Tri(1-butyl-3-methylimidazolium) gadolinium hexachloride, ([bmim]3[GdCl6]), a magnetic ionic liquid as a green salt and reusable catalyst for the synthesis of tetrasubstituted imidazoles

Article abstract of DOI:10.1016/j.tetlet.2015.12.053

The magnetic ionic liquid, tri(1-butyl-3-methylimidazolium) gadolinium hexachloride, ([bmim]₃[GdCl₆]), has been used as an efficient green catalyst for the one-pot synthesis of 1,2,4,5-tetrasubstituted imidazoles via the condensation of benzil, an aromatic aldehyde, aniline, and ammonium acetate. Good to excellent yield, mild reaction conditions, as well as ease of operation and work-up are some advantages of the protocol.

Full text of DOI:10.1016/j.tetlet.2015.12.053

Accepted Manuscript
Tri(1-butyl-3-methylimidazolium) gadolinium hexachloride,
([bmim]3[GdCl6]), a magnetic ionic liquid as a green salt and reusable catalyst
for the synthesis of tetrasubstituted imidazoles
Ali Akbari
PII:
S0040-4039(15)30468-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.053
TETL 47100
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 April 2015
29 November 2015
9 December 2015
Please cite this article as: Akbari, A., Tri(1-butyl-3-methylimidazolium) gadolinium hexachloride,
([bmim]3[GdCl6]), a magnetic ionic liquid as a green salt and reusable catalyst for the synthesis of tetrasubstituted
imidazoles, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.053
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Tri (1-butyl-3-methylimidazolium)
gadolinium hexachloride, ([bmim]3[GdCl6]),
a magnetic ionic liquid as a green salt and
reusable catalyst for the synthesis of
tetrasubstituted imidazoles
Ali Akbari

1
Tetrahedron Letters
journal homepage: www.els evier.com
Tri(1-butyl-3-methylimidazolium) gadolinium hexachloride, ([bmim]3[GdCl6]), a
magnetic ionic liquid as a green salt and reusable catalyst for the synthesis of
tetrasubstituted imidazoles
Ali Akbari ∗
a
Department of Chemistry, Faculty of Science, University of Jiroft, Jiroft, P. O. Box 8767161167, Iran.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The magnetic ionic liquid, tri(1-butyl-3-methylimidazolium) gadolinium hexachloride,
([bmim]3[GdCl6]), has been used as an efficient green catalyst for the one-pot synthesis of
1,2,4,5-tetrasubstituted imidazoles via the condensation of benzil, an aromatic aldehyde, aniline
and ammonium acetate. Good to excellent yield, mild reaction conditions, as well as ease of
operation and work-up are some advantages of the protocol.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Magnetic ionic liquid
Tri (1-butyl-3-methylimidazolium) gadolinium
hexachloride,
Imidazoles,
Green process
———
∗ Corresponding author: Tel.: +98-348-326-0061; fax: +98-348-326-0065; E-mail: a.akbari@ujiroft.ac.ir

2
Tetrahedron Letters
1. Introduction
Imidazole derivatives have a wide range of biological
activities and are used as anti-inflammatory,1,2 antipyretic,3
Figure 1. Chemical structure of [bmim]3[GdCl6].
antidepressant,4 antibacterial,5-7 anticonvulsant,8 antitumor,9-12
16, 17
anticancer,13-15 antimicrobial,3,
antimalarial,18 antiviral,19
herbicide,20 pesticide,21 antifungal6, 22, 23 and antioxidant agents.24-
26 A number of methods have been developed for the synthesis of
To the best of our knowledge, ([bmim]3[GdCl6]) has not been
used as
a
catalyst in organic synthesis.
A
one-pot
1,2,4,5-tetrasubstituted imidazoles.27
Generally,
1,2,4,5-
multicomponent reaction for the synthesis of tetrasubstituted
imidazoles catalyzed by ([bmim]3[GdCl6]) in excellent yields is
reported herein.
tetrasubstituted imidazoles are synthesized by the four-
component condensations of a 1,2-diketone derivative with an
aldehyde, primary amine, and ammonium acetate employing
various Lewis acid catalysts, polymer-supported catalysts, zeolite
supported reagents, microwave irradiation and ionic liquids.28,29
However, there still remains the necessity of finding new
methods. Ionic liquids (ILs) have recently attracted increased
interest in the context of green organic synthesis.30,31 Although
ionic liquids were initially introduced as an alternative green
reaction media because of their unique chemical and physical
properties of nonvolatility, nonflammability, thermal stability,
and controlled miscibility, they have since moved beyond this,
showing a significant role in controlling reactions as solvent or
catalysts.32-37 Ionic liquids are used in both homogeneous and
heterogeneous catalysts as well as transition metal-mediated
catalysts in organometallic reactions.38,39 Due to the high
reactivity of ionic liquids, they are also applied as solvents in
organic and bio-organic reactions.40,41 Magnetic ionic liquids
(MILs) are one group of room temperature ionic liquids (RTILs)
which show new magnetic properties with a wide range of
applications. The facile separation of MILs from the reaction
media by an external magnet make them more practical than
conventional ILs.44 Del Sesto and co-workers45,46 have described a
large variety of MILs with iron, Fe(III), cobalt, Co(II),
manganese, Mn(II) and gadolinium, Gd(III)-containing anions.
Furthermore, the incorporation of lanthanide ions into MILs
offers the advantage of a metal ion that has a considerably higher
effective magnetic moment than transition metals.47 Tri(1-butyl-
2. Results and discussion
Initially, the reaction was investigated by reacting benzil 1 (5
mmol), benzaldehyde 2a (5 mmol), benzylamine 3a (5 mmol),
ammonium acetate 4 (5 mmol) and the magnetic ionic liquid
([bmim]3[GdCl6]) (1 mmol) under solvent-free conditions. This
mixture was stirred at room temperature for 5 h which provided
the desired 1,2,4,5-tetrasubstituted imidazole 5a in 60% yield.
When the reaction was performed at an elevated temperature (60
°C), complete conversion of the starting material to the desired
product in 75% yield was achieved within 5 h, while at 120 °C
the reaction was complete within 2 h in 90% yield. To optimise
the reaction conditions, the temperature, and catalyst loading
were then examined (Table 1). It was observed that in the
absence of catalyst, the product was only detected by TLC (Table
1, entry 12). Although the reaction proceeded in solvents, the
obtained yields were lower (Table 1, entries 9-11). It was found
that the best conditions were 0.75 mmol of the magnetic ionic
liquid under solvent-free conditions at 120 °C for 2 hours (Table
1, entry 6).
3-methylimidazolium)
gadolinium
hexachloride,
([bmim]3[GdCl6]), is a representative of this class of ionic liquids
(Figure 1).
Figure 2. Reaction scope
Table 1. Optimization of the reaction conditions a
Entry
Catalyst (mol%)
4 (mmol)
Temp. (°C)
25
60
Solvent
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Ethanol
Toluene
Ethyl acetate
Neat
Neat
Neat
Time (h)
Yieldb (%)
60
75
81
90
94
93
89
76
74
55
77
trace
93
93
92
92
1
2
3
4
5
6
7
8
[bmim]3[GdCl6] (20)
[bmim]3[GdCl6] (20)
[bmim]3[GdCl6] (20)
[bmim]3[GdCl6] (20)
[bmim]3[GdCl6] (20)
[bmim]3[GdCl6] (15)
[bmim]3[GdCl6] (10)
GdCl3.6H2O (15)
[bmim]3[GdCl6] (15)
[bmim]3[GdCl6] (15)
[bmim]3[GdCl6] (15)
None
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (7)
NH4OAc (7)
NH4OAc (7)
NH4OAc (7)
NH4OAc (7)
NH4OAc (7)
NH4OAc (7)
NH4OAc (7)
NH4OAc (7)
NH4OAc (7)
NH4OAc (7)
NH4OAc (7)
5
5
5
2
2
2
2
2
5
5
5
5
2
2
2
2
90
120
120
120
120
120
80
9
10
11
12
13
14
15
16
115
80
120
120
120
120
120
[bmim]3[GdCl6] (15) 2nd run
[bmim]3[GdCl6] (15) 3nd run
[bmim]3[GdCl6] (15) 4nd run
[bmim]3[GdCl6] (15) 5nd run
Neat
Neat
a Reaction conditions: 1a (5 mmol), 2a (5 mmol), 3a (5 mmol) and ammonium acetate were heated with stirring, with varying catalyst
loading, either in solvent or under solvent-free conditions.
b Isolated yield.
A tentative mechanism for this multicomponent reaction was
proposed (Figure 3). Initially the counter-cation, bmim+, of the
ionic liquid, [bmim]3[GdCl6], acts as a Lewis acid, catalysing the
condensation of the NH2 group of substrate 2 with the carbonyl
group of aldehyde 1 to furnish intermediate 3. The ionic liquid
also acts as a Lewis acid, catalysing the condensation of the NR2
group of substrate 4 with the carbonyl group of 1,2-dicarbonyl 5
to furnish intermediate 6, and catalyses the condensation of the
NH2 group of substrate 6 with the carbonyl group to furnish
intermediate 7. In the next step, the reaction can also proceed in
an E1 like fashion (7), with the elimination of oxygen occurring
at the same time as the counter-anion deprotonates the nitrogen
so it can form a new N=C bond, forming the imine which after
tautomerism gives 9.

3
c-hex
11
12
2c
2c
3c
2.0
2.0
90
Ph
Ph
N
p-Cl-C6H4
N
3d
9151
a benzil (5 mmol), aldehyde (5 mmol), amine (5 mmol), ammonium acetate (7
mmol), [bmim]3[GdCl6] (0.75 mmol), 120°C, 2 h.52
b Isolated yield.
The recyclability of the catalyst was also studied in the
synthesis of 1,2,4,5-tetrasubstituted imidazoles 5a under the
optimized conditions. The recycled catalyst could be reused 5
times without appreciable loss in the catalytic activity of
magnetic ionic liquid (Table 1, entry 13-16).
Figure 3. Plausible mechanism for the formation of
Conclusions
tetrasubstituted imidazoles
An efficient, solvent-free, one-pot, multicomponent reaction,
catalyzed by
a
magnetic ionic liquid, tri(1-butyl-3-
methylimidazolium) gadolinium hexachloride was described for
the synthesis of 1,2,4,5-tetrasubstituted imidazoles derivatives.
The catalyst could be readily separated by use of magnetic force
and reused without any significant loss of catalytic activity after
5 runs. This method offers several advantages including good to
excellent yield, short reaction time, mild reaction condition,
simple work-up procedure, ease of separation, green process, and
recyclability of the magnetic catalyst, as well as the ability to
tolerate a wide variety of substitution in the starting materials.
The suitability of this method was investigated for several
aromatic aldehydes and amines (Table 2). It was clearly observed
that substitution of the aldehyde did not appreciably affect the
yield of the desired product. In all cases, the products were
characterized by 1H and 13C NMR, FT–IR and CHN analyses.
Table 2. Synthesis of tetra substituted imidazole derivativesa
Entry
Reactant
Product 5
Time
(h)
Yieldb
(%)
9448
1
2a
3a
3b
3c
2.5
Acknowledgements
The financial support of this project by University of Jiroft is
appreciated.
2
3
2a
2a
2.5
2.5
9549
9149
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General procedure for the synthesis of 1,2,4,5-
tetrasubstituted imidazoles: Benzil (5 mmol), aldehyde (5 mmol),
amine (5 mmol), ammonium acetate (7 mmol), and the magnetic
ionic liquid ([bmim]3[GdCl6]) (0.75 mmol) were added to a round
bottom flask. This mixture was heated at 120 °C for 2 h. After
reaction completion, EtOAc (20 mL) was added to the reaction
mixture. The magnetic ionic liquid was magnetically separated from
the product solution, washed with EtOAc (20 mL), and used for
subsequent reactions after drying under vacuum at 45 °C for 6 h.
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