Trifluoroacetic acid as an efficient catalyst for one-pot, four-component synthesis of 1,2,4,5-tetrasubstituted imidazoles under microwave-assisted, solvent-free conditions

Article abstract of DOI:10.1080/00397910902737122

An efficient method for synthesis of various tetrasubstituted imidazoles, using trifluoroacetic acid (TFA) as a catalytic support, by four-component condensation of benzil, aldehydes, amines, and ammonium acetate under microwave-irradiated, solvent-free conditions is described. Copyright Taylor & Francis Group, LLC.

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Trifluoroacetic Acid as an
Efficient Catalyst for One-Pot,
Four-Component Synthesis
of 1,2,4,5-Tetrasubstituted
Imidazoles Under Microwave-
Assisted, Solvent-Free
Conditions
Mohammad R. Mohammadizadeh a , Alireza
Hasaninejad a & M. Bahramzadeh a
a Department of Chemistry, Faculty of Sciences,
Persian Gulf University, Bushehr, Iran
Published online: 12 Aug 2009.
To cite this article: Mohammad R. Mohammadizadeh , Alireza Hasaninejad & M.
Bahramzadeh (2009): Trifluoroacetic Acid as an Efficient Catalyst for One-Pot, Four-
Component Synthesis of 1,2,4,5-Tetrasubstituted Imidazoles Under Microwave-
Assisted, Solvent-Free Conditions, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:18, 3232-3242
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Synthetic Communications1, 39: 3232–3242, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902737122
Trifluoroacetic Acid as an Efficient Catalyst
for One-Pot, Four-Component Synthesis of
1,2,4,5-Tetrasubstituted Imidazoles Under
Microwave-Assisted, Solvent-Free Conditions
Mohammad R. Mohammadizadeh, Alireza Hasaninejad,
and M. Bahramzadeh
Department of Chemistry, Faculty of Sciences,
Persian Gulf University, Bushehr, Iran
Abstract: An efficient method for synthesis of various tetrasubstituted
imidazoles, using trifluoroacetic acid (TFA) as
a catalytic support, by
four-component condensation of benzil, aldehydes, amines, and ammonium
acetate under microwave-irradiated, solvent-free conditions is described.
Keywords: Four-component,
imidazoles, trifluoroacetic acid
microwave,
solvent-free,
tetrasubstituted
INTRODUCTION
The imidazole moiety, as a part of the side chain in histidine, plays a
major role in the biological activity of many peptides and proteins.
Functionalized imidazoles also comprise an important class of
pharmacologically active compounds that have a variety of interesting
properties.[1,2] Because of their widespread applications as green solvents
by means of ionic liquids[3] and in organometallic chemistry as
N-heterocyclic carbenes,[4] there is an increasing interest in research on
imidazoles.
Received October 14, 2008.
Address correspondence to Mohammad R. Mohammadizadeh, Department
of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran.
E-mail: mrmohamadizadeh@pgu.ac.ir
3232

Trifluoroacetic Acid as Efficient Catalyst
3233
Preparation of tetrasubstituted imidazoles has been the subject of both
industrial and academic studies. As a result, numerous solution-phase
syntheses of these compounds have been reported.[5,6] The most well-known
and classical method for preparation of these compounds involves
four-component condensations of a 1,2-diketone derivative with an
aldehyde, primary amine, and ammonium acetate in refluxing HOAc,
which is known to have poor yields and long reaction times.[7] Improve-
ments occurred using other acidic conditions, such as FeCl3 ꢀ 6H2O,[8]
heteropolyacid,[9] silica gel,[10] zeolite,[10] alumnia,[11] HClO4 ꢀ SiO2,[12]
molecular iodine,[13] BF3 ꢀ SiO2,[14] InCl3 ꢀ 3H2O,[15] K5CoW12O40 ꢀ 3H2O,[16]
and copper acetate[17] under microwave-irradiated, solvent-free or classical
conditions. However, most of these synthetic methods suffer from some
serious drawbacks, such as laborious and complex workup and purification,
significant amounts of waste materials, strongly acidic conditions, occur-
rence of side reactions, poor yields, and the use of expensive reagents. There-
fore, the development of a new catalytic system to overcome these
shortcomings and fulfill the criteria of a mild, efficient, and environmentally
benign protocol for the synthesis of highly substituted imidazoles is an
important task for organic chemists.
Because of its interesting properties, such as low toxicity, solubility in
organic solvents, and strength, trifluoroacetic acid (TFA) is considered
to be a special reagent for highly sensitive microsequencing of proteins,[18]
as well as a special catalyst for promotion of numerous organic
reactions.[19–30]
Since the introduction of controlled precise microwave reactors,
microwave-assisted organic synthesis (MAOS) has had a significant
impact on synthetic chemistry. Reductions in reaction time, increases in
yield, and suppression of side-product formation have all been described
for microwave conditions relative to conventional thermal heating.
Although the basis of these practical benefits remains speculative,
the preparative advantages are obvious and have motivated a large
and continuing survey of nearly all classes of thermal reactions for
improvement upon microwave heating. This exploration has extended
to cross-coupling reactions, cycloadditions, condensations, and
heterocycle-forming reactions.[31]
RESULTS AND DISCUSSION
In continuing our interest on microwave-assisted synthesis of nitrogen-
containing heterocycles,[32,33] we developed a one-pot reaction catalyzed
by silica gel–supported sodium bisulfate for the synthesis of tri- and tetra-
substituted imidazoles.[34] In the present work, we concluded that TFA is

3234
M. R. Mohammadizadeh, A. Hasaninejad, and M. Bahramzadeh
Scheme 1. TFA-catalyzed, microwave-assisted, solvent-free synthesis of
1,2,4,5-tetrasubstituted imidazoles 4a–n.
a highly efficient catalyst for the one-pot synthesis of tetrasubstituted
imidazoles 4 from benzil 1, aldehydes 2, amine 3, and ammonium acetate
under microwave-assisted, solvent-free conditions (Scheme 1). The
multicomponent nature of the procedure together with the existence of
a wide variety of commercially available aldehydes and amines make this
reaction an ideal candidate for the combinatorial synthesis technology.
To achieve the best conditions for this reaction (Scheme 1), we
examined the efficiency of different reaction media and catalyst amounts
for the condensation reactions of benzil, benzaldehyde, benzylamine, and
ammonium acetate as a model reaction (Table 1). For each reaction
Table 1. Comparison of the reaction of benzil, benzaldehyde, benzylamine, and
ammonium acetate under various TFA loadings and reaction conditions
Catalyst
(mol %)
Time
(min)
Conversion
(%)b
Entrya
Conditions
1
2
3
4
5
6
7
8
10
20
30
20
0
10
20
30
Solvent-free, 100ꢁC
90
90
90
90
15
6
35
35
68
20
35
52
100
100
Solvent-free, 100ꢁC
Solvent-free, 140ꢁC
DMF, 110ꢁC
MW (150 W), solvent-free
MW (150 W), solvent-free
MW (150 W), solvent-free
MW (150 W), solvent-free
4
4
aAll reactions were run using benzil=benzaldehyde=benzylamine=ammonium
acetate, molar ratio of 1=1=1=1.
bAll measured by GC.

Trifluoroacetic Acid as Efficient Catalyst
3235
condition, conversion of initial reactants to 1-benzyl-2,4,5-triphenylimi-
dazole was measured by gas–liquid chromatography using 0.01 M
solution of the product[35] in chloroform as a standard. Reactions at
different conditions and various molar ratios of substrates in the presence
of TFA revealed that the best conditions were a molar ratio of
benzil=aldehyde=amine=ammonium acetate=TFA of 1:1:1:1:0.20 under
microwave-assisted, solvent-free conditions.
The optimal conditions were then applied for the preparation of a
series of 1,2,4,5-substituted imidazoles 4a–n. The product yields are
shown in Table 2. It should be noted that this method is effective for
the preparation of tetrasubstituted imidazoles from both aliphatic and
aromatic amines. In each case, no side product formation (for example,
2,4,5-trisubstituted imidazoles) was observed, as is normally the case in
such reactions under the influence of strong acids. This method not only
affords the products in excellent yields but also avoids the problems
associated with catalyst cost, handling, safety, and pollution.
It is worth mentioning that the desired products could be easily
separated in this condition. Trifluoroacetic acid is completely soluble in
Table 2. Synthesis of imidazoles 4a–n under microwave-irradiated,
solvent-free conditions
[Ref.]
Product 4a,b
Ar
R
Yield (%)c
Mp
a
b
c
d
e
f
Ph
Ph
Ph-CH2
Ph
Ph-CH2
Ph
Ph-CH2
Ph
Ph-CH2-CH2
Ph-CH2
iso-Bu
iso-Bu
Et
Ph
4-Cl-Ph
4-Br-Ph
92
88
94
85
89
83
88
80
85
85
79
88
91
90
157–159[17]
216–217[10]
166–167[10]
186–188[10]
163–165[14]
148–151[14]
126–127[12]
147–150[14]
134–136[10]
151–152[10]
122–123[10]
145–147
4-Me-Ph
4-Me-Ph
4-Cl-Ph
4-Cl-Ph
4-Me-Ph
3-Cl-Ph
Ph
4-Me-Ph
4-Me-Ph
2-Me-Ph
2-Me-Ph
2-Me-Ph
g
h
i
j
k
l
m
n
165–166
190–192
aBenzil–aldehyde–amine–ammonium acetate–catalyst (1:1:11:1:0.2).
bThe structure of known imidazoles 4a–k were characterized by their
1H NMR and comparison of their physical properties with reported
data. For new imidazoles 4l–n, the structures of the products were fully
characterized by NMR and mass spectroscopy.
cAll referred to isolated pure products.

3236
M. R. Mohammadizadeh, A. Hasaninejad, and M. Bahramzadeh
water at room temperature, but the products are not. Water was added to
the cooled reaction mixture, and the products were separated by simple
filtration.
1
All known products 4a–k were characterized by their H NMR and
comparison of their physical properties with previously reported data.
For new imidazoles 4l–n, the structures of the products were fully
characterized by NMR and mass spectroscopy, (MS). Physical properties
and spectral data of new compounds 4l–n are reported.
To show the advantages of TFA as a catalyst in this reaction, our
obtained results and employed reaction conditions for synthesis of
1-benzyl-2,4,5-triphenylimidazole (4a) were compared with previously
reported data in Table 3. The results show that our method is quite
comparable with the former methods in yields and reaction times.
In accordance with a delineated mechanism,[35] it may be proposed
that the CF3CO2H catalyst facilitates the formation of diamine inter-
mediate [A] by increasing the electrophilicity of the carbonyl group of
the aldehydes and benzil. Intermediate [A], in the presence of CF3CO2H,
condenses with benzil to form imidazol-5-ol intermediate [C], which in
turn changes to tetrasubstituted imidazoles by elimination of water
(Scheme 2).
In conclusion, we have developed a simple, fast, and efficient
procedure for synthesis of 1,2,4,5-tetrasubstituted imidazoles based on
Table 3. Synthesis of 1-benzyl-2,4,5-triphenylimidazole 4a using different cata-
lysts and reaction conditions
Time
(min)
Yield
(%)
Entry
Solvent and catalyst (loading)
Ref.
1a
2
3
4
5
6
7
8
Ethanol, reflux, FeCl3 ꢀ 6H2O (5 mol%),
Ethanol, reflux, H4[PMo11VO40] (1 mol%)
MW, solvent-free, silica gel (5 mol%)
MW, solvent-free, Zeolite HY (5 mol%)
MW, solvent-free, alumina (3.4 g per 1 mmol)
Solvent-free, HClO4–SiO2 (1 mol%)
Ethanol, reflux, I2 (5 mol%)
60
8
6
6
20
6
98
88
87
83
80
96
––
80
8
9
10
10
11
12
13
14
—
120
ꢁ
Solvent-free, 140 C, 37% BF3ꢂSiO2
(0.08 g per 1ꢁmmol)
9
Methanol, 25 C, InCl3 ꢀ 3H2O (10 mol%)
360
120
84
90
15
16
ꢁ
10 Solvent-free, 140 C, K5CoW12O40 ꢀ 3H2O
(0.1 mol%)
11 MW, solvent-free, TFA (5 mol%)
5
86 this work
aEntry 1 is GC-measured yield, and all others are isolated yields.

Trifluoroacetic Acid as Efficient Catalyst
3237
Scheme 2. Plausible mechanism for the formation of tetrasubstituted imidazoles.
TFA-catalyzed, one-pot, four-component condensation of benzil,
benzaldehydes, primary amines, and ammonium acetate under micro-
wave-assisted, solvent-free conditions. The short reaction times, easy
workup, clean reaction profiles, and good product yields make our
methodology a valid contribution to the existing processes in the field
of 1,2,4,5-tetrasubstituted imidazoles synthesis.
EXPERIMENTAL
General Procedure
In a typical procedure appropriate amounts of benzil 1 (1 mmol),
aldehydes 2 (1 mmol), primary amine 3 (1 mmol), ammonium acetate
(1 mmol), and TFA (0.2 mmol) in a beaker were mixed thoroughly and
exposed to microwave irradiation (150 W, 20% power) for 4 min in a
four-step mode with interval (1 min–40 s–1 min). Then the reaction
mixture was allowed to cool down to room temperature, 20 mL water
were added, and the resulting solid was filtered off and washed with
10 mL of hot water. Resulting products have sufficient purity, but if more
purification is necessary, the products can be recrystallized from ethanol.
Spectral Data of New Compounds 4 l–N
1,4,5-Triphenyl-2-o-tolyl-1 H-imidazole 4 l
Colorless solid; mp 173–174; 1H NMR (CDCl3, 500 MHz) d: 2.28 (s, 3H,
CH3), 6.93 (m, 2H, arom), 7.11–7.30 (m, 15H, arom), 7.66 (m, 2H, arom);

3238
M. R. Mohammadizadeh, A. Hasaninejad, and M. Bahramzadeh
13C NMR (CDCl3, 125 MHz) d 20.7, 125.7, 126.9, 127.8, 128.1, 128.3,
128.4, 128.5, 128.8, 129.0, 129.3, 129.7, 130.5, 131.2, 131.3, 131.5,
131.7, 135.1, 137.0, 138.2, 138.6, 147.7; MS m=z: 386 ([M]þ, 100), 165
(50), 77 (23).
1-(4-Chlorophenyl)-4,5-diphenyl-2-O-tolyl-1H-imidazole 4 m
Colorless solid; mp 205–206; 1H NMR (CDCl3, 500 MHz) d: 2.27 (s, 3H,
CH3), 6.79 (m, 2H, arom), 7.14–7.33 (m, 14H, arom), 7.64 (m, 2H, arom);
13C NMR (CDCl3, 63 MHz) d: 20.7, 122.0, 125.9, 127.1, 127.8, 128.6,
129.1, 129.5, 129.6, 129.7, 130.7, 130.8, 131.0, 131.4, 131.6, 132.3,
134.8, 136.1, 138.4, 138.6, 147.6; MS m=z: 422 ([M þ 2]þ, 33), 420
([M]þ, 100), 165 (60), 77 (24).
1-(4-Bromophenyl)-4,5-diphenyl-2-o-tolyl-1 H-imidazole 4n
Colorless solid; mp 209–211; 1H NMR (CDCl3, 500 MHz) d: 2.27 (s, 3H,
CH3), 6.86 (m, 2H, arom), 7.13–7.33 (m, 14H, arom), 7.65 (m, 2H, arom);
13C NMR (CDCl3, 63 MHz) d: 20.7, 125.8, 127.1, 127.8, 128.5, 128.6,
129.0, 129.3, 129.4, 129.5, 129.6, 130.7, 130.8, 131.0, 131.4, 131.6,
133.9, 134.8, 135.6, 138.6, 147.7; MS m=z: 466 ([M þ 2]þ, 98), 464
([M]þ, 100), 165 (45), 77 (25).
ACKNOWLEDGMENTS
The authors thank the Research Committee of Persian Gulf University
for financial support of this work.
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