Simple, efficient, and applicable route for synthesis of 2-Aryl(Heteroaryl)-benzimidazoles at room temperature using copper nanoparticles on activated carbon as a reusable heterogeneous catalyst

Article abstract of DOI:10.1007/s10562-011-0671-6

A series of 2-(hetero)arylbenzimidazoles were synthesized by the catalytic condensation of (hetero)aryl aldehydes with 1,2-phenylenediamine derivatives at room temperature in the presence of air as the oxidant. Copper nanoparticles on charcoal was employed as an efficient and mild catalyst for this methodology. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-011-0671-6

Catal Lett (2011) 141:1845–1850
DOI 10.1007/s10562-011-0671-6
Simple, Efficient, and Applicable Route for Synthesis of
2-Aryl(Heteroaryl)-Benzimidazoles at Room Temperature Using
Copper Nanoparticles on Activated Carbon as a Reusable
Heterogeneous Catalyst
•
Hashem Sharghi Reza Khalifeh
•
•
Seyed Gholamhossein Mansouri
•
Mahdi Aberi Mohammad Mehdi Eskandari
Received: 25 April 2011 / Accepted: 18 July 2011 / Published online: 12 October 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of 2-(hetero)arylbenzimidazoles were
synthesized by the catalytic condensation of (hetero)aryl
aldehydes with 1,2-phenylenediamine derivatives at room
temperature in the presence of air as the oxidant. Copper
nanoparticles on charcoal was employed as an efficient and
mild catalyst for this methodology.
Because of their importance and wide applications, the
synthesis of these benzimidazole derivatives has become a
focus of synthetic organic chemistry.
Two main synthetic routes could be observed in all of
these reported procedures. One route that is common to the
2-aryl benzimidazoles synthesis typically involves direct
coupling of a carboxylic acid or carboxylic acid derivatives
with an appropriate 1,2-phenylenediamine under the
influence of a strong acid such as hydrochloric acid [11] or
polyphosphoric acid [12] at high temperature or under
microwave irradiation [13]. The other important way
involves a two-step procedure that includes the oxidative
cyclo-dehydrogenation of Schiff bases, which are often
generated from the condensation of o-phenylenediamines
and aryl aldehydes. Various oxidative and catalytic
reagents have been employed in the second route [14–35].
Albeit several reports [25–33], the direct condensation
of o-aryldiamines and aromatic aldehydes at room tem-
perature is less developed because as previously reported
[36] this superficially simple reaction is a complex
sequence of competing reactions and leads to the formation
of a complex mixture of products containing 1,2-disubsti-
tuted benzimidazoles and 1,2-disubstituted benzimidazo-
lines as main byproducts. Moreover, most of the catalysts
have been used for this purpose are not recoverable and
destroyed in the work-up procedure. Therefore, the dis-
covery of such mild and practicable routes for selective
synthesis of 2-aryl(heteroaryl)-benzimidazoles continues to
attract the attention of researchers.
Keywords 2-Aryl(heteroaryl)benzimidazoles ꢀ Copper
nanoparticles ꢀ Cu/C ꢀ Heterogeneous catalysis
1 Introduction
2-Aryl(heteroaryl)-substituted benzimidazoles have received
a considerable amount of attention in diverse areas of
chemistry. These compounds exhibit a wide spectrum of
biological and pharmacological activities [1–7]. Also, 2-aryl
benzimidazole derivatives are fluorescent acid–base indica-
tors [8], dopants for plastic scintillation applications [9] and
subunits of polybenzimidazoles as thermally stable polymers
[10].
H. Sharghi (&) ꢀ S. G. Mansouri ꢀ M. Aberi
Department of Chemistry, Shiraz University, 71454 Shiraz,
Islamic Republic Iran
e-mail: shashem@chem.susc.ac.ir
R. Khalifeh (&)
Department of Chemistry, Shiraz University of Technology,
75555-313 Shiraz, Islamic Republic Iran
e-mail: khalifeh@sutech.ac.ir
In the recent years, the use of heterogeneous catalysts
has received considerable interest in various disciplines
including organic synthesis. Synthetic organic routes fol-
lowed by using heterogeneous catalysts have advantages
over their counterparts in which, used-catalyst can be easily
M. M. Eskandari
Chemistry and Petrochemicals Division, Research Institute of
Petroleum Industry (RIPI), Tehran, Islamic Republic Iran
123

1846
H. Sharghi et al.
Scheme 1
O
NH2
NH2
N
H
Cu/C
+
EtOH, r.t.
N
H
Table 1 Effect of different solvents in the condensation reaction of
o-phenylenediamine (1.0 mmol) with benzaldehyde (1.0 mmol) at
room temperature using Cu/C
at room temperature. The catalyst we used in this project
was previously introduced [38], copper nanoparticles on
charcoal (Cu/C), as an efficient recyclable heterogeneous
catalyst in organic synthesis.
Entry
Mol %
of catalyst
Solvent
Time (h)
Yielda (%)
The catalyst was synthesized in two steps. In a general
procedure the activated carbon was refluxed with a nitric
acid solution for several hours and washed with deionized
water until pH 6–7 and then dried in an oven at 110 °C
overnight under vacuum. The oxidized activated carbon
was refluxed with a solution of CuI under a N2 atmosphere
in absolute EtOH, washed with ethanol and finally dried
under vacuum in an oven overnight at 110 °C.
In order to ascertain the optimum conditions of the
reaction, we optimized various parameters including the
solvent and the amount of catalyst for reaction of o-phen-
ylenediamine (1.0 mmol) with benzaldehyde (1.0 mmol)
as the model reactants (Scheme 1).
1
2
5
5
Acetonitrile
Chloroform
Dioxane
Ethyl acetate
Toluene
DMF
18
24
24
24
24
4
89
18
55
82
52
93
92
92
64
79
93
3
5
4
5
5
5
6
5
7
5
THF
18
3
8
5
Ethanol
9
1
Ethanol
3
10
11
a
3
Ethanol
3
10
Ethanol
3
Isolated yield
During our optimization studies, various solvents were
examined, and it was found that these reactions appeared to
be largely dependent on the nature of the solvent. Ethanol
appeared as the solvent of choice due to its fast reaction
rate, high yield, selectivity, cheapness, and environmental
acceptability. The optimal amount of catalyst was found to
be 5.0 mol%. A decrease in the amount of catalyst resulted
in a significant reduction of the yield while an increased
amount of catalyst revealed negligible effect on the effi-
ciency of the reaction (Table 1). The best yield and purity
of desired product was obtained in the presence of
5.0 mol% of the catalyst in 10.0 mL of ethanol as the
appropriate solvent. The product was isolated by simple
washing by ethanol followed by the usual work-up.
Structural assignments of benzimidazole 3a were made
by comparison of the 1H- and 13C NMR spectra with those
reported previously.
recycled [21]. As a part of our continued efforts to utilize
heterogeneous catalysts for developing organic reactions
[37–50], herein we report on a new and reused catalyst
system based on copper on charcoal (Cu/C). This hetero-
geneous catalyst system exhibits an excellent catalytic
performance for the construction of the 2-arylbenzimidaz-
oles framework. Moreover, Cu/C can be repeatedly used
for this transformation and subsequently recovered after
the reaction.
2 Results and Discussion
Previously we have reported several practical methods for
synthesis of a series of 2-arylbenzimidazoles in high yield
O
R1
R
R
NH2
NH2
R
N
N
N
H
Cu/C
+
+
EtOH, r.t.
R1
N
H
R1
4
2
3
1
1a: R = H
R1
1b: R = COOH
1c: R = COOEt
1d: R = COPh
(exclusively formed)
(not formed)
Scheme 2
123

Synthesis of 2-Aryl(Heteroaryl)-Benzimidazoles
1847
Table 2 Condensation reaction of o-phenylenediamines (1.0 mmol) with different aryl(heteroaryl) aldehydes (1.0 mmol) using Cu/C
(5.0 mol%) in ethanol at room temperature
Entry
1
Aldehyde
Diamine
Product
N
Time (h)
3
Yielda (%)
92
NH2
CHO
N
H
NH2
NH2
NH2
NH2
NH2
3a
N
CHO
2
3
6
89
91
N
H
3b
CHO
N
6.5
N
H
3c
N
NH2
NH2
HO
CHO
4
4
93
N
H
OH
3d
N
NH2
NH2
NH2
NH2
CHO
CHO
OH
5
6
7
5
94
90
N
H
HO
Cl
3e
N
Cl
N
H
3f
N
NH2
NH2
CHO
7
8
7
97
90
N
H
Cl
Cl
3g
N
NH2
NH2
O2N
CHO
9.5
N
H
NO2
3h
N
CHO
CHO
NH2
NH2
NH2
NH2
NO2
9
7
6
84
95
N
O2N
H
3i
N
OCH3
10
N
H3CO
H
3j
N
NH2
CHO
11
12
13
3
88
92
85
N
H
N
N
NH2
3k
N
NH2
NH2
CHO
CHO
18
3.5
N
S
S
H
3l
O
O
N
NH2
HO
HO
N
H
NH2
3m
123

1848
H. Sharghi et al.
Table 2 continued
Entry
Aldehyde
Diamine
Product
N
Time (h)
Yielda (%)
O
O
CHO
NH2
EtO
EtO
14
15
3
94
N
H
NH2
3n
3o
O
O
NH2
CHO
N
Ph
Ph
4.5
90
NH2
N
H
O
H
N
O
O
N
H
NH2
NH2
O
N
O
CHO
CHO
N
H
O
N
N
N
O
O
N
N
N
N
O
N
16
17
12
12
82
85
H
N
O
H
N
H
N
N
O
O
O
3p
O
O
H
N
OEt
OEt
O
O
O
N
O
CHO
CHO
N
H
N
H
O
N
O
O
N
N
N
N
NH2
N
N
O
N
EtO
H
N
O
H
N
H
N
NH2
N
O
O
O
3q
3r
O
O
O
O
O
NH2
O
O
H
O
18
4
93
N
O
O
NH2
O
N
H
O
O
O
O
O
O
O
O
O
O
O
NH2
H
H
H
EtO
EtO
O
O
O
19
20
21
7
6
3
92
90
96
N
O
O
NH2
N
H
O
O
3s
3t
O
O
O
O
O
O
O
NH2
NH2
Ph
Ph
N
O
O
N
H
O
O
O
H3C
NH2
O
O
O
O
H3C
N
O
NH2
O
N
O
H
3u
a
Isolated yield
Under the optimized reaction conditions, we obtained
exclusively 2-substituted products 3, and either no N-
alkylated products 4 were observed or they could be found
only in trace amounts in just a few cases (Scheme 2).
To investigate the generality and versatility of this
method, the reaction was extended to various structurally
diverse aldehydes and o-phenylenediamines derivatives. In
all cases, reactions were complete in a reasonable time and
2-arylbenzimidazole derivatives were isolated in good to
high yields. The use of this methodology in the reaction of
the o-phenylenediamines with different aldehydes produced
only one of the possible regioisomers, as expected (Table 2).
123

Synthesis of 2-Aryl(Heteroaryl)-Benzimidazoles
1849
Table 3 Catalyst recyclability
studies in ethanol at room
temperature
In order to assess the feasibility of applying this
method on a preparative scale, we carried out the coupling
of o-phenylenediamine with benzaldehyde in a 30 mmol
scale in the presence of the heterogenous catalyst. As
expected, the reaction proceeded smoothly, similar to the
case in a smaller scale (Table 2, entry 1), and the desired
2-phenylbenzimidazole was obtained in 92% isolated
yield in 3 h.
Reaction
run
Time
(h)
Yielda
(%)
1
2
3
4
5
6
7
3
3
3
3
3
3
3
3
92
92
92
92
91
91
91
90
We also studied catalyst recyclability. The Cu/C can
be recovered and recycled by simple filtration of the
reaction mixture and reused for at least eight consecutive
trial runs without significant decrease in the activity
(Table 3).
8
a
Isolated yield
As shown in Table 2, the generality and selectivity of
this catalysis method is excellent. Electronic variation in
the aldehydes or o-phenylenediamines was tolerated and
did not change the efficiency of the reaction and afforded
the desired benzimidazoles in high yields. Heteroaryl
aldehydes, such as 2-pyridinyl- and 2-thiophenylcarboxal-
dehydes (Table 2, entries 11 and 12), also show good
results under these conditions.
A comparison of the catalytic efficiency of Cu/C with
selected previously known catalysts is collected in Table 4
to demonstrate that the present protocol is indeed superior
to several of the other protocols.
Most of the listed methodologies suffer from some
limitations such as prolonged reaction times, elevated
temperatures, or use hazardous materials. For example,
preparation of benzimidazole has carried out in CH2Cl2 as
a solvent and SOCl2/SiO2 as reagent that both solvent and
reagent are hazardous material (Table 4, entry 1).
Additionally, some of protocols require high temperature
using previous catalysts (Table 4 entries 2, 3, 4, and 5).
It was also observed that, the preparations of those
catalysts and their ligands are very difficult (Table 4,
entries 3, 6–11). But the present method shows a new,
ligand free, cheap, and easy procedure for preparation of
catalyst and introduces a general, simple and efficient
synthetic method for preparation of 2-arylben
zimidazoles.
We felt that this methodology could then be extended
to synthesize azacrown ether-containing benzimidazoles.
The azacrown ether, which has a 1,3,5-triazine sub-
stituent, containing dialdehydes, at the nitrogen position,
gave the corresponding dibenzimidazole in good yield
(Table 2, entries 16 and 17). We decided to extend the
scope of this methodology to the 40-formyl-benzo-15-
crown-5 as starting material; the reaction proceeded with
various o-phenylenediamine derivatives smoothly in
good yield. The structures of the products were deter-
mined from their spectral (1H NMR, 13C NMR, IR, and
mass) analysis.
Table 4 Comparison of protocols for synthesis of 2-phenylbenzimidazole
Entry
Reagent/catalyst
Solvent
Time (min)
Temperature (°C)
Yielda (%)
Ref.
1
2
3
SOCl2/SiO2
CH2Cl2
H2O
240–360
45
25
92
75
70
90
89
95
96
95
96
84
89
85
97
93
15
16
20
I2/KI/K2CO3
90
Cu3/2PMo12O40/SiO2
1,4-dioxane
Solvent-free
EtOH
15
Reflux
25
15
4
5
Graphite/TsOH
NH4OAc
40
75
23
24
25
26
27
29
31
33
34
EtOH
270
25
75
6
CoxO–Co (salen)
T(o-Cl)PPFeIII-SiO2
Cu(BHPPDAH)H2O
ZrOCl2ꢀnH2O/montmorillonite K10
DMP
EtOH
25
7
EtOH
90
25
8
EtOH
120
10
25
9
H2O
25
10
11
12
13
a
1,4-dioxane
Solvent-free
Solvent-free
EtOH
10
25
H3PW12O40/ZrPO4
H2O2/CAN
15
25
12
50
Cu/C
180
25
Isolated yield
123

1850
H. Sharghi et al.
18. Han X, Ma H, Wang Y (2008) Russ J Org Chem 44:863
19. Khan AT, Parvin T, Choudhury LH (2009) Synth Commun
3 Conclusion
39:2339
20. Fazaeli R, Aliyan H (2009) Appl Catal A: General 353:74
21. Gadekar LS, Arbad BR, Lande MK (2010) Chin Chem Lett
21:1053
22. Luo X, Zhang Z, Yang Y, Xue F, Xiu N, She Y (2009) Front
Chem Eng Chin 3:305
23. Sharghi H, Asemani O, Hossein Tabaei SM (2008) J Heterocyclic
Chem 45:1
24. Sharghi H, Asemani O, Khalifeh R (2008) Synth Commun
38:1128
25. Sharghi H, Aberi M, Doroodmand MM (2008) Adv Synth Catal
350:2380
26. Sharghi H, Beyzavi MH, Doroodmand MM (2008) Eur J Org
Chem 24:4126–4138
As a brief statement, we introduced a general, simple, and
efficient synthetic method for preparation of 2-arylbenz-
imidazoles from phenylenediamines and aromatic alde-
hydes using Cu/C as catalyst. The mild reaction conditions,
excellent yields, large-scale synthesis, easy and quick iso-
lation of products, recyclability of the catalyst, employ-
ment of atmospheric air as the oxidant, cost-effectiveness,
environmentally friendly, high generality, and good selec-
tivity are the main advantages of this procedure. So we
believe that it will find wide application in organic syn-
thesis as well as in industry.
27. Sharghi H, Hosseini-Sarvari M, Moeini F (2008) Can J Chem
86:1044
Acknowledgments We gratefully acknowledge the support of this
study by the Shiraz University and Shiraz University of Technology
Research Council.
28. Bahrami K, Khodaei MM, Kavianinia
4:547–550
I (2007) Synthesis
29. Rostamizadeh S, Amani AM, Aryan R, Ghaieni HR, Norouzi L
(2009) Monatsh Chem 140:547
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31. Dabhade SK, Bora RO, Farooqui M, Gill CH (2009) Chin Chem
Lett 20:893
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Heterocyclic Chem 46:74
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37. Sharghi H, Khalifeh R, Doroodmand MM (2009) Adv Synth
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