benzimidazoles; Aryl aldehydes; Microwave.
INTRODUCTION
Benzimidazole and its derivatives are important class
efficient methodology for the synthesis of 2-substituted
benzimidazoles by coupling of o-phenylenediamine with
aryl aldehydes using aqueous HCl and H O as oxidant sys-
of bioactive molecules in the field of drugs and pharma-
1
ceuticals. The spectrum of the pharmacological activity of
2
2
tem in acetonitrile solvent under microwave irradiation.
The route for the synthesis of 2-substituted benzimidazoles
by this procedure is shown in Scheme I.
2
-5
benzimidazole has been reviewed by several authors.
These heterocycles show various pharmaceutical proper-
6
ties such as, antiviral, antibacterial, antitumor antifun-
7
8
9
gal, anticancer, antibiotic, and anti-inflammatory.
10
11
12
Scheme I
They have been also used as ligands in asymmetric synthe-
1
sis.
3
Due to their wide range of pharmacological activity,
industrial and synthetic applications, a number of methods
have been reported for the synthesis of benzimidazoles,
which include the reaction between N-ethoxycarbonylthio-
The optimized microwave irradiation power level
was used 100 W and the corresponding benzimidazoles
were obtained in excellent yields and short reaction times.
Firstly, in order to find the effect of solvent on this re-
action, several solvents including acetone, acetonitrile, di-
chloromethane, and ethanol were investigated during the
course of this study. After screening different solvents, it
was found that the best solvent is acetonitrile in this reac-
tion (Table 1). We also tried to carry out this reaction with-
out any solvent, in which the product yield was very low
even with continuation of the reaction until 2 hours (entry
1
4
mides with 1,2-diamines, the coupling of phenylenedi-
1
5,16
amines and carboxylic acids
or their derivatives (ni-
However, most of these
1
7,18
triles, imidates, or orthoesters).
procedures have some drawbacks such as low yields of
products, long reaction times and tedious work-up proce-
dures.
Microwave as heating source has been used for the
rapid synthesis of a variety of heterocyclic compounds
both in solution phase as well as under solvent-free condi-
1
9
tions. Using microwave irradiation, the rates of reactions
involving polar components are usually very fast. Reac-
tions that require hours or even days by conventional heat-
ing may often be accomplished in seconds by microwave
5
, Table 1).
In contrast, microwave along with conventional ther-
mal heating, microwave irradiation produces efficient in-
ternal heating (in core volumetric heating) by direct cou-
pling of microwave energy with the molecules (solvents,
reagents, catalysts) that are present in the reaction mixture.
Microwave irradiation, therefore, raises the temperature of
the whole volume simultaneously (bulk heating) whereas
2
0
heating, and that is the reason why this technology is
widely applied to drug discovery.
RESULTS AND DISCUSSION
In this research, we herein, report a facile, rapid and
*
Corresponding author. Fax: +983615552935; E-mail: naeimi@kashanu.ac.ir
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1

Article
Naeimi and Alishahi
a
Table 1. Optimization of solvent effect on the reaction
reaction probably involves the formation of hypochlorous
acid by the reaction of aqueous hydrogen peroxide with hy-
drochloric acid, in which then reacts with the cyclic hydro-
benzimidazoles 1 to afford intermediate 2 followed by the
abstraction of hydrogen to yield the corresponding benz-
imidazoles (Scheme II).
Entry
Solvent
Time (min)
Yield (%)
1
2
3
4
5
a
Ethanol
Acetone
18
17
3
61
59
Acetonitrile
Dichloromethane
None
94
15
120
54
very low
Reaction of 4-methylbenzaldehyde with o-phenylenediamine in
Scheme II
presence of different solvent.
in the conventionally heated vessel, the reaction mixture in
contact with the vessel wall is heated first. Since the reac-
tion vessels employed in modern microwave reactors are
typically made out of (nearly) microwave transparent mate-
rials such as borosilicate glass, quartz or Teflon, the radia-
tion passes through the walls of the vessel and an inverted
temperature gradient as compared to conventional thermal
heating results. If the microwave cavity is well designed,
the temperature increase will be uniform throughout the
sample. The very efficient internal heat transfer results in
minimized wall effects (no hot vessel surface) which may
lead to the observation of so-called specific microwave ef-
In this research, we have developed a simple, rapid
and efficient method for the preparation of 2-substituted-
1H-benzimidazole compounds using readily available and
inexpensive reagents under microwave irradiation condi-
tions. The corresponding products have been obtained in
excellent yields, high purity and short reaction times.
2
1
fects.
Then, to ascertain the scope and limitation of the
present reaction, several aromatic aldehydes were reacted
with o-phenylenediamine in the presence of HCl and H O
2
2
as oxidant system under microwave irradiation in aceto-
nitrile solvent and the desired products including 2-substi-
tuted benzimidazole derivatives were prepared. The corre-
sponding results are summarized in Table 2. As shown in
this Table, the reaction of the various aldehydes with o-
phenylenediamine in this reaction, were accelerated by mi-
crowave irradiation in comparison with this reaction under
thermal condition. The corresponding products were ob-
tained in excellent yields and short reaction times under mi-
crowave irradiation. While, the reaction under heating con-
dition were produced the benzimidazoles in good yields
and long reaction times. It seems this method for prepara-
tion of 2-substituted benzimidazoles has some advantages
such as; highly efficient, mild and useful as compared to
EXPERIMENTAL
Materials
All the materials were of commercial reagent grade.
The aromatic aldehydes, and o-phenylenediamine were pu-
rified by standard procedures and purity determined by thin
layer chromatography (TLC).
Apparatus
IR spectra were recorded as KBr pellets on a Perkin-
Elmer 781 spectrophotometer and an Impact 400 Nicolet
1
13
FTIR spectrophotometer. H NMR and C NMR were re-
corded in DMSO solvent on a Bruker DRX-400 spectrome-
ter with tetramethylsilane as internal reference. Melting
points obtained with a Yanagimoto micro melting point ap-
paratus are uncorrected. The purity determination of the
substrates and reaction monitoring were accomplished by
TLC on silica-gel polygram SILG/UV 254 plates (from
Merck Company). Microwave irradiations were carried out
in microwave oven specially designed for the organic syn-
thesis (Milestone LAVIS 1000 Basic Microwave).
1
4-18
previously reported methods.
All compounds were
confirmed by their physical and spectroscopic data and
2
were in good agreement with those of authentic samples.
2-28
The proposed reaction mechanism
2 2
A ratio of 7:3.5:1:1 of H O /HCl/aryl aldehyde/1,2-
phenylendiamine was found to be optimum for the reac-
tion. Regarding to the mechanism of the oxidation step, the
2
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CHEMICAL SOCIETY
One-Pot Synthesis of 2-Substituted Benzimidazoles
Table 2. Reaction of various aryl aldehydes with o-phenylenediamine
Microwave
Time (min) Yield (%) Time (min) Yield (%)
Heating
a
Entry
Substrate
Product
b
b
H
N
1
2
3
OHC
3.1
1.1
1.8
96
98
96
44
23
31
83
88
84
N
H
N
OHC
NO2
NO2
NO
N
NO2
2
H
N
OHC
N
O N
O N
2
2
H
N
4
1.6
97
28
80
OHC
N
H
N
5
6
7
OHC
Br
Cl
Br
2
1.5
2
97
95
93
33
32
34
81
83
79
N
H
N
OHC
Cl
N
Cl
Cl
H
N
OHC
N
Cl
Cl
Cl
Cl
H
N
8
9
0.66
1.3
1.6
2
98
93
96
92
93
23
25
27
35
30
86
84
87
80
81
OHC
N
H
N
OHC
NMe
NMe2
2
N
HO
OH
H
N
1
1
1
0
1
2
OHC
N
H
N
OHC
OH
OH
OH
N
OH
H
N
1.8
OHC
N
H
N
1
1
1
3
4
5
OHC
Me
Me
3
2.5
2
94
95
95
43
42
36
76
78
80
N
H
N
OHC
OMe
OMe
OMe
N
OMe
H
N
OHC
N
OMe
MeO
H
N
1
6
OHC
3.3
96
45
82
N
OMe
OMe
a
All compounds are known and their physical and spectroscopic data were in good agreement with those of
b
authentic samples. Yields refer to pure isolated products.
Typical procedure for the Synthesis of benzimida-
aryl aldehyde (1.0 mmol) in MeCN (4 mL) was prepared.
zoles from aryl aldehydes
Aq. 30% H
2 2
O (7.0 mmol) and aq. 37% HCl (3.5 mmol)
A solution of o-phenylenediamine (1.0 mmol), and
were added and introduced in an open Erlenmeyer flask.
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Naeimi and Alishahi
The mixture was irradiated in a microwave oven. The prog-
ress of the reaction was monitored by TLC. When the start-
ing materials had completely disappeared, the mixture was
2-(2-Choloro-phenyl)-benzimidazole
Yellow solid; m.p. = 231-233 °C (m.p = 232-234
2
°C); IR (KBr)/n (cm ) 3444 (NH), 1591 (C=N), 1575,
6
-1
1
1440 (C = C, Ar); H NMR (DMSO, 400 MHz)/d ppm: 7.2
+
(2H, m, Ar), 7.50-7.89 (6H, m, Ar); MS: m/z: 228.5 (M ).
quenched by adding H
10 mL). The corresponding products were identified by
physical and spectroscopic data.
2
O (10 mL), extracted with EtOAc (4
×
2-(2,3-Dicholoro-phenyl)-benzimidazole
-
1
Yellow solid; m.p. = 224-226 °C; IR (KBr)/n (cm )
2
-Phenyl-benzimidazole
1
3095 (NH), 1624 (C=N), 1540, 1433 (C = C, Ar); H NMR
Pale yellow solid; m.p.= 289-290 °C (m.p = 288-290
2
C); IR (KBr)/n (cm ) 3446 (NH), 1622 (C=N), 1590,
2
-1
°
(DMSO, 400 MHz)/d ppm: 7.2 (2H, m, Ar), 7.53 (1H, m,
Ar), 7.64 (2H, m, Ar), 7.82 (2H, m, Ar).
1
445 (C = C, Ar); H NMR (DMSO, 400 MHz)/d ppm: 7.19
1
1
3
(
2H, m, Ar), 7.48-7.64 (5H, m, Ar), 8.17 (2H, m, Ar);
C
2-(N,N-dimethyl-phenyl)-benzimidazole
NMR (100 MHz, DMSO)/d ppm: 111.1, 118.6, 121.9,
Yellow solid; m.p. = 277-279 °C (m.p = 294.2-296.3
2
4
-1
°C); IR (KBr)/n (cm ) 3391 (NH), 1605 (C=N), 1518,
1
1
2
26.2, 128.6, 129.5, 130.0, 134.8, 143.5, 151.0; MS: m/z:
93 (M-H, 100 %).
1
1459 (C = C, Ar); H NMR (DMSO, 400 MHz)/d ppm: 6.84
-(4-Nitro-phenyl)-benzimidazole
(2H, d, Ar), 7.43 (2H, m, Ar), 7.70 (2H, m, Ar), 8.21 (2H, d,
Pale yellow solid; m.p. = 307-309 °C (m.p = 312-314
Ar).
2
3
-1
C); IR (KBr)/n (cm ) 3421 (NH), 1606 (C=N), 1524,
°
2-(2-Hydroxy-phenyl)-benzimidazole
1
451 (C = C, Ar); H NMR (DMSO, 400 MHz)/d ppm:
28
1
7
8
2
White solid; m.p. = 238-240 °C (m.p = 240-242 °C);
-
1
IR (KBr)/n (cm ) 3325 (OH), 3055 (NH), 1593 (C=N),
1
1530, 1491 (C = C, Ar); H NMR (DMSO, 400 MHz)/d
.51-7.54 (2H, m, Ar), 7.83 (2H, m, Ar), 8.47 (2H, d, Ar),
+
.48-8.64 (2H, d, Ar); MS: m/z: 239 (M ).
-(3-Nitro-phenyl)-benzimidazole
ppm: 6.99-7.05 (2H, m, Ar), 7.27 (2H, m, Ar), 7.37 (1H, t,
Ar), 7.66 (2H, m, Ar), 8.06 (1H, d, Ar), 13.19 (1H, s, OH);
Yellow solid; m.p. = 309-310 °C (m.p = 310-311
2
2
-1
C); IR (KBr)/n (cm ) 3308 (NH), 1630 (C=N), 1531,
+
MS: m/z: 210 (M ).
°
1
482 (C = C, Ar); H NMR (DMSO, 400 MHz)/d ppm: 7.47
1
2-(4-Hydroxy-phenyl)-benzimidazole
(
2H, m, Ar), 7.79 (2H, m, Ar), 7.92-7.95 (1H, m, Ar), 8.1-
White solid; m.p. = 254-255 °C (m.p = 254.1-256.6
1
.9 (2H, m, Ar), 9.1 (1H, s, Ar); C NMR (DMSO, 100
3
24
°C); IR (KBr)/n (cm ) 3383 (OH), 3202 (NH), 1668
-1
8
1
(C=N), 1600, 1457 (C = C, Ar); H NMR (DMSO, 400
MHz)/d ppm: 114.3, 121.2, 122.1, 123.2, 130.1, 131.6,
1
33.6, 138.9, 148.9, 152.7; MS: m/s: 238 (M-H, 100%).
-(2-Nitro-phenyl)-benzimidazole
MHz)/d ppm: 6.91-7.50 (4H, m, Ar), 7.73-8.21 (4H, m,
Ar), 9.7 (1H, s, OH).
2
Pale yellow solid; m.p. = 212-214 °C (m.p =209-210
2-(3-Hydroxy-phenyl)-benzimidazole
-1
Yellow solid; m.p. = 245-247 °C; IR (KBr)/n (cm )
2
C); IR (KBr)/n (cm ) 3428 (NH), 1622 (C=N), 1530,
3
-1
°
1
458 (C = C, Ar); H NMR (DMSO, 400 MHz)/d ppm:
1
7
3434 (OH), 3243 (NH), 1588 (C=N), 1541, 1445 (C = C,
1
Ar); H NMR (DMSO, 400 MHz)/d ppm: 6.9 (1H, d, Ar),
.54-7.57 (2H, m, Ar), 7.85-7.87 (2H, m, Ar), 7.99 (1H, t,
Ar), 8.05 (1H, m, Ar), 8.12 (1H, d, Ar), 8.37 (1H, d, Ar);
+
MS: m/z: 239 (M ).
7.18 (2H, m, Ar), 7.33 (1H, t, Ar), 7.59 (4H, d, Ar).
2-(4-Methyl-phenyl)-benzimidazole
2
6
2
-(4-Boromo-phenyl)-benzimidazole
White solid; m.p. = 260-261 °C (m.p = 261-263 °C);
-
1
IR (KBr)/n (cm ) 3429 (NH), 1620 (C=N), 1587, 1433 (C
Pale yellow solid; m.p. = 292-293 °C (m.p = 250-252
2
C); IR (KBr)/n (cm ) 3449 (NH), 1628 (C=N), 1598,
7
-1
1
= C, Ar); H NMR (DMSO, 400 MHz)/d ppm: 2.36 (3, s,
°
1
1
456 (C = C, Ar); H NMR (DMSO, 400 MHz)/d ppm: 7.53
2H, m, Ar), 7.83 (2H, m, Ar), 7.95 (2H, d, Ar), 8.28 (2H, d,
Ar).
-(4-Choloro-phenyl)-benzimidazole
Yellow solid; m.p. = 290-291 °C (m.p = 291-293
Me), 7.18 (2H, m, Ar), 7.34 (2H, d, Ar), 7.57 (2H, m, Ar),
8.06 (2H, d, Ar),
(
2-(4-Methoxy-phenyl)-benzimidazole
2
Yellow solid; m.p. = 229-230 °C (m.p = 229.2-231.1
2
°C); IR (KBr)/n (cm ) 3344 (NH), 1608 (C=N), 1506,
4
-1
2
5
-1
1
1461 (C = C, Ar); H NMR (DMSO, 400 MHz)/d ppm: 3.89
°
C); IR (KBr)/n (cm ) 3442 (NH), 1598 (C=N), 1580,
1
429 (C = C, Ar); H NMR (DMSO, 400 MHz)/d ppm: 7.2
1
(3H, s, Me), 7.2 (2H, d, Ar), 7.52 (2H, m, Ar), 7.79 (2H, m,
1
Ar), 8.38 (2H, d, Ar); C NMR (DMSO, 100 MHz)/d ppm:
3
(
(
2H, m, Ar), 7.50-7.89 (6H, m, Ar); MS: m/z: 229.0
+
M+H) .
56.24, 114.06, 115.34, 115.53, 126.03, 130.62, 132,
4
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J. Chin. Chem. Soc. 2012, 59, 000-000

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
One-Pot Synthesis of 2-Substituted Benzimidazoles
Bioorg. Med. Chem. 2002, 10, 3997.
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1
48.91, 163.61.
1
2
-(3-Methoxy-phenyl)-benzimidazole
Med. Chem. 2004, 39, 291.
Yellow solid; m.p. = 200-202 °C (m.p = 205-206
7
1
1
2. Terzioglu, N.; Rijn, R. V.; Bakker, R. A.; Esch, I. J. P.; Leurs,
De R. Bioorg. Med. Chem. Lett. 2004, 14, 5251.
3. Figge, A.; Altenbach, H. J.; Braauer, D. J.; Tielmann, P. Tet-
rahedron: Asymmetry 2002, 13, 137.
2
C); IR (KBr)/n (cm ) 3437 (NH), 1596 (C=N), 1541,
-1
°
1
1
464 (C = C, Ar); H NMR (DMSO, 400 MHz)/d ppm: 3.9
3H, s, Me), 7.05 (1H, m, Ar), 7.19 (2H, m, Ar), 7.45 (1H,
s, Ar), 7.59 (2H, m Ar), 7074 (2H, m, Ar).
(
14. George, B.; Papadopoulos, E. P. J. Org. Chem. 1977, 42, 441.
1
5. Middleton, R. W.; Wibberley, D. G. J. Heterocycl. Chem.
1980, 17, 1757-1760.
2
-(2,5-Dimethoxy-phenyl)-benzimidazole
-
1
Yellow solid; m.p. = 197-198 °C; IR (KBr)/n (cm )
1
408 (NH), 1622 (C=N), 1511, 1458 (C = C, Ar); H NMR
16. Geratz, J. D.; Stevens, F. M.; Polakoski, K. L.; Parrish, R. F.
3
Arch. Biochem. Biophys. 1979, 197, 551-559.
(
DMSO, 400 MHz)/d ppm: 4.02 (3H, s, Me), 3.85 (3H, s,
Me), 7.33 (2H, d, Ar), 7.55 (2H, m, Ar), 7.89 (2H, m, Ar),
.02 (1H, s, Ar).
1
1
7. Tidwell, R. R.; Geratz, J. D.; Dann, O.; Volz, G.; Zeh, D.;
Loewe, H. J. Med. Chem. 1978, 21, 613-623.
8
8. Fairley, T. A.; Tidwell, R. R.; Donkor, I.; Naiman, N. A.;
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ACKNOWLEDGMENT
1
2
2
9. Mavandadi, F.; Lidstro, M.; Curr, P. Top. Med. Chem. 2004,
We are grateful to the University of Kashan Research
Council for the partial support of this work.
4
, 773.
0. Yu, H.; Kawanishi, H.; Koshima, H. Heterocycl. 2003, 60,
457.
1
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