γ-Alumina nanoparticle catalyzed efficient synthesis of highly substituted imidazoles

Article abstract of DOI:10.3390/molecules201019221

γ-Alumina nano particle catalyzed multi component reaction of benzil, arylaldehyde and aryl amines afforded the highly substituted 1,2,4,5-tetraaryl imidazoles with good to excellent yield in less reaction time under the sonication as well as the conventional methods. Convenient operational simplicity, mild conditions and the reusability of catalyst were the other advantages of this developed protocol.

Full text of DOI:10.3390/molecules201019221

Molecules 2015, 20, 19221-19235; doi:10.3390/molecules201019221
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
γ-Alumina Nanoparticle Catalyzed Efficient Synthesis of Highly
Substituted Imidazoles
Bandapalli Palakshi Reddy 1, Vijayaparthasarathi Vijayakumar 1,*, Mariadhas Valan Arasu 2
and Naif Abdullah Al-Dhabi 2
1
Center for Organic and Medicinal Chemistry, VIT University, Vellore 632014, Tamil Nadu, India;
E-Mail: palakshireddy@gmail.com
2
Department of Botany and Microbiology, Addiriyah Chair for Environmental Studies,
College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia;
E-Mails: mvalanarasu@gmail.com (M.V.A.); naifaldhabi2014@gmail.com (N.A.A.)
* Author to whom correspondence should be addressed; E-Mail: kvpsvijayakumar@gmail.com;
Tel.: +91-944-391-6746; Fax: +91-416-220-3091.
Academic Editor: Derek J. McPhee
Received: 6 September 2015 / Accepted: 14 October 2015 / Published: 21 October 2015
Abstract: γ-Alumina nano particle catalyzed multi component reaction of benzil, arylaldehyde
and aryl amines afforded the highly substituted 1,2,4,5-tetraaryl imidazoles with good to
excellent yield in less reaction time under the sonication as well as the conventional methods.
Convenient operational simplicity, mild conditions and the reusability of catalyst were the
other advantages of this developed protocol.
Keywords: benzil; arylaldehydes; γ-Alumina NPs; one pot synthesis; 1,2,4,5-tetraaryl
imidazoles
1. Introduction
The imidazole ring system was reported [1] as an active component of several drugs such as Losartan,
Olmesartan, Eprosartan and Trifenagrel (Figure 1), and many biologically important compounds like
histidine, histamine and biotin. The potency and pertinence of imidazole pharmacophore was largely
due to its hydrogen-bond donor acceptor nature as well as its high affinity towards the metals existing
in the protein active sites (e.g., Fe, Zn, Mg). The imidazole derivatives were reported to function as

Molecules 2015, 20
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inhibitors of p38 MAP kinase, B-Raf kinase [2], transforming growth factor b1 (TGF-b1) type 1
activin receptor-like kinase (ALK5) [3], cyclooxygenase-2 (COX-2) [4] and were also reported to be
involved in the biosynthesis of interleukin-1 (IL-1) [5,6]. Appropriately substituted imidazoles were used
as glucagon receptors [7], CB1 cannabinoid receptor antagonists [8] and modulators of P-glycoprotein
(P-gp) mediated multidrug resistance (MDR) [9]. The imidazole core was also reported to exhibit
anti-allergic [10], anti-inflammatory [11], analgesic, antifungal, antimycotic, antibiotic, anti-ulcerative,
antibacterial and antitumor activity [12].
OH
Cl
N
N
RO
HOH2C
N
N
N
N
N
N
HN
N
O
HN
N
Losartan
Olmesartan
Ph
Ph
N
S
Cl
N
N
H
HOOC
N
NMe2
O
Trifenagrel
Eprosartan
COOH
Figure 1. Some of the imidazole based drugs.
A number of methods have been developed for the synthesis of 1,2,4,5-tetrasubstituted imidazoles. The
catalysts, such as silica gel or Zeolite HY [13], silica gel/NaHSO4 [14], I2 [15], K5CoW12O40•3H2O [16],
heteropoly acids [17], HClO4-SiO2 [18], InCl3·3H2O [19], ZrCl4 [20], BF3•SiO2 [21], DABCO [22],
PEG-400 [23] and silica-bonded propylpiperazine N-sulfamic acid (SBPPSA) [24], were also served for
this purpose, all these methods suffered by several disadvantages like the usage of expensive moisture
sensitive catalysts, hazardous organic solvents, laborious workup, longer reaction duration, larger volume
of catalyst. Hence the development of a mild, simple, more efficient and green procedure for the synthesis
of 1,2,4,5-tetrasubstituted imidazoles was highly desirable.
In recent years, nano catalysts have gained prominence due to their efficiency and selectivity. The easy
work up and reusability were the added advantages associated with the usage of this type of catalysts.
Alumina is one of the inert biomaterial used in implants due to its biocompatible nature [25–30]. It exists
in many metastable forms (γ, δ, θ, κ, ε, η, χ) and in particular γ-Al2O3 has significant applications as a
catalyst [31]. γ-Al2O3 is iso-structural with γ-Fe2O3 and perhaps the most important nano material used
as a support for metal catalysts; in view of its inherent properties like environmental compatibility, greater
selectivity, moisture-insensitivity and operational simplicity, we intend to explore the catalytic behavior
of γ-Al2O3 NPs in the synthesis of imidazoles. We anticipated that the Lewis acid behavior and the smaller

Molecules 2015, 20
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particle size of Al2O3 NPs (with large surface area) may efficiently catalyze the chemical reaction. Hence
we attempted the γ-Al2O3 NPs catalyzed synthesis of tetraaryl imidazoles which is hitherto unreported.
2. Results and Discussion
To the aqueous the solution of Al(NO3)3•9H2O (1.72 g dissolved in 460 mL of distilled water) ammonia
solution (30 mL) was added in drop wise using peristaltic pump under stirring with a propeller at 500 rpm
for 30 min. The resulted turbid solution was warmed at 90 °C (using a temperature controlled water bath)
till all the aluminum hydroxide was precipitated. The precipitate was collected by centrifugation and
washed with distilled water followed by ethanol and then calcinated at 80 °C for four hours. The overall
reaction for the synthesis of Al2O3 NPs from Al(NO3)3 can be depicted as,
Al(NO3)3 + 3NH4OH → Al(OH)3 ↓ + 3NH4NO3
2Al(OH)3 → 2AlOOH(boehmite) + 2H2O
2AlOOH(boehmite) → γ-Al2O3+ H2O
(1)
(2)
(3)
The synthesized Al2O3 NPs were characterized using Power X-ray Diffractometer with Cu Kα radiation
(λ = 1.54 Å) over a 2θ range of 10°–90°. The XRD pattern exhibited seven distinct diffraction peaks at
19.79, 32.54, 37.53, 39.01, 45.81, 60.92 and 66.98 which could be assigned to (1 1 1), (2 2 0), (3 1 1),
(2 2 2), (4 0 0), (5 1 1) and (4 4 0) of cubic nano γ-Al2O3 respectively and found to be in agreement
with the database of JCPDS No. 00-010-0425 (Joint Committee on Powder Diffraction Standards)
(Figure 2). The images of γ-Al2O3 NPs were observed using SEM (Carl Zeiss oxford instrument, (Oxford,
UK) at various magnifications (Figure 3). The micrograph at lower magnification revealed the formation
of well dispersed rod shaped γ-Al2O3 NPs. After confirming the formation of γ-Al2O3 NPs it was subjected
as a catalyst in the synthesis of tetraaryl imidazoles via multi component reaction (Scheme 1) of benzil
(1 mmol), arylaldehyde (1 mmol), ammonium acetate (2.0 mmol), and aniline (1 mmol) in ethanol.
The observed yield and reaction duration of γ-Al2O3 NPs catalyzed reaction conferred that the γ-Al2O3
was an effective and efficient catalyst as anticipated. The observed efficiency may be attributed to
Lewis acid behavior of γ-Al2O3 NPs and its smaller particle size (larger surface area). For optimization
the reaction of benzil (1 mmol), 4-hydroxybenzaldehyde (1 mmol), ammonium acetate (2.0 mmol) and
4-methylaniline (1 mmol) in ethanol was chosen as a representative reaction for the synthesis of
4-(4,5-diphenyl-1-(4-methylphenyl)-1H-imidazol-2-yl)phenol. Catalytic efficiency was investigated
under sonication and conventional heating methods. In conventional method the reaction mixture was
refluxed for 240 min in the absence of catalyst, in this the observed yield was 33% of imidazole 8, but
the same reaction under similar conditions in the presence of 5 mol % of Al2O3 NPs could yield 82%
of imidazole 8 in 60 min. The increase in mol % of Al2O3 NPs from 5 mol % to 10 mol % not only
decreased the reaction time from 60 min to 40 min but also increased the yield of imidazole 8 from
82% to 93% (Table 1). Further increase in concentration of γ-Al2O3 NPs has no effect on the yield and
time of the reaction.

Molecules 2015, 20
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225
200
175
150
125
100
75
50
0
10
20
30
40
50
60
70
80
90
2θ
Figure 2. XRD pattern of γ-Al2O3 NPs.
Figure 3. SEM micrographs of synthesized γ-Al2O3 NPs at various magnifications.
N
Ph
O
H
O
+
N
Al2O3 NPs
Ethanol
+
R
CH3COONH4
+
RNH2
Ph
O
Scheme 1. Tetraaryl substituted imidazoles using multi-component reaction.

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Table 1. Catalytic activity evaluation at 78 °C for synthesis of tetraaryl imidazole 8 in ethanol.
In Conventional Method
Entry Al2O3 (mol %) Time (min)
Under Ultrasonication
Yield (%) b Entry Al2O3 (mol %) Time (min) Yield (%) b
1
2
3
4
5
20
15
10
05
00
40
40
93
93
93
82
33
1
2
3
4
5
20
15
10
05
00
25
25
95
94
94
80
35
40
25
60
45
240
120
b Isolated yield.
The effect of temperature on the reaction was investigated by carrying out the representative reaction
at different temperatures (RT (25 °C), 50 °C, 80 °C and 100 °C) in solvents like acetonitrile and ethanol
separately with 10 mol % of the catalyst and found that the yield was not affected with the increase of
temperature (Table 2). To investigate the effects of media, the reaction was carried out in polar and
non-polar solvents at RT using 10 mol % γ-Al2O3 NPs the catalyst at 80 °C (maximum of 78 °C
temperature was maintained when ethanol was used as solvent). The polar solvents were found to be
much better than non-polar solvents. Though acetonitrile, dichloromethane or ethanol were found to be
good solvents (Table 3), ethanol was opted as a suitable solvent since it is relatively environmental
benign and it required only the aqueous work up. The same model reaction was carried under sonication
(to compare the general conventional process) and found that the yields were significantly increased
under sonication (Table 1); this may be due to the dispersion phenomenon. The required concentration of
catalyst under the sonication was investigated by changing its concentration in the synthesis of imidazole
8 and found that 10 mol % was sufficient to afford imidazole with 94% yield in 35 min (Table 1). The
excellent yield in lesser time (compared to the conventional process) may be due to the availability of
large surface area of catalyst and the sonication assisted dispersion of NPs. The reaction of benzil with
various arylaldehydes bearing electron withdrawing groups (such as nitro, halide, etc.) or electron releasing
groups (methyl, hydroxyl; mono, di, or tri methoxy groups, etc.), benzyl amine, aniline derivatives and
ammonium acetate were also successfully carried out in the presence of γ-Al2O3 NPs. After optimizing
the conditions a series of tetraaryl imidazoles from 1–22 were synthesized successfully (Table 4). Good to
excellent yield of desired products was observed (without the formation of 2,4,5-trisubstituted imidazoles
as side products, which were normally observed under the influence of the strong acids [19]). Plausible
mechanism of the synthesis of tetraaryl imidazoles given in (Figure 4). The protocol described for the
synthesis of tetraaryl imidazoles possesses its scope in the context of ease, generality and the simplicity.
Waste generation and side products were largely avoided and hence the products were obtained with
high yield and purity. In this experiment, after the completion of reaction, the reusability of the catalyst
was assessed by washing the filtered catalyst (Figure 5) thoroughly with ethanol and distilled water
followed by activation of the catalyst at 250 °C for 2 h (Figure 6). The separated catalyst was reused
efficiently for four cycles with consistent activity (yields were 93%, 93%, 91% and 90%). All these
tetraaryl imidazoles 1–22 were synthesized using the same methodology and characterized through IR,
1H-NMR, 13C-NMR and Mass spectral data and were available as supplementary data.

Molecules 2015, 20
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Al2O3 NPs
Al2O3 NPs
H
H
O
H
H2N
OH
O
H
NH2
H2N
NH
Al2O3 NPs
NH3
H2O
Al2O3 NPs
-2H2O
H
Al2O3 NPs
O
O
N
N
Al2O3 NPs
N
N
-H2O
HO
Figure 4. Plausible mechanism for synthesis of tetraaryl imidazoles.
250
200
150
100
50
0
0
10
20
30
40
50
60
70
80
90
2
θ
Figure 5. XRD pattern of recovered γ-Al2O3 NPs after four runs.
Figure 6. Reusability of catalyst.

Molecules 2015, 20
Table 2. Temperature evaluation and effect of solvent in the synthesis of tetraaryl imidazole 8.
19227
Temperature Evaluation a
Entry Temperature (°C) Time (min) Yield (%) c
1
2
3
25
50
78
90
60
40
88
90
93
a in ethanol and 10 mol % catalyst; c Isolated yields.
Table 3. Effect of solvent on the yield of tetraaryl imidazole 8 at 10 mol % catalyst.
Effect of Solvent b
Entry
Solvent
Ethanol
Yield (%) c
1
2
3
4
93
88
86
88
Methanol
Dichloromethane
Acetonitrile
b at reflux temp, time 40 min; c Isolated yields.
Table 4. Synthesis of tetraaryl imidazoles (1–22) a.
Reaction Time (min)
Yield (%) b
Entry
R
Ph
mp (°C)
Conventional US Conventional US
1
2
-CH2Ph
-CH2Ph
-CH2Ph
-CH2Ph
-CH2Ph
Ph
40
40
50
50
40
45
55
40
45
55
40
60
55
60
60
60
50
45
50
50
45
40
25
25
30
35
25
25
30
25
30
35
25
45
35
40
45
50
35
25
30
25
30
30
92
92
92
92
92
90
90
93
91
93
89
91
92
91
87
91
93
89
93
93
94
94
95 161–163
94 165–167
94 155–157
93 180–182
93 144–146
94 180–182
93 212–214
4-ClPh
3
4-OC2H5Ph
3,5-(OCH3)2Ph
3-Cl Ph
4
5
6
4-CH3Ph 4-OH-3-OC2H5Ph
7
4-CH3Ph
4-CH3Ph
4-CH3Ph
4-CH3Ph
4-CH3Ph
4-C2H5Ph
4-OHPh
8
94
>275
9
3,5-(OCH3)2Ph
3,4,5-(OCH3)3Ph
2-Thienyl
94 140–142
93 102–104
92 200–201
92 123–125
93 181–182
93 123–125
89 112–114
91 98–100
10
11
12
13
14
15
16
17
18
19
20
21
22
4-OCH3Ph 3,4,5-(OCH3)3Ph
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-IPh
4-C2H5Ph
3,4,5-(OCH3)3Ph
4-CNPh
AllyloxyPh
4-BrPh
91
92 109–111
94 96–98
93 260–162
92 85–87
94 169–170
80–82
2,4-(Cl)2Ph
4-OH-3-OCH3Ph
3-OHPh
4-IPh
4-CH3Ph
4-ClPh
4-ClPh
3-OHPh
4-OH-3-OC2H5Ph
a
Reaction conditions: aldehyde (1 mmol), aniline (1 mmol) and γ-Al2O3 NPs (10 mol %), ethanol (10 mL),
ammonium acetate (2.0 mmol); b Isolated and unoptimized yields.

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In summary, the reaction of arylaldehyde, aryl amine and ammonium acetate with benzil in the presence
of γ-Al2O3 NPs as efficient and effective catalyst provided a simple one-pot entry into the synthesis of
biologically active highly substituted imidazoles. The simplicity, efficiency, generality, high yield,
eco-friendly procedure, reusability of the catalyst was the promising points of the described methodology.
3. Experimental Section
3.1. Chemicals and Apparatus
Solvents and reagents were commercially sourced and used without further purification. Melting
points were recorded on Elchem Microprocessor (Chennai, India) based DT apparatus in open capillary
tubes and are uncorrected. IR spectra recorded on Avatar-330 FTIR spectrophotometer (Thermo Nicolet,
Madison, WI, USA) using KBr pellets, and only noteworthy absorption levels (reciprocal centimeters)
has been listed. Sonication was carried out by using E-Chrom ultrasonic horn (10F-8, No. 20, Minchuan
W. Road, Taipei 104, Taiwan), 22 kHz frequency. The NMR spectra were recorded on Bruker (Bruker
Corporation, Billerica, MA, USA) 400 & 500 MHz spectrometers using TMS as internal standard (chemical
shifts δ in ppm). CDCl3 and DMSO-d6 are used as NMR solvents. Mass spectra were recorded on an
HRMS MicromasszQ (San Diego, CA, USA) spectrometer. TLC was performed on preparative plates
of silica gel (s.d.fine). Visualization was made with an iodine chamber.
3.2. Preparation of Al2O3 NPs
In a typical preparation, Al(NO3)3•9H2O (1.72 g) was dissolved in 460 mL distilled water and 30 mL
of ammonia solution added drop wise using peristaltic pump under stirring using a propeller at 500 rpm
for 30 min. The resulting turbid solution was warmed for two hours using a temperature controlled water
bath at 90 °C till all aluminum hydroxide settled. The resulting precipitate was harvested by centrifugation,
washed with distilled water followed by ethanol. The precipitate was then calcined at 800 °C for
four hours.
General procedure for the synthesis of 1,2,4,5-tetraaryl imidazoles (1–22) under the conventional
heating: An aldehyde (1 mmol), aniline (1 mmol) and γ Al2O3 NPs (10 mol %) in ethanol (10 mL), were
added, stirred for 10 min. To this ammonium acetate (2.0 mmol) followed by 1,2-diketone (1 mmol)
were added, then the reaction mixture was heated at 80 °C until completion of the reaction. Completion
of the reaction was monitored by TLC. The reaction mixture was cooled to RT and catalyst was filtered,
the solvent was removed by rotary evaporator. The crude product was dissolved in ethyl acetate and
water (3 × 10 mL:10 mL). The organic layer was separated and dried over anhydrous Na2SO4 and then
the solvent was distilled under reduced pressure to get crude product. The crude product was purified
by column chromatography to afford the corresponding imidazoles in good to excellent yield.
General procedure for the synthesis of 1,2,4,5-tetraaryl imidazoles (1–22) under the ultrasonication:
To ethanol (10 mL), aldehyde (1 mmol), aniline (1 mmol) and γ Al2O3 NPs (10 mol %) in ethanol (10 mL)
were added and stirred for 10 min. To this ammonium acetate (2.0 mmol) followed by 1,2-diketone
(1 mmol) were added, then the reaction mixture was kept under sonicationup to the completion of the
reaction (Table 4). Completion of the reaction was monitored by TLC. The reaction mixture was cooled
to RT and catalyst was filtered, the solvent was removed by rotary evaporator. The crude product was

Molecules 2015, 20
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dissolved in ethyl acetate and water (3 × 10 mL:10 mL). The organic layer was separated and dried
over anhydrous Na2SO4 and then the solvent was distilled under reduced pressure to get crude product.
The crude product was purified by column chromatography to afford the corresponding imidazoles in
good to excellent yield. The identity as well as purity of the product was confirmed by 1H-, 13C-NMR,
and mass spectra.
4. Spectral Data
1-Benzyl-2,4,5-triphenyl-1H-imidazole (1): Yield: 95%. m.p.: 161–163 °C; IR (KBr, cm−1): 2956, 1613,
1560, 1416. 1H-NMR (400 MHz, CDCl3) δH: 5.11 (s, 2H), 6.80 (d, J = 7.4 Hz, 3H), 7.10 (t, J = 7.4 Hz,
1H), 7.2–7.4 (m, 10H), 7.52 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.6 Hz, 3H), 7.18–7.24 (m, 8H), 7.28–7.34
13
(m, 3H) 7.63 (d, J = 6.8 Hz, 2H). C-NMR (100 MHz, CDCl3) δC: 31.03, 48.41, 76.84, 77.16, 77.47,
115.85, 116.06, 116.15, 116.38, 124.60, 124.63, 126.00, 126.11, 126.46, 126.61, 126.88, 127.61, 128.18,
128.23, 128.67, 128.69, 128.80, 128.88, 128.97, 129.14, 130.01, 130.25, 130.33, 130.62, 130.85, 131.14,
133.03, 133.08, 133.11, 134.36, 135.02, 137.35, 138.39, 146.73, 146.75, 161.55, 164.00, 194.70, 207.12.
HRMS (m/z): Calcd. for C28H22N2: 386.1783. Found: 386.1788 (M+).
1-Benzyl-2-(4-chlorophenyl)-4,5-diphenyl-1H-imidazole (2): Yield: 94%. m.p.: 165–167 °C; IR (KBr, cm−1):
2986, 1618, 1563, 1417, 802. 1H-NMR (500 MHz, DMSO-d6) δH: 5.12 (s, 2H), 6.83 (d, J = 7.4 Hz, 2H),
7.19 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.20–7.40 (m, 6H), 7.52 (d, J = 7.6 Hz, 3H), 7.56
(t, J = 7.6 Hz, 3H), 7.69 (d, J = 6.8 Hz, 3H). 13C-NMR (125 MHz, DMSO) δC: 48.30, 125.88, 126.03,
126.36, 126.50, 126.80, 127.35, 127.52, 128.07, 128.13, 128.23, 128.57, 128.58, 128.61, 128.72, 128.76,
128.78, 128.83, 128.86, 128.90, 129.03, 129.09, 129.90, 130.07, 130.43, 130.98, 131.05, 131.10, 134.30,
134.48, 135.00, 137.34, 137.56, 138.11, 138.32, 138.50, 146.86. HRMS (m/z): Calcd. for C28H21ClN2:
420.1393. Found: 420.1387 (M+).
1-Benzyl-2-(4-ethoxyphenyl)-4,5-diphenyl-1H-imidazole (3): Yield: 94%. m.p.: 155–157 °C; IR (KBr, cm−1):
1
2965, 1629, 1598, 1423, 1134. H-NMR (400 MHz, CDCl3) δH: 1.41 (t, J = 7.2 Hz, 3H), 4.10 (q,
J = 7.2 Hz, 2H), 5.10 (s, 2H), 6.79 (d, J = 7.4 Hz, 2H), 6.89 (d, J = 7.4 Hz, 2H), 7.23–7.56 (m, 10H),
7.54 (d, J = 7.4 Hz, 2H), 7.97 (d, J = 7.2 Hz, 4H). 13C-NMR (100 MHz, CDCl3) δC: 14.91, 29.50, 48.38,
63.64, 114.70, 123.33, 126.17, 126.42, 126.94, 127.45, 128.19, 128.67, 128.71, 128.89, 129.17, 129.23,
129.87, 130.06, 130.57, 131.24, 131.30, 134.67, 137.82, 137.94, 148.22, 159.65. HRMS (m/z): Calcd.
for C30H26N2O: 430.2045. Found: 430.2033 (M+).
1-Benzyl-2-(3,5-dimethoxyphenyl)-4,5-diphenyl-1H-imidazole (4): Yield: 93%. m.p.: 180–182 °C; IR
(KBr, cm−1): 2945, 1685, 1531, 1492, 1176. 1H-NMR (500 MHz, DMSO-d6) δH: 3.67 (s, 3H), 3.87 (s,
3H), 5.08 (s, 2H), 6.87 (d, J = 6.8 Hz, 3H), 7.10 (d, J = 7.2 Hz, 1H), 7.14 (s, 1H), 7.18–7.24 (m, 8H),
13
7.28–7.34 (m, 3H), 7.56 (d, J = 6.8 Hz, 2H). C-NMR (125 MHz, DMSO) δC: 48.31, 55.71, 55.99,
111.05, 112.29, 121.69, 123.56, 125.99, 126.44, 126.91, 127.44, 128.17, 128.73, 128.77, 128.92, 130.02,
131.13, 134.57, 137.89, 138.01, 148.06, 148.84, 149.67. HRMS (m/z): Calcd. for C30H26N2O2: 446.1994.
Found: 446.1980 (M+).

Molecules 2015, 20
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1-Benzyl-2-(3-chlorophenyl)-4,5-diphenyl-1H-imidazole (5): Yield: 93%. m.p.: 144–146°C; IR (KBr, cm−1):
2980, 1610, 1521, 1410, 1122, 790. 1H-NMR (400 MHz, CDCl3) δH: 5.12 (s, 2H), 6.82 (s, 2H), 7.19–7.29
13
(m, 8H), 7.34–7.41 (m, 8H), 7.61 (t, J = 7.4 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H). C-NMR (100 MHz,
CDCl3) δC: 48.30, 125.87, 126.02, 126.40, 126.53, 126.81, 127.38, 127.54, 128.11, 128.16, 128.26,
128.59, 128.62, 128.64, 128.73, 128.80, 128.82, 128.85, 128.89, 128.95, 129.08, 129.41, 129.90, 130.11,
130.26, 130.48, 130.76, 130.93, 131.03, 131.08, 134.31, 134.47, 134.98, 137.32, 137.53, 138.06, 138.28,
138.48, 146.85, 148.09, 148.45. HRMS (m/z): Calcd. for C28H21ClN2: 420.1393. Found: 420.1399 (M+).
4-(4,5-Diphenyl-1-(4-methylphenyl)-1H-imidazol-2-yl)-2-ethoxyphenol (6): Yield: 94%. m.p.: 180–182 °C;
1
IR (KBr, cm−1): 2956, 1613, 1560, 1416, 1139. H-NMR (500 MHz, DMSO-d6) δH: 1.32 (t, 3H,
J = 7.6 Hz), 2.30 (s, 3H), 3.90 (q, 2H, J = 7.6 Hz), 6.84 (d, 1H, J = 7.6 Hz), 6.75 (s, 1H), 6.91 (d, 2H,
J = 7.6 Hz), 7.00–7.06 (m, 3H), 7.10–7.25 (m, 6H), 7.58 (d, 2H, J = 7.6 Hz), 7.97 (d, 2H, J = 7.6 Hz).
13C-NMR (125 MHz, DMSO) δC: 14.89, 21.23, 31.06, 64.42, 112.70, 114.13, 122.46, 122.79, 126.60,
127.53, 127.93, 128.23, 128.35, 128.41, 129.16, 129.79, 130.03, 130.65, 130.94, 131.26, 133.10, 134.66,
134.84, 135.03, 137.92, 138.20, 145.41, 146.13, 147.14, 194.72, 207.16. HRMS (m/z): Calcd. for
C30H26N2O2: 446.1994. Found: 446.1981 (M+).
2-(4-Ethylphenyl)-4,5-diphenyl-1-(4-methylphenyl)-1H-imidazole (7): Yield: 93%. m.p.: 212–214 °C;
IR (KBr, cm−1): 2967, 1694, 1523, 1461, 1245. 1H-NMR (400 MHz, CDCl3) δH: 1.19 (s, 3H), 2.31 (s, 3H),
2.61 (m, 2H), 6.90 (d, J = 7 Hz, 1H), 7.00 (d, J = 8.2 Hz, 2H), 7.15–7.42 (m, 6H), 7.52 (d, J = 7.4 Hz,
2H), 7.58 (d, J = 7.4 Hz, 2H), 7.65 (t, J = 8 Hz, 2H), 8.00 (d, J = 8 Hz, 2H). 13C-NMR (100 MHz, CDCl3)
δC: 15.36, 21.31, 28.70, 31.06, 125.47, 126.59, 127.53, 127.70, 127.92, 127.98, 128.11, 128.23, 128.27,
128.40, 128.45, 128.68, 128.95, 129.16, 129.78, 130.04, 130.84, 130.99, 131.27, 133.11, 134.72, 135.04,
138.17, 144.43, 147.24. HRMS (m/z): Calcd. for C30H26N2: 414.2096. Found: 414.2090 (M+).
4-(4,5-Diphenyl-1-(4-methylphenyl)-1H-imidazol-2-yl)phenol (8): Yield: 94%. m.p.: >280 °C; IR
1
(KBr, cm−1): 2956, 1619, 1562, 1414, 1287. H-NMR (400 MHz, CDCl3) δH: 2.26 (s, 3H), 6.65 (d,
J = 7.4 Hz, 2H), 7.08–7.24 (m, 7H), 7.32 (d, J = 7.4 Hz, 3H), 7.49 (d, J = 7.4 Hz, 2H), 7.68 (t, J = 7.2 Hz,
2H), 7.81 (t, J = 7 Hz, 3H), 7.95 (d, J = 5.6 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δC: 21.09, 115.40,
121.86, 126.69, 126.77, 128.53, 128.71, 128.87, 128.93, 129.97, 130.01, 130.05, 130.23, 131.08,
131.20, 131.60, 132.74, 134.79, 135.12, 135.99, 136.83, 138.33, 158.01. HRMS (m/z): Calcd. for
C28H22N2O: 402.1732. Found: 402.1720 (M+).
2-(3,5-Dimethoxyphenyl)-4,5-diphenyl-1-(4-methylphenyl)-1H-imidazole (9): Yield: 94%. m.p.: 140–142 °C;
1
IR (KBr, cm−1): 2923, 1609, 1567, 1495, 1165. H-NMR (400 MHz, CDCl3) δH: 2.20 (s, 3H), 3.60 (s,
6H), 5.55 (d, 1H), 6.71 (d, J = 7.2 Hz, 2H), 6.95 (d, J = 7.2 Hz, 2H), 7.22 (d, J = 7.4 Hz, 2H), 7.40–7.60
13
(m, 6H), 7.97 (d, J = 7.2 Hz, 4H). C-NMR (100 MHz, CDCl3) δC: 29.83, 56.14, 106.16, 126.70,
127.56, 128.02, 128.28, 128.46, 128.49, 129.17, 129.83, 130.06, 130.86, 131.28, 133.14, 135.03, 138.02,
138.32, 146.63, 147.04. HRMS (m/z): Calcd. for C30H26N2O2: 446.1994. Found: 446.1980 (M+).
4,5-Diphenyl-1-(4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)-1H-imidazole (10): Yield: 93%. m.p.:
102–104 °C; IR (KBr, cm−1): 2934, 1693, 1567, 1436, 1173. 1H-NMR (400 MHz, CDCl3) δH: 2.30 (s,
3H), 3.61 (s, 6H), 3.81 (s, 3H), 6.70 (s, 3H), 6.90 (d, J = 8 Hz, 3H), 7.10 (d, J = 8 Hz, 2H), 7.30–7.50

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(m, 5H), 7.50 (t, J = 6.8 Hz, 2H), 7.60 (d, J = 6.8 Hz, 2H), 7.70 (d, J = 6.8 Hz, 1H), 8.00 (d, J = 7.4 Hz,
2H). 13C-NMR (100 MHz, CDCl3) δC: 21.16, 55.88, 60.96, 106.28, 125.91, 126.72, 127.51, 128.04,
128.26, 128.39, 128.44, 129.13, 129.83, 130.01, 130.72, 131.01, 131.21, 133.08, 134.51, 134.87, 135.01,
138.08, 138.11, 138.37, 146.74, 152.77. HRMS (m/z): Calcd. for C31H28N2O3: 476.2100. Found:
476.2109 (M+).
4,5-Diphenyl-2-(thiophen-2-yl)-1-(4-methylphenyl)-1H-imidazole (11): Yield: 92%. m.p.: 200–201 °C;
1
IR (KBr, cm−1): 2959, 1643, 1562, 1414, 1165. H-NMR (400 MHz, CDCl3) δH: 2.30 (s, 3H), 6.9
(d, J = 7.6 Hz, 2H), 7.1 (d, J= 7.6 Hz, 2H), 7.3–7.5 (m, 6H), 7.51 (t, J = 6.8 Hz, 2H), 7.57 (d, J = 7.2 Hz,
2H), 7.65 (t, J = 6.8 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 7.2 Hz, 4H), 8.47 (d, J = 7.4 Hz,
1H), 8.59 (s, 1H). 13C-NMR (100 MHz, CDCl3) δC: 14.24, 126.89, 123.12, 126.99, 127.41, 128.10,
128.23, 128.33, 128.51, 129.13, 130.01, 130.14, 130.41, 131.16, 131.75, 133.07, 134.02, 134.29, 135.01,
136.07, 138.87, 138.92, 144.14, 149.00, 149.51. HRMS (m/z): Calcd. for C27H22N2S: 406.1501. Found:
406.1501 (M+).
1-(4-Methoxyphenyl)-4,5-diphenyl-2-(3,4,5-trimethoxyphenyl)-1H-imidazole (12): Yield: 92%. m.p.:
123–125 °C; IR (KBr, cm−1): 2909, 1667, 1549, 1492, 1174. 1H-NMR (500 MHz, DMSO-d6) δH: 3.68
(s, 6H), 3.78 (s, 3H), 3.84 (s, 3H), 6.71 (s, 2H), 6.82 (d, J = 6 Hz, 3H), 7.00 (d, J = 7.2 Hz, 2H),
7.19–7.32 (m, 7H), 7.50 (t, J = 7.2 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.98 (d,
13
J = 6 Hz, 3H) C-NMR (125 MHz, DMSO) δC: 55.48, 55.88, 60.86, 106.23, 114.29, 125.90, 126.61,
127.39, 127.95, 128.16, 128.37, 129.03, 129.58, 129.91, 130.15, 130.69, 131.08, 131.13, 133.02, 134.46,
134.89, 137.94, 138.10, 146.74, 152.73, 159.25. HRMS (m/z): Calcd. for C31H28N2O4: 492.2049. Found:
492.2040 (M+).
1-(4-Chlorophenyl)-2-(4-ethylphenyl)-4,5-diphenyl-1H-imidazole (13): Yield: 93%. m.p.: 181–182 °C;
IR (KBr, cm−1): 2996, 1687, 1564, 1436, 802. 1H-NMR (400 MHz, CDCl3) δH: 1.41 (t, J = 6.8 Hz, 3H),
4.03 (d, J = 6.8 Hz, 2H), 6.78 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8 Hz, 2H), 7.31
(m, 3H), 7.52 (d, J = 8 Hz, 2H), 7.55 (m, 3H), 7.64 (d, J = 7.6 Hz, 2H), 7.97 (d, J = 7.6 Hz, 2H).
13C-NMR (100 MHz, CDCl3) δC: 63.57, 114.34, 121.15, 122.73, 126.78, 127.52, 128.24, 128.30, 128.65,
129.17, 129.44, 129.78, 130.06, 130.35, 130.53, 130.64, 131.26, 133.14, 134.14, 134.45, 135.04, 135.93,
138.37, 147.16, 159.30.HRMS (m/z): Calcd. for C29H23ClN2: 434.1550. Found: 434.1558 (M+).
1-(4-Chlorophenyl)-4,5-diphenyl-2-(3,4,5-trimethoxyphenyl)-1H-imidazole (14): Yield: 93%. m.p.:
1
123–125 °C; IR (KBr, cm−1): 2990, 1667, 1513, 1454, 782. H-NMR (400 MHz, CDCl3) δH: 3.64
(s, 3H), 3.75 (s, 6H), 3.87 (s, 3H), 6.68 (s, 2H), 6.80 (d, J = 8.2 Hz, 3H), 7.00 (d, J = 8.2 Hz, 2H),
7.01–7.03 (m, 4H), 7.50 (t, J = 7.4 Hz, 2H), 7.60 (d, J = 7.4 Hz, 2H), 7.96 (d, J = 8 Hz, 1H), 7.98 (d,
13
J = 8 Hz, 2H). C-NMR (100 MHz, CDCl3) δC: 55.61, 56.00, 61.00, 106.30, 114.40, 126.01, 126.74,
127.51, 128.07, 128.29, 128.50, 129.16, 129.70, 130.04, 130.24, 130.78, 131.19, 131.25, 133.11, 134.55,
135.04, 138.04, 138.16, 146.87, 152.84, 159.35. HRMS (m/z): Calcd. for C30H25ClN2O3: 496.1554.
Found: 496.1540 (M+).
4-(1-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazol-2-yl)benzonitrile (15): Yield: 89%. m.p.: 112–114 °C;
IR (KBr, cm−1): 2947, 1698, 1512, 1498, 805.1H-NMR (400 MHz, CDCl3) δH: 6.98 (d, 1H, J = 7.2 Hz)

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7.11 (d, 1H, J = 7.2 Hz), 7.21–7.31 (m, 4H), 7.51–7.56 (m, 6H), 7.66 (t, 2H, J =7.4 Hz), 7.97 (d, 4H,
13
J =7.4 Hz). C-NMR (100 MHz, CDCl3) δC: 111.89, 118.68, 121.14, 127.24, 127.41, 128.44, 128.72,
128.82, 129.11, 129.14, 129.17, 129.56, 129.90, 130.05, 131.14, 132.12, 133.11, 133.82, 134.56, 135.05,
135.27, 136.62, 139.42, 144.77, 168.43, 194.75, 207.20. HRMS (m/z): Calcd. for C28H18ClN3: 431.1189.
Found: 431.1180 (M+).
2-(4-(Allyloxy)phenyl)-1-(4-chlorophenyl)-4,5-diphenyl-1H-imidazole (16): Yield: 91%. m.p.: 98–100 °C;
IR (KBr, cm−1): 2956, 1613, 1560, 1416, 1187. 1H-NMR (400 MHz, CDCl3) δH: 4.51 (s, 2H), 5.27 (d,
J = 7.6 Hz, 1H), 5.38 (d, J = 7.6 Hz, 1H), 6.03 (t, J = 8 Hz, 1H), 6.80 (d, J = 8 Hz, 2H), 6.95 (d, J = 8 Hz,
2H), 7.18 (d, J = 8 Hz, 2H), 7.32 (d, J = 7.2 Hz, 2H), 7.4–7.6 (m, 6H), 7.97 (d, J = 7.2 Hz, 4H).
13C-NMR (100 MHz, CDCl3) δC: 68.88, 114.61, 117.97, 121.15, 123.05, 126.80, 127.51, 128.26, 128.30,
128.65, 129.08, 129.17, 129.45, 129.77, 130.05, 130.39, 130.51, 130.60, 131.25, 133.07, 133.13, 134.18,
134.41, 135.04, 135.89, 138.39, 147.05, 158.93. HRMS (m/z): Calcd. for C30H23ClN2O: 462.1499.
Found: 462.1490 (M+).
2-(4-Bromophenyl)-1-(4-chlorophenyl)-4,5-diphenyl-1H-imidazole (17): Yield: 91%. m.p.: 80–82 °C; IR
1
(KBr, cm−1): 2956, 1665, 1560, 1489, 783. H-NMR (400 MHz, CDCl3) δH: 6.98 (d, J = 7.4 Hz, 2H),
7.13 (d, J = 7.4 Hz, 2H), 7.41–7.55 (m, 6H), 7.68 (t, J = 7.2 Hz, 4H), 7.99 (d, J = 7.2 Hz, 4H). 13C-NMR
(100 MHz, CDCl3) δC: 24.58, 121.21, 123.08, 127.02, 127.48, 128.37, 128.48, 128.72, 129.06, 129.17,
129.64, 130.03, 130.50, 131.18, 131.62, 133.12, 134.11, 134.61, 135.04, 135.51, 136.69, 138.85, 168.53.
HRMS (m/z): Calcd. for C27H18BrClN2: 484.0342. Found: 484.0349 (M+).
2-(2,4-Dichlorophenyl)-1-(4-iodophenyl)-4,5-diphenyl-1H-imidazole (18): Yield: 92%. m.p.: 109–111 °C;
1
IR (KBr, cm−1): 2945, 1609, 1554, 1417, 786. H-NMR (400 MHz, CDCl3) δH: 6.66 (d, J = 7.2 Hz,
1H) 7.14 (d, J = 7.2 Hz, 1H), 7.17–7.33 (m, 3H), 7.46–7.58 (m, 7H), 7.66 (t, J = 7.4 Hz, 2H), 7.97 (d,
J = 7.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δC: 93.86, 121.75, 127.05, 127.24, 127.54, 128.35,
128.49, 128.82, 128.99, 129.16, 129.47, 129.72, 129.92, 130.03, 131.00, 133.07, 133.66, 133.95,
135.05, 135.54, 135.86, 136.33, 137.93, 138.07, 138.59, 143.92, 168.57. HRMS (m/z): Calcd. for
C27H17Cl2IN2: 565.9813. Found 565.9819 (M+).
5. Reusability of the Catalyst
In the experiment, after the reaction was completed, the γ-Al2O3 NPs catalyst was isolated from the
reaction mixture by filtration in the work-up stage. The reusability of the catalyst was assessed by
washing thoroughly by ethanol and distilled water followed by activating the catalyst at 250 °C for 2 h.
The separated catalyst was reused efficiently for four cycles with consistent activity and yields are
93%, 93%, 91% and 90% (Figure 6).
6. Conclusions
In conclusion, the reaction of aldehyde, aryl amine and ammonium acetate with benzyl in ethanol in
the presence of γ Al2O3 NPs as an efficient and effective catalyst provides a simple one-pot entry into the
synthesis of highly substituted imidazole derivatives. The promising points of the present methodology

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were efficiency, generality, high yield, eco-friendliness, reusability of the catalyst and simplicity process
for the preparation of 1,2,4,5-tetrasubstituted imidazoles.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/10/19221/s1.
Acknowledgments
The Project was full financially supported by king Saud University, through Vice Deanship of
Research Chairs.
Author Contributions
Authors B.P.R. M.V.A. and V.V. conceived, designed and performed the experiments; Authors
V.V. and N.A.A. wrote the paper.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors.
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This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).