Glutamic acid as an efficient and green catalyst for the one-pot synthesis of 1,2,4,5-tetrasubstituted imidazoles under thermal, solvent-free conditions

Article abstract of DOI:10.3184/174751917X15105690662854

A high-yielding synthesis of 1,2,4,5-tetrasubstituted imidazoles is described, involving the reaction of 1,2-dicarbonyl compounds, aryl aldehydes, amines and ammonium acetate in the presence of a catalytic amount of glutamic acid under thermal, solvent-free conditions. The salient features of this protocol are aerobic conditions, a non-hazardous green catalyst, short reaction times and mild reaction conditions.

Full text of DOI:10.3184/174751917X15105690662854

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 NOVEMBER, 673–675
RESEARCH PAPER 673
Glutamic acid as an efficient and green catalyst for the one-pot synthesis of
1,2,4,5-tetrasubstituted imidazoles under thermal, solvent-free conditions
Fahimeh Khazaee Feizabad, Khatereh Khandan-Barani* and Alireza Hassanabadi
Department of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978, Zahedan, Iran
A high-yielding synthesis of 1,2,4,5-tetrasubstituted imidazoles is described, involving the reaction of 1,2-dicarbonyl compounds, aryl
aldehydes, amines and ammonium acetate in the presence of a catalytic amount of glutamic acid under thermal, solvent-free conditions.
The salient features of this protocol are aerobic conditions, a non-hazardous green catalyst, short reaction times and mild reaction
conditions.
Keywords: glutamic acid, 1,2,4,5-tetrasubstituted imidazoles, solvent-free, green catalyst, ammonium acetate, 1,2-dicarbonyl compounds
Multi-component reactions (MCRs) have been demonstrated to
be highly successful in generating products in a single synthetic
operation.1 The development of new MCRs2 and the modification
of existing MCRs are areas of notable current interest. One such
reaction is the synthesis of imidazole rings. Tetrasubstituted
imidazoles are core parts of many biologically active molecules,
such as Losartan and Olmesartan.3 The presence of an
imidazole ring in natural products and pharmacologically active
compounds has established a diverse array of synthetic methods
for obtaining these heterocycles.4 The synthesis, reactions and
biological attributes of substituted imidazoles constitute an
important part of modern heterocyclic chemistry.5 However,
despite substantial efforts, only a handful of general techniques
exist for the construction of tetrasubstituted imidazoles.
Recently, the synthesis of 1,2,4,5-tetrasubstituted imidazoles
has been catalysed by silica gel or Zeolite HY,6 silica gel/
NaHSO4,7 molecular iodine,8 InCl3-3H2O,9 K5CoW12O40.3H2O,10
[bmim]3[CdCl6],11 NaNO2,12 L-proline,13 HClO4–SiO2,14 SbCl5.
SiO215 and 1,4-diazabicyclo[2.2.2]octane (DABCO).16
The methods reported previously for the synthesis of
1,2,4,5-tetrasubstituted imidazoles suffer from severe
disadvantages, such as long reaction times, hazardous organic
solvents, complex work-up and purification, strongly acidic
conditions, high temperatures, use of toxic metal catalysts
and inadequate yields. Based on the above information and
because of our interest in developing synthetic strategies for
the construction of heterocyclic compounds, we have now
used a glutamic acid-catalysed condensation as a new and
rapid method affording excellent yields for the synthesis of
1,2,4,5-tetrasubstituted imidazoles under thermal, solvent-free
conditions.
Initially, we began with the condensation of benzil (1 mmol),
benzaldehyde (1 mmol), aniline (1 mmol) and ammonium
acetate (1 mmol) in solvent-free conditions at 30 °C for 24 h in
the absence of catalyst, which led to a very poor yield (10%)
of 1,2,4,5-tetraphenylimidazole. To enhance the yield of the
desired product, the temperature of the reaction was increased
to 60 °C, but no appreciable increment in the product yield
was observed. It was then thought worthwhile to carry out the
reaction in the presence of an organocatalyst, glutamic acid.
We also increased the amount of catalyst required for this
transformation, and it was found, from using 5 mol%, 10 mol%,
15 mol%, 20 mol% and 25 mol% catalyst, that the maximum
yield (90%) was obtained when the reaction mixture was loaded
with 10 mol% of the catalyst (Table 1). Further increasing the
amount of catalyst adversely affected the yield and slowed down
the reaction slightly. The detailed results obtained are given in
Table 1.
The substrate scope of the reaction was then evaluated using
a variety of structurally diverse 1,2-dicarbonyl compounds,
aryl aldehydes and primary amines (Table 2). The strategy was
tolerant of electron-donating and electron-withdrawing groups
in the aryl aldehyde. Both aromatic and aliphatic primary
amines have been successfully subjected to this protocol.
Table 1 Optimisation of the reaction conditions for synthesis of 5a
Entry Catalyst (mol%)
Solvent/conditions
Solvent-free/30 °C
Solvent-free/60 °C
Solvent-free/30 °C
Solvent-free/60 °C
Time (h)
Yield (%)
10
25
55
70
90
90
80
65
1
2
3
4
5
6
7
8
9
10
Glutamic acid (0)
Glutamic acid (0)
Glutamic acid (5)
Glutamic acid (5)
Glutamic acid (10) Solvent-free/60 °C
Glutamic acid (15) Solvent-free/60 °C
Glutamic acid (20) Solvent-free/60 °C
Glutamic acid (25) Solvent-free/60 °C
Glutamic acid (10) Solvent-free/30 °C
Glutamic acid (10) Solvent-free/90 °C
24
24
10
6
4
4
4
4
7
4
Results and discussion
In continuation of our studies on MCRs,17–19 we report here the
reaction between 1,2-dicarbonyl compounds 1, aryl aldehydes
2, amines 3 and ammonium acetate 4 in the presence of a
catalytic amount of glutamic acid under thermal, solvent-free
conditions (Scheme 1).
60
45
Ar
Ar
O
N
(10 mol%)
glutamic acid
Solvent-free,
O
R' NH2
+ NH4OAc
4
+
+
O
Ar
R
60
H
o C, 2-4 h
R
N
Ar
R'
5
3
2
1
Scheme 1 Synthesis of 1,2,4,5-tetrasubstituted imidazoles in the presence of glutamic acid under thermal, solvent-free conditions.
* Correspondent. E-mail: kh_khandan_barani@yahoo.com

674 JOURNAL OF CHEMICAL RESEARCH 2017
Table 2 Reaction between 1,2-dicarbonyl compounds, aryl aldehydes, amines and ammonium acetate in the presence of a catalytic amount of glutamic
acid under thermal, solvent-free conditions
M.p. (°C)
Reported
Product
Ar
R
R’
Time (h)
Yield (%)a
Found
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-Cl-C6H4
4-Me-C6H4
C6H5
C6H5
4-Cl-C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
4
2
3
2
4
4
4
3
2
3
3
3
4
2
3
3
3
90
95
85
90
80
85
75
92
90
80
85
80
75
95
91
86
80
217–219
165–167
186–188
155–157
187–189
189–191
290–292
161–163
163–165
131–133
129–131
165–167
162–164
171–173
186–188
181–183
220–222
216–218 (Ref. 20)
164–166 (Ref. 21)
184–186 (Ref. 22)
152–154 (Ref. 23)
185–188 (Ref. 24)
186–188 (Ref. 24)
287–289 (Ref. 25)
163–165 (Ref. 14)
162–164 (Ref. 22)
134–135 (Ref. 14)
128–130 (Ref. 20)
164–165 (Ref. 26)
165–166 (Ref. 20)
172–174 (Ref. 14)
185–186 (Ref. 26)
183–184 (Ref. 26)
-
4-No2-C6H4
4-Br-C6H4
4-OMe-C6H4
4-Me-C6H4
4-OH-C6H4
C6H5
4-Cl-C6H4
4-OH-C6H4
3-OMe-C6H4
4-OMe-C6H4
4-Me-C6H4
4-Br-C6H4
4-Me-C6H4
4-OMe-C6H4
2-OH-4-NO2-C6H3
aYields refer to the pure isolated products.
1
The compounds 5a–p were characterised by their H NMR
and IR spectra and also by elemental analyses.20–26
and filtered to remove the catalyst. The crude product was
recrystallised from hot ethanol to obtain the pure compound.
1-Benzyl-2- (2’-hydroxy-5’-nitrobenzyl) -4,5-diphenyl-1H-
imidazole (5o): Pale yellow solid; FTIR (νmax/cm−1): 3425, 3032, 2940,
Compound 5q was new, and its structure was deduced by
elemental and spectral analysis. The mass spectrum of 5q
1
1
2867, 1619, 1468; MS (m/z, %): 447 (5); H NMR (CDCl3): δ 5.03
showed the molecular ion peak at m/z 447. The H NMR
(s, 2H), 6.70–7.44 (m, 18H), 9.43 (s, 1H); 13C NMR (CDCl3): δ 48.3,
118.9, 119.4, 125.9, 126.2, 126.7, 127.4, 127.9, 128.7, 128.8, 129.1,
129.8, 130.3, 130.5, 131.2, 131.8, 134.0, 139.6, 140.4, 146.4, 159.9,
166.2; Anal. calcd for C28H21N3O3: C, 75.15; H, 4.73; N, 9.39; found: C,
75.31; H, 4.90; N, 9.27%.
spectrum of 5q exhibited a methylene proton signal at 5.03
ppm, and the OH proton was observed at 9.43 ppm, which
disappeared after addition of some D2O. Also observed were
multiplets between 6.70 and 7.44 ppm, which are related to the
aromatic protons. The 13C NMR spectrum of 5q showed 22
signals, in agreement with the proposed structure, while the IR
spectrum also supported the suggested structure.
Acknowledgement
We gratefully acknowledge financial support from the
Research Council of the Islamic Azad University of Zahedan
of Iran.
Conclusions
In summary, we have shown that glutamic acid has several
advantages in the preparation of 1,2,4,5-tetrasubstituted
imidazoles, such as short reaction times, simple work-up,
aerobic conditions, and is a non-hazardous, green catalyst
that affords excellent yields. Also, the present method does
not involve any hazardous organic solvent. Therefore, this
procedure can be classified as green chemistry.
Received 14 May 2017; accepted 5 November 2017
Paper 1704772
https://doi.org/10.3184/174751917X15105690662854
Published online: 16 November 2017
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