Ultrasound assisted one pot synthesis of imidazole derivatives using diethyl bromophosphate as an oxidant

Article abstract of DOI:10.1016/j.ultsonch.2011.05.009

A one pot, three-component condensation of benzoin/benzyl, an aldehyde, and ammonium acetate using diethyl bromophosphate as a mild oxidant is achieved to form trisubstituted imidazole compounds. Under ultrasound irradiation, a smooth condensation occurs to get the 2, 4, 5-triaryl-1H-imidazole compounds in good to excellent yields. The study explores the scope and limitation of diethyl bromophosphate as an oxidant and suggests advantages, viz., simplicity of operation, reduction in time, and an increase in product yields.

Full text of DOI:10.1016/j.ultsonch.2011.05.009

Ultrasonics Sonochemistry 19 (2012) 94–96
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound assisted one pot synthesis of imidazole derivatives
using diethyl bromophosphate as an oxidant
a,
⇑
a
b
a
a
Deepak Nagargoje , Priyanka Mandhane , Savita Shingote , Pravin Badadhe , Charansingh Gill
a
Dept. of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
National Chemical Laboratory, Pune 411 007, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A one pot, three-component condensation of benzoin/benzyl, an aldehyde, and ammonium acetate using
diethyl bromophosphate as a mild oxidant is achieved to form trisubstituted imidazole compounds.
Under ultrasound irradiation, a smooth condensation occurs to get the 2, 4, 5-triaryl-1H-imidazole com-
pounds in good to excellent yields. The study explores the scope and limitation of diethyl bromophos-
phate as an oxidant and suggests advantages, viz., simplicity of operation, reduction in time, and an
increase in product yields.
Received 23 January 2011
Received in revised form 14 May 2011
Accepted 14 May 2011
Available online 19 May 2011
Keywords:
Diethyl bromophosphate (DEP)
Imidazole
Ó 2011 Elsevier B.V. All rights reserved.
Ultrasound
One pot synthesis
1
. Introduction
Imidazole and benzimidazole molecules are important sub-
every method has its own inadequacies, viz., prolonged reaction
time, excess heating, tedious and cumbersome work-up proce-
dures and the use of expensive lanthanide salts. Thus, there is am-
ple scope to develop an efficient and convenient method to
construct these scaffolds.
During the last three decades, ultrasound-accelerated organic
chemical reactions have been increasingly developed by research-
ers across the globe for the synthesis of organic molecules. Ultra-
sound irradiation offers an alternative energy source for organic
reactions which are ordinarily accomplished by heating. Ultra-
sound-assisted reactions proceed by the formation, growth and
collapse of acoustic bubbles in the reaction medium. These directly
help in shortening the time span of reactions and increasing the
yield of products. Many homogeneous and heterogeneous as well
as transition metal-catalyzed organic reactions have been con-
ducted efficiently by sonication.
structures in a number of molecules which exhibit an array of bio-
logic and pharmacological activities. The imidazole ring system is
an important constituent of numerous natural products and
medicinally important compounds, such as Cimetidine [1], which
acts as antiulcerative agent. Omeprazole [2] a proton pump inhib-
itor, and the benzodiazepine antagonist flumazenil [3]. A platelet
coagulation drug in animal and human beings, trifenagrel [4], is a
2
, 4, 5 trisubstituted aryl-1H-imidazole derivative.
The development of synthetic protocols for imidazole deriva-
tives has been a subject of concern since the 19th century. Radi-
ziszewski and Japp independently reported a classical method in
early 1882 to obtain 2, 4, 5 triphenyl imidazoles by condensing
1
, 2 dicarbonyl compounds with different aldehydes and ammonia
in acidic medium [5,6]. Afterwards, several new modified proce-
dures were developed over the past two centuries for the synthesis
of these biologically important scaffolds starting from benzyl/ben-
zoin, aldehydes and ammonium acetate. These includes acidic, ba-
2
. Experimental
2.1. Apparatus and analysis
sic and Lewis acid catalysts like AcOH [7], acidic Al
silicagel [9], sodium bisulfite [10], ZrCl [11], NiCl .6H
dine [13] and Yb(OTf) [14], and boric acid using ultrasound irradi-
2
O
3
[8], HY/
4
2
2
O [12], io-
The uncorrected M.P. of compounds were taken in an open cap-
3
illary in a paraffin bath and compared with those in the literature
values. IR spectra were recorded using a Perkin–Elmer FT spectro-
photometer with KBr discs. H NMR were recorded on a 200 MHz
ation [15] and potassium dihydrogen phosphate [16]. A very recent
report exploits the use of ionic liquids as an alternative to tradi-
tional procedures [17]. Although these methods were developed,
1
3
FT-NMR in CDCl as a solvent and TMS as an internal standard.
Mass spectra were recorded on a Micromass Quattro II using ESI
technique. GC analysis was carried on HP-6890 Instrument using
HP-1 column.
⇑
Corresponding author.
E-mail address: dnagargoje@gmail.com (D. Nagargoje).
1
350-4177/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2011.05.009

D. Nagargoje et al. / Ultrasonics Sonochemistry 19 (2012) 94–96
95
O
O
O
DEP
US, rt
N
OR
H
R
NH OAc
4
R
N
H
O
2
3
4
OH
1
Scheme 1.
2
.2. General procedure
Table 1
Optimization of molar ratios of reactants and oxidant in synthesis of 2, 4, 5,-triaryl-
H-imidazole.
1
To benzil/benzoin (1 mmol) and ammonium acetate (3 mmol)
which were dissolved in acetonitrile were added (1 mmol)
diethyl bromophosphate. This reaction mixture was then irradi-
ated under ultrasonication at room temperature. The progress of
the reaction was monitored using TLC. After completion of the
reaction, the solvent was evaporated. The reaction mixture
was quenched in water and neutralized by aqueous sodium
bicarbonate solution. The mixture was extracted with ethyl
acetate (3–10 ml) eluted over silica gel using ether–ethyl acetate
Sr.
No.
Molar ratio 1/2
NH OAc
Oxidant DEP
(mol)
Time
(min)
Yield
(%)
a
4
a
b
c
1:1:3
1:1:3
1:1:3
0.25
0.50
1
30
30
30
61
79
97
a
Isolated yield of products.
as eluting solvent.
Compound (3a): IR (KBr): v 3450, 3050, 1600, 1580 cm ; 1
À1
H
Table 2
Screening of solvent effect on model reaction.
a
NMR (200 MHz, CDCl
NH); EI-MS: m/z, 297 (M ).
Compound (3b): IR (KBr): v 3458, 1617, 1581 cm ; 1H NMR
200 MHz, CDCl ): d 7.5–7.65 (m, 10H, Ph), 7.42 (d, 1H, J = 10 Hz,
Ar), 7.33 (d, 1H, J = 10 Hz, Ar), 7.20 (t, 1H, J = 10 Hz, Ar), 7.10 (t,
3
): d 7.15–8.00 (m, 15H, Ph), 9.20 (s, br,
+
Yield (%)b
Entry
Solvent
Time (min)
À1
1
2
3
4
5
6
Ethanol
Methanol
DCM
DMF
THF
30
30
30
30
30
30
60
58
85
63
86
97
(
3
+
1
H, J = 10 Hz, Ar), 9.4 (s, br, NH); EI-MS: m/z 331 (M ).
Compound (3c): IR (KBr): v 3399, 1611, 1584 cm ; 1H NMR
À1
Acetonitrile
(
200 MHz, CDCl ): 7.10–7.60 (m, 10H, Ph), 7.35 (d, 2H,
3
d
a
J = 10 Hz, Ar), 7.85 (d, 2H, J = 10 Hz, Ar), 9.27(s, br, NH); EI-MS:
Reaction of benzil, benzaldehyde and ammonium acetate (1:1:3) in presence of
+
m/z, 331 (M ).
DEP (1 mol) under ultrasonic waves (45 KHz).
b
Compound (3d): IR (KBr): v 3450, 1600, 1585 cm ; 1H NMR
À1
Yields based on GC analysis after 30 min.
(
3 3
200 MHz, CDCl ): d 2.30 (s, CH ), 7.10–7.60 (m, 10H, Ph), 7.70
(
d, 2H, J = 10 Hz, Ar), 7.30 (d, 2H, J = 10 Hz, Ar), 9.19 (s, br, NH).
+
EI-MS: m/z, 311 (M ).
sound irradiation conditions, the condensation reaction occurs
very smoothly to afford the 2, 4, 5-triaryl-1H-imidazole products
(4) in more than 90% yield (Scheme 1).
3
. Results and discussion
To study the efficacy of diethyl bromophosphate, the ratios of
the reactants and catalyst were optimized. On optimization of cat-
alyst to substrate ratio, it was found that the molar ratio of 1:1:3:1
works well for all the reactions (Table 1). Different solvents were
also screened for the model reaction. Among the different solvents
screened, including ethanol, methanol, DCM, DMF, THF and aceto-
nitrile, only acetonitrile was found to be the solvent of choice un-
der ultrasound irradiation condition (Table 2). In order to gauge the
effect of different irradiation frequencies, the model reaction was
performed under three different frequencies of 35, 45 and
60 kHz. The product yield for these frequencies was 97%, 89% and
75% respectively. It seems that the lower frequency of ultrasound
irradiation can improve the yield of imidazole derivatives. These
results are consistence with the literature, because as the ultra-
sonic frequency is increased, the production of cavitation in liquids
In the past few years, our group has become interested in devel-
opment of new methods for the synthesis of numerous heterocy-
clic molecules by non-conventional means [18]. As part of our
ongoing research, herein we describe the synthesis of 2, 4, 5-tri-
aryl-1H-imidazole by condensing benzyl/benzoin, aldehyde and
ammonium acetate in the presence of diethyl bromophosphate
as a mild oxidant under ultrasound irradiation (Scheme 1). Diethyl
bromophosphate is used for oxidative cyclization reactions, and
few reports are available in the literature where it is used as an
important oxidant [19]. Its use as an oxidant for the condensation
of benzyl/benzoin, aldehyde and ammonium acetate has not been
explored until now. For this reason, the reaction of benzaldehyde
(
1), benzyl or benzoin (2) and ammonium acetate (3) was chosen
as a model reaction. By using diethyl bromophosphate under ultra-

9
6
D. Nagargoje et al. / Ultrasonics Sonochemistry 19 (2012) 94–96
Table 3
Syntheses of 2, 4, 5-triaryl-1H-imidazoles using DEP under ultrasonication at room temperature.
Entry
Aldehyde
Reaction time (min)
Yield (%)
Benzil
M. P. (°C)
Benzil
Benzoin
Benzoin
Found
Lit.
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
Benzaldehyde
40
35
30
45
35
30
40
45
35
25
45
35
50
45
50
65
70
50
80
60
40
35
50
45
95
96
95
92
98
93
96
98
90
97
94
97
93
91
94
90
94
94
93
97
92
95
91
95
275–276
195–197
262–264
230–232
233–234
215–217
232
260–261
269–270
191
276–277
195–196
260–262
231–232
227–228
219–220
232–233
257–258
268–270
190
o-Chlorobenzaldehyde
p-Chlorobenzaldehyde
p-Toluldehyde
4-Methoxy benzaldehyde
2,4-Dimethoxy benzaldehyde
4-Nitrobenzaldehyde
4-N, N-Dimethyl benzaldehyde
4-Hydroxy benzaldehyde
4-Fluorobenzaldehyde
Furfuraldehyde
j
k
i
201–202
261–263
199–201
260–261
2-Formyl thiophene
decreases [20]. From the results above, the optimum reaction
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irradiation for the synthesis of 2, 4, 5-triaryl-1H-imidazole deriva-
tives. The method offer several advantages, including a simple
experimental process, easy work up and improved yields under
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DRN thanks Council of Scientific and Industrial Research, New
Delhi for providing JRFship to him.