One-pot synthesis of 1,2,4,5-tetrasubstituted and 2,4,5-trisubstituted imidazoles by zinc oxide as efficient and reusable catalyst

Article abstract of DOI:10.1007/s00706-010-0428-8

ZnO is an efficient, readily available, and reusable catalyst for the one-pot synthesis of 1,2,4,5-tetrasubstituted and 2,4,5-trisubstituted imidazoles. This procedure is very simple and affords excellent yields.

Full text of DOI:10.1007/s00706-010-0428-8

Monatsh Chem (2011) 142:159–162
DOI 10.1007/s00706-010-0428-8
ORIGINAL PAPER
One-pot synthesis of 1,2,4,5-tetrasubstituted
and 2,4,5-trisubstituted imidazoles by zinc oxide
as efficient and reusable catalyst
•
Kiumars Bahrami Mohammad M. Khodaei
•
Akbar Nejati
Received: 3 August 2010 / Accepted: 18 November 2010 / Published online: 16 December 2010
Ó Springer-Verlag 2010
Abstract ZnO is an efficient, readily available, and
reusable catalyst for the one-pot synthesis of 1,2,4,5-tet-
rasubstituted and 2,4,5-trisubstituted imidazoles. This
procedure is very simple and affords excellent yields.
Because of their wide range of biological, industrial,
and synthetic applications, multisubstituted imidazoles
have recently received a great deal of attention. There
are numerous classical methods for the synthesis of
multisubstituted imidazoles [11–41]. Despite their tremen-
dous success, however, some of their drawbacks still remain.
For example, some of the catalysts employed are expensive,
toxic, complex, or unavailable and organic solvents are
always used. Hence the challenge for a sustainable envi-
ronment calls for the use of alternative procedures avoiding
the use of harmful solvents and catalysts.
Keywords Multicomponent reactions Á
Multisubstituted imidazoles Á Biological activity Á
Environmentally friendly procedure
Introduction
Zinc oxide, a very economical, safe, and easily available
Lewis acid catalyst, has been widely used in organic
transformations [42–46], but it has not been studied as a
catalyst in the synthesis of 1,2,4,5-tetrasubstituted imida-
zoles until now. In continuation of our work on solvent-free
conditions [47–50], we present here, for the first time, a
simple, mild, and efficient synthesis of 1,2,4,5-tetraaryl-
imidazoles in excellent yields using ZnO as an extremely
efficient and reusable catalyst (Scheme 1).
There has been a long-standing desire in preparative
chemistry to avoid wastage, to substitute benign chemicals
for toxic ones, and to use solvent-free reactions. Multi-
component reactions have proved to be notably successful
in generating products in a single synthetic operation [1, 2].
The development of new MCRs [3] and improvement of
known multicomponent reactions are an area of consider-
able current interest. One such reaction is the synthesis of
imidazoles. Multisubstituted imidazoles, an important class
of pharmaceutical compounds, exhibit a wide spectrum of
biological activity such as anti-inflammatory [4], anti-
allergic [5], antibacterial [6], antitumor [7], and analgesic
[8] activities. Furthermore, they act as inhibitors of p38
MAP kinase [9] and glucagon receptors [10].
Results and discussion
To optimize the reaction conditions, the reaction of benz-
aldehyde, aniline, benzil, and ammonium acetate was used
as a model reaction. Reactions at different temperatures
and various molar ratios of substrates in the presence of
ZnO showed that the best conditions were solvent-free at
110 °C and a molar ratio of aryl aldehyde/amine/benzil/
ammonium acetate/ZnO of 1:1:1:1:0.1. An increase in the
reaction temperature and time did not improve the yields
significantly. The results are depicted in Table 1.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-010-0428-8) contains supplementary
material, which is available to authorized users.
K. Bahrami (&) Á M. M. Khodaei Á A. Nejati
Department of Chemistry, Razi University,
67149-67346 Kermanshah, Iran
The reusability of the ZnO catalyst was also examined
under the optimized conditions, and the desired product
e-mail: kbahrami2@hotmail.com
123

160
K. Bahrami et al.
RNH2
2
Table 2 ZnO-catalyzed
imidazoles
synthesis
of
1,2,4,5-tetrasubstituted
N
N
Ph
Ph
O
O
Ph
Ph
ZnO
+
+
NH4OAc
Ar
Ph
Ph
O
+
O
O
N
Ph
Ph
110 o
C
R-NH2
+
Ar
+
NH4OAc
Ar
4
O
H
N
R
1
5a 5p
-
R
Ar
H
5a-5p
Entry
Amine
Aldehyde Product Yield (%)a
Ref.
M.p. (°C)
3
t (min)
NH2
CHO
Scheme 1
1
2
3
4
5a
5b
5c
5d
98 (20)
98 (20)
95 (25)
95 (30)
218–220 [29]
166 [30]
CHO
NH2
Table 1 Effect of increasing amount of ZnO on the preparation of
1,2,4,5-tetraarylimidazoles at different reaction temperatures
NH2
CHO
140 –151 [29]
139–141 [30]
Cl
Cl
NH2
Entry
ZnO (mmol)
T (°C)
Yield (%)a
CHO
CHO
NH2
NH2
5
6
7
8
5e
5f
97 (27)
90 (30)
95 (23)
99 (20)
163–164 [31]
1
2
3
4
5
6
0
110
90
Trace
Cl
Cl
Br
CHO
CHO
CHO
0.05
0.05
0.1
0.1
0.2
60
187
171–172 [32]
220 [32]
[32]
Cl
NH2
NH2
110
100
110
110
70
5g
5h
87
98, 95, 94b
Me
O2
N
CHO
CHO
CHO
CHO
NH2
9
5i
5j
5k
5l
95 (24)
94 (22)
94 (22)
99 (13)
134–136 [30]
98
HO
HO
Me
NH2
10
11
12
280
167
[31]
[31]
Reaction conditions The reactions were performed with benzaldehyde
(1 mmol), aniline (1 mmol), benzil (1 mmol), and ammonium acetate
(1 mmol) for 20 min under solvent-free conditions
NH2
NH2
188–190 [32]
168 [32]
a
Me
Cl
Me
Isolated yields
NH2
CHO
CHO
CHO
13
14
15
16
b
5m
5n
5o
95 (20)
98 (15)
98 (15)
98 (25)
Catalyst was reused three times
Me
NH2
NH2
159–161 [30]
151–152 [30]
161–162 [31]
MeO
Me2
N
was obtained in 98, 95, and 94% yields after one to three
runs, respectively (Table 1, entry 5).
NH2
CHO
5p
Me
The substrate scope of the reaction was then evaluated
by using a variety of structurally diverse aldehydes and
primary amines. The results obtained are illustrated in
Table 2.
The products were characterized by comparison of their spectroscopic
and physical data with authentic samples synthesized by reported
procedures
a
Isolated yields
Both aromatic aldehydes and primary amines could be
subjected successfully to this protocol. Aromatic aldehydes
carrying either electron-donating groups (such as N,N-
dimethylamino, methyl, hydroxy, and methoxy) or elec-
tron-withdrawing groups (such as nitro and halides) reacted
efficiently and gave excellent yields of 1,2,4,5-tetrasubsti-
tuted imidazoles. Steric effects did not influence the yield
significantly; for example, in the reaction of 2- and
4-chlorobenzaldehyde (Table 2, entries 4 and 5) the cor-
responding condensation products were obtained in 95 and
97% yields, respectively. Cyclohexylamine, an aliphatic
amine, produced excellent yield of the corresponding
imidazole (Table 2, entry 16). In general, the reactions
were clean and no side products were detected. With ali-
phatic aldehydes, for example hexanal and decanal, only
trace amounts of imidazoles were observed and could not
be isolated.
carbonyl group resulted in formation of intermediate
I. This intermediate in the presence of ZnO condenses
with benzil to form intermediate II, which in turn releases a
H2O molecule to form the tetrasubstituted imidazole
(Scheme 2).
The same reaction conditions were applied for the
synthesis of 2,4,5-trisubstituted imidazoles via the one-pot,
three-component condensation of benzil (1 mmol), an aryl
aldehyde (1 mmol), and ammonium acetate (2 mmol).
Aromatic aldehydes bearing electron-donating (Table 3,
entries 5–8) and electron-withdrawing (Table 3, entries
2–4) substituents undergo this reaction to furnish excellent
yields of 2,4,5-trisubstituted imidazoles in high purity.
Acid-sensitive aldehydes such as furfural worked well
without the formation of any side products, which are
normally observed either in the presence of protic or Lewis
acids (Table 3, entry 9). The limitations on the use of the
aldehydes were similar to those for the formation of tet-
rasubstituted imidazoles.
In accordance with the mechanism proposed by Srini-
vasan et al. [23], the ZnO catalyst increases the
electrophilicity of the carbonyl group of the aryl aldehyde.
Nucleophilic attack of the nitrogen atoms of ammonia,
obtained from NH4OAc, and aniline on the activated
As shown in Tables 2 and 3, aryl amines and ammonium
acetate undergo this reaction with benzil and aryl aldehydes
123

One-pot synthesis of 1,2,4,5-tetrasubstituted and 2,4,5-trisubstituted imidazoles
161
NH4OAc
ZnO
2 NH4OAc
ZnO
NH2
NH2
O
NH2
NH2
O
NH3
2 NH3
- H2O
H
N
H
H
+
- H2O
I
III
O
N
O
I
+
N
O
N
H
- H2O
III
+
OH
N H
-2 H2O
O
IV
II
[1,5]-H shift
- H2O
N
N
N
H
N
Scheme 3
Scheme 2
In conclusion, we have described a simple and efficient
method for the synthesis of 1,2,4,5- and 2,4,5-substituted
imidazoles using ZnO as a reusable catalyst. Excellent
yields, environmentally friendly procedure, short reaction
times, simple work-up procedure, and easy isolation and
recycling of the catalyst are some advantages of this
method. Hence, it is a useful addition to the existing
methods.
Table 3 ZnO-catalyzed synthesis of 2,4,5-trisubstituted imidazoles
Ph
Ph
Ph
O
O
N
O
+
Ar
+
2 NH4OAc
H
Ph
Ar
N
H
6a-6i
Entry
Aldehyde
CHO
Product
Yield (%)a
t (min)
Ref.
M.p. (°C)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
99 (15)
271–272
260 –262
241–244
264–266
261–262
226–228
221–224
256 –258
231–234
[29]
[33]
[33]
[29]
[29]
[33]
[29]
[34]
[41]
CHO
98 (23)
98 (20)
95 (25)
96 (15)
99 (14)
98 (15)
99 (15)
98 (20)
Cl
Experimental
CHO
Br
O2
N
CHO
CHO
Zinc oxide, ammonium acetate, amines, and all aldehydes
employed are commercial products (Merck) and were used
without further purification. Melting points were deter-
HO
Me
CHO
CHO
1
mined in a capillary tube. H NMR spectra were recorded
6g
6h
6i
MeO
CHO
on a Bruker 200 MHz NMR spectrometer using TMS as
internal standard.
Me2
N
CHO
O
General procedure for synthesis of 1,2,4,5-tetra-
substituted and 2,4,5-trisubstituted imidazoles
The products were characterized by comparison of their spectroscopic
and physical data with authentic samples synthesized by reported
procedures
a
Isolated yields
Benzil (1 mmol), amine (1 mmol), aryl aldehyde (1 mmol),
ammonium acetate (1 mmol), and ZnO (0.1 mmol) were
heated at 110 °C under stirring for the time indicated in
Table 2. The progress of the reaction was monitored by
TLC. After completion of the reaction, the mixture was
cooled to room temperature. Then, 15 cm3 ethanol was
added to the reaction mixture and it was stirred for 5 min at
80 °C. The reaction mixture was filtered to remove the
catalyst and the filtrate was poured into cold water. The solid
was filtered by suction to afford crude product. The crys-
talline pure tetrasubstituted imidazoles were obtained by
further recrystalization from acetone/water. An otherwise
identical procedure was employed for the synthesis of 2,4,5-
trisubstituted imidazoles by using benzil (1 mmol), aryl
in equal efficiency. For example, 1,2,4,5-tetraphenyl-1H-
imidazole was produced in 98% yield in 20 min (Table 2,
entry 1) and 2,4,5-triphenyl-1H-imidazole in 99% yield in
15 min (Table 3, entry 1).
In a similar manner, a plausible mechanism for the
synthesis of the trisubstituted imidazole is presented in
Scheme 3. As shown, the reaction of aryl aldehyde and
ammonium acetate in the presence of ZnO produces
intermediate III. This intermediate condenses with benzil
to form intermediate IV, which in turn rearranges itself to
the trisubstituted imidazole by a [1,5]-H shift.
123

162
K. Bahrami et al.
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Acknowledgments We are thankful to the Razi University
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