Deep eutectic solvent for multi-component reactions: A highly efficient and reusable acidic catalyst for synthesis of 2,4,5-triaryl-1H-imidazoles

Article abstract of DOI:10.1007/s11164-013-1467-7

Efficient synthesis of 2,4,5-trisubstituted imidazoles has been achieved by three-component cyclocondensation of benzil or benzoin, an aldehyde, and ammonium acetate by use of an acidic catalyst. The catalyst is a deep eutectic mixture of choline chloride and oxalic acid that is non-toxic and biodegradable. Crucial advantages of this process are high yields, shorter reaction times, easy work-up, purification of products by non-chromatographic methods, and reusability of the catalyst.

Full text of DOI:10.1007/s11164-013-1467-7

Res Chem Intermed
DOI 10.1007/s11164-013-1467-7
Deep eutectic solvent for multi-component reactions:
a highly efficient and reusable acidic catalyst
for synthesis of 2,4,5-triaryl-1H-imidazoles
•
Mehdi Bakavoli Hossein Eshghi
•
•
Mohammad Rahimizadeh
Mohammad Reza Housaindokht
•
•
Ali Mohammadi Hassan Monhemi
Received: 14 August 2013 / Accepted: 20 October 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Efficient synthesis of 2,4,5-trisubstituted imidazoles has been achieved
by three-component cyclocondensation of benzil or benzoin, an aldehyde, and
ammonium acetate by use of an acidic catalyst. The catalyst is a deep eutectic
mixture of choline chloride and oxalic acid that is non-toxic and biodegradable.
Crucial advantages of this process are high yields, shorter reaction times, easy work-
up, purification of products by non-chromatographic methods, and reusability of the
catalyst.
Keywords 2,4,5-Trisubstituted imidazoles Á Multi-component reactions Á
Choline chloride Á Deep eutectic solvent Á Oxalic acid
Introduction
The imidazole nucleus is a fertile source of biologically important molecules.
Compounds containing the imidazole group have many pharmacological properties
and are important in biochemical processes. They are well known as inhibitors of
P38MAP kinase, and act as fungicides, herbicides, anti-inflammatory agents,
antithrombotic agents, plant-growth regulators, and therapeutic agents. They are
also used in photography as photosensitive compounds. Some substituted triary-
limidazoles are selective antagonists of the glucagons receptor and inhibitors of IL-1
biosynthesis [1]. Radziszewski and Jaap [2, 3] proposed the first synthesis of the
M. Bakavoli (&) Á H. Eshghi Á M. Rahimizadeh Á M. R. Housaindokht Á A. Mohammadi (&) Á
H. Monhemi
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, P.O. Box 91775,
Mashhad, Iran
e-mail: mbakavoli@yahoo.com
A. Mohammadi
e-mail: a.mohammady62@yahoo.com
123

M. Bakavoli et al.
imidazole core in 1882, starting from 1,2-dicarbonyl compounds, aldehydes, and
ammonia to obtain 2,4,5-triphenylimidazole. Several methods are used for synthesis
of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles; these entail use of
such catalysts as ZrCl4 [4], zeolite HY and silica gel [5], NaHSO3 [6], sulfanilic acid
[7], iodine [8], ceric ammonium nitrate [9], oxalic acid [10], ionic liquids [11],
acetic acid with microwave irradiation [12], and polymeric catalysts [13]. Each of
these methods has its own merits, but some suffer from such limitations as poor
yield, long reaction time, difficult work-up, and effluent pollution [1]. Development
of a new mild method which overcomes these disadvantages is, therefore, still a
challenge for organic chemists.
One of our objectives is to introduce a new cost-effective catalyst for synthesis
of 2,4,5-trisubstituted imidazoles in high yields under mild condition. In an
attempt to achieve this, we have investigated the catalytic activity of deep eutectic
solvent (DES) for multi-component synthesis of 2,4,5-trisubstituted imidazoles.
Multicomponent reactions (MCRs) have attracted much interest, and are highly
important in modern organic synthesis and medicinal chemistry, because these
one-pot processes involving three or more components have high atom economy
and are highly selective [14, 15]. MCRs have made a large contribution in
convergent synthesis of complex and important organic molecules from simple
and readily available starting materials, and have emerged as powerful tools for
drug discovery [16, 17]. DESs are simple ionic mixtures of quaternary ammonium
salts, for example choline chloride, with either hydrogen bond donors, for
example urea and glycerol, or with Lewis acids, for example zinc chloride. The
ability to form a hydrogen bond with the halide ion leads to a eutectic
combination, because these hydrogen-bonding interactions lead to depression in
freezing point. Thus formation of the eutectic is more energetically favored
relative to the lattice energies of the pure constituents [18, 19]. DESs derived from
choline chloride are biodegradable, non-toxic, insensitive to moisture, recyclable,
and cost-effective [18].
We report here the one-pot synthesis of 2,4,5-trisubstituted imidazoles using a
DES of choline chloride and oxalic acid as a novel catalyst (Fig. 1). We examined a
wide variety of aromatic aldehydes with a variety of substituents to establish the
importance of this catalyst in this reaction.
Experimental
Melting points were measured with an Electrothermal 9100 apparatus. IR spectra
were recorded with a Varian 3100 FT-IR spectrometer. CHN analysis was
performed with an Exeter Analytical Model CE-400 CHN Analyzer. 1H NMR
spectra were recorded with a Bruker DRX-400 Avance spectrometer at 298 K, with
DMSO-d6 as solvent. All the products are known compounds [8, 10, 20–22], and
were characterized by use of IR and NMR spectral data and comparison of their
melting points with literature data.
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Deep eutectic solvent for multi-component reactions
Preparation of catalyst
The DES catalyst was prepared in accordance with the literature [23]. Choline
chloride (10 g, 71.4 mmol) and oxalic acid (6.5 g, 71.4 mmol) were heated with
stirring at 100 °C until a homogeneous colorless liquid was obtained. The DES
formed (16.5 g, 100 %) was cooled and used in reactions without any purification
(Fig. 2). This liquid can be characterized on the basis of such physical properties as
freezing point, viscosity, and conductivity [23]. The freezing point of this DES,
taken as the temperature at which the first solid began to form, was 34 °C. FTIR
data for the liquid were (cm-1): 3361, 2962, 1751, 1479.
General procedure for preparation of 2a–h
A mixture of aldehyde (1 mmol), benzil or benzoin (1 mmol), ammonium acetate
(5 mmol), and the DES (0.5 ml), as catalyst, was stirred in a 20-ml glass tube at
110 °C for 60 min. After completion of the reaction, appropriate amounts of
distilled water were added and the mixture was stirred for 10 min. The residue was
O
O
CHO
N
R
DES catalyst
or
NH4OAc
+
+
110 o
C
N
H
R
O
2a - h
OH
Fig. 1 Deep eutectic solvent catalyzed synthesis of 2,4,5-trisubstituted imidazole
CH3
H3C
CH3
N
HO
HO
O
O
Cl
OH
Fig. 2 Deep eutectic solvent of choline chloride and oxalic acid
123

M. Bakavoli et al.
then isolated by filtration, washed with cold water, and crystallized from hot ethanol
to afford the pure product.
Spectral data
2,4,5-Triphenyl-1H-imidazole (2a)
Color: white; Mp 273–275 °C; FTIR (KBr, cm-1): 3451, 3034, 2962, 1601, 1490;
1H NMR (400 MHz, DMSO-d6): d 12.69 (s, 1H), 8.09 (d, J = 7.7 Hz, 2H),
7.56–7.22 (m, 13H); Anal. Calcd for C21H16N2: C, 85.11; H, 5.44; N, 9.45. Found:
C, 85.18; H, 5.49; N, 9.33.
2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (2b)
1
Color: white; Mp 264–266 °C; FTIR (KBr, cm-1): 3080, 1597, 1485; H NMR
(400 MHz, DMSO-d6): d 12.78 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.56–7.23 (m,
12H); Anal. Calcd for C21H15N2Cl: C, 76.24; H, 4.57; N, 8.47. Found: C, 76.20; H,
4.61; N, 8.41.
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (2c)
Color: white; Mp 230–233 °C; FTIR (KBr, cm-1): 3425, 3029, 2956, 1610, 1495,
1
1249; H NMR (400 MHz, DMSO-d6): d 12.50 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H),
7.50–7.05 (m, 12H), 3.82 (s, 3H); Anal. Calcd for C22H18N2O: C, 80.96; H, 5.56; N,
8.58. Found: C, 80.90; H, 5.51; N, 8.63.
2-(4-Nitrophenyl)-4,5-diphenyl-1H-imidazole (2d)
Color: orange; Mp 238–240 °C; FTIR (KBr, cm-1): 3400, 3088, 2928, 1597, 1515;
1H NMR (400 MHz, DMSO-d6): d 11.82 (s, 1H), 8.08 (d, J = 7.1 Hz, 2H),
7.65–7.30 (m, 12H); Anal. Calcd for C21H15N3O2: C, 73.89; H, 4.43; N, 12.31.
Found: C, 73.84; H, 4.47; N, 12.39.
2-(4-(Dimethylamino)phenyl)-4,5-diphenyl-1H-imidazole (2e)
Color: white; Mp 260–262 °C; FTIR (KBr, cm-1): 3455, 3060, 2933, 1616, 1507;
1H NMR (400 MHz, DMSO-d6): d 12.85 (s, 1H), 8.08 (d, J = 7.1 Hz, 2H),
7.65–7.10 (m, 12H), 2.8 (s, 6H); Anal. Calcd for C23H21N3: C, 81.38; H, 6.24; N,
12.38. Found: C, 81.45; H, 6.15; N, 12.41.
2-(4-Isopropylphenyl)-4,5-diphenyl-1H-imidazole (2f)
1
Color: white; Mp 255–257 °C; FTIR (KBr, cm-1): 3030, 2960, 1605, 1490; H
NMR (400 MHz, DMSO-d6): d 12.60 (s, 1H), 8.01 (d, J = 7.1 Hz, 2H), 7.65–7.10
(m, 12H), 2.96 (sep, J = 6.5, 1H), 1.26 (d, J = 6.5, 6H); Anal. Calcd for C24H22N2:
C, 85.17; H, 6.55; N, 8.28. Found: C, 85.21; H, 6.59; N, 8.20.
123

Deep eutectic solvent for multi-component reactions
2-(2-Chlorophenyl)-4,5-diphenyl-1H-imidazole (2g)
1
Color: white; Mp 196–198 °C; FTIR (KBr, cm-1): 3450, 3064, 1593, 1479; H
NMR (400 MHz, DMSO-d6): d 12.50 (s, 1H), 8.53 (s, 1H), 7.65–7.28 (m, 13H);
Anal. Calcd for C21H15N2Cl: C, 76.24; H, 4.57; N, 8.47. Found: C, 76.33; H, 4.55;
N, 8.50.
2-(3-Nitrophenyl)-4,5-diphenyl-1H-imidazole (2h)
1
Color: yellow; Mp 301–302 °C; FTIR (KBr, cm-1): 3400, 3056, 1601, 1522; H
NMR (400 MHz, DMSO-d6): d 13.12 (s, 1H), 8.90 (s, 1H), 8.56 (d, J = 7.4 Hz,
1H), 8.21 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.56–7.30 (m, 10H); Anal.
Calcd for C21H15N3O2: C, 73.89; H, 4.43; N, 12.31. Found: C, 73.84; H, 4.47; N,
12.39.
Results and discussion
The efficiency of this reaction is mainly affected by amount of catalyst, temperature,
and reaction time. To determine the best conditions, we initially investigated
condensation of benzil (1 mmol), 4-chlorobenzaldehyde (1 mmol), and ammonium
acetate (5 mmol) in the presence of the DES catalyst (0.2 ml) at room temperature.
Even after 24 h, however, only a trace of product was obtained. When the reaction
temperature was increased to 70 °C the desired product, i.e. 2b, was obtained in
30 % yield. When the reaction temperature was again increased, to 130 °C, reaction
time decreased but the yield was still not very high (Table 1, entry 4). Hence, it was
thought worthwhile to perform the reaction in the presence of a larger amount of the
catalyst. As indicated in Table 1, the maximum yield (95 %) was obtained when the
reaction was performed with 0.5 ml DES catalyst at 110 °C. A further increase of
the amount of catalyst did not affect the yield (entry 9, Table 1).
After optimizing the conditions, we used this catalyst for synthesis of
trisubstituted imidazoles from different aromatic aldehydes with a wide range of
substituents to establish the catalytic importance of the DES in this reaction. The
Table 1 Optimization of one-
pot synthesis of trisubstituted
imidazoles by DES catalyst
Entry
DES catalyst (ml)
T (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
0.2
0.2
0.2
0.2
0.2
0.3
0.4
0.5
0.6
rt
24
3
Trace
30
70
90
1
45
110
130
110
110
110
110
1
50
1
50
1
65
1
80
Benzil (1 mmol),
1
95
4-chlorobenzaldehyde
(1 mmol), and ammonium
acetate (5 mmol)
1
95
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M. Bakavoli et al.
Table 2 Synthesis of 2,4,5-triaryl-1H-imidazoles (2a–h) by use of the DES catalyst (0.5 ml)
Producta
R
Yield (%)b
Mp (°C)
Benzil
Benzoin
Found
Reported
2a
2b
2c
2d
2e
2f
2g
2h
a
4-H
90
95
85
85
90
85
90
85
90
90
80
80
80
80
85
80
273–275
264–266
230–233
238–240
260–262
255–257
196–198
301–302
272–274 [8]
262–264 [8]
228–231 [8]
239–242 [20]
259–260 [10]
253–255 [21]
197–199 [21]
[300 [22]
1
4-Cl
4-OCH3
4-NO2
4-N(CH3)2
4-CH(CH3)2
2-Cl
3-NO2
All the isolated products were characterized on the basis of their physical properties, IR and H NMR
spectroscopic analysis, and direct comparison with authentic materials
b
Reaction time (1 h)
Table 3 Reusability of the
DES catalyst for synthesis of 2b
Entry
Time (h)
Yielda (%)
1
2
3
4
1
1
1
1
95
95
93
87
a
Isolated yields
Table 4 Comparison of results using the DES catalyst with literature results
Entry
Catalyst
Conditions
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
ZrCl4
CH3CN, RT
600
6
93 [4]
Zeolite HY and silica gel
NaHSO3
Microwave irradiation
Ethanol/water, 80 °C
Ethanol/water, 80 °C
Ethanol, 75 °C
Ethanol/water, 65 °C
Ethanol/water, 80 °C
Solvent free, 110 °C
Solvent free, 110 °C
85 [5]
30
50
28
50
60
60
60
90 [6]
Sulfanilic acid
95 [7]
Iodine
98 [8]
Ceric ammonium nitrate
Oxalic acid
95 [9]
90 [10]
90 [13]
90 [this work]
Polymeric catalyst
Choline chloride and oxalic acid
corresponding results are given in Table 2. Also, direct use of benzoin, rather than
benzil, resulted in a synthesis which was much more environmentally benign but of
almost equal efficiency. As indicated in Table 2, when benzoin was used instead of
benzil, the yield of the reaction decreased slightly.
In the next step, we investigated the reusability of the DES catalyst. For this
purpose, the catalyst was used for synthesis of product 2b. When the reaction
123

Deep eutectic solvent for multi-component reactions
[NH4OAc]
H
OH
H
O
H
OH
NH3 + HOAc
DES
H2N
Ph
Ph
Ph
DES
(1) NH3
H
OH2
H2N
NH2
- H O
(2)
2
H2N
H
Ph
Ph
Ph
Ph
O
O
Ph
Ph
(1)
DES
(1)
+ DES
+
OH
O
(2)
- 2 H2O
- 2 H2O
(2)
Ph
Ph
Ph
N
H
N
N
H
air oxidation
H
Ph
Ph
N
H
Ph
H [1,5]
Ph
Ph
N
Ph
N
H
Fig. 3 Possible mechanism of synthesis of trisubstituted imidazoles by use of the DES catalyst
was completed, the mixture was washed with distilled water and the crude
product was separated by simple filtration. The DES catalyst was recovered from
the filtrate by removing the aqueous layer by distillation under vacuum. The
123

M. Bakavoli et al.
recycled catalyst was used consecutively in subsequent reactions; the results are
given in Table 3.
Finally, the efficiency of the DES catalyst was compared with that of other
catalysts reported elsewhere for synthesis of 2,4,5-triphenyl-1H-imidazole by one-
pot, three-component condensation of 2-chlorobenzaldehyde, benzil, and ammo-
nium acetate. The data listed in Table 4 show that the DES is a suitable catalyst for
this reaction.
A possible mechanism of the DES-catalyzed synthesis of trisubstituted imida-
zoles is depicted in Fig. 3 [13, 18].
In summary, in this paper we report a convenient and efficient process for one-
pot synthesis of trisubstituted imidazoles by three-component coupling of benzil or
benzoin, aldehydes, and ammonium acetate using a DES catalyst. The reaction
profile is very clean and no by-products are formed. All the synthesized imidazoles
were characterized on the basis of elemental analysis and spectral studies. We
believe this procedure enables convenient, economic, and user-friendly synthesis of
trisubstituted imidazoles of biological and medicinal importance.
Conclusion
We report an efficient and environmentally friendly approach for synthesis of
biologically active trisubstituted imidazoles by condensation of benzil or
benzoin, a variety of aromatic aldehydes, and ammonium acetate using a deep
eutectic mixture of choline chloride and oxalic acid as catalyst. High yields,
easy work-up, purification of compounds by a non-chromatographic method
(crystallization only), and reusability of the catalyst are crucial advantages of
this method.
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