One-pot synthesis of tetrasubstituted imidazoles catalyzed by preyssler-type heteropoly acid

Article abstract of DOI:10.1155/2011/980546

A simple one-pot four-component synthetic method was reported for the preparation of tetrasubstituted imidazole derivatives from benzil, aromatic aldehydes, primary amines and ammonium acetate in the presence of Preyssler-type heteropoly acid catalyst. This method was proved to be ecobenign, easy work-up, convenient, relatively short reaction times and the products were isolated with high yields.

Full text of DOI:10.1155/2011/980546

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(2), 547-552
http://www.e-journals.net
One-Pot Synthesis of Tetrasubstituted Imidazoles
Catalyzed by Preyssler-Type Heteropoly Acid
ALI JAVID§*, MAJID M. HERAVI#,
F. F. BAMOHARRAM and MOHSEN NIKPOUR§
§Department of Chemistry, School of Sciences
Islamic Azad University, Ahvaz Branch, Ahvaz 6134968875, Iran
#Department of Chemistry
Azzahra University, Vanak, Tehran, Iran
Department of Chemistry, School of Sciences
Islamic Azad University, Mashhad Branch, Mashhad, Iran
alijavids@yahoo.com
Received 27 June 2010; Accepted 2 September 2010
Abstract: A simple one-pot four-component synthetic method was reported
for the preparation of tetrasubstituted imidazole derivatives from benzil,
aromatic aldehydes, primary amines and ammonium acetate in the presence of
Preyssler-type heteropoly acid catalyst. This method was proved to be eco-
benign, easy work-up, convenient, relatively short reaction times and the
products were isolated with high yields.
Keywords: Multi-component reactions (MCRs), One-pot synthesis, tetrasubstituted imidazoles,
Preyssler catalyst, Heteropoly acid (HPA)
Introduction
Imidazole, at first, has been prepared by debus1 in 1858. Over the century, imidazole
derivatives have received significant attention due to their synthesis, reactions and
biochemical properties. The imidazoles are one of the most important substructures found in
a large number of natural products and pharmacologically active compounds. For example,
histidine, histamine and biotin, an active component in several drug molecules2, anti-allergic
activity3, hypnotic agent etomidate4, proton pump inhibitor omeprazole5 and the
benzodiazepine antagonist flumazenil6 are imidazole derivatives. Recent advances in green
chemistry and organometallic catalysis has extended the application of imidazoles as ionic
liquids7 and N-heterocyclic carbenes8. Also, tetrasubstituted imidazole scaffold is a core
constituent in many biological systems such as olmesartan9 as well as many natural products
and pharmacologically active compounds10. Therefore, the imidazole and its adjective
structures are attractive compounds for organic chemists.

548
ALI JAVID et al.
Despite the availability of wide variety of synthetic routes towards imidazoles11, only
few studies exist for the synthesis of 1,2,4,5-tetrasubstituted imidazoles. The mostly used
methods in the last decades are as follows: N-alkylation of trisubstituted imidazoles12,
condensation of β-carbonyl-N-acyl-N-alkylamines with ammonium acetate in refluxing
HOAc13 and hetero-cope rearrangement14. Also, tetrasubstituted imidazoles can be prepared
by four-component condensation of diones(such as benzil or benzoin), aldehydes, primary
amines and ammonium acetate
catalyzed by HOAc under reflux conditions15,
silicagel/NaHSO416, silica gel or zeolite HY17, molecular iodine18, InCl3.3H2O19, Keggin-
type heteropoly acids20, K5CoW12O40.3H2O21, high surface area SiO2 and L-proline23.
22
Recently, a solvent free convenient method has been reported using a silica-supported boron
triflouride (BF3-SiO2) as a catalyst at 140 °C24.
In the classic approach for the synthesis of tetrasubstituted imidazoles, four-component
reaction proceeds with low yields after many hours in refluxing HOAc15. Other methods also
use of hazardous, toxic, special and often expensive reagent or acid catalysts, long reaction
time, occurrence of side reactions, moderate yield and were not suitable for, or were not
applied for the synthesis of structurally diverse imidazoles. Therefore, the development of a
new catalytic system to overcome these shortcomings and fulfill the criteria of a mild, clean,
efficient, high-yielding, environmentally friendly and recoverable catalyst benign protocol
for the synthesis of highly substituted imidazoles is an important task for organic chemists.
In the last decade, heteropoly acids (HPAs) have found numerous applications as useful
and versatile as homogeneous and heterogeneous acid and oxidation catalysts. Heteropoly
acids are more reactive catalysts than conventional inorganic and organic acids for reactions in
solution25. They are usually solids that are insoluble in non-polar solvents but highly soluble in
polar ones. Heteropoly acids have many advantages finding economically and environmentally
attractive in both academic and industrial significance. They are non-volatile, non-toxic, non-
explosive, highly stable towards humidity, thermally robust, air stable, recyclable, eco-friendly
compatible with the environment, ease of handling and experimental simplicity26.
Preyssler structure (H14[NaP5W30O110]) is one member of the heteropoly acids group. A
Preyssler acid is a highly acidic catalyst from heteropoly acid family with excellent catalytic
activity in a variety of acid-catalyzed reactions27.
Experimental
All products are known compound, which were satisfactory characterized by physical and
spectra data23,28 and the melting points and spectral data of products in this work is in full
agreement with the reported literatures.
General procedure
Preparation of tetrasubstituted imidazoles
To a solution of benzyl (1 mmol), amine (1 mmol), aldehyde (1 mmol) and ammonium
acetate (1 mmol) in ethanol (10 mL) was added Preyssler heteropoly acid (1 mol%). The
mixture was heated with stirring at reflux temperature for 10-30 min. After completion of
the reaction (the progress of the reaction was monitored by TLC), the mixture was cooled to
room temperature and the precipitated products were separated by filtration; then washed
with water and dried. The solid products were then recrystallized from ethanol to obtain the
pure products. Also, the catalyst could be recycled after evaporation of solvent from the
residue solution, washed with diethyl ether and dried. Physical and spectroscopic data of
some 1,2,4,5-tetrasubstituted imidazoles are given below:

One-Pot Synthesis of Tetrasubstituted Imidazoles
549
1-Benzyl-2,4,5-triphenyl-1H-imidazole(4a)
1
M.p: 163-166 °C; H NMR(500 MHz, CDCl3) δ(ppm): 5.15(s, 2H, CH2), 6.82-7.60 (m, 20H,
Ph); IR (KBr) (νmax, cm-1): 3052, 2921, 1604; MS (m/z): 386(M+); Anal. Calcd. for
C28H22N2: C, 87.01; H, 5.74; N, 7.25. Found: C, 87.11; H, 5.79; N, 7.40.
1-Methyl-4,5-diphenyl-2-p-tolyl-1H-imidazole(4i)
1
M.p: 222-225 °C; H NMR(500 MHz, CDCl3) δ(ppm): 2.38(s, 3H, CH3Ph), 3.63(s, 3H,
CH3N), 7.08-7.68(m, 14H, Ph); IR (KBr) (νmax, cm-1): 3061, 2929, 1635; MS (m/z):
324(M+); Anal. Calcd. for C23H20N2: C, 85.15; H, 6.21; N, 8.63. Found: C, 85.21; H, 6.28;
N, 8.50.
4-(1,4,5-Triphenyl-1H-imidazol-2-yl)phenol(4l)
M.p: 279-282 °C; 1H NMR(500 MHz, CDCl3) δ(ppm): 6.79-7.78(m, 19H, Ph), 8.28(s, 1H,
OH); IR (KBr) (νmax, cm-1): 3442, 3059, 1587; MS (m/z): 388(M+); Anal. Calcd. for
C27H20N2O: C, 83.48; H, 5.19; N, 7.21. Found: C, 83.55; H, 5.11; N, 7.29.
Results and Discussion
In continuation of our study27 in exploring application of heteropoly acids in fine
organic chemistry, we have suggested this method for synthesis of 1,2,4,5-
tetrasubtituted imidazoles by using inexpensive and reusable Preyssler heteropoly acid
catalyst in high yields (Scheme 1).
Scheme 1. One-pot synthesis of 1,2,4,5-tetrasubtituted imidazoles using Preyssler catalyst
To find simple and suitable conditions for synthesis of 1,2,4,5-tetrasubstituted
imidazoles, the reaction of benzil (1), benzaldehyde (2a), benzyl amine (3a) and ammonium
acetate was chosen as a model to form the 1-benzyl-2,4,5-triphenyl-1H-imidazole (4a) and
reaction progress was studied under different conditions by thin layer chromatography (TLC).
A summary of obtained results have been shown in Table 1. Entries 1-4 in this table
show the effect of various amounts of Preyssler acid catalyst on the rate and yield of the
reaction. As is observable, if the amount of catalyst is two-fold from 0.5 mol%, amount of
product increased perceptibly, but if also increase, amount of product increased very slowly.
Then the best ratio of benzil, aldehyde, primary amine, NH4OAc and catalyst at mole is
1:1:1:1:0.01.
Table 1. Effect of Preyssler acid catalyst amount
Entry Amount of catalyst, mol % a
Yield, % b
1
2
3
4
0.5
1
2
48
95
97
95
5
a Reaction of benzyl 1 (1 mmol), benzaldehyde 2a (1 mmol), benzyl amine 3a (1 mmol) and ammonium
acetate (1 mmol) in presence of different amount of Preyssler acid catalyst. b) Isolated yield after 0.5
hour reflux

550
ALI JAVID et al.
Because of the mechanism of action for this catalyst in a solvent, we also studied the
rate and yield of the reaction in different solvents such as water, dichloromethane,
chloroform, acetonitrile and ethanol. Thus, among the tested solvents, ethanol was applied as
acceptable solvent for this reaction. Also, the yield increased as the reaction temperature was
raised. So, in other studies all reactions carried out in refluxing ethanol.
A comparative study with a few samples literature reported methods for this one-pot
four-component reaction to synthesis 1,2,4,5-tetra subtituted imidazoles is compiled in Table 2.
As can be seen, our method is more efficient in time of reaction and amount of yield than
other catalysts that reported (Table 2, entry 1-6).
Table 2. Comparison of different catalysts reported in literatures for one-pot synthesis of
1,2,4,5-tetrasubtituted imidazoles
Conversion, %
Entry
Catalyst
Conditions
Time
[Ref.]
80-93 [21]
1
2
3
4
5
6
K5CoW12O40.3H2O
silicagel/NaHSO4
InCl3-3H2O
CH2Cl2/reflux
CH2Cl2/reflux
MeOH/r.t.
2-2.5 h
2 h
85-92 [16]
8-9.5 h
2-2.5 h
8.5-10 h
10-30 min
69-82 [19]
84-93 [22]
78-88 [23]
85-97, this work
high surface SiO2 CH2Cl2/sunlight
MeOH/reflux
EtOH/reflux
L-Proline
H14[NaP5W30O110
]
The results of our work are presented in Table 3. As can be seen, aromatic aldehydes
bearing both electron-donating and electron-withdrawing groups readily undergo the reaction
giving excellent yields of corresponding to these reactions. Also, it should be noted that, this
method is effective for the preparation of tetrasubstituted imidazoles from both aliphatic and
aromatic amines. However, the catalytic system approximately works best for aromatic amines.
Table 3. Synthesis of 1,2,4,5-tetrasubstituted imidazoles using Preyssler acid as catalyst in
refluxing ethanol
Time, Yield
M.P.,°C
Entry
Ar
R
Product
min
10
20
20
20
10
30
20
30
20
20
30
%
95
88
97
92
93
88
85
86
85
85
89
91
87
Found/Reported[Ref]
163-166/165-167[24]
163-165/162-165[24]
159-162/157-160[24]
161-164/165-168[24]
134-137/134-136[24]
145-148/147-148[24]
168-171/170-172[24]
142-145/144-145[23]
222-225/221-223[23]
202-205/201-203[23]
189-191/187-189[28]
279-282/284-286[28]
192-195/191-193[28]
1
2
3
C6H5
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
CH3
4a
4b
4c
4d
4e
4f
4-Cl-C6H4
4-CH3O-C6H4
4-CH3-C6H4
4-OH-C6H4
2-OH-C6H4
4-Br-C6H4
C6H5
4-CH3-C6H4
4-Br-C6H4
4-CH3-C6H4
4-OH-C6H4
4-NO2-C6H4
4
5
6
7
4g
4h
4i
8
9
CH3
CH3
10
11
12
13
4j
Ph
Ph
4k
4l
Ph
4m
It should be mentioned that the products of this reaction could be easily separated from
catalyst. Preyssler heteropoly acid is soluble in ethanol at room temperature but the products
are not. So, finally reaction when the mixture cooled to room temperature, the products were
insoluble and could be separated by a simple filtration. H14[NaP5W30O110] catalyst was also
found to be reusable several times. However, little reduction in activity of catalyst was
observed (Table 4).

One-Pot Synthesis of Tetrasubstituted Imidazoles
551
Table 4. Investigation of the feasibility of reusing Preyssler acid catalyst in synthesis of
1-benzyl-2,4,5-triphenyl-1H-imidazole (4a) in ethanol
Run a
Yield, %
1
95
2
91
3
83
4
65
a
Catalyst could be recycled: the product filtered off, the solvent was evaporated and the remained
catalyst was washed with diethyl ether and dried at 100 °C for 1 h
Conclusion
Preyssler-type heteropoly acid H14[NaP5W30O110] is a highly efficient solid acid catalyst for
the synthesis of 1,2,4,5-tetrasubstituted imidazoles. Excellent yields, enhanced reaction rates
and short reaction times, compatibility with various functional groups, simplicity of
operation and easy work-up are some advantages of this protocol. Also, preyssler is a
gettable, cheap, stable, reusable and agreeable with environment catalyst. Hence, we believe
that this method will find wide application in organic synthesis as well as industry.
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