Highly efficient, four component, one-pot synthesis of tetrasubstituted imidazoles using a catalytic amount of FeCl3 ? 6H2O

Article abstract of DOI:10.1007/s00706-007-0736-9

An efficient and improved procedure for the synthesis of tetrasubstituted imidazoles by FeCl₃ ? 6H₂O catalyzed four-component one-pot synthesis in refluxing ethanol is described.

Full text of DOI:10.1007/s00706-007-0736-9

Monatshefte f u¨ r Chemie 139, 31–33 (2008)
DOI 10.1007/s00706-007-0736-9
Printed in The Netherlands
Highly Efficient, Four Component, One-pot Synthesis of Tetrasubstituted
à
Imidazoles Using a Catalytic Amount of FeCl 6H O
3
2
ꢀ
Majid M. Heravi , Fatemeh Derikvand, and Masoumeh Haghighi
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
Received May 5, 2007; accepted (revised) May 29, 2007; published online November 14, 2007
#
Springer-Verlag 2007
Summary. An efficient and improved procedure for the syn-
thesis of tetrasubstituted imidazoles by FeCl ꢁ 6H O catalyzed
ditions [11]. In the classic approach for the synthesis
of tetrasubstituted imidazoles, cyclocondensations
proceed with low yields after many hours in reflux-
ing HOAc [9]. Other methods also need special
and complex reagents. Therefore the development
of clean, high-yielding, and environmentally friendly
approaches is still desirable and much in demand.
In recent years, the use of solid acid catalysts [12]
has received considerable importance in organic syn-
thesis because of their ease of handling, enhanced
reaction times, simple workup, and recoverability of
the catalysts.
3
2
four-component one-pot synthesis in refluxing ethanol is
described.
Keywords. Multi component reactions; Highly substituted
imidazoles; Ferric chloride.
Introduction
In recent years, considerable interest has been devot-
ed to finding a new methodology for the synthesis
of highly substituted imidazoles [1, 2]. These five-
membered heterocycles belong to an important class
of compounds due to their biological activities [3, 4].
Numerous methods for the synthesis of highly sub-
stituted imidazoles have been reported. Widely used
methods are: (a) condensation of diones, aldehydes,
primary amines, and ammonia [5]; (b) N-alkylation
of trisubstituted imidazoles [6]; (c) condensation of
benzoin or benzoin acetate with aldehydes, primary
amines, and ammonia in the presence of copper
acetate [7]; (d) cyclization of sulfonamides with
mesoionic 1,3-oxazolium-5-olates [8]; (e) four-com-
ponent condensations of diones, aldehydes, primary
amines, and ammonium acetate in refluxing acetic
acid [9]; (f) condensation of ꢀ-carbonyl-N-acyl-N-
alkylamines with ammonium acetate in refluxing
HOAc [10]; and (g) conversion of N-(2-oxo)amides
with ammonium trifluoroacetate under neutral con-
Following our previous work on the synthesis of
tri=tetrasubstituted imidazoles [13, 14], in view of
the importance of solid acids as reusable catalysts
in organic synthesis, and in continuation of our work
on catalytic properties of solid acids [15–25] here
we report the four-component condensation of ben-
zil, benzaldehyde derivatives, primary amines, and
ammonium acetate catalyzed by FeCl ꢁ 6H O, as
3
2
an efficient and facile one-pot synthesis of tetrasub-
stituted imidazoles (Scheme 1).
Results and Discussion
The synthesis is based on the condensation of benzil
(
1) with aldehydes (2) and amines (3) resulting in
,2,4,5-substituted imidazoles using ammonium ac-
1
etate (4) as the ammonia source and FeCl ꢁ 6H O as
3
2
the catalyst (Scheme 1). The multi-component na-
ture of the synthesis of 1,2,4,5-substituted imida-
ꢀ Corresponding author. E-mail: mmh1331@yahoo.com

3
2
M. M. Heravi et al.
Scheme 1
zoles together with the existence of a wide variety of
commercially available aldehydes and amines makes
this reaction an ideal candidate for the combinatorial
synthesis technology.
that ethanol was the most suitable solvent for the
synthesis of 5a, and therefore it was used in all sub-
sequent experiments.
The effect of temperature was studied by carry-
ing out both reactions at different temperatures
Preliminary optimization of reaction conditions
was done using the pair benzil=benzaldehyde and
ꢂ
(room temperature, 45, and 78 C). It was observed
1
2
benzylamine (R ¼ R ¼ Ph). Comparison of two sol-
(Table 2) that yield is a function of temperature and
it was increased as the reaction temperature was
raised. Thus, in the subsequent studies all reactions
were carried out using refluxing ethanol.
The optimal conditions were then applied for the
preparation of a series of 1,2,4,5-substituted imi-
dazoles 5a–5h. The product yields are shown in
Table 3. The results show that this method provides
an efficient way to access diverse, highly functiona-
lized imidazoles.
vents and solvent-free conditions (Table 1) showed
Table 1. Synthesis of 1,2,4,5-tetraphenylimidazole (5a) in
the presence of FeCl ꢁ 6H O in different solvents
3
2
ꢂ
a
Entry
Solvent (T= C)
t=min
Yield=%
1
2
3
EtOH (78.3)
CHCl (61)
solvent-free (70)
90
180
180
80
75
70
3
a
Yields were determined by GC
As could be expected, FeCl ꢁ 6H O is not soluble
3
2
in ethanol and all of the reactions are heterogeneous-
ly catalyzed, so it could be easily recovered by a
simple filtration and reused in another reaction after
washing with chloroform.
Table 2. Synthesis of 1,2,4,5-tetraphenylimidazole (5a) in
the presence of FeCl ꢁ 6H O in ethanol and at different
3
2
temperatures
Entry
ꢂ
a
In order to show the advantages of FeCl ꢁ 6H O
3
2
T= C
t=min
Yield=%
as a catalyst in this reaction, the obtained results
for 1-(2-naphtyl)-2,4,5-triphenylimidazole (5h) were
compared with those obtained in refluxing ethanol
and refluxing acetic acid [9] without any catalyst,
and results are summarized in Table 4.
1
2
3
25
45
78
90
90
90
60
70
80
a
Yields were determined by GC
Table 3. Synthesis of tetrasubstituted imidazoles using a catalytic amount of FeCl ꢁ 6H O
3
2
a
ꢂ
Product
Ar
R
t=min
Yield=%
mp= C
Found
Reported [Ref.]
5
5
5
a
b
c
Ph
Ph
Ph
Me
Ph
PhCH2
Me
Ph
PhCH2
Me
Ph
40
90
60
90
40
60
90
90
95
80
98
80
98
90
80
85
144–145
218
165
221–223
189
165–166
201–202
244
143–144 [26]
216–218 [26]
158–160 [26]
218–220 [26]
185–188 [26]
165–166 [26]
199–200 [26]
240–241 [9]
5
d
4-MePh
4-MePh
4-MePh
4-BrPh
2-naphtyl
5
5
e
f
g
5
5
h
a
Yields were determined by GC

One-pot Synthesis of Tetrasubstituted Imidazoles
33
Table 4. Comparison of the synthesis of 1-(2-naphtyl)-2,4,5-
triphenylimidazole (5h) under different conditions
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JL, Young PR (1994) Nature 372: 739
Entry
Solvent (catalyst)
t=h Yield=%
Ref.
1
2
3
AcOH
EtOH
2
5
45
[9]
this work
this work
a
60
80
a
[5] Stoeck V, Schunack W (1974) Arch Pharmaz 307: 922
EtOH (FeCl ꢁ 6H O) 1.5
3
2
[
[
[
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: 319
7] Stoeck V, Schunack W (1976) Arch Pharmaz 309:
21
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J Chem Res (S) 188: 7
a
2
Yields were determined by GC
4
Experimental
Melting points were measured by using the capillary tube
1
method with an electro thermal 9200 apparatus. H NMR
[9] Schubert H, Stodolka H (1963) J Prakt Chem 22: 130
[10] Evans DA, Lundy KM (1992) JAm Chem Soc 114: 1495
[11] Claiborne CF, Liverton NJ, Nguyen KT (1998) Tetrahe-
dron Lett 39: 8939
[12] Wilson K, Clark JH (2000) Pure Appl Chem 72: 1313
[13] Oskooie HA, Alimohammadi Z, Heravi MM (2006)
Heteroatom 17: 699
spectra were recorded on a Bruker AC-80 MHz spectrometer
using TMS as an internal standard (CDCl solution). IR spec-
3
tra were recorded from KBr disk on the FT-IR Bruker Tensor
2
7. GC spectra were carried out on a Network GC System-
Agilent 5973 spectrometer. All products were known and
characterized by comparison of their physical and spectro-
scopic data with those already reported [26].
[14] Heravi MM, Derikvand F, Bamoharram FF (2007) J Mol
Catal A: Chem 263: 112
Synthesis of Tetrasubstituted Imidazoles: General Procedure
A mixture of 10 mmol benzil, 10mmol amine, 10mmol alde-
hyde, 10 mmol ammonium acetate, and 5 mol% FeCl ꢁ 6H O
[15] Heravi MM, Derikvand F, Bamoharram FF (2005) J Mol
Catal A: Chem 242: 173
[
[
[
[
[
[
[
[
[
16] Heravi MM, Taheri Sh, Bakhtiari Kh, Oskooie HA
3
2
3
(2007) Catal Commun 8: 211
was refluxed in 10cm ethanol. After completion of the reac-
tion (monitored by TLC) the mixture was filtered to separate
the catalyst, then cooled to room temperature, and the precipi-
tated products were separated by filtration. The resulting solid
residue was purified by recrystallization from EtOH.
The recycled catalyst could be washed with chloroform and
reused in another reaction. Such procedure applied for 5a in a
second run resulted in 75% yield.
17] Heravi MM, Behbahani FK, Bamoharram FF (2006)
J Mol Catal A: Chem 253: 16
18] Bamoharram FF, Heravi MM, Roshani M, Tavakoli N
(
2006) J Mol Catal A: Chem 252: 219
19] Heravi MM, Ranjbar L, Derikvand F, Bamoharram FF
2007) Catal Commun 8: 289
(
20] Oskooie HA, Heravi MM, Bakhtiari K, Zadsirjan V,
Bamoharram FF (2006) Synlett 11: 1768
21] Heravi MM, Behbahani FK, Oskooie HA, Shoar RH
(2005) Tetrahedron Lett 46: 2775
22] Heravi MM, Ranjbar L, Derikvand F, Bamoharram FF
Acknowledgements
The authors are grateful for the partial financial support from
Azzahra Research Council.
(2007) Catal Commun 8: 289
23] Heravi MM, Derikvand F, Bamoharram FF (2006) Synth
Commun 36: 3109
24] Oskooie HA, Heravi MM, Derikvand F, Khorasani M,
Bamoharram FF (2006) Synth Commun 36: 2819
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