A solvent-free synthesis of 1,2,4,5-tetrasubstituted imidazoles using molecular iodine as catalyst

Article abstract of DOI:10.3184/030823410X12659021476402

An efficient method for the synthesis of 1,2,4,5-tetrasubstituted imidazoles by three-component condensation of benzil, benzonitrile derivatives and primary amines under solvent-free conditions using molecular iodine as catalyst is described with high product yields. The significant features of the iodine-catalysed condensation are operational simplicity, inexpensive reagents, high yield of products and use of non-toxic reagents.

Full text of DOI:10.3184/030823410X12659021476402

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 133
MARCH, 133–134
A solvent-free synthesis of 1,2,4,5-tetrasubstituted imidazoles using
molecular iodine as catalyst
Yi-Ming Rena* and Chun Caib
aDepartment of Biochemical Engineering, Anhui University ofTechnology and Science, Wuhu, 241000, P. R. China
bChemical Engineering College, Nanjing University of Science &Technology, Nanjing, 210094, P. R. China
An efficient method for the synthesis of 1,2,4,5-tetrasubstituted imidazoles by three-component condensation of
benzil, benzonitrile derivatives and primary amines under solvent-free conditions using molecular iodine as catalyst
is described with high product yields. The significant features of the iodine-catalysed condensation are operational
simplicity, inexpensive reagents, high yield of products and use of non-toxic reagents.
Keywords: molecular iodine, 1,2,4,5-tetrasubstituted imidazoles, solvent-free
Imidazoles are very useful intermediates for the development
of molecules of pharmaceutical or biological interest. Differ-
ent substituted imidazole derivatives show variable biological
activities such as antiulcer, antihypertensive, antiviral, anti-
allergic, antifungal, anticancer, and antihistaminic.1–7 Due to
their wide range of pharmacological activity and industrial and
synthetic applications, a number of methods have been reported
for the synthesis of highly substituted imidazoles, which
include the condensation of β-carbonyl-N-acyl-N-alkylamines
with ammonium acetate in refluxing HOAc;8 three-component
condensation of benzil or benzoin with aldehydes and ammo-
nium acetate;9–11 four-component condensation of benzil or
benzoin, aldehydes, amines and ammonium acetate;12–15 1,2-
amino alcohols in the presence of PCl ;16 and conversion
of N-(2-oxo)amides with ammonium tri5fluoroacetate under
neutral conditions.17 However, many of the synthetic protocols
reported so far suffer from disadvantages, such as needing
use of organic solvents, harsh reaction conditions, prolonged
reaction times, use of metals and expensive reagents, etc.
Previously, Balalaie, S. and co-workers had reported a novel
one-pot synthesis of 1,2,4,5-tetrasubstituted imidazoles from
three-component condensation of benzil, benzonitrile and
primary amine on the surface of silica gel under solvent-free
conditions and microwave irradiation.18 But a microwave irra-
diation process was difficult to apply in the industrial process
until now.
With the increasing public concern over environmental
degradation, the use of environmentally benign solvents like
water and solvent-free reactions represent very powerful green
chemical technology procedures from both the economical
and synthetic point of view. Recently, solvent-free has been
proven to be an efficient medium for synthesis of highly
substituted imidazoles.12,13,19
In recent years, the usage of molecular iodine has drawn
considerable attention as an inexpensive, nontoxic, readily
available catalyst for various organic transformations to
afford the corresponding products in excellent yields with high
selectivity. The mild Lewis acidity associated with iodine
enhances its usage in organic synthesis to realise several
organic transformations using stoichiometric levels to catalytic
amounts. Owing to numerous advantages associated with this
eco-friendly element, iodine has been explored as a powerful
catalyst for various organic transformations.20–28 Given the
large number of similar condensation reactions that have
been reported to proceed readily under solvent-free con-
ditions,19,29–31 we proceeded to examine the synthesis of 1,2,4,5-
tetrasubstituted imidazoles by three-component condensation
of benzil, benzonitrile derivatives and primary amines in
the presence of a catalytic amount of molecular iodine under
solvent-free conditions.
Initially, the synthesis of 1-benzyl-2,4,5-triphenylimidazole
4a was explored in order to search for the optimal conditions.
The reactions were carried out under solvent-free conditions
(Table 1). Table 1 showed that the appropriate amount of I2 for
synthesis of 1-benzyl-2,4,5-triphenylimidazole was 10 mol%
to benzil, A longer reaction time would be necessary and
lower yield was obtained with less I2. And the reaction yields
and rates were not increased when a larger amount of I2 was
employed. However, in the absence of iodine, few products
were synthesised even after 5h (Table 1, entry 1). The reaction
temperature has also a great influence on the reaction. A low
yield was obtained when it was carried out at room tempera-
ture. Increasing the reaction temperature could remarkably
enhance both reaction yield and rate. The reaction could
be completed within 1h with a high yield (85%) at 100 °C
(Table 1, entry 3).
To generalise our reagent system, the products 4a–f were
synthesised from the three-component condensation of benzil,
benzonitrile derivatives and primary amines (Table 2). It was
found that primary aliphatic amines reacted efficiently with
benzil and benzonitrile derivatives promoted by I2 within 1h.
However, the reaction failed to proceed with aniline deriva-
tives under the same reaction conditions (Table 2, entries 7, 8
and 9), this may be due to the conjugated Schiff base formation
by aniline and carbonyl derivatives making difficult further
reaction with the benzonitrile derivatives. And a plausible
reaction pathway for the reation is not clear.18
In conclusion, the present synthetic method is a simple,
inexpensive, effective and green synthesis of 1,2,4,5-
tetrasubstituted imidazoles. The advantages of the present
method are the elimination of the metals, organic solvents and
toxic reagents, operational simplicity and high yields of prod-
ucts. Further study on the synthetic application of the present
reaction is now in progress.
Table 1 Studies on the synthesis of 1-benzyl-2,4,5-
triphenylimidazolea
Entry
Iodine/mol%
T/°C
Time/min
Yield/%b
1
2
3
4
5
6
7
8
9
0
5
100
100
100
100
RT
300
120
60
15
80
85
85
10
53
67
85
85
10
20
10
10
10
10
10
60
300
120
120
60
80
90
100
110
60
aProduct 1-benzyl-2,4,5-triphenylimidazole from 1 equiv benzil:
1.5 equiv benzyl amine: 1.5 equiv benzonitrile; The reactions
were accomplished in 100 °C under solvent-free conditions.
bIsolated yields.
* Correspondent. E-mail: yimingren@auts.edu.cn

134 JOURNAL OF CHEMICAL RESEARCH 2010
Table 2 I2 catalysed solvent-free synthesis of 1,2,4,5-
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Received 25 December 2009; accepted 8 February 2010
Paper 090928 doi: 10.3184/030823410X12659021476402
Published online: 22 March 2010

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