Solvent-free chemoselective synthesis of some novel substituted 2-arylbenzimidazoles using amino acid-based prolinium nitrate ionic liquid as catalyst

Article abstract of DOI:10.1002/jhet.35

A simple and eco-friendly protocol for the synthesis of substituted 2-arylbenzimidazoles is described. In this process, 2-arylbenzimidazoles were prepared in the presence of a newly introduced ionic liquid prolinium nitrate [Pro]NO₃ as catalyst, under solvent-free condition. This process was performed under mild condition without using any oxidant with good to excellent yields and remarkable chemoselectivity in the absence of any byproduct. The ionic liquid can be recovered easily and reused.

Full text of DOI:10.1002/jhet.35

74
Solvent-Free Chemoselective Synthesis of Some Novel
Substituted 2-Arylbenzimidazoles Using Amino Acid-Based
Prolinium Nitrate Ionic Liquid as Catalyst
Vol 46
Shahnaz Rostamizadeh,* Reza Aryan, Hamid Reza Ghaieni,
and Ali Mohammad Amani
Department of Chemistry, Faculty of Science, K.N. Toosi University of Technology, Tehran, Iran
*E-mail: shrostamizadeh@yahoo.com
Received February 26, 2008
DOI 10.1002/jhet.35
Published online 11 February 2009 in Wiley InterScience (www.interscience.wiley.com).
A simple and eco-friendly protocol for the synthesis of substituted 2-arylbenzimidazoles is described.
In this process, 2-arylbenzimidazoles were prepared in the presence of a newly introduced ionic liquid
prolinium nitrate [Pro]NO3 as catalyst, under solvent-free condition. This process was performed under
mild condition without using any oxidant with good to excellent yields and remarkable chemoselectivity
in the absence of any byproduct. The ionic liquid can be recovered easily and reused.
J. Heterocyclic Chem., 46, 74 (2009).
INTRODUCTION
environmentally harmful byproducts, which often
require laborious work-up to remove them from the
reaction mixture, and/or suffer from low yields of isola-
tion product. Molecular oxygen as oxidant has also been
used but drawbacks such as prolonged reaction times
and high temperature make it less useful [16]. In the
case of I2/KI/K2CO3/H2O system, the yields for alde-
hydes with electron-donating groups were poor [17].
Very recently, iodobenzene diacetate (IBD) as oxidant
in dioxane as solvent has led to significant results but
the use of dioxane as a toxic solvent is the major limita-
tion for this process from the environmental viewpoint
[18]. In another report, application of L-proline in
CHCl3 as organocatalyst was presented but this route
led to the formation of 1,2-di-substituted benzimidazoles
exclusively not the 2-aryl derivatives [19].
The benzimidazole ring system is an important phar-
macophore in medicinal chemistry and modern drug
discovery. Benzimidazole derivatives exhibit activities
against several viruses such as influenza [1a], human
cytomegalovirus [1b], and HIV [1c]. Benzimidazole and
its derivatives have also been known to act as topoisom-
erase inhibitors [2], selective neuropeptide Y Y 1 recep-
tor antagonists [3], potential antitumor [4] and antimi-
crobial agents [5], and factor Xa inhibitor [6]. The wide-
spread interest in benzimidazole-containing structures
has led to extensive studies toward their synthesis. The
most important methodology toward synthesis of benzi-
midazoles is the oxidative cyclo-dehydrogenation of ani-
line Schiff bases, which are often generated in situ from
the coupling reaction between o-phenylenediamines and
aldehydes. Various oxidants have been examined for
this two step process which we hereby refer to some of
them such as nitrobenzene (high-boiling oxidant/solvent)
[7], 1,4-benzoquinone [8] DDQ [9], tetracyanothylene
[10], benzofuroxan [11], MnO2 [12], Pb(OAc)4 [13],
oxone [14], and NaHSO3 [15]. The availability of a vast
number of aldehydes has certainly caused this two-step
process to be extensively investigated by chemists.
However, most of these procedures produce toxic or
The drive to environmentally sustainable, or so-called
‘‘green chemistry,’’ has provided one of the greatest
challenges for the chemists of today [20a]. One of the
major areas of research in this field is using ionic liquids
(ILs) as both solvents and catalysts [20b]. There is only
one report regarding formation of these compounds
using an imidazolium IL (butylimidazolium tetrafluoro-
borate, ([Hbim]BF4) as medium. In this process, the
yields are good and the reaction times were short, and
C
V
2009 HeteroCorporation

January 2009
Solvent-Free Chemoselective Synthesis of Some Novel Substituted 2-Arylbenzimidazoles
75
Scheme 1
tants and examined the effect of the amount of proli-
nium nitrate ([Pro]NO3) IL as catalyst in the absence of
solvent under various temperatures (Scheme 1, Table 1).
To determine the optimum reaction conditions, three
moles of phenylenediamines and three moles of 4-chlor-
obenzaldehyde together with a specified amount of IL
were reacted under different temperatures. The results in
Table 1 showed some interesting points. First of all,
increasing amount of IL did not improve obviously the
yield of 3e. So, the optimum amount of IL was found to
be 20% relative to reactants. The second important point
which could be elicited evidently from these results is
that raising the reaction temperature from r.t. to 60ꢀC
did not increase the yield and also did not improve the
reaction rates. Moreover, the chemoselectivity decreased
and formation of the byproduct 4 was observed in the
process. These results indicates that the reaction is better
to be carried out at r.t. using 20 mol % amount of IL
without solvent to achieve the best results for the prepa-
ration of desired product 3 not product 4.
Then, we continued our study to examine the reus-
ability and recoverability of the catalyst as an additional
important factor in the field of ILs. To achieve this, the
model reaction of o-phenylenediamine (4 mmol) with
4-chlorobenzaldehyde (4 mmol) was carried out in the
presence of IL (0.8 mmol). After completion of the
reaction, the IL could be recovered as specified in Ex-
perimental section. The results of which are given in Ta-
ble 2. These results showed a good recoverability and
reusability for the synthesis of product 3e. It can clearly
be seen that even after four runs, the recovery percent-
age is high. However, the yield decreased significantly
after four runs (Table 2, Run No. 4).
formation of byproducts had a negative effect on the
yield [21].
ILs based on amino acids such as proline are one of the
most important groups of recently developed ILs referred
to as fully green ILs based on natural products. Their im-
portance includes two different aspects. Bio-renewability
and economical benefits are the major features of materials
of this kind. Moreover, ILs of this type do not show
defects such as air- or water-sensitivity of chloroaluminate
ILs nor the potential HF releasing of hexafluorophosphate
ILs. So, because of these advantages, attempts for the de-
velopment and introduction of novel ILs based on natural
products such as amino acids have been intensively inves-
tigated [22]. The main thrust of this work was to provide a
new oxidant-free, selective and more sustainable protocol
for the synthesis of 2-arylbenzimidazoles.
To the best of our knowledge, benzimidazole deriva-
tives have rarely been synthesized with electron with-
drawing substituents such as NO2 and CO2H on the
fused benzo ring of benzimidazole. So, our other goal
was to synthesize such derivatives using 4-nitro-1,2-phe-
nyl-enediamine and 3,4-diaminobenzoic acid as reactant.
The decrease in the yields of the reaction after each
use of IL could possibly be due to the fact that we could
not manage to recover the catalyst quantitatively after
each run. Consequently, we repeated the reaction with
lower amounts of catalyst. To test this idea, we repeated
the reaction by adding some fresh catalyst to the IL
recovered after the first use and the result was the same
as the first run (Table 2, No. 1). Moreover, we observed
a slight change in appearance for the recovered IL,
RESULTS AND DISCUSSION
During our investigation, at first, we chose o-phenyl-
enediamine and 4-chlorobenzaldehyde as model reac-
Table 1
Prolinium nitrate ([Pro]NO3) promoted preparation of
2-(4-chlorophenyl)benzimidazole (3e) under various conditions.
Amount
of IL
(mol %)
Product (%)a
Table 2
Temperature
(ꢀC)
Time
(min)
Results for reusability of IL [Pro]NO3 in the process
of 2-(4-chlorophenyl)benzimidazole (3e) synthesis.
Entry
3
4
1
2
20
20
r.t.
60
20
20
25
25
25
25
50
40
89
89
89
89
85
70
85
80
–
Trace
–
Trace
Trace
20
Recovery
percent
Reaction
time (min)
Yield
(%)a
4
5
40
40
r.t.
60
Run no.
7
8
60
60
r.t.
60
1
2
3
4
95
90
90
90
30
40
55
60
89
82
78
70
10
11
100
100
r.t.
100
15
20
a Isolated yield.
a Isolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

76
S. Rostamizadeh, R. Aryan, H. R. Ghaieni, and A. M. Amani
Vol 46
Scheme 2
which would be due to trace impurities from the reac-
tion. These changes in appearance were observed more
obviously after any recovery.
To evaluate the scope and limitations of this IL under
solvent-free condition various benzaldehyde derivatives
and different derivatives of o-phenylenediamines were
examined (Table 3, entries 1–17). Among the various
benzaldehydes tested, the best yields were achieved for
benzaldehydes with electron-withdrawing substituents
(Table 3, entries 4–7). While among o-phenylenedi-
amine derivatives the yield of products obtained from 4-
nitro-o-phenylenediamine were high and the rates of
reactions were also remarkable (Table 3, entries 8–12).
In all reactions, byproduct 4 was not observed by TLC.
Only in the case of 4-methylbenzaldehyde as reactant
(Table 3, entry 11), the reaction rate was relatively long
and the yield was moderate not high. Repeating the
reaction with 3,4-diaminobenzoic acid showed the best
yield and reactivity for 4-nitrobenzaldehyde (Table 3,
entry 17) and the other derivatives were also synthesized
with interesting yield. These results demonstrate a great
level of versatility and efficiency for the synthesis of 2-
arylbenzimidazole derivatives.
analysis showed only the presence of products 3 (3e, 3i,
and/or 3n) with the excess amount of benzaldehydes
used.
According to these findings, a proposed reaction path-
way for the synthesis of 2-arylbenzimidazoles is shown
in Scheme 2. As can be seen, prolinium cation from IL
first interacts with both reactants to form the Schiff base
intermediate (A) which then undergoes cyclization via
intramolecular attack by another amino moiety on Schiff
base to form protonated benzimidazoline intermediate
(B). Then, this intermediate would be deprotonated to
2,3-dihydrobenzimidazoline (C). Finally, the intermedi-
ate (C) would be aromatized by air oxidation under
reaction vessel conditions.
To complete evaluation of chemoselectivity, our
attempts were focused on performing the reaction with a
new variation. At this stage, we carried out the model
reaction of o-phenylenediamine derivatives (1 mmol)
with 4-chlorobenzaldehyde (2 mmol) under optimal con-
ditions (r.t. and 20% of IL relative to o-phenylenedi-
amine derivatives). Surprisingly, even after 3 h, no
byproduct 4 (4e, 4i, and/or 4n) were formed and TLC
In summary, we have developed an efficient, eco-
friendly as well as solvent and oxidant-free protocol for
the synthesis of 2-arylbenzimidazole derivatives starting
from phenylenediamine derivatives and diverse benzal-
dehydes using fully ‘‘green’’ IL L-prolinium nitrate as
catalyst. The yields of products are very good to excel-
lent and use of toxic solvents is avoided. Synthesis of
some novel 2-arylbenzimidazole derivatives under mild
conditions is the most important aspect of this study.
Simple work-up and high degree of IL reusability are
other interesting points of the developed procedure.
Table 3
Synthesis of 2-phenylbenzimidazole derivatives using
amino acid based IL [pro]NO3.
Entry
R1
R2
Time (min) Product Yield (%)a
1
H
H
H
Me
Ome
Br
50
45
45
30
30
20
25
60
50
45
80
25
45
45
30
60
20
3a
3b
3c
3d
3e
3f
85
82
85
93
89
81
90
92
93
95
76
85
86
90
88
80
92
2
3
4
H
H
5
6
H
H
Cl
F
EXPERIMENTAL
7
8
H
NO2
Br
3g
3h
3i
Melting points were recorded on a Buchi B-540 apparatus.
IR spectra were recorded on an ABB Bomem Model
FTLA200-100 instrument. 1H and 13C NMR spectra were
measured with a Bruker DRX-300 Avance spectrometer at 300
and 75 MHz using TMS as an internal standard. Chemical
shifts (d) are reported relative to TMS, and coupling constants
(J) are reported in Hertz (Hz). Mass spectra were recorded on
a Shimadzu QP 1100 EX mass spectrometer with 70 eV ioni-
zation potential. Elemental analyses of new compounds were
performed with a Vario EL III 0 Serial No. 11024054
instrument.
NO2
NO2
NO2
NO2
NO2
CO2H
CO2H
CO2H
CO2H
CO2H
9
Cl
10
11
12
13
14
15
16
17
CN
Me
NO2
Br
3j
3k
3l
3m
3n
3o
3p
3q
Cl
CN
Me
NO2
a Isolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009
Solvent-Free Chemoselective Synthesis of Some Novel Substituted 2-Arylbenzimidazoles
77
DMSO-d6): d 108.05, 112.88, 113.13, 115.60, 124.55, 125.20,
128.24, 128.87, 131.00, 131.71, 132.20, 133.47, 133.96, 135.26,
135.90, 142.81, 143.36, 151.18, 158.54. MS (EI): m/e ¼ 318
(Mþ), 272, 162, 116. Anal. Calcd. For C13H8BrN3O2: C, 49.06;
H, 2.52; N, 13.21. Found: C, 48.89; H, 3.0; N, 13.23.
Typical experimental procedure for the preparation of
substituted 2-arylbenzimidazoles using [Pro]NO3 as
catalyst. To a mixture of 4-chlorobenzaldehyde (3 mmol) and
o-phenylenediamine (3 mmol) was added prolinium nitrate
(prepared according to literature [22]) (0.6 mmol, 20% relative
to reactants). The reaction mixture was stirred at 30ꢀC and
monitored by TLC (ethyl acetate:petroleum ether, 1:4). After
completion of the reaction, water (10 mL) was added and the
mixture was scratched and stirred for at least 30 min. The
aqueous layer was filtered and the residues were purified by
crystallization from EtOH:Water mixture. The product 3e was
obtained with 89% yield.
2-(4-Chlorophenyl)-5-nitrobenzimidazole (3i). Yellow solid;
mp 277–281ꢀC. IR (KBr): 1601 (C¼¼N), 3281 cmꢁ1(NH). 1H
NMR (300 MHz, DMSO-d6): d 13.60 (s, 1H), 8.41 (s, 1H),
8.16 (d, 2H, J ¼ 7.5 Hz), 8.08 (d, 1H, J ¼ 8.4 Hz), 7.71 (d,
1H, J ¼ 8.4 Hz), 7.62 (d, 2H, J ¼ 7.5 Hz). 13C NMR (75
MHz, DMSO-d6): d 118.08, 120.60, 122.3, 123.64, 127.85,
128.63, 129.23, 135.66, 136.59, 142.75, 154.62. Ms (EI): m/e
¼ 273 (Mþ), 227, 192, 111. Anal. Calcd. for C13H8ClN3O2: C,
57.05; H, 2.95; N, 15.35. Found: C, 57.44; H, 2.61; N, 15.62.
2-(4-Cyanophenyl)-5-nitrobenzimidazole (Mixture of tauto-
meric 3j and 4j). Yellow solid; mp 190–193ꢀC. IR (KBr):
1602 (C¼¼N), 2228 (CBN), 3363 cmꢁ1 (NH). 1H NMR (300
MHz, DMSO-d6): d 13.73 (s, 1H), 8.88 (s, 1H), 8.41–7.73 (m,
12H), 6.88 (s, 1H). 13C NMR (75 MHz, DMSO-d6): d 112.88,
113.20, 118.39, 118.66, 124.93, 127.46, 129.60, 132.52,
132.73, 133.00, 135.85, 139.96, 142.98, 151.43, 153.73,
157.75. MS (EI): m/e ¼ 264 (Mþ), 218, 192, 162, 118. Anal.
Calcd. for C14H8N4O2: C, 63.64; H, 3.05; N, 21.20. Found: C,
63.98; H, 2.77; N, 20.88.
Aqueous layer containing IL was concentrated in vacuo to
recycle and reuse the prolinium nitrate in another reaction.
Spectral and analytical data for substituted 2-arylbenzi-
midazoles.
2-Phenylbenzimidazole (3a). Light yellow solid; mp 283–
285ꢀC (Lit. [19] mp 289–291ꢀC). IR (KBr): 1621 (C¼¼N),
1
3447 cmꢁ1 (NH). H NMR (300 MHz, DMSO-d6): d 13.31 (s,
1H), 8.27 (d, 2H, J ¼ 3.0), 7.69 (m, 2H), 7.59 (s, 3H), 7.34
(m, 2H). 13C NMR (75 MHz, DMSO-d6): d ¼ 114.65, 123.62,
127.13, 127.35, 129.20, 131.23, 136.34, 150.16.
2-(4-Methylphenyl)benzimidazole (3b). Light yellow solid;
mp 268–270ꢀC (Lit. [24] mp 277ꢀC). IR (KBr): 1617 (C¼¼N),
3060, 3435 (NH) cmꢁ1 1H NMR (300 MHz, DMSO-d6): d
.
2-(4-Methylphenyl)-5-nitrobenzimidazole (3k).
Yellow
solid; mp 211–214ꢀC. IR (KBr): 1637 (C¼¼N), 3435
cmꢁ1(NH). 1H NMR (300 MHz, DMSO-d6): d 13.53 (s, 1H),
7.39 (d, 2H, J ¼ 9.0 Hz), 6.54 (d, 1H, J ¼ 12.0 Hz), 6.04 (s,
2H), 5.06 (s, 2H), 2.39 (s, 3H). 13C NMR (75 MHz, DMSO-
d6): d 21.08, 108.03, 111.44, 115.61, 126.98, 129.78, 133.96,
136.79, 143.36, 153.14. MS (EI): m/e ¼ 253 (Mþ), 153, 107,
80. Anal. Calcd. for C14H11N3O2: C, 66.39; H, 4.38; N, 16.59.
Found: C, 66.28; H, 4.09; N, 16.34.
12.87 (s, 1H), 8.10 (d, 2H, J ¼ 8.1 Hz), 7.61 (m, 2H), 7.33 (d,
2H, J ¼ 8.1 Hz), 7.19 (m, 2H), 2.35 (s, 3H). 13C NMR (75
MHz, DMSO-d6): d 20.96, 111.21, 118.72, 121.59, 126.42,
127.50, 129.52, 139.56, 151.45.
2-(4-Methoxyphenyl)benzimidazole (3c). Light yellow solid;
mp 217–220ꢀC (Lit. [19] mp 224–226ꢀC). IR (KBr): 1612
1
(C¼¼N), 3420 cmꢁ1 (NH). H NMR (300 MHz, DMSO-d6): d
12.73 (s, 1H), 8.11 (d, 2H, J ¼ 9.0 Hz), 7.54 (s, 2H), 7.16 (m,
2H), 7.11 (d, 2H, J ¼ 9.0 Hz), 3.82 (s, 3H).
2-(4-Nitrophenyl)-5-nitrophenylbenzimidazole (Mixture of
tautomeric 3l and 4l). Red solid; mp 222–224ꢀC. IR (KBr):
2-(4-Bromophenyl)benzimidazole (3d). Light yellow solid;
mp 294–296ꢀC (Lit. [19] mp 299–300ꢀC). IR (KBr): 1597
1612 (C¼¼N), 3101, 3388, 3486 (NH) cmꢁ1
.
1H NMR (300
1
(C¼¼N), 3420 cmꢁ1 (NH). H NMR (300 MHz, DMSO-d6): d
MHz, DMSO-d6): d 8.98 (s, 2H), 8.32 (s, 4H), 8.11 (s, 1H),
7.94 (d, 1H, J ¼ 9 Hz), 6.91 (s, 2H), 6.78 (d, 1H, J ¼ 9 Hz).
13C NMR (75 MHz, DMSO-d6): d 113.26, 113.39, 122.27,
123.63, 123.77, 125.09, 130.11, 132.72, 135.88, 136.49,
141.69, 148.77, 151.51, 157.41. MS (EI): m/e ¼ 284 (Mþ),
238, 192, 164, 118. Anal. Calcd for C13H8N4O4: C, 51.41; H,
3.77; N 18.59. Found: C, 51.88; H, 4.13; N, 18.20.
12.99 (s, 1H), 8.12 (d, 2H, J ¼ 9.0 Hz), 7.75 (d, 2H, J ¼ 9.0
Hz), 7.65 (m, 1H), 7.53 (m, 1H), 7.21 (m, 2H). 13C NMR (75
MHz, DMSO-d6): d 111.43, 118.98, 121.86, 123.26, 128.35,
129.39, 131.98, 150.22.
2-(4-Chlorophenyl)benzimidazole (3e). Light yellow solid;
mp 283–286ꢀC (Lit. [19] mp 292–294ꢀC). IR (KBr): 1597
1
(C¼¼N), 3420 cmꢁ1 (NH). H NMR (300 MHz, DMSO-d6): d
2-(4-Bromophenyl)benzimidazole-5-carboxylic acid (3m). Pale
yellow solid; mp 183–185ꢀC. IR (KBr): 1635 (C¼¼N), 1678
12.98 (s, 1H), 8.18 (d, 2H, J ¼ 9.0 Hz), 7.62 (d, 3H, J ¼ 9.0
Hz), 7.52 (d, 1H, J ¼ 6.0 Hz), 7.21 (m, 2H).
1
(C¼¼O), 3091, 3379 (NH) cmꢁ1. H NMR (300 MHz, DMSO-
d6): d 13.49 (s, 1H), 12.74 (s, 1H), 8.14 (m, 3H), 7.80 (m,
3H), 7.65 (m, 1H). 13C NMR (75 MHz, DMSO-d6): d 123.88,
124.79, 128.64, 128.82, 132.09, 151.95, 167.76. MS (EI): m/e
2-(4-Fluorophenyl)benzimidazole (3f). Light yellow solid;
mp 242–245ꢀC (Lit. [19] mp 250–251ꢀC). IR (KBr): 1602
1
(C¼¼N), 3405 cmꢁ1 (NH). H NMR (300 MHz, DMSO-d6): d
¼
316 (Mþ
ꢁ
1), 273, 271, 191. Anal. Calcd. for
12.92 (s, 1H), 8.22 (m, 2H), 7.58 (m, 2H), 7.39 (t, 2H, J ¼
6.0 Hz), 7.19 (d, 2H, J ¼ 6.0 Hz).
C14H9BrN2O2: C. 53.02; H, 2.86; N, 8.83. Found: C. 53.11; H,
2.54; N, 8.75.
2-(4-Nitrophenyl)benzimidazole (3g). Light red solid; mp
307–309ꢀC (Lit. [19] mp 316ꢀC). IR (KBr): 1606 (C¼¼N),
2-(4-Chlorophenyl)benzimidazole-5-carboxylic acid (3n). Pale
yellow solid; mp 168–169ꢀC. IR (KBr): 1622 (C¼¼N), 1683
1
3409 cmꢁ1 (NH). H NMR (300 MHz, DMSO-d6): d 13.28 (s,
1H), 8.40 (m, 4H), 7.65 (m, 2H), 7.26 (m, 2H).
1
(C¼¼O), 3101, 3414 (NH) cmꢁ1. H NMR (300 MHz, DMSO-
d6): d 13.29 (s, 1H), 12.76 (s, 1H), 8.20 (d, J ¼ 9 Hz, 3H),
7.84 (m, 1H), 7.64 (d, J ¼ 9 Hz, 3H). 13C NMR (75 MHz,
DMSO-d6): d 123.67, 124.55, 128.45, 128.51, 129.20, 135.10,
147.1, 154.32, 156.63, 167.80. MS (EI): m/e ¼ 272 (Mþ), 227,
192. Anal. Calcd. for C14H8ClN2O2: C, 61.89; H, 2.97; N,
10.31. Found: C, 62.14; H, 2.69; N, 10.12.
2-(4-Bromophenyl)-5-nitrobenzimidazole (Mixture of tauto-
meric 3h and 4h). Yellow solid; mp 161–164ꢀC. IR (KBr):
1
1608 (C¼¼N), 3481 cmꢁ1 (NH). H NMR (300 MHz, DMSO-
d6): d 13.64 (s, 1H), 8.11 (d, 1H, J ¼ 8.4 Hz), 8.01 (d, 3H, J
¼ 9 Hz), 7.91 (dd, 1H, J1 ¼ 9.0 Hz, J2 ¼ 2.4 Hz), 7.78 (d,
1H, J ¼ 8.4 Hz), 7.70 (d, 3H, J ¼ 9 Hz). 13C NMR (75 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

78
S. Rostamizadeh, R. Aryan, H. R. Ghaieni, and A. M. Amani
Vol 46
[2] Kim, J. S.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.; LaVioe,
E. J Med Chem 1996, 39, 992.
2-(4-Cyanophenyl)benzimidazole-5-carboxylic acid (Mix-
ture of tautomeric 3o and 4o). Pale yellow solid; mp 183–
185ꢀC. IR (KBr): 1606 (C¼¼N), 2228 (CBN), 3368 cmꢁ1
(s, 1H), 8.14 (m, 3H), 7.82 (m, 3H), 7.67 (m, 1H). 13C NMR
(75 MHz, DMSO-d6): d 112.43, 112.80, 113.72, 117.28,
118.54, 118.76, 125.23, 127.32, 129.33, 130.21, 132.57,
133.06 (2 ꢂ C), 133.72, 140.44, 148.96, 151.68, 155.43,
167.51, 167.71. MS (EI): m/e ¼ 263 (Mþ), 246, 218, 116.
Anal. Calcd. for C15H9N3O2: C, 64.76; H, 3.64; N, 15.11.
Found: C, 64.27; H, 3.94; N, 14.66.
[3] Zarrinmayeh, H.; Zimmerman, D. M.; Cantrell, B. E.;
Schober, D. A.; Bruns, R. F Bioorg Med Chem Lett 1999, 9, 647.
[4] Denny, W. A.; Rewcastle, G. W.; Bagley, B. C J Med
Chem 1990, 33, 814.
1
(NH). H NMR (300 MHz, DMSO-d6): d 13.48 (s, 1H), 13.05
[5] Forseca, T.; Gigante B.; Gilchrist T. L. Tetrahedron 2001,
57, 1793.
[6] 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.
[7] (a) Grimmet, M. R. In Comprehensive Heterocyclic Chem-
istry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford,
1984; Vol. 5, pp 457–480; (b) Harapanhalli, R. S.; McLaughlin, L.
W.; Howell, R. W.; Rao, D. V.; Adelstein, S. J.; Kassis, A. I. J Med
Chem 1996, 39, 4804.
2-(4-Methylphenyl)benzimidazole-5-carboxylic acid (mixture
of tautomeric 3p and 4p). Pale yellow solid; mp 200–205ꢀC.
IR (KBr): 1628 (C¼¼N), 1689 (C¼¼O), 3369 (NH), 3426 (OH)
1
cmꢁ1. H NMR (300 MHz, DMSO-d6): d 12.70 (s, 1H), 8.16
(s, 1H), 8.08 (d, 2H, J ¼ 6.0 Hz), 7.82 (d, 1H, J ¼ 6.0 Hz),
7.63 (d, 1H, J ¼ 6.0 Hz), 7.36 (d, 2H, J ¼ 6.0 Hz), 2.49 (s,
2H), 2.37 (s, 3H). 13C NMR (75 MHz, DMSO-d6): d 18.56,
21.01, 123.47, 124.46, 126.69, 126.86, 129.82, 140.27, 153.70,
167.87. MS (EI): m/e ¼ 252 (Mþ), 237, 207. Anal. Calcd. for
C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C, 71.35; H,
4.61; N, 10.98.
[8] Verner, E.; Katz, B. A.; Spencer, J. R.; Allen, D.; Hataye,
J.; Hruzewicz, 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. J Med Chem
2001, 44, 2753.
[9] Vanden Eynde, J. J.; Delfosse, F.; Lor, P.; Van Haverbeke,
Y. Tetrahedron 1995, 51, 5813.
[10] Chikashita, H.; Nishida, S.; Miyazaki, M.; Morita, Y.; Itoh,
K. Bull Chem Soc Jpn 1987, 60, 737.
2-(4-Nitrophenyl)benzimidazole-5-carboxylic acid (mixture
of tautomeric 3q and 4q). Pale red solid; mp 270–272ꢀC. IR
(KBr): 1602 (C¼¼N), 1671(C¼¼O), 3394 (NH), 3501(OH)
[11] Patzold, F.; Zeuner, F.; Heyer, T. H.; Niclas, H. J. Synth
Commun 1992, 22, 281.
1
cmꢁ1. H NMR (300 MHz, DMSO-d6): d 13.62 (s, 1H), 12.50
[12] Bhatnagar, I.; George, M. V. Tetrahedron 1968, 24, 1293.
[13] Stephens, F. F.; Bower, J. D. J Chem Soc 1949, 2971.
(s, 1H), 8.92 (s, 1H), 8.44 (m, 3H), 8.32 (s, 4H), 8.24 (s,
0.5H), 8.14 (m, 0.8H), 7.88 (m, 0.5H), 7.72 (s, 0.7H), 7.61 (d,
1H, J ¼ 6.0 Hz), 6.75 (d, 1H, J ¼ 6.0 Hz).13C NMR (75
MHz, DMSO-d6): d 113.80, 117.32, 118.54, 123.80 (2 ꢂ C),
124.37, 127.82, 129.75, 130.36, 130.66, 133.01, 142.18,
148.18, 148.54, 149.05, 154.96, 167.49, 167.69. MS (EI): m/e
¼ 283 (Mþ), 238, 192. Anal. Calcd. for C14H9N3O4: C, 56.43;
H, 3.28; N, 13.79. Found: C, 56.07; H, 3.67; N, 13.41.
´
[14] Beaulieu, P. L.; Hache, B.; von Moos, E. A. Synthesis
2003, 1683.
[15] Weidner-Wells, M. A.; Ohemeng, K. A.; Nguyen, V. N.;
Fraga-Spano, S.; Macielag, M. J.; Werblood, H. M.; Foleno, B. D.; Webb,
G. C.; Barrett, J. F.; Hlasta, D. J. Bioorg Med Chem Lett 2001, 11, 1545.
[16] Lin, S.; Yang, L. Tetrahedron Lett 2005, 46, 4315.
[17] Gogoi, P.; Konwar, D. Tetrahedron Lett 2006, 47, 79.
[18] Du, L-.H.; Wang, Y.-G. Synthesis 2007, 675.
[19] Varala, R.; Nasreen, A.; Enugala, R.; Adapa, S. R. Tetrahe-
dron Lett 2007, 48, 69.
Acknowledgments. The authors gratefully acknowledge
Research Council of K. N. Toosi University of Technology for
partial financial support and Dr. Khosrow Jadidi from Shahid
Beheshti University for helpful consultations.
[20] (a) Anastas, P. T.; Kirchhoff, M. M. Acc Chem Res 2002,
35, 686; (b) Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.;
Weaver, K. J.; Forbes, D. C.; Davis, J. H., Jr. J Am Chem Soc 2002,
124, 5962.
REFERENCES AND NOTES
[21] Ma, H. Q.; Wang, Y. L.; Li, J. P.; Wang, J. Y. Heterocycles
2007, 71, 135.
[1] (a) Tamm, I. Science 1954, 126, 1235; (b) Migawa, M. T.;
Giradet, J. L.; Walker, J. A.; Koszalka, G. W.; Chamberlain, S. D.;
Drach, J. C.; Townsend, L. B. J Med Chem 1998, 41, 1242; (c) Por-
cari, A. R.; Devivar R. V.; Kucera, L. S.; Drach, J. C.; Townsend, L.
B. J Med Chem 1998, 41, 1252.
[22] Tao, G.-H.; He, L.; Liu, W.; Xu, L.; Xiong, W.; Wang, T.;
Kou, Y. Green Chem 2005, 8, 639.
[23] Alloum, A. B.; Bougrin, K.; Soufiaoui, M. Tetrahedron Lett
2003, 44, 5935.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet