Potassium dihydrogen phosphate catalyzed one-pot synthesis of 2,4,5-triaryl-1H-imidazoles

Article abstract of DOI:10.1016/j.cclet.2009.11.012

A simple and efficient method has been developed; benzil/benzoin undergoes smooth condensation with various substituted aldehyde and ammonium acetate in the presence of potassium dihydrogen phosphate (KH₂PO₄) under mild reaction conditions to afford the corresponding trisubstituted imidazole in excellent yields. The method for synthesis of product, the reaction mixture was reflux in ethanol for 40-90 min. The present method is simple, efficient, and cost-effective.

Full text of DOI:10.1016/j.cclet.2009.11.012

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 429–432
www.elsevier.com/locate/cclet
Potassium dihydrogen phosphate catalyzed one-pot synthesis
of 2,4,5-triaryl-1H-imidazoles
Ratnadeep S. Joshi, Priyanka G. Mandhane, Mohammad U. Shaikh,
*
Rajesh P. Kale, Charansingh H. Gill
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra 431 004, India
Received 26 August 2009
Abstract
A simple and efficient method has been developed; benzil/benzoin undergoes smooth condensation with various substituted
aldehyde and ammonium acetate in the presence of potassium dihydrogen phosphate (KH2PO4) under mild reaction conditions to
afford the corresponding trisubstituted imidazole in excellent yields. The method for synthesis of product, the reaction mixture was
reflux in ethanol for 40–90 min. The present method is simple, efficient, and cost-effective.
# 2009 Charansingh H. Gill. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Potassium dihydrogen phosphate (KH2PO4); 2,4,5-Triaryl-1H–imidazole; Benzil; Benzoin; Aldehyde; Ammonium acetate
Recently interest in imidazole-containing structures stems from their widespread occurrence in molecules have been
exhibits significant activity and their use in synthetic chemistry. Substituted imidazoles are well known as inhibitors of
P38MAP kinase [1], fungicides and herbicides [2], plant growth regulators [3], and therapeutic agents [4]. In addition,
they are of interest due to their herbicidal, analgesic, fungicidal, antiinflammatory, and antithrombotic activities [5].
Trifenagre [6] is a 2,4,5-triaryl-1H-imidazole that reduces platelet aggregation in several animal species and humans.
Despite their importance have been developed from pharmacological, industrial, and synthetic points of view, recently,
there are several methods reported in the literature for the synthesis of 2,4,5-triaryl-1H-imidazoles from benzil/benzoin,
aldehydes and ammonium acetate using different catalyst such as zeolite HY/silica gel [7], ZrCl4 [8], NiCl2Á6H2O [9],
ionic liquid [10], iodine [11], sodium bisulfite [12], acidic Al2O3 [13], acetic acid [14], NH4OAc [15], Yb(OTf)3[16].
However, these methods require prolonged reaction time, exotic reaction condition and high cost of catalysts and. Thus,
the development of a new method for the synthesis of 2,4,5-triaryl-1H-imidazoles derivatives would be highly desirable.
Accordingly multi-component condensations (MCCs) constitute an especially attractive synthesis strategy for
rapid and efficient generation of products due to the fact that the products are formed in a single step and also the
diversity could be achieved simply by varying the reacting components. The use of solid acid catalysts [17] has gained
a vast importance in organic synthesis due to their several advantages including operationally simplicity, no toxicity,
reusability, low cost, and ease of isolation after completion of the reaction.
* Corresponding author.
E-mail address: prof_gill@rediffmail.com (C.H. Gill).
1001-8417/$ – see front matter # 2009 Charansingh H. Gill. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.11.012

430
R.S. Joshi et al. / Chinese Chemical Letters 21 (2010) 429–432
Potassium dihydrogen phosphate (KH2PO4) was a buffer, neutralizing agent, yeast food also emerged as an efficient
heterogeneous acid catalyst [18,19]. Potassium dihydrogen phosphate was found to be mild and effective catalyst in
synthesis of 2,4,5-Triaryl-1H -imidazoles at reflux condition and commercial availability of this catalyst provides
clean conversion; greater selectivity and easy workup make this protocol practical and economically attractive.
1. Experimental
All chemicals were purchased from Merck, Aldrich and Rankem chemical companies and used without further
purification. The uncorrected melting points of compounds were taken in an open capillary in a paraffin bath. The
progresses of the reactions were monitored by thin layer chromatography (TLC). IR spectra were recorded on
PerkinElmer FT spectrophotometer in KBr disc.1H NMR spectra were recorded on an 400 MHz FT–NMR
spectrometer in CDCl3 and DMSO-d6 as a solvent and chemical shift values are recorded in units (d) relative to
tetramethylsilane (Me4Si) as an internal standard (Scheme 1).
2. General procedure of synthesis of substituted imidazole
A mixture of substituted aldehyde (10 mmol), benzil/benzoin (10 mmol), ammonium acetate (20 mmol), and
potassium dihydrogen phosphate (5 mol %) were reflux with stirring in ethanol. The progress of reaction was
monitored by TLC and after completion of reaction the mixture was cooled and ice-cold water was added (2 Â 25 mL)
and the residue crystallized from ethanol to afford the pure product.
ꢀ 3d: IR (KBr, cmÀ1): 3450 (N–H), 1600 (C C), 1580 (C N) 1H NMR (CDCl3, 400 MHz): d 7.10–7.60 (m, 10H,
2 C6H5), 7.35 (d, 2H, J = 10 Hz), 7.85 (d, 2H, J = 10 Hz) 11.86 (s, NH). EIMS (m/z): 331 (M + 1). 333 (M + 3).
1
ꢀ 3g: IR (KBr, cmÀ1): 3405 (N–H), 1597 (C C), 1562 (C N). H NMR (400 MHz, DMSO-d6): d 3.28 (s, 3H),
7.21–7.49 (m, 10H, 2C6H5), 7.22 (d, 2H, J = 7.3 Hz), 7.92 (d, 2H, J = 7.4 Hz), 12.56 (s, NH). EIMS (m/z): 327
(M + 1).
ꢀ 3l: IR (KBr, cmÀ1): 3400 (N–H), 1580 (C N), 1515 (NO2), 1335 (NO2). 1H NMR (CDCl3, 400 MHz): d 7.15–7.70
(m, 10H, 2C6H5), 7.90–8.25 (d, 4H, J = 9 Hz), 11.45 (s, 1H, N–H). EIMS (m/z): 342 (M + 1).
3. Result and discussion
As a part of our program [23] aimed at developing useful novel, selective and synthesis methods based on the use of
functionalized KH2PO4 as catalysts. In this report, we have studied using the multi-component reaction (MCR)
strategy for the synthesis of 2,4,5-triaryl-1H-imidazole by using benzil/benzoin, various substituted aldehydes and
ammonium acetate in presence of KH2PO4 as catalyst, in ethanol at reflux condition.
We have initially studied the catalytic efficiency of potassium dihydrogen phosphate for the synthesis of 2,4,5
triphenyl-1H-imidazole (Table 3 entry 3a) using benzil, benzaldehyde and ammonium acetate in different solvents and
various mol% of KH2PO4 (Scheme 1).
To determine the role of catalyst, on the model reaction the same reaction was carried in the absence of catalyst. The
desired product was not observed after long reaction time (2–3 h), this indicates that the catalyst exhibits a high
catalytic activity in this transformation and the employ of 5 mol% of the catalyst was enough to endorse the reaction.
The elevated amount of the catalyst did not progress the yield. The best result was obtained with 5 mol % of KH2PO4
the results are summarized in (Table 1, entries 1–7).
Scheme 1. Synthesis of substituted 2,4,5-triaryl-1H -imidazoles.

R.S. Joshi et al. / Chinese Chemical Letters 21 (2010) 429–432
431
Table 1
Effect of KH2PO4 on the synthesis of 2,4,5-triphenyl-1H –imidazole 3a.a.
Entry
Catalyst (mol%)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
0
1
2
3
4
5
6
40
40
40
40
40
40
40
–
24
36
58
80
93
93
a
Reaction condition: Reaction of benzaldehyde (10 mmol) with benzil (10 mmol) and ammonium acetate (20 mmol) in presence of KH2PO4 in
ethanol at reflux.
b
Isolated yield.
Table 2
Effect of solvent on the synthesis of 2,4,5-triphenyl-1H –imidazole 3a.a.
Entry
Solvent
Time (min)
Yieldb (%)
1
2
3
4
5
6
Water
40
40
40
40
40
40
–
Toluene
20
33
72
78
93
Dichloromethane
Methanol
Acetonitrile
Ethanol
a
Reaction condition: Reaction of benzaldehyde (10 mmol) with benzil (10 mmol) and ammonium acetate (20 mmol) in presence of KH2PO4
(5 mol %) at reflux.
b
Isolated yield.
The effect of different solvents like water, toluene, dichloromethane, methanol, acetonitrile, and ethanol are shown
in (Table 2 entries 1–6). It was found that ethanol stands out as the solvent of choice, with its fast conversion, high yield
and low toxicity. The presence of electron donating groups on the aldehyde resulted in the corresponding products in
low yields and the reaction was sluggish, however the presence of electron-withdrawing groups afforded the
corresponding trisubstituted imidazole in shorter reaction time with higher yields. Also, there was no effect of benzoin/
benzil on reaction give corresponding products in good yields.
Table 3
Synthesis of 2,4,5-triaryl-1H –imidazole 3(a–n) catalyzed by KH2PO4 (5 mol %) in ethanol at reflux.a.
Entry
Ar-CHO
Time (min)
Benzil
Yield (%)b
Benzil
MP (8C)
Benzoin
Benzoin
3a
3b
3c
3d
3e
3f
Benzaldehyde
40
45
50
40
50
50
50
55
55
40
55
35
55
55
55
50
60
55
65
60
60
70
65
50
70
40
65
60
93
92
92
94
90
88
90
92
89
91
90
92
90
90
90
91
90
91
88
90
86
89
85
87
86
89
90
86
277–278[20]
195–197[20]
241–242[23]
260–262[20]
268–269[20]
230–232[20]
229–230[20]
219–221[20]
260–262[21]
189–190[20]
200–201[20]
200–202[20]
260–261[20]
257–258[20]
2-Chlorobenzaldehyde
2-Napthaldehyde
4-Chlorobenzaldehyde
4-Hydroxybenzaldehyde
4-Methylbenzaldehyde
4-Methoxybenzaldehyde
3,4-Dimethoxy benzaldehyde
4-Bromobaenzaldehyde
4-Flurobenzaldehyde
Furan-2-carbaldehyde
4-Nitrobenzaldehyde
Thiopenealdehyde
3g
3h
3i
3j
3k
3l
3m
3n
4-(Dimethylamino)benzaldyde
a
All the products were characterized by 1H NMR and mass spectroscopy and compared with previously reported data [20–22].
Isolated yield.
b

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R.S. Joshi et al. / Chinese Chemical Letters 21 (2010) 429–432
After optimizing the conditions, the generality of this method was examined by the reaction of several substituted
aryl/heteroaryl aldehydes with benzil/benzoin and ammonium acetate in the 5 mol% of catalyst KH2PO4 in ethanol at
70 8C and the results are shown in Table 3. The results of synthesized compounds were compared (MP, MS, NMR, and
IR) with compounds that were reported in the literature. This comparison revealed that the compounds synthesized by
this newly developed method were exactly similar in all aspects to the reference compounds.
In conclusion, the present procedure using potassium dihydrogen phosphate as catalyst provides an efficient one-
pot synthesis of 2,4,5 trisubstituted-1H-imidazole in ethanol at reflux conditions. The advantages of this procedure are
operational simplicity, wide substrate scope, and high yields. In many cases, the products crystallized directly from the
reaction mixture having high purity. We believe that this method presents a practical alternative to existing procedures
for the synthesis of 2,4,5 trisubstituted-1H-imidazole.
Acknowledgments
The authors are thankful to University Grants Commission, New Delhi, for financial support and to the Head,
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, for his valuable support
and laboratory facilities.
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