Facile and rapid synthesis of polysubstituted imidazoles by employing Y(NO3)3×6H2O as catalyst

Article abstract of DOI:10.5562/cca1979

An efficient and environmentally adapted synthesis of polysubstituted imidazoles in one-pot and multicomponent reaction of various aldehydes, benzil, aliphatic and aromatic primary amines and ammonium acetate under solvent-free condition is reported. Highly efficient role of Y(NO₃) ₃×6H₂O as catalyst in this synthesis was shown. By this advantage, several polysubstituted imidazoles as pharmaceutical important molecules can be prepared in high yield and high purity. This method is very easy and rapid for the synthesis of imidazole derivatives. All products were deduced from their IR and NMR spectroscopic and elemental analysis data. The catalyst exhibited remarkable reusable activity.

Full text of DOI:10.5562/cca1979

CROATICA CHEMICA ACTA
CCACAA, ISSN 0011-1643, e-ISSN 1334-417X
Croat. Chem. Acta 85 (2) (2012) 147–153.
http://dx.doi.org/10.5562/cca1979
Original Scientific Article
Facile and Rapid Synthesis of Polysubstituted Imidazoles by
Employing Y(NO3)3 ×6H2O as Catalyst
*
Bahador Karami, Fatemeh Mohammadpour Dehghani, and Khalil Eskandari
Department of Chemistry, Yasouj University, Yasouj, IR-75918-74831, P. O. Box 353, Iran
RECEIVED AUGUST 15, 2011; REVISED DECEMBER 18, 2011; ACCEPTED DECEMBER 22, 2011
Abstract. An efficient and environmentally adapted synthesis of polysubstituted imidazoles in one-pot and
multicomponent reaction of various aldehydes, benzil, aliphatic and aromatic primary amines and ammo-
nium acetate under solvent-free condition is reported. Highly efficient role of Y(NO3)3 ×6H2O as catalyst
in this synthesis was shown. By this advantage, several polysubstituted imidazoles as pharmaceutical im-
portant molecules can be prepared in high yield and high purity. This method is very easy and rapid for
the synthesis of imidazole derivatives. All products were deduced from their IR and NMR spectroscopic
and elemental analysis data. The catalyst exhibited remarkable reusable activity. (doi: 10.5562/cca1979)
Keywords: catalyst, Y(NO3)3 ×6H2O, benzil, polysubstituted imidazoles
INTRODUCTION
polysubstituted imidazoles have been shown.
A new method for the synthesis of polysubstituted
Multicomponent reactions (MCRs) are the special type
of organic reactions which afford complex products
from reaction of three or more simple starting materials
in one pot. Because of atom-economy, convergent char-
acter, operational simplicity, structural diversity and
complexity of the molecules in these reactions, they
have attracted much attention.1,2
The imidazoles and their derivatives are very im-
portant molecules because many applications in chemi-
cal processes, especially in pharmaceuticals.3,4 Various
substituted imidazoles act as inhibitors of p38 MAP
kinase,5 B-Raf kinase,6 glucagon receptors,7 plant growth
regulators,8 antitumor9 and pesticides.10
imidazoles was obtained by condensation of benzil with
aldehydes, primary amines and ammonium acetate in
the presence of Y(NO3)3 ×6H2O as an effective catalyst
in solvent free condition (Scheme 1).
Herein, we report a simple, rapid and one-pot pro-
cedure for the synthesis of three and four substituted
imidazoles by using Y(NO3)3 ×6H2O with high yields
and short reaction times. While using benzil 1, aromatic
aldehydes 2, aromatic and aliphatic amine 3, ammonium
acetate 4 and Y(NO3)3 ×6H2O as catalyst under solvent-
free condition lead to tetrasubstituted imidazoles 5, that
in the absence of aromatic and aliphatic amine 3,
trisubstituted imidazoles 6 were obtained (Scheme 1).
There are many methods for the synthesis of
polysubstituted imidazoles such as condensation of
diones, aldehydes, primary amines and ammonia in the
presence of various acid catalysts,11–13 N-alkylation of
trisubstituted imidazoles,14 condensation of benzil or
benzoin acetate with aldehydes, primary amines and
ammonia in the presence of copper acetate15,16 etc. The
first mention method is the most well-known and classi-
cal method.
However, some of these methods, involved long
reaction times, and unsatisfactory yields. Therefore,
improvements in these syntheses have been sought
continuously. In this work, high activation, and reusabil-
ity of Y(NO3)3 ×6H2O as a catalyst in the synthesis of
EXPERIMENTAL SECTION
Melting points were measured on an elecrtothermal
KSB1N apparatus. IR spectra were recorded in the ma-
trix of KBr with JASCO FT-IR-680 plus spectrometer.
1H NMR and 13C NMR spectra were recorded on a FT-
NMR Bruker Avance Ultra Shield Spectrometer at
400.13 and 100.62 MHz in CDCl3 and DMSO-d6 as
solvent in the presence of tetramethylsilane as internal
standard. TLC was performed on TLC-Grade silica gel-
G/UV 254 nm plates. The products were isolated and
characterized by physical and spectral data and they
were compared with authentic samples (Table 1).
* Author to whom correspondence should be addressed. (E-mail: karami@mail.yu.ac.ir)

148
B. Karami et al., Synthesis of Polysubstituted Imidazoles
Scheme 1. Synthesis of polysubstituted imidazoles in the presence of Y(NO3)3 ×6H2O as catalyst.
Table 1. Synthesis of polysubstituted imidazoles catalyzed by Y(NO3)3 ×6H2O
M.p. / °C
(from literature)
Compound
R1
R2
t / min
Yield(a) / %
C6H5
4-BrC6H4
C6H5CH2
30
25
55
60
25
20
40
50
25
95
45
25
50
10
30
25
100
60
35
140
25
10
96
90
98
85
85
80
75
90
98
96
95
93
90
89
90
92
70
68
97
83
90
91
162–164 (Ref. 13)
169–170 (Ref. 13)
156–158 (Ref. 17)
160–162 (Ref. 17)
193–195 (Ref. 18)
150–152(b)
5a
5b
5c
5d
5e
5f
C6H5CH2
4-CH3C6H4
4-ClC6H4
C6H5CH2
C6H5CH2
2-ClC6H4
C6H5CH2
3-NO2C6H4
4-CH3C6H4
4-OCH3C6H4
2-OH-5-BrC6H3
4-Benzyloxyphenyl
2,4-Dichlorophenyl
4-CH3C6H4
C6H5
C6H5CH2
Cyclohexyl
160–161 (Refs. 19,20)
148–151 (Ref. 21)
156–158(b)
138–139(b)
216–219(b)
5g
5h
5i
C6H5CH2
4-ClC6H4
C6H5CH2
5j
C6H5CH2
5k
5l
C6H5
182–184 (Ref. 20)
272–273 (Ref. 22)
120–122 (Ref. 23)
209–211 (Ref. 24)
204–206 (Ref. 21)
227–230 (Ref. 22)
235–236 (Ref. 25) (c)
283–286(b)
–
–
–
–
–
–
–
–
–
–
6a
6b
6c
6d
6e
6f
3-BrC6H4
2-OHC6H4
2-OCH3C6H4
4-OCH3C6H4
4-Benzyloxyphenyl
2-Fluorenyle
3-Indolyl
6g
6h
6i
311–313(b)
4-ClC6H4
257–259 (Ref. 26)
308–309 (Ref. 27)
3-NO2C6H4
6j
(a) Refers to isolated yields.
(b) Novel compound.
(c) Melting point of this compound was not reported by author.
Croat. Chem. Acta 85 (2012) 147.

B. Karami et al., Synthesis of Polysubstituted Imidazoles
149
General Procedure for Synthesis of 1,2,4,5-Tetrasub-
stituted Imidazoles by Y(NO3)3 × 6H2O
129.13, 129.31, 130.28, 130.43, 130.74, 131.04, 134.18,
135.04, 136.81, 137.30, 138.22.
A mixture of aromatic aldehyde (1 mmol), benzil (1
mmol), primary amine (1 mmol), ammonium acetate (1
mmol) and Y(NO3)3 ×6H2O (mole ratio, r = 15 %) were
stirred at 140 °C in solvent-free condition. The progress
of reaction was monitored by TLC. After completion of
reaction, the mixture was coolled to room temperature
and was solved in 50 mL water then was filtered. Ob-
tained products were purified by crystallization from
acetone-water mixture (V(acetone) :V(water) =10 : 1).
The products were characterized by IR, NMR, and
through comparison of their physical properties with
those reported in literature.13,17–27
Hence, general procedure for the synthesis of
2,4,5-trisubstituted imidazoles is same to the 1,2,4,5-
tetrasubstituted imidazoles, but it needs to 10 % of cata-
lyst, 2 mmol of ammonium acetate instead of 1 mmol in
the absence of primary amine.
1-Benzyl-2-(2-chlorophenyl)-4,5-diphenyl-1H-
imidazole (5e)
M.p. 139–140 °C (Ref. 18) 140–142 °C; IR (KBr) νmax

/
cm–1: 3062, 3026, 2930, 1602, 1485, 1349, 1079, 758,
690. 1HNMR (400.13 MHz, DMSO-d6) δ /ppm: 4.74 (s,
2H), 6.42–7.42 (m, 19H). 13CNMR (100.62 MHz,
DMSO-d6) δ/ppm: 43.17, 126.00, 126.50, 126.68,
127.48, 128.44, 128.69, 128.99, 129.15, 129.36, 129.74,
129.81, 130.33, 130.61, 130.89, 131.08, 131.15, 132.92,
133.80, 134.24, 134.95, 136.80, 137.65, 145.13.
1-Benzyl-2-(3-nitrophenyl)-4,5-diphenyl-1H-
imidazole (5f)
M.p. 150–152 °C; IR (KBr) νmax /cm–1: 3061, 3026,
2308, 1601, 1521, 1497, 1350, 810, 730, 696. H NMR

1
(400.13 MHz, DMSO-d6) δ /ppm: 5.19(s, 2H), 6.89 (d,
J = 6.15 Hz, 2H), 7.21–7.63 (m, 14H), 8.04 (d, J =
7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.57 (s, 1H).
13CNMR (100.62 MHz, DMSO-d6) δ/ppm: 47.42,
122.30, 122.59, 124.71, 125.67, 125.73, 126.71, 127.15,
127.84, 127.97, 128.56, 129.36, 129.93, 130.24, 131.57,
132.98, 133.51, 135.78, 144.23, 147.20. Anal. Calcd.
mass fractions of elements, w / %, for C28H21N3O2
(Mr = 431.49): C 77.94, H 4.91, N 9.74. Found: C 77.87,
H 4.83, N 9.62.
Representative Spectral Data
1-Benzyl-2,4,5-triphenyl-1H-imidazole (5a)

M.p. 162–164 °C (Ref. 13) 163–165 °C; IR (KBr) νmax
/
cm–1: 3061, 3026, 2308, 1601, 1521, 1497, 1350, 761,
1
696. H NMR (250 MHz, DMSO-d6) δ /ppm: 5.13 (s,
2H), 7.18–8.41 (m, 20H). 13CNMR (62.69 MHz, DMSO-
d6) δ /ppm: 48.29, 126.00, 126.38, 126.81, 128.11,
129.08, 129.58, 129.90, 130.09, 130.98, 131.09, 135.09,
137.57, 148.09.
1-Cyclohexyl-4,5-diphenyl-2-p-tolyl-1H-imidazole (5g)

M.p. 160–161 °C (Ref. 20) 162–164 °C; IR (KBr) νmax
/
cm–1: 3058, 3020, 2930, 1600, 1495, 1349, 825, 766,
1
1-Benzyl-2-(4-bromophenyl)-4,5-diphenyl-1H-
695. HNMR (400.13 MHz, CDCl3) δ /ppm: 0.95 (m,
imidazole (5b)
2H), 1.35–1.55 (m, 6H), 1.75 (m, 2H), 2.35 (s, 3H),
3.80–3.97 (m, 1H), 6.70–7.45 (m, 14H). 13CNMR
(100.62 MHz, CDCl3) δ /ppm: 21.45, 25.12, 26.21,
33.59, 58.31, 125.94, 126.01, 126.68, 127.60, 127.89,
127.97, 128.18, 128.65, 128.76, 128.89, 129.01, 129.04,
129.15, 129.50, 129.87, 132.25, 132.81, 134.77, 137.68,
138.74, 147.84.

M.p. 169–170 °C (Ref. 13) 170–172 °C; IR (KBr) νmax
/
cm–1: 3059, 3027, 2938, 1599, 1479, 1358, 1070, 835,
1
758, 694. H NMR (400.13 MHz, DMSO-d6) δ /ppm:
4.86 (s, 2H), 6.61–7.46 (m, 19H). 13CNMR (100.62
MHz, DMSO-d6) δ /ppm: 49.41, 125.86, 126.51,
126.78, 127.53, 128.14, 128.25, 128.74, 128.87, 130.48,
130.79, 131.03, 131.79, 137.33.
1-Benzyl-2-(4-methoxyphenyl)-4,5-diphenyl-1H-
1-Benzyl-4,5-diphenyl-2-p-tolyl-1H-imidazole (5c)
imidazole (5h)


M.p. 156–158 °C (Ref. 17) 156–157 °C; IR (KBr) νmax
/
M.p. 163–166 °C (Ref. 21) 164–165 °C; IR (KBr) νmax
/
cm–1: 3060, 3027, 2926, 1600, 1496, 1349, 826, 767,
694. 1HNMR (400.13 MHz, DMSO-d6) δ /ppm: 2.08 (s,
3H), 4.91 (s, 2H), 6.61–7.40 (m, 19H). 13CNMR (100.62
MHz, DMSO-d6) δ /ppm: 22.52, 49.41, 127.15, 127.47,
127.94, 128.46, 129.22, 129.72, 129.92, 130.10, 130.45,
131.03, 132.23, 138.80, 140.01, 146.34.
cm–1: 3063, 3019, 2295, 1609, 1519, 1493, 1354, 696.
1H NMR (400.13 MHz, CDCl3) δ /ppm: 3.81 (s, 3H),
5.08 (s, 2H), 6.82–7.56 (m, 15H), 7.58 (d, J = 2.3 Hz,
4H). 13CNMR (100.62 MHz, CDCl3) δ /ppm: 47.16,
54.26, 112.95, 122.40, 124.94, 125.21, 125.71, 126.26,
127.00, 127.49, 127.52, 127.71, 128.02, 128.70, 129.37,
130.03, 130.12, 133.53, 136.64, 136.78, 146.94, 159.04.
1-Benzyl-2-(4-chlorophenyl)-4,5-diphenyl-1H-
imidazole (5d)
1-(4-Chlorophenyl)-2-(2-hydroxy-5-bromophenyl)-4,5-

M.p. 160–162 °C (Ref. 17) 157–158 °C; IR (KBr) νmax
/
diphenyl-1H-imidazole (5i)
cm–1: 3059, 3029, 2936, 1600, 1480, 1357, 1089, 835,
M.p. 156–158 °C; IR (KBr) νmax /cm–1: 3458, 3063,

1
1
758, 693. HNMR (400.13 MHz, DMSO-d6) δ /ppm:
1659, 1593, 1578, 1211, 1174, 1096. HNMR (400.13
4.9 (s, 2H), 6.60–7.50 (m, 19H). 13CNMR (100.62 MHz,
MHz, DMSO-d6) δ/ppm: 6.92–8.53 (m, 17H), 13.06 (s,
DMSO-d6) δ/ppm: 48.31, 125.88, 126.55, 127.54,
1H). 13CNMR (100.62 MHz, DMSO-d6) δ/ppm: 115.17,
Croat. Chem. Acta 85 (2012) 147.

150
B. Karami et al., Synthesis of Polysubstituted Imidazoles
123.92, 125.53, 127.64, 134.31, 137.31, 139.26, 140.54,
151.31, 164.74, 166.94. Anal. Calcd. mass fractions of
elements, w / %, for C27H18BrClN2O (Mr = 501.80): C
64.62, H 3.62, N 5.58. Found: C 64.51, H 3.53, N 5.49.
2-(2-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (6d)

M.p. 204–206 °C (Ref. 24) 210–211 °C; IR (KBr) νmax
/
cm–1: 3388, 3062, 2933, 1584, 1530, 1481, 1240, 1099.
1HNMR (400.13 MHz, DMSO-d6) δ /ppm: 4.05 (s, 3H),
7.03–7.69 (m, 13H), 8.50 (d, J = 8 Hz, 1H), 10.51 (s,
1H). 13CNMR (100.62 MHz, DMSO-d6) δ /ppm:
126.45, 126.83, 127.33, 128.22, 128.59, 129.07, 129.67,
129.91, 130.26, 131.02, 132.98, 133.97.
1-Benzyl-2-(4-benzyloxyphenyl)-4,5-diphenyl-1H-
imidazole (5j)
M.p. 138–139 °C; IR (KBr) νmax /cm–1: 2857, 1601,

1
1575, 1526, 1289, 1247, 1177. HNMR (400.13 MHz,
DMSO-d6) δ /ppm: 2.18 (s, 2H), 5.06 (s, 2H), 6.83–7.82
(m, 24H). 13CNMR (100.62 MHz, DMSO-d6) δ /ppm:
48.29, 70.03, 115.05, 123.79, 126.06, 126.38, 126.85,
127.41, 127.53, 128.11, 128.16, 128.68, 128.86, 129.89,
130.50, 131.14, 131.23, 134.70, 136.76, 137.75, 137.94,
148.02, 159.33. Anal. Calcd. mass fractions of elements,
w / %, for C35H28N2O (Mr = 492.61): C 85.34, H 5.73, N
5.69. Found: C 85.18, H 5.61, N 5.54.
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (6e)

M.p. 227–230 °C (Ref. 22) 228–230 °C; IR (KBr) νmax
/
cm–1: 3433, 3027, 1613, 1578, 1542, 1248, 1176.
1HNMR (400.13 MHz, DMSO-d6) δ /ppm: 3.87 (s, 3H),
6.98–7.86 (m, 10H), 7.55 (s, 2H), 7.85 (d, J = 8.4 Hz,
2H), 9.23 (s, 1H). 13CNMR (100.62 MHz, DMSO-d6)
δ /ppm: 55.36, 114.27, 122.78, 126.78, 127.30, 127.80,
128.55, 146.14, 160.16.
1-Benzyl-2-(2,4-dichlorophenyl)-4,5-diphenyl-1H-
imidazole (5k)
2-(4-Benzyloxyphenyl)-4,5-diphenyl-1H-imidazole (6f)
M.p. 235–236 °C (Ref. 25); IR (KBr) νmax /cm–1: 3054,

1
M.p. 216–219 °C; IR (KBr) νmax /cm–1: 3069, 2924,
3018, 2930, 1608, 1578, 1541, 1230, 1181. HNMR

1557, 1523, 1459, 1092. 1HNMR (400.13 MHz, DMSO-
d6) δ /ppm: 2.18 (s, 2H), 7.45–8.41 (m, 13H), 8.64 (d, J
= 7.6 Hz, 1H), 8.77 (t, J = 8.4 Hz, 2H). 13CNMR
(100.62 MHz, DMSO-d6) δ /ppm: 120.88, 121.13,
122.98, 123.47, 123.76, 125.00, 126.03, 126.82, 127.20,
127.39, 127.43, 127.56, 129.00, 129.58, 131.28, 132.31,
133.77, 135.20, 136.93, 145.22. Anal. Calcd. mass frac-
tions of elements, w / %, for C28H20Cl2N2 (Mr = 455.38):
C 73.85, H 4.43, N 6.15. Found: C 73.71, H 4.36, N 6.09.
(400.13 MHZ, DMSO-d6) δ/ppm: 5.16 (s, 2H), 7.11–
7.54 (m, 17H), 8.01 (d, J = 8.8 Hz, 2H), 12.51 (s, 1H).
13CNMR (100.62 MHz, DMSO-d6) δ/ppm: 69.78,
115.42, 123.82, 126.09, 127.18, 127.52, 128.26, 128.36,
128.63, 128.82, 128.93, 129.10, 135.79, 137.41, 146.06,
158.99.
2-Fluorenyl-4,5-diphenyl-1H-imidazole (6g)
M.p. 283–286 °C; IR (KBr) νmax /cm–1: 3350, 3054,

2950, 1601, 1532, 1500. 1HNMR (400.13 MHz, DMSO-
d6) δ /ppm: 4.01 (s, 2H), 7.33–8.00 (m, 15H), 8.130 (d,
J = 7.6 Hz, 1H), 8.32 (s, 1H), 12.733 (s, 1H). 13CNMR
(100.62 MHz, DMSO-d6) δ /ppm: 39.92, 120.36,
120.68, 122.37, 124.57, 125.64, 126.73, 127.42, 128.28,
128.90, 129.36, 141.23, 141.63, 143.88, 143.95, 146.42.
Anal. Calcd. mass fractions of elements, w / %, for
C28H20N2 (Mr = 384.47): C 87.47, H 5.24, N 7.29.
Found: C 87.41, H 5.29, N 7.22.
1,4,5-Triphenyl-2-p-tolyl-1H-imidazole (5l)

M.p. 182–184 °C (Ref. 20) 185–188 °C; IR (KBr) νmax
/
cm–1: 3055, 3022, 2930, 1600, 1495, 1349, 826, 767,
1
694. H NMR (400.13 MHz, CDCl3) δ /ppm: 2.34 (s,
3H), 7.07–7.36 (m, 17H), 7.64 (d, J = 7.1 Hz, 2H).
13CNMR (100.62 MHz, CDCl3) δ /ppm: 20.23, 124.24,
125.49, 126.39, 126.67, 126.85, 127.09, 127.12, 127.27,
127.45, 127.77, 127.79, 127.98, 128.46, 129.74, 130.11,
136.23, 137.10, 146.06.
3-Indolyl-4,5-diphenyl-1H-imidazole (6h)
M.p. 311–313 °C; IR (KBr) νmax /cm–1: 3413, 3055,
1598, 1490, 1451. HNMR (400.13 MHZ, DMSO-d6)

2-(3-Bromophenyl)-4,5-diphenyl-1H-imidazole (6b)
1

M.p. 120–122 °C (Ref. 23) 118–122 °C; IR (KBr) νmax
/
cm–1: 3387, 3062, 1584, 1529, 1480, 1241, 1100.
1HNMR (400.13 MHz, CDCl3) δ /ppm: 7.26–7.78 (m,
14H), 9.40 (s, 1H). 13CNMR (100.62 MHz, CDCl3)
δ /ppm: 121.86, 125.62, 126.02, 126.75, 127.41, 127.70,
127.76, 128.11, 131.05.
δ /ppm: 7.128–7.587 (m, 13H), 8.006 (d, J = 2.4 Hz,
1H), 8.462 (d, J = 7.2 Hz, 1H), 11.404 (s, 1H), 12.4
(s, 1H). 13CNMR (100.62 MHz, DMSO-d6) δ /ppm:
106.95, 112.13, 120.24, 121.92, 122.40, 124.53, 125.51,
127.36, 128.05, 128.92, 136.75, 144.11. Anal. Calcd.
mass fractions of elements, w / %, for C23H17N3
(Mr = 335.40): C 82.36, H 5.11, N 12.53. Found: C
82.29, H 5.21, N 12.40.
2-(2-Hydroxyphenyl)-4,5-diphenyl-1H-imidazole (6c)
M.p. 209–211 °C (Ref. 24) 209–210 °C; IR (KBr) νmax

/
cm–1: 3450, 3385, 1584, 1529, 1480, 1240, 1098.
1HNMR (400.13 MHz, CDCl3) δ /ppm: 6.92 (d, J =
7.28 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.26–7.62 (m,
12H), 9.36 (s, 1H), 12.83 (s, 1H). 13CNMR (100.62
MHz, CDCl3) δ /ppm: 111.39, 116.80, 117.92, 122.00,
126.32, 127.14, 127.38, 128.07, 129.54, 144.67, 156.45.
2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (6i)

M.p. 257–259 °C (Ref. 26) 257–260 °C; IR (KBr) νmax
/
cm–1: 3386, 3062, 1584, 1529, 1481, 1240, 1099.
1HNMR (400.13 MHZ, CDCl3) δ /ppm: 6.99–7.36 (m,
12H), 7.86 (d, J = 7 Hz, 2H), 12.09 (s, 1H). 13CNMR
Croat. Chem. Acta 85 (2012) 147.

B. Karami et al., Synthesis of Polysubstituted Imidazoles
151
Table 2. The effect of solvents in synthesis of polysubstituted
imidazoles for model reaction
optimum condition for this synthesis. In model reaction,
in the presence of Y(NO3)3×6H2O (15 %) as catalyst,
the mixture of benzil (1 mmol), benzaldehyde (1 mmol),
ammonium acetate (1 mmol), benzylamine (1 mmol)
carried out in different solvents such as water, ethanol,
methanol, chloroform, acetonitrile and solvent-free
conditions. From these experiments, it was clearly
demonstrated that the solvent-free conditions offer the
best conditions to accomplish this synthesis (Table 2).
Carrying out the model reaction in the absence of
catalyst at solvent-free conditions and room temperature
for 24 h lead to a very poor yield (12 %) of the product.
In the absence of catalyst for enhance the yield of the
desired product, temperature of the reaction was in-
creased to 200 °C, but no appreciable increment in the
product yield was observed. Therefore, we found that
the presence of the catalytic amount of Y(NO3)3 ×6H2O
and solvent-free condition are the best conditions for
this synthesis.
Solvent
Water
t / min
90
Yield / %
46
75
78
49
73
96
Ethanol
35
Methanol
Chloroform
Acetonitrile
Solvent-free
40
120
80
30
(100.62 MHz, CDCl3) δ /ppm: 125.94, 126.72, 127.39,
127.68, 128.24, 132.70, 144.31.
2-(3-Nitrophenyl)-4,5-diphenyl-1H-imidazole (6j)

M.p. 308–309 °C (Ref. 27) >295 °C; IR (KBr) νmax
/
cm–1: 3380, 3065, 1580, 1527, 1479, 1239, 1099, 810,
1
758. HNMR (400.13 MHZ, DMSO-d6) δ/ppm: 7.30–
We also evaluated quantity of required catalyst in
synthesis of tetrasubstituted imidazoles for model reac-
tion (compound 5a). It was found that maximum yield
(96 %) obtained, when the reaction was carried out with
15 % of Y(NO3)3 ×6H2O, but for the synthesis of 2,4,5-
trisubtitutedimidazoles, the best amount of the catalyst
was found 10 % of catalyst, when the reaction between
benzil 1 (1 mmol), aromatic aldehydes 2 (1 mmol) and
ammonium acetate 4 (2 mmol) was chosen as a model
reaction (Table 3).
7.53 (m, 10H), 7.78 (t, J = 8 Hz, 1H), 8.51 (d, J = 8 Hz,
1H), 8.95 (t, J = 1.8 Hz, 1H), 9.41 (d, J = 8 Hz, 1H),
13.10 (s, 1H), 13CNMR (100.62 MHz, DMSO-d6)
δ /ppm: 119.40, 122.61, 127.13, 128.44, 128.68, 130.44,
131.17, 131.82, 143.38, 148.37.
RESULTS AND DISCUSSION
Firstly, synthesis of 1-benzyl-2,4,5-triphenyl imidazoles
was chosen as a model reaction (compound 5a) in the
synthesis of polysubstituted imidazoles to determine the
We also examined the model reactions at various
temperatures to find out its effect on the progress of the
Table 3. Optimization of mole ratio of the catalyst in synthesis of tri and tetrasubstituted imidazoles
Trisubstituted imidazole
Tetrasubstituted imidazole
Mole ratio of
Y(NO3)3 × 6H2O / %
t / min
Yield / %
t / min
120
110
60
Yield / %
0.5
1
110
90
60
50
50
40
75
80
88
90
90
90
50
60
80
90
96
80
5
10
15
20
40
30
25
Table 4. Optimization of temperature for model reaction
Trisubstituted imidazole
Tetrasubstituted imidazole
ϑ / °C
t / min
225
160
100
50
Yield / %
t / min
180
110
80
Yield / %
80
70
85
85
90
88
65
80
85
96
90
100
120
140
160
30
60
40
Croat. Chem. Acta 85 (2012) 147.

152
B. Karami et al., Synthesis of Polysubstituted Imidazoles
Table 5. Reusability results of Y(NO3)3 ×6H2O on the reaction
Reusability of the Catalyst
process for the model reaction
At the end of the reaction, the catalyst was filtered,
washed with diethyl ether, dried at 130 °C for 1 h,
and reused in another reaction. We found that
Y(NO3)3 ×6H2O showed high catalytic activity. Moreo-
ver, it can be recovered and reused several times with-
out significant loss of activity. The results of these ob-
servations for the model reaction are shown in Table 5.
A probable mechanism for the synthesis of
tetrasubstituted imidazoles may be postulated as shown
below (Scheme 2).
As can be seen in Scheme 2, Y(NO3)3 ×6H2O is a
Lewis acid so that it can activated the carbonyl group of
aldehydes 2 to decrease the energy of transition state.
Then nucleophilic attack of amine 3 on the activated
carbonyl of aldehydes, resulted to the formation of
imine, and it followed by nucleophilic attack of the
insitu generated ammonia from 4 to the imine, giving
the intermediate 7. From condensation of intermediate 7
with benzil 1 and dehydration of it, corresponding
imidazoles 5 are produced.
Total reusability
t / min
30
Yield / %
1
2
3
4
5
96
95
95
97
97
30
35
45
55
reaction in the presence of optimized amount of catalyst
(Table 4). The maximum rate of reaction was obtained
at 140 °C as the optimum temperature for tri and tetra-
substituted imidazoles.
As can be concluded from Table 4, the reaction
proceeded slowly at 80 °C. With increasing temperature
to 140 °C, reaction yield was increased and time of
reaction was decreased, when the reaction was heated
above 140 °C, so high temperatures did not further
improved yield and decrease time of reaction.
According to the archived optimal condition, we
conducted the synthesis of polysubstituted imidazoles in
the presence of Y(NO3)3 ×6H2O as catalyst in solvent-
free condition at 140 °C.
The probable mechanism for synthesis of
trisubstituted imidazoles is the same (amine was substi-
tuted with ammonium acetate).
Scheme 2. The suggested mechanism for synthesis of tetrasubstituted imidazoles.
Croat. Chem. Acta 85 (2012) 147.

B. Karami et al., Synthesis of Polysubstituted Imidazoles
153
7. S. E. De Laszlo, C. Hacker, B. Li, D. Kim, M. MacCoss, N.
Mantlo, J. V. Pivnichny, L. Colwell, G. E. Koch, M. A. Cascieri,
and W. K. Hagmenn, Bioorg. Med. Chem. Lett. 9 (1999) 641–646.
8. R. Schmierer, H. Mildenberger, and H. Buerstell, German Patent
361464, 1987; Chem. Abstr. 108 (1988) p. 37838.
9. L. Wang, K. W. Woods, Q. Li, K. J. Barr, R. W. McCroskey, S.
M. Hannick, L. Gkerke, R. B. Credo, Y. H. Hui, K. Marsh, R.
Warener, J. Y. Lee, N. Zielinsky Mozng, D. Frost, S. H. Rosen-
berg, and H. L. Sham, J. Med. Chem. 45 (2002) 1697–1711.
10. T. Maier, R. Schmierer, K. Bauer, H. Bieringer, H. Buerstell, B.
Sachse, U.S. Patent 4820335, 1989, Chem. Abstr. 111 (1989)
19494w.
11. V. Stoeck and W. Schunack, Arch. Pharmaz. 307 (1974) 922–925.
12. A. Hasaninejad, A. Zare, M. Shekouhy, and J. Ameri Rad,
J. Comb. Chem. 12 (2010) 844–849.
13. P. P. Reddy, K. Mukkanti, and K. Purandar, Rasayan J. Chem. 3
(2010) 335–340.
CONCLUSION
In this work, we found a thermal exposure synthetic
method of polysubstituted imidazoles, that it is a simple,
efficient and green chemistry via multicomponent one-
pot reaction in the presence of Y(NO3)3 ×6H2O as an
inexpensive and eco-friendly catalyst in solvent-free
condition. Products were isolated in excellent yields,
and the catalyst efficiently recovered and reused. That is
considered as economic advantages of this synthesis. It
is believed that this procedure will find important appli-
cations in the synthesis of wide range of polysubstituted
imidazoles.
Supplementary Materials. – Supporting informations to the
paper are enclosed to the electronic version of the article.
These data can be found on the website of Croatica Chemica
Acta (http://public.carnet.hr/ccacaa).
14. D. Davidson, M. Weiss, and M. Jelling, J. Org. Chem. 2 (1937)
319–327.
15. V. Stoeck and W. Schunack, Arch. Pharmaz. 309 (1976) 421–425.
16. B. H. Lipshutz and M. C. Morey, J. Org. Chem. 48 (1983) 3745–
3750.
Acknowledgement. Financial support from Yasouj University
of Iran was greatly acknowledged.
17. A. R. Karimi, Z. Alimohammadi, and M. M. Amini, J. Mol. Div.
14 (2010) 635–641.
18. S. Kantevari, S. V. N. Vuppalapati, D. O. Biradar, and L.
Nagarapu, J. Mol. Catal. A: Chem. 266 (2007) 109–113.
19. J. W. Blank, G. J. Durant, J. C. Emmett, and C. R. Ganellin, Na-
ture 248 (1974) 65–67.
REFERENCES
20. S. Balalaie and A. Arabanian, Green Chem. 2 (2000) 274–276.
21. S. Samai, G. C. Nandi, P. Singh, and M. S. Singh, Tetrahedron
65 (2009) 10155–10161.
22. K. F. Shelke, S. B. Sapkal, and M. S. Shingare, Chin. Chem. Lett.
20 (2009) 283–287.
23. A. K. Jain, V. Ravichandran, M. Sisodiya, and R. K. Agrawal,
Asian Pacific J. Tropical Med. 3 (2010) 471–474.
24. M. Shen, C. Cai, and W. Yi, J. Fluorine. Chem. 129 (2008)
541–544.
25. A. R. Khosropour, Ultrason. Sonochem. 15 (2008) 659–664
26. S. Ahmad and R. Abbas, J. Mol. Catal. A: Chem. 249 (2006)
246–248.
1. L. Weber, Curr. Med. Chem. 9 (2002) 2085–2093.
2. C. Hulme and V. Gore, Curr. Med. Chem. 10 (2003) 51–80.
3. U. Domanska and M. K. Kozlowska, Fluid Phase Equilib. 206
(2003) 253–266.
4. I. Isikdag and A. Meric, Boll. Chim. Farm. 138 (1999) 24–29.
5. J. C. Lee, J. T. Laydon, P. C. McDonnell, T. F. Gallagher, S.
Kumar, D. Green, D. McNulty, M. J. Blumenthal, J. R. Keys, S.
W. L. Vatter, J. E. Strickler, M. M. McLughlin, I. R. Siemens, S.
M. Fisher, G. P. Livi, J. R. White, J. L. Adams, and P. R. Young,
Nature 372 (1994) 739–746.
6. A. K. Tackle, M. J. B. Brown, S. Davies, D. K. Dean, G. Francis,
A. Gaiba, A. W. Hird, F. D. King, P. J. Lovell, A. Naylor, A. D.
Reith, J. G. Steadman, and D. M. Wilson, Bioorg. Med. Chem.
Lett. 16 (2006) 378–381.
27. L. M. Wang, Y. H. Wang, H. Tian, Y. F. Yao, J. H. Shao, and
B. Liu, J. Fluorine Chem. 127 (2006) 1570–1573.
Croat. Chem. Acta 85 (2012) 147.