An efficient and one-pot synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles catalyzed via solid acid nano-catalyst

Article abstract of DOI:10.1016/j.molcata.2011.06.007

A simple highly versatile and efficient synthesis of 2,4,5-trisubstituted imidazoles is achieved by three component cyclocondensation of 1,2-dicarbonyl compounds, aldehydes and NH4OAc, as ammonia source using clays, zeolite, nano-crystalline sulfated zirc

Full text of DOI:10.1016/j.molcata.2011.06.007

Journal of Molecular Catalysis A: Chemical 346 (2011) 39–45
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An efficient and one-pot synthesis of 2,4,5-trisubstituted and
1,2,4,5-tetrasubstituted imidazoles catalyzed via solid acid nano-catalyst
Abbas Teimouria,∗, Alireza Najafi Chermahinib
a Chemistry Department, Payame Noor University, 19395-4697 Tehran, Iran
b Department of Chemistry, Faculty of Science, Yasouj University, Yasouj, P.O. Box 75918-671671, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 March 2011
Received in revised form 13 June 2011
Accepted 19 June 2011
Available online 24 June 2011
A simple highly versatile and efficient synthesis of 2,4,5-trisubstituted imidazoles is achieved by three
component cyclocondensation of 1,2-dicarbonyl compounds, aldehydes and NH4OAc, as ammonia source
using clays, zeolite, nano-crystalline sulfated zirconia (SZ) as catalyst in ethanol at moderate temperature.
Moreover, the utility of this protocol was further explored conveniently for the one-pot, four component
synthesis of 1,2,4,5-tetrasubstituted imidazoles in high yields, short reaction times and milder condi-
tions, easy work-up and purification of products by non-chromatographic methods. The catalysts can be
recovered for the subsequent reactions and reused without any appreciable loss of their efficiency.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Keywords:
Clay
Zeolite
Sulfated zirconia
Green synthesis
2,4,5-Trisubstituted imidazoles
1,2,4,5-Tetrasubstituted imidazoles
1. Introduction
attention recently, and new preparative methods have appeared
[12].
Imidazoles are a class of heterocyclic compounds that con-
tain nitrogen and are currently under intensive focus due to
their wide range of applications, because they have many phar-
macological properties and play important roles in biochemical
processes [1,2]. The potential and wide range of application of
the imidazole pharmacophore may be attributed to its hydro-
gen bond donor–acceptor ability as well as its high affinity
for metals. Many of the substituted imidazoles are known as
inhibitors of p38 MAP kinase, fungicides, herbicides, plant growth
regulators, antibacterial, antitumour, pesticides and therapeutic
agents [3–9]. In recent years, alkylated imidazoliums are sub-
stantially used in ionic liquids [10] that have been given a
new approach to ‘Green Chemistry’. The imidazole compounds
were also used in photography as photosensitive compound
[11]. They also serve as useful building blocks for the synthe-
sis of other classes of compounds. Owing to the wide range of
pharmacological and biological activities, the synthesis of imida-
zoles has become an important target in current years. Among
them, tri- and tetrasubstituted imidazoles have received much
There are several methods reported in literature for the
synthesis of imidazoles. 2,4,5-Trisubstituted imidazoles are gen-
erally synthesized by three component cyclocondensation of
a 1,2-diketone, ␣-hydroxyketone or ␣-ketomonoxime with an
aldehyde and ammonium acetate, which comprise the use of
ionic liquids, [13] refluxing in acetic acid, [14] silica sulfuric
acid, [15] InCl3·3H2O, [16]. On the other hand, the synthesis of
1,2,4,5-tetrasubstituted imidazoles have been carried out by four-
component condensation of a 1,2-diketone, ␣-hydroxyketone or
␣-ketomonoxime with an aldehyde, primary amine and ammo-
nium acetate using microwaves, [17a] heteropolyacid, [17b]
BF3·SiO2, [12l] silica gel/NaHSO4 [17c] or HClO4–SiO2 [17d]. In
addition, they can also be accessed by the cycloaddition reaction
of mesoionic 1,3-oxazolium-5-olates with N-(arylmethylene)-
benzenesulfonamides, [18a] hetero-Cope rearrangement, [18b]
condensation of a 1,2-diketone with an aryl nitrile and primary
amine under microwave irradiation [18c] and by N-alkylation
of trisubstituted imidazoles [18d]. Recently PEG-400 is found
to be an interesting solvent system. It is inexpensive, ther-
mally stable, non-volatile, non-toxic and easily degradable,
has emerged as reaction medium in organic synthesis [19].
Many of the synthetic methods for imidazoles suffer from one
or more disadvantages such as low yields, harsh reaction con-
ditions, prolonged time period and application of hazardous
and expensive catalysts. Therefore the development of greener,
∗
Corresponding author at: Department of Chemistry, Payame Noor University
(PNU), Isfahan, P.O. Box 81395-671, Iran. Tel.: +98 311 3521804;
fax: +98 311 3521802.
E-mail addresses: a teimouri@pnu.ac.ir, a teimoory@yahoo.com (A. Teimouri).
1381-1169/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2011.06.007

40
A. Teimouri, A.N. Chermahini / Journal of Molecular Catalysis A: Chemical 346 (2011) 39–45
clean, and environmentally friendly approaches is still desir-
able and much in demand [20]. Nowadays, more and more
heterogeneous Bronsted acids, e.g., zeolites and montmorilonite
clay are preferred from an economical perspective as well as
from an ecological viewpoint. Due to its high protonic acidity
and unique shape-selective behavior, HZSM-5, have been shown
to be a highly active and stable catalyst for many reactions
[21,22]. In addition zirconia is attracting considerable interest on
account of its potential use as a catalyst support. Recent inves-
tigations reveal that promoted zirconia is an exceptionally good
solid acid catalyst for various organic synthesis and transfor-
mation reactions having enormous industrial applications [23].
Reusable heterogeneous catalysts have attracted a great deal
of interest in recent years. Since most of the catalysts are
expensive and contaminate the environment, the development
of efficient methods for recovery and reuse of the catalysts
Fig. 1. XRD pattern of sulfated-zirconia catalyst.
ions. Over the course of this process, zeolite should turn from a
white to brown/black color [25].
is
a very important aspect in this chemistry. In continua-
2.2.3. Synthesis of nano-crystalline sulfated zirconia
tion of our ongoing research for the development of simple
and efficient methods for the synthesis of various hetero-
cyclic compounds [24] herein we wish to report
economic, and efficient one-pot method for the synthesis of
2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles from
benzil, ammonium acetate, aromatic aldehydes and using solid acid
catalysts.
Nano-crystalline sulfated zirconia has been prepared by one
step sol–gel technique [26]. A typical synthesis involves the
addition of concentrated sulfuric acid (1.02 mL) to zirconium n-
propoxide precursor (30 wt%) followed by the hydrolysis with
water. After 3 h aging at room temperature, the resulting gel was
dried at 110 ◦C for 12 h followed by calcination at 600 ◦C for 2 h.
a simple,
2.2.4. Characterization
X-ray diffraction pattern were recorded on diffractometer
(Philips X’pert) using Cu K␣ radiation (ꢀ = 1.5405 A), angle range
2. Experimental
˚
was between 0 and 80◦ (Fig. 1), Crystallite size of the crys-
talline phase was determined from the peak of maximum intensity
(2ꢁ = 30.18) by using Scherrer formula [27], with a shape factor (K)
of 0.9, as below: Crystallite size = K·ꢀ/W·cos ꢁ, where, W = Wb − Ws
and Wb is the broadened profile width of experimental sample and
Ws is the standard profile width of reference silicon sample. FTIR
spectra of the catalysts were recorded by FTIR spectrophotome-
ter in the range of 400–4000 cm−1 with a resolution of 4 cm−1 by
mixing the sample with KBr (Fig. 2).
Specific surface area, pore volume and pore size distribution
of sulfated zirconia samples calcined at 600 ◦C were determined
from N2 adsorption–desorption isotherms at 77 K (ASAP 2010
Micromeritics) (Fig. 3). Surface area was calculated by using BET
equation; pore volume and pore size distribution were calculated
by BJH method [28]. The samples were degassed under vacuum at
120 ◦C for 4 h, prior to adsorption measurement to evacuate the
physisorbed moisture. The detailed imaging information about the
morphology and surface texture of the catalyst was provided by
SEM (Philips XL30 ESEM TMP) (Fig. 4).
2.1. Instruments and characterization
All reagents were purchased from Merck and Aldrich and used
without further purification. Montmorilonite K10 was purchased
from Aldrich. Products were characterized by spectroscopy data
(Mass, FTIR, 1H NMR and 13C NMR spectra), elemental analysis
(CHN) and melting points. A JASCO FT/IR-680 PLUS spectrome-
ter was used to record IR spectra using KBr pellets. NMR spectra
were recorded on a Bruker 400 Ultrasheild NMR and DMSO-d6
was used as solvent. Melting points reported were determined by
open capillary method using a Galen Kamp melting point apparatus
and are uncorrected. Mass Spectra were recorded on a Shimadzu
Gas Chromatograph Mass Spectrometer GCMS-QP5050A/Q P5000
apparatus.
2.2. Catalyst preparation
2.2.1. Activation of montmorilonite K10 clay catalyst
This catalyst activated with 2 M HCl in the solid to liquid ratio 1:4
(400 mL, 2 M HCl for 100 g clay) for a period of 45 min and filtered.
It was then washed thoroughly with distilled water for removing
chloride ions and dried in an air oven at 110 ◦C for 2 h. Then acid
activated clay was again calcined at 430 ◦C for a period of 2 h and
used for the reaction.
2.2.2. Synthesis of ZSM-5 and HZSM-5
For synthesis of ZSM-5, hydrated aluminum sulfate and sodium
silicate solution were the sources of aluminum and silicon,
respectively. The tetrapropylammonium bromide was used as the
structure-directing template [25]. ZSM-5 zeolite was synthesized
according to the procedure described earlier. The solid phase
obtained was filtered, washed with distilled water several times,
dried at 120 ◦C for 12 h and then calcined at 550 ◦C for 6 h and fol-
lowed by ion exchange with NH4NO3 solution (three times), The
acid hydrogen form of the compound is prepared by transferring
the oven-dried compound to a tube furnace. Heat the ammonium
+
Fig. 2. FTIR spectra sulfated-zirconia catalyst.
zeolite for 3 hours to ensure the thermal decomposition of NH4

A. Teimouri, A.N. Chermahini / Journal of Molecular Catalysis A: Chemical 346 (2011) 39–45
41
Table 1
Effect of catalyst type and amount of catalyst on the synthesis of imidazoles in the
reaction of benzaldehyde, ammonium acetate and benzil.
Entry
Catalyst
K10
Catalyst loading (mg)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
10
25
50
10
25
50
10
25
50
–
95
65
75
110
80
95
100
75
90
85
96
89
84
92
86
82
96
87
–
ZMS-5
SZ
No catalyst
120
a
Yields after isolation of products.
Reaction condition benzaldehyde (1 mmol), ammonium acetate (2 mmol), benzil
(1 mmol), in the ethanol as the solvent.
128.5, 127.4, 127.0, 126.4, 125.5, 125.2, 123.3, 116.3; ESI MS (m/z):
330.1 (M+); Anal. Calcd. for C21H15ClN2: C, 76.24; H, 4.57; N, 8.47.
Found: C, 76.20; H, 4.61; N, 8.41.
Fig. 3. N2 adsorption–desorption isotherm of sulfated-zirconia catalyst.
2.3. General procedure for the synthesis of 2,4,5-trisubstituted
imidazoles
2.3.3. 2-(4-Bromophenyl)-4,5-diphenyl-1H-imidazole (1c)
Mp 254–256 ◦C. FTIR (KBr, cm−1): 3450, 3070, 1615, 1320; 1H
NMR (400 MHz, DMSO-d6): ı 12.68 (s, 1H), 8.15 (d, 2H), 7.50–7.13
(m, 12H); 13C (400 MHz, DMSO-d6): ı 146.1, 130.5, 129.6, 129.1,
128.4, 127.2, 127.0, 126.6, 125.5, 125.1, 123.0, 116.2; ESI MS (m/z):
375.2 (M+); Anal. Calcd. for C21H15BrN2: C, 67.21; H, 4.03; N, 7.47.
Found: C, 67.06; H, 3.71; N, 7.21.
In a 50 mL round bottom flask 1,2-diketone (1 mmol), aldehyde
(1 mmol) and ammonium acetate (2 mmol) and catalyst (50 mg)
stirred and refluxed in ethanol (10 mL). Then the reaction mix-
ture was stirred for the stipulated period of time. The progress of
the reaction was monitored by TLC. After completion of the reac-
tion, the mixture was filtered and the filtrate was cooled to room
temperature and organic layer was dried over anhydrous MgSO4
and concentrated. The product was purified by chromatography
through a column of silica-gel using ethyl acetate/cyclohexane
ether as an eluent.
2.3.4. 2-(4-Nitrophenyl)-4,5-diphenyl-1H-imidazole (1d)
Mp 234–236 ◦C. FTIR (KBr, cm−1): 3402, 2928,1598,1519,1346,
856; 1H NMR (400 MHz, DMSO-d6): ı 12.81 (s, 1H), 8.01–7.42 (m,
14H); 13C NMR (400 MHz, DMSO-d6): ı 148.9, 143.7, 131.6, 130.6,
129.7, 128.4, 127.8, 127.4, 126.9, 126.1, 125.4, 124.3, 122.2, 118.5;
ESI MS (m/z): 341.2 (M+); Anal. Calcd. for C21H15N3O2: C, 73.89; H,
4.43; N, 12.31. Found: C, 73.81; H, 4.44; N, 12.37.
2.3.1. 2,4,5-Triphenyl-1H-imidazole (1a)
Mp 274–276 ◦C. FTIR (KBr, cm−1): 3451, 2856, 1636, 1490; 1H
NMR (400 MHz, DMSO-d6): ı 12.69 (s, 1H), 8.09 (d, 2H), 7.56–7.22
(m, 13H); 13 C NMR (400 MHz, DMSO-d6): ı 145.6, 137.2, 135.2,
131.2, 130.4, 128.7, 128.5, 128.3, 128.2, 127.8, 127.2, 126.6, 125.3;
ESI MS (m/z): 296.3 (M+); Anal. Calcd. for C21H16N2: C, 85.11; H,
5.44; N, 9.45. Found: C, 85.18; H, 5.49; N, 9.33.
2.3.5. 4-(4,5-Diphenyl-1H-imidazol-2-yl)-phenol (1e)
Mp 268–270 ◦C. FTIR (KBr, cm−1): 3590, 3454, 3284, 3064, 1701,
1283; 1H NMR (400 MHz, DMSO-d6): ı 12.40 (s, 1H), 9.70 (s, 1H),
7.90 (d, J¼8.4 Hz, 2H), 7.54–7.21 (m, 10H), 6.86 (d, J¼8.4 Hz, 2H);
13C NMR (400 MHz, DMSO-d6): ı 157.7, 146.1, 136.6, 135.4, 131.3,
128.6, 128.3, 127.5, 127.3, 127.0, 126.8, 126.3, 121.6, 115.4; ESI MS
(m/z): 312.2 (M+); Anal. Calcd. for C21H16N2O: C, 80.75; H, 5.16; N,
8.97. Found: C, 80.79; H, 5.22; N, 8.91.
2.3.2. 2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (1b)
Mp 260–262 ◦C. FTIR (KBr, cm−1): 3452, 3065, 1635, 1323; 1H
NMR (400 MHz, DMSO-d6): ı 12.78 (s, 1H), 8.11 (d, 2H), 7.56–7.23
(m, 12H); 13C (400 MHz, DMSO-d6): ı 146.3, 130.3, 129.9, 129.2,
2.3.6. 4,5-Diphenyl-2-p-tolyl-1H-imidazole (1f)
Mp 232–234 ◦C. FTIR (KBr, cm−1): 3449, 3034, 1611, 1495, 1320;
1H NMR (400 MHz, DMSO-d6): ı 12.59 (s, 1H), 7.98 (d, J¼7.8 Hz, 2H),
7.54–2.21 (m, 12H), 2.35 (s, 3H); 13C NMR (400 MHz, DMSO-d6): ı
145.6, 137.6, 136.9, 135.2, 131.1, 129.2, 128.6, 128.3, 128.1, 127.9,
127.6, 127.0, 126.4, 125.1, 20.8; ESI MS (m/z): 310.3 (M+); Anal.
Calcd. for C22H18N2: C, 85.13; H, 5.85; N, 9.03. Found: C, 85.23; H,
5.79; N, 8.97.
2.3.7. 2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (1g)
Mp 228–230 ◦C. FTIR (KBr, cm−1): 3415, 3042, 1610, 1490, 1189;
1H NMR (400 MHz, DMSO-d6): ı 12.48 (s, 1H), 8.02 (d, J = 8.1 Hz, 2H),
7.50–7.33 (m, 10H), 7.04 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H); 13C NMR
(400 MHz, DMSO-d6): ı 159.5, 145.7, 128.4, 127.7, 126.7, 123.1,
114.1, 55.2; ESI MS (m/z): 326.2 (M+); Anal. Calcd. for C22H18N2O:
C, 80.96; H, 5.56; N, 8.58. Found: C, 80.90; H, 5.51; N, 8.63.
Fig. 4. SEM micrograph of sulfated-zirconia catalyst.

42
A. Teimouri, A.N. Chermahini / Journal of Molecular Catalysis A: Chemical 346 (2011) 39–45
Table 2
The catalyst could be directly used with the same efficiency for
four times after that a gradable decline in activity was observed. The
products were characterized by IR, NMR and through comparison
of their physical properties with those reported in literature.
Effect of solvent on the reaction times and yields.
Entry
Solvent
Time (min)
Yield (%)a
1
2
3
4
5
6
H2O
EtOH
MeOH
CH3CN
DCM
180
80
95
110
110
150
60
95
70
75
65
60
2.4.1. 2-(4-Phenyl)-1,4,5-triphenyl-1H-imidazole (2a)
Mp 218–220 ◦C. FTIR (KBr, cm−1): 3052, 1576, 1460; 1H NMR
(400 MHz, CDCl3): ı 7.65–7.55 (m, 4H), 7.38–7.13 (m, 14H), 6.80
(d, J¼7.5 Hz, 2H); 13C NMR (400 MHz, CDCl3): ı 148.1, 137.9, 137.3,
134.1, 132.7, 131.0, 130.7, 130.4, 129.1, 128.9, 128.4, 128.2, 128.6,
128.2, 127.8, 126.6, 126.2, 126.0; ESI MS (m/z): 372.1 (M+); Anal.
Calcd. for C27H20N2: C, 87.01; H, 5.41; N, 7.52. Found: C, 86.81; H,
5.19; N, 7.20.
Toluene
Benzaldehyde (2.0 mmol), benzil (2.0 mmol), and ammonium acetate (4 mmol) in
the presence of catalyst (25 mg) under reflux condition in various solvents.
2.4.2. 2-(4-Chlorophenyl)-1,4,5-triphenyl-1H-imidazole (2b)
Mp 156–158 ◦C. FTIR (KBr, cm−1): 3056, 1596, 1516, 1440; 1H
NMR (400 MHz,CDCl3): ı 7.98 (d, 2H), 7.43–7.17 (m, 17H); 13C NMR
(400 MHz, CDCl3): ı 147.0, 144.2, 139.1, 136.5, 136.0, 133.6, 132.4,
131.0, 130.0, 129.5, 129.3, 129.2, 129.1, 128.9, 128.5, 128.4, 128.4,
128.3, 128.1, 127.2, 126.0, 125.5, 124.0, 123.2; ESI MS (m/z): 406.2
(M+); Anal. Calcd. for C27H19ClN2: C, 79.70; H, 4.71; N, 6.88. Found:
C, 79.40; H, 4.36; N, 6.61.
2.4.3. 2-(4-Bromophenyl)-1,4,5-triphenyl-1H-imidazole (2c)
Mp 152–154 ◦C. FTIR (KBr, cm−1): 3056, 1584, 1526, 1432; 1H
NMR (400 MHz, CDCl3): ı 7.94 (d, 2H), 7.40–7.12 (m, 17H); 13C NMR
(400 MHz, CDCl3): ı 147.0, 144.6, 139.7, 136.1, 136.3, 133.2, 132.6,
131.0, 130.3, 129.6, 129.4, 129.2, 129.1, 128.9, 128.6, 128.5, 128.4,
128.3, 128.1, 127.4, 126.0, 125.2, 124.4, 123.0; ESI MS (m/z): 450.1
(M+); Anal. Calcd. for C27H19BrN2: C, 71.85; H, 4.24; N, 6.26. Found:
C, 71.32; H, 4.16; N, 6.21.
Fig. 5. The results obtained from catalyst reuse nano-crystalline sulfated zirco-
nia (black bars), Zeolite (white bars) and montmorilonite K10 (dash bars) in the
imidazole formation.
2.4. General procedure for the synthesis of
1,2,4,5-tetrasubstituted imidazoles
2.4.4. 2-(4-Nitrophenyl)-1,4,5-triphenyl-1H-imidazole (2d)
Mp 184–186 ◦C. FTIR (KBr, cm−1): 3054, 1595, 1514, 1340; 1H
NMR (400 MHz, CDCl3): ı 8.10 (d, J¼8.7 Hz, 2H), 7.61–7.07 (m, 17H);
13C NMR (400 MHz, CDCl3): ı 147.0, 144.3, 139.3, 136.6, 136.5,
133.8, 132.4, 131.0, 129.9, 129.5, 129.4, 129.3, 129.2, 128.8, 128.6,
128.5, 128.4, 128.3, 128.2, 127.9, 127.0, 124.2, 124.0, 123.4; ESI MS
(m/z): 417.2 (M+); Anal. Calcd. for C27H19N3O2: C, 77.68; H, 4.59;
N, 10.07. Found: C, 77.60; H, 4.56; N, 10.11.
In a 50 mL round bottom flask 1,2-diketone (1 mmol), aromatic
aldehyde (1 mmol), phenyl amine (1 mmol) and ammonium acetate
(1 mmol) and catalyst (25 mg) stirred and refluxed in ethanol
(10 mL). Then the reaction mixture was stirred. The progress of
the reaction was monitored by TLC. After completion of the reac-
tion, the mixture was filtered and the filtrate was cooled to room
temperature and organic layer was dried over anhydrous MgSO4
and concentrated. The product was purified by chromatography
through a column of silica-gel using ethyl acetate/cyclohexane
ether as an eluent.
2.4.5. 4-(1,4,5-Triphenyl-1H-imidazol-2-yl)-phenol (2e)
Mp 282–284 ◦C. FTIR (KBr, cm−1): 3448, 3057, 1582; 1H NMR
(400 MHz, CDCl3): ı 8.37 (s, 1H), 7.76 (d, J¼8.4 Hz, 2H), 7.50–6.84
Table 3
Acid-catalyzed synthesis of 2,4,5-trisubstituted imidazolesa
Ph
O
Ph
Ph
N
N
Catalyst
NH4OAC
RCHO
+
R
+
EtOH, reflux
Ph
O
H
.
Entry
Product
R
Time (min)/Yeild (%)b
Montmorilonite K10
MP ◦C (lit.) [Ref.]
Zeolite
Nano-crystalline SZ
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
C6H5
90/70
95/75
110/75
90/73
90/75
100/70
120/70
60/80
75/82
90/75
80/75
70/80
90/85
120/78
45/87
60/92
75/81
70/80
85/82
90/93
90/85
274–276 (280–281) [12f]
260–262 (262–264) [12f]
254–256 (261.5–263.5) [12j]
234–236 (239–242) [12k]
268–270 (265–267) [12k]
232–234 (229–231) [12j]
228–230 (226–228) [12k]
4-ClC6H5
4-BrC6H5
4-NO2C6H5
4-OHC6H5
4-CH3C6H5
4-OCH3C6H5
1g
a
The products were characterized by IR, 1H NMR, 13C NMR and mass spectroscopy.
Isolated yields. The reaction conditions: aromatic aldehyde (1 mmol), 1,2-diketone (1 mmol), ammonium acetate (2 mmol) 25 mg catalysts in the ethanol as the solvent
b
and under reflux condition.

A. Teimouri, A.N. Chermahini / Journal of Molecular Catalysis A: Chemical 346 (2011) 39–45
43
Catalyst
NH2
H
O
NH2
H
Catalyst
NH4OAC
+
EtOH, reflux
(I)
Ph
Ph
O
-2H2O
O
Ph
N
Ph
Ph
N
N
H
-H2O
Ph
N
H
(II)
Scheme 1. A plausible mechanism for the formation of trisubstituted imidazoles.
(m, 17H); 13C NMR (400 MHz, CDCl3): ı 158.1, 144.4, 139.2, 136.9,
136.2, 134.0, 132.1, 131.0, 130.1, 129.6, 129.4, 129.1, 128.8, 128.5,
128.1, 127.7, 127.4, 127.3, 127.1, 124.3, 123.9, 123.2; ESI MS (m/z):
388.3 (M+); Anal. Calcd. for C27H20N2O: C, 83.48; H, 5.19; N, 7.21.
Found: C, 83.55; H, 5.11; N, 7.29.
2.4.6. 1,4,5-Triphenyl-2-p-tolyl-1H-imidazole (2f)
Mp 182–184 ◦C. FTIR (KBr, cm−1): 3044, 2923, 1665, 1593; 1H
NMR (400 MHz, CDCl3): ı 7.60 (d, J¼7.2 Hz, 2H), 7.31–7.02 (m,
17H), 2.30 (s, 3H); 13C NMR (400 MHz, CDCl3): ı 147.1, 138.1, 137.2,
134.5, 131.1, 130.7, 130.6, 128.9, 128.8, 128.4, 128.2, 128.1, 127.8,
Catalyst
O
NH2
Ph
N
H
H
Catalyst
H
PhNH2
NH4OAC
+
+
EtOH, reflux
(III)
Ph
Ph
O
O
Ph
N
Ph
Ph
N
N
H
-H2O
Ph
N
HO
Ph
Ph
(IV)
Scheme 2. A plausible mechanism for the formation of tetrasubstituted imidazoles.

44
A. Teimouri, A.N. Chermahini / Journal of Molecular Catalysis A: Chemical 346 (2011) 39–45
Table 4
Acid-catalyzed synthesis of 1,2,4,5-tetrasubstituted imidazolesa
Ph
O
Ph
Ph
N
N
Catalyst
NH4OAC
+
+
NH2
R
RCHO
Ph
+
EtOH, reflux
Ph
O
Ph
.
Entry
Product
R
Time (min)/Yeild (%)b
Montmorilonite K10
MP ◦C (lit.) [Ref.]
Zeolite
Nano-crystalline SZ
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
C6H5
4-ClC6H5
4-BrC6H5
4-NO2C6H5
4-OHC6H5
4-CH3C6H5
4-OCH3C6H5
90/75
100/80
90/73
90/70
90/75
100/78
110/70
60/80
80/88
75/83
90/72
90/80
90/83
100/76
45/87
60/92
60/85
75/76
80/85
85/87
90/80
218–220 (216–218) [12m]
156–158 (164–166) [12f]
152–154
184–186
282–284 (287–289) [12f]
182–184 (186–188) [12m]
180–182 (185–188) [12m]
2g
a
The products were characterized by IR, 1H NMR, 13C NMR and mass spectroscopy.
Isolated yields. The reaction conditions: aromatic aldehyde (1 mmol), 1,2-diketone (1 mmol), aniline (1 mmol), ammonium acetate (1 mmol) 25 mg catalysts in the ethanol
b
as the solvent and under reflux condition.
127.6, 127.4, 126.5, 21.3; ESI MS (m/z): 386.3 (M+); Anal. Calcd. for
C28H22N2: C, 87.01; H, 5.74; N, 7.25. Found: C, 87.03; H, 5.81; N,
7.16.
150 min, respectively (Table 2, entries 5 and 6). Although the yields
were moderate in case of methanol and acetonitrile under reflux
condition (Table 2, entries 3 and 4).
The best results were obtained when the reaction was car-
ried out in ethanol at reflux during 80 min in the presence of
catalyst (Table 2, entry 2). Therefore, ethanol was selected as a
solvent for this reaction. Although water is a desirable solvent for
chemical reactions for reasons of cost, safety and environmental
concerns, we found that using water in this reaction gave mod-
erate yields of products under reflux condition after long reaction
times.
2.4.7. 1,4,5-Triphenyl-2-(4-methoxyphenyl)-1H-imidazole (2g)
Mp 180–182 ◦C. FTIR (KBr, cm−1): 3029, 2934, 1600; 1H NMR
(300 MHz, CDCl3): ı 7.50 (d, 2H), 7.21–7.00 (m, 17H), 3.81 (s, 3H);
13C NMR (75 MHz, CDCl3): ı 147.1, 137.2, 136.9, 134.5, 131.1, 130.9,
130.6, 129.5, 129.1, 128.4, 128.2, 128.1, 127.8, 127.6, 127.4, 126.5,
20.8; ESI MS (m/z): 402.3 (M+); Anal. Calcd. for C28H22N2O: C, 83.56;
H, 5.51; N, 6.96. Found: C, 83.23; H, 5.21; N, 6.36.
One of the most important advantages of heterogeneous
catalysis over the homogeneous counterpart is the possibility of
reusing the catalyst by simple filtration, without loss of activity.
The recovery and reusability of the catalyst was investigated in
the imidazole formation. After completion of the reaction, the
catalyst was separated by filtration, washed 3 times with 5 mL
acetone, then with doubly distilled water several times and dried
at 110 ◦C. Then the recovered catalyst was used in the next run.
The results of three consecutive runs showed that the catalyst
can be reused several times without significant loss of its activity
(see Fig. 5).
Several substituted aromatic aldehydes reacted with benzyl and
ammonium acetate in the presence of solid acid catalysts to give
the corresponding 2,4,5-trisubstituted imidazoles in good yields.
The nature of the substituents on the aromatic aldehyde has not
significant effect on yield of reaction. However the nature of catalyst
is significant. As you can see from Table 3, the best results obtained
from sulfated zirconia. The range of isolated yields that obtained
was found 70–75, 75–85 and 81–93% for the K10, zeolite and SZ,
respectively.
The results of synthesis of 1,2,4,5-tetrasubstituted imidazoles
from benzyl, aniline, ammonium acetate and various aromatic alde-
hydes tabulated in Table 4. Again, it can be seen that electron
donating and electron withdrawing groups does not show any dif-
ference on the reaction yields. Moreover the range of isolated yields
was found 73–80, 72–88 and 76–92% for the K10, zeolite and SZ,
respectively (see Table 4).
In accordance with the mechanism proposed that the solid
acid facilitates the formation of diamine intermediate [I] cata-
lyst by increasing the electrophilicity of the carbonyl group of
the aldehyde. Intermediate [I], condenses with benzil to form
intermediate [II], which in turn rearranges to the trisubstituted
imidazole (Scheme 1).
3. Results and discussion
In a model reaction and in the reaction between benzil, ammo-
nium acetate and benzaldehyde as an aromatic aldehyde, effect of
the catalyst amount was investigated (Table 1). To minimize the
formation of byproducts and to achieve good yield of the desired
product, the reaction is optimized by varying the amount of cata-
lyst (10, 25 and 50 mg). The percentage of the product formation
using K10 as the catalyst was found 85, 96 and 82%, respectively
(Table 1, entries 1–3). These values by using zeolite as the cata-
lyst was obtained and 84, 92 and 86%, respectively (Table 1, entries
4–6). Product formation by application of 10, 25 and 50 mg of SZ as
catalyst was found 82%, 96% and 87%, respectively (Table 1, entries
7–9). As you can see from Table 1. The same reaction when per-
formed without catalyst for 3 h gave no product (Table 1, entry 10).
When the catalyst content was increased to 50 mg, the product for-
mation decreased to 87% (Table 1, entry 9). Therefore, it was found
that the use of 25 mg of the catalyst was sufficient to promote the
reaction, and greater amounts of the catalyst did not improve the
yields.
We found ethanol and 25 mg of zeolite catalyst and K10 an
efficient reaction medium in terms of reaction time as well as
yield (Table 1, entries1–6). It is noteworthy to mention that in the
absence of catalyst, no product was found even after 120 min. These
results indicate that the catalyst exhibits a high catalytic activity in
this transformation.
In order to optimize the reaction conditions, including solvents
and temperature, the reaction of benzil, ammonium acetate and
aromatic aldehydes was optimized by time of the reaction and
using various solvents such as EtOH, MeOH, CH3CN, and toluene
(Table 2, entries 1–6). Reaction in toluene and dichloromethane
(DCM) solvent gave low product yields even after 110 min and

A. Teimouri, A.N. Chermahini / Journal of Molecular Catalysis A: Chemical 346 (2011) 39–45
45
Similarly, the plausible mechanism for the synthesis of the tetra-
substituted imidazole involves the formation of intermediate [III]
by the reaction of an aldehyde, phenyl amine and ammonium
acetate in the presence of catalyst. Intermediate [III] condenses
with benzil to form intermediate [IV], and then the tetrasubstituted
imidazole (Scheme 2).
In conclusion, a one-pot, multicomponent methodology has
been developed for the synthesis of 2,4,5-trisubstituted and
1,2,4,5-tetrasubstituted imidazoles catalyzed by clays, zeolite and
nano-crystalline SZ as catalyst in high yields. Compared to previ-
ously reported methods, Moreover, the mild reaction conditions,
easy work-up, clean reaction profiles, lower catalyst loading and
cost efficiency render this approach as an interesting alternative to
the existing methods.
[15] A. Shaabani, A. Rahmati, J. Mol. Catal. A: Chem. 249 (2006) 246.
[16] S.D. Sharma, P. Hazarika, D. Konwar, Tetrahedron Lett. 49 (2008) 2216.
[17] (a) S.A. Balalaie, Arabanian, Green Chem. 2 (2002) 274;
(b) M.M. Heravi, F. Derikvand, F.F. Bamoharram, J. Mol. Catal. A: Chem. 263
(2007) 112;
(c) A.R. Karimi, Z. Alimohammadi, J. Azizian, et al., Catal. Commun. 7 (2006)
728;
(d) S. Kantevari, S.V.N. Vuppalapati, D.O. Biradar, et al., J. Mol. Catal. A: Chem.
266 (2007) 109.
[18] (a) R. Consonni, P.D. Croce, R. Ferraccioli, et al., J. Chem. Res. (S) 188 (1991) 7;
(b) I. Lantos, W.-Y. Zhang, X. Shui, et al., J. Org. Chem. 58 (1993) 7092;
(c) S. Balalaie, M.M. Hashemi, M. Akhbari, Tetrahedron Lett. 44 (2003)
1709;
(d) U. Ucucu, N.G. Karaburun, I. Iskdag, Il Farmaco 56 (2001) 285.
[19] X.C. Wang, H.P. Gong, Z.J. Quan, et al., Chin. Chem. Lett. 20 (2009) 44.
[20] M. Doble, A. Kumar, Green Chemistry and Engineering, Elsevier, 2007.
[21] (a) T. Joseph, G.V. Shanbhag, D.P. Sawant, et al., J. Mol. Catal. A: Chem. 250 (2006)
210;
(b) G.V. Shanbhag, S.B. Halligudi, J. Mol. Catal. A: Chem. 222 (2004) 223;
(c) T. Joseph, G.V. Shanbhag, S.B. Halligudi, J. Mol. Catal. A: Chem. 236 (2005)
139;
Acknowledgement
(d) S. Albertazzi, I. Baraldini, G. Busca, et al., Appl. Clay Sci. 29 (2005) 224;
(e) N. Jagtap, V. Ramaswamy, Appl. Clay Sci. 33 (2006) 89;
(f) C.R. Reddy, B. Vijayakumar, P. Iyengar, et al., J. Mol. Catal. A: Chem. 223
(2004) 117;
Supports from the Payame Noor University in Isfahan research
council and helps of Yasouj University are gratefully acknowledged.
(g) S. Lal, K.S. Anisia, M. Jhansi, et al., J. Mol. Catal. A: Chem. 265 (2006)
15;
(h) C.R. Reddy, P. Iyengar, G. Nagendrappa, et al., J. Mol. Catal. A: Chem. 229
(2005) 31;
(i) G. Sharma, R. Kumar, A.K. Chakraborti, J. Mol. Catal. A: Chem. 263 (2006)
143;
(j) N.N. Binitha, S. Sugunan, Micropor. Mesopor. Mater. 93 (2006) 82;
(k) C.R. Reddy, G. Nagendrappa, B.S. Jai Prakash, Catal. Commun. 8 (2007)
241;
References
[1] J.G. Lambardino, E.H. Wiseman, J. Med. Chem. 17 (1974) 1182.
[2] A. Puratchikody, M. Doble, Bioorg. Med. Chem. Lett. 15 (2007)
1083.
[3] M. Antolini, A. Bozzoli, C. Ghiron, et al., Bioorg. Med. Chem. Lett. 9 (1999) 1023.
[4] L. Wang, K.W. Woods, Q. Li, et al., J. Med. Chem. 45 (2002) 1697.
[5] T. Maier, R. Schmierer, K. Bauer, et al. U.S. Patent 4820335, 1989; Chem. Abstr.
111 (1989) 19494w.
[6] J.C. Lee, J.T. Laydon, P.C. McDonnell, et al., Nature 372 (1994) 739.
[7] T. Maier, R. Schmierer, K. Bauer, et al. US Patent 4820335, 1989; Chem. Abstr.
111 (1989) 19494.
[8] R. Schmierer, H. Mildenberger, H. Buerstell, German Patent 361464, 1987;
Chem. Abstr. 108 (1988) 37838.
[9] J. Heeres, L.J.J. Backx, J.H. Mostmans, et al., J. Med. Chem. 22 (1979)
1003.
[10] (a) P. Wasserscheid, W. Keim, Angew. Chem. Int. Ed. Eng. 39 (2000) 37872;
(b) D. Bourissou, O. Guerret, F.T. Ggabbai, et al., Chem. Rev. (2000) 100.
[11] I. Satoru, Japn Kokkai Tokyo Koho JP 01, 117, 867, May 10, 1989; Chem. Abstr.
111 (1989) 214482.
[12] (a) S. Samai, G.C. Nandi, P. Singh, et al., Tetrahedron 65 (2009) 10155;
(b) S.A.A. Mansour, K.U. Sadek, Chin. Chem. Lett. 20 (2009) 812;
(c) D.V. Paone, A.W. Shaw, Tetrahedron Lett. 49 (2008) 6155;
(d) A. Shaabani, A. Rahmati, E. Farhangi, et al., Catal. Commun. 8 (2007) 1149;
(e) X.C. Wang, H.P. Gong, Zh.J. Quan, et al., Chin. Chem. Lett. 20 (2009) 44;
(f) N.J. Sangshetti, N.D. Kokare, S.A. Kotharkar, et al., Chin. Chem. Lett. 19 (2008)
762;
(l) R.I. Kureshy, N.H. Khan, S.H.R. Abdi, et al., J. Catal. 221 (2004) 234;
(m) B. Singh, J. Patial, P. Sharma, et al., J. Mol. Catal. A: Chem. 266 (2006)
215.
[22] (a) M.F.V. Marques, S.C. Moreira, J. Mol. Catal. A: Chem. 192 (2003) 93;
(b) V. Mavrodinova, M. Popova, R.M. Mihalyi, et al., Appl. Catal. A: Gen. 248
(2003) 197;
(c) A. Corma, A.V. Orchilles, Micropor. Mesopor. Mater. 21 (2000) 35;
(d) H.H. Ingelsten, D. Zhao, A. Palmqvist, et al., J. Catal. 232 (2005) 68;
(e) D. Zhao, H.H. Ingelsten, M. Skoglundh, et al., J. Mol. Catal. A: Chem. 249
(2006) 13.
[23] (a) V. Indovina, D. Pietrogiacomi, M.C. Campa, Appl. Catal. B: Environ. 39 (2002)
115;
(b) D. Pietrogiacomi, M.C. Campa, S. Tuti, Appl. Catal. B: Environ. 41 (2003)
301;
(b) N. Li, A. Wang, J.X. Tang, Appl. Catal. B: Environ. 43 (2003) 195;
(c) B. Tsyntsarski, V. Avreyska, H. Kolev, et al., J. Mol. Catal. A: Chem. 193 (2003)
139;
(d) U.B. Demirci, F. Garin, J. Mol. Catal. A: Chem. 188 (2002) 233.
[24] (a) H.A. Dabbagh, A. Teimouri, A. Najafi Chermahini, J. Appl. Catal. B: Environ.
76 (2007) 24;
(g) A.R. Khosropour, Ultrason. Sonochem. 15 (2008) 659;
(h) M. Ghaemy, R. Alizadeh, Eur. Pol. J. 45 (2009) 1681;
(i) M.M. Heravi, K. Bakhtiari, H.A. Oskooie, et al., J. Mol. Catal. A: Chem. 263
(2007) 279;
(b) A. Najafi Chermahini, A. Teimouri, F. Momenbeik, et al., J. Heterocycl. Chem.
47 (2010) 913.
[25] (a) R. J. Argauer, G.R. Landolt, US Patent No. 3 702 886, 1972;
(b) J. Dwyer, Chem. Ind. 2 (1984) 258;
(j) H. Zang, Q. Su, Y. Mo, et al., Ultrason. Sonochem. 17 (2010) 749;
(k) M. Xia, Y.-d. Lu, J. Mol. Catal. A: Chem. 265 (2007) 205;
(l) B. Sadeghi, B.F. Mirjalili, M.M. Hashemi, Tetrahedron Lett. 49 (2008) 2575;
(m) M. Ghaemy, H. Behmadi, R. Alizadeh, Chin. Chem. Lett. 20 (2009) 961.
[13] (a) S.A. Siddiqui, U.C. Narkhede, S.S. Palimkar, et al., Tetrahedron 61 (2005)
3539;
(b) X. Min, Y.-d. Lu, J. Mol. Catal. A: Chem. 265 (2007) 205.
[14] (a) J. Wang, R. Mason, D.V. Derveer, et al., J. Org. Chem. 68 (2003) 5415, 68;
(b) S. Sarshar, D. Siev, A.M.M. Mjalli, Tetrahedron Lett. 37 (1996) 835;
(c) T.F. Gallagher, G.L. Seibel, S. Kassis, et al., Bioorg. Med. Chem. (1997) 49;
(d) E.A. Steck, A.R. Day, J. Am. Chem. Soc. (1943) 452.
(c) J.L. Guth, Non-Conventional Crystalline Microporous Solids, Zeolite Micro-
porous Solids: Synthesis, Structure, and Reactivity, Kluwer Academic, The
Netherlands, 1992, p. 49;
(d) V.R. Choudhary, D. Panjala, S. Banerjee, Appl. Catal. A: Gen. 231 (2002) 243.
[26] (a) M.K. Mishra, B. Tyagi, R.V. Jasra, J. Mol. Catal. A: Chem. 223 (2004) 6;
(b) B. Tyagi, M.K. Mishra, R.V. Jasra, Catal. Commun. 7 (2006) 52.
[27] B.D. Cullity, S.R. Stock, Elements of X-ray Diffraction, third edition, Prentice
Hall, Upper Saddle River, NJ, 2001, p. 388.
[28] S.J. Gregg, K.S.W. Sing, Adsorption, Surface Area and Porosity, second edition,
Academic Press, New York, 1982.