M(HSO4)n-promoted synthesis of 2-aryl-1-arylmethyl- 1H-1,3-benzimidazole derivatives

Article abstract of DOI:10.1080/00397910801993743

We have developed a highly selective synthesis of 2-aryl-1-arylmethyl-1H-1, 3-benzimidazoles from the reaction of o-phenylenediamines and aromatic aldehydes in the presence of metal hydrogen sulfates [M(HSO4)n] in water and also under solvent-free conditions in good to excellent yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801993743

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M(HSO ) -Promoted Synthesis
4
n
of 2-Aryl-1-arylmethyl-1H-1,3-
benzimidazole Derivatives
a
b
Khodabakhsh Niknam , Mohammad Ali Zolfigol
&
a
Negar Safikhani
a
Department of Chemistry , Faculty of Sciences,
Persian Gulf University , Bushehr, Iran
b
Faculty of Chemistry, Bu-Ali Sina University ,
Hamedan, Iran
Published online: 28 Aug 2008.
To cite this article: Khodabakhsh Niknam , Mohammad Ali Zolfigol & Negar
Safikhani (2008) M(HSO ) -Promoted Synthesis of 2-Aryl-1-arylmethyl-1H-1,3-
4
n
benzimidazole Derivatives, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:17, 2919-2928, DOI:
10.1080/00397910801993743
To link to this article: http://dx.doi.org/10.1080/00397910801993743
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1
Synthetic Communications , 38: 2919–2928, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801993743
M(HSO ) -Promoted Synthesis of 2-Aryl-1-
4
n
arylmethyl-1H-1,3-benzimidazole Derivatives
1
Khodabakhsh Niknam, Mohammad Ali Zolfigol,
2
1
and Negar Safikhani
Department of Chemistry, Faculty of Sciences, Persian Gulf University,
Bushehr, Iran
1
2
Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
Abstract: We have developed a highly selective synthesis of 2-aryl-1-arylmethyl-
H-1,3-benzimidazoles from the reaction of o-phenylenediamines and aromatic
1
aldehydes in the presence of metal hydrogen sulfates [M(HSO
also under solvent-free conditions in good to excellent yields.
4 n
) ] in water and
Keywords: Aryl aldehydes, benzimidazole derivatives, metal hydrogen sulfates
M(HSO , 1,2-phenylenediamine, water
[
4 n
)
INTRODUCTION
In recent years, the search for environmentally benign chemical processes
or methodologies has received much attention from chemists, because
they are essential for the conservation of the global ecosystem. The devel-
opment of heterogeneous catalysts for fine chemical synthesis has become
a major area of research, as the potential advantages of these materials
(
simplified recovery and reusability; the potential for incorporation in
continuous reactors and microreactors) over homogeneous systems can
lead to novel environmentally benign chemical procedures for academia
[
1]
and industry. From this viewpoint, the catalytic reaction is a valuable
process because the use of stoichiometric reagents that are often toxic
Received February 8, 2008.
Address correspondence to Khodabakhsh Niknam, Department of Chemistry,
Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran. E-mail:
niknam@pgu.ac.ir and khniknam@gmail.com
2
919

2920
K. Niknam, M. A. Zolfigol, and N. Safikhani
poses problems from both economical and environmental viewpoints
[
regarding product purification and waste management.
2]
Application of solid acids in organic transformations are very impor-
tant because solid acids have many advantages such as simplicity in hand-
ling, decreased reactor and plant corrosion problems, and more
environmentally safe disposal. On the other hand, a reduction in the
amount of liquid acid needed and=or any simplification in handling pro-
cedures is required for risk reduction, economic advantage, and environ-
[
3–13]
ment protection.
Among solid acids, metal hydrogen sulfates
[
13]
M(HSO4)n are alternatives for very dangerous concentrated liquid sul-
furic acid, and there are several reports about using these solid acidic salts
in organic transformation.
The benzimidazole nucleus is of significant importance to medicinal
chemistry. Several publications report benzimidazole-containing com-
pounds showing biological activities such as selective neuropeptide
[14]
YY1 receptor antagonism and as 5-lipoxygenase inhibitors for use as
[
15]
[16]
novel antiallergic agents,
factor Xa (FXa) inhibitors,
poly (ADP-
and human cytomegalovirus
HCNV) inhibitors. Substituted benzimidazole derivatives have found
[17]
ribose) polymerase (PARP) inhibitors,
[18]
(
commercial applications in veterinarian medicine as anthelmintic agents
and in diverse human therapeutic areas such as treatment of ulcers and
[19]
as antihistamineics. In light of the affinity they display toward a var-
iety of enzymes and protein receptors, medicinal chemists would certainly
[
20,21]
classify them as ‘‘privileged sub structures’’ for drug design.
The traditional synthesis of benzimidazoles involves the reaction
between o-phenylenediamines and a carboxylic acid or its derivatives
(nitriles, amidates, orthoesters) under harsh dehydrating con-
ditions.
[
21–26]
Benzimidazoles have also been prepared on solid phase to
[27,28]
provide a combinatorial approach.
for their synthesis utilize o-nitroanilines as intermediates or resort to
direct N-alkylation of an unsubstituted benzimidazole.
of synthetic protocols that involve intermediate o-nitroanilines have
evolved to include the synthesis of benzimidazoles on solid support.
Another method for the synthesis of these compounds is the reaction of
o-phenylenediamines with aldehydes in the presence of acidic catalysts
under various reaction conditions.
In connection with our interest in the use of solid acidic salts as
The most popular strategies
[
29,30]
A number
[
31,32]
[33–38]
[
6–13]
efficient catalysts in various transformations
ation of our studies on the preparation of benzimidazole derivatives,
and also in continu-
[
39]
we report here a selective synthesis of 2-aryl-1-arylmethy-1H-1,3-benzi-
midazoles in water and also under solvent-free conditions (Scheme 1).
Condensation of o-phenylenediamine and benzaldehyde was per-
formed with different molar ratio of solid acids to optimize the reaction

Synthesis of Benzimidazole Derivatives
2921
Scheme 1. Condensation of o-phenylenediamine derivatives with aromatic
aldehydes.
conditions. In a preliminary study, the effect of various solid acids on the
yields and times of condensation was investigated with the previously
mentioned substrate as a model compound. As shown in Table 1,
Al(HSO ) , Mg(HSO ) , and Ca(HSO ) are the best solid acid catalysts
4
3
4 2
4 2
ꢀ
for this purpose in water at 80 C.
Also, Zn (HSO ) , NaHSO , and CH SO H catalyze this conden-
4
2
4
3
3
sation with a longer reaction time. The required molar ratio, 1:2:0.3,
was applied for o-phenylenediamine, benzaldehyde, and catalyst
M(HSO4)n respectively under the previously mentioned conditions.
When o-phenylenediamine derivatives 1 and aromatic aldehydes 2 in
the presence of metal hydrogen sulfates and different organic solvents
ꢀ
were allowed to react at 80 C, both expected products were obtained
whose ratios depended on the nature of the solvent (Scheme 1, 3 and
4
). As can be seen in Table 2, the best overall yields and selectivities were
obtained in solvent-free conditions, water and ethanol, in which only N-
substituted benzimidazoles 3 were produced. There is an urgent need to
develop alternative solvents and technologies because of pressure from
governmental organizations and other regulatory bodies to protect the
Table 1. Effect of different solid acids on the condensation of o-phenylene-
ꢀ
diamine (1 mmol) with benzaldehyde (2 mmol) in water at 80 C to produce 3a
a
Entry
Solid acid
Al(HSO4)3
Amount of catalyst (mmol) Time (min) Yield (%)
b
1
2
3
4
5
6
7
8
9
0.1
0.2
0.3
0.1
0.3
0.3
0.3
0.3
0.3
600
540
150
600
45
50
70
92
60
92
90
48
83
63
b
b
Al(HSO
Al(HSO
4
4
)
)
3
3
Mg(HSO
Mg(HSO4)2
4 2
)
Ca(HSO
Zn(HSO
4
4
)
)
2
60
2
180
170
210
NaHSO ꢁ H O
4
2
CH
3
3
SO H
a
Isolated yields.
Conversion.
b

2922
K. Niknam, M. A. Zolfigol, and N. Safikhani
Table 2. Effect of solvent on the time and yield of the reaction of o-phenylene-
ꢀ
diamine and benzaldehyde in the presence of Mg (HSO
4
)
2
at 80 C
a
Yield (%)
Entry
Solvent
EtOH
CH CN
Time (min)
3
4
1
2
3
4
5
6
7
150
360
210
600
45
90
65
60
—
92
30
92
—
<5
<10
—
—
<10
—
3
MeOH
CCl
H O
4
2
C
Solvent-free
H
6 5
CH
3
600
10
a
Isolated yield.
environment. Use of green solvents such as water showed both economi-
cal and synthetic advantages. Solvent-free organic reactions have been
[
40]
applied as a useful protocol in organic synthesis.
Solvent-free con-
ditions often lead to shorter reaction times, increased yields, and easier
work up, match green chemistry protocols, and may enhanced region-
[40]
and stereoselectivity of the reactions.
Thus, we decided to investigate
the reaction in water and also in solvent-free conditions. Consequently
several aromatic aldehydes with different substituents on the aromatic
ring were subjected to the condensation reaction. As Table 3 shows, ary-
laldehydes without substituents gave the desired benzimidazoles in excel-
lent yields (3a, 3e). Aldehydes bearing electron-donating substituents
gave more desired benzimidazoles (3b–3d and 3i) than electron-withdraw-
ing substituents (Table 3). Arylaldehydes with electron-withdrawing sub-
stituents such as 4-nitro- or 3-nitro-benzaldehyde gave a mixture of both
benzimidazoles 3, 4 by this methodology.
As described before, compound 3 may be produced through a tan-
dem sequence of reactions starting with the formation of dibenzylidene-
[
34]
o-phenylenediamine followed by ring closure.
took place via deprotonation and 1,3-hydride transfer (Scheme 2).
Finally, aromatization
[
36]
The production of monosubstituted benzimidazole 4 in some cases
could be visualized to occur by condensation of o-phenylenediamine with
the aldehyde followed by air oxidation of the dihydrobenzimidazole
[41]
derivative, as previously reported.
In summary, we have reported a new and effective methodology for
the ecocompatible preparation of 2-aryl-1-arylmethyl-1H-1,3-benzimida-
zoles. The easy purification of the products by simple filtration and
recrystallization, the use of water as the solvent or use of solvent-free

2
923

2924
K. Niknam, M. A. Zolfigol, and N. Safikhani
Scheme 2. Proposed mechanism for the condensation of phenylenediamine with
arylaldehydes.
conditions, and metal hydrogen sulfates as catalysts suggest good pro-
spects for the applicability of this process.
EXPERIMENTAL
General
Chemicals were purchased from Merck, Fluka, and Aldrich chemical com-
panies. IR spectra were run on a Shimadzu infrared spectroscope IR-435.
1
The H NMR was run on Bruker Avance (DRX 500-MHz) and Bruker
Avance (400-MHz) instruments. Melting points were recorded on an
SMP1 melting-point apparatus in open capillary tubes and are uncorrected.
With thin-layer chromatography (TLC) using silica gel SILG=UV 254
plates, the progress of the reaction was followed. The benzimidazole pro-
1
ducts were characterized by comparison of their spectral (IR, H-NMR),
[
TLC, and physical data with the authentic samples.
29,30,34–37]
General Procedure for the Synthesis of 2-Aryl-1-arylmethyl-1H-1,3-
benzimidazoles in Water
A mixture of o-phenylenediamine derivatives (1 mmol), aromatic alde-
hyde (2 mmol), and metal hydrogen sulfate (M ¼ Al, Mg, Ca) (0.3 mmol)

Synthesis of Benzimidazole Derivatives
2925
was added in 5 mL of water, and the reaction was stirred in a round-
ꢀ
bottomed flask in an oil bath at 80 C for the appropriate time (see
Table 3). The progress of the reaction was followed by TLC. After
completion of the reaction, the mixture was neutralized with NaHCO3
(
(
10%). The precipitates were then filtered, washed with water
2 ꢂ 15 mL), and air dried to afford the desired product. Finally the crude
product was recrystallized from ethanol.
General Procedure for the Synthesis of 2-aryl-1-arylmethyl-1H-1,3-
benzimidazoles Under Solvent-Free Conditions
A mixture of o-phenylenediamine derivatives (1 mmol), aromatic alde-
hyde (2 mmol), and metal hydrogen sulfate (M ¼ Al, Mg, Ca) (0.3 mmol)
was mixed in a mortar, placed in a round-bottomed flask, and heated in
ꢀ
an oil bath at 80 C for the appropriate time (see Table 3). The progress of
the reaction was followed by TLC. After completion of the reaction, the
mixture was neutralized with NaHCO (10%). The precipitates were then
3
filtered, washed with water (3 ꢂ 15 mL), and air dried to afford the
desired product. Finally the crude product was recrystallized from
ethanol.
Selected Spectra Data
1
Compound (3a) (C H N ): H NMR (DMSO-d , 500 MHz), d: 5.61
2
0
16
2
6
(
(
s, 2H), 6.29 (d, 2H, J ¼ 8.5 Hz), 6.62 (d, 2H, J ¼ 7.2 Hz), 7.23–7.30
m, 10H).
1
Compound (3d) (C H N O ): H NMR (DMSO-d , 500 MHz), d:
2
2
20
2
2
6
3
1
7
7
1
1
1
.66 (s, 3H), 3.67 (s, 3H), 5.24 (s, 2H), 6.61 (d, 1H, J ¼ 8.3 Hz), 6.76 (t,
H, J ¼ 7.5 Hz), 6.91 (d, 1H, J ¼ 8.3 Hz), 7.08 (t, 1H, J ¼ 7.5 Hz),
.16–7.24 (m, 4H), 7.38 (d, 1H, J ¼ 7.5 Hz), 7.45 (d, 1 H, J ¼ 7.5 Hz),
1
3
.52 (t, 1H, J ¼ 7.5 Hz), 7.71 (d, 1H, J ¼ 7.5 Hz). C NMR (DMSO-d ,
6
25 MHz), d: 43.68, 56.10, 56.12, 111.54, 111.74, 112.34, 119.97, 120.45,
20.96, 121.39, 122.43, 123.06, 125.06, 128.35, 129.56, 132.41, 132.81,
36.12, 143.82, 152.75, 157.25, 157.95.
1
Compound (3g) (C H Cl N ): H NMR (DMSO-d , 500 MHz), d:
2
0
14
2
2
6
5
.41 (s, 2H), 6.29 (d, 2H, J ¼ 8.5 Hz), 6.68 (d, 2H, J ¼ 8.5 Hz), 7.13–7.32
(
m, 8H).
Compound (3h) (C H Cl N ): H NMR (DMSO-d , 400 MHz), d:
1
2
2
18
2
2
6
2
.36 (s, 3H), 2.40 (s, 3H), 5.37 (s, 2H), 6.99–7.02 (m, 2H), 7.16 (d, 2H,
J ¼ 8.0 Hz), 7.25 (d, 2H, J ¼ 8.0 Hz), 7.58 (d, 2H, J ¼ 8.0 Hz), 7.65 (s,
1
3
2
1
H). C NMR (DMSO-d , 100 MHz), d: 14.5, 47.8, 119.9, 128.6,
6
28.9, 129.1, 129.3, 129.6, 129.8, 131.7, 133.0, 135.9, 136.0, 150.7.

2926
K. Niknam, M. A. Zolfigol, and N. Safikhani
1
Compound (3i) (C H N ): H NMR (DMSO-d , 400 MHz), d: 1.76
2
4
24
2
6
(
s, 6H), 2.49 (s, 6H), 5.39 (s, 2H), 7.12–7.14 (m, 4H), 7.29 (d, 2H,
1
3
J ¼ 8.0 Hz), 7.34–7.41 (m, 2H), 7.49 (d, 2H, J ¼ 8.0 Hz). C NMR
(DMSO-d , 100 MHz), d: 20.3, 20.6, 21.1, 21.4, 48.1, 110.6, 119.6,
6
1
25.3, 125.7, 129.1, 129.3, 129.4, 129.7, 132.2, 134.5, 137.3, 139.9, 153.2.
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