A novel and an efficient catalyst for one-pot synthesis of 2,4,5- trisubstituted imidazoles by using microwave irradiation under solvent-free conditions

Article abstract of DOI:10.1007/s12039-010-0051-6

(NH₄)₆Mo₇O₂₄·4H ₂O has been used as an efficient catalyst for an improved and rapid synthesis of 2,4,5-trisubstituted imidazoles by a three-component, one-pot condensation of benzil, aryl aldehydes an

Full text of DOI:10.1007/s12039-010-0051-6

J. Chem. Sci., Vol. 122, No. 3, May 2010, pp. 437–441. © Indian Academy of Sciences.
A novel and an efficient catalyst for one-pot synthesis of 2,4,5-
trisubstituted imidazoles by using microwave irradiation under
solvent-free conditions
JAVAD SAFARI*, SHIVA DEHGHAN KHALILI and SAYED HOSSEIN BANITABA
Laboratory of Organic Chemistry Research, Department of Organic Chemistry, College of Chemistry,
University of Kashan, 87317-51167, Kashan, IR Iran
e-mail: safari@kashanu.ac.ir
MS received 5 August 2009; revised 11 January 2010; accepted 19 February 2010
Abstract. (NH ) Mo O ⋅4H O has been used as an efficient catalyst for an improved and rapid synthe-
4 6 7 24 2
sis of 2,4,5-trisubstituted imidazoles by a three-component, one-pot condensation of benzil, aryl alde-
hydes and ammonium acetate in good yields under solvent-free conditions using microwave irradiation.
The reactions in conventional heating conditions were compared with the microwave-assisted reactions.
Keywords. 2,4,5-Trisubstituted imidazoles; ammonium heptamolybdate tetrahydrate; one-pot conden-
sation; microwave irradiation; solvent-free conditions.
1. Introduction
applicability highlights the importance of access to
efficient synthetic routes to well-designed and
highly substituted imidazole derivatives. There are
several methods for the synthesis of highly substi-
The toxicity and volatile nature of many organic
solvents, particularly chlorinated hydrocarbons that
are widely used in huge amounts for organic reac-
tions have posed a serious threat to the environ-
26
tuted imidazoles. A number of methods have been
developed for the synthesis of 2,4,5-trisubstituted
imidazoles. 2,4,5-Trisubstituted imidazoles are gen-
erally synthesized by three-component cycloconden-
sation of a 1,2-diketone, α-hydroxyketone or α-
ketomonoxime with an aldehyde and ammonium
1
ment. Thus, the design of solvent-free catalytic
reaction has received more attention in recent times
2,3
in the area of green synthesis. The emergence of
microwave technology as a tool for increasing reac-
4,5
tion rates is well documented. Microwave-assisted
27–30
acetate, which comprise the use of microwaves,
31–35
36–38
reactions are extremely attractive to synthetic or-
ganic chemists due to their ability to shorten reac-
ionic liquids,
refluxing in acetic acid,
silica
39,40
41
42
sulfuric acid,
NiCl2⋅6H2O/Al2O3, Yb(OTf)3,
44 45 46
Yb(OPf)3, iodine, Zr(acac)4, InCl3⋅3H2O, het-
43
tion times and in some cases improve regio-and/
6,7
47
48
or chemoselectivity.
Reactions that previously
eropolyacid, sodium bisulfite, potassium alumi-
49
required hours to run for completion can now be
num sulfate (alum),
ceric ammonium nitrate
8
finished within minutes. Imidazoles are commonly
50,51
52
(CAN),
polymer-supported ZnCl2
and L-
53
proline. Moreover, they have also been prepared
utilized substructures within the pharmaceutical in-
dustry, as these heterocycles impart unique physical
by the addition of a substituted amino alcohol to a
9–13
54
thioamide and subsequent oxidation with PDC or
and biological properties to compounds of interest.
Trisubstituted imidazole derivatives are widely used
as organic materials, such as to resist composition
by the reaction of aryl nitriles and α,α-dilithio-
55
arylnitromethanes or by multistep syntheses
56,57
.
14 15
on textile, fluorescent whiteners on textile, pho-
Khodaei and co-workers in 2007 described the
synthesis of 2,4,5-trisubstituted imidazoles from 1,2-
diketone or α-hydroxyketone, aldehyde and ammo-
nium heptamolybdate tetrahydrate in tetrabutylam-
16–18
tographic materials,
electroluminescent materi-
19,20
21,22
als
and optical materials.
Meantime, it was
found that these compounds play roles in many
23–25
58
kinds of biological activities.
This versatile
monium iodide using catalytic amounts of p-TSA.
Despite their potential utility, most of these syn-
thetic methods suffer from one or more serious
*For correspondence
437

438
Javad Safari et al
drawbacks, such as laborious and complex work-up (0⋅12 g, 0⋅1 mmol) were placed in a round bottom
and purification, significant amounts of waste mate- flask. The reactants were mixed and heated at
rials, strongly acidic conditions, occurrence of side 100°C. The progress of the reaction was monitored
reactions, low yields, high temperature, long reac- by TLC (ethyl acetate/petroleum ether = 3 : 7). After
tion time and the use of expensive reagents. We completion the reaction mixture was washed with
were promoted a facile, mild and efficient method cool water and filtered. The solid residue was then
for one-pot synthesis of 2,4,5-trisubstituted imida- crystallized from 9 : 1 acetone-water solution. Pure
zole derivatives starting from 1,2-diketone and vari- product was obtained as crystalline in good yields.
ous aromatic aldehydes under solvent-free and Most of the products are known and were identified
microwave conditions in the presence of (NH4)6 by comparing with their physical and spectral data
Mo7O24⋅4H2O as catalyst (figure 1).
with those of authentic samples.
2. Experimental
2.4 General procedure for synthesis of 2,4,5-
trisubstituted imidazoles under microwave
irradiation
2.1 Materials
Chemical reagents were purchased from the Merck
Chemical Company in high purity. All the materials
were of commercial grade reagent.
A mixture of benzil (0⋅21 g, 1 mmol), ammonium
acetate (0⋅15 g, 2 mmol), aldehyde (1 mmol) and
(NH4)6Mo7O24.4H2O (0⋅12 g, 0⋅1 mmol) put in the
hole of the microwave reactor. The mixture was
irradiated at 100 W for 10 min. The progress of the
reaction was monitored by TLC (ethyl acetate/
petroleum ether = 3 : 7). After cooling, the reaction
mixture was washed with cool water and filtered.
The solid residue was then crystallized from 9 : 1
acetone-water solution. Pure product was obtained
in good yields.
2.2 Apparatus
Melting points were determined in an open capillar-
ies using an Electrothermal Mk3 apparatus. Infrared
(IR) spectra were recorded using a Perkin-Elmer FT-
1
13
IR 550 spectrometer. H NMR and C NMR spectra
were recorded in DMSO-d6 using Bruker DRX-400
spectrometer at 400 and 100 MHz respectively. The
elemental analyses (C, H, N) were obtained from a
Carlo ERBA Model EA 1108 analyzer carried out
on Perkin-Elmer 240c analyzer. UV spectra were re-
corded on a Hitachi 200-20 spectrophotometer using
spectrophotometeric grade chloroform (Baker). Mi-
crowave synthesis was carried out on a ETHOS
1600, Milestone microwave reactor.
2.5 Spectral data for new derivatives of 2,4,5-
trisubstituted imidazoles
2.5a 2-(3-methoxyphenyl)-4,5-diphenyl-1H-imida-
–1
zole (4b): m.p.: 259–262°C; IR (cm , KBr):
3431⋅80, 3058⋅38, 2926⋅27, 1591⋅31, 1482⋅73,
1241⋅06, 768⋅39, 686⋅84; UV (CDCl3): λmax = 314,
240 nm; H NMR (400 MHz, DMSO-d6): δ = 12⋅70
1
2.3 General procedure for synthesis of 2,4,5-
trisubstituted imidazoles under conventional
heating conditions
(s, 1H, NH), 6⋅80–7⋅80 (m, 14H, Ar-H), 3⋅80 (s, 3H,
OMe) ppm;
13
C NMR (100 MHz, DMSO-d6):
δ = 160⋅00, 145⋅86, 137⋅63, 135⋅60, 132⋅15, 130⋅27,
129⋅20, 128⋅86, 127⋅70, 118⋅13, 114⋅70, 110⋅70,
55⋅70 ppm; Anal. Calcd. for C22H18N2O: C, 80⋅96;
H, 5⋅56; N, 8⋅58. Found: C, 80⋅94; H, 5⋅55; N, 8⋅57.
Benzil (0⋅21 g, 1 mmol), ammonium acetate (0⋅15 g,
2 mmol), aldehyde (1 mmol) and (NH4)6Mo7O24⋅4H2O
2.5b 2-(2-naphthyl)-4,5-diphenyl-1H-imidazole (4g):
–1
m.p.: 273–276°C; IR (cm , KBr): 3429⋅00, 3054⋅16,
1600⋅50, 1500⋅35, 1447⋅26, 752⋅89, 697⋅10; UV
1
(CDCl3): λmax = 330, 288, 244 nm; H NMR
(400 MHz, DMSO-d6): δ = 12⋅80 (s, 1H, NH), 8⋅61
3
(s, 1H, Ar-H), 8⋅25 (d, 1H, J = 8⋅00 Hz, Ar-H),
7⋅92–8⋅02 (m, 3H, Ar-H), 7⋅53–7⋅61 (m, 6H, Ar-H),
7⋅46 (t, 2H, J = 7⋅90 Hz, Ar-H), 7⋅39 (t, 1H,
Figure 1. (NH ) Mo O ⋅4H O catalysed synthesis of
4 6 7 24 2
2,4,5-trisubstituted imidazoles under microwave irradia-
tion.
3

A novel and an efficient catalyst for one-pot synthesis of 2,4,5-trisubstituted imidazoles
439
Table 1. Synthesis of 2,4,5-trisubstituted imidazoles in the presence of various
a
catalysts .
Entry
Catalyst
Time (min)
Temperature (°C)
Yield
1
2
3
4
5
6
None
30
20
20
20
20
20
100
100
100
100
100
100
25
80
45
50
48
42
(NH ) Mo O ⋅4H O
4 6 7 24 2
VCl
3
ZrCl
4
WCl
6
AlCl
3
a
One equiv. benzil 1, 1 equiv. benzaldehyde 3a, 2 equiv. NH OAc 2 and 0⋅1 equiv.
4
catalyst.
Table 2. Optimization of reaction conditions for synthesis of 2,4,5-trisubstituted
a
imidazoles .
(NH ) Mo O ⋅4H O
4 6 7 24 2
Entry
(mmol)
Temperature (°C)
Time (min)
Yield (%)
1
2
0⋅0
0⋅05
0⋅1
0⋅2
0⋅0
0⋅05
0⋅1
0⋅2
0⋅0
0⋅05
0⋅1
0⋅2
0⋅0
0⋅05
0⋅1
0⋅2
60
60
60
35
35
35
45
25
25
25
30
20
20
20
20
20
20
20
10
35
50
50
20
47
60
60
25
58
80
80
40
60
80
80
3
60
4
60
5
80
6
80
7
80
8
80
9
100
100
100
100
130
130
130
130
10
11
12
13
14
15
16
a
One equiv. benzil 1: 1 equiv. benzaldehyde 3a: 2 equiv. NH OAc 2.
4
3. Results and discussion
In this study, to choose the appropriate catalyst
some of the Lewis acids such as AlCl3, WCl6, ZrCl4,
VCl3 were selected. Then, a comparative study was
made by using benzaldehyde, benzil and ammonium
acetate in the presence of these materials as catalyst
(figure 2). The samples were heated under conven-
tional conditions at 100°C in the presence of each
catalysts, separately. The corresponding results are
summarized in table 1. The results indicated that
(NH4)6Mo7O24⋅4H2O was the best catalyst and con-
sequently it was selected for subsequent experi-
ments. In the absence of catalyst, the yield of the
product was found to be very low. In the course of
this study we found that (NH4)6Mo7O24⋅4H2O was
the most effective catalyst in obtaining the yield of
triphenylimidazole (80%). The catalytic activity of
Figure 2. Catalysed synthesis of 2,4,5-triphenyl-1H-
imidazole under conventional heating conditions.
3
3
J = 7⋅60 Hz, Ar-H), 7⋅32 (t, 2H, J = 7⋅90 Hz, Ar-
3
13
H), 7⋅24 (t, 1H, J = 7⋅60 Hz, Ar-H) ppm; C NMR
(100 MHz, DMSO-d6): δ = 146⋅00, 137⋅90, 135⋅60,
133⋅50, 132⋅20, 131⋅50, 129⋅10, 129⋅00, 128⋅90,
128⋅70, 128⋅60, 128⋅30, 128⋅20, 127⋅60, 127⋅10,
127⋅00, 126⋅80, 124⋅10, 123⋅90 ppm; Anal. Calcd.
for C25H18N2: C, 86⋅68; H, 5⋅24; N, 8⋅09. Found: C,
86⋅66; H, 5⋅22; N, 8⋅08.

440
Javad Safari et al
Table 3. (NH ) Mo O ⋅4H O catalysed synthesis of 2,4,5-trisubstituted imidazoles under sol-
4 6 7 24 2
vent-free conditions.
a
Yield (%) Time (min)
M.p. (°C)
Found Reported
b
c
Entry
Aldehyde
Ar
Product
Δ
MW
f
1
2
3a
3b
3c
3d
3e
3f
C H
6
4a
4b
4c
4d
4e
4f
80 (20)
78 (15)
85 (25)
79 (20)
78 (20)
87 (25)
78 (20)
77 (30)
78 (20)
79 (20)
74 (15)
76 (30)
82 (25)
94 (10)
93 (10)
98 (10)
94 (10)
94 (10)
99 (10)
94 (10)
93 (10)
92 (10)
93 (10)
89 (10)
91 (10)
96 (10)
270–272
259–262
272–273
5
m-MeOC H
6
–
4
d
d
d
d
3
p-MeC H
6
230–233 232–235
260–261 262–264
282–283 285–287
228–231 230–232
4
4
p-ClC H
6 4
5
m-ClC H
6 4
6
p-MeOC H
6
4
7
3g
3h
3i
2-Naphthyl
2,4-Cl C H
3
4g
4h
4i
273–276
–
d
d
d
f
8
170–172 174–176
261–264 262–266
263–265 261–263
2
6
9
2-Thienyl
p-BrC H
10
11
12
13
3j
4j
6
4
3k
3l
m-O NC H
2 4 6
4k
4l
269–271
265–267
f
o-HOC H
4
198–201
203–205
6
e
3m
p-(Me) NC H
2 6 4
4m
255–257 257–258
a
b c
Isolated yield based on aldehyde, Under classical heating conditions at 100°C, Using microwave
d
irradiation, Ref. 24, Ref. 42, Ref. 44.
e
f
(NH4)6Mo7O24⋅4H2O is remarkable for both quanti- are higher than other aromatic aldehydes. For some
tative and qualitative advantages such as cheap of the aromatic aldehydes with high electron-
availability and non-toxicity. withdrawing and steric effects such as p-O2NC6H5
To optimize the reaction conditions, the reaction and 2,6-Cl2C6H4, no reaction took place. The struc-
of benzaldehyde, benzil and ammonium acetate was ture of the 2,4,5-trisubstituted imidazole products
used as a model reaction (table 2). In the following have been confirmed by their spectroscopic data and
study, we examined the reaction at different tem- their melting points compared with literature reports.
–1
perature to find out the effect on the reaction. It was The presence of signal at 3400–3430 cm in IR spec-
1
found that at lower temperature, even if the reaction tra and 12⋅5–12⋅8 ppm in H NMR spectra, due to NH
time was prolonged, it gave only low yield, and related to the imidazole ring are observed.
higher the temperature, higher the yield. The effi-
ciency of the reaction is mainly affected by the
4. Conclusions
amount of catalyst and temperature. As indicated in
table 2, the best results have been obtained at 100°C
In summary, we presented an efficient, mild and
with 0⋅1 mmol (NH4)6Mo7O24⋅4H2O. Increasing the
rapid approach for the synthesis of 2,4,5-
amount of (NH4)6Mo7O24⋅4H2O and temperature has
trisubstituted imidazoles via condensation of a rep-
not shown in the increase of yield.
resentative 1,2-diketone (benzil) with various aro-
For more examination of the influence of micro-
matic aldehydes and ammonium acetate, by using
wave irradiation on the reaction, a comparison was
(NH4)6Mo7O24⋅4H2O as a new and highly effective
made between microwave irradiation and heating
catalyst under solvent-free and microwave condi-
conditions. The successful results of (NH4)6Mo7O24⋅
tions. Non-corrosiveness, safe, low waste, easy for
4H2O catalysed syntheses of 2,4,5-trisubstituted
separation, short time, high yields and environmen-
imidazoles under solvent-free classical heating con-
tally benign are some of the advantages of this
ditions or using microwave irradiation are given in
methodology.
table 3. As shown, microwave irradiation has shown
better yields and especially in the reaction times.
Acknowledgements
Also, it is observed that by using a wide range of
aromatic aldehydes all imidazoles were obtained in
moderate to good yields. Therefore, this is a general
method that tolerates both electron-withdrawing and
electron-donating constituents. The yield of products
for p-MeOC6H4 and p-MeC6H4 (table 3, entry 3, 6)
We gratefully acknowledge the financial support
from the Research Council of University of Kashan.
We also thank from Dr F Davar for her helpful
comments.

A novel and an efficient catalyst for one-pot synthesis of 2,4,5-trisubstituted imidazoles
441
30. Oskooie H A, Alimohammadi Z and Heravi M M
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