1710 Dhawale et al.
Asian J. Chem.
used as CB1 cannabinoid receptor antagonists [13] and
glucagon receptors [14], antibacterial and antitumor agents
[15] and modulators of P-glycoprotein (P-gp)-mediated
multidrug resistance (MDR) [16] and also as pesticides [17].
Recent advances in green chemistry and organometallic
catalysis has extended the application of imidazoles as ionic
liquids [18] and N-heterocyclic carbenes [19]. Due to their
wide range of pharmacological activity, industrial and synthetic
applications, a number of methods [20-22] have been reported
for the synthesis of imidazoles and its derivatives. These
methods include the coupling of benzil and aromatic aldehydes.
We report here a simple, mild, green and efficient method for
synthesis of imidazoles in presence of natural organic acids
under solvent free condition by using microwave heating.
RESULTS AND DISCUSSION
Screening of naturally occurring organic acid promoters:
The screening of the catalysts, for synthesis of imidazoles
derivatives 1a, 2a and 3a was selected as a model reaction.
Initially, 1a (0.5 g, 2.378 mmol), 2a (0.25 g, 2.378 mmol), 3a
(0.22 g, 2.85 mmol) and citric acid (0.45 g, 2.378 mmol)
(Table-1, entry 1), were heated either in an oil bath, preheated
at 160 °C for 20 min or in microwave reactor for 10 min to
yield imidazoles 4a (76 % and 85 % respectively) (Table-1,
entry 1). The results with other organic acids indicate that all
the acids act as effective promoters to give imidazoles 4a in
good to excellent yields (Table-1, entry 2-7). Microwave irra-
diation reduces time (10 min) and improves the yields as com-
pared to conventional heating. In this screening study citric
acid (Table-1, entry 1), malonic acid (Table-1, entry 4) and
oxalic acid (Table-1, entry 5) turned out to be better catalysts
than fumaric acid (Table-1, entry 2), succinic acid (Table-1,
entry 7) and tartaric acid (Table-1, entry 6), whereas best results
were obtained by using malic acid (Table-1, entry 3).
EXPERIMENTAL
Reactions were performed in oven-dried glassware and
monitored by TLC silica gel plates (60 F254) which were
visualized by UV and KMnO4 solution. All the solvents and
reagents were used as obtained from commercial source.
Melting points (uncorrected) were determined in open capillary
tubes using paraffin oil bath. All the microwave-assisted
reactions were performed in Discover Lab Met microwave
system (CEM Corporation, USA) at the specified temperature
using the standard mode of operation. Standard 1H NMR and
13C NMR were recorded on a Varian mercury spectrometer at
300 and 75 MHz respectively in CDCl3 solution and with TMS
as an internal standard. Infrared spectra were recorded on
Perkin Elmer Model 1600 series FTIR instrument.
Standardization of reaction condition and preparation
of compounds: For standardization of imidazoles derivatives,
initially 1a (0.5 g, 2.378 mmol), 2a (0.25 g, 2.378 mmol), 3a
(0.22 g, 2.85 mmol) were heated either in an oil bath, preheated
at 140 °C for 20 min or in microwave reactor for 10 min For
this, we first examined the synthesis of 2,4,5-triphenyl-1H-
imidazole 4a in the presence of 0.1 (0.03 g, 0.238 mmol)
equivalent of malic acid. While performing conventional
heating, after 60 min of reaction time, the desired product 4a
was formed in a low amount (Table-2, entry 1). Using 0.2
(0.06 g, 0.47 mmol) and 0.4 (0.13 g, 0.95 mmol) equivalent
of malic acid afforded the preferred product with moderate
yields (Table-2, entries 2 and 3), while using 0.6 (0.19 g, 1.42
mmol) and 0.8 (0.25 g, 1.90 mmol) equivalent of malic acid
there was slight but not considerable increase in the yield of
the product (Table-3, entry 4 and 5). To see the effect of amount
of catalyst on reaction yield, we used 1.2 (0.38 g, 2.85 mmol)
equivalents of malic acid under same reaction condition. But
we were surprise to found that there was no further improve-
ment in the reaction.
General procedure for synthesis of imidazoles: The
mixture of aromatic aldehyde 1a (0.5 mL, 4.904 mmol), urea
2 (0.30 g, 4.904 mmol), ethyl acetoacetate 3 (0.62 mL, 4.904
mmol) and malic acid (0.657g, 4.904 mmol) was heated either
in an oil bath, preheated at 140 °C for 10 min or in microwave
reactor for 5 min After completion of reaction (TLC check),
the reaction mixture was allowed to cool at room temperature
and water (10 mL) was added. The solid obtained on stirring
was filtered and washed with water. Crude product was purified
by recrystallization using aqueous ethanol.
TABLE-1
SCREENING OF CATALYSTS FOR IMIDAZOLES SYNTHESIS UNDER SOLVENT FREE CONDITIONa
H
O
O
Ph
Ph
N
Ph
+
Organic acid
NH4OAc
Ph
Cl
O
N
H
Cl
2a
3a
1a
4a
Temperatureb
(°C)
Conventional heating
Time (min)
Yieldc (%)
Microwave heating
Entry
Acid
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
Citric
160
290
140
140
110
190
180
20
20
20
20
20
20
20
76
65
78
80
77
68
75
10
10
10
10
10
10
10
85
75
89
83
86
74
79
Fumaric
Malic
Malonic
Oxalic
Succinic
Tartaric
aReagents: 1a (0.5 g, 2.378 mmol), 2a (0.25 g, 2.378 mmol), 3a (0.22 g, 2.85mmol), acid (1.0 eq.); bHeating was done in preheated oil bath or in
microwave reactor; c Isolated yields.
Dhawale, Kiran D.
