Synthesis of 2,4,5-trisubstituted imidazoles catalyzed by [Hmim]HSO 4 as a powerful Broensted acidic ionic liquid

Article abstract of DOI:10.1139/V08-009

An efficient and green procedure for the synthesis of 2,4,5-trisubstituted imidazoles with various aldehydes using a catalytic amount of 1-methylimidazolium hydrogenesulfate as an active and low cost Broensted acidic room temperature ionic liquid has been developed. The ionic liquid was easily separated from the reaction mixture and was recycled five times without any loss in activity.

Full text of DOI:10.1139/V08-009

264
Synthesis of 2,4,5-trisubstituted imidazoles
catalyzed by [Hmim]HSO4 as a powerful
Brönsted acidic ionic liquid
Ahmad R. Khosropour
Abstract: An efficient and green procedure for the synthesis of 2,4,5-trisubstituted imidazoles with various aldehydes
using a catalytic amount of 1-methylimidazolium hydrogenesulfate as an active and low cost Brönsted acidic room tem-
perature ionic liquid has been developed. The ionic liquid was easily separated from the reaction mixture and was recy-
cled five times without any loss in activity.
Key words: ionic liquid, 2,4,5-trisubstituted imidazoles, [Hmim]HSO4, aldehyde, benzil.
Résumé : On a mis au point une méthode efficace et environnementalement correcte pour la synthèse d’imidazoles
2,4,5-trisubstitués utilisant divers aldéhydes et une quantité catalytique d’hydrogénosulfate de 1-méthylimidazolium actif
comme acide de Brönsted à la température ambiante et comme liquide ionique de faible coût. On peut facilement sépa-
rer le liquide ionique du mélange réactionnel et le recycler au moins cinq fois sans la moindre perte d’activité.
Mots-clés : liquide ionique, imidazoles 2,4,5-trisubstitués, [Hmim]HSO4, aldéhyde, benzile.
[Traduit par la Rédaction] Khosropour 269
Introduction
organic reactions in environmentally friendly media, syn-
thetic manipulations are required to minimize the use of haz-
ardous chemicals, such as replacing toxic catalysts or
organic solvents in reactions and their subsequent workup
with other nontoxic solvents like water (21) or super critical
CO2 (22). In recent years, ionic liquids have attracted in-
creasing interest in the context of green synthesis (23). Al-
though ionic liquids were initially introduced as alternative
green reaction media because of their unique chemical and
physical properties of nonvolatility, nonflammability, ther-
mal stability, and controlled miscibility (24–26), today they
have evolved beyond this, showing their significant role in
controlling reactions as catalysts (27, 28). However, sensi-
tivity to moisture and decomposition of some ionic liquids
under normal atmospheric conditions are two major draw-
backs to their practical use (29). On the other hand, the high
cost of most conventional room temperature (RT) ionic liq-
uids and apprehension about their toxicity (30, 31) have led
us to explore the use of more benign salts as practical alter-
natives. Recently, Binnemans and co-workers (32) reported
that 1-methylimidazolium hydrogenesulfate ([Hmim]HSO4),
a powerful Brönsted acidic RT ionic liquid (BARTIL) is rel-
atively nontoxic, readily available at low cost, and fairly sta-
ble in water, unlike some ionic liquids (e.g., [bpy]AlCl4) that
decompose readily in aqueous media.
The imidazole nucleus constitutes the core unit of many
natural products (1–3). Also, this moiety is a popular build-
ing block for the construction of pharmaceutically interest-
ing compounds and has attracted the attention of synthetic
chemists for over a century (4–7). Multi-aryl substituted
imidazoles, especially trisubstituted ones, could potentially
have novel therapeutic activities (8, 9). In addition, many of
the 2,4,5-triarylimidazoles are known as herbicides, fungi-
cides (10), or as inhibitors of IL-1 or P38 MAP kinase (11–
13). This class of compounds can be prepared by the con-
densation of benzil, ammonium acetate, and aldehydes in the
presence of either protic or Lewis acids (14–20). However,
many of these methods still suffer from some disadvantages,
such as the use of toxic or expensive catalysts or reaction
media, drastic reaction conditions, unsatisfactory yields, and
limited scopes. This is especially true with alkyl aldehydes
and some aryl aldehydes, such as nitrobenzaldehydes, that
limit these methods. Therefore, the introduction of a new
and efficient method for this transformation is still in demand.
Results and discussion
Since there is a growing demand for the development of
Received 2 September 2007. Accepted 9 December 2007. Published on the NRC Research Press Web site at canjchem.nrc.ca on
22 February 2008.
A.R. Khosropour.1 Catalysis Division, Department of Chemistry, Faculty of Science, University of Isfahan, Isfahan 81746–73441,
Iran.
1Corresponding author (e-mail: khosropour@chem.ui.ac.ir).
Can. J. Chem. 86: 264–269 (2008)
doi:10.1139/V08-009
© 2008 NRC Canada

Khosropour
265
Scheme 1.
Table 1. Synthesis of 2-(phenyl)-4,5-diphenylimidazole in the
presence of [Hmim]HSO4 under different conditions.
Ph
Ph
O
[Hmim]HSO4
(mol%)
Solvent
(3 mL)
Temprature
(°C)
Yield
(%)a
[Hmim]HSO (10 mol%)
4
Ph
RCHO
+
+
NH 4OAc
N
NH
Entry
EtOH, 75 °C
Ph
1
2
3
4
5
6
7
8
30
30
30
30
30
30
30
25
20
15
10
5
CH3CN
CH2Cl2
CHCl3
CH3OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
CH3CH2OH
80
40
61
60
75
70
60
75
75
75
75
75
72
18
36
86
95
92
89
95
95
95
95
89
O
R
These results, in combination with our recent examination
to design new synthetic methodologies (33–41) especially in
RT ionic liquid (42–45), led us to develop a simple and effi-
cient procedure for the direct synthesis of 2,4,5-trisubstituted
imidazoles with various aldehydes using a catalytic amount
of [Hmim]HSO4 (Scheme 1).
The experimental procedure for this reaction is remark-
ably simple and does not require the use of toxic or expen-
sive organic solvents or reagents. The reactions were carried
out at 75 °C by taking a 1:1:10 mole ratio mixture of alde-
hydes, benzil, and ammonium acetate, respectively, in the
presence of only 10 mol% of [Hmim]HSO4 in ethanol to
give the desired products in high to excellent yields.
9
10
11
12
Note: After 3 h.
aIsolated yields.
It is important to note that the use of 10 mol% of
[Hbim]BF4 instead of [Hmim]HSO4 resulted in no reaction.
To investigate the influence of the media, temperature,
and amount of catalyst in this synthesis, for example, the
condensation reaction of benzaldehyde with benzil and am-
monium acetate was carried out (Table 1). Among all the
systems tested, using 10 mol% of [Hmim]HSO4 in EtOH
(3 mL) at 75 °C proved to be the optimum condition (Ta-
ble 1, entry 11). Using these optimized conditions, a wide
range of substituted and structurally diverse aldehydes were
subjected to this procedure to afford the corresponding prod-
ucts in good to excellent yields (Table 2).
The scope and generality of this process are illustrated by
a series of 30 trisubstituted imidazoles, as can be seen in Ta-
ble 2. The high-yield transformations were carried out with-
out any significant amounts of undesirable side products.
Unlike previously reported methods, the present method
does not require toxic or anhydrous organic solvents to pro-
duce the 2,4,5-trisubstituted imidazoles derivatives. All the
products were characterized by NMR, IR, and mass spec-
troscopy and also by comparison with authentic samples. A
wide range of aromatic aldehydes were employed and all
imidazoles were obtained in high to excellent yields (Ta-
ble 2, entries 1–22), yielding a general method that tolerates
both electron-withdrawing and electron-donating constitu-
ents. Another important aspect is that various functionalities
such as ether, halide, nitro, nitrile, and hydroxyl, survived
under the present reaction conditions.
isomerization for conjugated aldehydes or damage to moi-
eties, such as methoxy that often undergoes cleavage in
strongly acidic reaction media (Table 2, entries 16–18, 20,
and 23–25).
In addition, the synthesis of imidazoles on a large scale
(50 mmol) was tested. The reaction was demonstrated to be
very efficient on this scale, and the products were obtained
in excellent yields using the same reaction conditions. An-
other advantage of this promoter system is the recycleability
of the catalyst; [Hmim]HSO4 can be reused in five runs
without any loss of activity.
In summary, we have developed an efficient, economical,
and environmentally friendly procedure for the synthesis of
2,4,5-trisubstituted imidazoles. This involves the use of
[Hmim]HSO4 as an inexpensive, stable, and easily available
Brönsted acidic RT ionic liquid. The use of a powerful, easy
accessible, and recyclable ionic liquid makes this procedure
quite simple, more convenient, and environmentally benign.
Experimental
General experimental procedure
A mixture of aldehyde (1 mmol), benzil (1 mmol), ammo-
nium acetate (10 equiv.), and [Hmim]HSO4 (0.1 mmol) in
ethanol (3 mL) was stirred at 75 °C for the appropriate time,
according to Table 1. After completion of the reaction, as in-
dicated by TLC, the mixture was concentrated in vacuo to
remove the solvent. The resulting solution was extracted by
Et2O (3 × 10 mL). The organic layer was dried (Na2SO4),
concentrated under vacuum, and recrystallized by 25% ethyl
acetate/petroleum ether to give the corresponding imidazoles
in 80%–97% yields.
Also, depending on the reaction times, terephthaldi-
aldehydes can be selectively converted to their correspond-
ing mono- or bis-(4,5-diphenyl)-1H-imidazole (Table 2,
entries 9 and 10). Interestingly, we achieved that in the case
of 4-(diethoxymethyl)benzenaldehyde (Table 2, entry 11); a
one-pot deprotection–cyclization reaction was carried out in
the reaction conditions. On the other hand, aliphatic alde-
hydes and unsaturated ones (Table 2, entries 23–30), which
normally show extremely poor yields using previous meth-
ods, gave the corresponding imidazoles in high yields. The
reaction conditions are mild enough not to induce any
Recycling of ionic liquid [Hmim]HSO4
Residual ionic liquid was washed with Et2O (3 × 10 mL)
to remove any organic impurity and dried at 80 °C. Under
this procedure, [Hmim]HSO4 can be reused in five runs
without any loss of its activity.
© 2008 NRC Canada

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Can. J. Chem. Vol. 86, 2008
Table 2. Synthesis of 2,4,5-trisubstituted imidazoles catalyzed by 10 mol% of [Hmim]HSO4 in
EtOH.
Entry Aldehyde
Time (h)
3
Yield (%)b
95
Producta
H
N
Ph
CHO
1
N
Ph
Ph
H
N
F
CHO
2
2.5
3
93
80
85
F
N
Ph
Ph
H
N
Cl
CHO
3
Cl
N
Ph
Ph
H
N
CHO
4
5
6
7
3
N
Ph
Ph
Cl
Cl
H
N
CHO
2.5
2.5
2.5
90
96
97
N
Ph
Ph
Cl
Cl
Cl
H
N
CHO
Cl
N
Ph
Ph
Cl
Cl
H
N
CHO
O2N
NO2
CN
N
Ph
Ph
H
N
CHO
CHO
NC
8
9
4
4
93
97
N
Ph
Ph
H
N
OHC
CHO
N
N
Ph
Ph
H
N
Ph
Ph
OHC
CHO
10
8.5
82
N
N
H
Ph
Ph
H
N
C2H5O
C2H5O
CHO
11
12
4
3
96
89
CHO
N
Ph
Ph
OH
Br
H
N
CHO
N
Ph
Br
HO
Spectroscopic data
2,2-(1,4-phenylene)-bis(4,5-diphenyl)-1H-imidazole
Table 2, entry 10, mp > 360 °C. IR (KBr, cm–1) νmax
:
3390, 3172, 3054, 1600, 1481, 762, 690. 1H NMR
(400 MHz, DMSO-d6) δH: 12.81 (s, 2H), 8.20 (s, 4H), 7.20–
7.72 (m, 20H). 13C NMR (100 MHz, DMSO-d6) δC: 125.2,
126.5, 127.0, 127.7, 128.3, 128.6, 129.5, 129.7, 129.9,
130.9, 135.1, 137.3, 144.9. EIMS m/z: 514 (M+, 71), 411,
307, 257.
2-(2,4-dichlorophenyl)-4,5-diphenylimidazole
Table 2, entry 6, mp 174 to 175 °C. IR (KBr, cm–1)
ν
max: 3427, 3068, 1593, 824, 767, 698. 1H NMR
(400 MHz, DMSO-d6) δH: 12.8 (s, 1H), 7.80 (d, J =
8.4 Hz, 1H), 7.81 (s, 1H), 7.61–7.22 (m, 12H). 13C NMR
(100 MHz, DMSO-d6) δC: 126.7, 127.2, 127.4, 127.9,
128.2, 128.2, 128.3, 128.7, 128.8, 129.6, 130.6, 132.4,
132.6, 133.9, 134.8, 137.1, 142.4. EIMS m/z: 364 (M+ – 2,
100), 165, 123, 69, 55.
2-(4-methoxyphenyl)-4,5-diphenylimidazole
Table 2, entry 16, mp 230 to 231 °C. IR (KBr, cm–1) νmax
:
© 2008 NRC Canada

Khosropour
267
Table 2 (continued).
1
3400, 3060, 1611, 1490, 1179, 1028, 830, 761. H NMR
(400 MHz, DMSO-d6) δH: 12.48 (s, Br, 1H), 8.00 (dt, J =
8.8 Hz, 2.0 Hz, 2H), 7.51 (d, J = 7.2 Hz, 4H), 7.35 (t, J =
7.2 Hz, 4H), 7.27 (t, J = 7.2 Hz, 2H), 7.04 (dt, J =
8.8 Hz, 2.0 Hz, 2H), 3.80 (s, 3H). 13C NMR (100 MHz,
DMSO-d6) δC: 55.2, 114.1, 122.9, 126.7, 127.0, 127.7,
128.4, 145.6, 159.4. EIMS m/z: 326 (M+, 100), 311, 283,
235, 97.
© 2008 NRC Canada

268
Can. J. Chem. Vol. 86, 2008
Table 2 (concluded).
Yield (%)b
Entry Aldehyde
Producta
Time (h)
4
H
N
Ph
OHCCH
26
80
CH
CH3
N
Ph
Ph
CH3
H
N
OHCCH2
27
4
79
83
81
84
83
81
84
CH2
N
Ph
Ph
H
N
OHCCH2CH2
28
4.5
5
CH2CH2
N
Ph
Ph
H
N
OHC(CH2)5CH3
29
CH2(CH2)4CH3
CH2(CH2)6CH3
CH2CH2
N
Ph
Ph
H
N
OHC(CH2)7CH3
30
5.5
4.5
5
N
Ph
Ph
H
N
OHCCH2CH2
28
N
Ph
Ph
H
N
OHC(CH2)5CH3
29
CH2(CH2)4CH3
N
Ph
Ph
H
N
OHC(CH2)7CH3
30
5.5
CH2(CH2)6CH3
N
Ph
1
aAll products wre characterized by H NMR, 13C NMR, IR, and mass spectroscopy.
bIsolated yields.
S.W. Landvatter, J.E. Strikler, M.M. McLaughlin, I.R.
Siemen, S.M. Fisher, G.P. Livi, J.R. White, J.L. Adams, and
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Acknowledgement
We are grateful to the Center of Excellence of Chemistry
(Catalyst and Fuel Cell), University of Isfahan (CECUI) and
also Research Council of University of Isfahan (research
project No. 860306) for financial support of this work. In
addition, the author thanks Professor Iraj Mohammadpoor-
Baltork for his advice.
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