A practical and green approach toward synthesis of 2,4,5-trisubstituted imidazoles without adding catalyst

Article abstract of DOI:10.1080/10826068.2010.525418

A simple, efficient, and inexpensive procedure has been developed for the synthesis of 2,4,5-triaryl imidazoles by a three-component, one-pot condensation of benzil, aldehydes, and ammonium acetate in refluxing ethanol without adding catalyst. The catalyzed-by-itself approach shows a new direction in green synthesis of the title products. Copyright Taylor & Francis Group, LLC.

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A PRACTICAL AND GREEN APPROACH
TOWARD SYNTHESIS OF 2,4,5-
TRISUBSTITUTED IMIDAZOLES WITHOUT
ADDING CATALYST
a
a
b
Min Wang , Jingjing Gao & Zhiguo Song
a
College of Chemistry and Chemical Engineering, Bohai University,
Jinzhou, Liaoning, P.R. China
b
Center for Science & Technology Experiment, Bohai University,
Jinzhou, Liaoning, P.R. China
Version of record first published: 24 Nov 2010.
To cite this article: Min Wang , Jingjing Gao & Zhiguo Song (2010): A PRACTICAL AND GREEN
APPROACH TOWARD SYNTHESIS OF 2,4,5-TRISUBSTITUTED IMIDAZOLES WITHOUT ADDING CATALYST,
Preparative Biochemistry and Biotechnology, 40:4, 347-353
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Preparative Biochemistry & Biotechnology, 40:347–353, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 1082-6068 print/1532-2297 online
DOI: 10.1080/10826068.2010.525418
A PRACTICAL AND GREEN APPROACH TOWARD
SYNTHESIS OF 2,4,5-TRISUBSTITUTED IMIDAZOLES
WITHOUT ADDING CATALYST
1
Min Wang, Jingjing Gao, and Zhiguo Song
1
2
1
College of Chemistry and Chemical Engineering, Bohai University,
Jinzhou, Liaoning, P.R. China
2
Center for Science & Technology Experiment, Bohai University,
Jinzhou, Liaoning, P.R. China
&
A simple, efficient, and inexpensive procedure has been developed for the synthesis of
2,4,5-triaryl imidazoles by a three-component, one-pot condensation of benzil, aldehydes, and
ammonium acetate in refluxing ethanol without adding catalyst. The ‘‘catalyzed-by-itself’’
approach shows a new direction in green synthesis of the title products.
Keywords catalyzed by itself, multicomponent reaction, one-pot synthesis, 2,4,5-
trisubstituted imidazoles
INTRODUCTION
Imidazole and their derivatives are one of the most important hetero-
cyclic compounds, which possess diverse biological and pharmacological
[
1,2]
properties.
Substituted imidazoles can be used as biocides, in particular,
[3]
herbicides, fungicides, and growth regulators,
receptor antagonist, glucagon receptor antagonist, and inhibitors of
potent angiotensin II
[
4]
[5]
[6]
interleukin (IL)-1 and 5-lipoxygenase. Therefore, the synthesis of these
imidazole derivatives has attracted much attention in organic synthesis.
In 1882, Radziszewski and Japp and Robinson simultaneously pro-
posed that 2,4,5-triphenyl imidazole 3a (Lophine) could be synthesized by
the reaction of benzil with aryl aldehyde in alcoholic ammonia solution.
The procedure was modified later by refluxing benzil with substituted alde-
[
7]
[8]
[9]
hydes and ammonium acetate in glacial acetic acid. Recently, numerous
methods for the synthesis of this class of compounds were reported by the
Address correspondence to Min Wang, College of Chemistry and Chemical Engineering, Bohai
University, Jinzhou, Liaoning 121000, P. R. China. E-mail: minwangszg@yahoo.com.cn

348
M. Wang et al.
SCHEME 1 General synthetic scheme of trisubstituted imidazoles.
condensation of benzil, aryl aldehyde, and ammonium acetate in the pres-
[
10–12]
[13–19]
[20,21]
ence of protonic acid,
Lewis acids,
and ionic liquids.
How-
ever, all of these methods have problems such as harsh reaction conditions,
low yields, long reaction time, and large excess of ammonium acetate (10
equivalents). Additionally, a majority of synthetic procedures also involve
[
22–26]
[27]
the use of microwave
and ultrasound.
These methods promote
the condensation efficiently. However, the use of high temperature or
expensive instruments limits their application. Obviously, many of the
reported methods are not at all acceptable in the context of green syn-
thesis. Hence, as a part of our program toward green chemistry, we have
discovered that trisubstituted imidazoles 3(a–o) could be synthesized by
the three-component one-pot condensation of benzil 1, aldehyde 2(a–o),
and ammonium acetate in refluxing ethanol, requiring no catalyst, which
afforded the corresponding products in very good yields and purity
(
Scheme 1).
EXPERIMENTAL
Melting points were determined using RY-1 micro-melting-point appar-
atus and were uncorrected. Infrared spectra were recorded on a Scimitar
1
2
000 series Fourier transform instrument (VARIAN). H-Nuclear magnetic
resonance (NMR) spectra were recorded on Bruker ARX-300 spectrometer
in dimethyl sulfoxide (DMSO)-d using trimethylsilyl (TMS) as internal
6
standard. Mass spectra were obtained with an Agilent 1100 series liquid
chromatography=massselective detector (LC-MSD) VL ESI instrument.
Elemental analyses were carried out on an EA 2400II elemental analyzer
(
Perkin-Elmer).
General Procedure for the Synthesis of 2,4,5-Trisubstituted
Imidazoles 3(a-o)
A mixture of benzil 1 (10 mmol, 2.143 g), aldehyde 2 (10 mmol), and
NH OAc (60 mmol, 4.672 g) was stirred and refluxed in 10 mL ethanol.
4

Synthesis of 2,4,5-Trisubstituted Imidazoles
349
After completion of the reaction (monitored by TLC), the mixture was
cooled to room temperature and poured into cold water. The resulting
solid was filtered under suction and washed thoroughly with H O to give
2
pure product (single spot on TLC). They were further purified by recrystal-
lization in 7:1 (v:v) ethanol-water mixture. All the products (3a–3o) were
1
fully characterized by melting point (mp), infrared (IR), H-NMR, mass
spectroscopic, and elemental analysis. They have been identified by
1
the comparison with the reported spectral data. The H-NMR, IR, mass
spectroscopic, and elemental analysis data for the new compound are
presented next.
2-(2-Nitrophenyl)-4,5-diphenylimidazole (3k): Yellow solid. IR (KBr):
3
458 (NH), 1584 (C ¼ N), 1507 (C ¼ C), 1481 (C ¼ C), 1525 (NO ), 1352
2
ꢀ
1
1
(
v
), 852 (Ar-H), 777 (Ar-H), 694 cm
(Ar-H). H NMR (300 MHz,
C-N
DMSO-d ) d: 7.23–7.52 (m, 10H, 2C H ), 7.61–7.66 (t, 1H, J ¼ 7.5 Hz,
6
6
5
C H ), 7.76–7.81 (t, 1H, J ¼ 7.5 Hz, C H ), 7.92–7.94 (d, 1H, J ¼ 7.8 Hz,
6
4
6
4
C H ), 7.99–8.01 (d, 1H, J ¼ 7.5 Hz, C H ), 12.97 (s, 1H, NH). ESI-MS
6
4
6
4
þ
(
1
m=z): 342 (M þ 1). Anal. calcd. for C H N O : C, 73.89; H, 4.43; N,
21
15
3
2
2.31. Found: C, 73.92; H, 4.43; N, 12.30%.
RESULTS AND DISCUSSION
In order to achieve the most appropriate reaction conditions, a model
reaction of benzil, benzaldehyde, and ammonium acetate was carried out
under different reaction conditions (Table 1). The best result was obtained
with 1:1:6 molar ratio of benzil, benzaldehyde, and ammonium acetate in
10 mL EtOH at reflux temperature (Entry 5). It can be seen that the excess
amount of NH OAc would promote the reaction (Entries 1–5). Only EtOH
4
a
TABLE 1. Optimization of Reaction Conditions for Synthesis of 2,4,5-triphenyl Imidazole
Amount of
Isolated
Entry
n
benzil:nbenzaldehyde:nNH OAc
Solvent
solvent (mL)
yield (%)
4
1
2
3
4
5
6
7
8
9
1:1:2
1:1:3
1:1:4
1:1:5
1:1:6
1:1:6
1:1:6
1:1:6
1:1:6
1:1:6
1:1:6
EtOH
EtOH
EtOH
EtOH
EtOH
—
10
10
10
10
10
0
48
62
78
89
96
0
93
86
74
31
0
EtOH
EtOH
EtOH
5
15
20
10
10
1
1
0
1
2
EtOH-H O (1=1)
2
H O
a
All reactions were carried out at reflux temperature for 1 hr.

350
M. Wang et al.
TABLE 2. Synthesis of Different Imidazoles Derivatives Without Catalyst
ꢁ
Mp ( C)
Time
(hr)
Product
(3)
Yield
(%)
Entry
R
Found
Reported
[
28]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
C
2-ClC
4-ClC
2,4-Cl
2-OCH
4-OCH
6
H
5
1
1
1
1
1
2
1
1
3
3
1
1
3
1
6
3a
3b
3c
3d
3e
3f
3 g
3 h
3i
3j
3k
3 l
3 m
3n
3o
96
95
98
91
98
97
96
90
78
81
65
96
89
90
92
273–274
187–188
260–262
173–174
212–213
221–223
229–230
203–205
264–266
258–261
231–233
311–313
194–196
256–258
196–198
272–273
[
16]
6
H
H
4
4
188
262–263
[
28]
6
[
29]
2
C
6
H
4
178
[
[
[
[
15]
3
3
C
C
6
H
4
4
212–214
222–224
230–231
203–205
28]
30]
28]
6
H
4-CH
3
C
6
H
4
2-OHC
3-OHC
4-OHC
2-NO
3-NO
4-NO
6
6
6
H
H
H
4
[
29]
4
4
259
[
28]
1
1
1
1
1
1
260–261
—
2
2
2
C
C
C
6
6
6
H
H
H
4
[31]
4
313–315
[
21]
4
196.8
[
29]
4-OH-3-OCH
2-Furyl
3
C
6
H
3
243
199–202
[30]
and H O, the relatively benign organic solvent and clean solvent, were
2
investigated to standardize the reaction condition (Entries 5–11). It seems
that EtOH is a much better solvent than all others tested. Minimum
amount of EtOH was used to facilitate the homogeneous stirring. More-
over, the solvent could be quantitatively recovered from the reaction
mixture and reused for successive reactions.
Several 2,4,5-trisubstituted imidazoles were successfully synthesized in
high yields (65–98%) by following our method (Table 2). The crude pro-
ducts obtained are of high purity (by TLC). Various functional groups such
as –Cl, -OCH , -CH , -OH, and -NO survived under the reaction con-
3
3
2
ditions. Substrates having -OH group in para and meta positions decreased
both the rate of reaction and the yields of products (Entries 9 and 10). It
is worth mentioning that aromatic aldehyde with nitro the strong
electron-withdrawing substituent gave the corresponding imidazoles in
moderate to high yields (Entries 11–13), which normally gave trace or even
[11–13]
no products in the previous methods.
In addition, the reactions of
benzil, aliphatic aldehydes (propionaldehyde and phenylacetaldehyde),
and ammonium acetate were also investigated; only a trace amount of
imidazoles was observed and could not be isolated.
A mechanism for this reaction can be postulated as shown in Scheme 2.
The first step in this reaction is the nucleophilic attack of the nitrogen of
ammonia obtained from NH OAc on the activated carbonyl group, which
4
results the formation of aryl aldimine 4 and a-imino ketone 5. Then the
intermediate 6 was formed by the nucleophilic attack of the in
situ-generated imine 5 to carbonyl of aryl aldimine 4 in the presence of

Synthesis of 2,4,5-Trisubstituted Imidazoles
351
SCHEME 2 A proposed mechanism for the formation of trisubstituted imidazoles.
HOAc, followed by cyclization 7 and dehydration 8, which affords the
corresponding trisubstituted imidazoles 3. This reaction was catalyzed by
itself and does not need an added catalyst.
CONCLUSIONS
In conclusion, we have developed a simple and efficient synthesis of
2,4,5-trisubstituted imidazoles via a one-pot, three-component conden-
sation of benzil, aldehydes, and ammonium acetate in refluxing ethanol
without adding catalyst. After reaction, the solvent could be recovered
quantitatively and could be reused for successive reactions. The method
is environmentally benign. We believe our procedure will find important
application in the synthesis of imidazole and their derivatives.
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ꢂ 6H
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2