Facile and rapid synthesis of some novel polysubstituted imidazoles by employing magnetic Fe3O4 nanoparticles as a high efficient catalyst

Article abstract of DOI:10.3906/kim-1112-49

Multicomponent, one-pot, highly efficient, and environmentally adapted synthesis of some novel polysubstituted imidazoles by the use of various aldehydes, benzil, aliphatic, and aromatic primary amines and ammonium acetate in the presence of Fe₃O₄ nanoparticles as catalyst under solvent-free condition is explained. A highly efficient role of Fe3O4 nanoparticles 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 data. The Fe₃O₄ nanoparticles were characterized by powdered X-ray diffraction (XRD), transmission electron microscopy (TEM), and FT-IR spectroscopy. TUeBITAK.

Full text of DOI:10.3906/kim-1112-49

Turk J Chem
36 (2012) , 601 – 614.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1112-49
Facile and rapid synthesis of some novel polysubstituted
imidazoles by employing magnetic Fe3O4 nanoparticles
as a high efficient catalyst
Bahador KARAMI1,2,∗, Khalil ESKANDARI1, Abdolmohammad GHASEMI2
1Department of Chemistry, Yasouj University, Yasouj, Zip Code 75918-74831,
P. O. Box: 353-IRAN
2Department of Chemistry, Gachsaran Branch, Islamic Azad University, Gachsaran-IRAN
e-mail: karami@mail.yu.ac.ir
Received: 20.12.2011
Multicomponent, one-pot, highly efficient, and environmentally adapted synthesis of some novel poly-
substituted imidazoles by the use of various aldehydes, benzil, aliphatic, and aromatic primary amines and
ammonium acetate in the presence of Fe3 O4 nanoparticles as catalyst under solvent-free condition is ex-
plained. A highly efficient role of Fe3 O4 nanoparticles 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 data. The Fe3 O4 nanoparticles were
characterized by powdered X-ray diffraction (XRD), transmission electron microscopy (TEM), and FT-IR
spectroscopy.
Key Words: Benzil, polysubstituted imidazoles, aldehydes, amines, heterogeneous catalyst
Introduction
Multicomponent reactions (MCRs) are a special type of organic reaction that afford complex products from
reaction of 3 or more simple starting materials in 1 pot. Because of the atom-economy, convergent character,
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 important molecules because of their
∗Corresponding author
601

Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
many applications in chemical 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 antitumorals,9
and pesticides.10
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 and condensation of benzil or benzoin acetate with aldehydes, primary amines,
and ammonia in the presence of copper acetate.15,16 The first mentioned method is the most well-known
and classical method. However, some of these methods involve long reaction times and unsatisfactory yields.
Therefore, improvements in these syntheses have been sought continuously.
In recent years, magnetic nanoparticles (MNPs) of Fe3 O4 have been attracting increasing interest in
many different fields due to their intrinsic properties such as high surface area, low toxicity, superparamagnetic
behavior, and easy separation and recovery from the reaction medium by magnetic decantation.17
In this work, the preparation, high activation, and regeneration of Fe3 O4 nanoparticles as a high efficient
catalyst in organic synthesis are shown. Using magnetic Fe3 O4 nanoparticles not only gives high yield, purity,
and short reaction time but also is a cheap, speedy, facile, and eco-friendly method throughout the course of
the reaction.
In the scope of our previous works for the synthesis of heterocyclic compounds by inorganic solid acids
and heterogeneous catalyst,18 herein we report a new, simple, rapid, and one-pot procedure for the synthesis
of tri- and tetrasubstituted imidazoles by using magnetic Fe3 O4 nanoparticles with short reaction times, and
high yields and purities (Scheme 1).
R1CHO
2
Fe3O4 nanoparticles
(1 mol %)
N
O
NH4OAc
O
heat
R1
N
solvent-free
R2
4
R2NH2
5
3
1
O
O
1
Fe3O4 nanoparticles
N
(1 mol %)
heat
2 NH4OAc
R1
N
solvent-free
4
H
R1CHO
2
5'
Scheme 1. Synthesis of polysubstituted imidazoles in the presence of magnetic nanoparticles Fe3 O4 as catalyst.
602

Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
Using benzil 1, aromatic aldehydes 2, aromatic and aliphatic amine 3, ammonium acetate 4, and magnetic
Fe 3 O4 nanoparticles as catalyst under solvent-free conditions led to tetrasubstituted imidazoles 5; in the absence
of aromatic and aliphatic amine 3, trisubstituted imidazoles 5’ were obtained.
Experimental
Transmission electron microscopy (TEM) studies of the nanostructures were carried out with a JEOL JEM 3010
instrument operating at an accelerating voltage of 300 kV. X-ray diffraction (XRD, D8, Avance, Bruker, axs)
patterns were obtained for characterization of the heterogeneous catalyst. Melting points were measured on an
electrothermal KSB1N apparatus. IR spectra were recorded in the matrix of KBr with a JASCO FT-IR-680
plus spectrometer. 1 H-NMR and 13 C-NMR spectra were recorded on a FT-NMR Bruker Avance Ultra Shield
Spectrometer at 400.13 and 100.62 MHz in CDCl3 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).13,19−29
Table 1. Synthesis of polysubstituted imidazoles catalyzed by magnetic Fe3 O4 nanoparticles.
Product
5a
R1
R2NH2
Time (min) Yielda (%) Mp (◦C)/(lit.)
C6H5
C6H5CH2NH2
20
25
45
30
25
20
40
20
25
25
25
50
30
35
45
30
35
25
55
40
25
10
96
90
98
85
85
80
75
90
98
96
95
93
90
89
90
92
70
68
97
83
90
91
170-17218
169-17013
163-16619
160-16219
193-19520
150-152b
160-16121,22
148-15123
156-158b
5b
5c
4-Br-C6H4
C6H5CH2NH2
4-CH3-C6H4
4-Cl-C6H4
C6H5CH2NH2
5d
5e
C6H5CH2NH2
2-Cl-C6H4
C6H5CH2NH2
5f
3-NO2-C6H4
4-CH3-C6H4
4-OCH3-C6H4
2-OH-5-Br-C6H3
4-Benzyloxy-C6H4
2,4-di-Cl-C6H3
4-CH3-C6H4
C6H5
C6H5CH2NH2
5g
CyclohexylNH2
5h
5i
C6H5CH2NH2
4-Cl-C6H4NH2
5j
C6H5CH2NH2
138-139b
216-219b
5k
C6H5CH2NH2
5l
C6H5NH2
182-18422
272-27318
120-12224
209-21125
204-20623
227-23018
235-23626
283-286b
5’a
5’b
5’c
5’d
5’e
5’f
5’g
5’h
5’i
5’j
—
—
—
—
—
—
—
—
—
—
3-Br-C6H4
2-OH-C6H4
2-OCH3-C6H4
4-OCH3-C6H4
4-Benzyloxy-C6H4
2-Fluorenyle
3-Indolyl
311-313b
257-25927
308-30928
4-Cl-C6H4
3-NO2-C6H4
aRefers to isolated yields, bNovel compound
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Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
General procedure for preparation of Fe3 O4 nanoparticles
To prepare Fe 3 O4 nanoparticles, 5.2 g of FeCl3 and 2.0 g of FeCl2 were successively dissolved in 25 mL of
distilled water containing 0.85 mL of 12.1 N HCl. The resulting solution was added dropwise into 250 mL of 1.5
M NaOH solution under vigorous stirring. The last step generated an instant black precipitate. The precipitate
was isolated in the magnetic field, and the supernatant was removed from the precipitate by decantation.30
General procedure for the facile and rapid synthesis of 1,2,4,5-tetra-
substituted imidazoles by Fe3 O4 nanoparticles
A mixture of aromatic aldehyde (1 mmol), benzil (1 mmol), primary amine (1 mmol), ammonium acetate (1
mmol), and magnetic Fe3 O4 nanoparticles (1 mol%) was stirred at 80 ◦ C in solvent-free conditions. The
progress of reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to room
temperature and was solved in 50 mL of acetone and then was filtered. The obtained products were purified
by crystallization from acetone-water (10:1). The products were characterized by IR, NMR, and through
comparison of their physical properties with those reported in the literature. 13,19−29
Hence, the general procedure for the synthesis of 2,4,5-trisubstituted imidazoles is the same as that for
1,2,4,5-tetrasubstituted imidazoles, but it needs 2 mmol of ammonium acetate instead of 1 mmol in the absence
of primary amine.
Representative spectral data
1-Benzyl-2,4,5-triphenyl-1H-imidazole (compound 5a): mp 162-164 ◦ C; IR (KBr) (νmax , cm−1): 3061, 3026,
2308, 1601, 1521, 1497, 1350, 761, 696. 1 H-NMR (250 MHz, DMSO-d6): δ (ppm) 5.13(s, 2H), 7.18-8.41 (m,
20H). 13 C-NMR (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-Benzyl-2-(4-bromophenyl)-4,5-diphenyl-1H-imidazole (compound 5b): mp 169-170 ◦ C; IR (KBr)
(νmax , cm−1): 3059, 3027, 2938, 1599, 1479, 1358, 1070, 835, 758, 694. 1 H-NMR (400.13 MHz, DMSO-
d6): δ (ppm) 4.86 (s, 2H), 6.61-7.46 (m, 19H). 13 C-NMR (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-4,5-diphenyl-2-p-tolyl-1H-imidazole (compound 5c): mp 156-158 ◦ C; IR (KBr) (νmax , cm−1):
3060, 3027, 2926, 1600, 1496, 1349, 826, 767, 694. 1 H-NMR (400.13 MHz, DMSO-d6)δ (ppm): 2.08 (s, 3H),
4.91 (s, 2H), 6.61-7.40 (m, 19H). 13 C-NMR (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.
1-Benzyl-2-(4-chlorophenyl)-4,5-diphenyl-1H-imidazole (compound 5d): mp 160-162 ◦ C; IR (KBr) (νmax
cm−1): 3059, 3029, 2936, 1600, 1480, 1357, 1089, 835, 758, 693. 1 H-NMR (400.13 MHz, DMSO-d6)δ (ppm):
4.9 (s, 2H), 6.60-7.50 (m, 19H). 13 C-NMR (100.62 MHz, DMSO-d6)δ (ppm): 48.31, 125.88, 126.55, 127.54,
129.13, 129.31, 130.28, 130.43, 130.74, 131.04, 134.18, 135.04, 136.81, 137.30, 138.22.
,
1-Benzyl-2-(2-chlorophenyl)-4,5-diphenyl-1H-imidazole (compound 5e): mp 139-140 ◦ C; IR (KBr) (νmax
,
604

Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
cm−1): 3062, 3026, 2930, 1602, 1485, 1349, 1079, 758, 690. 1 H-NMR (400.13 MHz, DMSO-d6)δ (ppm): 4.74
(s, 2H), 6.42-7.42 (m, 19H). 13 C-NMR (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 (compound 5f): mp 150-152 C; IR (KBr) (νmax
,
cm−1): 3061, 3026, 2308, 1601, 1521, 1497, 1350, 810, 730, 696. 1 H-NMR (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). 13 C-NMR (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 for C28 H21 N3 O2 (431.49): C, 77.94; H, 4.91; N, 9.74. Found: C, 77.87; H, 4.83; N, 9.62.
1-Cyclohexyl-4,5-diphenyl-2-p-tolyl-1H-imidazole (compound 5g): mp 160-161 ◦ C; IR (KBr) (νmax
,
cm−1): 3058, 3020, 2930, 1600, 1495, 1349, 825, 766, 695. 1 H-NMR (400.13 MHz, CDCl3)δ (ppm): 0.95 (m,
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). 13 C-NMR (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.
1-benzyl-2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole (compound 5h): mp 163-166 ◦ C; IR (KBr)
(νmax , cm−1): 3063, 3019, 2295, 1609, 1519, 1493, 1354, 696. 1 H-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). 13 C-NMR (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-(4-Chlorophenyl)-2-(2-hydroxy-5-bromophenyl)-4,5-diphenyl-1H-imidazole (compound 5i): mp 156-
158 ◦ C; IR (KBr) (νmax , cm−1): 3458, 3063, 1659, 1593, 1578, 1211, 1174, 1096. 1 H-NMR (400.13 MHz,
DMSO-d6)δ (ppm): 6.92-8.53 (m, 17H), 13.06 (s, 1H). 13 C-NMR (100.62 MHz, DMSO-d6)δ (ppm): 115.17,
123.92, 125.53, 127.64, 134.31, 137.31, 139.26, 140.54, 151.31, 164.74, 166.94. Anal. Calcd for C27 H18 BrClN2 O
(501.80): C, 64.62; H, 3.62; N, 5.58. Found: C, 64.51; H, 3.53; N, 5.49.
1-Benzyl-2-(4-(benzyloxy)phenyl)-4,5-diphenyl-1H-imidazole (compound 5j): mp 138-139 ◦ C; IR (KBr)
(νmax , cm−1): 2857, 1601, 1575, 1526, 1289, 1247, 1177. 1 H-NMR (400.13 MHz, DMSO-d6) δ (ppm): 2.18
(s, 2H), 5.06 (s, 2H), 6.83-7.82 (m, 24H). 13 C-NMR (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 for C35 H28 N2 O (492.61): C, 85.34; H, 5.73; N,
5.69. Found: C, 85.18; H, 5.61; N, 5.54.
1-Benzyl-2-(2,4-dichlorophenyl)-4,5-diphenyl-1H-imidazole (compound 5k): mp 216-219 ◦ C; IR (KBr)
(νmax , cm−1): 3069, 2924, 1557, 1523, 1459, 1092. 1 H-NMR (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). 13 C-NMR (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 for C28 H20 Cl2 N2 (455.38): C, 73.85; H,
4.43; N, 6.15. Found: C, 73.71; H, 4.36; N, 6.09.
1,4,5-Triphenyl-2-p-tolyl-1H-imidazole (compound 5l): mp 182-184 ◦ C; IR (KBr) (νmax , cm−1): 3055,
3022, 2930, 1600, 1495, 1349, 826, 767, 694. 1 H-NMR (400.13 MHz, CDCl3): δ (ppm) 2.34 (s, 3H), 7.07-7.36
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Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
(m, 17H), 7.64 (d, J = 7.1 Hz, 2H). 13 C-NMR (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.
2-(3-Bromophenyl)-4,5-diphenyl-1H-imidazole (compound 5’b): mp 120-122 ◦ C; IR (KBr) (νmax
,
cm−1): 3387, 3062, 1584, 1529, 1480, 1241, 1100. 1 H-NMR (400.13 MHz, CDCl3) δ (ppm): 7.26-7.78 (m,
14H), 9.40 (s, 1H). 13 C-NMR (100.62 MHz, CDCl3)δ (ppm): 121.86, 125.62, 126.02, 126.75, 127.41, 127.70,
127.76, 128.11, 131.05.
2-(2-Hydroxyphenyl)-4,5-diphenyl-1H-imidazole (compound 5’c): mp 209-211 ◦ C; IR (KBr) (νmax
,
cm−1): 3450, 3385, 1584, 1529, 1480, 1240, 1098. 1 H-NMR (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). 13 C-NMR (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-(2-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (compound 5’d): mp 204-206 ◦ C; IR (KBr) (νmax
,
cm−1): 3388, 3062, 2933, 1584, 1530, 1481, 1240, 1099. 1 H-NMR (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). 13 C-NMR (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.
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (compound 5’e): mp 227-230 ◦ C; IR (KBr) (νmax
,
cm−1): 3433, 3027, 1613, 1578, 1542, 1248, 1176. 1 H-NMR (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). 13 C-NMR (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.
2-(4-Benzyloxyphenyl)-4,5-diphenyl-1H-imidazole (compound 5’f): mp 235-236 ◦ C; IR (KBr) (νmax
,
cm−1): 3054, 3018, 2930, 1608, 1578, 1541, 1230, 1181. 1 H-NMR (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). 13 C-NMR (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 (compound 5’g): mp 283-286 ◦ C; IR (KBr) (νmax , cm−1): 3350,
3054, 2950, 1601, 1532, 1500. 1 H-NMR (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). 13 C-NMR (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 for C28 H20 N2 (384.47): C, 87.47; H, 5.24; N, 7.29. Found: C, 87.41; H, 5.29; N, 7.22.
3-Indolyl-4,5-diphenyl-1H-imidazole (compound 5’h): mp 311-313 ◦ C; IR (KBr) (νmax , cm−1): 3413,
3055, 1598, 1490, 1451. 1 H-NMR (400.13 MHZ, DMSO-d6)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). 13 C-NMR (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 for
C23 H17 N3 (335.40): C, 82.36; H, 5.11; N, 12.53. Found: C, 82.29; H, 5.21; N, 12.40.
2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (compound 5’i): mp 257-259 ◦ C; IR (KBr) (νmax , cm−1):
3386, 3062, 1584, 1529, 1481, 1240, 1099. 1 H-NMR (400.13 MHZ, CDCl3)δ (ppm): 6.99-7.36 (m, 12H), 7.86
(d, J = 7 Hz, 2H), 12.09 (s, 1H). 13 C-NMR (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 (compound 5’j): mp 308-309 ◦ C; IR (KBr) (νmax , cm−1):
606

Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
3380, 3065, 1580, 1527, 1479, 1239, 1099, 810, 758. 1 H-NMR (400.13 MHZ, DMSO-d6) δ (ppm): 7.30-7.53 (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), 13 C-NMR (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
Based on the importance of heterogeneous catalyst in the synthesis of organic compounds,31 herein we found
a new application of Fe3 O4 nanoparticles as a highly efficient catalyst for the synthesis of novel and known
polysubstituted imidazoles with high yields. After the preparation of Fe3 O4 nanoparticles, firstly this catalyst
was characterized. Figure 1a shows the XRD patterns of the Fe3 O4 nanoparticles. A number of prominent
Bragg reflections by their indices ((220), (311), (400), (422), (511), and (440)) reveal that the resultant
nanoparticles were Fe3 O4 with a spinel structure.32 The size of the Fe3 O4 nanoparticles was also determined
from X-ray line broadening using the Debye–Scherrer formula given as D = 0.9 λ/β cosθ, where D is the
average crystalline size, λ the X-ray wavelength used, β the angular line width at half maximum intensity,
and θ the Bragg’s angle. For (311) reflection, the average size of the Fe3 O4 nanoparticles is estimated to be
around 13 nm. In Figure 1b transmission electron microscopy (TEM) analyses were used for characterization.
The TEM image reveals the spherical Fe3 O4 nanoparticles with average size ∼10 nm. The FT-IR spectra of
Fe 3 O4 nanoparticles are shown in Figure 2. The absorbance bands at 584.3 cm−1 are ascribed to Fe+2 O−2
which are consistent with the reported IR spectra for spinel Fe3 O4 .33,34
,
Figure 1. (a) The powder X-ray diffraction pattern of the Fe3 O4 nanoparticles; (b) TEM image shows spherical Fe3 O4
nanoparticles with approximately ∼10 nm.
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Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
Figure 2. FT-IR spectra of Fe3 O4 nanoparticles.
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 optimum condition for this synthesis. The model
reaction, in the presence of an optimized molar ratio of magnetic Fe3 O4 nanoparticles (1 mol%), benzaldehyde
(1 mmol), ammonium acetate (1 mmol), and benzylamine (1 mmol), was carried out in different solvents such
as water, ethanol, methanol, chloroform, and acetonitrile under refluxing and solvent-free conditions at 80 ◦ C.
From these experiments, it was clearly demonstrated that the solvent-free condition is the best for accomplishing
this synthesis (Table 2).
Table 2. Solvent effect in the synthesis of 1-benzyl 2,4,5-triphenyl imidazole as a model reaction (compound 5a).
Entry
Solvent
Water
Time (min) Yield (%)
1
2
3
4
5
6
90
35
46
75
78
49
73
96
Ethanol
Methanol
Chloroform
Acetonitrile
Solvent-free
40
120
80
20
Moreover, the reaction in the presence of small amount of acetic acid was tested both in the presence and
absence of magnetic Fe3 O4 nanoparticles at different temperatures. The results showed that the catalyst and
temperature are 2 key factors for the progress of the reaction and the best temperature for catalytic activity of
magnetic Fe3 O4 nanoparticles is 80 ◦ C (Table 3).
We carried out the model reaction in the absence of catalyst in solvent-free conditions and at room
temperature for 24 h, which led to very poor yield (12%) of 1-benzyl 2,4,5-triphenyl imidazoles as 1,2,4,5-
tetrasubstituted imidazoles. In the absence of catalyst for enhancing the yield of the desired product, the
temperature of the reaction was increased to 200 ◦ C, but no appreciable increment in the product yield was
observed. Therefore, we found that presence of a catalytic amount of magnetic Fe3 O4 nanoparticles and
solvent-free conditions are the best conditions for this synthesis.
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Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
Table 3. Effects of catalyst and temperature in the synthesis of imidazole derivatives (model reaction).
In the absence of catalyst In the presence of catalysta
Entry Temp. (◦C)
Time (min)
300
Yield (%)
Trace
Trace
20
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
r.t.
30
40
50
60
70
80
90
120
100
80
72
72
78
80
85
90
96
92
240
240
240
35
60
180
45
25
180
50
25
180
60
20
180
65
25
a
Optimized molar ratio of catalyst (1 mol%)
We also evaluated the quantity of required catalyst in this synthesis for the model reaction. It was
found that maximum yield (96%) obtained when the reaction was loaded with 1 mol% of magnetic Fe3 O4
nanoparticles (Table 4).
Table 4. Optimization of molar ratio of the catalyst for model reaction (compound 5a).
Entry Fe3O4 nanoparticles (mol%) Time (min) Yield (%)
1
2
3
4
5
6
0.1
1
60
20
30
30
45
50
90
96
96
95
95
95
2
5
10
20
In the following study of the model reaction, we examined the reaction at various temperatures to find
out its effect on the progress of the reaction (Table 5). The maximum rate of reaction was obtained at 80 ◦ C
as the optimum temperature.
Table 5. Optimization of temperature for model reaction (compound 5a).
Entry Temp. (◦C) Time (min) Yield (%)
1
2
3
4
5
r.t.
60
120
25
70
85
96
96
90
80
20
100
120
30
30
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Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
As can be seen from Table 5, at room temperature the reaction was completed slowly. With increasing
temperature to 80 ◦ C, the reaction yield was increased and time of the reaction decreased; when the reaction
was heated above 80 ◦ C there was no further improvement in yield or decrease in the time of the reaction.
According to the optimal conditions, we conducted the synthesis of polysubstituted imidazoles in the
presence of magnetic Fe3 O4 nanoparticles as catalyst in solvent-free conditions at 80 ◦ C.
Reusability of the catalyst
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 the magnetic Fe3 O4 nanoparticles showed high catalytic activity
with a very short reaction time. Moreover, it can be recovered and reused several times without significant loss
of activity. The results of these observations for the model reaction are shown in Table 6 and Figure 3.
Table 6. Reusability results of Fe3 O4 nanoparticles on the reaction process for the model reaction (compound 5a).
Total
Yield
(%)
Time
(min)
product
reusability
1
2
3
4
96
95
95
97
20
20
25
40
Ph
Ph
N
N
5
97
45
Figure 3. The reusability of the catalyst for model reaction.
A probable mechanism for the synthesis of tetrasubstituted imidazoles may be postulated as shown below
(Scheme 2).
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Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
Fe2+
Fe3+
O
C
O
O
R2NH2
H
NH2R2
Fe3O4 nanoparticles
3
H
H
-Fe3+
2
OH
C
H
C
H
C
H
NHR
NH2
Fe3O4 nanoparticles
NH3
-H2O
NR
NHR
6
-AcOH
O
-H2O
NH4OAc
O
1
4
H
N
N
N
N
-H2O
R2
OH
R2
5
Scheme 2. The suggested mechanism for the synthesis of tetrasubstituted imidazoles.
As can be seen in Scheme 2, magnetic Fe3 O4 nanoparticle is a Lewis acid and so it can active the
carbonyl group of aldehydes 2 to decrease the energy of transition state. Then the nucleophilic attack of amine
3 on the activated carbonyl of aldehydes resulted in the formation of imine, and it was followed by nucleophilic
attack of the in situ generated ammonia from 4 on the imine, giving the intermediate 6. From condensation of
intermediate 6 with benzil 1 and dehydration of it, corresponding imidazoles 5 were produced.
Moreover, the probable mechanism for synthesis of trisubstituted imidazoles is the same as that for
tetrasubstituted imidazoles but in this case ammonium acetate was handled instead of primary amine.
Conclusions
In this work, we found a thermal exposure synthetic method for polysubstituted imidazoles that is simple,
efficient, and green via a multicomponent one-pot reaction in the presence of magnetic Fe3 O4 nanoparticles
as an inexpensive and eco-friendly catalyst in solvent-free conditions. Furthermore, products were isolated
611

Facile and rapid synthesis of some novel polysubstituted imidazoles by..., B. KARAMI, et al.
in excellent yields. Also the catalyst was efficiently recovered and reused, which is considered an economic
advantage of this synthesis. It is thought that this procedure will find important applications in the synthesis
of a wide range of polysubstituted imidazoles.
Acknowledgment
Financial support from Yasouj University, Iran, is gratefully acknowledged.
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