An appropriate one-pot synthesis of dihydropyrimidinones catalyzed by heteropoly acid supported on zeolite: An efficient and reusable catalyst for the Biginelli reaction

Article abstract of DOI:10.1016/j.crci.2011.11.015

A mild and efficient catalytic method has been developed for the synthesis of 3,4-dihydropyrimidin-2 (1H)-ones (DHPM) by a one-pot three-component cyclocondensation reaction using molybdophosphoric acid (MPA) supported on Y zeolite in high to excellent yi

Full text of DOI:10.1016/j.crci.2011.11.015

C. R. Chimie 15 (2012) 444–447
Contents lists available at SciVerse ScienceDirect
Comptes Rendus Chimie
www.sciencedirect.com
´
Full paper/Memoire
An appropriate one-pot synthesis of dihydropyrimidinones catalyzed by
heteropoly acid supported on zeolite: An efficient and reusable catalyst
for the Biginelli reaction
Maryam Moosavifar
Department of Chemistry, Faculty of Science, University of Maragheh, P.O. Box 55181-83111, Maragheh, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A mild and efficient catalytic method has been developed for the synthesis of 3,4-
dihydropyrimidin-2 (1H)-ones (DHPM) by a one-pot three-component cyclocondensation
reaction using molybdophosphoric acid (MPA) supported on Y zeolite in high to excellent
yields. The reaction investigated in the presence of molybdophosphoric acid encapsulated
in the supercage of zeolite for comparison. In the second method, no appreciable progress
was observed due to large size of dihydropyrimidinone compounds towards the supercage
dimension of Y zeolite. In addition, the catalyst was recovered and reused for several times
without efficient loss in catalytic activity.
Received 19 September 2011
Accepted after revision 23 November 2011
Available online 23 February 2012
Keywords:
Biginelli reaction
Dihydropyrimidinones
Heterogeneous
ß 2012 Published by Elsevier Masson SAS on behalf of Acade´mie des sciences.
Heteropolyacid (HPA)
Dealuminated zeolite
1. Introduction
variety of Lewis acid catalysts have been devoted. These
catalytic systems involve ytterbium(III) resin [6], Mn(OA-
Dihyropyrimidinones derivatives known as ‘‘Biginelli
compounds’’ have received significant attention because of
their wide range of pharmacologically potent calcium
c)3.2H2O [7], trifluoroacetic acid (TFA) [8], boric acid [9],
CeCl3.7H2O [10], Cu(OTf)2 [11], lithium bromide [12], silica/
sulfuric acid [13], indium (III) bromide [14], lanthanum
chloride [15], vanadium(III) chloride [16], ionic liquids
BMImPF6 and BMImBF4 [17], montmorillonite-KSF [18],
zinc triflate [19], I2 [20], NBS [21], bismuth triflate [22],
LiClO4 [23], NH4Cl [24], zirconium(IV) chloride [25],
indium(III) bromide [26], heteropolyacid Ag3PW12O40
[27], supported polyoxometal [28], benzyltriethylammo-
nium chloride [29], Y(OAc)3 [30], AlCl3:ZnCl2 (3:1) [31],
etidronic acid [32], silica-chloride [5] and -SmCl3.6H2O [33].
Among support systems, zeolite Y is an appropriate
candidate for the immobilization of HAP because it
produces heterogeneous catalysts that are recoverable
and reusable.
channel blockers, antihypertensive agents and a-adrener-
gic antagonists, and neuropeptide Y (NPY) antagonists.
These compounds also have been found to have a broad
range of biological activities such as antiviral, antitumor,
cardiovascular antibacterial, anti-inflammatory and anti-
oxidant properties [1–4]. Therefore, the preparation of these
materials has attracted the significant attention of many
chemists. The classical Biginelli synthesis involves three-
component one-pot condensation of
b-ketoester with an
aldehyde and urea under strongly acidic conditions, but the
reaction suffer from drawbacks such as low yields, long
reaction time, and strong corrosion equipment [5]. In order
to improve the efficiency of these reactions, many efforts
including various solid-phase modifications and use of a
In a continuation of our previous work on heteroge-
neous catalysts [34–36], we wish to report a cheap,
recoverable and efficiency catalytic system for the
synthesis of dihydropyrimidinone from aldehyde in the
presence of supported polyoxometal on external zeolite
surface as a solid acid catalyst.
E-mail addresses: m.moosavifar90@gmail.com,
m.moosavifar@maragheh.ac.ir.
1631-0748/$ – see front matter ß 2012 Published by Elsevier Masson SAS on behalf of Acade´mie des sciences.
doi:10.1016/j.crci.2011.11.015

M. Moosavifar / C. R. Chimie 15 (2012) 444–447
445
Table 1
2. Experimental
Synthesis of ethyl-6-methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxilate in the presence of zeolite-supported
molybdophosphoric acid in various solvent after 6 h under reflux
conditions.a
Polyoxometalates including molybdophosphoric acid,
tangestophosphoric acid and tangestosilisic acid, denoted
as molybdophosphoric acid (MPA), tangestophosphoric
acid (TPA) and tangestosilisic acid (TSA), respectively, were
purchased from Merck and purified by extraction with
dimethyl ether from aqueous solution and then dried
under reduced pressure. Other materials were of the
commercial reagent grade and used without further
purification. The NaY-zeolite was purchased from Sigma-
Aldrich Chemical Company. Melting points were recorded
on a Barnstead Electrothermal 9200 apparatus and are
uncorrected. All of the reactions were performed under
magnetically stirring and the progress of the reactions was
monitored by thin layer chromatography (TLC). All
products were known compounds and identified by
comparing their physical data to their authentic samples.
Yieldb (%)
Solvent
Entry
55
25
45
74
97
Ethylacetate
dichloromethane
Chloroform
Methanol
1
2
3
4
5
Acetonitrile
a
Reaction conditions: 4-Nitro benzaldehyde (1 mmol), acetoacetate
(1 mmol), urea (1.5 mmol), solvent (10 mL), catalyst (0.7 mol%).
b
Isolated yield.
product. Products were identified by comparison with
melting points of the authentic compounds.
In addition, the Biginelli reaction was performed in the
presence of zeolite-encapsulated HPA for comparison.
Synthesis of this catalyst is discussed in our previous works
[34–36].
2.1. General procedure for the preparation of supported
polyoxometalate
The catalysts were prepared by the incipient wetness
3. Results and discussion
method [28]. The framework of
Y zeolite involves
aluminum atoms that show basicity. Thus, they may
decompose as a heteropolyacid structure [37]. Therefore, Y
zeolite was modified by acid treatment. In the typical
procedure, aqueous NaY suspension was prepared (8 wt%)
and dealuminated by additing HClO4 to suspension of
zeolite in water following 0.5 mM heteropolyacid (HPA)
addition [38]. The mixture of HPA was supported on
dealuminated zeolite (HY), stirred for 24 h followed by
drying at 383 K and calcined for 4 h at 250 8C to obtain the
support catalyst.
Catalysts were prepared by the impregnation of HPA in
an acidic suspension with zeolite as a support. The zeolite
structure shows basicity because of aluminum atoms so
that it causes the decomposition of HPA. Therefore, Y
zeolite was dealuminated by adding perchloric acid
according to the reported procedure [38]. The reaction
of aldehydes with acetoacetate and urea in the presence of
HPA supported on dealuminated zeolite produced corre-
sponding dihyropyrimidinone compounds (Scheme 1).
Several solvents were used with 4-Nitro benzaldehyde as a
model substrate and zeolite supported-MPA as a model
catalyst at reflux conditions. The best results were
obtained with acetonitrile (Table 1). Under this condition,
a wide range of aromatic aldehyde bearing electron-
withdrawing or electron-donating groups was reacted to
obtain the corresponding compounds in good to excellent
yield (Table 2). Zeolite-encapsulated HPA was used in
these reactions for comparison. The result proved in the
presence of zeolite-encapsulated HPA, the yield of
dihyropyrimidinone is very negligible that proved dihyro-
pyrimidinone molecules cannot be formed in the superc-
age of zeolite because of the large size of these molecules.
Therefore, the supported system was chosen as the
catalytic system. The reusability of catalyst was investi-
gated using 3-nitrobenzaldehyde (1 mmol) as a model
2.2. General procedure for the synthesis of
dihydropyrimidinones
In a typical procedure, ethyl acetoacetate (1 mmol),
aldehyde (1 mmol) and urea (1.5 mmol) were mixed with
HPA supported on Y zeolite (8 wt% NaY + 0.5 mM HPA) and
refluxed in the presence of acetonitrile (10 mL) as a solvent
for an appropriate time. The progress of reaction was
monitored by TLC. At the end of reaction, heteropoly acid
(HPA) supported on HY filtered off and washed with hot
water and ethanol to remove urea from the surface of the
catalyst. Then, the catalyst dried and was maintained for
new runs. The filtrate was concentrated and the crude
product was recrystallized from ethanol to afford the pure
R
O
O
O
O
O
zeolite-supported HPA
+
+
H
R
H2N
NH2
H3C
OCH 2CH3
CH3CH2O
H3C
NH
CH3CN,
N
H
O
Scheme 1. Synthesis of conventional dihydropyrimidinones in the presence of zeolite-supported heteropolyacid under reflux condition.

446
M. Moosavifar / C. R. Chimie 15 (2012) 444–447
Table 2
Synthesis of 3,4-dihydropyrimidin-2 (1H)-ones, catalyzed by zeolite-supported heteropolyacid.
Entry
1
Substrate
MPA-supported HY
TPA-supported HY
TSA-supported HY
Melting point
Foundb
Time (h)
10
Yielda (%)
Time (h)
7
Yielda (%)
Time (h)
11
Yielda (%)
Reported
220 [7]
94
65
72
223
O
H
NO2
2
8.5
95
9.5
95
10.5
94
225–227
227–228 [14]
O
H
NO2
3
4
5
6
97
95
93
5
80
95
95
6
92
92
93
208–210
213–215
206
209–211 [13]
214–216 [26]
207–208 [30]
O
H
O2N
H3C
6.5
7.5
6.5
7.5
8.5
8.5
O
H
O
H
OMe
6
7.5
90
92
4.5
8.5
90
213
215–216 [7]
O
H
Cl
7
8
7.5
95
70
8
5
80
70
12
11
97
70
198
199–202 [17]
156–158 [30]
O
H
O
MeO
11
157–159
H
CH(CH3)3
9
8
90
80
9.5
93
90
10
80
90
217–218
198–199
215–216 [7]
199–201 [28]
O
H
OH
10
7.5
6
5.5
O
H
OH
MPA: molybdophosphoric acid;TPA: tangestophosphoric acid; TSA: tangestosilisic acid; HY: dealuminated zeolite.
a
Isolated yield.
b
Compounds are known and were characterized by their physical and spectral data.

M. Moosavifar / C. R. Chimie 15 (2012) 444–447
447
[3] K.S. Atwal, C.G. Rovnyak, B.C. O’Reilly, A.J. Schwartz, Org. Chem 54
(1989) 5898.
[4] C.O. Kappe, Tetrahedron 49 (1993) 6937.
[5] H.N. Karade, M. Sathe, M.P. Kaushik, Molecules 12 (2007) 1341.
[6] A. Dondoni, A. Massi, Tetrahedron Lett 42 (2001) 7975.
[7] K.A. Kumar, M. Kasthuraiah, C.S. Reddy, C.D. Reddy, Tetrahedron Lett 42
(2001) 7873.
Table 3
The results obtained in the reusability of zeolite-supported molybdopho-
sphoric acid catalyst in the synthesis of ethyl-6-methyl-4-(4-nitrophe-
nyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxilate after 6 h.
Yielda (%)
Run
[8] J.C. Bussolari, P.A. McDonnel, J. Org. Chem 65 (2000) 6777.
[9] S. Tu, F. Fang, C. Miao, H. Jiang, Y. Feng, D. Shi, X. Wang, Tetrahedron Lett
44 (2003) 6153.
[10] D.S. Bose, L. Fatima, C. Miao, H. Jiang, Y. Feng, D. Shi, X.J. Wang, Org.
Chem 68 (2003) 587.
97
95
94
95
90
1
2
3
4
5
[11] A.S. Paraskar, G.K. Dewkar, A. Sudalai, Tetrahedron Lett 44 (2003) 3305.
[12] G. Maiti, P. Kundu, C. Guin, Tetrahedron Lett 44 (2003) 2757.
[13] P. Salehi, M. Dabiri, M.A. Zolfigol, M.A. Bodaghi Fard, Tetrahedron Lett
44 (2003) 2889.
a
Isolated yield.
[14] N.Y. Fu, M.L. Pang, Y.F. Yuan, J.T. Wang, Chin. Chem. Lett 13 (2002) 921.
[15] J. Lu, Y. Bai, Z. Wang, B. Yang, H. Ma, Tetrahedron Lett 41 (2000) 9075.
[16] G. Sabitha, G.S.K. Reddy, K.B. Reddy, J.S. Yadav, Tetrahedron Lett 44
(2003) 6497.
[17] J. Peng, Y. Deng, Tetrahedron Lett 42 (2001) 5917.
[18] F. Bigi, S. Carloni, B. Frullanti, R. Maggi, G. Sartori, Tetrahedron Lett 40
(1999) 3465.
[19] H. Xu, Y. Wang, Chin. J. Chem 21 (2003) 327.
[20] K.V.N. Srinivas, B. Das, Synthesis 13 (2004) 2091.
[21] H. Hazarkhani, B. Karimi, Synthesis 8 (2004) 1239.
[22] R. Varala, M.M. Alam, S.R. Adapa, Synlett 1 (2003) 67.
[23] J.S. Yadav, B.V.S. Reddy, R. Srinivas, C. Venugopal, T. Ramalingam,
Synthesis 9 (2001) 1341.
substrate in the presence of recovered catalyst (0.7 mol%)
and acetonitrile (10 mL) as solvent under reflux conditions.
At the end of the reaction, the catalyst was filtered and
washed by hot water and ethanol to remove unreacted
species. Then, the catalyst was activated by drying at
120 8C for 3 h and was used for new runs. No appreciable
loss in the catalytic activity was detected, which means
that HPA is still present on the support system (Table 3).
[24] A. Shaabani, A. Bazgir, F. Teimouri, Tetrahedron Lett 44 (2003) 857.
[25] C.V. Reddy, M. Mahesh, P.V.K. Raju, T.R. Babu, V.V.N. Reddy, Tetrahe-
dron Lett 43 (2002) 2657.
4. Conclusion
In conclusion, in this paper, we reported a mild and
efficient protocol for the synthesis of dihydroprimidinone
[26] N.Y. Fu, Y.F. Yuan, Z. Cao, S.W. Wang, J.T. Wang, Tetrahedron 58 (2002)
4801.
[27] J.S. Yadav, B.V.S. Reddy, P. Sridhar, J.S.S. Reddy, K. Nagaiah, N. Lingaiah,
P.S. Saiprasad, Eur. J. Org. Chem 3 (2004) 552.
compounds that utilizes
a multicomponent coupling
reaction catalyzed by HPA supported on Y zeolite in
refluxing acetonirtile. In the presence of zeolite-encapsu-
lated HPA, the yield of reaction is very negligible due to the
size of dihydropyrimidinone compounds being larger than
the supercage of zeolite. Then, support system was chosen
as the catalytic system. The catalyst was recoverable and
reused for several times without losing effective catalytic
activity.
[28] R. Fazaeli, S. Tangestaninejad, H. Aliyan, M. Moghadam, Appl. Catal. A:
General 309 (2006) 44.
[29] D.S. Bose, M. Sudharshan, S.W. Chavhan, ARKIVOC iii (2005) 228.
[30] G. Aridoss, Y.T. Jeong, Bull. Korean Chem. Soc 31 (2010) 863.
[31] S. Balalaie, M. Soleiman-Beigi, F.J. Rominger, Iran. Chem. Soc 2 (2005) 319.
[32] A.M. Pansuriya, M.M. Savant, C.V. Bhuva, J. Singh, Y.T. Naliapara,
ARKIVOC vii (2009) 79.
[33] Y.X. Li, W.L. Bao, Chinese Chem. Lett 14 (2003) 993.
[34] M. Moghadam, S. Tangestaninejad, V. Mirkhani, I. Mohammadpoor, M.
Moosavifar, C. R. Chimie 14 (2011) 489.
[35] M. Moghadam, S. Tangestaninejad, V. Mirkhani, I. Mohammadpoor, M.
Moosavifar, Appl. Catal A: general 358 (2009) 157.
[36] M. Moosavifar, S. Tangestaninejad, M. Moghadam, V. Mirkhani, I.
Mohammadpoor, C. R. Chimie 14 (10) (2011) 953.
[37] S.R. Mukai, T. Masuno, I. Ogina, K. Hashimoto, Appl. Catal. A: general
165 (1997) 219.
References
[1] K.S. Atwal, B.N. Swanson, S.E. Unger, D.M. Floyed, S. Moreland, A.
Hedberg, B.C. O’Reilly, J. Med. Chem 34 (1991) 806.
[2] C.O. Kappe, W.M.F. Fabian, M.A. Semones, Tetrahedron 53 (1997) 2803.
[38] R.R. Ozer, J.L. Ferry, J. Phys. Chem. B 106 (2002) 4336.