One-pot synthesis of polysubstituted imidazoles in a bronsted acidic deep eutectic solvent

Article abstract of DOI:10.3184/174751913X13636339694414

A Bronsted acidic deep eutectic solvent based on choline chloride and p-toluenesulfonic acid was prepared and was found to be effective for the one-pot synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles with high yields. In addition, the deep eutectic solvent is non-toxic, cost-effective and recyclable.

Full text of DOI:10.3184/174751913X13636339694414

236 RESEARCH PAPER
APRIL, 236–238
JOURNAL OF CHEMICAL RESEARCH 2013
One-pot synthesis of polysubstituted imidazoles in a Brønsted acidic
deep eutectic solvent
Liang Wang, Xia Zhong, Min Zhou, Wei-you Zhou, Qun Chen and Ming-Yang He*
Jiangsu Province Key Laboratory of Fine Petro-ChemicalTechnology, Changzhou University, Changzhou 213164, P. R. China
A Brønsted acidic deep eutectic solvent based on choline chloride and p-toluenesulfonic acid was prepared and was
found to be effective for the one-pot synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles with high
yields. In addition, the deep eutectic solvent is non-toxic, cost-effective and recyclable.
Keywords: deep eutectic solvent, polysubstituted imidazoles, multicomponent reactions, one-pot synthesis
The imidazole moiety is present in a wide range of naturally
occurringmoleculesandpharmaceuticallyactivecompounds.1,2
Among them, polysubstituted imidazoles are of great interest
due to their chemical and biological activities making them
common structures in numerous synthetic compounds such as
inhibitors of p38MAPkinase, herbicides, plant growth regula-
tors and therapeutic agents.3,4 In the last decade, numerous
methods have been developed for the synthesis of highly sub-
stituted imidazoles by using various catalytic systems. Meth-
ods utilising microwave irradiation,5 ultrasound irradiation,6
solid acids7 and supported catalysts8 have also been described.
However, many of the methods reported above suffer from one
or more disadvantages such as the use of expensive metallic
reagents, longer reaction times, tedious separation procedures,
and large amount of catalyst loadings which in turn results in
the generation of huge amount of wastes.
which was used for reactions without any purification.
This method gave this DES with 100% atom economy since
it completely forms a eutectic mixture with no by-product
formation.
With the DES in hand, we started to optimise the reaction
conditions via condensation of benzil (1 mmol), benzaldehyde
(1 mmol) and ammonium acetate (2 mmol) in different catalytic
system (Table 1). The solvent played an important role for
the reaction. Good yields were obtained when methanol
and ethanol were used as the solvent (89 and 95% yield,
respectively). Other solvents such as H2O, ethyl acetate and
toluene gave much lower yields. This can be attributed to DES
showing excellent solubility in polar solvents and the reaction
proceeding in a homogeneous system. Various deep eutectic
It is evident from the recent literature that deep eutectic
solvent has invoked enormous interest as a green and potential
solvent or catalyst in organic reactions. Deep eutectic solvents
(DES) are similar to conventional ionic liquids in terms of low
vapour pressure and low flammability. In addition, they are
biodegradable, non-toxic, and inexpensive. Generally, DES
are mainly prepared by combining choline chloride with dif-
ferent hydrogen bond donors, such as urea, Lewis acids as well
as Brønsted acids.9 It should be noted that choline is a naturally
occurring biocompatible compound and choline chloride
is commercially produced on a large scale as a chicken feed
additive.10 However, their ability to serve as catalysts as well
as solvents has not been adequately explored in the field
of synthetic organic chemistry except for a few reported
examples.11–14
Table 1 Optimisation of reaction conditionsa
Entry Reaction medium DES catalyst/mol%
Yield/%b
1
2
CH3OH
CH3CH2OH
H2O
ChCl/p-TsOH (5)
ChCl/p-TsOH (5)
ChCl/p-TsOH (5)
ChCl/p-TsOH (5)
ChCl/p-TsOH (5)
ChCl/p-TsOH (5)
-
89
95
Trace
65
10
3
4
CH3CN
5
EtOAc
Toluene
6
Trace
Trace
Trace
51
7
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
8
ChCl (5)
9
p-TsOH (5)
ChCl/urea (5)
ChCl/malonic acid (5)
ChCl/glycerol (5)
ChCl/p-TsOH (10)
ChCl/p-TsOH (15)
10
11
12
13
14
15
We now report an efficient and reusable catalytic system
for one-pot synthesis of polysubstituted imidazoles using
deep eutectic solvents based on choline chloride and
p-toluenesulfonic acid (Scheme 1).
72
25
95
93
The DES ChCl/p-TsOH was readily prepared by mixing
the choline chloride 1 (0.1 mol) with p-toluenesulfonic acid
(0.1 mol) at 100 °C until a clear solution was obtained (40 min)
a Reaction conditions: Benzil (1 mmol), benzaldehyde (1 mmol),
ammonium acetate (2 mmol), solvent (3 mL) reflux for 2 h.
b Isolated yields.
Scheme 1 ChCl/p-TsOH catalysed the one-pot synthesis of polysubstituted imidazoles.
* Correspondent. E-mail: lwcczu@126.com

JOURNAL OF CHEMICAL RESEARCH 2013 237
mixtures as well as the catalyst amount were also evaluated
(Table 1, entries 7–14).A trace amount of product was obtained
in the absence of any catalyst. p-Toluenesulfonic acid, when
used alone, could also promote the reaction, however, with a
moderate (51%) yield. Other deep eutectic mixtures generated
from urea, malonic acid and glycerol gave lower yield
owing to the lower acidity compared to ChCl/p-TsOH. The
optimisation for the quantity of catalyst suggested that 5% of
ChCl/p-TsOH in ethanol is enough.
One of the most important advantages of employing DES as
a solvent or catalyst is their recyclability. The batch of reaction
between benzil, benzaldehyde and ammonium acetate was
scaled up to 10 mmol to examine the recycling process. The
recovery was very simple involving evaporation of the ethanol
and water after isolation of product by extraction with ethyl
acetate. The DES was reused without obvious loss in activity
in five consecutive runs (95%, 93%, 90%, 90% and 86% yield,
respectively).
Next, a wide variety of aldehydes (both aromatic and
aliphatic) with various substituents were examined to construct
2,4,5-trisubstituted imidazoles. The results are summarised in
Table 2. It was obvious that this protocol showed good substrate
compatibility for aromatic aldehydes. Both aromatic aldehydes
bearing electron-donating groups and electron-withdrawing
groups at the para-position gave the products in high yields
(Table 2, entries 1–6). The aliphatic aldehydes, however, gave
the corresponding products in lower yields (36 and 45%,
respectively).
On the basis of the successful application of ChCl/p-TsOH
in the synthesis of 2,4,5-trisubstitued imidazoles, this protocol
was then applied to the synthesis of 1,2,4,5-tetrasubstituted
imidazoles (Table 3). As can been seen from Table 3, this
strategy tolerated well the presence of electron-donating
and electron-withdrawing groups on the aromatic aldehydes.
Both aromatic and aliphatic primary amines have also been
successfully subjected to this protocol.
In summary, we have developed a simple, green and
efficient catalytic system using deep eutectic mixtures for
rapid synthesis of polysubstituted imidazoles. The reaction
gave high yields in short reaction times. In addition, the DES
catalyst could be easily recycled and reused at least up to five
runs without any considerable loss in yields.
Experimental
All reagents were obtained from local commercial suppliers and used
1
without further purification. H and 13C NMR spectra were recorded
on a Bruker Advance III 500 analyser. All the products are known
compounds and were identified by comparing their physical and
spectra data with those reported in the literature.
Synthesis of 2,4,5-trisubstituted imidazoles; typical procedure
In a 25-mL round bottom flask, 1,2-diketone (1 mmol), aldehyde
(1 mmol) and ammonium acetate (2 mmol) were added to 5 mol% of
ChCl/p-TsOH in ethanol (3 mL). Then the reaction mixture was
stirred at 78 °C for an appropriate time as monitored by TLC. After
completion of the reaction, the volume of the reaction mixture was
reduced, diluted with water and extracted with ethyl acetate. The
organic layer was dried over anhydrous MgSO4 and then the solvent
was removed under reduced pressure. The crude product was washed
with n-hexane and recrystallised from ethanol to obtain the pure prod-
uct.
Table 2 Synthesis of 2,4,5-trisubstituted imidazolesa
Entry
R1
Time/h Yield/%b
M.p./°Clit.
Synthesis of 1,2,4,5-tetrasubstituted imidazoles; typical procedure
In a 25-mL round bottom flask, 1,2-diketone (1 mmol), aldehyde
(1 mmol), primary amine (1 mmol) and ammonium acetate (1 mmol)
were added to 5 mol% of ChCl/p-TsOH in ethanol (3 mL). Then the
reaction mixture was stirred at 78 °C for an appropriate time as moni-
tored by TLC. After completion of the reaction, the volume of the
reaction mixture was reduced, diluted with water and extracted with
ethyl acetate. The organic layer was dried over anhydrous MgSO4 and
then the solvent was removed under reduced pressure. The water:
ethanol mixture (50:50) was added to the oily residue, a milky to
yellow solid was obtained. The solid was then recrystallised from
ethanol to obtain the pure product.
1
2
3
4
5
6
7
8
C6H5-
4-CH3C6H4-
4-OHC6H4-
4-CH3OC6H4-
4-NO2C6H4-
4-ClC6H4-
n-C2H5-
2
3
3
3
2
2
6
6
95
91
85
82
86
83
36
45
>260 (267–269)15
226–228 (227–228)15
232–234 (232–233)15
227–228 (220–223)15
235–236 (239–242)16
258–260 (262–264)15
225–227 (223–224)17
255–257 (256–258)17
n-C3H7-
a Reaction conditions: Benzil (1 mmol), aldehyde (1 mmol),
ammonium acetate (2 mmol), solvent (3 mL) under reflux.
b Isolated yields.
Recycling study
The batch reaction between benzil (10 mmol), benzaldehyde
(10 mmol) and ammonium acetate (20 mmol) were added to 5 mol%
of ChCl/p-TsOH in ethanol (30 mL) under reflux for an appropriate
time as monitored by TLC. After completion of the reaction, the
mixture was condensed, diluted with water and extracted with ethyl
acetate. The recovery was very simple by the evaporation of water.
Table 3 Synthesis of 1,2,4,5-tetrasubstituted imidazolesa
Entry
R2
R3
Time Yield
Mp/°Clit.
/h
/%b
This project was funded by the Priority Academic Program
Development (PAPD) of Jiangsu Higher Education Institutions
which is fully acknowledged.
1
2
C6H5-
4-CH3C6H4-
4-OHC6H4-
C6H5-
C6H5-
C6H5-
2
3
3
3
2
2
2
2
3
3
2
92 218–220 (218–220)18
89 184–186 (187–189)15
84 282–284 (284–286)15
82 180–182 (185–188)18
85 186–188 (191–193)15
85 160–162 (156–158)19
90 163–164 (163–165)15
87 168–170 (167–168)15
85 136–138 (134–135)20
81 163–164 (164–165)15
82 161–162 (161–163)15
3
4
4-CH3OC6H4- C6H5-
5
4-NO2C6H4-
4-ClC6H4-
C6H5-
C6H5-
C6H5-
C6H5CH2-
Received 19 January 2013; accepted 11 February 2013
Paper 1301732 doi: 10.3184/174751913X13636339694414
Published online: 19 April 2013
6
7
8
4-CH3C6H4- C6H5CH2-
4-OHC6H4- C6H5CH2-
4-CH3OC6H4- C6H5CH2-
4-ClC6H4- C6H5CH2-
9
10
11
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