One-pot synthesis of tri- and tetra-substituted imidazoles using sodium dihydrogen phosphate under solvent-free conditions

Article abstract of DOI:10.1016/j.cclet.2010.06.012

Sodium dihydrogen phosphate (NaH₂PO₄) efficiently catalyzes the condensation reaction of benzil, aldehydes, amines and ammonium acetate in a four-component reaction under solvent-free conditions. The reaction proceeds rapidly and affords the corresponding tetra-substituted imidazoles in high yields. Also an efficient route was developed for the synthesis of tri-substituted imidazoles from condensation of benzil, aldehydes and ammonium acetate using NaH₂PO₄.

Full text of DOI:10.1016/j.cclet.2010.06.012

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1183–1186
www.elsevier.com/locate/cclet
One-pot synthesis of tri- and tetra-substituted imidazoles using
sodium dihydrogen phosphate under solvent-free conditions
*
Zahed Karimi-Jaberi , Mohammad Barekat
Department of Chemistry, Islamic Azad University, Firoozabad Branch, P.O. Box 74715-117, Firoozabad, Fars, Iran
Received 24 February 2010
Abstract
Sodium dihydrogen phosphate (NaH2PO4) efficiently catalyzes the condensation reaction of benzil, aldehydes, amines and
ammonium acetate in a four-component reaction under solvent-free conditions. The reaction proceeds rapidly and affords the
corresponding tetra-substituted imidazoles in high yields. Also an efficient route was developed for the synthesis of tri-substituted
imidazoles from condensation of benzil, aldehydes and ammonium acetate using NaH2PO4.
# 2010 Zahed Karimi-Jaberi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Sodium dihydrogen phosphate; Imidazoles; Benzil; Solvent-free
The developing of new multi-component reactions, and improving known multi-component reactions are an area of
considerable current interest [1,2]. One such reaction is the synthesis of imidazoles. The prevalence of imidazoles in
natural products and pharmacologically active compounds has instituted a diverse array of synthetic approaches to
these heterocycles [3]. Substituted imidazoles have been identified as potent inhibitors of p38 MAP kinase [4], a core
section in some biological systems such as Losartan and Olmesartan [5], modulators of P-glycoprotein (P-gp)-
mediated multi-drug resistance (MDR) [6] and antibacterial agents [7].
There are several methods for the synthesis of highly substituted imidazoles [8]. Tetra-substituted imidazoles are
generally synthesized in a four-component condensation of aldehydes, 1,2-diketones, amines, and ammonium acetate
using a catalyst. In this context some methods and catalysts have been reported [9–16]. No doubt, these methods are
good in terms of reactivity; however they suffer from the drawbacks of long reaction time, moderate yield, use of toxic
organic solvents, the requirement of special apparatus, or harsh reaction conditions. Thus, there is a certain need for the
development of an alternate route for the production of imidazole derivatives, which surpasses those limitations.
Following our systematic studies directed towards the development of practical, safe, and environmentally friendly
procedures for several important organic transformations [17–19], in this paper we report a simple and
environmentally benign methodology for the synthesis of tetra-substituted imidazoles via direct four-component
condensation reaction between aldehydes, 1,2-diketones, amines, and ammonium acetate using catalytic amounts of
NaH2PO4 under solvent-free conditions (Scheme 1).
* Corresponding author.
E-mail address: zahed.karimi@yahoo.com (Z. Karimi-Jaberi).
1001-8417/$ – see front matter # 2010 Zahed Karimi-Jaberi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.06.012

1[(Schme_1)TD$FIG] 184
Z. Karimi-Jaberi, M. Barekat / Chinese Chemical Letters 21 (2010) 1183–1186
Scheme 1. Synthesis of tetra-substituted imidazoles.
Table 1
Synthesis of tetra-substituted imidazoles using NaH2PO4.
Entry
R
R0
Time (min)
Yield (%)
Product [Ref.]
m.p. (8C)
1
2
H
C6H5
35
35
40
35
25
35
45
40
40
40
35
90
92
89
90
92
88
80
80
82
80
92
4a [13]
4b [11]
4c [14]
4d [12]
4e [9]
215–217
164–166
150–152
183–185
186–189
165–167
143–145
208–210
124–126
164–165
140–142
H
C6H5CH2
C6H5
3
4-Cl
4-CH3
4-CH3
4-CH3
H
4
C6H5
5
4-CH3C6H4
4-ClC6H4
CH3
6
4f [9]
7
4g [12]
4h [9]
4i [9]
8
4-CH3
4-CH3
4-CH3
2-Cl
CH3
9
CH3CH2
cyclo-C6H11
C6H5CH2
10
11
4j [9]
4k [14]
To optimize the reaction conditions, the synthesis of 1,2,4,5-tetraphenylimidazole by the reaction of benzil,
benzaldehyde, aniline and ammonium acetate was used as a model reaction. Reactions at different temperatures and
various molar ratios of substrates in the presence of H2NaPO4 revealed that the best conditions were solvent-free at
120 8C. To show the generality of this method the optimized system used for the synthesis of other imidazoles
derivatives 4a–k (Table 1).
This method offers some advantages in term of simplicity of performance, solvent-free condition, and low reaction
time. Several examples illustrating this novel and general method for the synthesis of tetra-substituted imidazoles are
summarized in Table 1. It should be noted that, this method is effective for the preparation of tetra-substituted
imidazoles from both aliphatic as well as aromatic amines. All products are known compounds and structures of them
were confirmed by comparison with their known physical and spectral (NMR and IR) data.
Under the same conditions, this approach can be repeated for synthesis of 2,4,5-tri-substituted imidazoles 5a–c by
condensation reaction between benzil, aldehydes and ammonium acetate (Scheme 2). The optimize molar ratio of
benzil/aldehyde/ammonium acetate/NaH2PO4 was 1:1:2:0.33. Thus, ammonium acetate effectively participated in the
condensation with aldehyde, and benzil to give the corresponding tri-substituted imidazoles 5a–c. The results of the
condensation of benzil, aldehydes and 2 equivalent of ammonium acetate are represented in Table 2.
Table 3 compares our results for the synthesis of 1-benzyl-2,4,5-triphenylimidazole 4b with the results of different
catalysts and reaction conditions obtained by other groups.
In conclusion a convenient and efficient protocol for the synthesis of tri- and tetra-substituted imidazoles in the
presence of sodium dihydrogen phosphate under solvent-free conditions at 120 8C has been developed. The catalyst is
readily available and inexpensive and can conveniently be handled and removed from the reaction mixture. The simple
procedure combined with low reaction times, solvent-free condition and low cost make this method economic, benign,
and a user-friendly process for the synthesis of substituted imidazoles of biological and medicinal importance.
[(Schme_2)TD$FIG]
Scheme 2. Synthesis of tri-substituted imidazoles.

Z. Karimi-Jaberi, M. Barekat / Chinese Chemical Letters 21 (2010) 1183–1186
1185
Table 2
Synthesis of tri-substituted imidazoles using NaH2PO4.
Entry
R
Time (min)
Yield (%)
1
2
3
H
30
25
35
99
99
98
4-CH3
4-Br
Table 3
Comparison of efficiency of various catalysts in the synthesis of 1-benzyl-2,4,5-triphenylimidazole 4b.
Catalyst
Conditions
Time (min)
Yield (%)
Ref.
NaHSO4ꢀSiO2
K5CoW12O40ꢀ3H2O
HClO4–SiO2
BF3ꢀSiO2
140 8C/solvent-free
140 8C/solvent-free
140 8C/solvent-free
140 8C/solvent-free
Methanol/r.t.
120
120
6
92
90
96
80
79
88
92
[9]
[11]
[13]
120
440
8
[14]
InCl3ꢀ3H2O
[15]
H4[PMo11VO40
]
Ethanol/reflux
[12]
NaH2PO4
120 8C/solvent-free
35
This work
1. Experimental
1.1. General procedure for the synthesis of 1,2,4,5-tetra-substituted imidazoles 4a–k
A mixture of benzil (1 mmol), amine (1 mmol), aldehyde (1 mmol), ammonium acetate (1 mmol) and NaH2PO4
(0.33 mmol) was stirred at 120 8C for the appropriate time indicated in Table 1. The progress of reaction was
monitored by TLC (ethyl acetate/n-hexane = 1/4). After completion of the reaction, the reaction mixture was cooled to
room temperature. Acetone was added to the mixture which was filtered to remove the catalyst. After evaporation of
the solvent under reduced pressure, the resulting solid residue was recrystalized from acetone–water (15:1) to obtain
pure product 4. Products were characterized by comparison of their physical and spectral data with those of authentic
samples.
1.2. General procedure for the synthesis of 2,4,5-tri-substituted imidazoles 5a–c
A mixture of benzil (1 mmol), aldehyde (1 mmol), ammonium acetate (2 mmol) and NaH2PO4 (0.33 mmol) was
stirred at 120 8C for the appropriate time indicated in Table 2. The progress of reactions was monitored by TLC (ethyl
acetate/n-hexane = 1/4). After completion of the reaction, the reaction mixture was cooled to room temperature.
Acetone was added to the mixture which was filtered to remove the catalyst. After separation of solid, the solvent was
evaporated under reduced pressure. The resulting solid residue was purified by recrystallization from acetone–water
(15:1). Products were characterized by comparison of their physical and spectral data with those of authentic samples.
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