Silica immobilized nickel complex: An efficient and reusable catalyst for microwave-assisted one-pot synthesis of dihydropyrimidinones

Article abstract of DOI:10.1016/j.inoche.2011.12.014

Dihydropyrimidinones (DHPM's) have been prepared by one-pot condensation of aldehydes, urea and 1,3-dicarbonyl compounds in presence of covalently anchored nickel complex on silica as catalyst in microwave under solvent-free conditions. The prepared catal

Full text of DOI:10.1016/j.inoche.2011.12.014

Inorganic Chemistry Communications 17 (2012) 58–63
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Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Silica immobilized nickel complex: An efficient and reusable catalyst for
microwave-assisted one-pot synthesis of dihydropyrimidinones
R.K. Sharma ⁎, Deepti Rawat
Green Chemistry Network Centre, Department of Chemistry, University of Delhi, Delhi-110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2011
Accepted 16 December 2011
Available online 23 December 2011
Dihydropyrimidinones (DHPM's) have been prepared by one-pot condensation of aldehydes, urea and 1,3-
dicarbonyl compounds in presence of covalently anchored nickel complex on silica as catalyst in microwave
under solvent-free conditions. The prepared catalyst was characterized by elemental analysis, BET surface
13
area, atomic absorption spectroscopy (AAS), FT-IR spectroscopy and C CPMAS spectral studies. This method
in comparison to previously reported methods offers high yields, eliminates the use of organic solvents,
reduces reaction time from several hours to few minutes and also the catalyst can be reused without
appreciable loss in catalytic activity.
Keywords:
Biginelli reaction
Dihydropyrimidinones
Microwave
© 2011 Elsevier B.V. All rights reserved.
Nickel complex
Silica
One-pot
The catalysts which make the organic reactions environmentally
benign and economically feasible are extremely demanded by chemical
industries [1,2]. Homogeneous catalysis is gaining considerable interest
due to their high activity and selectivity at milder reaction conditions
for a wide variety of reactions. However, their practical applications
have been limited due to difficulties in achieving industrially viable
catalyst-product separation [3]. Heterogenization of homogeneous
catalysts is one of the means to integrate the advantages of both
homogeneous and heterogeneous catalysis into one chemical process
which would lead to clean chemical synthesis from both environmental
and commercial point of view. The massive increase in the use and the
broad range of applications for polymeric supports in chemistry
illustrate the immense significance of the techniques to the chemists.
In this present work, silica gel is chosen as solid support for immobiliza-
tion of catalysts due to their tunable pore sizes and surface areas, high
thermal and mechanical stability, and the ease with which the surfaces
can be functionalized [2,4–9]. In the present work, we have designed
and synthesized sustainable silica immobilized nickel complex and
investigated its catalytic activity for synthesis of dihydropyrimidinones
with an aryl aldehyde and urea (or thiourea) in ethanol using a strong
acidic catalyst i.e. HCl. The major drawback of this procedure includes
long reaction times, reflux temperatures, lower yields of the desired
product particularly in case of substituted aldehydes and loss of
sensitive functional groups during the reaction. This has led to the
development of a number of improved protocols, many of them
involving Lewis acids [13–17] including metal triflates [18,19]; silica-
4 2 2
sulfuric acid [20], ion exchange resin [21], KAl(SO ) .12H O supported
on silica gel [22], alumina supported MoO [23], poly(4-vinylpyridine-
3
co-divinylbenzene)–Cu(II) complex [24], l-proline [25] and
microwave-assisted reactions [26,27].
Synthesis of silica immobilized nickel complex is illustrated
in Scheme 1. Activated silica gel was first reacted with 3-
aminopropyltriethoxysilane to obtain aminopropyl silica gel [28].
2-acetylpyridine was then directly anchored to functionalized silica
through its ketone functionality followed by metallation with nickel
chloride [29]. The efficacy of heterogenized catalyst was investigated
for Biginelli reaction in microwave under solvent-free conditions
which is an efficient and environmental friendly procedure for the
synthesis of 3,4-dihydropyrimidinones [30].
The structure of catalyst was characterized by surface area analysis
(BET), atomic absorption spectroscopy (AAS), elemental analysis, FTIR
and 13C CPMAS spectral studies.
Incorporation of organic groups onto the surface of silica gel blocks
the access of nitrogen gas molecules and results in progressive decrease
in their surface area in the sequential order of silica gel (SG)>amino-
(
DHPM's).
The production of DHPM's via well established Biginelli reaction
certainly ranks as one of the most recognized and often used multi-
component reactions (MCR) for the generation of novel pyrimidine
scaffolds that possess wide range of biological activities, pharmaceutical
and therapeutic properties [10–12]. The standard procedure for the
Biginelli condensation involves one-pot condensation of β-ketoester
propyl silica gel (SG-NH
Table 1).
Chemical analysis of SG-NH
1.37%) corresponds to 0.79 mmolg
2 2
)>ligand immobilized silica (SG-NH -AcPy)
(
(Anal. Found: C: 4.22%, N: 1.11%, H:
⁎
Corresponding author. Tel./fax: +91 011 27666250.
E-mail address: rksharmagreenchem@hotmail.com (R.K. Sharma).
2
−
1
of aminopropyl group based
1387-7003/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.inoche.2011.12.014

R.K. Sharma, D. Rawat / Inorganic Chemistry Communications 17 (2012) 58–63
59
Scheme 1. Synthesis of covalently anchored nickel complex onto functionalized silica.
on the nitrogen percentage; whereas for the catalyst (Anal Found:
C: 9.36%, N: 1.96%, H: 1.86%), the loading of organic moiety onto the
numbered sequentially in Fig. 2c. First three peaks are attributed to
the precursor carbon atoms numbered 1, 2 and 3 as indicated in
−
1
silica gel is only 0.42 mmolg . The metal loading in catalyst was
determined by atomic absorption spectrometer (AAS) and found to
2
Fig. 2c. On complexation, the –N–CH – peak shifts to 57.9 ppm,
whereas the peak at 42.8 ppm refers to the uncomplexed –N–CH
2
–
−
1
be 0.40 mmol g
of nickel.
group. The aromatic carbon atoms at meta position to nitrogen were
assigned to that numbered 5 at 121.8 ppm whereas the one at para
position was assigned 6th peak at 134.7 ppm. The aromatic carbons
bonded to nitrogen were numbered 7 and 8 with the peaks at 147.0
and 157.1 ppm respectively. The Schiff base condensation was also
confirmed by the presence of C=N peak (assigned number 9) at
165.4 ppm. The peak with asterisk sign (*) in Fig. 2c has been merged
into the aminopropyl peaks.
FT-IR spectrum of silica gel displays characteristic bands at 3467, 1083
−
1
and 967 cm which corresponds to the OH-stretching, asymmetric and
symmetric stretching of siloxane group and bending vibrations of silanol
groups (Si–OH) respectively (Fig. 1a). The significant feature observed for
the aminopropyl silica gel is characterized by the appearance of peaks at
−
1
2
(
924 and 2851 cm
assigned to −CH
2
stretch of the propyl group
Fig. 1b). No significant changes in peaks are observed for silica gel or
modified silica which is an indication that its framework remained
Catalytic activity
unchanged. The spectrum of the immobilized ligand shows a strong
The model reaction of benzaldehyde (15 mmol), ethyl acetoacetate
(15 mmol) and urea (20 mmol) was studied under microwave
radiation and solvent-free conditions using different types of catalysts
(Table 2). The reaction did not proceed in the absence of catalyst or
only silica as the catalyst. When nickel chloride or silica immobilized
catalyst was used, high yield of the product was obtained. Lack of
recyclability of homogenously catalyzed nickel chloride as catalyst
limits its application for further use. We further examined the effect
of microwave power and irradiation time on Biginelli reaction.
100 W power was optimized for carrying out the reaction. Increasing
the power did not show a significant yield enhancement. We next
dealt with the issue of reaction time and temperature. After a few
optimization cycles, we found that 80 °C proved to be efficient
reaction temperature. Higher temperatures would lead to decreased
yields because of the formation of undesired by-products; lower
reaction temperatures on the other hand required longer reaction
times for complete conversion. For the model system, the total
irradiation time of 5 min at 80 °C in presence of silica immobilized
nickel catalyst resulted in 96% isolated yield of pure product.
Based on the optimization results, variety of aldehydes with ethyl
acetoacetate and urea were run and variety of substituted DHPM's
was obtained (Table 3). Both electron-withdrawing and electron-
−
1
band at 1647 cm
due to C=N stretching vibration (Fig. 1c). This
confirms that 2-acetylpyridine functionalized group is chemically
bonded to the surface of functionalized silica. On complexation of nickel
with the ligand, prominent C=N stretching frequency shifted to lower
wave number, indicating strong metal–ligand interaction [31].
Signals at 9.3, 22.3 and 42.9 ppm observed in the 13C CPMAS NMR
spectrum of SG-NH
respectively authenticate the synthesis of aminopropyl silica
Fig. 2a). In the spectrum of ligand grafted silica gel (SG-NH -AcPy),
2 2 2 2
due to –Si–CH –, –CH – and –N–CH – groups,
(
2
nine well-formed peaks were observed (Fig. 2b). These peaks are
Table 1
Physico-chemical parameters of silica gel, aminopropyl silica gel and catalyst.
2
Material
Elemental analysis (wt.%)
BET surface area (m /g)
%C
%N
%H
SG
SG-NH
SG-NH
–
–
–
235.67
151.91
141.93
2
2
4.22
9.36
1.11
1.97
1.37
1.86
-AcPy

60
R.K. Sharma, D. Rawat / Inorganic Chemistry Communications 17 (2012) 58–63
donating substituents on the aldehyde aryl ring produced the desired
products in high yields (90%-quantitative). Thiourea also gave similar
results for the generation of S-analogues of dihydropyrimidinones.
As evident from Table 4, our catalyst showed good results in terms
of reaction conditions compared to those reported in literature so
far.
2 2
Fig. 1. FTIR spectra of a) silica gel (SG) b) aminopropyl silica gel (SG-NH ) c) ligand grafted silica gel (SG-NH -AcPy).

R.K. Sharma, D. Rawat / Inorganic Chemistry Communications 17 (2012) 58–63
61
Fig. 1 (continued)
[
7] R.K. Sharma, C. Sharma, A highly efficient synthesis of oxindoles using a functio-
nalized silica gel as support for indium(III) acetylacetonate catalyst in an
aqueous- acetonitrile medium, J. Mol. Catal. A: Chem. 332 (2010) 53–58.
Recyclability of the catalyst is another important parameter while
using heterogeneous catalyst from an industrial point of view. The
silica immobilized nickel catalyst was recovered from reaction
media by simple filtration after dilution of with ethyl acetate. The
recovered catalyst was dried in vacuum oven at 100 °C and was
reused for further catalytic cycles. The results showed that catalyst
can be effectively used for five consecutive cycles without much
appreciable loss in its catalytic activity (shown in Fig. 3). The filtrate
[8] R.K. Sharma, C. Sharma, Zirconium(IV)-modified silica gel: preparation, charac-
terization and catalytic activity in the synthesis of some biologically important
molecules, Catal. Commun. 12 (2011) 327–331.
[
9] R.K. Sharma, D. Rawat, P. Pant, Synthesis, characterization and catalytic behaviour
of silica supported zinc salicylaldimine complex, J. Macromol. Sci. Part A Pure
Appl. Chem. 45 (2008) 394–399.
[
10] C.O. Kappe, Biologically active dihydropyrimidones of the Biginelli-type-a litera-
ture survey, Eur. J. Med. Chem. 35 (2000) 1043–1052.
(
after removal of catalyst) was tested for the presence of nickel
[
11] G.C. Rovnyak, K.S. Atwal, A. Hedberg, S.D. Kimball, S. Moreland, J.Z. Gougoutas,
B.C. O' Reilly, J. Schwartz, M.F. Malley, Dihydropyrimidine Calcium Channel
Blockers. 4. Basic 3-Substituted-4-aryl-1,4-dihydropyrimidine-5-carboxyAliccid
Esters. Potent Antihypertensive Agents, J. Med. Chem. 35 (1992) 3254–3263.
12] G.C. Rovnyak, S.D. Kimball, B. Beyer, G. Cucinotta, J.D. Dimarco, J. Gougoutas, A.
Hedberg, M. Malley, J.P. Mccarthy, R.A. Zhang, S. Morreland, Calcium Entry
Blockers and Activators: Conformational and Structural Determinants of Dihydro-
pyrimidine Calcium Channel Modulators, J. Med. Chem. 38 (1995) 119–129.
13] C. Liu, J. Wang, Y. Li, One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-(thio)ones
using strontium(II) nitrate as a catalyst, J. Mol. Catal. A: Chem. 258 (2006) 367–370.
after each catalytic cycle by AAS. Negligible leaching was observed
which indicates the true heterogeneous nature of the catalyst.
In conclusion, we have developed a greener method for the synthesis
of DHPM's using silica immobilized nickel catalyst in microwave.
Reduced reaction times, high yields of products, absence of solvent
and recyclability of catalyst make our catalyst a valuable system addition
to previously reported methods. This green methodology should be
amenable to construct new substituted DHPM scaffolds with potential
biological applications.
[
[
[
5
14] N. Ahmed, J.E.v. Lier, TaBr -catalyzed Biginelli reaction: one-pot synthesis of 3,4-
dihydropyrimidin-2-(1H)-ones/thiones under solvent-free conditions, Tetrahe-
dron Lett. 48 (2007) 5407–5409.
[
15] B.C. Ranu, A. Hajra, U. Jana, Indium(III) Chloride-Catalyzed One-Pot Synthesis of
Dihydropyrimidinones by a Three-Component Coupling of 1,3-Dicarbonyl Com-
pounds, Aldehydes, and Urea: An Improved Procedure for the Biginelli Reaction,
J. Org. Chem. 65 (2000) 6270–6272.
Acknowledgement
We are grateful to IISc (Banglore) for carrying out solid state NMR
analysis.
[16] Q. Sun, Y. Ge, Z. Wang, T. Cheng, R. Li, A highly efficient solvent-free synthesis of
dihydropyrimidinones catalyzed by zinc chloride, Synthesis (2004) 1047–1051.
[
17] G. Salitha, G.S.K.K. Reddy, K.B. Reddy, J.S. Yadav, Vanadium(III) chloride catalyzed Bigi-
nelli condensation: solution phase library generation of dihydropyrimidin-(2H)-ones,
Tetrahedron Lett. 44 (2003) 6497–6499.
References
[
18] Y. Ma, C. Qian, L. Wang, M. Yang, Lanthanide triflate catalyzed biginelli reaction.
one-pot synthesis of dihydropyrimidinones under solvent-free conditions,
J. Org. Chem. 65 (2000) 3864–3868.
[
[
[
[
1] A. Corma, Inorganic Solid Acids and Their Use in Acid-Catalyzed Hydrocarbon
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3305–3308.
[20] P. Salehi, M. Dabiri, M.A. Zolfigolc, M.A.B. Fard, Silica sulfuric acid: an efficient and
reusable catalyst for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones,
Tetrahedron Lett. 44 (2003) 2889–2891.
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62
R.K. Sharma, D. Rawat / Inorganic Chemistry Communications 17 (2012) 58–63
A
B
C
O
O
Si
3
NH
O
OH
OH
O
*
5
6
4
1
8
5
O
O
Si
N
9
2
N
7
Fig. 2. a) 13C CP MAS NMR spectrum of aminopropyl silica gel (SG-NH
). b) 13C CP MAS NMR spectrum of ligand grafted silica gel (SG-NH
-AcPy). c) Labelling of carbon atoms in
2
2
SG-NH -AcPy in order of the peaks obtained in the spectrum of panel b.
2

R.K. Sharma, D. Rawat / Inorganic Chemistry Communications 17 (2012) 58–63
63
Table 2
Screening of catalysts on the model reaction .
a
Entry
Catalyst
Amount
Yieldb (%)
1.
2.
3.
4.
No catalyst
Silica gel
–
Nil
Nil
98
96
0.5 g
10 mol%
5 mol%
NiCl2.6H
2
O
SG-NH -AcPy-Ni
2
a
Reaction conditions: benzaldehyde (15 mmol), urea (20 mmol) and ethyl acetoacetate
(
15 mmol), catalyst under microwave radiation (100 W) for 5 min.
Isolated yields.
b
[
[
[
[
[
23] S.L. Jain, V.V.D.N. Prasad, B. Sain, Alumina supported MoO3: an efficient and reus-
able heterogeneous catalyst for synthesis of 3,4-dihydropyridine-2(1H)-ones
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Catal. Commun. 5 (2004) 511–513.
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biginelli reaction: one-pot synthesis of 3,4-dihydropyrimidin-2(1H)- ones under
solvent-free conditions, Chem. Lett. 33 (2004) 1168–1169.
Fig. 3. Recyclability of catalyst for the synthesis of dihydropyrimidinones.
room temperature for 24 h. The solid was filtered, washed with methanol and
dried in vacuum at 120 °C for 4 h to obtain silica supported nickel catalyst
2
(SG-NH -AcPy-Ni) was filtered and washed with ethanol and dried under vac-
26] K.K. Pasunooti, H. Chai, C.N. Jensen, B.K. Gorityala, S. Wang, X.W. Liu,
A
uum at 120 °C for 4 h.
microwave-assisted, copper-catalyzed three-component synthesis of dihydro-
pyrimidinones under mild conditions, Tetrahedron Lett. 52 (2011) 80–84.
27] B. Liang, X. Wang, J.X. Wang, Z. Dua, New three-component cyclocondensation
reaction: microwave assisted one-pot synthesis of 5-unsubstituted-3,4-
dihydropyrimidin- 2(1H)-ones under solvent-free conditions, Tetrahedron
[
[
30] General experimental procedure: A mixture of aldehyde (15 mmol), urea
(20 mmol), ethyl acetoacetate (15 mmol), and catalyst (5 mol%) was placed in
a microwave vessel and irradiated in the microwave reactor (100 W) at 80 C
for 5 minutes. After the completion of reaction, the mixture was diluted with
ethyl acetate and the catalyst was removed by filtration. The mixture was con-
centrated and the crude product was kept into crushed ice. The solid was then fil-
tered and washed with cold water and recrystallized from ethanol to afford pure
product.
6
3 (2007) 1981–1986.
[28] B.S. Garg, R.K. Sharma, N. Bhojak, S. Mittal, Chelating resins and their applications
in the analysis of trace metal ions, Microchem. J. 61 (1999) 94–114.
[
29] Aminopropyl silica (5 g) was added to absolute ethanol (100 ml) followed by
addition of 2-acetylpyridine (0.302 g, 2.5 mmol) and the reaction mixture was
stirred at 60 °C for 24 h to obtain corresponding ligand grafted silica gel (SG-
31] E.B. Mobofu, J.H. Clark, D.J. Macquarrie, A novel Suzuki reaction system based on a
supported palladium catalyst, Green Chem. 3 (2001) 23–25.
2
NH -AcPy). The catalyst was prepared by stirring mixture of appropriate ligand
grafted silica (4 g) and nickel chloride (0.2 mmol) in methanol (100 ml) at
Table 3
One-pot synthesis of 3,4-dihydropyrimidinone catalyzed by covalently anchored nickel catalyst under microwave radiation.a
Entry
1c
Product
R′
R″
X
Yieldb (%)
Observed Mp (°C)
Reported Mp (°C)
.
4a
4b
4c
4 d
4e
4f
4 g
4 h
4i
C
6
H
5
C
C
C
C
C
C
C
C
2
2
2
2
2
2
2
2
H
H
H
H
H
H
H
H
5
5
5
5
5
5
5
5
O
O
O
O
O
O
O
O
O
O
S
96,96,95,94,93
201–203
212–214
202–204
208–210
207–209
231–233
213–215
228–230
208–210
228–230
207–209
216–218
180–183
200–202 [25]
213–216 [20]
202–204 [25]
211–213 [26]
207–209 [25]
230–232 [25]
215 [28]
229–230 [27]
208–211 [28]
225–227 [25]
208–210 [25]
–
2
3
4
5
6
7
8
9
1
1
1
1
.
.
.
4-(CH
4-(CH
3
)-C
O)-C
H
6 4
6
H
4
95
94
94
93
93
94
92
96
80
96
95
93
3
6
H
4
4-(Cl)-C
4-(NO )-C
4-(OH)-C
4-(Br)-C
3-(NO )-C
d.
.
2
6
H
4
6 4
H
H
6 4
.
d.
.
H
2
6
4
C
C
C
6
6
6
H
5
H
5
H
5
CH
3
d
0 .
1.
2.
4j
CH=CH
C
C
C
2
2
2
H
H
H
5
5
5
4 k
4 l
4 m.
4-Br-C
4-Cl-C
6
H
4
S
S
3.
6
H
4
CH
3
184–185 [26]
a
Reaction conditions: aldehyde (15 mmol), urea (20 mmol) and 1,3-dicarbonyl compound (15 mmol), catalyst (5 mol%) under microwave radiation (100 W) for 5 min.
Isolated yields. All the products obtained were fully characterized by spectroscopic methods such as IR, 1H NMR and also comprised the reference compounds.
Recycling experiments.
b
c
d
10 min.
Table 4
Comparison of catalytic activity of nickel supported catalyst with other catalysts reported in literature for synthesis of 3,4 DHPM's.
Catalyst
Conditions
Time (h)
Yield (%)
Reference
Silica/sulphuric acid
Ethanol/reflux
6.0 h
7.0 h
4 h
1.0 h
5 min
91
95
92
95
98
[20]
[15]
[22]
[24]
InCl
KAl(SO
3
THF/reflux/under N
Solvent free/80 °C
Acetonitrile/80 °C
2
/100 °C
4 2
) .12H
2
O supported on silica gel
Silica supported tungstophosphoric acid
Our catalyst
Solvent free/microwave
[Present work]