Synthesis of 2-Substituted benzimidazoles catalyzed by FeCl 3/Al2O3 under ultrasonic irradiation

Article abstract of DOI:10.2174/157017811796504882

2-substituted benzimidazoles have been synthesized in a single pot from aromatic aldehydes and ophenylenediamine catalyzed by FeCl₃/Al ₂O₃ in DMF under ultrasonic irradiation and afforded good yields in a short period of t

Full text of DOI:10.2174/157017811796504882

464
Letters in Organic Chemistry, 2011, 8, 464-469
Synthesis of 2-Substituted Benzimidazoles Catalyzed by FeCl3/Al2O3
Under Ultrasonic Irradiation
Guo-Feng Chen*, Xiao-Yun Dong, Fan-Zhu Meng, Bao-Hua Chen, Ji-Tai Li, Shu-Xiang Wang and
Guo-Yi Bai
College of Chemistry and Environmental Science, Hebei University, Key Laboratory of Chemical Biology of Hebei
Province, Key Laboratory of Medical Chemistry and Molecular Diagnosis, Ministry of Education, Baoding 071002,
P.R. China
Received November 10, 2010: Revised March 02, 2011: Accepted May 12, 2011
Abstract: 2-substituted benzimidazoles have been synthesized in a single pot from aromatic aldehydes and o-
phenylenediamine catalyzed by FeCl3/Al2O3 in DMF under ultrasonic irradiation and afforded good yields in a short pe-
riod of time.
Keywords: Aromatic aldehydes, benzimidazoles, FeCl3/Al2O3, o-phenylenediamine, ultrasonic.
INTRODUCTION
Catalysts and reagents supported on inorganic substrates
have received increasing attention in recent years as a means
to develop more convenient or selective catalysts or reagents
[35]. In particular, FeCl3/Al2O3 has been used as an efficient
catalyst for a number of organic reactions and offered several
advantages over classic acid, employing a reusable catalyst
and minimally environmental pollution. As reported in pre-
vious papers, ferric chloride adsorbed on alumina has been
used as the catalyst in the preparation of 2-amino-2-hydroxy-
1,1'-binaphthyl [36], 1,1'-binaphthalene-2,2'-diol [37] and
diphenylmethane [38] to afford the desired products in
higher yields. In continuation of a broad programme being
pursued in our laboratory on ultrasound-induced organic
reactions, herein we wish to report a new method for the
condensation of o-phenylenediamine and aldehydes cata-
lyzed by FeCl3/Al2O3 under ultrasonic irradiation (Scheme
1).
Benzimidazole derivatives have received much interest in
the field of medicinal chemistry [1]. They exhibit significant
activity against several viruses such as HIV [2], herpes
(HSV-1) [3] and RNA influenza [4-5]. Because of their im-
portance, the synthesis of substituted benzimidazoles has
become a focus of synthetic organic chemistry. A number of
methods have been reported for the synthesis of benzimida-
zoles. These include the coupling of o-aryldiamines and car-
boxylic acids [6] or its derivatives [7] in the presence of
strong acids and even sometimes combined with very high
temperature [8]. Subsequently, because of the availability of
a vast number of aldehydes, several improved protocols have
been developed for the synthesis of benzimidazoles via the
condensation of o-aryldiamine with aldehydes. Various oxi-
dative reagents, such as nitrobenzene [9], 1,4-benzoquinone
[10], DDQ [11], tetracyanoethylene [12], NH4OAc [13],
MnO2 [14], silica-supported thionyl chloride [15], Oxone
[16], sulfamic acid [17], sulfonic acid functionalized silica
[18], I2 [19], In(OTf)3 [20], Yb(OTf)3 [21], Sc(OTf)3 [22],
KHSO4 [23], IL [24], (bromodimethyl)sulfonium bromide
[25], iodobenzene diacetate [26], H2O2/HCl [27], air [28],
AlKIT-5 [29], mono and bifunctional solid catalysts [30] and
scolecite [31] etc have been employed in these procedures.
However, a number of these methods have some drawbacks
such as expensive reagents, drastic reaction conditions, low
yields, tedious work up procedures and co-occurrence of
several side reactions. As a consequence, the introduction of
new methods to overcome the limitations is still an important
experimental challenge.
NH2
N
FeCl3/Al2O3, air
+
R
RCHO
DMF, u.s.
N
H
NH2
1
3(a-n)
2(a-n)
Scheme 1. Synthesis of 2-substituted benzimidazoles.
RESULTS AND DISCUSSION
In order to get the best experimental condition, we have
considered the reaction of o-phenylenediamine (1) and
benzaldehyde (2a) in the presence of FeCl3/Al2O3 under ul-
trasonic irradiation as a standard model reaction. To evaluate
the effect of the solvent, we carried out the model reaction in
different solvents including DMF, CH3CN, MeOH, 1,4-
dioxane, EtOH and CH2Cl2. The use of CH2Cl2, CH3CN and
MeOH as solvent gave poor yields (Table 1, Entries 1-3).
Solvents like 1,4-dioxane, ethanol gave moderate yields (Ta-
ble 1, Entries 4, 5). When the reaction was run in DMF, the
yield of 2-phenyl-1H-benzimidazole (3a) was relatively bet-
ter (Table 1, Entry 6). Therefore, DMF was selected as the
best solvent for this reaction.
In the last two decades, ultrasound has been widely used
in organic synthesis [32]. Compared with traditional meth-
ods, this procedure is more convenient and easily controlled.
A large number of organic reactions can be carried out in
higher yields, shorter reaction times or using milder condi-
tions under ultrasound than classical conditions [33-34].
*Address correspondence to this author at the College of Chemistry and
Environmental Science, Hebei University, Baoding, 071002, Hebei Prov-
ince, P.R. China; Tel: +86-312-5079361; Fax: +86-312-5079628;
E-mail: chenguofeng@hbu.cn
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers

Synthesis of 2-Substituted Benzimidazoles
Letters in Organic Chemistry, 2011, Vol. 8, No. 7
465
Table 1. The Effect of Solvent and Temperature on the Synthesis of 2-phenyl-1H-benzimidazole(3a)A
Entry
Solvent
T[oC]
Time[h]
Yield B [%]
1
2
CH2Cl2
CH3CN
CH3OH
1,4-Dioxane
CH3CH2OH
DMF
38-41
38-41
38-41
38-41
38-41
38-41
20-25
30-35
38-41
8.0
1.3
1.0
3.0
3.0
1.5
2.7
2.0
1.5
21.3
53.5
42.1
77.2
65.5
83.6
82.3
83.2
47.9
3
4
5
6
7
DMF
8
DMF
9C
DMF
Ao-phenylenediamine (1.0 mmol) and benzaldehyde (1.0 mmol), FeCl3/Al2O3 was 0.1 mmol (based on FeCl3)，the reactions were carried out in the presence of air. BIsolated yields.
COperated in nitrogen atmosphere.
The effect of the temperature on the reaction was also
time under ultrasonic irradiation. The reason may be the phe-
nomenon of cavitation produced by ultrasound [32].
observed. As shown in Table 1, the reactions were carried
o
out using FeCl3/Al2O3 in the temperature range of 20~41 C
The same scale reaction using only FeCl3 without any
neutral Al2O3 being present yielded 63.3% of 3a after 1.5 h
under ultrasound (Table 2, Entry 2), The alumina support
itself showed very little activity (34.2%) in the synthesis of
3a after 1.5 h under ultrasound (Table 2, Entry 3), however,
the catalytic activity was increased drastically because of the
impregnation of FeCl3 (Table 2, Entry 1). The conversion
which was catalyzed by the alumina-supported FeCl3 is
higher than without any support. These data showed that
both FeCl3 alone and neutral Al2O3 alone were anything but
satisfactory for the synthesis of 2-substituted benzimida-
zoles. Encouraged by these results, the condensation of fur-
furaldehyde (2n) and o-phenylenediamine (1) was also ex-
amined to extend the scope of this method, 2-(2'-
furanylphenyl)benzimidazole (3n) was obtained in moderate
yields (76.8%) within 1.4 h. Aliphatic aldehyde was less
reactive than arylaldehyde in this reaction, no product was
obtained when aliphatic aldehyde was used. The results were
summarized in Table 2 (Entries 25, 26).
under ultrasonic irradiation. The temperature had a signifi-
cant effect on the reaction time of 3a (Table 1, Entries 6-8).
It was found that the reaction time became longer at lower
o
temperature. Increasing the temperature from 20~25 C to
o
38~41 C, the reaction time for formation 3a decreased from
2.7 h to 1.5 h as expected. When the reaction was run in ni-
trogen atmosphere, 2-phenyl-1H-benzimidazole (3a) was
obtained in 47.9% yield (Table 1, Entry 9). These results
suggest that aerial oxygen played an oxidant role in this reac-
tion. Using the optimized reaction conditions, a range of 2-
substituted benzimidazoles 3(a–n) were synthesized (Table
2).
Most products described herein were previously reported
in the literature. As shown in Table 2, the condensation of o-
phenylenediamine with a series of aromatic aldehydes af-
forded 2-substituted benzimidazoles in excellent yields cata-
lyzed by FeCl3/Al2O3 in DMF under ultrasonic irradiation.
However, the most dramatic changes observed were with
regard to reaction time. In the reaction catalyzed by Sc(OTf)3
[22b], 3l was obtained in 55% yield under O2 after stirring
for 44 h at room temperature, whereas the present procedure
At the end of the reaction, the catalyst was separated by
filtration, thoroughly washed with ethyl acetate and reused
under similar conditions. As shown by the formation of 2-
(3'-bromo phenyl)benzimidazole (3g), there was an appre-
ciable loss in the activity in the reuse of these catalysts
(79.8% on the second run for 3 h and 77.3% on the third run
for 5 h, Table 2, Entries 12, 13). This is because of the leach-
ing of the active catalyst component (i.e. iron) in the entire
treatment process [38], which is in our expectation. Further
work is necessary to strongly bind the active component on
the support.
o
resulted in 97.5% yield of 3l at 38-41 C within 1.7 h. In the
reaction catalyzed by activated carbon (Darco KB) in xylene
under an oxygen atmosphere [39], 3a was obtained in 64%
o
yield at 120 C for 26 h, whereas the present procedure af-
forded 3a in 83.6% yield within 1.5 h. It is worth noting that
increasing the amount of benzaldehyde (2a) did not give
better yield (Table 2, Entry 5).
In order to verify the effect of ultrasonic irradiation, we
o
also did the experiments under silent conditions at 38-41 C.
In summary, we have found a practical procedure for the
preparation of 2-substituted benzimidazoles catalyzed by
FeCl3/Al2O3 under ultrasonic irradiation. Our procedure is
characterized by milder conditions, shorter reaction time,
higher yield and involvement of non toxic and expensive
catalyst.
As shown in Table 2, 3a, 3j and 3l were obtained in 51.5%,
64.0% and 51.8% yields within 1.5 h, 1.2 h and 1.7 h respec-
tively. Whereas under ultrasonic irradiation, 3a, 3j and 3l
were obtained in 83.6%, 87.3% and 97.5% yields within 1.5
h, 1.2 h and 1.7 h respectively. It is obvious that the conden-
sation can be finished in good yeild within short reaction

466 Letters in Organic Chemistry, 2011, Vol. 8, No. 7
Chen et al.
Table 2. The Synthesis of 2-substituted Benzimidazole Derivatives Catalyzed by FeCl3/Al2O3 Under Ultrasound
Entry
R
Time[h]
Product
3a
Yield A [%]
Mp[oC] (lit)
1
2
C6H5
C6H5
1.5
1.5
1.5
1.5
2.0
6.5
1.4
1.4
1.0
2.2
0.9
3.0
5.0
0.9
0.9
1.0
1.2
1.2
1.2
4.5
1.7
1.7
2.7
1.4
3.0
3.0
83.6
63.3B
34.2C
51.5D
66.9E
86.5
298(298)[19b]
3
C6H5
4
C6H5
5
C6H5
6
2-ClC6H4
3-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
4-CH3OC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
4-BrC6H4
3-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-OHC6H4
4-CH3C6H4
4-CH3C6H4
4-(Me)2NC6H4
2-Furyl
3b
3c
3d
3e
3f
233-235(233-234)[13]
237-238(238)[6c]
7
99.5
8
82.5
300-301 (302-303)[13]
237-238(230-232)[18]
227-228(226)[13]
9
86.6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
99.5
3g
85.7
250-252(252)[6c]
79.8F
77.3G
70.4H
80.2I
81.4
3h
3i
300-301(299)[6c]
205-207(201)[13]
83.7
3j
87.3
64.0D
300-301(298-300)[19b]
3k
3l
91.7
239-240(236-237)[19b]
268-269(270)[15]
97.5
51.8D
3m
3n
80.7
242-243 (233-236)[17]
310-312(310-312)[19b]
76.8
CH3CH2CH2
trace
CH3(CH2)5
trace
AIsolated yield. BFeCl3 as catalyst. CAl2O3 as catalyst. D Stirred without ultrasound. Eo-phenylenediamine (1.0 mmol) and benzaldehyde (2.0 mmol). FFirst recycled FeCl3/Al2O3 was
used. GSecond recycled FeCl3/Al2O3 was used. HUltrasonic cleaner with a frequency of 25 KHz. IUltrasonic cleaner with a frequency of 59 KHz.
EXPERIMENTAL
removed under reduced pressure. The resulting yellow-
brown powder was dried at 120 oC for 4 h.
All chemicals were obtained from commercial suppliers
and were used without further purification and melting
points were uncorrected. IR spectra were recorded on a
NICOLET 380 FT-IR spectrometer using KBr discs. 1H
NMR spectra were recorded on a Bruker AVANCE 600 (600
MHz) spectrometer using TMS as internal standard and d-
DMSO as solvent. Mass spectrometric data were determined
on Agilent Technologies 6310 Lon Trap LC/MS. Sonication
was performed in Shanghai Branson-CQX ultrasonic cleaner
(with a frequency of 25, 40 and 59 kHz and a nominal power
250 W). The reaction flask was located in the ultrasonic
bath, where the surface of reactants is slightly lower than the
level of the water. The reaction temperature was controlled
by addition or removal of water from ultrasonic bath.
General Procedure for Synthesis of 2-Substituted Ben-
zimidazole Derivatives
Aromatic aldehydes (2, 1.0 mmol) and o-
phenylenediamine (1, 1.0 mmol) were dissolved in DMF (2
mL) in a 25 mL conical flask. The FeCl3/Al2O3 (160 mg, 0.1
mmol, based on FeCl3) was then added and the mixture was
irradiated in the water bath of an ultrasonic cleaner at 38-41
oC (bath temperature, the temperature inside the reactor was
o
also 38-41 C) for a period time as indicated in Table 1-2
(sonication was continued until aromatic aldehydes disap-
peared as indicated by TLC). The mixture was dissolved in
ethyl acetate. The catalyst was removed by filtration and
washed with ethyl acetate. The solvent was evaporated under
reduced pressure. The crude product was subjected to chro-
matography on silica gel (200–300 mesh) eluted with petro-
leum ether or the mixture of petroleum ether and ethyl ace-
tate. The authenticity of the products was established by
Preparation of the Catalyst (FeCl3/Al2O3)
The FeCl3/Al2O3 was prepared by mixing with ~10% its
.
weight of hydrated ferric chloride (FeCl3 6H2O) 4.8 g in ace-
tone (72 mL) and adding 26 g neutral Al2O3. The mixture
was stirred at room temperature for 1 h. The acetone was

Synthesis of 2-Substituted Benzimidazoles
Letters in Organic Chemistry, 2011, Vol. 8, No. 7
467
1
spectroscopic data and by comparing their melting points
with literature values.
273 [M+H]+; H NMR (600 MHz, DMSO-d6) ꢀH: 13.01 (s,
1H, N-H), 8.37 (t, 1H, J = 1.7 Hz, Ar-H), 8.19 (d, 1H, J =
7.9 Hz, Ar-H), 7.69 (t, 2H, J = 7.8 Hz, Ar-H), 7.52-7.56 (m,
2H, Ar-H), 7.21-7.27 (m, 2H, Ar-H).
Compound 3a
2-phenyl-1H-benzimidazole, Isolated as white crystal. IR
(KBr, cm-1): 3049, 2965, 2921, 2848, 2718, 2671, 1589,
1542, 1446, 1313, 1275, 1224, 1115, 969, 928, 743; m/z
Compound 3h
2-(4'-bromophenyl)benzimidazole, Isolated as light yel-
low crystal. IR (KBr, cm-1): 3164, 3087, 3050, 2992, 2948,
2908, 1598, 1587, 1491, 1427, 1394, 1384, 1367, 1273,
1
(ESI): 195 [M+H]+; H NMR (600 MHz, DMSO-d6) ꢀH:
12.91 (s, 1H, N-H), 8.19 (d, 2H, J = 6.0 Hz, Ar-H ), 7.68 (d,
1H, J = 6.0 Hz, Ar-H), 7.54 (m, 4H, Ar-H), 7.21 (m, 2H, Ar-
1069, 1011, 827; m/z (ESI): 273 [M+H]+; H NMR (600
1
H).
MHz, DMSO-d6) ꢀH: 12.98 (s, 1H, N-H), 8.11-8.14 (m, 2H,
Ar-H), 7.76-7.78 (m, 2H, Ar-H), 7.68 (d, 1H, J = 7.6 Hz, Ar-
H), 7.54 (d, 1H, J = 7.6 Hz, Ar-H), 7.20-7.24 (m, 2H, Ar-H).
Compound 3b
2-(2'-chlorophenyl)benzimidazole, Isolated as white crys-
tal. IR (KBr, cm-1): 3054, 2919, 1621, 1441, 1386, 1317,
1274, 1229, 1221, 1052, 974, 878, 746; m/z (ESI): 229
Compound 3i
2-(3'-nitrophenyl)benzimidazole, Isolated as yellow crys-
tal.IR (KBr, cm-1): 3333, 1620, 1517, 1434, 1385, 1349,
1279, 886, 807, 740; m/z (ESI): 240 [M+H]+; 1H NMR (600
MHz, DMSO-d6) ꢀH: 13.29 (s, 1H, N-H), 9.00 (t, 1H, J = 1.8
Hz, Ar-H ), 8.60 (d, 1H, J = 7.9 Hz, Ar-H), 8.31 (dd, 1H, J1
= 8.0 Hz, J2 = 1.6 Hz, Ar-H), 7.84 (t, 1H, J = 8.0 Hz, Ar-H),
7.72 (d, 1H, J = 7.8 Hz, Ar-H), 7.58 (d, 1H, J = 7.7 Hz, Ar-
H), 7.22-7.29 (m, 2H, Ar-H);
1
[M+H]+; H NMR (600 MHz, DMSO-d6) ꢀH: 12.73 (s, 1H,
N-H), 7.90 (dd, 1H, J1 = 7.4 Hz, J2= 1.9 Hz, Ar-H), 7.71 (d,
1H, J = 7.8 Hz, Ar-H), 7.65-7.67 (m, 1H, Ar-H), 7.51-7.58
(m, 3H, Ar-H), 7.21-7.27 (m, 2H, Ar-H).
Compound 3c
2-(3'-chlorophenyl)benzimidazole, Isolated as white crys-
tal. IR (KBr, cm-1): 3043, 2964, 2920, 2786, 1599, 1441,
1389, 1275, 1121, 1081, 892, 744; m/z (ESI): 229 [M+H]+;
1H NMR (600 MHz, DMSO-d6) ꢀH: 13.05 (s, 1H, N-H), 8.23
(d, 1H, J = 1.0 Hz, Ar-H), 8.15 (dd, 1H, J1 = 7.5 Hz, J2 = 0.9
Hz, Ar-H), 7.69 (s, 1H, Ar-H), 7.56-7.61 (m, 3H, Ar-H),
7.24 (s, 2H, Ar-H).
Compound 3j
2-(4'-nitrophenyl)benzimidazole, Isolated as light yellow
crystal. IR (KBr, cm-1): 2920, 2850, 1600, 1514, 1435, 1384,
1341, 1101, 965, 852, 744, 709; m/z (ESI): 240 [M+H]+; H
1
NMR (600 MHz, DMSO-d6) ꢀH:13.31 (s, 1H, N-H), 8.41-
8.44 (m, 4H, Ar-H), 7.74 (d, 1H, J = 7.9 Hz, Ar-H), 7.60 (d,
1H, J = 7.9 Hz, Ar-H), 7.24-7.31(m, 2H, Ar-H).
Compound 3d
2-(4'-chlorophenyl)benzimidazole, Isolated as light yel-
low crystal. IR (KBr, cm-1): 3053, 2924, 2850, 1593, 1427,
1385, 1316, 1270, 1222, 1088, 1011, 961, 828, 741; m/z
Compound 3k
2-(2'-hydroxyphenyl)benzimidazole, Isolated as white
crystal. IR (KBr, cm-1): 3325, 3055, 1596, 1518, 1490, 1449,
1422, 1321, 1262, 1132, 1038, 840, 727; m/z (ESI): 211
1
(ESI): 229 [M+H]+; H NMR (600 MHz, DMSO-d6) ꢀH:
13.01 (s, 1H, N-H), 8.19-8.21 (m, 2H, Ar-H), 7.68 (s, 1H,
Ar-H), 7.63-7.65 (m, 2H, Ar-H), 7.52-7.58 (m, 1H, Ar-H ),
7.23 (s, 2H, Ar-H).
1
[M+H]+; H NMR (600 MHz, DMSO-d6) ꢀH: 13.17 (s, 2H,
N-H, OH), 8.06 (dd, 1H, J1 = 7.9 Hz, J2 = 1.5 Hz, Ar-H)
7.62-7.72 (m, 2H, Ar-H), 7.38-7.40 (m, 1H, Ar-H), 7.29 (s,
2H, Ar-H), 7.01-7.05 (m, 2H, Ar-H).
Compound 3e
2-(2,4-dichlorophenyl)-1H-benzimidazole, Isolated as
white crystal. IR (KBr, cm-1): 3052, 2841, 1929, 1892, 1775,
1622, 1590, 1427, 1362, 1386, 1348, 1316, 1268, 1139,
1008, 978, 882, 820; m/z (ESI): 263 [M+H]+; 1H NMR (600
MHz, DMSO-d6) ꢀH: 13.08 (s, 1H, N-H), 8.40 (d, 1H, J = 2.0
Hz, Ar-H), 8.15 (dd, 1H, J1 = 8.4 Hz, J2 = 2.1 Hz, Ar-H ),
7.84 (d, 1H, J = 2.1 Hz, Ar-H), 7.54-7.69 (m, 2H, Ar-H),
7.25 (s, 2H, Ar-H).
Compound 3l
2-(4'-methylphenyl)benzimidazole, Isolated as light yel-
low crystal.IR (KBr, cm-1): 2920, 2850, 1552, 1500, 1431,
1385, 1316, 1273, 963, 821, 744; m/z (ESI): 209 [M+H]+; 1H
NMR (600 MHz, DMSO-d6) ꢀH: 12.83 (s, 1H, N-H), 8.07 (d,
2H, J = 8.1 Hz, Ar-H), 7.64 (s, 1H, Ar-H), 7.52 (s, 1H, Ar-
H), 7.36 (d, 2H, J = 7.9 Hz, Ar-H), 7.20 (s, 2H, Ar-H), 2.38
(s, 3H, CH3).
Compound 3f
Compound 3m
2-(4'-methoxyphenyl)benzimidazole, Isolated as white
crystal. IR (KBr, cm-1): 3055, 2919, 2850, 1739, 1609, 1500,
1438, 1386, 1293, 1253, 1178, 1121, 1032, 964, 847, 742;
m/z (ESI): 225 [M+H]+; 1H NMR (600 MHz, DMSO-d6) ꢀH:
12.75 (s, 1H, N-H), 8.11-8.13 (m, 2H, Ar-H), 7.62 (d, 1H, J
= 5.2 Hz, Ar-H), 7.49 (d, 1H, J = 5.2 Hz, Ar-H), 7.18 (s, 2H,
Ar-H), 7.11-7.13 (m, 2H, Ar-H), 3.85 (s, 3H, CH3);
2-[4'-(N,N-dimethylaminophenyl)]benzimidazole,
Iso-
lated as light yellow crystal. IR (KBr, cm-1): 2922, 1609,
1566, 1500, 1440, 1380, 1273, 1200, 1110, 946, 823, 746;
m/z (ESI): 238 [M+H]+; 1H NMR (600 MHz, DMSO-d6) ꢀH:
12.54 (s, 1H, N-H), 7.99-8.01 (m, 2H, Ar-H), 7.50 (s, 2H,
Ar-H), 7.12-7.14 (m, 2H, Ar-H), 6.80-6.88 (m, 2H, Ar-H),
2.97 (s, 6H, CH3).
Compound 3g
Compound 3n
2-(3'-bromophenyl)benzimidazole, Isolated as white crys-
tal. IR (KBr, cm-1): 3043, 2917, 2784, 2662, 1564, 1401,
1360, 1264, 1228, 1120, 1072, 1009, 973, 893; m/z (ESI):
2-(2'-furanylphenyl)benzimidazole, Isolated as light yel-
low crystal. IR (KBr, cm-1): 3060, 2823, 2774, 2664, 1628,

468 Letters in Organic Chemistry, 2011, Vol. 8, No. 7
Chen et al.
[8]
(a) Bougrin, K.; Loupy, A.; Soufiaoui, M. Trois nouvelles voies de
synthèse des dérivés 1,3-azoliques sous micro-ondes. Tetrahedron,
1998, 54, 8055. (b) Venkat Reddy, G.; Rama Rao, V. V. V. N. S.;
Narsaiah, B.; Shanthan Rao, P. A simple and efficient method for
the synthesis of novel trifluoromethyl benzimidazoles under mi-
crowave irradiation conditions. Synth. Commun., 2002, 32, 2467.
(c) Ben-Alloum, A.; Bakkas, S.; Soufiaoui, M. Benzimidazoles:
oxydation hétérocyclisante par le nitrobenzène ou le diméthylsul-
foxyde sur silice et sous irradiation micro-ondes ou ultra-violet.
Tetrahedron Lett., 1998, 39, 4481.
1588, 1524, 1415, 1317, 1276, 1231, 1168, 1116, 1075,
1014, 977, 907, 738; m/z (ESI): 185 [M+H]+; 1H NMR (600
MHz, DMSO-d6) ꢀH: 12.93 (s, 1H, N-H), 7.95 (d, 1H, J = 1.2
Hz, Furanyl), 7.57 (s, 2H, Ar-H), 7.19-7.22 (m, 3H, Ar-H,
Furanyl), 6.73-6.74 (m, 1H, Furanyl).
ACKNOWLEDGEMENTS
[9]
Yadagiri, B.; William Lown, J. Convenient routes to substituted
benzimidazoles and imidazolo[4,5-b]pyridines using nitrobenzene
as oxidant. Synth. Commun., 1990, 20, 955.
The project was supported by Natural Science Founda-
tion of Hebei Province (B2011201072), National Natural
Science Foundation of China (20806018), the Science Pro-
ject of the Hebei Education Department (ZD200910) andꢀ
Foundation of Hebei University (2009-163).
[10]
Verner, E.; Katz, B. A.; Spencer, J. R.; Allen, D.; Hataye, J.; Hru-
zewicz, W.; Hui, H. C.; Kolesnikov, A.; Li, Y.; Luong, C.; Mar-
telli, A.; Radika, K.; Rai, R.; She, M.; Shrader, W.; Sprengeler, P.
A.; Trapp, S.; Wang, J.; Young, W. B.; Mackman, R. L. Develop-
ment of serine protease inhibitors displaying a multicentered short
(<2.3 A) hydrogen bond binding mode: inhibitors of urokinase-type
plasminogen activator and factor Xa. J. Med. Chem., 2001, 44,
2753.
(a) Eynde, J. J. V.; Delfosse, F.; Lor, P.; Haverbeke, Y. V. 2,3-
Dichloro-5,6-dicyano-1,4-benzoquinone, a mild catalyst for the
formation of carbon-nitrogen bonds. Tetrahedron, 1995, 51, 5813.
(b) Lee, K. J.; Janda, K. D. Traceless solid-phase synthesis of 5-
benzoylbenzimidazoles. Can. J. Chem., 2001, 79, 1556.
REFERENCES
[1]
(a) Zarrinmayeh, H.; Nunes, A. M.; Ornstein, P. L.; Zimmerman,
D. M.; Brian Arnold, M.; Schober, D. A.; Gackenheimer, S. L.;
Bruns, R. F.; Hipskind, P. A.; Britton, T. C.; Cantrell, B. E.; Geh-
lert, D. R. Synthesis and evaluation of a series of novel 2-[(4-
chlorophenoxy)methyl]-benzimidazoles as selective neuropeptide
Y Y1 receptor antagonists hamideh zarrinmayeh. J. Med. Chem.,
1998, 41, 2709. (b) White, A. W.; Almassy, R.; Calvert, A. H.;
Curtin, N. J.; Griffin, R. J.; Hostomsky, Z.; Maegley, K.; Newell,
D. R.; Srinivasan, S.; Golding, B. T. Resistance-modifying agents.
9.1 synthesis and biological properties of benzimidazole inhibitors
of the DNA repair enzyme poly (ADP-ribose) polymerase. J. Med.
Chem., 2000, 43, 4084. (c) Koc, Z. E.; Bingol, H.; Saf, A. O.; Tor-
lak, E.; Coskun, A. Synthesis of novel tripodal-benzimidazole from
2,4,6-tris(p-formylphenoxy)-1,3,5-triazine: structural, electro-
chemical and antimicrobial studies. J. Hazard. Mater., 2010, 183,
251. (d) Nannapaneni, D.; Gupta Atyam, V.; Reddy, M.; Raidu, S.
Synthesis, characterization, and biological evaluation of benzimi-
dazole derivatives as potential anxiolytics. J. Young Pharmacists,
2010, 2, 273.
[11]
[12]
Chikashita, H.; Nishida, S.; Miyazaki, M.; Morita, Y.; Itoh, K. In
situ
generation
and
synthetic
application
of
2-
phenylbenzimidazoline to the selective reduction of carbon–carbon
double bonds of electron-deficient olefins. Bull. Chem. Soc. Jpn.,
1987, 60, 737.
Sharghi, H.; Asemani, O.; Khalifeh, R. New one-pot procedure for
the synthesis of 2-substituted benzimidazoles. Synth. Commun.,
2008, 38, 1128.
Bhatnagar, I.; George, M. V. Oxidation with metal oxides—II :
oxidation of chalcone phenylhydrazones, pyrazolines, o-
aminobenzylidine anils and o-hydroxy benzylidine anils with man-
ganese dioxide. Tetrahedron, 1968, 24, 1293.
Alloum, A. B.; Bougrinb, K.; Soufiaouib, M. Synthèse chimiosé-
lective des benzimidazoles sur silice traitée par le chlorure du thio-
nyle. Tetrahedron Lett., 2003, 44, 5935.
Beaulieu, P. L.; Haché, B.; von Moos, E. A Practical Oxone®-
Mediated, High-Throughput, Solution-Phase Synthesis of Benzi-
midazoles from 1,2-Phenylenediamines and Aldehydes and its Ap-
plication to Preparative Scale Synthesis. Synthesis, 2003, 1683.
Chakrabarty, M.; Karmakar, S.; Mukherji, A.; Arima, S.; Harigaya,
Y. Application of sulfamic acid as an eco-friendly catalyst in an
expedient synthesis of benzimidazoles. Heterocycles, 2006, 68,
967.
Das, B.; Kanth, B. S.; Reddy, K. R.; Kumar, A. S. Sulfonic acid
functionalized silica as an efficient heterogeneous recyclable cata-
lyst for one-pot synthesis of 2-substituted benziimidazoles. J. Hete-
rocycl. Chem., 2008, 45, 1499.
(a) Gogoi, P.; Konwar, D. An efficient and one-pot synthesis of
imidazolines and benzimidazoles via anaerobic oxidation of car-
bon–nitrogen bonds in water. Tetrahedron Lett., 2006, 47, 79. (b)
Ponnala, S.; Sahu, D. P. Iodine-mediated synthesis of 2-
arylbenzoxazoles, 2-arylbenzimidazoles, and 1,3,5-trisubstituted
pyrazoles. Synth. Commun., 2006, 36, 2189.
Trivedi, R.; De, S. K.; Gibbs, R. A. A convenient one-pot synthesis
of 2-substituted benzimidazoles. J. Mol. Cat. A: Chem., 2006, 245,
8.
Curini, M.; Epifano, F.; Montanari, F.; Rosati, O.; Taccone, S.
Ytterbium triflate promoted synthesis of benzimidazole derivatives.
Synlett, 2004, 1832.
(a) Itoh, T.; Nagata, K.; Ishikawa, H.; Ohsawa, A. Synthesis of 2-
arylbenzothiazoles and imidazoles using scandium triflate as a cata-
lyst for both a ring closing and an oxidation steps. Heterocycles,
2004, 63, 2769. (b) Nagata, K.; Itoh, T.; Ishikawa, H.; Ohsawa, A.
Synthesis of 2-substituted benzimidazoles by reaction of o-
phenylenediamine with aldehydes in the presence of Sc(OTf)3.
Heterocycles, 2003, 61, 93.
Ma, H. Q.; Wang, Y. L.; Wang, J. Y. A simple KHSO4 promoted
synthesis of 2-arylsubstituted benzimidazoles by oxidative conden-
sation of alde hydes with o-phenylenediamine. Heterocycles, 2006,
68, 1669.
[13]
[14]
[15]
[16]
[2]
(a) Porcari, A. R.; Devivar, R. V.; Kucera, L. S.; Drach, J. C.;
Townsend, L. B. Design, synthesis, and antiviral evaluations of 1-
(substituted benzyl)-2-substituted-5,6-dichlorobenzimidazoles as
nonnucleoside
analogues
of
2,5,6-trichloro-1-(ꢁ-d-
ribofuranosyl)benzimidazole. J. Med. Chem., 1998, 41, 1252. (b)
Roth, T.; Morningstar, M. L.; Boyer, P. L.; Hughes, S. H.; Buck-
heit, R. W. Jr.; Michejda, C. J. Synthesis and biological activity of
novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 2-
aryl-substituted benzimidazoles. J. Med. Chem., 1997, 40, 4199.
Migawa, M. T.; Girardet, J. L.; Walker II, J. A.; Koszalka, G. W.;
Chamberlain, S. D.; Drach, J. C.; Townsend, L. B. Design, synthe-
sis, and antiviral activity of ꢂ-nucleosides: D- and L-isomers of
lyxofuranosyl- and (5-deoxylyxofuranosyl)benzimidazoles. J. Med.
Chem., 1998, 41, 1242.
[17]
[18]
[19]
[3]
[4]
[5]
Tamm, I.; Seghal, P. B. Halobenzimidazole ribosides and RNA
synthesis of cells and viruses. Adv. Virus Res., 1978, 22, 187.
Tamm, I. Inhibition of influenza and mumps virus multiplication
by 4,5,6-(or 5,6,7-) trichloro-1-ꢁ-D-ribofuranosylbenzimidazole.
Science, 1954, 120, 847.
[6]
(a) Wright, J. B. The chemistry of the benzimidazoles. Chem. Rev.,
1951, 48, 397. (b) Middleton, R. W.; George Wibberley, D.
Synthesis of imidazo[4,5-b]- and [4,5-c]pyridines. J. Heterocycl.
Chem., 1980, 17, 1757. (c) Rope, M.; Isensee, R. W.; Joseph, L.
Derivatives of 2-phenylbenzimidazole. J. Am. Chem. Soc., 1952,
74, 1095.
[20]
[21]
[22]
[7]
(a) Czarny, A.; Wilson, W. D.; Boykin, D. W. Synthesis of mono-
cationic and dicationic analogs of hoechst 33258. J. Heterocycl.
Chem., 1996, 33, 1393. (b) Tidwell, R. R.; Geratz, J. D.; Dann, O.;
Volz, G.; Zeh, D.; Loewe, H. Diarylamidine derivatives with one or
both of the aryl moieties consisting of an indole or indole-like ring.
Inhibitors of arginine-specific esteroproteases. J. Med. Chem.,
1978, 21, 613. (c) Fairley, T. A.; Tidwell, R. R.; Donkor, I.; Nai-
man, N. A.; Ohemeng, K. A.; Lombardy, R. J.; Bentley, J. A.;
Cory, M. Structure, DNA minor groove binding, and base pair
specificity of alkyl- and aryl-linked bis(amidinobenzimidazoles)
and bis(amidinoindoles). J. Med. Chem., 1993, 36, 1746.
[23]

Synthesis of 2-Substituted Benzimidazoles
Letters in Organic Chemistry, 2011, Vol. 8, No. 7
469
[24]
[25]
Ma, H. Q.; Wang, Y. L.; Li, J. P.; Wang, J. Y. Selective synthesis
of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles promoted by ionic
liquid. Heterocycles, 2007, 71, 135.
Das, B.; Holla, H.; Srinivas, Y. Efficient (bromodi-
methyl)sulfonium bromide mediated synthesis of benzimidazoles.
Tetrahedron Lett., 2007, 48, 61.
Du, L. H.; Wang, Y. G. A rapid and efficient synthesis of benzimi-
dazoles using hypervalent iodine as oxidant. Synthesis, 2007, 675.
Bahrami, K.; Khodaei, M. M.; Kavianinia, I. A simple and efficient
one-pot synthesis of 2-substituted benzimidazoles. Synthesis, 2007,
547.
Lin, S. N.; Yang, L. H. A simple and efficient procedure for the
synthesis of benzimidazoles using air as the oxidant. Tetrahedron
Lett., 2005, 46, 4315.
Chari, M. A.; Shobha, D.; Kenawy, E. R.; Al-Deyab, S. S.; Subba
Reddy, B. V.; Vinu, A. Nanoporous aluminosilicate catalyst with
3D cage-type porous structure as an efficient catalyst for the syn-
thesis of benzimidazole derivatives. Tetrahedron Lett., 2010, 51,
5195.
Ruiz, V. R.; Corma, A.; Sabater, M. J. New route for the synthesis
of benzimidazoles by a one-pot multistep process with mono and
bifunctional solid catalysts. Tetrahedron, 2010, 66, 730.
Gadekar, L. S.; Arbad, B. R.; Lande, M. K. Eco-friendly synthesis
of benzimidazole derivatives using solid acid scolecite catalyst.
Chin. Chem. Lett., 2010, 21, 1053.
[33]
[34]
[35]
[36]
Li, J. T.; Wang, S. X.; Chen, G. F.; Li, T. S. Some applications of
ultrasound irradiation in organic synthesis. Curr. Org. Synth., 2005,
2, 415.
Ratoarinoro, N.; Wilhelm, A. M.; Berlan, J.; Delmas, H. Effects of
ultrasound emitter type and power on a heterogeneous reaction.
Chem. Eng. J., 1992, 50, 27.
Bergbreiter, D. E.; Lalonde, J. J. Michael additions of nitroalkanes
to .alpha.,.beta.-unsaturated carbonyl compounds using potassium
fluoride/basic alumina. J. Org. Chem., 1987, 52, 1601.
Jiang, Y.; Wang, J. Y.; Chen, J. H.; Wang, W. J.; Yan, H.; Zhang,
X. X.; Wang, C.; Zhang, G. L.; Li, B. G. Study on synthesis of 2-
amino-2'-hydroxy-1,1'-binaphthyl by two-phase oxidative coupling
with a cyclic solid oxidant. Acta Chim. Sinica, 2007, 65, 1925.
Li, T. S.; Duan, H. Y.; Li, B. Z.; Tewari, B. B.; Li, S. H. Novel
oxidative coupling of 2-naphthols to 1,1'-bi-2-naphthols catalysed
by solid Lewis acids using atmospheric oxygen as oxidant. J.
Chem. Soc., Perkin Trans. 1, 1999, 291.
Salavati-Niasari, M.; Hasanalian, J.; Najafian, H. Alumina-
supported FeCl3, MnCl2, CoCl2, NiCl2, CuCl2, and ZnCl2 as cata-
lysts for the benzylation of benzene by benzyl chloride. J. Mol.
Catal. A Chem., 2004, 209, 209.
Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Direct
and practical synthesis of 2-arylbenzoxazoles promoted by acti-
vated carbon. Org. Lett., 2003, 5, 3713.
[26]
[27]
[28]
[29]
[37]
[38]
[39]
[30]
[31]
[32]
(a) Luche, J. L. Synthetic Organic Sonochemitry, Plenum Press,
New York, 1998, 3. (b) Mason, T. J.; Peter, D. Pratical Sonochem-
istry, second ed., Eills Horwood, London, 2002.