Green, one-pot, solvent-free synthesis of 1,2,4,5-tetrasubstituted imidazoles using a bronsted acidic ionic liquid as novel and reusable catalyst

Article abstract of DOI:10.1080/00397910903289271

3-Methyl-1-(4-sulfonic acid)butylimidazolium hydrogen sulfate [(CH ₂)₄SO₃HMIM][HSO₄], a Brnsted acidic ionic liquid, has been used as an efficient, green, and reusable catalyst for the synthesis of 1,2,4,5-tetrasubstituted imidazoles using benzil, an aromatic aldehyde, and a primary amine in the presence of ammonium acetate under solvent-free conditions. The catalyst could be recycled and reused several times without noticeably decreasing the catalytic activity. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903289271

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Green, One-Pot, Solvent-Free Synthesis
of 1,2,4,5-Tetrasubstituted Imidazoles
Using a Brønsted Acidic Ionic Liquid as
Novel and Reusable Catalyst
a
b
a
Abolghasem Davoodnia , Majid M. Heravi , Zahra Safavi-Rad
&
a
Niloofar Tavakoli-Hoseini
a
Department of Chemistry, Faculty of Sciences, Islamic Azad
University, Mashhad Branch, Mashhad, Iran
b
Department of Chemistry, School of Sciences, Azzahra University,
Vanak, Tehran, Iran
Version of record first published: 05 Aug 2010.
To cite this article: Abolghasem Davoodnia , Majid M. Heravi , Zahra Safavi-Rad & Niloofar Tavakoli-
Hoseini (2010): Green, One-Pot, Solvent-Free Synthesis of 1,2,4,5-Tetrasubstituted Imidazoles
Using a Brønsted Acidic Ionic Liquid as Novel and Reusable Catalyst, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:17, 2588-2597
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1
Synthetic Communications , 40: 2588–2597, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903289271
GREEN, ONE-POT, SOLVENT-FREE SYNTHESIS OF
,2,4,5-TETRASUBSTITUTED IMIDAZOLES USING
1
A BRØNSTED ACIDIC IONIC LIQUID AS NOVEL
AND REUSABLE CATALYST
1
Abolghasem Davoodnia, Majid M. Heravi,
2
1
Zahra Safavi-Rad, and Niloofar Tavakoli-Hoseini
1
1
Department of Chemistry, Faculty of Sciences, Islamic Azad University,
Mashhad Branch, Mashhad, Iran
2
Department of Chemistry, School of Sciences, Azzahra University, Vanak,
Tehran, Iran
3
-Methyl-1-(4-sulfonic acid)butylimidazolium hydrogen sulfate [(CH
2 4 3
) SO HMIM]
[
HSO ], a Brønsted acidic ionic liquid, has been used as an efficient, green, and reusable
4
catalyst for the synthesis of 1,2,4,5-tetrasubstituted imidazoles using benzil, an aromatic
aldehyde, and a primary amine in the presence of ammonium acetate under solvent-free
conditions. The catalyst could be recycled and reused several times without noticeably
decreasing the catalytic activity.
Keywords: Brønsted acidic ionic liquids; multicomponent reactions; one-pot synthesis; solvent-free
conditions; tetrasubstituted imidazole
INTRODUCTION
Multicomponent reactions (MCRs) have emerged as efficient and powerful tools
in modern synthetic organic chemistry because the synthesis of complex organic
molecules from simple and readily available substrates can be achieved in a very
[
1–3]
fast and efficient manner without the isolation of any intermediate.
Therefore,
developing new MCRs and improving known MCRs are popular areas of research
in current organic chemistry. One such reaction is the synthesis of imidazoles. In recent
years, imidazoles have attracted attention because the compounds with the imidazole
ring system have many pharmacological properties and play important roles in
[4]
biochemical processes. Different substituted imidazoles show variable biological
[
5]
[6]
[7]
activities such as anti-inflammatory, anti-allergic, analgesic, antibacterial, and
[8]
[
9]
[10]
antitumor activities. Also, some of them are known as inhibitors of P38 kinase.
Recent advances in green chemistry and organometallic catalysis has extended the
application of imidazoles as ionic liquids and N-heterocyclic carbenes.
[11]
[12]
Received June 15, 2009.
Address correspondence to Abolghasem Davoodnia, Department of Chemistry, Faculty of
Sciences, Islamic Azad University, Mashhad Branch, Mashhad 91735-413, Iran. E-mail: adavoodnia@
yahoo.com
2
588

SYNTHESIS OF 1,2,4,5-TETRASUBSTITUTED IMIDAZOLES
2589
Despite the availability of a wide variety of synthetic routes toward imidazoles,
few studies exist on the synthesis of 1,2,4,5-tetrasubstituted imidazoles. These
compounds are generally synthesized in a four-component condensation of alde-
hydes, 1,2-diketones, amines, and ammonium acetate in the presence of several
[
13]
[14]
[15]
catalysts such as HY zeolite,
K CoW O Á 3H O,
silica gel=NaHSO ,
4
molecular iodine,
[18]
[
16]
[17]
[19]
heteropolyacids,
HClO -SiO ,
2
InCl Á 3H O,
5
12 40
2
4
3
2
[
20]
BF -SiO , AlCl , and MgCl .
3
In addition, they can also be accessed by the
3
2
2
cycloaddition reaction of mesoionic 1,3-oxazolium-5-olates with N-(arylmethylene)-
benzenesulfonamides, hetero-Cope rearrangement, condensation of a 1,2-diketone
with an aryl nitrile and primary amine under microwave irradiation, and
[21,22]
N-alkylation of trisubstituted imidazoles.
However, some of these synthetic
methods have limitations such as harsh reaction conditions, use of hazardous and
often expensive acid catalysts, long reaction times, and moderate yields. Moreover,
the synthesis of these compounds is usually carried out in polar solvents such as
ethanol, methanol, acetic acid, dimethylformamide (DMF), and dimethylsulfoxide
(DMSO), leading to complex isolation and recovery procedures. Therefore, the
development of simple, efficient, clean, high-yielding, and environmentally friendly
approaches using new catalysts for the synthesis of these compounds is an important
task for organic chemists.
Ionic liquids (ILs), which are recognized as environmentally benign media,
have been widely applied in many reactions as catalysts or dual catalyst–solvents
because of their low vapor pressure, reusability, and high thermal and chemical stab-
[
23,24]
ility.
anions of the ILs, especially the SO H functional groups, obviously enhanced their
The introduction of Brønsted acidic functional groups into cations or
3
[
25–28]
acidities and water solubilities.
Therefore, Brønsted acidic ILs can be used as
highly efficient acid catalysts. Moreover, their polar nature makes them suitable
for use under solvent-free conditions. In fact, the use of Brønsted acidic ILs as
catalysts is an area of ongoing activity; however, development and exploration
of Brønsted acidic ILs are currently in the preliminary stage. To the best of our
knowledge, there are no examples of the use of Brønsted acidic ILs as catalysts
for the synthesis of tetrasubstituted imidazoles.
In continuation of our previous work on the applications of reusable acid
[
29–31]
catalysts in the synthesis of heterocyclic compounds,
here we report the eco-
friendly synthesis of tetrasubstituted imidazoles 5a–j by 3-methyl-1-(4-sulfonic acid)-
butylimidazolium hydrogen sulfate [(CH ) SO HMIM][HSO ] (Fig. 1), a Brønsted
2
4
3
4
acidic IL, using a one-pot, four-component condensation of benzil 1, benzaldehyde
derivatives 2, primary amines 3, and ammonium acetate 4 under solvent-free
conditions (Scheme 1).
Figure 1. Brønsted acidic IL structure.

2590
A. DAVOODNIA ET AL.
Scheme 1. Synthesis of 1,2,4,5-tetrasubstituted imidazoles.
RESULTS AND DISCUSSION
For our investigations, [(CH ) SO HMIM][HSO ] was prepared according to
2
4
3
4
[32]
the literature procedure. Initially, to optimize the reaction conditions, the reaction
of benzil, 4-methyl benzaldehyde, aniline, and ammonium acetate was used as a
model reaction (Scheme 2).
The efficiency of the reaction is mainly affected by the amount of
(CH ) SO HMIM][HSO ] (Table 1). It showed that no product could be detected
2 4 3 4
[
in the absence of this catalyst (entry 1), which indicated that the catalyst
should be absolutely necessary for this condensation reaction. When the amount
of [(CH ) SO HMIM][HSO ] was increased, a ramp in the yield of the product
2
4
3
4
5
c was observed. The optimal amount of [(CH ) SO HMIM][HSO ] was
2 4 3 4
1
(
5 mol%; greater amounts of the catalyst did not increase the yield noticeably
entries 5, 6).
Scheme 2. Synthesis of 2-(4-methylphenyl)-1,4,5-triphenyl-1H-imidazole 5c as model reaction.
a
Table 1. Effect of the amounts of [(CH
2
)
4
SO
3
4
HMIM][HSO ] on the reaction
b
Entry
Catalyst (mol%)
Time (h)
Yield (%)
1
2
3
4
5
6
None
5
10
3
0
71
82
94
94
95
2.5
2
15
20
2
2
30
2
a
2
ammonium acetate at 140 C.
mmol benzil, 2 mmol 4-methyl benzaldehyde, 2 mmol aniline, and 2 mmol
ꢀ
b
Isolated yields.

SYNTHESIS OF 1,2,4,5-TETRASUBSTITUTED IMIDAZOLES
2591
Table 2. Synthesis of 2-(4-methylphenyl)-1,4,5-triphenyl-1H-imidazole 5c in
] (15 mol%) in different solvents
the presence of [(CH
2
)
4
SO
3
HMIM][HSO
4
ꢀ
a
Entry
Solvent
Temperature ( C)
Time (h)
Yield (%)
1
2
3
4
5
6
MeOH
EtOH
64
78
9
7
56
62
CH
CH
3
CN
Cl
81
40
9
60
2
2
10
10
2
Trace
Trace
94
CHCl
Solvent-free
3
61
140
a
Isolated yields.
Also, the reaction was carried out in various solvents and also under
solvent-free conditions. As shown in Table 2, in comparison to conventional
methods, the yields of the reaction under solvent-free conditions are greater and
the reaction time is shorter.
The effect of temperature was studied by carrying out the same model reaction
in the presence of 15 mol% of this catalyst and at different temperatures in
solvent-free conditions. It was observed (Table 3) that yield is a function of tempera-
ꢀ
ture, so the yield increased as the reaction temperature was raised, and at 140 C the
product 5c was obtained in excellent yield. In other studies, all reactions were carried
ꢀ
out at 140 C in the presence of 15 mol% of [(CH ) SO HMIM][HSO ] under
2
4
3
4
solvent-free conditions.
To show the generality of this method, the optimized system was used for the
synthesis of other imidazoles derivatives with various aromatic aldehydes and
primary amines (Table 4). The yields obtained were good to excellent without
formation of any side products such as 2,4,5-trisubstituted imidazoles.
Although we did not investigate the reaction mechanism, based on Sharma
[
19]
et al.’s suggestion,
a plausible mechanism for the present reaction may proceed
as depicted in Scheme 3. The addition of nucleophiles to the aldehydes and
ketones is promoted by protonation of the carbonyl group using a Brønsted acid,
enhancing the electrophilicity of this moiety. Therefore, it may be proposed
that the [(CH ) SO HMIM][HSO ] ꢁ HA catalyst facilitates the formation of
2
4
3
4
diamine intermediate I by increasing the electrophilicity of the carbonyl group
of the aldehyde. This intermediate condenses with the activated benzil to form
Table 3. Synthesis of 2-(4-methylphenyl)-1,4,5-triphenyl-1H-imidazole 5c in
] (15 mol%) at different tempera-
tures in solvent-free conditions
the presence of [(CH
2
)
4
SO
3
HMIM][HSO
4
ꢀ
a
Entry
Temperature ( C)
Time (h)
Yield (%)
1
2
3
4
25
50
12
7
21
41
53
94
100
140
3
2
a
Isolated yields.

2592
A. DAVOODNIA ET AL.
Table 4. Synthesis of 1,2,4,5-tetrasubstituted imidazoles 5a–j
ꢀ
Mp ( C)
b
Time Yield
(h)
a
Entry
Ar
R
Products
(%) Found Reported Ref.
1
C
6
H
5
6 5
C H
2.5
88 213–215 216–218 20
2
C
6
H
5
CH
2
C
6
H
5
2
90 161–163 163–165 20
3
3
4-CH C
6
H
4
C
6
H
5
2
94 183–184 185–188 20
4
3
4-CH C
6
H
4
CH
2
C
6
H
5
2
91 163–165 165–166 20
5
3
4-CH C
6
H
4
4-CH
3
C
6
H
4
2
91 190–192 188–191 16
6
3
4-CH C
6
H
4
4-ClC
6
H
4
2
94 168–170 167–169 16
(
Continued )

SYNTHESIS OF 1,2,4,5-TETRASUBSTITUTED IMIDAZOLES
2593
Table 4. Continued
ꢀ
Mp ( C)
b
Time Yield
(h)
a
Entry
Ar
R
Products
(%) Found Reported Ref.
7
4-ClC
6
H
4
C
6
H
5
2
87 146–148 149–151 20
8
4-ClC
6
H
4
4-ClC
6
H
4
2
95 188–190 187–189 16
9
4-CH OC
3
6
H
4
CH
2
C
6
H
5
2.5
85 155–157 157–160 18
10
6
4-HOC H
4
CH
2
C
6
H
5
2.5
87 131–132 134–135 20
a 1
All the products were characterized by H NMR and IR spectral data and comparision of their melting
points with those of authentic samples.
b
Isolated yields.
the intermediate II, which can be converted to the desired product by dehy-
dration. In the absence of a primary amine and using the greater amount of
ammonium acetate, 2,4,5-trisubstituted imidazoles can be formed by a similar
[
19]
mechanism.
Reusability of the catalyst was also investigated. For this purpose, the model
reaction was again studied in the optimized conditions. After the completion of
the reaction, the catalyst was recovered (Experimental section) and reused for the
similar reaction. This process was carried out over three runs without appreciable
reduction in the catalytic activity of the catalyst.

2594
A. DAVOODNIA ET AL.
Scheme 3. Plausible mechanism for the formation of 1,2,4,5-tetrasubstituted imidazoles in the presence of
(CH SO HMIM][HSO
] ꢁ HA as catalyst.
[
2
)
4
3
4
CONCLUSION
In conclusion, we have reported here a new efficient catalyst for the synthesis
of tetrasubstituted imidazoles through the four-component condensation of
benzil, benzaldehyde derivatives, primary amines, and ammonium acetate using
[
(CH ) SO HMIM][HSO ], a Brønsted acidic IL. No organic solvent was used,
2 4 3 4
resulting in an ecofriendly process. The catalyst can be reused after a simple workup,
with a gradual decline of its activity being observed. Good yields, relatively short
reaction times, simplicity of operation, and easy workup are some advantages of
this protocol.
EXPERIMENTAL
All chemicals were commercially available and used without further purifi-
cation. The Brønsted acidic ionic liquid [(CH ) SO HMIM][HSO ] was synthesized
2
4
3
4
according to the literature. Melting points were recorded on an Electrothermal type
100 melting-point apparatus. The IR spectra were obtained on a 4300 Shimadzu
9
1
spectrophotometer as KBr disks. The H NMR (100-MHz) spectra were recorded
on a Bruker AC 100 spectrometer.
Preparation of Brønsted Acidic Ionic Liquid [(CH ) SO HMIM][HSO ]
2
4
3
4
A mixture of 1-methylimidazole (200 mmol) and 1,4-butane sultone (200 mmol)
was charged into a 150-mL conical flask. The mixture was stirred at room tempera-
ture for 4 days until it turned into solid. The white solid zwitterion that formed was
washed repeatedly with ether, filtered to remove nonionic residues, and dried in vac-
uum. Then, a stoichiometric amount of concentrated sulfuric acid (98%, 10.9 mL)
ꢀ
was added dropwise to the white solid zwitterion at 0 C. The mixture was stirred

SYNTHESIS OF 1,2,4,5-TETRASUBSTITUTED IMIDAZOLES
2595
ꢀ
ꢀ
at 80 C for 6 h. Product was washed with diethyl ether and dried in vacuo at 50 C
for 2 h to get the viscous clear [(CH ) SO HMIM][HSO ].
2
4
3
4
General Procedure for the Synthesis of Tetrasubstituted Imidazoles
A mixture of benzil (2 mmol), primary amine (2 mmol), aromatic aldehyde
2 mmol), ammonium acetate (2 mmol), and [(CH ) SO HMIM][HSO ] (15 mol%)
(
2
4
3
4
ꢀ
was heated on the oil bath at 140 C for 2–2.5 h. The reaction was monitored by
thin-layer chromatography (TLC). After completion of the reaction, the reaction
mixture was cooled to room temperature, and then water was added. The precipitate
was filtered off and recrystallized from ethanol to give compounds 5a–j in good to
excellent yields. All products were known and characterized by comparison of their
[
16,18,20]
physical and spectroscopic data with those already reported.
1
Selected H NMR Data
1
Compound 5b. H NMR (DMSO-d ) d: 5.15 (s, 2H, CH ), 6.65–7.65
6
2
(m, 20H, ArH).
1
Compound 5c. H NMR (DMSO-d ) d: 2.23 (s, 3H, CH ), 6.90–7.60
6
3
(m, 19H, ArH).
1
Compound 5d. H NMR (DMSO-d ) d: 2.35 (s, 3H, CH ), 5.14 (s, 2H, CH ),
6
3
2
6
.60–7.65 (m, 19H, ArH).
1
Compound 5i. H NMR (DMSO-d ) d: 3.76 (s, 3H, CH ), 5.13 (s, 2H, CH ),
6
3
2
6
.65–7.70 (m, 19H, ArH).
1
Compound 5j. H NMR (DMSO-d ) d: 5.12 (s, 2H, CH ), 6.65–7.60 (m, 19H,
6
2
ArH), 9.80 (br, 1H, OH).
Recycling of the Catalyst
The catalyst is soluble in water and therefore could be recycled. The catalyst
was recovered by evaporation of the water, washed with diethyl ether, and dried
ꢀ
at 50 C under vacuum for 1 h.
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