Ceria/vinylpyridine polymer nanocomposite: An ecofriendly catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2005.09.100

The three-component condensation of aldehydes, β-ketoesters and urea has been carried out in water using ceria (cerium oxide, CeO₂) nanoparticles supported on poly(4vp-co-dvb) as a catalyst for the preparation of 3,4-dihydropyrimidin-2(1H)-ones

Full text of DOI:10.1016/j.tetlet.2005.09.100

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8221–8224
Ceria/vinylpyridine polymer nanocomposite: an ecofriendly
catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-onesq
a
a
b,
Gowravaram Sabitha,a,* K. Bhaskar Reddy, J. S. Yadav, D. Shailaja and
*
K. Samba Sivudub
aOrganic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bOrganic Coatings and Polymers Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 25 July 2005; revised 8 September 2005; accepted 16 September 2005
Available online 10 October 2005
Abstract—The three-component condensation of aldehydes, b-ketoesters and urea has been carried out in water using ceria (cerium
oxide, CeO2) nanoparticles supported on poly(4vp-co-dvb) as a catalyst for the preparation of 3,4-dihydropyrimidin-2(1H)-ones in
good yields. The catalyst was recovered easily and reused without loss of its activity.
Ó 2005 Elsevier Ltd. All rights reserved.
The development of efficient and environmentally
acceptable synthetic methods is an important task of
modern chemistry. Conventional organic syntheses are
generally based on homogeneous catalysts. However,
homogeneous reactions suffer disadvantages in separa-
tion, regeneration, etc. From the viewpoint of green
chemistry, the use of heterogeneous catalysts is desir-
able. The consequent advantages of heterogeneous catal-
ysts from the environmental and economic points of
view are clearly understandable, since these procedures
allow money to be saved and the production of waste
at source to be minimized. In addition to this, the use
of water as a reaction medium represents a remarkable
benefit. In recent years, metal nanoparticles supported
on polymers1 have attracted much attention in organic
transformations.
emerged as potent calcium channel blockers,4 antihyper-
tensive agents,5 adrenergic6 and neuropeptide Y antago-
nists.7 Apart from this they are also of interest as agents
for treating anxiety,8 and optic nerve dysfunction.9
Therefore, many research groups have focused their
attention on the synthesis of these compounds. How-
ever, this one-pot, one-step protocol often provides
low yields of the products, when substituted aromatic
or aliphatic aldehydes are employed. Therefore, the
use of catalysts has become essential to obtain higher
yields.
3,4-Dihydropyrimidines have previously been synthe-
sized by Biginelli reaction in the presence of strong acids
and Lewis acids. These have included BF3ÆEt2O/CuCl,10
InCl3,11 LaCl3ÆH2O,12 ZrCl4,13 Yb(OTf)4,14 boric acid15
and silica-sulfuric acid.16 However, many of these re-
agents are expensive, harmful and difficult to handle
especially on a large scale and moreover are homo-
geneous in nature. Recently, we have reported a
room temperature protocol using and a library genera-
tion using TMSI17 and VCl3,18 respectively, for the syn-
thesis of Biginelli compounds. We now report the three-
component synthesis of dihydropyrimidines in water in
the presence of a heterogeneous catalyst [ceria (cerium
oxide, CeO2) nanoparticles supported on poly(4vp-
co-dvb) via in situ polymerization],19 under mild condi-
tions (Scheme 1). The catalyst can be prepared easily
and has added advantages of recovery, reusability and
high activity.
The Biginelli reaction2 was first reported more than a
century ago and involves the synthesis of 3,4-dihydro-
pyrimidin-2(1H)-ones by a one-pot condensation reac-
tion of ethyl acetoacetate, benzaldehyde and urea in
ethanol. The synthesis of dihydropyrimidinones has
gained much attention due to their wide range of phar-
macological and biological properties.3 They have
Keywords: Biginelli reaction; Water; Heterogeneous catalysis; Ceria
nanoparticles; Reusability.
q IICT Communication No. 050726.
*
Corresponding authors. Tel./fax: +91 40 27160512; e-mail: sabitha@
iictnet.org
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.100

8222
G. Sabitha et al. / Tetrahedron Letters 46 (2005) 8221–8224
N
N
N
.
CeCl3 7H2O +NaOH
CeO
2
CeO
CeO
2
2
2
89 oC
+
PVP+Initiator
N
N
N
N
CeO
CeO
CeO
2
2
Catalyst : Ceria nanoparticles supported on poly(4vp-co-dvb) via in situ
polymerization
O
R
O
10 mol% catalyst
2
O
O
R
NH
+
+
1
R
R-CHO
2
1
NH2
R
H2N
˚
H2O, 80 C, 4.5-10 h
R
N
H
O
2
1
4
3
Scheme 1.
Table 1. Polymer supported ceria nanoparticles-catalyzed synthesis of dihydropyrimidinones 4a
Entry
Esters 2
Aldehydes 1
Time (h)
4.5
Yield (%)b
92
4
CHO
O
O
a
OEt
OEt
CHO
CHO
O
O
O
O
b
c
5.0
5.0
5.0
84
88
86
O2N
Me
O
O
OEt
CHO
d
OEt
O
MeO
CHO
O
O
e
f
10
10
55
51
OMe
CHO
O
OMe
F
O
O
g
6.0
82
CHO
OEt
O
S
O
O
O
O
O
O
O
O
h
i
6.0
5.5
4.5
5.0
78
76
89
87
CHO
OEt
OEt
CHO
CHO
j
OMe
OMe
Me
CHO
k
MeO
CHO
O
O
l
5.0
78
a All products are characterized by IR, 1H NMR and mass spectroscopy.
b Isolated yields after purification.

G. Sabitha et al. / Tetrahedron Letters 46 (2005) 8221–8224
8223
6. (a) Sidler, D. R.; Larsen, R. D.; Chartrain, M.; Ikemoto,
N.; Roberg, C. M.; Taylor, C. S.; Li, W.; Bills, G. F. PCT
Int. WO 99 07,695, 1999; (b) Nagarathnam, D.; Wong, W.
C.; Miao, S. W.; Patance, M. A.; Gluchowski, C. PCT Int.
Appl. WO 97 17,969, 1997.
Thus, the reaction of benzaldehyde 1a, ethyl acetoace-
tate 2a and urea 3 was performed in water at 80 °C
for 4.5 h in the presence of 10 mol % catalyst to give
3,4-dihydropyrimidine 4a in 92% yield. After cooling
to room temperature, the reaction mixture was diluted
with ethyl acetate. The catalyst was recovered from the
water by simple filtration and reused. The product was
isolated from ethyl acetate and purified by recrystalliza-
tion. To investigate the generality of the catalyst, vari-
ous aldehydes were used to prepare the corresponding
Biginelli products in good yields under similar con-
ditions (Table 1). A variety of substituted aromatic,
aliphatic and heteroaromatic aldehydes carrying
either electron-donating or -withdrawing groups afforded
high yields of products. Acid-sensitive aldehydes such
as furfural worked well without the formation of any
side products. It is noteworthy that this catalyst was
also successfully used for the synthesis of methyl 6-
cyclopropyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-5-pyrim-
idine carboxylate (Table 1, entry e) in moderate yield.20
The products 4e and 4f have not been previously
reported.
7. Bruce, M. A.; Pointdexter, G. S.; Johnson, G. PCT Int.
Appl. WO 98 33,791, 1998.
8. Horovitz, Z. P. (Squibb, E. R. and Sons). Eur. Pat. Appl.
EP 1990,400,665; Chem. Abstr. 1991, 115, 64793.
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Aberg, G. (Houston Biotechnology Inc.; Sqiubb, E. R.
and Sons). PCT Int. Appl. WO 1990,06,118; Chem. Abstr.
1991, 114, 157224w.
10. Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem.
1998, 63, 3454–3457.
11. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270–6272.
12. Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron
Lett. 2000, 41, 9075–9078.
13. Reddy, Ch. V.; Mahesh, M.; Raju, P. V. K.; Babu, T. R.;
Reddy, V. V. N. Tetrahedron Lett. 2002, 43, 2657–2659.
14. Ma, Y.;Qian, C.; Wang, L.;Yang, M. J. Org. Chem.2000, 65,
3864–3868.
15. Tu, S.; Fang, F.; Miao, C.; Jiang, H.; Feng, Y.; Shi, D.;
Wang, X. Tetrahedron Lett. 2003, 44, 6153–6155.
16. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Fard, M. A. B.
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17. Sabitha, G.; Reddy, G. S. K. K.; Reddy, Ch. S.; Yadav, J.
S. Synlett 2003, 6, 858–860.
We also examined the reusability of the catalyst. As a
model reaction, the condensation reaction of ethyl aceto-
acetate, benzaldehyde and urea was repeated three times
with the regenerated catalyst and the yields were 92%,
89% and 85%, respectively, indicating that it is indeed
a recyclable catalyst.
18. Sabitha, G.; Reddy, G. S. K. K.; Reddy, K. B.; Yadav, J.
S. Tetrahedron Lett. 2003, 44, 6497–6499.
19. Materials: 4-Vinyl pyridine (4VP), divinyl benzene
(DVB), t-amylperoxy 2-ethylhexane carbonate (Luperox
101) and 2,5-bis(tert-butylperoxy) 2,5-dimethylhexane
(Lupersol TAEC) were purchased from Aldrich Chemi-
cals, USA. Polyvinylpyrrolidone (K-30) (PVP), cerium
trichloride heptahydrate (CeCl3Æ7H2O), sodium hydroxide
(NaOH) and reagent grade methanol were procured from
SD Fine Chemicals, India. 4VP was purified by distillation
under vacuum prior to use while the others were used as
obtained without further purification.
In conclusion, the three-component condensation has
been efficiently performed in water as a ꢀgreenꢁ solvent
and by using ceria nanoparticles supported on poly
(4vp-co-dvb) via in situ polymerization. The easy purific-
ation of products, easy catalyst handling, reusabilility
of the catalyst, the use of water as solvent combined
with the exploitation of a multi-component strategy
open good prospects to this process for industrial
applicability.
Preparation of poly(4vp-co-dvb)/CeO2nanocomposite:21
The nanocomposite was prepared by the suspension
copolymerization method using 4vp and dvb (2mol %
with respect to 4vp). To a four-neck resin kettle, fitted
with a half moon Teflon blade agitator, a nitrogen purge
adaptor and a reflux condenser containing 2.5% (by
weight) PVP distilled aqueous solution, a mixture of 4vp,
dvb, CeCl3Æ7H2O (5 mol % on monomers) and 2%
Lupersol TAEC initiator (w/w on monomers) was added
dropwise while operating the blade agitator at 650 rpm at
room temperature. The nitrogen purge was continued
throughout the reaction. A pH of 10 was maintained
using 0.1 N NaOH for 30 min in order to obtain
nanosized ceria particles. The bath temperature was
raised to 89 °C and maintained for 1 h before increasing
further to 100 °C. The second initiator, 1% Luperox 101
(w/w based on monomers) was then added to the reaction
mixture. The reaction was allowed to proceed for 5 h with
continuous agitation. The ceria nanoparticles supported
on the copolymer thus formed were filtered and washed
thoroughly with hot water to remove the water soluble
PVP followed by methanol to remove the linear polymer
and traces of unreacted monomers. The yellow coloured
composite was dried overnight under vacuum at 65 °C.
20. Typical procedure: To a mixture of benzaldehyde 1
(4.7 mol, 500 mg), methyl 3-cyclopropyl-3-oxo-propionate
2e (4.7 mmol, 670 mg), urea 3 (7.1 mmol, 425 mg) and
ceria nanoparticles (0.47 mmol, 650 mg) was added 5 mL
Acknowledgements
K.B.R. thanks UGC, New Delhi, for the award of
fellowship.
References and notes
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1991, 34, 806–811.

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G. Sabitha et al. / Tetrahedron Letters 46 (2005) 8221–8224
of distilled water and the reaction mixture was stirred for
10 h at 80 °C. After cooling to room temperature, ethyl
acetate was added to the reaction mixture which was then
filtered through a Buchner funnel. The organic layer was
separated, washed with water, dried over sodium sulfate
and concentrated under reduced pressure. The crude
product was recrystallized from a hexane:ethyl acetate
mixture to afford pure 4e.
Spectral data for compound 4e: White solid, mp 113–
1
115 °C; IR (KBr) mmax 3245, 1735, 1647 cmÀ1; H NMR
(300 MHz, CDCl3): d 0.80–1.04 (m, 4H), 3.04 (m, 1H),
3.60 (s, 3H), 5.34 (s, 1H), 6.55 (br s, NH), 7.15–7.31 (m,
5H); LS–MS: m/z 273.2 (M+1).
21. Sivudu, K. S.; Reddy, K. B.; Sabitha, G.; Yadav, J. S.;
Shailaja, D. Macromol. Rapid Commun. submitted for
publication.