Simple and mild procedures for synthesis of benzimidazole derivatives using heterogeneous catalyst systems

Article abstract of DOI:10.1002/jhet.5570450506

(Chemical Equation Presented) TsOH/graphite and N,N-dimethylaniline/ graphite were found to be catalyst systems for condensation reaction of o-phenylendiamine with different aldehydes to form benzimidazole derivatives under mild and simple conditions. The graphite was easily recovered by a simple extraction and could be reused without decrease of activity in the presence of fresh TsOH and N,N-dimethylaniline.

Full text of DOI:10.1002/jhet.5570450506

Sep-Oct 2008
1293
Simple And Mild Procedures For Synthesis Of Benzimidazole
Derivatives Using Heterogeneous Catalyst Systems
Hashem Sharghi*, aOmid Asemanib, c and Seyed Mohammad Hossein Tabaeib, c
aDepartment of Chemistry, College of Sciences, Shiraz University, Shiraz, 71454, Iran.
bDepartment of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
cMedicinal and Natural Products Chemistry, Research Centre, Shiraz University of Medical Sciences, Shiraz,
Iran e-mail: shashem@chem.susc.ac.ir
Tel.: +98-711-2282380, fax: +98-711-2280926
Received August 4, 2007
H
Method A: P-toluensufonic acid/graphite,
N
N
N
75 0C
O
R
R
N
R
NH2
NH2
H
R
3
4
H
Method B: N,N-dimethylaniline/graphite,
N
2
EtOH, 75 0C
1
R
N
3
Abstract: TsOH/graphite and N,N-dimethylaniline/graphite were found to be catalyst systems for
condensation reaction of o-phenylendiamine with different aldehydes to form benzimidazole derivatives
under mild and simple conditions. The graphite was easily recovered by a simple extraction and could be
reused without decrease of activity in the presence of fresh TsOH and N,N-dimethylaniline.
J. Heterocyclic Chem., 45, 1293 (2008).
INTRODUCTION
almost all exiting protocols is that the catalysts are
destroyed in the work-up procedure and cannot be
recovered or reused.
The benzimidazole ring is an important pharmacophore in
modern drug discovery [1]. Attempts for identifying new
compounds containing this nucleus have gained
importance in recent years because many of these
derivatives have shown various spectrum of pharmaco-
logical activities such as: antiviral effects [2], antagonistic
and inhibitory activities [3], potential antitumor agents
[4], antibacterial agents [5], a treatment for interstitial
cystitis [6], as anthelmintic agents in veterinarian
medicine and in diverse human therapeutic areas such as
treatment of ulcers and as antihistaminics [7].
In continuation with our work to develop new synthetic
methodologies [10], we report herein simple and mild
methods for the synthesis of 2-aryl-1-arylmethyl-1H-1,3-
benzimidazole derivatives (N-substituted benzimidazoles
4) in the presence of an available and cheap hetero-
geneous catalyst system, p-toluenesulfonic acid/graphite,
under solvent-free condition and 2-aryl-1,3-benzimidazole
derivatives (benzimidazoles 3) using a second catalyst
system, N,N-dimethylaniline/graphite, in ethanol by
condensation of o-phenylenediamine with different
aldehydes.
In spite of their importance as a pharmacological
incorporated motif, comparatively few methods for the
synthesis of benzimidazole derivatives have been
reported. The conventional synthesis of benzimidazoles
involve the reaction between an o-phenylenediamine and
a carboxylic acid or its derivatives (nitriles, amidates,
orthoesters) under severe dehydrating conditions [8].
Alternatively, a two-step procedure is employed wherein
the resulting mono-acylated product is subjected to
cyclodehydration under a variety of conditions [9].
However, many of these synthetic protocols reported so
far have disadvantages such as a) needing anhydrous
conditions b) use of organic solvents c) drastic reaction
conditions d) tedious work-up procedures and e)
involving more than one step in synthesis of these
compounds. Furthermore, the main disadvantage of
RESULTS AND DISCUSSION
The benzimidazoles 3 and 4 obtained inclusively in a
solvent-free catalytic condition using graphite/TsOH
system at 75 °C as sketched in Scheme I, method A. All
reactions conducted within 15-180 minutes. In the second
procedure for the selective preparation of 2-aryl-1,3-
benzimidazole derivatives, the reaction condition
performed in the presence of N,N-dimethylaniline and
ethanol as shown in Scheme I, method B. All reactions
led to excellent yield of corresponding benzimidazoles 3
within 3-20 hours.
Initially, we examined several reported reactions,
focusing on high efficacy under various catalytic
conditions (Table 1, entries 1-5). As can be seen, the

1294
H. Sharghi, O. Asemani and S. M. Hossein Tabaei
Vol 45
Scheme 1
H
Method A: P-toluensufonic acid/graphite,
N
N
N
75 0C
O
R
R
N
R
NH2
NH2
H
R
3
4
H
N
Method B: N,N-dimethylaniline/graphite,
2
EtOH, 75 0C
1
R
N
3
Table 1
The Condensation reaction of o-phenylenediamine with benzaldehyde under various reaction conditions
Entry
Condition
Condensing agent
Time
(min)
Total Yields
(mole ratio) a
1
2
3
4
5
6
7
8
9
10
11
12
13
I2/KI/K2CO3/H2O [11]
Silicasulfuric acid, EtOH, rt [12b]
Silicasulfuric acid, H2O, rt [12b]
EtOH, H2O, NaHSO3, 60 °C [13]
L-proline, CHCl3, rt [14]
TsOH (0.5 g) , 75 °C
Graphite (0.5 g), 75 °C
Graphite (0.5 g), TsOH (0.03 g, 0.19 mmol), 75 °C
Graphite (1.0 g), TsOH (0.03 g, 0.19 mmol), 75 °C
Graphite (1.0 g), TsOH (0.03 g, 0.19 mmol), EtOH (6 ml), 75 °C
Graphite (1.0 g), TsOH (0.03 g, 0.19 mmol), CH3CN (6 ml), 75 °C
Graphite (1.0 g), TsOH (0.03 g, 0.19 mmole), H2O (6 ml), 75 °C
Graphite (1.0 g), TsOH (0.03 g, 0.19 mmole), 75 °C
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
45
60
20
60
300
120
140
65
40
60
63% (1:0.7)
73% (1:5.1)
66% (1:5.3)
79% (1:0.3)
91% (1:0.7)
0.0% (.0:.0)
71% (1:1.8)
84% (1:2.6)
89% (1:2.9)
81% (1:1.6)
65% (1:1.8)
61% (1:2.2)
86% (1:3.0)
PhCHO
PhCHO
PhCHO
180
180
40
PhCHO(excess)
a) Isolated yields (mole ratio of products 3:4)
Table 2
Condensation reaction of o-phenylenediamine (1 mmol) with different aldehyds (1.6 mmol) using p-toluenesulfonic acid/graphite system
(1.0 g/0.03 g, 0.19 mmol) at 75 °C
Entry
Aldehyde
Time (min)
Total Yields
(mole ratio) a
Melthing points (°C)
Product 3
295 (295) [11]
226 (226-227) [16]
276-277 (275-276) [16]
302-303 (301) [17]
233-234 (234) [19]
218 (218) [19]
262
Product 4
a
b
c
d
e
f
g
h
i
C6H5CHO
40
20
20
45
15
60
180
10
89% (1:2.9)
90% (1:3.6)
88% (1:1.5)
79% (1:1.9)
81% (1:1.7)
75% (1:2.2)
79% (1:3.2)
91% (1:2.4)
78% (1:2.3)
85%(1:1.9)
87% (1:2.0)
89% (1:2.6)
132 (132) [15]
130 (129-130) [12a]
130 (128-130) [15]
136 (136) [18]
163 (163) [15]
130 (130) [12a]
221
4-MeOC6H4CHO
4-MeC6H4CHO
4-ClC6H4CHO
2-ClC6H4CHO
2-Pyridylaldehyde
4-CNC6H4CHO
4-iPrC6H4CHO
3-NO2C6H4CHO
2,6-DiClC6H3CHO
ꢀ-Naphtaldehyde
2-OHC6H4CHO
250-251
172
169-170
177
123
219
150
130
50
202-203 (200-202) [20]
279
217
j
k
l
90
242 (242) [19]
a ) Isolated yields (mole ratio of product 3:4)
coincidental production of benzimidazoles 3 and 4 is a
common issue in many previously reported papers. In our
case when the o-phenylenediamine 1 and aromatic
aldehydes 2 in the presence of p-toluenesulfonic acid/
graphite were allowed to react at 75 °C, both expected
products were obtained. Since the resulted proportions
showed a dominant trend towards the production of N-
substituted derivatives 4, several different amounts of
graphite and TsOH in the condensation reaction of
benzaldehyde with o-phenylenediamine were screened
for optimization and results are shown in Table 1 (entries
6-13). While no products were obtained in the presence of
TsOH alone, a 71% total yield was obtained using
graphite (entries 6 and 7). The yields were improved in
the best way when 1.0 g of graphite and 0.03 g of TsOH
were used (entry 9). The effect of solvents in this reaction

Sep-Oct 2008
Simple And Mild Procedures For Synthesis Of Benzimidazole Derivatives
1295
Table 4
Condensation of o-phenylenediamine (1 mmol) with different
aldehydes (1.05 mmol) using heterogeneous N,N-
dimethylaniline/graphite (1.0 mmol/1.0 g) system in ethanol at 75 °C.
was detrimental since overall yields have decreased in
CH3CN, H2O and even EtOH solutions (entries 10-12).
Using excess amount of benzaldehyde showed no
improvement in the yields as shown in Table 1 (entry 13).
Several examples of condensation reaction of o-phenyl-
enediamine with aromatic aldehydes containing different
electron-withdrawing and electron-donating groups in the
presence of a catalytic amount of TsOH and graphite are
shown in Table 2.
As can be seen in Table 2, aromatic aldehydes having
different substituents such as methoxy, chloro, methyl,
etc. were converted to the corresponding benzimidazoles
in reasonable yields. All reactions were carried out within
15 to 180 minutes. The time of reactions was depending
on the substituents present on the substrates. Reactions
with substrates having electron-withdrawing groups such
as chloro, cyano, etc. proceeded at slower rates than those
with electron-donating groups such as methyl, isopropyl,
etc.. From the yield point of view, aldehydes containing
electron-donating groups gave products in higher yields
than those containing electron-withdrawing groups.
According to our experiments, we found that excellent
selectivity towards the production of benzimidazoles 3
can be best achieved when using a basic agent in the
reaction media and ethanol as solvent, as shown in Table
3. Based on Table 3, aliphatic bases resulted in lower
yields compared to aromatic ones. Since N,N-
dimethylaniline provided the best condition, it was chosen
for further study (Table 3, entry 6).
Entry
Aldehyde
Time (h)
Yields of 3 (%)a
a
b
c
d
e
f
C6H5CHO
4
6
3
67
85
86
91
87
79
91
83
71
84
81
93
4-MeOC6H4CHO
4-MeC6H4CHO
4-ClC6H4CHO
2-ClC6H4CHO
2-Pyridylaldehyde
4-CNC6H4CHO
4-iPrC6H4CHO
3-NO2C6H4CHO
2,6-DiClC6H3CHO
ꢀ-Naphtaldehyde
2-OHC6H4CHO
15
13
17
16
3
20
17
14
8
g
h
i
j
k
l
a ) Isolated yields
In the case of yields, no significant difference could be
found in the products of the condensation reaction of
electron rich and electron deficient aldehydes. This is
noteworthy that the condensation reaction of o-
phenylenediamine with benzaldehyde on a 30 mmol scale
proceeded just as well as the 1 mmol reaction for both
methods A and B.
The mechanism of the reaction is a subject of a further
study. As for now, we believe that graphite acts as a
dehydration reagent or it serves as a heat conductor
surface for benzimidazoles synthesis.
Table 3
At the edge of the basal planes of carbon atoms in the
graphite structure, where bonding in the plane is
terminated, are unsaturated carbon atoms. These sites are
associated with high concentrations of unpaired electrons
and therefore play a significant role in chemisorption.
These carbons may chemisorb oxygen, producing
oxygen surface groups which are by far the most
important in influencing the surface characteristics and
adsorption behavior of graphite [21] (Scheme II).
The condensation reaction of o-phenylenediamine (1 mmol) with
4-Chlorobenzaldehyde (1.05 mmol) in the presence of different basic
agents (1.1 mmol), graphite (1.0 g) and ethanol as solvent at 75 °C.
Entry Base (1.1 mmol)
Time (h)
Yields of 3
(%)a
43
1
2
3
4
5
6
EtNH2
Et2NH
Et3N
Pyridine
Aniline
45
45
40
16
15
15
39
45
79
86
N,N-dimethylaniline
91
a) Isolated yields
Scheme II
OH
The results of condensation reaction of o-
phenylenediamine with the same aromatic aldehydes as
those used in method A are shown in Table 4. In all cases,
the production of N-substituted benzimidazoles 4 was
trace to a few percents. As can be seen in Table 4,
aromatic aldehydes having different substituents such as
methyl, hydroxyl, chloro, etc. were converted to the
corresponding 2-aryl-1,3-bezimidazoles in excellent
yields. All reactions were done within 3 to 20 hours. The
time of reactions was depending on the substituents
present on the substrates. Reactions with substrates
having electron-withdrawing groups such as chloro,
cyano, nitro, etc. produced at slower rates than those with
electron-donating groups such as methyl, isopropyl, etc.
OH
O
O
O
O
O
O
O
O
O
The surface groups most suggested are carboxyl,
phenolic hydroxyl and quinine carbonyl groups. Slightly
fewer in number are the reports of ether, peroxide, ester

1296
H. Sharghi, O. Asemani and S. M. Hossein Tabaei
Vol 45
groups, lactones, carboxylic acid anhydrides and cyclic
peroxides [22]. These structures exhibit a high affinity for
water [22e, 23]. As described in Scheme III we have
formulated a suggested mechanism for the solvent free
condensation reaction of o-phenylenediamine and
aldehyde molecules (method A).
the carbonyl group of a second aldehyde molecule led to
the formation of benzimidazoles 3 selectively.
Besides availability and cheapness of graphite, another
interesting behavior of graphite lies in the fact that it can
be reused after a simple washing with EtOH or
ethylacetate, thus rendering the process more economic.
The yields of the condensation reaction of o-phenylene-
diamine with benzaldehyde in the 2nd, 3rd and 4th use of
the graphite for both methods A and B were almost the
same as that in the first use (Table 5). It should be noted
that after extraction with ethylacetate or ethanol,
p-toluenesulfonic acid and N,N-dimethylaniline were not
found on the graphite; therefore it is necessary to add
them again for the 2nd use of recovered graphite.
As can be seen, at the initial stage, the aldehyde
molecule is protonated, subsequently one of the amine
groups attacks to the activated aldehyde then a water
molecule is lost to form the iminium intermediate. The
intermediate can go through two directions. Firstly, it can
be cyclized to form the dihydrobenzimidazole derivatives
B, following a subsequent oxidation to form benz-
imidazoles 3 [11, 24, 25]. Secondly, it may proceed further
and attack to the second activated aldehyde molecule to
form dibenzylidene-o-phenylenediamine derivatives C
followed by ring closure [12a, 14]. Finally aromatization
takes place via deprotonation and 1,3-hydrid transfer.
The role of TsOH as a co-activator seems to be a
provider of available proton for different stages of the
reaction like, dehydration stage or recovery of the
deprotonated carbon surface groups for subsequent
catalytic cycles.
Table 5
reuse of graphite in the condensation reaction of o-
phenylendiamine with benzaldehyde for both methods A and B
Number of
Total Yields (mol ratio
3:4 /yield of 3)a
Recovery of
graphite (% / %)a
98/96
use
1
89% (1:2.9)/67%
86% (1:2.6)/61%
87% (1:2.9)/60%
2
93/93
3
89/90
a) (method A/method B)
Conducting the reaction in the absence of TsOH (with a
longer time and lower yield) (Table 1, entry 7) and
presence of basic agents (with very longer times and
lower yields) (Table 3) may be able to confirm the proton
availability role.
So, we believe that N,N-dimethylaniline as a good base
not a nucleophile diminished the presence of available
proton, resulted in a good selectivity. Moreover, the
reduced number of activated aldehyde molecules,
provided the situation in which the attack of the free NH2
functional groups to the iminium carbon atom instead of
In conclusion, the present synthetic methods are simple,
inexpensive and mild procedures for preparation of
biologically active benzimidazole derivatives using
heterogeneous catalyst systems, TsOH/graphite and N,N-
dimethylaniline/graphite. The advantages of the present
reactions are the elimination of organic solvents (method
A), toxic reagents, using biologically and environmentally
safe solvent, ethanol, (method B) and reusability of
graphite.
Scheme III
..
H2N
R
C
H
O
H2N
R
NH2
NH2
H
O
N
OH
O
O
- H2O
O
O
H
C
C
C
..
NH2
R
C
H
OH
A
R C
H
O
H
O
C
H
N
O
N
O
R
R
N
H
N
H
- H2O
B
3
H
R
H
OH
N
N
O
N
N
N
C
R
R
- H
H
H
H
1,3-Hydrid
Shift
N
R
R
R
4
D
C

Sep-Oct 2008
Simple And Mild Procedures For Synthesis Of Benzimidazole Derivatives
1297
= 1.8 Hz); 13C NMR (DMSO-d6, 62.9 MHz): ꢀ 116.0, 120.8,
122.7, 124.2, 130.6, 131.6, 132.4, 136.9, 148.3, 149.0; Mass m/z
(%) 240 (M++1, 17), 239 (M+, 100), 193 (67); Anal. Calcd for
C13H9N3O2: C, 65.27; H, 3.79. Found: C, 65.41; H, 3.68.
2-(2,6-Dichlorophenyl)-1H-1,3-benzimidazole (3j). This
compound was obtained as white crystals; mp: 279 °C; IR
(KBr): 3430 (w), 3058 (w), 1553 (w), 1429 (s), 1329 (w), 777
(m), 741 (m) cm-1; 1H NMR (CDCl3, 250 MHz): ꢀ 7.11-7.30 (m,
6H), 7.54 (d, 2H, J = 2.32 Hz); 13C NMR (DMSO-d6, 62.9
MHz): ꢀ 115.4, 122.2, 128.3, 130.4, 132.4, 135.0, 137.0, 146.6;
Mass m/z (%) 267 (M++4, 0.1), 265 (M++2, 7), 263 (100) (M+),
228 (58), 193 (71); Anal. Calcd for C13H8Cl2N2: C, 59.34; H,
3.06. Found: C, 59.16; H, 3.15.
2-(2-Naphtyl)-1H-1,3-benzimidazole (3k). This compound
was obtained as white crystals; mp: 217 °C; IR (MBr): 3425 (w),
3047 (m), 1605 (w), 1447 (m), 1385 (m), 748 (s) cm-1; 1H NMR
(CDCl3, 250 MHz): ꢀ 7.19 (dd, 2H, J1 = 6.0 Hz, J2 = 3.0 Hz),
7.37-7.40 (m, 2H), 7.59-7.77 (m, 5H), 8.11 (dd, 1H, J1 = 8.6, J2
= 1.7), 8.49 (s, 1H); 13C NMR (CDCl3, 62.9 MHz): ꢀ 115.2,
123.2, 123.6, 126.5, 126.8, 127.2, 127.8,128.5, 129.0, 134.2,
138.1, 145.9, 151.6; Mass m/z (%) 245 (M++1, 43), 244 (M+,
100), 153 (58); Anal. Calcd for C17H12N2: C, 83.58; H, 4.95.
Found: C, 83.40; H, 4.97.
EXPERIMENTAL
Instrumentation, Analysis and Starting Material. Progress
of reactions was monitored by the using silica gel Polygram’s
SIL G/UV 254 plates. IR spectra were recorded on the Shimadzu
FT-IR 8300 spectrophotometer. NMR spectra were recorded on
a Bruker DPX 250 MHz instrument and Mass spectra on a
Shimadzu QP 1100 EX spectrometer using EI 70 ev modes.
Chemical materials were purchased from Fluka, Aldrich and
Merck Companies.
General procedure for method A: A mixture of graphite
(1.0 g), TsOH (0.03 g, 0.19 mmol), and o-phenylenediamine
(0.108 g, 1 mmol) was prepared, well mixed and grinded by a
mortar and pestle. Then aldehyde (1.6 mmol) was added to the
mixture and grinding was continued for another 10 minutes. The
mixture was transferred into a quickfit tube, capped and stirred
with a magnetic stirrer in an oil bath with a temperature of 75 °C
for the time specified in Table 2. Progress of reactions was
monitored by TLC using n-hexane/ethylacetate (7:1). After
reactions were completed, reaction mixtures were washed with
hot ethanol or ethylacetate (3 ꢀ 30 mL). After evaporating the
solvent, the mixtures of products 3 and 4 were obtained either by
recrystallization in ethanol or using short silica gel column
chromatography using n-hexane/ethylacetate (10:1) as eluent.
General procedure for method B. A mixture of o-
phenylenediamine (1.0 mmol) and graphite (1.0 g) was stirred in
ethanol (15 mL) in a quickfit tube. N,N-Dimethylaniline (1.0
mmol) and aldehydes (1.05) were then added respectively; tubes
were loosely capped and stirred with a magnetic stirrer in an oil
bath with a temperature of 75 °C for the time specified in Table
4. Progress of reactions was monitored by TLC using n-
hexane/ethylacetate (7:1). After the reactions were completed,
the reaction mixtures were filtered and washed with hot ethanol
(3 ꢀ 40 mL). The mixtures were concentrated under reduced
pressure to give the crude products, which were purified by
recrystallization or silica gel column chromatography (for
entries 3a and 3i, Table 4) using hexane/ethylacetate (10:1) as
eluent.
1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-1H-1,3-benz-
imidazole (4b). This compound was obtained as white Crystals;
mp: 130 °C; IR (KBr): 3047 (w), 2931 (m), 1604 (m), 1458 (s),
1
1245 (s), 1165 (m), 1022 (m), 825 (m), 737 (m) cm-1; H NMR
(DMSO-d6, 250 MHz): ꢀ 3.65 (S, 3H), 3.81 (S, 3H) , 5.46 (S,
2H), 6.83 (d, 2H, J = 7.7 Hz), 6.92 (d, 2H, J = 7.7 Hz), 7.05 (d,
2H, J = 7.5 Hz), 7.17-7.21 (m, 2H), 7.39-7.21 (m, 2H), 7.5 (d,
2H, J = 7.5 Hz); 13C NMR ( DMSO-d6, 62.9 MHz): ꢀ 46.8, 55.0,
55.2, 111.0, 114.1, 114.3, 118.9, 122.0, 122.3, 127.4, 128.0,
129.0, 130.4, 135.8, 142.7, 153.1, 158.5, 160.3; Mass m/z (%)
345 (M++1, 65), 344 (M+, 100), 224 (83), 133 (25); Anal. Calcd
for C22H20N2O2: C, 76.72; H, 5.85. Found: C, 76.59; H, 5.75.
4-(1-(4-Cyanobenzyl)-1H-1,3-benzimidazole-2-yl)benzo-
nitrile (4g). This compound was obtained as white crystals; mp:
221 °C; IR (KBr): 3059 (w), 2843 (m), 2642 (w), 2222 (m),
1
4-(1H-1,3-Benzimidazol-2-yl)benzonitrile (3g). This
compound was obtained as white crystals; mp: 262 °C; IR
(KBr): 3417 (m), 3047 (w), 2912 (w), 2222 (m), 1605 (m), 1454
1610 (w), 1431 (s), 837 (m), 748 (m) cm-1; H NMR: (DMSO-
d6, 250 MHz): ꢀ 5.62 (s, 2H), 7.14 (d, 2H, J = 8.3), 7.27-7.31
(m, 2H), 7.48-7.52 (m, 2H), 7.73-7.79 (m, 2H), 7.88 (d, 2H, J =
8.3), 7.97 (d, 2H, J = 8.1); 13C NMR (DMSO-d6, 62.9 MHz): ꢀ
47.2, 110.3, 111.1, 118.3, 118.4, 119.67, 122.8, 123.5, 127.0,
129.8, 132.7, 134.2, 135.9, 142.3, 150.5, 151.8; Mass m/z (%)
335 (40) (M++1, 40) 334 (M+, 100), 232 (10), 218 (58), 116
(87); Anal. Calcd for C22H14N4: C, 79.02; H, 4.22. Found: C,
78.81; H, 4.34.
1
(m), 1408 (s), 837 (s), 748 (s) cm-1; H NMR (DMSO-d6, 250
MHz): ꢀ 7.23-768 (m, 4H), 8.00 (d, 2H, J = 8.1 Hz), 8.32 (d,
2H, J = 8.1 Hz); 13C NMR (DMSO-d6, 62.9 MHz): ꢀ 111.7,
111.8, 118.6, 119.3, 122.2, 123.3, 127.0, 132.9, 134.2, 149.3;
Mass m/z (%) 220 (M++1, 14), 219 (M+, 100), 102 (20); Anal.
Calcd for C14H9N3: C, 76.70; H, 4.14. Found: C, 76.53; H, 4.22.
2-(4-IsoPropylphenyl)-1H-1,3-benzimidazole (3h). This
compound was obtained as white crystals; mp: 250-251 °C; IR
(KBr): 3425 (w), 3055 (w), 2873 (m), 2951 (s), 1439 (s), 1273
1-(4-isopropylbenzyl)-2-(4-isopropylphenyl)-1H-1,3-benz-
imidazole (4h). This compound was obtained as white Crytals;
mp: 172 °C; IR (KBr): 3039 (m), 2951 (s), 1462 (s), 829 (m),
1
1
(m), 741 (m) cm-1; H NMR (CDCl3, 250 MHz,): ꢀ 1.19 (d, 6H,
741 (m) cm-1; H NMR (DMSO-d6, 250 MHz): ꢀ 1.11 (d, 6H, J
J = 6.9 Hz), 2.85 (m, 1H), 7.17-7.26 (m, 4H), 7.57 (m, 2H), 7.96
(d, 2H, J = 8.3 Hz); 13C NMR (DMSO-d6, 62.9 MHz): ꢀ 23.6,
33.3, 121.9, 126.4, 127.7, 129.1, 129.4, 134.5, 150.3, 151.3;
Mass m/z (%) 237 (M++1, 17), 236 (M+, 62), 221 (100), 193
(13), 116 (72); Anal. Calcd for C16H16N2: C, 81.32; H, 6.82.
Found: C, 81.20; H, 6.74.
= 6.6 Hz), 1.21 (d, 6H, J = 6.1 Hz), 2.79 (m, 1H), 2.93 (m, 1H),
5.52 (S, 2H), 6.90 (d, 2H, J = 7.1 Hz), 7.14-7.20 (m, 4H), 7.39-
7.50 (m, 4H), 7.63 (d, 2H, J = 7.4 Hz); 13C NMR (DMSO-d6,
62.9 MHz): ꢀ 23.6, 23.7, 32.9, 33.2, 47.2, 111.0, 119.1, 122.1,
122.5, 125.9, 126.6, 128.7, 129.0, 133.2, 134.2, 135.8, 142.6,
147.5, 150.2, 153.0; Mass m/z (%) 369 (M++1, 29), 368 (M+,
100), 325 (9), 235 (14); Anal. Calcd for C26H28N2: C, 84.74; H,
7.66. Found: C, 84.85, H, 7.55.
2-(3-Nitrophenyl)-1H-1,3-benzimidazole (3i). This compound
was obtained as pale yellow crystals; mp: 202-203 °C; IR (KBr):
1
3437 (w), 3078 (w), 1529 (s), 1348 (s), 732 (m) cm-1; H NMR
1-(3-Nitrobenzyl)-2-(3-nitrophenyl)-1H-1,3-benzimidazole
(4i). This compound was obtained as pale yellow crystals; mp:
169-170 °C; IR (KBr): 3178 (w), 1523 (s), 1342 (s), 741 (m)
(CDCl3, 250 MHz): ꢀ 7.20-7.39 (m, 2H), 7.61-7.67 (m, 3H),
8.25 (d, 1H, J = 8.4 Hz), 8.43 (d, 1H, J = 7.8 Hz), 8.77 (t, 1H, J

1298
H. Sharghi, O. Asemani and S. M. Hossein Tabaei
Vol 45
cm-1. 1H NMR (DMSO-d6, 250 MHz): ꢀ 5.67 (s, 2H), 7.16-7.20
(m, 2H), 7.26 (d, 1H, J = 7.6 Hz), 7.37-7.49 (m, 2H), 7.64- 7.70
(m, 2H), 7.81 (s, 1H), 7.96-8.05 (m, 2H), 8.21 (d, 2H, J = 8.22
Hz), 8.30 (s, 1H); 13C NMR (DMSO-d6, 62.9 MHz): ꢀ 46.8,
111.1, 119.7, 121.2, 122.5, 122.8, 123.5, 123.7, 124.5, 130.6,
131.2, 132.7, 135.2, 136.0, 139.0, 142.4, 147.8, 150.9, 156.0;
Mass m/z (%) 375 (M++1, 23), 374 (M+, 100),328 (2), 282 (12),
239 (5); Anal. Calcd for C20H14N4O4: C, 64.17; H, 3.77. Found:
C, 64.01; H, 3.89.
E. J. Med. Chem. 1996, 39, 992; (b) Zarrinmayeh, H.; Zimmerman, D.
M.; Cantrell, B. E.; Schober, D. A.; Bruns, R. F. Bioorg. Med. Chem.
Lett. 1999, 9, 647; (c) Kohara, Y.; Kubo, K.; Imamiya, E.; Wada, T.;
Inada, Y.; Naka, T. J. Med. Chem. 1996, 39, 5228; (d) Elokdah, H. M.;
Chai, S. Y.; Sulkowski, T. S.; US Patent 1998, 5, 764.; Chem. Abstr.
1998, 129, 58784g; (e) Zhao, J.; Arnaiz, D.; Griedel, B.; Sakata, B.;
Dallas, J., Whitlow, M.; Trinh, L.; Post, J.; Liang, A.; Morrissey, M. ;
Shaw, K. Bioorg. Med. Chem. Lett. 2000, 10, 963
[4] Denny, W. A.; Rewcastle, G. W.; Bagley, B. C. J. Med.
Chem. 1990, 33, 814
1-(2,6-Dichlorobenzyl)-2-(2,6-dichlorophenyl)-1H-1,3-benz-
imidazole (4j). This compound was obtained as white crystals;
mp: 177 °C; IR (KBr): 3059 (w), 2923 (m), 1566 (w), 1423 (s),
[5] (a) Forseca, T. ; Gigante, B.; Gilchrist, T. L. Tetrahedron
2001, 57, 1793; (b) Parikh, A. R.; Khunt, M. D.; Proceedings of the
222nd ACS National Meeting, Chicago, IL 2001, p. 73
[6] Iyenger, S.; Nuhhauser, M. A.; Thor, K. B.; US Patent 1996,
13, 129; 1International PCT Patent, September 18 1997, 33, 873; Chem.
Abstr. 1997, 127, 293221P
1
779 (s), 737 (s) cm-1; H NMR (CDCl3, 250 MHz): ꢀ 5.56 (S,
2H), 7.09-7.20 (m, 1H), 7.26-7.41 (m, 7H), 7.85 (m, 2H); 13C
NMR (CDCl3, 62.9 MHz): ꢀ 44.0, 110.6, 121.0, 122.3, 123.2,
128.0, 128.5, 130.0, 130.65, 131.0, 131.4, 135.3, 137.0, 146.2;
Mass m/z (%) 428 (M++6, 0.06), 426 (M++4, 0.9), 224 (M++2,
11), 422 (M+, 74), 383 (86), 350 (8), 262 (100), 229 (81), 192
(54); Anal. Calcd for C20H12Cl4N2: C, 56.91; H, 2.87. Found: C,
56.82; H, 2.96.
2-(2-Naphtyl)-1-(2-naphtylmethyl)-1H-1,3-benzimidazole
(4k). This compound was obtained as white crystals; mp: 123
°C; IR (KBr): 3049 (s), 1604 (w), 1423 (s), 1388, 746 (s) cm-1;
1H NMR (CDCl3, 250 MHz): ꢀ 5.59 (s, 2H), 7.17-7.25 (m, 4H),
7.39- 7.46 (m, 4H), 7.48 (s, 1H), 7.63 (m, 2H), 7.77- 7.89 (m,
6H), 8.13 (s, 1H); 13C NMR (CDCl3, 62.9 MHz): ꢀ 48.8, 110.6,
120.0, 123.0, 123.3, 124.8, 126.0, 126.3, 126.6, 126.7, 127.3,
127.9, 128.6, 128.6, 129.1, 129.3, 133.9; Mass m/z (%) 384 (M+,
100), 243 (68), 153 (62), 141 (91); Anal. Calcd for C28H20N2: C,
87.47; H, 5.24. Found: C, 87.61; H, 5.31.
[7] Sposov, A. A.; Yozhitsa, I. N.; Bogaeva, L. I.; Anisimova, V.
A. Pharm. Chem. J. 1999, 33, 232
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Poliakoff, M. Green Chem. 2003, 5, 187
[9] (a) Philips, M. A. J. Chem. Soc. 1928, 2839 ;(b)
Kudryashova, N.; Piotrovskii, L. B.; Naumov, V. A.; Brovtsyna, N. B.;
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2282 (b) Sharghi, H.; Hosseini Sarvari, M. Synthesis 2003, 243 (c)
Sharghi, H.; Hosseini Sarvari, M. Synthesis 2004, 2165
[11] Gogoi, P.; Konwar, D. Tetrahedron Lett. 2006, 47, 79.
[12] (a) Perumal, S.; Mariappan, S.; Selvaraj, S. Arkivoc 2004, 8,
46; (b) Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Otokesh, S.;
Baghbanzadeh, M. Tetrahedron. Lett. 2006, 47, 2557
[13] Safonov, I. G.; Heering, D. A.; Keenan, R. M.; Price, A. T.;
Erickson-Miller, C. L.; Hopson, C. B.; Levin, J. L.; Lord, K. A.; Tapley,
P. M. Bioorg. Med. Chem. Lett. 2006, 16, 1212.
[14] Varala, R.; Nasreen, A.; Enugala, R.; Adapa, S. R.
Tetrahedron Lett. 2007, 48, 69.
[15] Kim, B. H.; Han, R.; Kim, J. S.; Jun, Y. M.; Baik, W.; Lee,
B. M. Heterocycles 2004, 63, 41
[16] George, B.; Papadopoulos, E. P. J. Org. Chem. 1977, 42, 441
[17] Cohen, V. I.; J. Heterocycl. Chem. 1977, 14, 1321.
[18] Itoh, T.; Nagata, K.; Ishikawa, H.; Ohsawa, A. Heterocycles
2004, 63, 2769.
[19] Alloum, A. B.; Bougrin, K.; Soufiaoui, M. Tetrahedron Lett.
2003, 44, 5935.
2-(1-(2-Hydroxybenzyl)-1H-1,3-benzimidazole-2-yl)phenol
(4l). This compound was obtained as white crystals; mp: 219 °C;
IR (KBr): 3302 (b), 3047 (w), 2932 (w), 1589 (m), 1454 (s), 1389
1
(m), 1250 (m), 740 (m) cm-1; H NMR (DMSO-d6, 250 MHz): ꢀ
5.39 (S, 2H), 6.39 (m, 1H), 6.57 (m, 1H), 6.79-6.87 (m, 2H), 7.01
(m, 2H), 7.20-7.23 (m, 2H), 7.36-7.42 (m, 3H), 7.68 (m, 1H),
10.08 (S, 1H), 10.88 (S.1H); 13C NMR (DMSO-d6, 62.9 MHz): ꢀ
43.2, 110.8, 115.0, 116.1, 116.4, 118.7, 118.9, 122.0, 122.6, 126.6,
128.3, 130.2, 131.3. 135.1, 141.8, 152.0, 154.4, 156.3; Mass m/z
(%) 316 (M+, 67), 219 (28), 210 (100); Anal. Calcd for
C20H16N2O2: C, 75.93; H, 5.10. Found: C, 76.08; H, 5.00.
Acknowledgement. We gratefully acknowledge the support
of this work by the Shiraz University Research Council and
Shiraz Faculty of Pharmacy. This work was also supported by a
grant from Shiraz University of Medical Sciences (grant No.:
86-3745). We are also grateful to Mr. H. Sajedian Fard and M.
S. Tafvizi for helpful cooperation.
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