A highly efficient synthesis of substituted imidazoles via a one-pot multicomponent reaction by using urea/hydrogen peroxide (UHP)

Article abstract of DOI:10.4067/S0717-97072016000300022

A simple, versatile and highly efficient synthesis of 2,4,5-trisubstituted imidazoles by a condensation reaction of benzil or benzoin, aldehydes and ammonium acetate in the presence of urea/hydrogen peroxide (UHP) as a mild and efficient molecular catalyst in refluxing ethanol is described. The present methodology offers several advantages such as green protocol, inexpensive catalyst, high-to-excellent yields, and simple and easy work-up procedure.

Full text of DOI:10.4067/S0717-97072016000300022

J. Chil. Chem. Soc., 61, Nº 3 (2016)
A HIGHLY EFFICIENT SYNTHESIS OF SUBSTITUTED IMIDAZOLES VIA A ONE-POT MULTICOMPONENT
REACTION BY USING UREA/HYDROGEN PEROXIDE (UHP)
ALI MALEKI* AND ZAHRA ALIREZVANI
Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry, Iran University of Science and Technology,
Tehran 16846-13114, Iran
ABSTRACT
A simple, versatile and highly efficient synthesis of 2,4,5-trisubstituted imidazoles by a condensation reaction of benzil or benzoin, aldehydes and ammonium
acetate in the presence of urea/hydrogen peroxide (UHP) as a mild and efficient molecular catalyst in refluxing ethanol is described. The present methodology
offers several advantages such as green protocol, inexpensive catalyst, high-to-excellent yields, and simple and easy work-up procedure.
Key words: Multicomponent reaction, imidazole, benzil, urea, hydrogen peroxide.
benign and green chemistry. Imidazoles are one of the most important five-
membered ring heteroaromatic nitrogen-bearing compounds that show a
broad range of pharmaceutical and industrial applications. Imidazole cores
are present in many compounds with pronounced biologic activities such as
angiotensin inhibitors [3], anti-inflammatory [4], glucagon antagonist [5],
antiviral [6], antimicrobial [7], fungicidal, and high cytotoxicity, which have
indicated them as new candidates in cancer therapy [8]. The structures of some
of the commercial imidazole-core drugs including Cimetidine (І), Trifenager
(Π) and Ketoconazole (Ш) are shown in Figure 1.
INTRODUCTION
Multicomponent reactions (MCRs) allow the assembly of complex
molecules in a one-pot process and show a facile execution, high atom-
economy and high selectivity. MCRs usually afford good-to-high yields,
deserve simple work-up procedure and are fundamentally different and more
efficient than classic two-component and stepwise reactions [1].
The chemistry of tri- and tetra-substituted 1H-imidazoles has been
reviewed recently [2]. In recent years, alkylated imidazoliums are substantially
used in ionic liquids that have been given a new approach to environmentally-
Figure 1. The structures of some of the commercial imidazole-core drugs.
This versatile applicability highlights the importance of access to
efficient synthetic routes to well-designed highly substituted imidazole
derivatives. A number of methods have been developed for the synthesis of
2,4,5-trisubstituted imidazoles. Some of these synthetic methods are associated
with one or more serious disadvantages such as tedious and complex work-up
and purification procedures, significant amounts of waste materials, occurrence
of side reactions, long reaction times, low yields and the use of expensive
reagents. Therefore, the development of simple, efficient, clean, high-yielding,
and environmentally friendly approaches using new catalysts for the synthesis
of highly substituted imidazoles is of prime importance.
In continuation of our interest in the application of new catalysts in MCRs
[9], herein, an efficient synthesis of highly substituted imidazoles 4 has been
developed by a condensation of benzil 1 or benzoin 2, various substituted
aldehydes 3 and ammonium acetate using urea/hydrogen peroxide (UHP)
as an efficient catalyst in refluxing ethanol under mild reaction conditions
in excellent yields (Scheme 1). As an important output of this work, UHP is
introduced as an efficient, inexpensive and mild homogenous catalyst in the
synthesis of substituted imidazoles.
Scheme 1. Synthesis of 2,4,5-trisubstituted imidazoles catalyzed by UHP.
variables affecting the reaction yield was carried out for the reaction of benzil or
benzoin, 4-chlorobenzaldehyde and NH4OAc (molar ratio: 1:1:4, respectively)
as a model reaction. The results are summarized in the Table 1.
RESULTS AND DISCUSSION
To find the optimum conditions, a systematic study considering different
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e-mail address: maleki@iust.ac.ir

J. Chil. Chem. Soc., 61, Nº 3 (2016)
Table 1. Optimization of the model reaction conditions.a
Catalyst loading (mol
Yieldb (%)
Benzil Benzoin
Entry
Solvent
Temp. (°C)
Time (h)
%)
1
2
-
-
r.t.
r.t.
24
24
10
7
-
-
-
EtOH
H2O
Trace Trace
Trace Trace
3
-
Reflux
Reflux
60/ultrasonic
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
120
4
-
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
-
35
30
51
57
79
95
80
40
56
20
19
40
45
70
90
69
31
49
5
-
8
6
1
4
7
2
4
8
5
4
9
10
20
10
10
2
10
11
12
3
2
5
a Reaction conditions: 4-chlorobenzaldehyde (1 mmol), benzil or benzoin (1 mmol), ammonium acetate (4 mmol), EtOH (3 mL) and UHP.
b The yields refer to the isolated product.
According to the results indicated in Table 1, the products were obtained
in higher yields in refluxing EtOH. By using H O as a solvent lower yield was
obtained in 10 mol% loading of UHP as an org2anic and water soluble catalyst.
It may be explained by the weakness of hydrogen bonding between urea and
hydrogen peroxide in the presence of H O.
A possible mechanism for the synthesis of imidazole derivatives 4a-n
in the presence of UHP is shown in Scheme 2. In both of the directions, the
UHP promotes the dissociation of ammonium acetate to ammonia is required
for the initial imine condensation. Then, UHP oxidizes benzoin to benzil. So,
the mechanism may proceed through two paths when benzoin was used as a
starting material. On the other hand, UHP has activated carbonyl groups for
nucleophilic attack through hydrogen bonding.
In order to optimize the reaction co2nditions, diverse imidazole derivatives
4a-n were prepared from the one-pot reaction of benzil 1 or benzoin 2, various
aldehyde 3 and ammonium acetate in the presence of a catalytic amount of
UHP (10 mol%) in refluxing EtOH. The results are summarized in Table 2.
Scheme 2. Suggested mechanism of the synthesis of 4a-n.
In summary, a rapid, highly efficient, one-pot and selective synthesis of
fully substituted imidazoles has been developed by the condensation reaction
of benzil or benzoin, various substituted aldehydes and ammonium acetate
in the presence of a catalytic amount of urea/hydrogen peroxide in refluxing
ethanol under mild reaction conditions in suitable times and good-to-excellent
yields.
The progress of the reaction was monitored by TLC. After completion of the
reaction, it was stopped and the crude product was isolated by filtration of the
reaction mixture and washing of the precipitate with H2O. Pure products 4a-n
were obtained via re-crystallization by EtOH.
Chemical characterization data of 4,5-diphenyl-2-p-tolyl-1H-
imidazole (4i)
Experimental section
MP: 231-233 °C; FT-IR (KBr, cm-1): 3033, 1600, 1496, 1446, 825, 767,
696; 1H NMR (500 MHz, CDCl3): δ (ppm); 2.39 (s, 3H), 7.23-7.74 (m, 12H),
7.78-7.79 (d, 2H), 9.64 (s, 1H); 13C NMR (125 MHz, CDCl3): δ (ppm); 21.8,
125.6, 127.59, 128.23, 129.0, 130.0, 139.2, 146.6.
General procedure for the synthesis of imidazole derivatives 4a-n
A mixture of benzil or benzoin (1.0 mmol), an aldehyde (1.0 mmol),
NH4OAc (4.0 mmol) and UHP (10 mol %) was carried out in refluxing EtOH.
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J. Chil. Chem. Soc., 61, Nº 3 (2016)
ACKNOWLEDGEMENTS
We are grateful for the financial support from the Research Council of the Iran University of Science and Technology, Tehran, Iran.
Supplementary data
Supplementary data associated with this article can be found, in the online version.
Table 2. Synthesis of imidazole derivatives 4a-n in the presence of UHP. a
Yield b (%)
Entry
Product
Time (h)
Melting point c (°C)
265-267
Benzil
Benzoin
N
Cl
1
2
95
90
N
H
a
4
N
2
4
88
78
214-216
N
H
4b
N
NO2
3
4
5
2
3
2
92
88
95
88
79
92
255-257
187-189
265-266
N
H
c
4
N
N
H
Cl
4d
N
N
H
NO2
e
4
N
e
OM
6
7
8
3
4
85
88
82
80
79
76
226-229
249-251
264-265
N
H
4f
N
e
NM
2
N
H
4
g
N
3.5
N
H
4h
S
N
e
M
9
3.5
89
80
231-233
N
H
4i
O2N
N
10
11
12
13
14
3
4.5
4
88
89
90
88
87
80
83
85
76
79
230-231
233-234
256-258
174-176
164-165
N
H
4
j
N
OH
N
H
4k
N
N
H
OH
4l
N
Cl
4
N
H
Cl
m
4
e
M
O
N
e
OM
4.5
N
H
n
4
a Reaction conditions: benzoin or benzil (1 mmol), aldehyde (1 mmol), ammonium acetate (4 mmol), EtOH (3 mL, reflux) and UHP (10 mol%).
b The yields refer to isolated product.
c All compounds were known and their structures were established from their spectral data and melting points as compared with literature values.
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J. Chil. Chem. Soc., 61, Nº 3 (2016)
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