BF3·SiO2: an efficient reagent system for the one-pot synthesis of 1,2,4,5-tetrasubstituted imidazoles

Article abstract of DOI:10.1016/j.tetlet.2008.02.100

Silica-supported boron trifluoride (BF₃·SiO₂) is an efficient, readily available and reusable catalyst for the synthesis of 1,2,4,5-tetrasubstituted imidazoles using benzil, an aromatic aldehyde and an amine in the presence of ammonium acetate. This one-pot procedure is very simple, affording good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.02.100

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2575–2577
BF3ꢀSiO2: an efficient reagent system for the one-pot synthesis
of 1,2,4,5-tetrasubstituted imidazoles
Bahareh Sadeghi a, Bi Bi Fatemeh Mirjalili b,*, Mohammad M. Hashemi c
a Faculty of Chemistry, Islamic Azad University, Science and Research Branch, Tehran, Iran
b Department of Chemistry, College of Science, Yazd University, Yazd, PO Box 89195-741, Iran
c Department of Chemistry, Sharif University of Technology, PO Box 11365-9516, Tehran, Iran
Received 7 December 2007; revised 29 January 2008; accepted 18 February 2008
Available online 21 February 2008
Abstract
Silica-supported boron trifluoride (BF3ꢀSiO2) is an efficient, readily available and reusable catalyst for the synthesis of 1,2,4,5-tetra-
substituted imidazoles using benzil, an aromatic aldehyde and an amine in the presence of ammonium acetate. This one-pot procedure is
very simple, affording good to excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 1,2,4,5-Tetrasubstituted imidazoles; BF3ꢀSiO2; Benzil; One-pot synthesis; Aromatic aldehyde
Multi-component reactions (MCRs) have proved to be
remarkably successful in generating products in a single
synthetic operation.1 The developing of new MCRs,2 and
improving known multi-component reactions are an area
of considerable current interest. One such reaction, is the
synthesis of imidazoles. Tetrasubstituted imidazole is a
core section in many biological systems such as Losartan
and Olmesartan.3 The presence of an imidazole ring in
natural products and pharmacologically active compounds
has instituted a diverse array of synthetic approaches to
these heterocycles.4 However, despite intensive efforts, only
a handful of general methods exist for the construction of
tetrasubstituted imidazoles. Recently, the synthesis of
1,2,4,5-tetrasubstituted imidazoles has been catalyzed by
silica gel or Zeolite HY,5 silica gel/NaHSO4,6 molecular
iodine,7 K5CoW12O40ꢀ3H2O,8 heteropolyacids9 and
HClO4–SiO2.10
form of BF3 is a bench-top reagent which is easy to handle
with better accessibility of the reactants to the active sites.
When BF3ꢀOEt2, or BF3ꢀ2H2O is added to a reaction mix-
ture, particularly a protic medium, it can also function as a
Bro¨nsted acid. Exposure of high surface area oxides such as
Si–O–Si or Al–O–Al to BF3 at room temperature results in
irreversible adsorption. The resulting surfaces possess
surface species such as Al–OBF2, Si–OBF2, or the ion
+
pairs, Al–OBF3 H+ or Si–OBF3ꢁH . It has been claimed
ꢁ
that supported BF3 is a solid superacid. If the complex
BF3ꢀOEt2 in EtOH is used to prepare a silica-supported
BF3 catalyst, Bro¨nsted surface sites are obtained.11
BF3 has been used for the rearrangement of 4-sub-
stituted-5,5-diphenyl-azepan-4-ols,12 the Beckmann rear-
rangement,13 the reduction of aromatic azides with
EtSH,14 the alkylation of acetals with manganate
(R3MnLi),15 the synthesis of 2-substituted benzimidazoles
and 3,1,5-benzoxadiazepines,16 the conversion of alcohols
to azides with NaN3,17 the reduction of 4,6-o-benzylidenes
using triethylsilane,18 the polymerization of styrene,19 and
the synthesis of 20-o-cyanoethyluridine.20 In continuation
of our studies on solid acids in organic synthesis,21 we inves-
tigated the synthesis of 1,2,4,5-tetrasubstituted imidazoles
in the presence of various solid acids under thermal and sol-
BF3, as a strong Lewis acid, has been used in small and
large-scale reactions as an acid catalyst. In many synthetic
reports, BF3ꢀEt2O has been used. The silica-supported
*
Corresponding author. Tel.: +98 351 8211674; fax: +98 351 8210644.
E-mail address: fmirjalili@yazduni.ac.ir (B. B. F. Mirjalili).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.100

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B. Sadeghi et al. / Tetrahedron Letters 49 (2008) 2575–2577
22
O
vent-free conditions. Herein, we report that BF3ꢀSiO2 is
an efficient and reusable catalyst for the synthesis of
1,2,4,5-tetrasubstituted imidazoles and is comparable with
other catalysts such as K5CoW12O40ꢀ3H2O, HClO4–SiO2
and SiO2/NaHSO4. To optimize the reaction conditions,
the reaction of 4-methyl benzaldehyde, benzyl amine, benzil
and ammonium acetate was used as a model reaction (Table
1). Reactions at different temperatures and various molar
ratios of substrates in the presence of BF3ꢀSiO2 revealed
that the best conditions were solvent-free at 140 °C and a
molar ratio of aldehyde/amine/benzil/ammonium acetate/
BF3ꢀSiO2 (37% w/w) of 1:1:1:1:0.21. The reusability of the
BF3ꢀSiO2 catalyst was also examined. After each run,
CHCl3 was added and the product was filtered, the solvent
evaporated and the residue (catalyst) was washed with
CHCl3 and reused. Apparently, treatment with CHCl3
removes tars more efficiently from the catalyst surface
(Table 1, entries 17 and 18). This catalyst was reusable,
although a gradual decline in activity was observed.
Next, various aldehydes and amines were used as sub-
strates for the synthesis of 1,2,4,5-tetrasubstituted imid-
azoles (Scheme 1 and Table 2).23
O
O
Ph
Ph
Ph
37%
BF3.SiO2
N
+ RNH2 NH4OAc
+
+
Ar
H
Ar
Ph
solvent free
140 oC, 2 h
N
R
Scheme 1.
Table 2
BF3/SiO2-catalyzed synthesis of 1,2,4,5-tetrasubstituted imidazolesa
Entry
Ar
R
Yieldb (%)
Ref.
Mp °C
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
C6H5
C6H5
C6H5
C6H5
C6H5
89
80
85
87
96
82
92
85
82
92
92
83
87
92
93
10
8
5
5
7
10
10
7
10
9
5
5
5
10
10
216–218
163–165
167–169
115–117
149–151
162–165
140–142
280–281
134–135
185–188
165–166
162–164
122–124
128–130
152–155
C6H5CH2
Cyclohexyl
CH3CH2
C6H5
C6H5CH2
C6H5CH2
C6H5
4-ClC6H4
4-ClC6H4
2-ClC6H4
4-HOC6H4
4-HOC6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
3-MeOC6H4
2-O2NC6H4
C6H5CH2
C6H5
C6H5CH2
Cyclohexyl
CH3CH2
C6H5CH2
C6H5CH2
The products are known and were characterized by IR
1
and H NMR and through comparison of their physical
Ratio of benzil (mmol)/aldehyde (mmol)/amine (mmol)/ammonium
acetate (mmol)/catalyst (g) is 1:1: 1:1:0.08.
properties with those reported in the literature.
b
Isolated yield.
Table 1
Acid-catalyzed synthesis of 1-benzyl-4,5-diphenyl-2-p-tolyl-1H-imidazolea
In conclusion, we have demonstrated a simple method
for the synthesis of 1,2,4,5-tetrasubstituted imidazoles
using BF3ꢀSiO2 as a reusable, eco-friendly, inexpensive
and efficient reagent. Short reaction times, high yields, sim-
plicity of operation and easy work-up are some advantages
of this method.
NH2
CHO
N
N
NH4OAc
Catalyst
CH3
+
+
O
O
CH3
Entry Catalyst
Temp (°C)/time
(min)
Yieldb
(%)
Ref.
Acknowledgments
1
2
H4[PMo11VO40] (1 mol %)
K5CoW12O40ꢀ3H2O
(0.1 mol %)
78/14
140/120
MW/2
140/120
MW/12
140/6
90
95
97
92
96
90
85
70
55
53
50
60
30
73
85
80
89
92
85
9
8
8
6
6
10
5
—
—
—
—
—
—
—
—
—
—
—
—
The support for this study by the research affairs of
Science and Research Branch of Azad University, Yazd
University and Sharif University of Technology is grate-
fully acknowledged.
3
SiO2/NaHSO4 (0.4 g)
4
5
6
7
8
SiO2/HClO4 (1 mol %)
Zeolite HY (1 g)
ZnCl2 (21 mol %)
MW/6
140/120
140/120
140/120
140/120
140/120
25/300
70/240
140/120
140/120
140/120
140/120
140/120
SnCl2ꢀ2H2O (21 mol %)
References and notes
AlCl3 (21 mol %)
9
MgCl2 (21 mol %)
SnCl4 (21 mol %)
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33% BF3/SiO2 (14 mol %)
28% BF3/SiO2 (12 mol %)
37% BF3/SiO2 (16 mol %)
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2nd run
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22. Preparation of silica-supported BF3: 5 ml of methanol containing 0.6 g
(4.2 mmol) of BF3ꢀOEt2 and 0.4 g of unpreheated silica gel was stirred
for 1 h at room temperature. The slurry was dried slowly on a rotary
evaporator at 40 °C. The obtained solid was dried at ambient
temperature for 2 h and then stored in a dry container for at least 3
months.
23. General procedure for the synthesis of 1,2,4,5-tetrasubstituted imid-
azoles: Benzil (4 mmol), amine (4 mmol), aldehyde (4 mmol), ammo-
nium acetate (4 mmol) and BF3ꢀSiO2 (37% w/w) (0.32 g) were placed
in a round bottom flask. The reactants were mixed and heated at
140 °C for 2 h (Table 2). The progress of the reaction was followed by
TLC. After completion of the reaction, the mixture was cooled to
room temperature. Chloroform was added to the mixture which was
filtered to remove the catalyst. After evaporation of the solvent, an
oily residue or an impure solid was obtained. By adding ethanol and
water to the residue, a milky to yellow solid was obtained. The solid
was then crystallized from ethanol. All the products are known and
were identified by comparison of their physical and spectral data with
those of authentic samples.