Lewis acid catalyst free synthesis of substituted imidazoles in 2,2,2-trifluoroethanol

Article abstract of DOI:10.1007/s00706-012-0834-1

A simple, inexpensive, environmentally friendly, and efficient route for the synthesis of highly substituted imidazoles by the condensation of 1,2-dicarbonyl compounds, aldehydes, and ammonium acetate using 2,2,2-trifluoroethanol as a solvent is described. The solvent can be readily separated from reaction products and recovered in excellent purity for direct reuse.

Full text of DOI:10.1007/s00706-012-0834-1

Monatsh Chem (2013) 144:395–398
DOI 10.1007/s00706-012-0834-1
ORIGINAL PAPER
Lewis acid catalyst free synthesis of substituted imidazoles
in 2,2,2-trifluoroethanol
•
Samad Khaksar Mandana Alipour
Received: 22 January 2012 / Accepted: 7 August 2012 / Published online: 28 August 2012
Ó Springer-Verlag 2012
Abstract A simple, inexpensive, environmentally friendly,
and efficient route for the synthesis of highly substituted
imidazolesbythecondensationof1,2-dicarbonylcompounds,
aldehydes, and ammonium acetate using 2,2,2-trifluoroetha-
nol as a solvent is described. The solvent can be readily
separated from reaction products and recovered in excellent
purity for direct reuse.
Recent development of green chemistry and organome-
tallic chemistry has expanded the utility of imidazoles as
ionic liquids [12, 13] and N-heterocyclic carbenes [14–16].
The classical method for the synthesis of 2,4,5-trisubstituted
imidazoles is the one-pot condensation of benzil with aryl
aldehyde in alcoholic ammonia solution [17]. The procedure
was later modified by refluxing benzil with substituted
aldehydes and ammonium acetate in glacial acetic acid [18].
However, this method involves long reaction times, harsh
reaction conditions, use of a large quantity of volatile organic
solvents and generally gives low yields. In recent years,
several new efficient methods have been developed includ-
ing the use of silica gel [19], zeolite [19], alumina [20],
NaHSO4/SiO2 [21], HClO4/SiO2 [22], molecular iodine [23,
24], FeCl3Á6H2O [25], BF3ÁSiO2 [26], InCl3Á3H2O [27],
K5CoW12O40Á3H2O [28], copper acetate [29], trifluoroacetic
acid [30], L-proline [31], zeolite-supported reagents [32],
mercaptopropyl silica (MPS) [33], Brønsted acidic ionic
liquid [34], MCM-41 or p-TsOH [35], DABCO [36], silica-
bonded propylpiperazineN-sulfamicacid[37],and1-butyl-3-
methylimidazolium bromide [38]. Despite their potential
utility, most of these methods are not environmentally
friendly. They require high temperature (180–200 °C), cre-
ated by microwave irradiation, complex work-up and
purification, strong acidic conditions, use of toxic metal cat-
alysts, and suffer from poor yields, occurrence of side
reactions, and use of expensive reagents. Hence, the devel-
opment of clean, high-yielding, and environmentally benign
approaches is still desirable and much in demand.
Keywords Imidazole Á Hydrogen bonding Á
Fluorinated solvent
Introduction
Imidazoles are important heterocyclic compounds which
influence numerous cellular processes [1]. They display a
broad range of biological, medicinal, and pharmacological
properties and are constituents of antitumor, antifungal,
antimycotic, antibiotic, antiulcerative, antibacterial, and
CB1 receptor antagonistic activities [2, 3]. Various substi-
tuted imidazoles act as inhibitors of p38 MAP kinase [4],
B-Raf kinase [5], glucagon receptors [6], plant growth
regulators [7, 8], therapeutic agents [9], and also pesticides
[10, 11]. In particular, imidazole drugs such as losartan,
omeprazole, olmesartan, eprosartan, and trifenagrel are
some of the leading drugs on the market with diverse
functionalization around the imidazole motif (Fig. 1).
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0834-1) contains supplementary
material, which is available to authorized users.
Over the last decade, significant progress has been made
in the application of fluorinated solvents as catalysts and
alternative solvents in organic synthesis given their unique
advantages of low nucleophilicity, high polarity, strong
hydrogen-bond-donating ability and ability to solvate water
[39, 40]. The use of fluorinated solvents as reaction media
S. Khaksar (&) Á M. Alipour
Chemistry Department, Ayatollah Amoli Branch,
Islamic Azad University, Amol, Iran
e-mail: samadkhaksar@yahoo.com
123

396
S. Khaksar, M. Alipour
Fig. 1 Typical imidazole drugs
Cl
HO
RO
N
O
S
HOH2C
N
N
N
N
N N
NH
N
N
N
N N
NH
O
H
O
N
O
Omeprazole
Losartan
Olmesartan
S
Ph
N
N
HOOC
Ph
N
N
O
NMe2
COOH
Eprosartan
Trifenagrel
R1
R1
Table 1 Synthesis of 2,4,5-trisubstituted imidazoles (Scheme 1)
R1
O
N
Entry R1
R2
Product Yield/% References
TFE
R2 CHO
+
+
NH4OAc
R2
reflux, 5 h
R1
N
O
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
95
97
97
85
90
90
92
95
96
90
95
95
85
85
80
85
[31]
[31]
[31]
[36]
[36]
[36]
[31]
[36]
[36]
[36]
[36]
[32]
[36]
[36]
[36]
[36]
H
2
4-Cl-Ph
2-Cl-Ph
2,4-Cl2-Ph
4-Br-Ph
4-F-Ph
1
2
4a-4p
3
Scheme 1
4
5
and/or catalysts for clean catalytic transformations would
have profound effects on reaction rates and product
selectivity [41–54]. Additionally, if the synthesis is carried
out with a fluorinated solvent as the catalyst and the
product is immiscible, separation and recycling of the
catalyst is facile. In response to the current challenges of
developing environmentally benign synthetic processes and
in continuation of our interest in the application of fluori-
nated solvents for various organic transformations [55–59],
we report a new, convenient, mild, and efficient procedure
for the synthesis of highly substituted imidazole derivatives
via a four-component, one-pot reaction in refluxing 2,2,2-
trifluoroethanol (TFE) (Scheme 1).
6
7
4-NO2-Ph
3-NO2-Ph
4-Me-Ph
4-MeO-Ph
4g
4h
4i
8
9
10
11
12
13
14
15
16
4j
3,4-(MeO)2-Ph 4k
2-Furanyl
4l
4-Me-Ph 4-Br-Ph
4-Me-Ph Ph
4m
4n
4o
4p
4-Cl-Ph
Ph
2-Furanyl Ph
efficiency of this methodology, a wide range of aromatic
aldehydes were employed and all imidazoles were obtained
in high to excellent yields, which demonstrated that this is
a general method that tolerates both electron-withdrawing
and electron-donating constituents. It is noteworthy to
mention that the structural variation of the aldehyde and
substituents on the aromatic ring did not show any obvious
effect on this conversion, because the desired products
were obtained in high yields in relatively short reaction
times. In contrast, aliphatic aldehydes such as n-hexanal
and cyclohexanecarboxaldehyde did not provide the
desired products. The experimental procedure is very
efficient, convenient, rapid, and has the ability to tolerate a
variety of other functional groups, such as alkyl, methoxy,
Results and discussion
In an initial endeavor, we started the condensation of benzil
(1 mmol), benzaldehyde (1 mmol), and ammonium acetate
(2 mmol) in TFE at room temperature for 24 h, which led
to very poor yield (10 %) of 2,4,5-trisubstituted imidazole.
When we attempted the same reaction in TFE at reflux the
reaction proceeded to completion within 5 h and yielded
the corresponding imidazole in 95 % yield. Further
experiments revealed that a similar procedure is applicable
for the preparation of a wide range of compounds analo-
gous to adduct 4a (Table 1). In order to evaluate the
123

Lewis acid catalyst free synthesis of substituted imidazoles
397
nitro, and halides under these reaction conditions. This
method not only affords the products in excellent yields but
also avoids the problems associated with catalyst cost,
handling, safety, and pollution. One of the major advan-
tages of this protocol is the isolation and purification of the
products, which have been achieved by simple filtration
and crystallization of the crude products. The results
illustrate the suitability of this method for the synthesis of
substituted imidazoles with different groups. Interestingly,
the reaction did not proceed to completion when either
ethanol or water alone was used as solvent, even at reflux.
In order to explore the applicability of this method, the
same reaction conditions were applied for the synthesis of
1,2,4,5-tetrasubstituted imidazoles via the one-pot, four-
component condensation of 1,2-diketone (1 mmol), alde-
hyde (1 mmol), primary amine (1 mmol), and ammonium
acetate (1 mmol) as depicted in Scheme 2. As expected,
these substrates underwent smooth, one-pot conversion to
give the corresponding 1,2,4,5-tetrasubstituted imidazoles
5a–5h in excellent yields. The substrate scope of the
reaction was then evaluated using a variety of structurally
diverse aldehydes and primary amines (Table 2).
trisubstituted imidazoles 4a–4p by the condensation of an
aldehyde, benzil, and ammonium acetate in refluxing TFE
in excellent yields. This protocol offers many attractive
features such as (1) avoiding the use of any base, metal, or
Lewis acid catalyst, (2) short reaction times, (3) ease of
product isolation/purification by non-aqueous work-up, (4)
high chemoselectivity, (5) no side reaction, and (6) low
costs and simplicity in process and handling. The recovered
TFE can be reused. Further studies and efforts to extend the
scope of this method for other useful reactions are currently
underway.
Experimental
NMR spectra were determined on a Bruker AV-400 Fou-
rier transform NMR spectrometer in CDCl3 or dimethyl
sulfoxide (DMSO-d6) and are expressed in d values relative
to tetramethylsilane; coupling constants (J) are measured in
hertz. Melting points were determined on an Electrother-
mal 9100 instrument. Infrared spectra were recorded on a
Rayleigh WQF-510 Fourier transform instrument. Com-
mercially available reagents were used throughout without
further purification.
After the reaction, TFE can be easily separated (by
distillation) and reused without decrease in its activity. For
example, the reaction of benzil, benzaldehyde, and
ammonium acetate afforded the corresponding substituted
imidazole derivative in 90, 90, and 88 % isolated yield
over three cycles. When we carried out the reaction in TFE
at room temperature, the reaction proceeded very slowly to
give very poor yields.
Typical experimental procedure
Benzil (1 mmol), aldehyde (1 mmol), and ammonium
acetate (2 mmol) were dissolved in 2 cm3 TFE and stirred
at reflux until complete dissolution of the reagents was
observed. After 10–15 min the precipitation of light-yellow
crystals occurred gradually and precipitation continued for
5 h. The mixture was cooled to room temperature and the
was precipitate filtered. The crude product was purified by
recrystallization from ethanol to yield the highly pure
2,4,5-trisubstituted imidazoles. The physical data (m.p., IR,
NMR) of known compounds were found to be identical
with those reported in literature [36].
In summary, we described herein a highly efficient, one-
pot, three-component protocol for the synthesis of 2,4,5-
Ph
R2 CHO
N
O
Ph
O
TFE
2
R2
NH4OAc
+
+
Ph
reflux, 5 h
N
R3
R3 NH2
Ph
1
3
5a-5h
Scheme 2
Acknowledgments This research was supported by the Islamic
Azad University, Ayatollah Amoli Branch.
Table 2 Synthesis of 1,2,4,5-tetrasubstituted imidazoles in TFE
(Scheme 2)
References
Entry
R2
R3
Product
Yield/%
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