Microwave-assisted solid-phase synthesis of 2,4,5-triaryl imidazoles in solventless system: An improved protocol

Article abstract of DOI:10.1002/hc.20237

The solventless microwave-assisted synthesis of 2,4,5-triaryl imidazoles from 1,2-diphenylethandione or 2-hydroxy-1,2-diphenylethanone in the presence of NH₄OAc/NaHSO₄ supported onto silica gel under microwave irradiation is reported.

Full text of DOI:10.1002/hc.20237

Heteroatom Chemistry
Volume 17, Number 7, 2006
M
icrowave-Assisted Solid-Phase Synthesis of
2
,4,5-Triaryl Imidazoles in Solventless System:
An Improved Protocol
Hossein A. Oskooie, Zahra Alimohammadi, and Majid M. Heravi
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
Received 9 August 2005; revised 14 January 2006
Microwave-assisted synthesis of the substituted
ABSTRACT: The solventless microwave-assisted
imidazoles on a solid support under solvent-free con-
ditions in a three-component reaction [6] and effi-
cient synthesis of imidazoles from aldehydes, 1,2-
diketones, and ammonium acetate in acetic acid
have been reported [7].
synthesis of 2,4,5-triaryl imidazoles from 1,2-diphen-
ylethandione or 2-hydroxy-1,2-diphenylethanone in
the presence of NH
silica gel under microwave irradiation is reported.
2006 Wiley Periodicals, Inc. Heteroatom Chem
7:699–702, 2006; Published online in Wiley InterScience
www.interscience.wiley.com). DOI 10.1002/hc.20237
4
OAc/NaHSO
4
supported onto
ꢀ
C
1
(
Khmelnitsky and co-worker [6a] were tested
several support for synthesis of 2,4,5-trisubstituted
imidazoles by a three-component reaction of 1,2-
diketones, aldehydes, and ammonium acetate,
which makes use of various supports such as acidic,
basic, and neutral alumina, bentonite, montmoril-
lonite K10, montmorillonite KSF, silica gel, and
florisil. It was found that the addition of a small
amount (several drops) of acetic acid was required
for the reaction to occur on neutral and basic sup-
ports, such as basic and neutral alumina, silica gel,
or florisil. On the other hand, when acidic supports
were used (bentonite, montmorillonite K10, mont-
morillonite KSF, or acidic alumina), the reaction was
successful without additional acid. No doubt, these
methods are good in terms of reactivity; however,
these methods suffer from the drawbacks of longer
reaction time and moderate yield. Among the re-
ported methods, the use of acidic alumina deserves
mention here as a convenient laboratory method for
the synthesis of these compounds in moderate to
high yields, but on longer time.
INTRODUCTION
The synthesis, reactions, and biological properties
of substituted imidazole constitute a significant part
of modern heterocyclic chemistry [1]. Compounds
with the imidazole ring system have many phar-
macological properties and play important roles in
biochemical processes [2]. Many of the substituted
diaryl imidazoles are known as inhibitors of P38
MAP kinase [3].
Research into imidazole chemistry has been
quite comprehensive, single-site functionalizations
and substitution as well as various annulation strate-
gies have been well documented [4]. Recently, the in-
terest in this heterocyclic system has been widened
as it is a precursor to a class of compounds, called
room temperature ionic liquids [5].
Recently, NaHSO
4
–SiO , as an inexpensive and
2
eco-friendly catalyst, has been effectively utilized
in organic synthesis as an acid catalyst or an ac-
celerator, which is easily separable from the reac-
tion products [8]. Among the various heterogeneous
Correspondence to: Majid M. Heravi; e-mail: mmh1331@yahoo.
com.
Contract grant sponsor: Azzhra University, Tehran, Iran.
ꢀ
c 2006 Wiley Periodicals, Inc.
6
99

7
00 Oskooie, Alimohammadi, and Heravi
SCHEME 1
catalysts, particularly, silica gel impregnated with
sodium bisulfate has advantages of low cost, ease
of preparation [8a], and catalyst recycling.
appropriate aldehyde, evaporating the solvent, and
heating the solid residue in a microwave oven
(Scheme 1). The results were excellent in terms
of yields and product purity in the presence of
In continuation of our previous work on the
applications of solid supports for development
of new synthetic methodologies [9], and hetero-
cyclic compounds containing nitrogen [10], and
due to the resultant pharmacological interest in
compounds that belong to the imidazole family,
in this paper we report the microwave-assisted
solvent-free synthesis of 2,4,5-trisubstituted imida-
NH
4
OAc/NaHSO
4
–SiO
2
as shown in Table 2.
Under the same conditions, this approach can be
repeated for synthesis of these imidazoles 3a–f when
2-hydroxy-1,2-diphenylethanone 4 is used as a start-
ing material. Thus, 2-hydroxy-1,2-diphenylethanone
effectively participated in the condensation with
aldehyde and ammonium acetate to give the corre-
sponding 2,4,5-substituted imidazoles 3a–f (Table 1).
The identity of imidazoles 3a–e was confirmed
by analytical comparison (melting points and mass
spectra) with authentic standards prepared accord-
ing to the established procedure [12]. The struc-
ture of 3f was confirmed by NMR and mass spectral
analysis.
zoles using NH
gel (Scheme 1).
4
OAc/NaHSO supported onto silica
4
Solvent-free reactions using organic or inorganic
solid media have been known for some time, and
the environmentally friendly goal of making organic
compounds without using solvents has come several
steps closer in recent years [11].
In summary, microwave-assisted solvent-free
(
under conditions of the so-called ‘Green Chemistry’)
RESULTS AND DISCUSSIONS
reactions were employed to synthesize substituted
imidazole derivatives. The method not only offers
substantial improvement in yield over conventional
heating but also eliminates the use of hazardous sol-
vents and excess of expensive acidic catalyst. Ad-
vantages of this method include the fact that it is
environmentally benign, being an economical pro-
cedure, has a short reaction times and the simplicity
of the performance with nonaqueous work-up. This
method not only affords the products in excellent
yields but also avoids the problems associated with
catalyst cost, handling, safety, and pollution. This
catalyst can act as eco-friendly for a variety of or-
ganic transformations, nonvolatile, recyclable, non-
explosive, easy to handle, and thermally robust.
The results were excellent in terms of yields and
product purity in the presence of NaHSO
while with NaHSO in pure form only 60% yield was
obtained after 6 min. On the other hand, when the
silica gel is employed as support in lieu of NaHSO
SiO , the reaction was not successful.
Comparison of different supports showed that
NaHSO –SiO was the most suitable support for the
4
–SiO ,
2
4
4
–
2
4
2
synthesis of 3a–f and, therefore, it was used in all
subsequent experiments (Table 1).
Generally, the synthetic procedure involves im-
pregnating the mixture of solid support, NaHSO
4
–
SiO , and ammonium acetate (ammonia source)
2
with dichloromethane solution of benzil and
EXPERIMENTAL
TABLE 1 Comparison of Different Conditions on Synthesis
of 3a
Melting points were measured on an Electrother-
mal 9100 apparatus and are uncorrected. IR spectra
were measured on a Shimadzu IR-470 spectropho-
Conditions
Time
Yield (%)
1
13
SiO (MW)
6 min
6 min
6 min
2 h
25
60
90
40
tometer. H NMR and C NMR spectra were deter-
mined on Bruker 300 DRX AVNCE instrument at 300
and 75 MHz, respectively. Elemental analyses were
performed using a Heraeus CHN-O-Rapid analyzer.
2
NaHSO (MW)
4
NaHSO –SiO (MW)
4
2
NaHSO –SiO (reflux in CH CN)
4
2
3
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Assisted Solid-Phase Synthesis of 2,4,5-Triaryl Imidazoles in Solventless System 701
TABLE 2 Synthesis of 2,4,5-Triaryl Imidazoles on Solid Support NH OAc/NaHSO –SiO
2
4
4
◦
◦
Entry
1/4
Time (min)
Product (3a–f)
Yield (%)
M.p. ( C)
Literature m.p. ( C)
1
6
3a
90
275–276
275 [12a]
2
3
4
5
6
7
8
9
5
6
3b
3c
3d
3e
3f
93
91
92
84
85
89
92
90
93
83
85
227–229
258–260
226–228
235–238
313–315
275–276
227–229
258–260
226–228
235–238
313–315
233 [12b]
261–263 [12c]
230–232 [12c]
240 [12b]
–
6
8
7
8
3a
3b
3c
3d
3e
3f
275 [12a]
233 [12b]
261–263 [12c]
230–32 [12c]
240 [12b]
–
8
8
1
1
1
0
1
2
8
10
9
General Procedure
In a typical reaction, a mixture of NaHSO
9.3 g) and ammonium acetate (4.4 g) was ground
in a mortar until a fine powder was formed. A so-
lution of 0.5 mmol of 1,2-dicarbonyl compound and
was evaporated under reduced pressure. The result-
ing solid residue was purified by recrystallization
from acetone–water (15:1 v/v) for 3a–e or ethanol
for 3f.
4
–SiO
2
(
◦
−1
0.5 mmol of aldehyde in 2 mL of methylene chloride
3f. M.p. 313–315 C; IR (KBr) (ν , cm ):
max
1
was added to 1 g of the NaHSO –SiO /ammonium
4
2
3415, 3050, 1535, 1517, 1344; H NMR (DMSO-d ,
6
acetate mixture in a 20 mL glass vial. The solvent
was allowed to evaporate and the dry residue was ir-
radiated in a domestic microwave oven at 600 W for
500 MHz) δ : 7.34–8.95 (14H, m, Harom), 12.99 (1H,
H
1
3
bs, NH); C NMR (DMSO-d , 75 MHz) δ : 119.85,
6
C
123.07, 127.63, 128.84, 129.69, 129.98, 130.89,
131.63, 132.26, 135.17, 138.18, 143.83, 148.80
6
–9 min in the open vial. The contents were cooled
to room temperature and mixed thoroughly with 3 ×
0 mL of acetone. The solid inorganic material was
+
(Carom); MS (m/z, %): 341 (M , 80), 294 (30), 190
1
(35), 89 (75). Anal. Calcd for C H N O : C, 73.89;
2
1
15
3
2
filtered off. After separation of the solid, the solvent
H, 4.43; N, 12.31. Found: C, 73.70; H, 4.40; N, 12.25.
Heteroatom Chemistry DOI 10.1002/hc

7
02 Oskooie, Alimohammadi, and Heravi
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