Polymer-supported benzimidazolium based ionic liquid: An efficient and reusable Br?nsted acid catalyst for Biginelli reaction

Article abstract of DOI:10.1039/c6ra23781a

A polymer-supported benzimidazolium based ionic liquid (PSBIL) was synthesized by reaction of poly(vinylbenzyl chloride) and benzimidazole followed by ring opening of 1,4-butane sultone and acidification with sulphuric acid. The resulting Br?nsted acid he

Full text of DOI:10.1039/c6ra23781a

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: P. R. Bhagat, A. G.
Khiratkar and P. N. Muskawar, RSC Adv., 2016, DOI: 10.1039/C6RA23781A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
RSC Advances
Page 1 of 9
View Article Online
DOI: 10.1039/C6RA23781A
RSC Advances
ARTICLE
Polymer-supported benzimidazolium based ionic liquid: an
efficient and reusable Brønsted acid catalyst for Biginelli reaction
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
*a
Avinash Ganesh Khiratkar, Prashant Narayan Muskawar and Pundlik Rambhau Bhagat
DOI: 10.1039/x0xx00000x
A polymer-supported benzimidazolium based ionic liquid (PSBIL) was synthesized by reaction of poly(vinylbenzyl chloride)
and benzimidazole followed by ring opening of 1,4-butane sultone and acidification with sulphuric acid. The resulting
Brønsted acid heterogeneous organocatalyst is very competent for the Biginelli reactions under mild conditions in high
yields of 3,4-dihydropyrimidine-2(1H)-one/thiones (DHPMs). Since poly(vinylbenzyl chloride) makes the catalyst bed, the
sulphonic acid catalyst will have high loading level of acidic groups compare to other heterogeneous acid catalysts.
www.rsc.org/
°
In spite of conventional heterogeneous ionic liquid catalysts, current PSBIL shows thermal stability up to 334 C and
recyclability up to 5 cycles. This PSBIL signifies a new class of heterogeneous catalyst which is particularly noticeable in
green chemistry. The present protocol highlights the easy separation of products without further purification.
Furthermore, the effectiveness of this protocol has demonstrated by synthesis of mitotic Kinesin EG5 inhibitor,
Monastrol under optimized conditions.
attention and several procedures have been illustrated.
Introduction
Some of these methods employ catalysts such as
5
polystyrenesulfonic acid, polystyrene-poly(ethylene glycol) resin
Dihydropyrimidinone (DHPM) products are commonly used in
various applications such as biological, calcium channel blockers,
α-adrenergic antagonists, antihypertensive agents, inhibitors of the
6
7
supported sulphonic acid, mesoporous silica MCM-41, silica
8
9
sulphuric acid, sulphonated carbon material and silica gel
1
0
1
supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sulphate.
fatty acid transporter and mitotic kinesin inhibition. Batzelladine
However, in spite of their potential ability, many of these methods
include expensive and/or toxic catalysts, non-stoichiometric
amount of catalyst, poor yields, tedious workup procedures and
alkaloids were recently found to be effective HIV gp-120-CD4
inhibitors among all the alkaloids obtained from the oceanic
2
sources which constitute the DHPM core unit. The DHPM was first
1
1
inconsistency with certain functional groups.
synthesized by the Italian chemist Pietro Biginelli in 1893 from the
reaction of aldehydes, β-ketoester and urea under strongly acidic
conditions. The major disadvantages related with acid-catalyzed
reactions were lower yields from 26% to 60%, mainly for tri and
tetra-substituted aldehydes of aromatic and aliphatic origins and
longer duration of reactions from 24 to 36 h. The developing
significance in this class of compound leads to the upgrading of
other synthetic multistep approaches with alternate catalysts in
In recent years, the use of non-aqueous room temperature
ionic liquids (RTILs) and task-specific ionic liquids (TSILs) have
executed as a powerful alternative to green solvents or catalysts in
organic synthetic processes due to their undetectable vapour
pressure, wide liquid range, solvating ability as well as the ease of
1
2-20
recovery and reuse.
Moreover, TSILs have been widely used in
21-29
the past few years for the synthesis of DHPMs.
3
Conversely, RTILs and TSILs with imidazole moiety are relatively
slightly better yields.
expensive, which hampers their industrial applications.
On the contrary, multicomponent reactions (MCR) are
convenient tools in organic synthesis giving direct, neat and simple
access to bioactive compound libraries. Combining multi-reagents
in one pot is noticeable practice, and important as the ecological
-
Also, specific ILs consist of halogen-containing anions such as [PF
6
] ,
-
-
-
[
BF
4
] , [CF
3
SO
3
0-32
] and [(CF
3
SO)
2
N] which in some respect limit their
3
greenness.
At the edge between heterogeneous and
4
homogeneous catalysis, there is a great opportunity for the
expansion of novel materials that combine the benefits and
minimize drawbacks related with each of these classes. The main
difficulty of the homogeneous catalysts is the concern of their
recovery from the reaction mixture. The product is separated from
the reaction medium either by precipitation and extraction using
other solvent or distillation with subsequent recovery.
Such work-up operations may deactivate the catalyst.
Opposite, leaching can occur in the reaction medium during
point of view but still suffers from several limitations. Therefore,
the reaction for the synthesis of DHPMs has attracted better
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 9
View Article Online
DOI: 10.1039/C6RA23781A
ARTICLE
Journal Name
extraction on the one hand and requests further struggle to Experimental
upgrade the extracted compound.
Materials
In recent years, the use of heterogeneous catalysis has received
4
-vinylbenzyl chloride (90%) and 1, 4-butane sultone were
universal attention that offers a clarification for the major drawback
of homogeneous catalysis. From both an industrial and an
environmental point of view, this method is very interesting, since it
allows the upcoming application of heterogeneous catalysts in the
synthesis of cost-effective products, leading to rapid, clean and
purchased from Sigma-Aldrich (India). Azobisisobutyronitrile (AIBN)
and sulphuric acid were obtained from Avra synthesis, India.
Sodium hydride (60% suspension in paraffin oil), benzimidazole and
all the substituted aromatic aldehydes, urea, thiourea, ethyl
acetoacetate, acetylacetone, anhydrous sodium sulphate and all
the solvents were purchased from S D Fine chemicals India.
TLC plate silica gel GF-254 was procured from Merck and Co.
3
3
selective green industrial processes. Supported ILs catalysis is an
idea which combines the benefits of ILs with those of
heterogeneous support materials. The feasibility of this model has
been established by several studies which have effectively Characterization techniques
restrained various ionic phases to the surface of support materials
6 3
NMR spectra were recorded in DMSO-d and CDCl on Bruker
and discovered their prospective catalytic uses. The majority of the
evaluated supports were silica based and several studies focused on
polymeric materials including Merrifield resin and polystyrene.
These materials were prepared by two different immobilization
methodologies. First method includes the covalent attachment of IL
to the support surface while another merely links the ILs phases
with catalytically active species on the peripheral of the support.
However, only a few protocols have been reported using
polymer supported ionic liquid for the synthesis of DHPM
spectrometer operating at 400 MHz and the chemical shifts are
given in ppm downfield from TMS (δ = 0.00). The molecular weight
of the DHPM derivatives was determined using Perkin Elmer GC
modal-Clarus 680 (EI). Elemental analysis (C, H, N, O and S) of the
PSBIL was performed on EURO VECTOR EA 3000 elemental analyzer.
Thermal stability of PSBIL was tested using TG/DTA thermoanalyser
SII, 7200 (Seiko, Japan). FT-IR spectra of the PSBIL and DHPM
derivatives were obtained from IR affinity-1 Shimadzu
FT-IR spectrophotometer using KBr pellet method.
3
4
derivatives. Wang et al. have reported PsMImBF
immobilizing 1-methyl-1H-imidazole on polystyrene-based
chloromethyl resin followed by ion exchange with NaBF or NH PF
4 6
or PsMImPF by
Synthesis of PSBIL
4
4
6
.
Synthesis of poly(vinylbenzyl chloride) (1)
This heterogeneous polymer supported ionic liquid catalyst was
found efficient for the synthesis of 1,2,3,4-tetrahydro-2-
Prior to polymerization of 4-vinylbenzyl chloride, inhibitor i. e. tert-
butyl catechol was removed by dissolving 4-vinylbenzyl chloride in
chloroform and extracted three times in 0.5% aqueous NaOH
3
5
oxopyrimidine-5-carboxylates. Pourjavadi et al. have synthesized a
dual acidic heterogeneous organocatalyst by copolymerization of
acidic IL monomer (vinyl-3-(3-sulfopropyl)imidazolium hydrogen
2 4
solution followed by the water. Anhydrous Na SO was added for
drying, filtered and chloroform was removed under rotary
evaporator to get the inhibitor free 4-vinylbenzyl chloride
monomer. The monomer (7.6 g, 50 mmol) was taken in two-necked
round bottom flask with 150 mL chloroform and AIBN (0.164 g) and
sulfate [VSim][HSO
4
] and IL crosslinker (1,4-butanediyl-3,3-bis-vinyl
imidazolium dihydrogen sulfate) and used successfully for the
3
6
Biginelli reaction. Moreover, methods using ultrasound and
microwave-assisted dry media technology containing
TiO nanoparticles supported on multi-walled carbon nanotubes
2
refluxed at 70 °C for 48 h under N atmosphere. After 48 h,
2
chloroform was removed by rotary evaporator and methanol was
added to the viscous liquid to get white solid polymer, which was
repeatedly washed with methanol (3 × 20 mL) to remove unreacted
monomer and dried under high vacuum to get the fine white
powder of poly(vinylbenzyl chloride). Yield: 6.3 g, 82.89%.
3
7
crystalline carbon materials TiO
reported.
2
–MWCNTs have also been
Prompted by the above effective themes and as part of our
persistent effort to develop new heterogeneous catalyst, we have
decided
to
synthesize
metal-free
polymer-supported
Synthesis of poly-1-(4-vinylbenyl)-1H-benzimidazole (2)
benzimidazolium based ionic liquid. On the basis of our experience
3
8
in the synthesis of ILs and concern in catalytic processes in this The synthesis of compound (2) was carried out based on the
3
9
ionic media. Herein we report the PSBIL is an excellent literature. THF solution of poly(vinylbenzyl chloride) (6.08 g, 40
heterogeneous catalyst with admirable results for the Biginelli mmol) was added dropwise to a stirred solution of benzimidazole
reaction. The efficiency of the developed catalyst has been tested (4.72 g, 40 mmol) and sodium hydride (1.6 g, 40 mmol). The above
for the Biginelli reaction by varying all the starting materials. reaction mixture was refluxed at 60 °C for 48 h. Precipitated NaCl
Also, the thermal stability and recyclability of the PSBIL has been was removed by filtration from the reaction mixture and THF was
examined, which shows the promising results compared to the removed by rotary evaporator under vacuum. Chloroform (150 mL)
other reported catalysts.
added to dark brown viscous oil and the organic layer was washed
with deionized water (5 × 150 mL). The reaction mixture was dried
2 4
using anhydrous Na SO , filtered and chloroform was removed by
rotary evaporator and polymer was washed with acetone, dried in
hot air oven for overnight to obtain a yellowish powder of
poly-1-(4-vinylbenyl)-1H-benzimidazole (2).
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 9
PleaseRd So Cn oA t da vd aj un s ct ems argins
View Article Online
DOI: 10.1039/C6RA23781A
Journal Name
ARTICLE
Synthesis of poly-(4-(1-(4-vinylbenzyl)-1H-benzimidazol-3-ium-3- of reaction was monitored by TLC using ethyl acetate: hexane (1:1)
yl)-butane-1-sulfonate (3)
as mobile phase till the disappearance of reactants.
After completion of reaction, the solid DHPM was separated from
the wall of RBF by simply scraping out with a spatula (Fig. S8; see
The synthesis of compound (3) was carried out according to
4
0
literature. The ring opening reaction of 1,4-butane sultone
2.58 g, 19 mmol) with poly-1-(4-vinylbenyl)-1H-benzimidazole (7 g)
o
the ESI†), washed with water and dried in an oven at 50 C.
(
Moreover, the ethanol containing DHPMs from the reaction
mixture poured onto the crushed ice, filtered and dried. The
recovered catalyst was washed with ethanol, followed by water and
at 50 °C for 48 h in 150 mL chloroform was performed. The reaction
mixture was concentrated using rotary evaporator and diethyl ether
was added. The off-white polymer (3) was precipitate which was
washed repeatedly with diethyl ether (3 × 40 mL) to remove
unreacted starting materials. Finally, it was dried overnight at 50 °C
o
dried in an oven at 50 C for 12 h to reuse for the next experiment.
in a hot air oven to afford off-white powder of poly-(4-(1-(4- Results and discussion
vinylbenzyl)-1H-benzimidazol-3-ium-3-yl)-butane-1-sulfonate (3).
Catalytic studies
Synthesis of PSBIL (4) from poly-(4-(1-(4-vinylbenzyl)-1H-
-
Sulphonic acid functionalized ionic liquids containing HSO
4
41
counter anion enhances the Brønsted acidity of the catalyst.
benzimidazol-3-ium-3-yl)-butane-1-sulfonate
Compound (3) (4 g) was taken in minimum amount of water in Accordingly, herein we would like to report the synthesis of
RB flask and stirred in cool condition using ice-crush bath and added polymer-supported Brønsted acid ionic liquid containing
-
slowly 2 equivalent of conc. H
2
SO
4
. The reaction mixture was stirred sulphonic acid functionality with HSO
o
4
as a counter anion for
under same condition for half an hour followed by at 70-80 C for Biginelli reaction. A range of aldehydes comprising substituted
2 h. The obtained yellowish solid was constantly washed with aromatic aldehydes, aliphatic aldehyde, heterocyclic aldehydes
1
deionized water until the pH of washed water gets neutral. Further, and aldehyde containing polycyclic aromatic hydrocarbon
the polymer was filtered under high vacuum and dried in an oven were selected and condensed with ethyl acetoacetate,
°
for 12 h at 60 C to get yellowish crystalline PSBIL as a product acetylacetone, urea and thiourea towards the synthesis of
(Scheme 1). Resulting PSBIL was insoluble in almost all organic 3,4-dihydropyrimidine-2(1H)-ones/thiones.
solvents except DMSO showing solubility at 90 °C.
Spectral Data of PSBIL
1
6
H NMR (400 MHz, DMSO-d ): δ 10.20 (br, 1H), 9.19 (br, 1H), 7.61
(
br, 4H), 7.11(br, 4H), 6.20 (br, 5H), 5.51 (br, 2H), 4.53 (br, 2H), 2.66
br, 2H), 2.05 (br, 2H), 1.68 (br, 2H), 1.59 (br, 1H) 1.23 (br, 2H).
(
Scheme 2 Biginelli reaction of benzaldehyde, urea and
ethylacetoacetate to get the 5-Ethoxycarbonyl-4-phenyl-6-
methyl-3,4-dihydropyrimidin-2(1H)-one.
30 2 7 2
Anal. Calcd for C22H N O S (%): C, 52.99, H, 6.06, N, 5.6, O, 22.46,
S, 12.86; Found: C, 60.796, H, 5.895, N, 8.036, O, 15.762, S, 5.670.
We initially assessed the use of different amounts of PSBIL
for the model reaction of benzaldehyde (1 mmol), ethyl
acetoacetate (1.2 mmol) and urea (1.5 mmol) to produce
DHPM under classical conditions (Table 1). From the data
presented in Table 1, it is clear that the high yield of product
(
91
while with 0 to 40 mg of catalyst, yields were not good (Table
, entries 1-5). From these results, it was obvious that the
%) (Table 1, entry 6) was perceived using 50 mg of catalyst
1
amount of catalyst plays a vital role to advance the result to a
larger extent. It was also found that there is no greater
alteration in yields of product greater than 50 mg of catalyst
(Table 1, entry 7).
Use of benzaldehyde, ethyl acetoacetate and urea in
1
1
:1.2:1.5 equivalent ratio with the proposed PSBIL (50 mg) at
10 C gave 5-Ethoxycarbonyl-4-phenyl-6-methyl-3,4-
yield in 18 h. The greater
°
dihydropyrimidin-2(1H)-one 91
%
Scheme 1. Schematic representation of the synthesis of PSBIL.
yield in this reaction is in accordance with atom economy
concept.
Typical Biginelli reaction
The mixture of benzaldehyde (0.106 g, 1 mmol), ethyl acetoacetate
(0.156 g, 1.2 mmol), urea (0.09 g, 1.5 mmol) and PSBIL (50 mg) in
ethanol (5 mL) were successively charged into a 50 mL single neck
round bottom flask (RBF) with magnetic stirring bar. The reaction
mixture was refluxed at 110 °C for the period of 18 h. The progress
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 9
View Article Online
DOI: 10.1039/C6RA23781A
ARTICLE
Journal Name
a
Table 1 Optimization of amount of catalyst, temperature and Table 2 Effect of solvent on Biginelli reaction.
a
b
time on the Biginelli reaction.
Entry Catalyst
amount
Solvent
Temperature Time Yields
b
Entry Catalyst
Solvent Temperature Time Yields
(°C)
(h)
(%)
(°C)
(%)
amount
(h)
(
PSBIL)
mg)
(
PSBIL)
(
(
mg)
-
5
5
5
0
0
0
1
3
4
5
6
7
8
Acetonitrile
Toluene
Water
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
18
18
18
18
18
18
18
41
44
45
72
39
32
20
Ethanol
Ethanol
Ethanol
Ethanol
1
2
3
4
5
6
7
8
9
110
110
110
110
110
110
110
70
24
24
24
24
24
24
24
24
24
24
24
24
24
4
36
52
60
69
74
91
91
60
64
69
77
91
71
20
65
89
1
2
3
4
0
0
0
0
50
50
Ethanol
THF
Ethanol
Ethanol
50
60
5
0
Methanol
n-hexane
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
50
5
5
5
5
5
5
5
5
5
5
0
0
0
0
0
0
0
0
0
0
a
Reaction conditions: Aldehydes (1 mmol), ethylacetoacetate or
acetylacetone (1.2 mmol), urea or thiourea (1.5 mmol) and PSBIL
50 mg) refluxing for 18 h.
80
(
b
1
0
1
2
3
4
5
6
90
Isolated yield of products.
1
1
1
1
1
1
100
110
120
110
110
110
With the optimized reaction conditions in hand, we then
studied the scope and constraints of this strategy for other diverse
substrates using combination of ethyl acetoacetate/acetylacetone,
a series of aldehydes comprising substituted aromatic aldehydes,
aliphatic aldehyde, heterocyclic aldehydes and aldehyde containing
polycyclic aromatic hydrocarbon and urea/thiourea in ethanol
°
medium at 110 C for 18 h and the results are summarized in
12
18
Table 3. All the reactions progressed well to afford good to
admirable yields with PSBIL as a catalyst. Aldehydes with the
electron-donating group (Table 3, entries 2-9) gave much higher
yields than those with an electron-attracting group. Then we vary
the aldehydes with electron withdrawing group keeping urea and
ethyl acetoacetate constant (Table 3, entries 10-12) to give the
corresponding products in 80% to 68% yields. An important
advantage of this protocol is that it shows an excellent group
tolerance capacity towards nitrobenzaldehyde.
1
7
8
110
110
24
28
91
88
1
50
a
Reaction conditions: benzaldehyde (1 mmol), urea (1.2 mmol),
ethyl acetoacetate (1.5 mmol) and ethanol (5 mL).
Isolated yield of products.
b
°
The increase of reaction temperature above 110 C had no
marginal effect on the yield of condensation product
(
Table 1, entry 13). Prolonging the time further up to 28 h
Table 1, entry 18) had practically no effect on the yield
(
showing that, reaction is complete in 18
h
(Table 1, entry 16). Finally, the effect of solvent on model
reaction was studied using different polar and non-polar
solvents at their respective reflux temperatures for 18 h.
As can be seen, in (Table 2) the condensation reaction
proceeded smoothly in the presence of ethanol (Table 2, entry
4) and gave the desired product in excellent yield.
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 9
PleaseRd So Cn oA t da vd aj un s ct ems argins
View Article Online
DOI: 10.1039/C6RA23781A
Journal Name
ARTICLE
a
Table 3 Biginelli reaction catalyzed by PSBIL.
compatible with various substrates and the products were obtained
in good to excellent yields (Table 3). The various aldehydes like
1
-naphthyl aldehyde, 2-furanyl aldehyde and 2-thianyl aldehyde
were also reacted well under the same conditions to give their
respective products (Table 3, entries 13–15). However, lower yield
were obtained in the case of aliphatic aldehyde (Table 3, entry 16).
Encouraged by these favourable results we next studied the
multicomponent reaction using 1,3-diketones instead of
β-ketoesters (Table 3, entries 17 and 18). In both the cases, the
reactions were complete in 18 h to furnish DHPMs with good yields.
Finally, the catalytic activity of PSBIL was examined for the Biginelli
reaction by using thiourea instead of urea that yields 84 to 88%
DHPMs demonstrating the excellent catalytic activity of catalyst
b
Entry
Aldehyde
X
O
O
R’
Product
Yield (%)
1
2
C
6
H
5
OEt
OEt
4a
4b
91
92
4-MeOC
2-MeO C
3,4- MeOC
6 4
H
(
Table 3, entries 19-24).
3
4
5
6
7
8
9
6
H
4
O
O
O
O
O
O
O
O
O
O
O
O
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
4c
4d
4e
4f
90
86
89
88
81
80
88
80
78
68
88
84
It is found that, most of the metal-based catalysts for the
4
2-44
Biginelli reaction were in solvent-free conditions.
But, the post-
6
H
4
treatment requires more volume of organic solvents and thus the
methodology not only made the work-up procedure complicated
but also brought more difficulty in separating the catalysts for their
recycling. Hence, it is opposite of the principle of green chemistry.
On the contrary, synthesis of DHPMs via the PSBIL catalyst in
ethanol requires neither tedious workup procedure nor column
chromatographic purification.
4-CH C H
3
6
4
4-OH C
6 4
H
4-BrC
6
6
H
H
4
4g
4h
4i
2-BrC
4
A plausible mechanism for the Biginelli reaction catalyzed by
PSBIL is shown in (Scheme 3). Initially, PSBIL facilitates the
formation of intermediate I via Knoevenagel condensation of
β-ketoester 1 and aldehyde 2. An intermediate I undergo the
6 4
4-ClC H
1
0
1
2
3
4
4-FC H4
4j
6
dehydration to give olefin II. Then, the conjugate addition of NH
2
1
1
1
1
4-O NC H
4k
4l
2
6
4
4
group in urea or thiourea 3 at the β-carbon of α, β-unsaturated
carbonyl group to form compound III which tautomerizes to more
stable keto form followed by cyclization via nucleophilic attack of
3-O
2
NC
6
H
2
NH on electrophilic carbonyl carbon. Finally elimination of another
1-Naphthyl
2-Furanyl
2-Thienyl
4m
4n
water molecule with regeneration of catalyst yields the DHPMs.
HA
R
O
15
16
17
O
O
O
OEt
OEt
Me
4o
4p
4q
82
56
88
O
O
H
H
O
R
O
O
R
2
H
R'
HA R'
R'
OH
-H2O
R'
n-CH
3
(CH
2
)
2
O
O
O
1
I
II
6 4
4-ClC H
HA
1
1
2
2
2
2
8
9
0
1
2
3
C
C
6
6
H
5
O
S
S
S
S
S
Me
Me
Me
Me
OEt
OEt
4r
4s
89
85
84
88
85
84
O
R
OH
R'
H
5
O
R
R'
NH
X
X
HA
R
R'
NH
4-ClC H4
4t
6
H2N NH2
OH NH2
X
O
OH NH2
3
4-MeOC
6
H
4
4
4u
4v
4w
III
6 5
C H
n
O
R
O
R
4-ClC
6
H
4
H
-H2O
HSO4
N
R'
3
SO H
NH
R'
NH
HA =
N
24
4-OMeC H
S
OEt
4x
87
HO
N
X
N
H
X
6
H
a
4a-4x
Reaction condition: Aldehydes (1 mmol), ethyl acetoacetate or
acetylacetone (1.2 mmol), urea or thiourea (1.5 mmol) and PSBIL (50 mg)
Scheme 3 Possible reaction pathway for the synthesis of DHPMs.
in 5 mL ethanol refluxing at 110 °C for 18 h.
Isolated yield of the products.
b
In order to prove the industrial applicability of this method, the
reaction of 3-hydroxy benzaldehyde, ethyl acetoacetate and
thiourea was carried out for the synthesis of mitotic Kinesin EG5
The optimized conditions were then employed to assess the
generalization of the method. The PSBIL was found to be
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 6 of 9
View Article Online
DOI: 10.1039/C6RA23781A
ARTICLE
Journal Name
inhibitor Monastrol under optimized conditions which yielded in
0% (Scheme 4). Thus, the present PSBIL catalyst is extremely
attractive for producing DHPMs of biological and pharmacological
interest. Also, yields obtained for PSBIL towards Biginelli reaction is
better than or comparable with the literature reports (Table 4).
1
00
9
1
90
2
88
8
6
82
8
6
4
2
0
0
0
0
0
Scheme 4 Synthesis of 5-Ethoxycarbonyl-4-(3-hydroxyphenyl)-6-
1
2
3
4
5
methyl-3,4-dihydropyrimidin-2(1H)-thione (Monastrol).
Runs
In order to ascertain any fundamental changes in the PSBIL
catalyst, we have verified FT-IR spectrum before and after
condensation reaction. The FT-IR spectrum (Fig. 1A) of synthesized
Fig. 2 Recyclability of PSBIL in Biginelli reaction.
Recyclability and stability of the PSBIL
-1
PSBIL makes clear that broad peak at 3452 cm corresponds to the
4
5
In view of an environmentally benign process, the recyclability
of the catalyst is an important benefit especially in the
heterogeneous system for commercial applications. The reusability
of the PSBIL was investigated in consecutive Biginelli reactions of
benzaldehyde, ethyl acetoacetate and urea (mole ratio 1:1.2:1.5)
under the optimized conditions. The reactions were carried out by
following the usual method. At the end of each reaction, the
heterogeneous catalyst was washed with ethanol followed by water
and dried in an oven for the next run. The results of reuse of PSBIL
are summarized in Fig. 2. As it is shown, the PSBIL can be used 5
times without significant loss of its catalytic activity. However, a
slight decrease in the catalytic activity from fourth 86 to 82% in the
fifth cycle could be due to the blocking of the active sites of the
PSBIL catalyst. As compared to traditional catalysts, the PSBIL
exhibits easy recovery from the reaction mixture which is a
perceptible asset of the heterogeneous catalyst for ecological
protection and cost-effective reasons.
–
2
3
OH stretching frequency of –SO H group. The peaks at 2850 and
3
-1
922 cm correspond to the aliphatic -C-H group while the peak at
-1
057 and 3126 cm is appeared due to =C-H of the aromatic ring.
-1
The peak at 1035 and 1168 cm is clearly observed in FT-IR
spectrum due to the S=O asymmetric and symmetric stretching
4
6
-1
frequency of the –SO H group whereas, peak at 615 cm is due to
3
4
7
the symmetric vibration of S-O of the –SO H group. The stretching
3
-1
frequency of C-N and C=N appeared at 1382 and 1612 cm
-1
respectively while the peak at 1492 and 1546 cm is due to the
C=C of aromatic ring which confirms the successful formation of
PSBIL.
It was found that, FT-IR spectrum of PSBIL obtained before and
after (Fig. 1, A and B) the Biginelli reaction shows no substantial
changes.
PSBIL before use
PSBIL after use
100
Table 4 Comparison of the Biginelli reaction using different
B
A
heterogeneous catalyst.
Catalyst
Yield
9
8
7
0
0
0
dosage
Entry
catalyst
Ref.
(%)
(in mg)
1
2
PS-PEG-OSO
3
H
300
79
98
6
Silica gel-supported
212
10
L-pyrrolidine-2-
carboxylic acid-4-
hydrogen sulfate
4
000 3500 3000 2500 2000 1500 1000 500
-
1
Wavenumber (cm )
3
4
(MCM-41-R-SO H)
100
250
94
89
48
49
3
Fig. 1 FT-IR spectra of the PSBIL A) before reaction B) after the
3
PPF-SO H
reaction.
5
6
PS-AFDPAT
PSBIL
650
50
94
92
50
Present
work
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 9
PleaseRd So Cn oA t da vd aj un s ct ems argins
View Article Online
DOI: 10.1039/C6RA23781A
Journal Name
ARTICLE
1
10
00
120
Acknowledgements
1
We gratefully acknowledge SIF DST-VIT-FIST, VIT University, Vellore
for providing NMR, GC-MS, FT-IR as well as other required facilities
and CDRI Lucknow for providing elemental analysis data. The
authors are also grateful for financial help provided by RGEMS, VIT
University, Vellore and other facilities provided by “Smart Materials
Laboratory for Bio-sensing and Catalysis.”
1
8
6
4
2
0
00
9
8
7
6
5
4
3
0
0
0
0
0
0
0
0
0
0
0
References
1
2
3
4
A. R. Gholap, K. Venkatesan, T. Daniel, R. J. Lahoti and K. V.
Srinivasan, Green Chem., 2004, 6, 147.
K. S. Atwal, G. C. Rovnyak, B. C. O’Reilly and J. Schwartz, J. Org.
Chem., 1989, 54, 5898.
B. Ahmed, R. A. Khan, Habibullah and M. Keshari, Tetrahedron
Lett., 2009, 50, 2889.
H. G. O. Alvim, G. A. Bataglion, L. M. Ramos, A. L. de Oliveira,
H. C. B. de Oliveira, M. N. Eberlin, J. L. de Macedo, W. A. da Silva
and B. A. D. Neto, Tetrahedron, 2014, 70, 3306.
V. Polshettiwar and R. S. Varma, Tetrahedron Lett., 2007, 48,
1
00 200 300 400 500 600 700 800
o
Temperature
( C)
Fig. 3 The TG and DTG thermogram of PSBIL.
Thermogravimetric analysis was studied for defining the
stability of synthesized PSBIL (Fig. 3). TG and DTG analysis of the
PSBIL was examined in the range of 30 to 800 °C and the
5
6
7
343.
Z. J. Quan, Y. X. Da, Z. Zhang and X. C. Wang, Catal. Commun.,
009, 10, 1146.
atmosphere. The thermogram shows the initial weight loss of 7 H. Murata, H. Ishitani and M. Iwamoto, Org. Biomol. Chem.,
010, 8, 1202.
-1
temperature was increased at the rate of 10 °C min in a
2
N
2
2
7
.0305% at 98.2 °C due to the physically adsorbed water.
8
9
S. Rostamnia and K. Lamei, Chin. Chem. Lett., 2012, 23, 930.
M. Moghaddas, A. Davoodnia, M. M. Heravi and N. T. Hoseini,
Chin. J. Catal., 2012, 33, 706.
The another weight loss of 42.4089% started from 334.1 °C to
74.9 C and this weight loss is due to the alkyl sulphonic groups
°
4
present in the PSBIL.
1
1
1
0 A. G. Choghamarani and P. Zamani, Chin. Chem. Lett., 2013, 24,
804.
1 N. Sharma, U. K. Sharma, R. Kumar, Richa and A. K. Sinha, RSC
Adv., 2012, 2, 10648.
The final weight loss 25.3954% observed from 474.9 to 713.2 °C
poly(1-(4-Vinylbenyl-1H-benzoimidazole) in the PSBIL. From TGA
analysis it is observed that the weight loss is negligible up to
2 P. Wasserscheid and W. Keim, Angew. Chem. Int. Ed. 2000,
°
3
34.1 C, therefore it is concluded that PSBIL catalyst is suitable for
3
9, 3772.
high-temperature reaction.
1
1
3 J. S. Wilkes, J. Mol. Catal. A: Chem., 2004, 214, 11.
4 Z. Andrade, K. Karlose and L. M. Alves, Curr. Org. Chem., 2005, 9,
1
95.
Conclusions
15 D. R. MacFarlane, J. M. Pringle, K. M. Johansson, S. A. Forsyth
and M. Forsyth, Chem. Commun., 2006, 18, 1905.
A polymer-supported benzimidazolium based ionic liquid was
successfully synthesized by reaction of poly(vinylbenzyl chloride)
and benzimidazole followed by ring opening of 1,4-butane sultone
and acidification with sulphuric acid. The resulting PSBIL was found
highly competent for the synthesis of DHPM derivatives via Biginelli
reaction under mild conditions. The present PSBIL catalyst has been
1
1
1
1
6 A. C. Cole, J. L. Jensen, I. Ntai, T. Tran, K. J. Weaver, D. C. Forbes
and J. H. Davis, J. Am. Chem. Soc., 2002, 124, 5962.
7 H. Wu, F. Yang, P. Cui, J. Tang and M. He, Tetrahedron Lett.,
2
004, 45, 4963.
8 H. Xing, T. Wang, Z. Zhou and Y. Dai, Ind. Eng. Chem. Res., 2005,
4 (11), 4147.
9 A. Atef and J. P. Bazureau, Org. Process Res. Dev., 2005, 9, 743.
4
tolerate aliphatic, aromatic, heterocyclic aldehydes and affords 20 Y. Jeong, D. Y. Kim, Y. Choi and J. S. Ryu, Org. Biomol. Chem.,
2
011, 9, 374.
good to excellent yields. Furthermore, the PSBIL catalyst exhibit
excellent thermal stability and reproducibility. The PSBIL catalyst
signifies a novel class of high loaded heterogeneous catalyst which
is particularly promising in green chemistry and found to be
2
2
1 A. R. Gholap, K. Venkatesan, T. Daniel, R. J. Lahoti and K. V.
Srinivasan, Green Chem., 2004, 6, 147.
2 P. Karthikeyan, S. S. Kumar, S. A. Aswar, P. N. Muskawar and P. R.
Bhagat, Res. Chem. Intermed., 2013, 39, 1335.
effective in terms of the yield, catalyst dose, simple work-up 23 M. Li, W. S. Guo, L. R. Wen, Y. F. Li and H. Z. Yang, J. Mol. Catal.
A: Chem., 2006, 258, 133.
procedure, separation and reusability of the catalyst. The DHPMs
2
2
4 F. Dong, L. Jun, Z. Xinli, Y. Zhiwen and L. Zuliang, J. Mol. Catal. A:
Chem., 2007, 274, 208.
5 L. D. S. Yadav, A. Rai, V. K. Rai and C. Awasthi, Tetrahedron, 2008,
was separated easily from the reaction medium using a spatula,
followed by washing with water and drying to get analytically pure
products. Also, the industrial applicability of this protocol has
6
4, 1420.
demonstrated by the synthesis of mitotic Kinesin EG5 inhibitor 26 L. M. Ramos, A. Y. Ponce de Leon y Tobio, M. R. dos Santos, H. C.
de Oliveira, A. F. Gomes, F. C. Gozzo, A. L. de Oliveira and B. A.
Neto, J. Org. Chem., 2012, 77, 10184.
Monastrol under optimized conditions.
2
2
7 H. Kefayati, F. Asghari and R. Khanjanian, J. Mol. Liq., 2012, 172,
47.
8 Z. Chen, R. Fu, W. Chai, H. Zheng, L. Sun, Q. Lu and R. Yuan,
1
Tetrahedron, 2014, 70, 2237.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 8 of 9
View Article Online
DOI: 10.1039/C6RA23781A
ARTICLE
Journal Name
2
3
3
3
3
3
3
3
9 J. K. Joseph, S. L. Jain, S. Singhal and B. Sain, Ind. Eng. Chem. Res.,
011, 50, 11463.
0 P. Wasserscheid, R. Hal and A. Bosmann, Green Chem., 2002, 4,
00.
1 J. F. Dubreuil, K. Bourahla, M. Rahmouni, J. P. Bazureau and
J. Hamelin, Catal. Commun., 2002, 3, 185.
2
4
2 M. T. Garcia, N. Gathergood and P. J. Scammells, Green Chem.,
2
005, 7, 9.
3 S. S. Shinde and S. N. Patil, Org. Biomol. Chem., 2014,
2, 9264.
4 Z. T. Wang, S. C. Wang and L. W. Xu, Hel. Chim. Acta,
005, 88, 986.
1
2
5 A. Pourjavadi, S. H. Hosseini and R. Soleyman, J. Mol. Catal. A:
Chem., 2012, 365, 55.
6 A. R. Gholap, K. Venkatesan, T. Daniel, R. J. Lahoti and K. V.
Srinivasan, Green Chem., 2004, 6, 147.
3
3
7 J. Safari and S. G. Ravandi, New J. Chem., 2014, 38, 3514.
8 P. Karthikeyan, P. N. Muskawar, S. A. Aswar, P. R. Bhagat and
S. K. Sythana, J. Mol. Catal., A: Chem., 2012, 358, 112.
9 P. N. Muskawar, K. Thenmozhi and P. R. Bhagat, Appl. Catal., A
3
4
4
4
4
2
015, 493, 158.
0 A. G. Khiratkar, S. S. Kumar and P. R. Bhagat, RSC Adv., 2016, 6,
44), 37757.
1 R. Kore, T. J. Dhilip Kumar and R. Srivastava, J. Mol. Catal. A:
Chem., 2012, 360, 61.
2 P. Karthikeyan, S. A. Aswar, P. N. Muskawar, P. R. Bhagat and S.
S. Kumar, J. Organomet. Chem., 2013, 723, 154.
3 V. R. Choudhary, V. H. Tillu, V. S. Narkhede, H. B. Borate and R. D.
Wakharkar, Catal. Commun., 2003, 4, 449.
(
4
4
4
4 N. Ahmed and J. E. van Lier, Tetrahedron Lett., 2007, 48, 5407.
5 Zillillah, G. Tana and Z. Li, Green Chem., 2012, 14, 3077.
6 A. Pourjavadi, S. H. Hosseini, M. Doulabi, M. Fakoorpour, S. M.
Fakoorpoor and F. Seidi, ACS Catal., 2012, 2, 1259.
7 M. Vafaeezadeh and M. M. Hashemi, Chem. Eng. J., 2014,
4
4
4
5
2
50, 35.
8 G. H. Mahdavinia and H. Sepehrian, Chin. Chem. Lett., 2008,
9, 1435.
9 M. Lei, D. Wu, H. Wei and Y. Wang, Synth. Commun., 2009,
9, 475.
0 X. L. Shi, H. Yang, M. Tao, and W. Zhang, RSC Adv., 2013, 3,
939.
1
3
3
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 9
RSC Advances
View Article Online
DOI: 10.1039/C6RA23781A
Polymer-supported benzimidazolium based ionic liquid: an efficient and
reusable Brønsted acid catalyst for Biginelli reaction
a
b
a,
Avinash Ganesh Khiratkar, Prashant Narayan Muskawar and Pundlik Rambhau Bhagat *
a
Department of Chemistry, School of Advanced Sciences, VIT University, Vellore-632014,
India.
b
Department of Chemistry, Amolakchand Mahavidyalaya,Yavatmal-445 001, India.
Tel.: +91-9047289073; Fax: +91-416-2240411; email: drprbhagat111@gmail.com