An expedient one-pot synthesis of highly substituted imidazoles using supported ionic liquid-like phase (SILLP) as a green and efficient catalyst and evaluation of their anti-microbial activity

Article abstract of DOI:10.1016/j.cclet.2013.06.005

An efficient method for the synthesis of imidazole derivatives by a three-component condensation of benzil or 9,10-phenanthrenequinone, aldehydes and ammonium acetate using supported ionic liquid-like phase (SILLP) catalyst under ultrasonic irradiation or classical heating conditions is reported. The present methodology offers several advantages, such as excellent yields, simple procedures, short reaction times, simple work-up and mild conditions. The catalyst is easily separated from the products by filtration and also exhibits remarkable reusable activity. These highly substituted imidazoles were also evaluated for their anti-microbial activity.

Full text of DOI:10.1016/j.cclet.2013.06.005

G Model
CCLET-2636; No. of Pages 4
Chinese Chemical Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
An expedient one-pot synthesis of highly substituted imidazoles using
supported ionic liquid-like phase (SILLP) as a green and efficient
catalyst and evaluation of their anti-microbial activity
a
Maryam Saffari Jourshari a, Manouchehr Mamaghani a, , Farhad Shirini ,
*
Khalil Tabatabaeian a, Mehdi Rassa b, Hadiss Langari a
a Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
b Department of Biology, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient method for the synthesis of imidazole derivatives by a three-component condensation of
benzil or 9,10-phenanthrenequinone, aldehydes and ammonium acetate using supported ionic liquid-
like phase (SILLP) catalyst under ultrasonic irradiation or classical heating conditions is reported. The
present methodology offers several advantages, such as excellent yields, simple procedures, short
reaction times, simple work-up and mild conditions. The catalyst is easily separated from the products
by filtration and also exhibits remarkable reusable activity. These highly substituted imidazoles were
also evaluated for their anti-microbial activity.
Received 7 April 2013
Received in revised form 23 May 2013
Accepted 24 May 2013
Available online xxx
Keywords:
SILLP
ß 2013 Manouchehr Mamaghani. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All
rights reserved.
Imidazole
Phenanthroimidazole
Ionic liquid
Three-component reaction
Anti-microbial activities
1. Introduction
compounds due to their lower solubility in organic solvents and the
steric hindrance in these molecules [24–26]. On the other hand one
Multi-substituted imidazoles, an important class of pharmaceu-
tical compounds [1–3], exhibit a wide spectrum of biological
activities such as nitric-oxide synthase inhibition [4], anti-inflam-
matory [5], anti-parasitic [6], antifungal [7], antidepressant [8],
antitubercular [9], anticancer [10] and antiviral activities [11] as
well as antileishmanial activity against Leshmaniadonovani [12].
Some of these compounds could also be used as organic optical
materials in many fields, for example as signaling, fluorescent
biosensory/chemosensory materials, molecular switches and or-
ganic light emitting diodes (OLEDs) [12–15]. They can also be useful
in asymmetric organic synthesis [16] and polymer and material
science [17]. Therefore, preparation of substituted imidazoles has
attracted considerable attention in recent years and numerous
methods for their synthesis have been reported [17–23]. Some of
these methods are associated with one or more disadvantages such
as using expensive reagents, long reaction time, tedious work-up
procedures and generation of large amount of toxic waste. However,
there are few reports on the synthesis of phenanthroimidazole
important aspect of clean technology is the use of environmentally
friendly catalysts, typically a solid catalyst that can be easily
recovered when the reaction is complete.
Due to the resistance of some microorganisms to imidazole
action because of outer membrane modifications [27], develop-
ment of new and different anti-microbial agents has become a
prime objective of medicinal and synthetic chemists. Therefore
much of the current research effort is oriented toward the design of
new and readily available drugs [28].
2. Experimental
Melting points were measured on an Electrothermal 9100
apparatus and are uncorrected. 1H NMR spectra were obtained on a
Bruker AVANCE III 400 MHz and 13C NMR spectra were collected
on an AVANCE III 100 MHz advanced spectrometer. FT-IR spectra
were recorded on a Shimadzu FT-IR 8400S spectrometer. Chemical
shifts on 1H NMR and 13C NMR were expressed in ppm downfield
from tetramethylsilane. Sonication was performed in an Elmasonic
S 40H ultrasonic cleaning unit. Elemental analyses were conducted
on a Carlo-Erba EA1110CNNO-S analyser and agreed with the
calculated values. All chemicals were purchased from Merck and
used without further purification.
* Corresponding author.
E-mail addresses: m-chem41@guilan.ac.ir, mchem41@gmail.com
(M. Mamaghani).
1001-8417/$ – see front matter ß 2013 Manouchehr Mamaghani. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.06.005
Please cite this article in press as: M. Saffari Jourshari, et al., An expedient one-pot synthesis of highly substituted imidazoles using
supported ionic liquid-like phase (SILLP) as a green and efficient catalyst and evaluation of their anti-microbial activity, Chin. Chem.
Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.005

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CCLET-2636; No. of Pages 4
2
M. Saffari Jourshari et al. / Chinese Chemical Letters xxx (2013) xxx–xxx
A mixture of benzil or 9,10-phenanthrenequinone (1 mmol),
corresponding aldehyde (1 mmol), ammonium acetate (4 mmol)
and a catalytic amount of supported ionic liquid-like phase (SILLP)
(0.1 g) in ethanol (3 mL) was stirred in an oil bath at 50 8C or under
ultrasonic irradiations (40 kHz, 50 8C) for a specified period of time.
The progress of the reaction was monitored by TLC analysis
(petroleum ether/ethyl acetate, 2/1). After the completion of the
reaction, the crude product from the reaction mixture was
dissolved in ethanol and the catalyst was separated by filtration.
The filtrate was evaporated under reduced pressure to remove
ethanol. The solid was then recrystallized from methanol to obtain
the pure product. The data of some new compounds are listed
below:
H
N
O
O
NH OAc, SILLP
4
Ar
ArCHO
+
o
EtOH, 50
or
C
N
Ultrasound
2a-j
3a-j
1
CH
3
SILLP:
Cl
CH
3
N
N
Scheme 1. Synthesis of tri-substituted imidazoles (3a–j).
4,5-Diphenyl-2-(1,3-diphenyl-1H-pyrazol-4-yl)-1H-imidazole
(3g): White solid, mp 239–240 8C; 1H NMR (DMSO-d6):
d
7.23–7.58
(m, 14H), 7.96–8.11 (m, 6H), 9.01 (s, 1H), 12.52 (s, 1H). 13C NMR
(DMSO-d6): 113.4, 119.7, 126.9, 127.1, 127.2, 127.4, 128.6, 128.7,
129, 129.2, 130.2, 133.1, 135.7, 136.8, 139.7, 140, 150.4. FT-IR (KBr,
cmÀ1):
3450, 3010, 2950, 1665, 1590, 1520, 1500, 1440, 1365,
Table 2
d
Comparison of efficiency of the catalysts in one-pot synthesis of 3b in ethanol at
50 8C under conventional heating.
n
Entry
Catalyst
Time (min)
Yield (%)a
1220, 1120, 1062, 960, 940, 910, 862, 800, 760, 750, 725, 690, 680.
Anal. Calcd. for C30H22N4 (438.52): C 82.17, H 5.06, N 12.78; found:
C 82.07, H 5.01, N 12.61.
2-(1-(4-Bromophenyl)-3-phenyl-1H-pyrazol-4-yl)-4,5-diphenyl-
1H-imidazole (3h): White solid, mp 259–261 8C; 1H NMR
1
2
3
4
SILLP
30
80
95
89
68
85
Fe3+-montmorillonite
Celloluse-sulfuric acid
120
540
L
-proline
a
Isolated yields.
(DMSO-d6):
8.15 (d, 2H), 9.03 (s, 1H), 12.54 (s, 1H). 13C NMR (DMSO-d6):
113.4, 118.9, 122.1, 128.2, 128.6, 128.8, 129.2, 130.1, 130.3, 130.8,
131.5, 132.3, 135.6, 136.9, 139.5, 139.8, 149.2. FT-IR (KBr, cmÀ1):
d 7.24–7.60 (m, 13H), 7.69 (d, 2H), 8.05 (d, 2H),
d
Calcd. for C21H13 ClN2 (328.79): C 76.71, H 3.98, N 8.52; found: C
76.45, H 4.22, N 8.33.
n
3400, 3010, 2950, 2068, 1662, 1586, 1500, 1465, 1440, 1362, 1300,
1220, 1065, 1005, 960, 940, 820, 760, 745, 735, 720, 693; Anal.
Calcd. for C30H21BrN4 (517.42): C 69.64, H 4.09, N 10.83; found:
C 69.80, H 4.14, N 11.05.
2-(1-(4-Nitrophenyl)-3-phenyl-1H-pyrazol-4-yl)-4,5-diphenyl-
1H-imidazole (3i): Yellow solid, mp 248–250 8C; 1H NMR
2-(4-Fluorophenyl)-1H-phenanthro[9,10-d]imidazole (6c): Milky
solid, mp > 300 8C; 1H NMR (DMSO-d6):
d
7.46 (t, 2H), 7.63 (t, 2H),
7.74 (s, br. 2H), 8.37 (dd, 2H), 8.57 (s, br., 2H), 8.84 (d, 2H), 13.49 (s,
1H). 13C NMR (DMSO-d6):
116.3, 116.6, 122.4, 122.9, 124.5, 125.7,
127.5, 127.6, 128.1, 128.8, 128.9, 148.7, 162, 164.4. FT-IR (KBr,
cmÀ1):
3455, 3050, 2900, 2070, 1600, 1520, 1485, 1450, 1420,
d
n
(DMSO-d6):
d
7.32–7.65 (m, 13H), 7.98 (d, 2H), 8.36 (d, 2H),
1378, 1347, 1225, 1132, 1100, 1038, 830, 750, 690, 610, 505. Anal.
Calcd. for C21H13FN2 (312.34): C 80.75, H 4.20, N 8.97; found: C
80.60, H 4.39, N 8.75.
2-(1,3-Diphenyl-1H-pyrazol-4-yl)-1H-phenanthro[9,10-d]imid-
azole (6d): Pale yellow solid, mp 228–230 8C; 1H NMR (DMSO-d6):
d
8.53 (d, 2H), 9.10 (s, 1H), 12.62 (s, 1H). 13C NMR (DMSO-d6):
d
113.1, 119.1, 123.8, 126.8, 127.5, 128.6, 128.8, 129.3, 129.8, 130.4,
130.5, 131, 135, 139.4, 145.1, 145.9, 147.4. FT-IR (KBr, cmÀ1):
n
3450, 3010, 2990, 2070, 1710, 1700, 1625, 1590, 1518, 1500,
1485, 1338, 1380, 1180, 1160, 1100, 1060, 1020, 960, 920, 850, 835,
760, 690. Anal. Calcd. for C30H21N5O2 (483.52): C 74.52, H 4.38,
N 14.48; found: C 74.65, H 4.25, N 14.19.
7.38–7.75 (m, 10H), 8.03 (m, 4H), 8.36 (d, 1H), 8.50 (d, 1H), 8.88 (m,
2H), 9.20 (s, 1H), 13.42 (s, 1H). 13C NMR (DMSO-d6):
113.4, 119.3,
122.6, 125.7, 126, 127.1, 127.2, 127.4, 127.5, 128.7, 130.1, 130.2,
130.4, 131.7, 132.3, 141.3, 143.5, 149.8. FT-IR (KBr, cmÀ1):
3455,
2900, 2850, 2065, 1658, 1620, 1600, 1540, 1460, 1378, 1270, 1180,
1080, 1060, 960, 820, 745, 720, 690. Anal. Calcd. for C30H20N4
(436.51): C 82.55, H 4.62, N 12.84; found: C 82.60, H 4.38, N 12.57.
2-(1-(4-Bromophenyl)-3-phenyl-1H-pyrazol-4-yl)-1H-phenan-
thro[9,10-d]imidazole (6e): Pale yellow solid, mp 122–124 8C; 1H
d
2-(4-Chlorophenyl)-1H-phenanthro[9,10-d]imidazole (6b): Milky
n
solid, mp > 300 8C; 1H NMR (DMSO-d6):
d
7.76–7.64 (m, 6H), 8.33
(d, 2H), 8.53 (d, 1H), 8.58 (d, 1H), 8.85 (d, 1H), 8.88 (d, 1H), 13.55 (s,
1H). 13C NMR (DMSO-d6):
122.3, 122.4, 122.8, 124.3, 124.6, 125.8,
126, 127.3, 127.7, 128.1, 128.3, 129.5, 129.7, 134.2, 148.4. FT-IR
(KBr, cmÀ1):
3450, 3050, 2950, 2360, 1610, 1508, 1468, 1450,
d
n
1420, 1370, 1230, 1100, 1090, 960, 825, 745, 720, 710, 680. Anal.
NMR (DMSO-d6): d 7.46 (t, 1H), 7.61–7.76 (m, 6H), 7.74 (m, 2H),
Table 1
One-pot synthesis of highly substituted benzimidazoles (3a–j) in the presence of supported ionic liquid-like phases as a solid green catalyst at 50 8C, under ultrasonic
irradiation and conventional condition.
Entry
Ar
Conventional
Time (min)
Ultrasound
Time (min)
MP (8C)
Yield (%)a
Yield (%)a
Found
Reportedc
3a
3b
3c
3d
3e
3f
Ph
30
97
5
95
270–272
259–262
195–196
240–242
238–240
234–235
239–240
259–261
248–250
272–273 [14]
261–262 [14]
190–191 [18]
239–241 [19]
242–244 [20]
235–236 [21]
–
4-ClC6H4
30 (60)b
35
95 (75)b
92
5 (5)b
94 (70)b
90
2-ClC6H4
6
6
6
6
6
6
6
4-FC6H4
35
96
92
4-OHCC6H4
40
90
87
4-MeO2CC6H4
40
90
89
3g
3h
3i
1,3-Diphenyl-1H-pyrazol-4-yl
1-(4-Bromophenyl)-3-phenyl-1H-pyrazol-4-yl
1-(4-Nitrophenyl)-3-phenyl-1H-pyrazol-4-yl
30
89
88
30
86
85
–
35
83
85
–
a
Isolated yields.
b
c
Reaction at room temperature.
Identified by comparison of their melting points and spectral data with those reported in the literature.
Please cite this article in press as: M. Saffari Jourshari, et al., An expedient one-pot synthesis of highly substituted imidazoles using
supported ionic liquid-like phase (SILLP) as a green and efficient catalyst and evaluation of their anti-microbial activity, Chin. Chem.
Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.005

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3
Table 3
One-pot synthesis of highly substituted phenanthroimidazoles (6a–e) in the presence of SILLP at 50 8C, under ultrasonic irradiation and conventional heating.
Entry
Ar
Conventional
Time (min)
Ultrasound
Time (min)
MP (8C)
Yield (%)a
Yield (%)a
Found
Reported
6a
6b
6c
6d
6e
Ph
20
20
20
20
20
95
93
95
92
90
3
3
3
4
4
94
93
94
89
91
>300
322–324 [24]
4-ClC6H4
>300
–
–
–
–
4-FC6H4
>300
4-(1,3-Diphenyl-1H-pyrazole)
1-(4-Bromophenyl)-3-phenyl-1H-pyrazol-4-yl
228–230
122–124
a
Isolated yields.
and ammonium acetate (4 mmol) in the presence of SILLP was
selected as a model reaction (Scheme 1). This study gave the
optimized amount of the catalyst (0.1 g per mmol of substrate).
The effect of different solvents was also examined for the model
reaction in the presence of SILLP and we obtained the maximum
yield of the product in shortest reaction time, when ethanol was
used as solvent. Therefore all the reactions described in this report
were carried out under these optimized conditions. The results of
this study using various aryl- and heteroaryl aldehydes are given in
Table 1.
H
N
O
O
NH OAc, SILLP
4
ArCHO
+
Ar
o
EtOH, 50
or
C
N
Ultrsound
5a-e
4
6a-e
Scheme 2. Synthesis of tri-substituted phenantroimidazoles (6a–e).
Table 2 compares efficiency of SILLP with other catalysts in the
synthesis of 3b. It is clear from the results that SILLP is more
efficient, and less time-consuming for the synthesis of the desired
product (3b).
In order to determine the scope of this protocol, the reaction of
9,10-phenanthrenequinone was also carried out in the presence of
SILLP with various aromatic and heteroaromatic aldehydes under
the optimized conditions (Scheme 2). The results are summarized
in Table 3. It can be easily seen that in all cases, regardless of the
nature of the substituents, the reactions gave the products in very
high yields.
8.04 (d, 2H), 8.09 (d, 2H), 8.39 (d, 1H), 8.52 (d, 1H), 8.88 (d, 1H), 8.92
(d, 1H), 9.24 (s, 1H), 13.43 (s, 1H). 13C NMR (DMSO):
d
113.6, 119.1,
122.2, 122.4, 124.7, 125.8, 127.5, 127.6, 127.7, 127.9, 128.1, 130.3,
130.7, 130.9, 131.7, 132.1, 139.5, 143.4, 149.6. FT-IR (KBr, cmÀ1):
n
3450, 2900, 2850, 2360, 1735, 1580, 1500, 1460, 1400, 1245, 1220,
1160, 1140, 1080, 960, 820, 750, 720, 680. Anal. Calcd. for
C30H19BrN4 (515.4): C 69.91, H 3.72, N 10.87; found: C 69.75, H
3.50, N 11.04.
Due to environmental concerns, ultrasonic reactions have
attracted more and more attention as clean, green and benign
routes for the preparation of organic compounds of synthetic and
biological value [31].
To improve the efficiency of the present method for the
synthesis of highly substituted imidazole derivatives, we also
carried out the reaction under ultrasonic irradiation (40 Hz, EtOH,
50 8C). The results are presented in Tables 1 and 3. Using
ultrasound gave comparable yields of products but with shorter
reaction time (3–6 min), compared to conventional heating.
In this study the catalyst was separated simply by filtration
from the reaction mixture, washed by ethanol and used in the next
3. Results and discussion
In the course of our search for the development of efficient and
environmentally friendly protocols for the synthesis of biologically
important heterocyclic products [29], we studied the synthesis of
highly substituted imidazole derivatives as potential drug
candidates, over a supported ionic liquid-like phase (SILLP) catalyst
(Scheme 1). Initially the SILLP was prepared by using Merrifield
resin (1% cross linked, 200–400 mesh, 1–1.3 mmol/g) and the
procedure employed by Luis et al. [30]. In order to optimize the
effect of the amount of catalyst on the efficiency of the reaction, the
condensation of benzil (1 mmol), 4-chlorobenzaldehyde (1 mmol)
Table 4
Antimicrobial activity of compounds 3a–i and 6a–e.
Compound
Conc. of compound (
m
g/well)
Antimicrobial activity (zone of inhibition in mm)
Escherichia coli
Micrococcus luteum
Bacillus subtillis
Pseudomonas aeruginosa
3a
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
15
9
10
9
11
3b
11
13
12
13
3c
11
12
12
13
3d
9
9
11
13
3e
10
10
12
12
3f
12
12
13
13
3g
17 (19)a (18)b
19 (18)a (20)b
18 (19)a (18)b
18 (17)a (19)b
3h
18 (18)a (17)b
19 (19)a (20)b
20 (18)a (19)b
18 (18)a (19)b
3i
19 (20)a (19)b
20 (19)a (21)b
20 (21)a (19)b
19 (18)a (20)b
6a
7
9
9
8
6b
11
11
10
9
6c
11
10
10
9
6d
17 (18)a (19)b
18(19)a (19)b
19 (18)a (19)b
18(20)a (19)b
6e
19 (19)a (18)b
18 (17)a (20)b
20 (21)a (19)b
18 (18)a (19)b
Erythromycin
Tetracycline
16
12
10
16
12
14
10
18
30
a
Data of duplicated experiments.
Data of triplicated experiments.
b
Please cite this article in press as: M. Saffari Jourshari, et al., An expedient one-pot synthesis of highly substituted imidazoles using
supported ionic liquid-like phase (SILLP) as a green and efficient catalyst and evaluation of their anti-microbial activity, Chin. Chem.
Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.005

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4. Conclusion
In summary the work reported here offers an efficient one-pot
multicomponent route for the synthesis of trisubstituted imidaz-
ole derivatives in the presence of supported ionic liquid-like phase
(SILLP) as a green catalyst. The simple procedures combined with
easy recovery and reuse of the catalyst make this method an
economical, environmentally benign and user-friendly process for
the synthesis of highly substituted imidazoles. Furthermore, some
of the synthesized products (3g, 3h, 3i, 6d and 6e) exhibited highly
potent antimicrobial activity, which needs further investigation.
Acknowledgment
The authors are grateful to the Research Council of University of
Guilan for the financial support of this research work.
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Please cite this article in press as: M. Saffari Jourshari, et al., An expedient one-pot synthesis of highly substituted imidazoles using
supported ionic liquid-like phase (SILLP) as a green and efficient catalyst and evaluation of their anti-microbial activity, Chin. Chem.
Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.06.005