Water-accelerated selective synthesis of 1,2-disubstituted benzimidazoles at room temperature catalyzed by Bronsted acidic ionic liquid

Article abstract of DOI:10.1080/00397910802326539

An environmentally benign method for the rapid and selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles by the reaction of o-phenylenediamines and aromatic aldehydes in the presence of 1-methylimidazolium triflouroacetate ([Hmim]TFA) at room temperature under aqueous conditions is described. The ionic liquid is reusable and could be recycled for several runs without any decrease in its efficiency. Copyright Taylor & Francis Group, LLC.

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Water-Accelerated Selective
Synthesis of 1,2-Disubstituted
Benzimidazoles at Room
Temperature Catalyzed by
Br⊘nsted Acidic Ionic Liquid
Minoo Dabiri a , Peyman Salehi b , Mostafa
Baghbanzadeh a & Maryam Shakouri Nikcheh a
a Department of Chemistry, Faculty of Science,
Shahid Beheshti University, G. C., Evin, Tehran, Iran
b Department of Phytochemistry, Medicinal Plants
and Drugs Research Institute, Shahid Beheshti
University, Tehran, Iran
Version of record first published: 31 Oct 2008.
To cite this article: Minoo Dabiri , Peyman Salehi , Mostafa Baghbanzadeh & Maryam
Shakouri Nikcheh (2008): Water-Accelerated Selective Synthesis of 1,2-Disubstituted
Benzimidazoles at Room Temperature Catalyzed by Br⊘nsted Acidic Ionic Liquid,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:23, 4272-4281
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Synthetic Communications1, 38: 4272–4281, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802326539
Water-Accelerated Selective Synthesis of
1,2-Disubstituted Benzimidazoles at
Room Temperature Catalyzed by
Brønsted Acidic Ionic Liquid
Minoo Dabiri,1 Peyman Salehi,2 Mostafa Baghbanzadeh,1 and
Maryam Shakouri Nikcheh1
1Department of Chemistry, Faculty of Science, Shahid Beheshti University,
G. C., Evin, Tehran, Iran
2Department of Phytochemistry, Medicinal Plants and Drugs Research
Institute, Shahid Beheshti University, Tehran, Iran
Abstract: An environmentally benign method for the rapid and selective synthesis
of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles by the reaction of o-phenylenedia-
mines and aromatic aldehydes in the presence of 1-methylimidazolium triflouroa-
cetate ([Hmim]TFA) at room temperature under aqueous conditions is described.
The ionic liquid is reusable and could be recycled for several runs without any
decrease in its efficiency.
Keywords: Aldehyde, benzimidazole, heterocycle, ionic liquid, water
INTRODUCTION
Benzimidazole derivatives are an important structural element in medic-
inal chemistry and show a broad spectrum of pharmacological activities.
Several compounds from this class have been used as antihistaminic, anti-
parasitic, antitumor, fungicide, immunosuppressant, antiviral, and anti-
convulsant agents.[1–5] They have also been used as ligands for asymmetric
Received May 3, 2008.
Address correspondence to Minoo Dabiri, Department of Phytochemistry,
Medicinal Plants and Drugs Research Institute, Shahid Beheshti University,
G. C., Evin, Tehran, Iran. E-mail: m-dabiri@sbu.ac.ir
4272

1,2-Disubstituted Benzimidazoles
4273
catalysis.[6] Many methods have been reported for the synthesis of these
heterocycles.[7–13] Among them, the condensation of 1,2-phenylenedia-
mines with aldehydes followed by oxidation is a common method,[14–22]
but the main problem of this method is the generation of 2-substituted
and 1,2-disubstituted benzimidazoles with poor selectivity. However, the
attempts to modify the reaction condition still suffer from some
drawbacks such as using expensive and toxic reagent, a special oxidation
process, tedious workup procedures, and long reaction times.
Ionic liquid (IL) technology, when used in place of classical organic
solvents, may offer an environmentally benign approach toward modern
synthetic chemistry.[23] The implementation of task-specific ionic liquids
(TSILs) further enhances the versatility of classical ILs where both
reagent and medium are coupled.[24] The union of reagent with medium
has been found to be a viable alternative approach toward modern syn-
thetic chemistry especially when considering the growing environmental
demands being placed on chemical processes. Previous reports have
documented the feasibility of the application and reuse of TSILs in clas-
sical organic processes.[25] A specific viewpoint focused on the use of
Brønsted acid TSILs in modern synthetic chemistry.[26]
In continuation of our interest in finding new environmentally
benign methods for the synthesis of heterocyclic compounds,[27–30] here
we report a new procedure for the rapid and selective synthesis of 2-
aryl-1-arylmethyl-1H-1,3-benzimidazoles in the presence of 1-methylimi-
dazoluim triflouroacetate ([Hmim]TFA)[31,32] as a Brønsted acidic ionic
liquid (BAIL) at room temperature. We also show that in the presence
of water an inconceivable decrease in the reaction time is observed.
RESULTS AND DISCUSSION
Our initial investigation focused on the use of ILs as the catalyst in the
reaction of o-phenylenediamine and benzaldehyde under solvent-free
conditions (Scheme 1). It is worth noting that ILs were dried carefully
before use in the experiments.
The data collected in Table 1 indicated that despite the presence of 1-
methylimidazolium p-toluenesulfonate ([Hmim]PTS) or 1-methylimida-
zolium perchlorate ([Hmim]ClO4) the reaction did not occur to a
significant extent within 12 h (Table 1, entries 1 and 2), 1-methylimidazo-
lium hydrogen sulfate ([Hmim]HSO4) gave the product 1a in low
yield and poor selectivity within the same reaction period (Table 1, entry
3). Further screening led to the observation that 1-methylimidazolium
tetraflouroborate ([Hmim]BF4) afforded 1a in 65% yield after 5 h, but
with a 80:20 ratio of 1a=2a (Table 1, entry 4). Further efforts with

4274
M. Dabiri et al.
Scheme 1. Checking different BAILs in the synthesis of benzimidazoles.
1-methylimidazolium triflouroacetate ([Hmim]TFA) afforded 1a in 86%
yield with no detectable production of 2a (Table 1, entry 5). Also we
found that the reaction ran in water rapidly with high selectivity (Table
1, entry 6). To evaluate the better catalytic activity of [Hmim]TFA, the
reaction was run in the presence of 10 mol% triflouroacetic acid (TFA)
under solvent-free and aqueous conditions and also in ethanol, and it
clearly demonstrated that under this condition the selectivity and yield
are not so good (Table 1, entries 7–9). Finally, acetic acid was checked
as an acidic catalyst in reaction in ethanol and under solvent-free condi-
tions, and it could be observed that no satisfactory results were obtained
under these conditions (Table 1, entries 10, 11).
Encouraged by these results, the highly selective synthesis of other
2-aryl-1-arylmethyl-1H-1,3-benzimidazole derivatives were conducted at
room temperature using 10 mol% of [Hmim]TFA (Scheme 2). Similarly,
various o-phenylenediamine (R1 ¼ H, Me, Cl) reacted with different
Table 1. Effect of different catalyst on the yield and selectivity in the reaction of
o-phenylenediamine and benzaldehyde
Entry
Catalyst (10 mol%)
Solvent
Time (h)
Yield (%)
1a=2aa
1
2
3
4
5
6
7
8
9
[Hmim]PTS
[Hmim]ClO4
[Hmim]HSO4
[Hmim]BF4
[Hmim]TFA
[Hmim]TFA
TFA
TFA
TFA
CH3COOH
CH3COOH
—
—
—
—
12
12
12
5
3
0.15
5
1
2
2
12
NR
40
60
75
86
88
70
82
—
60=40
60=40
80=20
99=1
—
Water
—
Water
Ethanol
Ethanol
—
99=1
60=40
90=10
80=20
80=20
—
76
76
NR
10
11
1
aThe 1a=2a ratio was determined by H NMR analysis.

1,2-Disubstituted Benzimidazoles
4275
Scheme 2. Selective synthesis of 2-substituted benzimidazoles.
aromatic and hetero-aromatic aldehydes to afford the desired adducts in
good yields (Table 2). In all cases, the reactions progressed smoothly at
ambient temperature with excellent selectivities.
The organic reactions in aqueous media have attracted much atten-
tion in synthetic organic chemistry, not only because water is one of the
most abundant, cheapest, and environmentally friendly solvents but also
because water exhibits unique reactivity and selectivity, which is different
from those conventional organic solvents.[33,34] In many reactions,
significant rate enhancements are observed in water compared to organic
solvents.[35]
When we conducted similar reactions in water, the expected pro-
ducts were obtained in good yields and selectivities and the reaction
times became shorter than those in the first condition (Table 2). Several
aromatic aldehydes carrying different functional groups and also het-
eroaromatic aldehydes (Table 2, 1i–k) were used in reactions, and in
all cases the desired products were obtained successfully. In addition
to the previously mentioned advantages, the simple workup procedure
makes this process environmentally friendly, as well as the easy purifica-
tion, which requires only filtration of the products followed by recrys-
tallization from ethanol.
To investigate the possibility of recycling the catalyst, an investi-
gation was made of the reaction of o-phenylenediamine and benzalde-
hyde in the presence of 10 mol% of [Hmim]TFA in water. After
completion of the reaction, the mixture was filtered to separate the
product. After washing the BAIL with the appropriate solvent
(for elimination of the unreacted starting products) and drying under
high vacuum, the recycled IL was used for further runs. No decrease
in catalytic activity of BAIL was observed even after four runs
(Table 2, 1a).
In conclusion, a simple, rapid, and environmentally friendly method
for the selective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles
is described. In this new procedure, water accelerated the reaction of
o-phenylenediamines and aromatic aldehydes in the presence of
[Hmim]TFA, as a BAIL. Also the workup procedure is very simple, and
chromatography is not required. Starting materials are inexpensive and

4276

1,2-Disubstituted Benzimidazoles
4277
commercially available. We hope that this approach may be of value to
others seeking novel synthetic fragments with unique properties for med-
icinal chemistry programs.
EXPERIMENTAL
Melting points were measured on an Electrothermal 9200 apparatus.
Mass spectra were recorded on a Finnigan-MAT 8430 mass spectrometer
operating at an ionization potential of 70 eV. The elemental analyses
were performed with an Elementar Analysensysteme GmbH Vario EL
1
CHNS mode. H and 13C NMR spectra were recorded on a Bruker
DRX-300 Avance spectrometer at 300.13 and 75.47 MHz. All chemical
reagents were obtained from Fluka and Merck and were used without
purification.
General Procedure for the Synthesis of 2-Aryl-1-arylmethyl-1H-1,3-
benzimidazoles in [Hmim]TFA
Aldehyde (2 mmol) and o-phenylenediamine (1 mmol) were mixed with
ionic liquid (0.02 g, 0.1 mmol) and placed in a round-bottomed flask.
The mixture was stirred at room temperature. After the completion of
the reaction as confirmed by thin-layer chromatography (TLC; eluent:
n-hexane=ethyl acetate: 3=1), cold water was added, and the precipitated
product was separated by simple filtration. Finally the crude product was
recrystallized from ethanol.
General Procedure for the Synthesis of 2-Aryl-1-arylmethyl-1H-1,3-
benzimidazoles in Water in the Presence of [Hmim]TFA
[Hmim]TFA (0.02 g, 0.1 mmol), o-phenylenediamine (1 mmol), and aro-
matic aldehyde (2 mmol) were added to 2 mL of water, and the reaction
was stirred in a round-bottomed flask for the appropriate time (see Table
2). After the completion of the reaction, the mixture was filtered, and the
resulting crude product was recrystallized from ethanol.
Spectral Data for New Compounds
Compound 1l (C22H20N2O2): IR (KBr) n=cmꢁ1: 3500, 3440, 1615, 1513,
1
1280. H NMR (DMSO-d6, 300 MHz) d (ppm): 2.27 (s, 3H, CH3), 2.30

4278
M. Dabiri et al.
(s, 3H, CH3), 5.34 (s, 2H, CH2), 6.67 (s, 2H, Ar-H), 6.78–6.88 (m, 4H,
Ar-H), 7.17 (s, 1H, Ar-H), 7.42–7.52 (m, 3H, Ar-H), 9.44 (s, 1H, OH),
9.97 (s, 1H, OH). 13C NMR (DMSO-d6, 75 MHz) d (ppm): 20.3, 20.6,
47.3, 111.3, 115.9, 119.4, 121.4, 127.7, 130.6, 130.8, 131.1, 134.9, 141.7,
153.1, 157.0, 159.0. MS (EI, 70 eV) (m=z, %): 238 (Mþ ꢁ106, 100), 223
(35), 119 (20), 78 (25), 51 (30). Anal. calcd. for C22H20N2O2 (344.41):
C, 76.72; H, 5.85; N, 8.13%. Found: C, 76.64; H, 5.81; N, 8.23%.
Compound 1o (C20H14Cl2N2O2): IR (KBr) n=cmꢁ1: 3558, 3405,
1
1611, 1513, 1280. H NMR (DMSO-d6, 300 MHz) d (ppm): 5.45 (s, 2H,
CH2), 6.67 (d, J ¼ 8.3 Hz, 2H, Ar-H), 6.81 (d, J ¼ 8.3 Hz, 2H, Ar-H), 6.91
(d, J ¼ 8.4 Hz, 2H, Ar-H), 7.58 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.81 (s, 1H,
Ar-H), 7.92 (s, 1H, Ar-H), 9.47 (s, 1H, OH), 10.03 (s, 1H, OH). 13C
NMR (DMSO-d6, 75 MHz) d (ppm): 47.7, 113.0, 116.0, 116.1, 120.3,
124.9, 125.0, 127.0, 131.1, 136.0, 142.7, 156.4, 157.2, 159.7. MS (EI,
70 eV) (m=z, %): 345 (Mþ, 5), 278 (100), 107 (20), 78 (25). Anal. calcd.
for C20H14Cl2N2O2 (385.24): C, 62.35; H, 3.66; N, 7.27%. Found: C,
62.28; H, 3.41; N, 7.23%.
Compound 1k (C20H18N4): IR (KBr) n=cmꢁ1: 3436, 2921, 1685,
1603, 1475, 1450. 1H NMR (DMSO-d6, 300 MHz) d (ppm): 2.33 (s,
3H, CH3), 2.35 (s, 3H, CH3), 5.71 (s, 2H, CH2), 7.03 (s, 1H, Ar-H),
7.32–7.68 (m, 4H, Ar-H), 8.12 (s, 1H, Ar-H), 8.52–8.76 (m, 4H, Ar-H).
13C NMR (DMSO-d6, 75 MHz) d (ppm): 20.1, 20.4, 47.2, 111.3, 120.2,
123.3, 132.0, 132.4, 135.2, 137.9, 138.2, 141.6, 146.7, 148.0, 150.1,
150.4. MS (EI, 70 eV) (m=z, %): 314 (Mþ, 100), 223 (80), 208 (40), 116
(20), 91 (25). Anal. calcd. for C20H18N4 (314.38): C, 76.41; H, 5.77; N,
17.82%. Found: C, 76.40; H, 3.61; N, 17.63%.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the Research Council
of Shahid Beheshti University.
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