Facile One Pot Multi-Component Solvent-Free Synthesis of 2,4,5-Trisubstituted Imidazoles Using “Green” and Expeditious Ionic Liquid Catalyst under Microwave Irradiation

Article abstract of DOI:10.1134/S1070363218030234

Acetic acid functionalized poly(4-vinylpyridinium) bromide is a highly efficient and recyclable catalyst for the construction of 2,4,5-trisubstituted imidazole derivatives by a three-component condensation of benzyl with various aldehydes and ammonium acetate under solvent free conditions. The microwave initiated process leads to analytically pure compounds within 2–5 min. The advantages of this “green” methodology are cost-effectiveness, simple procedure, low energy consumption, no involvement of organic solvents, safe operation, clean reaction profile, high yields, and recyclability of the catalyst.

Full text of DOI:10.1134/S1070363218030234

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 3, pp. 537–540. © Pleiades Publishing, Ltd., 2018.
Facile One Pot Multi-Component Solvent-Free Synthesis
of 2,4,5-Trisubstituted Imidazoles Using “Green” and Expeditious
1
Ionic Liquid Catalyst under Microwave Irradiation
B. Sonyanaik, K. Ashok, S. Rambabu, D. Ravi, A. Kurumanna, P. Madhu, and B. Sakram*
Department of Chemistry, Osmania University, Telangana, Hyderabad, 500007 India
*
e-mail: bschemou@gmail.com
Received February 17, 2017
Abstract—Acetic acid functionalized poly(4-vinylpyridinium) bromide is a highly efficient and recyclable
catalyst for the construction of 2,4,5-trisubstituted imidazole derivatives by a three-component condensation of
benzyl with various aldehydes and ammonium acetate under solvent free conditions. The microwave initiated
process leads to analytically pure compounds within 2–5 min. The advantages of this “green” methodology are
cost-effectiveness, simple procedure, low energy consumption, no involvement of organic solvents, safe
operation, clean reaction profile, high yields, and recyclability of the catalyst.
Keywords: one pot synthesis, solvent-free conditions, microwave irradiation, 2,4,5-trisubstituted imidazoles
DOI: 10.1134/S1070363218030234
Imidazole based compounds play a vital role in
biochemical processes [1, 2] and demonstrate a broad
range of beneficial biological activities such as
antibacterial [3], antiviral [4], antitumor [5], B-Raf
kinase [6], analgesic [7], anti-HIV [8], and
Alzheimer’s disease [9]. The imidazole ring system is
an active component of several drug molecules includes
Eprosartan, Losartan, Trifenagrel, and Olmesartan.
RESULTS AND DISCUSSION
2,4,5-Trisubstituted imidazole derivatives 4a–4m
were synthesized by the reaction of benzyl with
arylaldehydes and ammonium acetate under solvent-
free conditions supported by microwave irradiation
and the eco-friendly ionic liquid, acetic acid
functionalized poly (4-vinylpyridinium) bromide
(
Scheme 1). The catalyst was prepared according to the
Due to important biological applications of
imidazoles, various methods of their synthesis have
been developed for structurally related imidazole
derivatives [10–12, and many more]. However, most
of the methods were characterized by certain
disadvantages, including harsh reaction conditions,
low yields, long reaction time, and high expense. Thus,
for dismissing such restrictions and in continuation of
our earlier studies on the development of eco-friendly
synthetic methods [13], here in, we report the
construction of 2,4,5-trisubstituted imidazoles using
acetic acid functionalized poly(4-vinylpyridinium)
bromide catalyst under solvent-free microwave-
assisted conditions that led to the products 4a–4m
accumulated with high yields. To the best of our
knowledge, there are no reports on application of this
catalyst in the synthesis of 2,4,5-trisubstituted
imidazoles.
developed earlier procedure [14] (Scheme 2).
Optimization of the process conditions was carried
out for the synthesis of 2,4,5-triphenyl-1H-imidazole
4a by condensation of benzil 1 (1 mmol) with benz-
aldehyde 2 (1 mmol) and ammonium acetate 3
(3 mmol) in presence of the ionic liquid catalyst (Table 1).
It was determined that application of 10 mol % of the
catalyst efficiently led to the highest yield (92%) of the
product.
Amount of the catalyst 15 mol % did not improve
the yield of the process but somewhat slowed down the
reaction accompanied by formation of side products.
Comparative study was carried out for microwave
irradiation and heating conditions. The best results
were achieved under solvent-free microwave irradia-
tion conditions (Table 2). Structures of all synthesized
1
13
products were characterized by IR, H and C NMR,
and mass spectra. Elemental analyses results and
1
The text was submitted by the authors in English.
5
37

5
38
SONYANAIK et al.
Scheme 1. Synthesis of 2,4,5-trisubstituted imidazoles catalyzed by acetic acid functionalized poly(4-vinylpyridinium)
bromide.
O
O
N
MW 300 W, ionic liquid
Ar
+
Ar-CHO + NH OAc
4
solvent-free, 2−5 min
N
H
2
3
1
4
a−4m
Ar = C
6
H
5
(4a), C
9
H
6
NO (4b), 4-(OMe)C
H
6 4
(4c), 4-ClC H
6 4
(4d), C
6
H
5
CH=CH (4e), C ClN (4f), 4-FC
9
H
5
6 4 6 4
H (4g), 4-OHC H
(
4h), 2-ClC
6
H
4
(4i), 3-NO
2 6
C H
4
(4j), 4-Cl-2-OHC
6
H
3
(4k), 5-Me-C
5
H
5
N (4l), 5-Cl-C H N (4m).
5 4
Scheme 2. Synthesis of acetic acid functionalized poly(4-vinylpyridinium) bromide catalyst.
Br
O
H SO (2 mL)
2
4
O
Br
3
+
C H OH (10 mL)
2
5
O
N
OH
3
3
HCl (1 mL)
H SO
Diethylether (30 mL)
Reflux 24 h
Br3
Br
3
2
4
N
Reflux
N
O
OH
O
O
melting points of the synthesised compounds were in
good agreement with the literature data (Table 2).
the solvent of the filtrate (H O) was removed under
2
reduced pressure. The residue was washed with
ethanol and diethyl ether (2× 30 mL) and dried. Upon
addition of acetone the mixture was stirred and
refluxed for 4 min. Then, the mixture of a product with
the catalyst was centrifuged for separation of the
catalyst which was washed with warm acetone (3 mL)
and dried. The recycled this way catalyst could be
reused in five consequent cycles of the process (see the
figure).
Recyclability of acetic acid functionalized poly(4-
vinylpyridinum) bromide was studied after completion
of the process. The reaction mixture was filtered and
a
Table 1. Optimization of the reaction conditions
Conventional
method
Microwave
method
Solvent
b
b
time, h yield, %
time, min yield, %
EXPERIMENTAL
C
2
H
5
OH
OH
Cl
3.0
2.5
79
81
8
87
89
All solvents and chemicals were purchased from
Aldrich/Fisher and used without further purification.
Melting points were determined on a Buchi melting
point apparatus. The progress of the reaction, as well
as purity of the compounds, were monitored and tested
by TLC using F254 silica-gel pre-coated plates using
the mixture of hexane with ethyl acetate (8 : 3) as an
eluent. IR spectra were recorded on a Perkin Elmer
CH
CH
3
2
10
2
3.0
2.0
2.0
77
82
90
8
6
2
84
86
92
THF
Solvent-free
a
Reaction conditions: Ionic liquid catalyst (27.41 mg, 10 mol %
.1 mmoL), benzil 1 (1 mmoL), benzaldehyde 2 (1 mmoL) and
0
ammonium acetate 3 (3 mmoL) in solvent-free conditions.
Isolated yields.
b
1
FT-IR spectrophotometer using KBr pellets. H NMR
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 3 2018

FACILE ONE POT MULTI-COMPONENT SOLVENT-FREE SYNTHESIS
539
Table 2. Synthesis of imidazole derivatives 4a–4m in the presence of acetic acid functionalized poly (4-vinylpyridinum)
bromide catalyst
mp, °C
a
Analog
Aldehyde
Benzaldehyde
Time, min Yield, %
References
found
calculated
280–282
252–254
4
a
4.0
2.5
91
92
278–280
254–255
[12]
[11]
4
b
3-Indolebenzaldehyde
4
c
4-Methoxybenzaldehyde
4-Chlorobenzaldehyde
Cinnamaldehyde
5.0
4.0
2.5
3.0
2.0
3.5
4.0
3.0
2.5
4.0
5.0
89
92
90
91
92
91
90
87
90
91
90
227–229
262–264
74–76
228–230
260–262
70–72
[12]
[12]
[11]
[11]
[12]
[13]
[12]
[13]
[11]
–
4
d
4
e
4
f
2-Chloroquinolinecarbaldehyde
4-Fluorobenzaldehyde
4-Hydroxybenzaldehyde
2-Chlorobenzaldehyde
3-Nitrobenzaldehyde
218–220
190–192
270–272
191–193
317–319
176–178
219–221
169–171
219–221
187–189
268–270
190–192
315–317
177–178
–
4
g
4
h
4
i
4
j
4
k
4-Chloro-2-hydroxybenzaldehyde
5-Methylpicolinaldehyde
5-Chloropicolinaldehyde
4
l
4
m
–
–
a
Isolated yields of the pure compound based on aldehyde using microwave irradiation.
spectra were measured on a Bruker 400 MHz spectro-
meter. Mass spectra were measured on a Jeol JMSD-
irradiation. A mixture of benzil (210.23 mg, 1 mmol)
with ammonium acetate (231.24 mg, 3 mmol),
aldehyde (1 mmol), and acetic acid functionalized poly-
(4-vinylpyridinum) bromide (27.41 mg, 10 mol %,
4
00 spectrometer. Elemental analyses were performed
on a Carlo-Erb model EA1108 analytical unit.
0
.1 mmol) was loaded in a cell of the microwave
General procedure for the synthesis of 2,4,5-
trisubstituted imidazoles 4a–4m by the conven-
tional method. The mixture of benzil (210.23 mg,
reactor and irradiated at 300 W for 2–5 min (TLC).
The reaction mixture was washed with cool water and
1
mmol) with an aldehyde (1 mmol), ammonium
acetate (231.24 mg, 3 mmol), and acetic acid func-
tionalized poly (4-vinylpyridinum) bromide (27.41 mg,
9
2
100
80
90
8
8
8
7
85
1
0 mol %, 0.1 mmol) was stirred for an appropriate
time (Table 2). Upon completion of the reaction (as
monitored by TLC), 5 mL of water were added.
Following stirring at room temperature lasted for
6
4
2
0
0
0
0
5
min. The reaction mixture was filtered and the
solvent of the filtrate (H O) was removed under
2
reduced pressure. The mixture was washed with
ethanol and diethyl ether (2×30 mL) and dried. Upon
following addition of acetone, stirring and refluxing
lasted for 5 min. Then, the mixture of the product with
the catalyst was centrifuged for separation of the
catalyst from the product.
1
2
3
Run
4
5
Activity of the recycled acetic acid functionalized poly (4-
vinylpyridinum) bromide catalyst in the synthesis of 2,4,5-
triphenyl-1H-imidazole (4a).
General procedure for the synthesis of 2,4,5-
trisubstituted imidazoles 4a–4m under microwave
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 3 2018

5
40
SONYANAIK et al.
filtered. The solvent of the filtrate (H O) was removed
Central Facilities for Research and Development,
Osmania University for providing NMR facilities.
2
under reduced pressure. The reaction mixture was
washed with ethanol and diethyl ether (2×30 mL) and
dried. Upon addition of acetone, the mixture was
stirred and refluxed for 4 min. Then, the mixture of a
product and the catalyst was centrifuged for separation
of the catalyst from the product.
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We gratefully acknowledge the Head of the
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(
B. Sonyanaik) thanks the University Grant Commission,
New Delhi, India, for providing senior research
fellowship. Finally, the authors wish to express their
gratitude to Central facilities research and development
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 3 2018