Room temperature synthesis of tri-, tetrasubstituted imidazoles and bis-analogues by mercaptopropylsilica (MPS) in aqueous methanol: application to the synthesis of the drug trifenagrel

Article abstract of DOI:10.1016/j.tetlet.2010.05.102

The heterogeneous solid catalyst, mercaptopropylsilica (MPS), has been prepared by a modified procedure in water and its structure confirmed by solid state carbon-13 CP-MAS NMR spectrum. This catalyst has been efficiently utilized for the synthesis of a w

Full text of DOI:10.1016/j.tetlet.2010.05.102

Tetrahedron Letters 51 (2010) 3944–3950
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Room temperature synthesis of tri-, tetrasubstituted imidazoles
and bis-analogues by mercaptopropylsilica (MPS) in aqueous methanol:
application to the synthesis of the drug trifenagrel
a
b
Chhanda Mukhopadhyay a, , Pradip Kumar Tapaswi , Michael G. B. Drew
*
a Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009, India
b Department of Chemistry, The University, Whiteknights, Reading RG 6 6AD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The heterogeneous solid catalyst, mercaptopropylsilica (MPS), has been prepared by a modified proce-
dure in water and its structure confirmed by solid state carbon-13 CP-MAS NMR spectrum. This catalyst
has been efficiently utilized for the synthesis of a wide variety of tri-, tetrasubstituted imidazoles and
their bis-analogues at room temperature. The protocol was further explored for the synthesis of the drug
trifenagrel.
Received 17 April 2010
Revised 20 May 2010
Accepted 22 May 2010
Available online 27 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Mercaptopropylsilica (MPS)
Heterogeneous catalyst
Recyclable
Room temperature
2,4,5-Tri- and 1,2,4,5-tetrasubstituted
imidazoles
Aqueous methanol
Bis-imidazoles
Trifenagrel
1. Introduction
2. Results and discussion
A major area of research in present organic synthesis is the
application of solid catalysts in generating environmentally benign
methodologies which prove highly advantageous for both acade-
mia and industry.1 Although a number of solid catalysts have been
developed for varieties of useful synthetic transformations, a
majority of them possess several drawbacks including long hours
of reaction and rough reaction protocols. In addition, most of these
methodologies are sensitive towards moisture and not recoverable.
Such problems can be easily overcome by switching over to silica
chain possessing covalently anchored organic spacer to produce
organic–inorganic hybrid catalysts. In such catalysts, the reactive
centres are highly mobile similar to homogeneous catalysts, in
addition, possessing the recyclability like the heterogeneous cata-
lysts. On this basis, we decided to utilize a silica-bonded solid acid
catalyst preparing it by a modified procedure maintaining a green
protocol for the construction of a very important organic heterocy-
cle, the substituted imidazoles and bis-imidazoles.
In continuation of our studies on the synthesis of various phar-
macologically important chromophores,1c we chose the substi-
tuted imidazoles as it is a core molecule in many biological
systems such as biotin, histamine, histidine as well as active com-
ponent in potential drug molecules such as trifenagrel2 (Fig. 1) and
several pesticides.3 Various substituted imidazoles possess anti-
allergic,4 analgesic5 and anti-inflammatory activities.6 Of particular
interest is the 4,5-diaryl imidazoles which act as potential inhibi-
tors of p38 MAP kinase,7 B-Raf kinase, transforming growth factor
b1 (TGF-b1), type 1 activin receptor-like kinase (ALK-5) and cyclo-
oxygenase-2 (COX-2). This moiety is also a significant intermediate
in the biosynthesis of interleukin-1 (IL-1).8
N
N
O
N
H
* Corresponding author. Tel.: +91 33 23371104; fax: +91 33 23519755.
E-mail address: cmukhop@yahoo.co.in (C. Mukhopadhyay).
Figure 1. Trifenagrel.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.102

C. Mukhopadhyay et al. / Tetrahedron Letters 51 (2010) 3944–3950
3945
a
c
a
c
O
O
SH
(1)
OH
OH
OH
(MeO)3Si
SiO2
b
Si
SiO2
SH
b
O
water, reflux, 10 h
(2)
(MPS)
Scheme 1. Preparation of the catalyst: mercaptopropylsilica (MPS) (2) in water.
Recent advancements in organometallic catalysis and green
chemistry have extended the applicability of substituted imidazoles
as ionic liquids.9 Such wide applicability of tetrasubstituted imida-
zoles, in particular the 4,5-diaryl ones, triggered us to undertake
the synthesis of these systems. The existing methodologies for the
synthesis of the tetrasubstituted imidazoles are mostly multi-step
processes or derived from trisubstituted 1H-imidazole.5 The impor-
tant point that needs mentioning is that all the earlier reported
methods for the synthesis of the tetrasubstituted imidazoles require
high temperatures with catalysts such as ionic liquids,10 acetic
3
4
N
MPS (5 mg)
O
O
R
2
R
NH4OAc
O
1
+
+
N
H2O + MeOH (2+2mL)
room temperature
H
5
H
3
4
5
6
*
Scheme 2. Synthesis of 2,4,5-trisubstituted imidazoles with MPS (5 mg) per mmol
of starting aldehyde.
Table 1
Synthesis of 2,4,5-trisubstituted imidazoles at room temperature
Entry
1
Products (6)
Time (h)
2
Yield (%) (isolated)
65
Reference
20
N
H3C
H3C
N
H
OCH3
OCH3
N
H3C
H3C
2
3
2.5
61
92
—
N
H
N
NO2
3
21
N
H
H3CO
N
4
5
6
7
8
3
3
3
3
3
90
88
90
96
56
—
N
H
OCH3
N
CN
—
N
H
N
17
—
N
H
NO2
N
N
H
O
OH
N
CH3
18
N
H
Reaction conditions: aldehyde (1 mmol), benzil (1 mmol), ammonium acetate (3 mmol) and catalyst MPS (5 mg) in (water + methanol) (2 + 2 mL) at rt.

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C. Mukhopadhyay et al. / Tetrahedron Letters 51 (2010) 3944–3950
R1
R1
3
2' 3'
MPS (5 mg)
4
5
N
R2
2
O
O
+
1'
NH4OAc
+
+
1
4'
5'
H2O+MeOH (1:1)
room temperature
N
6'
1a
NH2
H
O
6a
2a
3
R2
5
4
7
3a
5a
4a
8
Scheme 3. Synthesis of 1,2,4,5-tetrasubstituted imidazoles.
Table 2
Synthesis of 1,2,4,5-tetrasubstituted imidazoles with MPSa at room temperature
Entry
Products
Time (h)
Yield (%) (isolated)
Reference
H3C
N
N
Br
Br
H3C
1
4
65
—
Cl
N
H3C
H3C
N
2
4
68
—
CH3
N
N
Cl
3
5
89
—
Cl
N
N
Br
4
5
6
5
6
7
89
92
91
—
—
—
Cl
N
N
N(CH3)2
Cl
OCH3
OCH3
N
N
Cl

C. Mukhopadhyay et al. / Tetrahedron Letters 51 (2010) 3944–3950
3947
Table 2 (continued)
Entry
Products
Time (h)
Yield (%) (isolated)
Reference
OCH3
N
N
OCH3
7
8
9
6
92
—
—
—
OCH3
OCH3
N
N
OCH3
6
93
CH3
N
N
N(CH3)2
5
92
CH3
N
Br
N
10
4
87
—
Cl
Cl
N
N
11
12
13
5
90
84
85
—
Cl
N
N
4
—
NO2
Cl
N
N
NO2
4
—
Cl
(continued on next page)

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C. Mukhopadhyay et al. / Tetrahedron Letters 51 (2010) 3944–3950
Table 2 (continued)
Entry
Products
Time (h)
Yield (%) (isolated)
Reference
N
N
N(CH3)2
14
5
92
—
Cl
N
N
15
6
89
—
CHO
Cl
a
Reaction conditions: aldehyde (1 mmol), benzil (1 mmol), aromatic amine (1 mmol) ammonium acetate (1.5 mmol) and catalyst MPS (5 mg) in (water + methanol)
(2 + 2 mL) at rt.
spectrum of the prepared catalyst mercaptopropylsilica (MPS) (2)
and the normal solution phase carbon-13 NMR spectrum of 3-
(mercaptopropyl)-trimethoxysilane (1). The normal solution phase
carbon-13 NMR spectrum of (1) showed peaks at d 50.3 (OCH3),
27.3 (b,c) and 8.0 (a). When the catalyst was prepared, the peak
at 50.3 vanished as the bonding took place through the methoxy
groups while the remaining two peaks remained with slight devi-
ations at d 27.1 (b,c) and 10.6 (a). Thus, there is no ambiguity
regarding structural proof of MPS (2). Earlier,19 the structure of
MPS has never been confirmed by solid state carbon-13 NMR spec-
trum. The elemental analysis of MPS was also done which showed
the carbon content to be 2.49%.
In order to optimize the amount of the catalyst per mmol of alde-
hyde, the synthesis of 2,4,5-triphenyl imidazole was chosen as a
model reaction. It was seen that MPS (2) is a highly effective catalyst
for this transformation and in the absence of this catalyst the reac-
tion proceeded to give trace amounts of product after 24 h. The opti-
mum loading was 5 mg of MPS per mmol of aldehyde in terms of
isolated yield and reaction time although a lower catalyst loading
(1 mg of MPS) could be used to furnish the reaction in much lower
yields. The model reaction was also studied in the presence of MPS
(5 mg per mmol of aldehyde) in various solvents such as water,
methanol, aqueous methanol (various percentages), DCM, ACN and
THF or even under solvent-free conditions. It was observed that by
using 50% aqueous methanol, the yield of the reaction was highest
and the reaction time shortest. The addition of water has some posi-
tive effect on the yield of the reaction as it probably helps in the
hydrolysis of ammonium acetate to ammonium hydroxide and ace-
tic acid both of which are required for the reaction.
CHO
NH2
O
O
2
+
NH4OAc
3
+
+
CHO
4
5
R1
7
3
9
1 equivalent for entries 1 and 2 (Table:3)
2 equivalent for entries 3,4,5 (Table:3)
MPS (10 mg)
Room temperature
8-9 hours.
H2O+MeOH (2 mL+ 2 mL)
N
N
4
N
3
R
N
1
R
R = H for entries 1,2
10
for entries 3,4,5 (Table:3)
R =
R1
Scheme 4. Synthesis of tetra–tri and tetra–tetra bis-imidazoles with MPS.
acid,11 silica–sulfuric acid12 or NiCl2–6H2O/Al2O3,13 HClO4–SiO2,14
heteropolyacid15 and silica gel/NaHSO416. There is only one report
till date, for the synthesis of the substituted imidazoles at room tem-
perature, that too using indium chloride,17 the recyclability of which
is rather difficult. A very recent paper18 for the synthesis of the
Once the optimum conditions were standardized, a variety of
2,4,5-trisubstituted imidazoles (6) were synthesized (Scheme 2,
Table 1) using this methodology in excellent yields.
substitutedimidazolesemploysL-prolineascatalystanddoesnotin-
clude the synthesis of the bis-imidazoles.
We have very efficiently prepared the known heterogeneous so-
lid acid catalyst (mercaptopropylsilica, MPS) (1) (Scheme 1) by a
modified procedure in water and employed it for the synthesis of
the tri-/tetrasubstituted imidazoles and their corresponding bis-
analogues in excellent yields at room temperature with easy
regeneration and recyclability of the catalyst. In addition, this is
the first report of the preparation of the catalyst in aqueous
medium in a shorter time.
On examination of Table 1 we find that almost all the 2,4,5-tri-
substituted imidazoles (except entry 8) were produced in high
yields. This methodology was also applicable on an aliphatic alde-
hyde (Table 1, entry 8). It is important to mention that the reaction
is carried out at room temperature. In almost all the earlier
reported procedures,18,20,21 high temperature is required for the
synthesis of the imidazole moiety.
After the initial studies, the methodology was applied for the
synthesis of 1,2,4,5-tetrasubstituted imidazoles (Scheme 3) using
structurally different aldehydes and primary amines (Table 2).
The prepared catalyst mercaptopropylsilica (MPS) (2) was char-
acterized by comparing the solid state carbon-13 CP-MAS NMR

C. Mukhopadhyay et al. / Tetrahedron Letters 51 (2010) 3944–3950
3949
Table 3
Synthesis of tetra–tri- and tetra–tetrasubstituted bis-imidazoles with MPSa at room temperature
Entry
Products
Time (h)
Yield (%) (isolated)
Reference
N
N
1
N
8
75
—
N
H
Cl
N
N
N
N
H
2
8
74
—
CH3
N
N
N
N
N
N
3
8
78
—
—
—
CH3
CH3
N
N
N
4
9
78
OCH3
OCH3
N
N
N
5
9
80
Cl
Cl
a
Reaction conditions: aldehyde (1 mmol), benzil (2 mmol), aromatic amine (1 mmol for entries 1, 2 and 2 mmol for entries 3–5) ammonium acetate (4.5 mmol for entries
1, 2 and 3 mmol for entries 3–5) and catalyst MPS (10 mg) in (water + methanol) (2 + 2 mL) at rt.
On examination of Table 2, it is obvious that the utility of this
catalyst for the synthesis of tetrasubstituted imidazoles is quite
general with variations in all the three components. This is the first
report of the synthesis of tetrasubstituted imidazoles with
phenanthraquinone.
The mechanism of formation of tri- and tetrasubstituted imida-
zoles involves protonation (probably due to proton exchange prop-
erty of the SH group in the catalyst) of the aldehydic carbonyl,
diimine formation of the corresponding diketo compound with
either only ammonium acetate or ammonium acetate and aromatic

3950
C. Mukhopadhyay et al. / Tetrahedron Letters 51 (2010) 3944–3950
ClCH2CH2Cl
K2CO3 / DMF
neous catalysts is their deactivation in addition to reusability
which shows their high stability. The recycled catalyst was reused
ten times without any other treatment.
CHO
OH
CHO
O
Cl
110-120 ºC / 3 hr
In conclusion, we have prepared MPS by a modified methodology
in aqueous medium. The catalyst has been utilized very efficiently
forthe synthesisof a large numberof tri- and tetrasubstituted imida-
zolesatroomtemperature. Thismethodologyhasalsobeenveryeffi-
ciently applied towards the synthesis of the corresponding bis-
analogues in addition to the drug trifenagrel which is a chemically
novel potent inhibitor of arachidonate and collagen-induced aggre-
gation of platelets.
4
11
HNMe2 / DMF
110 ºC / 2 hr
Ph
Ph
O
CHO
O
TRIFENAGREL
NH4OAc
aqueous MeOH
N
O
12
MPS (5 mg)
rt, 3 hr
Acknowledgements
Scheme 5. Synthesis of trifenagrel (overall yield: 91%).
One of the authors (P.K.T.) thanks the University Grants Com-
mission, New Delhi, for his fellowship (SRF). We thank the CAS
Instrumentation Facility, Department of Chemistry, University of
Calcutta, for spectral data. We also acknowledge grant received
from UGC funded Major project, F. No. 37-398/2009 (SR) dated
11-01-2010. Moreover, NMR Research Centre, IISc, Bangalore
560012, is gratefully acknowledged for the solid state carbon-13
CP-MAS NMR spectrum.
amine, cyclization involving aromatic aldehydes and finally loss of
water and ammonia to produce the final products. The more stable
diimine with aromatic amines is responsible for the selective for-
mation of tetrasubstituted imidazoles rather than trisubstituted
ones even in the presence of ammonium acetate. The X-ray struc-
tural analysis of a single crystal of 2-(40-bromophenyl)-1-(4a-chlo-
rophenyl)-4,5-diphenylimidazole (Table 2, entry 10) (given in
Supplementary data) further confirms its structure.
Once our catalyst was successful towards the synthesis of 2,4,5-
tri- and 1,2,4,5-tetrasubstituted imidazoles, we turned our atten-
tion towards the synthesis of the corresponding bis-analogues.
We could efficiently synthesize tetra–tri- and tetra–tetrasubstitut-
ed bis-analogues by simply varying the mole ratio of the aromatic
amine (Scheme 4, Table 3).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.102.
The most important aspect of our methodology besides being
room temperature synthesis is that we have successfully tuned the
formation of tetra–tri- and tetra–tetrasubstituted bis-imidazoles.
Thefinalconfirmationforthestructureofa bis-analogue comesfrom
the X-ray crystal structure analysis of a single crystal of 1-(4a-chlo-
rophenyl)-2-[30-(4,5-diphenyl-1H-imidazol-2-yl)-phenyl]-4,5-di-
phenyl-1H-imidazole (Table 3, entry 1) (given in Supplementary
data).
The cavities shown in the X-ray crystal structure are important
sources for encapsulation which could be utilized for further reac-
tions such as DNA-binding studies. Moreover, the formation of
such bis-analogues is very rare in the literature.
It has been already reported that the drug trifenagrel (Figure 1)
is a chemically novel potent inhibitor of arachidonate and colla-
gen-induced aggregation of platelets. We then started its synthesis
from salicaldehyde, the phenolic-OH group alkylated to obtain
the desired starting aldehyde,2 and simple application of our solid
heterogeneous catalyst MPS at room temperature (Scheme 5)
produced trifenagrel.2
To rule out the contribution of homogeneous catalysts towards
the synthesis of 2,4,5-triphenyl imidazole, the reaction of benzil,
benzaldehyde and ammonium acetate was carried out at room
temperature in the presence of MPS (2) until the conversion was
30% (by crude 1H NMR) and at that point, the solid was filtered
off. The liquid phase in (water/methanol) (2 mL + 2 mL) was al-
lowed to react, but no further conversion was observed. This
proves that MPS (2) is the active catalyst for this reaction. We ob-
served that the two most important points regarding the heteroge-
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