An efficient green MCR protocol for the synthesis of 2,4,5-trisubstituted imidazoles by Selectfluor under ultrasound irradiation

Article abstract of DOI:10.1016/j.crci.2012.12.007

A simple, efficient and eco-friendly procedure has been developed using Selectfluor (15% mol) as a novel catalyst under ultrasound irradiation and solvent-free conditions for the synthesis of 2,4,5-triaryimidazole by a three-component, one-pot condensation of benzil, aryl aldehydes and ammonium acetate. The present methodology offers several advantages such as excellent yields, shorter reaction times (10-15 min) and environmentally benign milder reaction conditions and easy work-up.

Full text of DOI:10.1016/j.crci.2012.12.007

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Full paper/Memoire
An efficient green MCR protocol for the synthesis of 2,4,5-trisubstituted
imidazoles by SelectfluorTM under ultrasound irradiation
a
b
Mohammad Reza Poor Heravi a, , Esmaeil Vessally , Gholam R. Rezaei Behbehani
*
a Payame Noor University, Department of Chemistry, 19395-4697 Tehran, Iran
b Imam Khomeini International University, Chemistry Department, Qazvin, Iran
A R T I C L E I N F O
A B S T R A C T
A simple, efficient and eco-friendly procedure has been developed using SelectfluorTM
(15% mol) as a novel catalyst under ultrasound irradiation and solvent-free conditions for
the synthesis of 2,4,5-triaryimidazole by a three-component, one-pot condensation of
benzil, aryl aldehydes and ammonium acetate. The present methodology offers several
advantages such as excellent yields, shorter reaction times (10–15 min) and environmen-
tally benign milder reaction conditions and easy work-up.
Article history:
Received 2 November 2012
Accepted after revision 5 December 2012
Available online xxx
Keywords:
Ultrsound irradiation
One-pot synthesis
Triarylmidazoles
Benzil
´
ß 2012 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
MCRs
Benzil
SelectfluorTM
1. Introduction
ammonia solution. The procedure was later modified by
Cook and Jones [13] by refluxing benzil with substituted
The use of ultrasound in organic transformation is now
well known to enhance reaction rates and yields, selectivity
of reaction [1,2]. The imidazole ring system and its
derivatives have emerged as an integral part of many
biological systems [3,4] viz, histidine, histamine and biotin;
active backbones in exciting drugs such as losartan,
olmesartan, eprosartan [5], trifenagrel [6] and large classes
of imidazole derivatives are also used as ionic liquids [7,8].
Thus, syntheses of this heterocylic nucleus have rekindled
our interest in obtaining trisubstituted imidazole. Various
methods have been reported [9] for the synthesis of 2,4,5-
trisubstituted imidazoles by condensation of benzil, alde-
hyde and ammonium acetate. Preparation of 2,4,5-triphenyl
imidazol 3a (Lophin) [10] was first reported by Oruu [11]
and simultaneously by Crouch [12] are synthesized by the
reaction of benzyil with aryl aldehyde in an alcoholic
aldehydes and ammonium acetate in glacial acetic acid.
Recently, the synthesis of 2,4,5-trisubstituted imidazoles
have been carried out by condensation of benzyl, aldehyde
and ammonium acetate in the presence of acetic acid [6],
some common Lewis acid catalysts like Yb(OTf)3 [14], NdCl3
[14], LaCl3 [14], FeCl3 [14], AlCl3 [14], Al2O3 [15], NiCl2 [16],
[Hbim]BF4 [17], molecular iodine [18], TBAB in isopropanol
[19] and polymer-supported ZnCl2 [20], oxalic acid [21],
boric acid [22], p-toluenesulfonic acid [23], L-proline [24], L-
proline triflate [25], Cu(NO3)2-zeolite [26], zinc (II) [tetra (4-
methylphenyl)]porphyrin with ultrasound irradiation [27].
Although these methods were derived from the early
success [28–30], the reaction suffered from low yields,
harsh conditions, high temperature and side reactions
leading to a mixture of products. Additionally, reagents for
these procedures are not readily or commercially available.
A majority of these procedures also involve microwave-
assisted synthesis [31–34]. Moreover, the synthesis of these
heterocyclic compounds has been usually carried out in
polar solvents such as ethanol, methanol, acetic acid, DMF
and DMSO, leading to complex isolation and recovery
* Corresponding author.
E-mail addresses: heravimr@yahoo.com, heravimr@gmail.com
(M.R.P. Heravi).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.12.007
Please cite this article in press as: Heravi MRP, et al. An efficient green MCR protocol for the synthesis of 2,4,5-
trisubstituted imidazoles by SelectfluorTM under ultrasound irradiation. C. R. Chimie (2013), http://dx.doi.org/10.1016/
j.crci.2012.12.007

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Table 1
procedures. Hence, the development of a clean, safe,
effective, economical, high yielding and mild environmental
benign protocol is still describable and is in demand. We
havediscovered thatMCR protocolfor thesynthesis of2,4,5-
trisubstituted imidazoles by SelectfluorTM under ultrasound
irradiation (Scheme 1).
Effect of the concentration of catalyst.
Yielda (%)
SelectfluorTM (mol%)
Entry
Without u.s.
With u.s.
4
23
32
31
31
0
88
96
95
95
0
5
1
2
3
4
5
10
15
20
2. Results and discussion
Reaction conditions: 1 (2.5 mmol), 2a (2.5 mmol), ammonium acetate 3
(2.5 mmol) and SelectfluorTM (0–20 mol%) in 10 mL ethanol with
ultrasound irradiation.
In terms of the amount of catalyst required for the
reaction of benzil 1, benzaldehyde 2a and ammonium
acetate 3 to afford 4a with ultrasound irradiation and
without ultrasound irradiation, we observed that the
concentration of the catalyst played a major role in
catalyzing the condensation reaction for the synthesis of
2,4,5-trisubstituted imidazoles. The reaction was per-
formed in the presence of 0, 5, 10, 15 and 20 mol% with
and without ultrasound irradiation. In the absence of
SelectfluorTM and with ultrasound irradiation we obtained
a 0% yield, but in the presence of SelectfluorTM as Lewis acid
and without ultrasound irradiation we observed a 4% yield
(Table 1, entry 1). The reason may be the phenomenon of
cavitations produced by ultrasounds. Cavitations are the
origin of sonochemistry, a physical process that creates,
enlarges, and implodes gaseous and vaporous cavities in an
irradiated liquid, thus enhancing the mass transfer and
allowing chemical reactions to occur. Applying ultrasound,
compression of the liquid is followed by rarefaction
(expansion), in which a sudden pressure drop forms small,
oscillating bubbles of gaseous substances. These bubbles
are small and rapidly collapse, they can be seen as micro
reactors that offer the opportunity of speeding up certain
reactions and also allow mechanistically novel reactions to
take place in an absolutely safe manner [37,38]. The best
results were obtained using 0.036 g (10 mol%) of the
catalyst under both conditions (Table 1, entry 3).
In order to investigate the effect of the ultrasonic
intensity power on the reaction, the reaction was also
performed at 20%, 40%, 60%, 80% and 100% of the power
rate of the ultrasonic bath (40, 80, 120, 160 and 200 W).
The results are shown in Table 2. The intensity of
sonication is proportional to the amplitude of vibration
of the ultrasonic source and, as such, an increment in the
amplitude of vibration will lead to an increase in the
intensity of vibration and to an increase in the sonochem-
ical effects. Increasing the ultrasound power intensity up
to 80% induces relatively higher yields and shorter reaction
times; beyond this level, the yield decreases slightly.
Generally, the increase in the acoustic power could
a
Isolated yields.
Table 2
Effect of ultrasound intensity power on the synthesis of 4aa.
Max power intensity (W) 20%
40%
60%
80%
100%
(40W) (80W) (120W) (160W) (200W)
Time (min) Yields (%)
30 (80) 25 (85) 10 (90) 5 (96) 5 (90)
Reaction conditions: 1 (2.5 mmol), 2a (2.5 mmol), ammonium acetate 3
(2.5 mmol) and SelectfluorTM (10 mol%) in 10 mL ethanol with ultrasound
irradiation.
a
Isolated yields.
increase the number of active cavitations bubbles and
also the size of the individual bubbles. Both increases can
be expected to result in an increase in the maximum
collapse temperature [39], and the respective reaction
could be accelerated. The results are summarized in Table
2. It can easily be seen that the condensation of a series of
aldehydes with benzil and ammonium acetate using
SelectfluorTM as a catalyst, leading to 2,4,5-trisubstituted
imidazoles, gives good yields under ultrasound irradiation
(Table 2).
As shown in Table 3, in order to introduce pharmaco-
logically relevant substitution patterns, several diversified
examples illustrating the present method for the synthesis
of 2,4,5-trisubstituted imidazoles 3 were studied. An
increase in the reaction rate was observed with
aldehyde-bearing electron donating groups (Table 3,
entries 7, 9, 10, 15 and 16) in comparison to the
unsubstantiated aldehyde (Table 3, entry 1). The electron
withdrawing nitro group (Table 3, entry 11) decreased
both the rate of reaction and the yield of product. The
procedure worked well without the formation of any side
products with a variety of structurally and electronically
divergent aldehydes. Use of just 10 mol% of SelectfluorTM
Scheme 1. Synthesis of 2,4,5-trisubstituted imidazoles catalysed by SelectfluorTM under ultrasound irradiation.
Please cite this article in press as: Heravi MRP, et al. An efficient green MCR protocol for the synthesis of 2,4,5-
trisubstituted imidazoles by SelectfluorTM under ultrasound irradiation. C. R. Chimie (2013), http://dx.doi.org/10.1016/
j.crci.2012.12.007

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3
Table 3
Synthesis of 2,4,5-trisubstituted imidazoles catalyzed by SelectfluorTM with ultrasound irradiation.
Entry
R
Product
Time
Yielda,b (%)
m.p (8C)
irradiation
(min)
Found
Reported
1
C6H5
3a
3b
3c
3d
3e
3f
5
3
96
97
95
92
91
89
95
94
94
90
84
82
92
92
93
93
99
272–273
201–202
223–224
265–266
192–193
296–297
262–263
262–263
242–243
258–259
298–299
242–243
241–242
296–297
286–287
271–272
227–228
(271–273 [14,16])
(189–190 [27,28])
–
2
4-FC6H4
3
4-CF3C6H4
4-BrC6H4
3
4
10
9
(264–265 [14,16])
(192–193 [16])
(295–296 [19])
(261–262 [19])
(263–264 [14])
(243–244 [14,16])
(259–260 [19])
(297–299 [14])
(241–242 [14,16])
(242–243 [19])
(297–298 [19])
(241–242 [35,36])
(272–273 [14])
(228–229 [14])
5
2-ClC6H4
6
3-ClC6H4
10
15
14
12
5
7
3,4,5-(CH3O)3C6H2
4-N(CH3)2C6H4
4-OHC6H4
3-OHC6H4
3-NO2C6H4
4-NO2C6H4
2-Furyl
3g
3h
3i
8
9
10
11
12
12
13
14
15
16
3j
3k
3l
5
3
3m
3n
3o
3p
3q
10
11
12
8
1-Naphthyl
2-Naphthyl
2,4-(OH)2C6H3
4-CH3OC6H4
10
a
Yield of corresponding isolated and purified product.
b
All compounds were fully characterized by IR, NMR and mass spectroscopy.
Scheme 2. Plausible mechanism for SelectfluorTM catalysis in the synthesis of 2,4,5-trisubstituted imidazoles under ultrasound irradiation.
Please cite this article in press as: Heravi MRP, et al. An efficient green MCR protocol for the synthesis of 2,4,5-
trisubstituted imidazoles by SelectfluorTM under ultrasound irradiation. C. R. Chimie (2013), http://dx.doi.org/10.1016/
j.crci.2012.12.007

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M.R.P. Heravi et al. / C. R. Chimie xxx (2013) xxx–xxx
under ultrasound irradiation is sufficient to push the
reaction forward.
irradiated in the water-bath of the ultrasonic cleaner for
some time. After completion of the reaction (indicated by
TLC), the mixture was dissolved in ethanol and poured into
ice-cold water. The resulting precipitate was filtered and
recrystallized from ethanol. All products were confirmed
by comparing their melting points.
A
mechanism explaining the catalytic activity of
SelectfluorTM under ultrasound irradiation in the synthesis
of trisubstituted imidazoles may be postulated as shown in
Scheme 2. The SelectfluorTM, as a Lewis, acid probably
induces the polarization of the carbonyl group in
aldehydes as well as in benzil under ultrasound irradiation.
Then nucleophilic attack of the nitrogen of ammonia
obtained from ammonium acetate, on activated carbonyl,
4.3. Spectral data of new compounds
4,5-diphenyl-2-(4-(trifluoromethyl)phenyl)-1H-im-
results in the formation of aryl aldimine and
a
–imino
idazole (4c). White solid; m.p.: 221–223 8C; IR (KBr) (nmax
cm–1): 3435 (N-H), 1618 (C=C), 1580 (C=N); 1H NMR
(CDCl3):
J = 10 Hz), 7.84 (2H, d, 10 Hz), 11.92 (s, NH); LC-MS: 387
[M +23]; Elemental analysis: Found (%): C, 72.63; H, 4.21,
N, 7.59; Calcd. for C22H15F3N2 (364.12): C, 72.52, H, 4.15, N,
7.69.
/
ketone. Their subsequent reaction followed by intermo-
lecular interaction leads to cyclization, and, eventually, to
the formed intermediate dehydrates to give the 2,4,5-
trisubstituted imidazoles 4a-q in excellent yields.
d
H 7.12–7.76 (10H, m, 2 Â C6H55); 7.44 (2H, d,
3. Conclusion
2-(4-fluorophenyl)-4,5-diphenyl-1H-imidazole (4b).
White solid; m.p.: 189–190 8C; IR (KBr) (
(N-H), 1624 (C=C), 1578 (C=N); 1H NMR (CDCl3):
n
max/cm–1): 3451
In summary, we have developed an efficient protocol
for the selective synthesis of 2,4,5-trisubstituted imida-
zoles under very mild conditions using SelectfluorTM as a
catalyst with ultrasound irradiation. The amount of
SelectfluorTM used for this reaction is truly catalytic
(10 mol%). SelectfluorTM with ultrasound irradiation is
sufficient to push the reaction forward. Because of the high
solubility of SelectfluorTM in water, a simple aqueous
work-up is enough to obtain most of the 2,4,5-trisubsti-
tuted imidazoles in analytically pure form.
d
H 7.23–
7.65 (10H, m, 2 Â C6H55); 7.65 (2H, d, J = 8.5 Hz), 7.92 (2H,
d, 8.5 Hz), 11.76 (s, NH); LC-MS: 337 [M +23]; Elemental
analysis: Found (%): C, 80.18; H, 4.93, N, 8.79; Calcd. for
C
21H15FN2 (314.12): C, 80.24; H, 4.81; N, 8.91.
Acknowledgments
We gratefully acknowledge the financial support of the
Payame Noor University (PNU), Zanjan, Abhar, Iran.
4. Experimental method
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Please cite this article in press as: Heravi MRP, et al. An efficient green MCR protocol for the synthesis of 2,4,5-
trisubstituted imidazoles by SelectfluorTM under ultrasound irradiation. C. R. Chimie (2013), http://dx.doi.org/10.1016/
j.crci.2012.12.007

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Please cite this article in press as: Heravi MRP, et al. An efficient green MCR protocol for the synthesis of 2,4,5-
trisubstituted imidazoles by SelectfluorTM under ultrasound irradiation. C. R. Chimie (2013), http://dx.doi.org/10.1016/
j.crci.2012.12.007