Nasr-Esfahani MASOUD et al. / Chinese Journal of Catalysis, 2011, 32: 1484–1489
ȕ-ketoester under acidic conditions [10]. One major drawback
1 Experimental
of this reaction, however, is the low to moderate yields that are
frequently obtained when using substituted aromatic or ali-
phatic aldehydes [11]. This has led to the development of more
complex multistep strategies that produce somewhat higher
overall yields but lack the simplicity of the one-pot Biginelli
protocol [11,12]. Thus, Biginelli’s reaction for the synthesis of
dihydropyrimidinone has received renewed interest and several
improved procedures have recently been reported [13–16]
although some of these methods involve the use of strong
Lewis acids such as BF3 [14], Bi(NO3)3 [15], and Ln(OTf)3
[16], protic acids such as AcOH [14], and additives [14].
However, there are several disadvantages associated with the
reported methodologies including unsatisfactory yields, long
conversion times, difficult handling of reagents, toxic and
inflammable organic solvents, and incompatibility with other
functional groups in the molecules that limit these methods to
small-scale synthesis. Thus, the development of facile and
environmentally friendly synthetic methods for the preparation
of dihydropyrimidinones and dihydropyrimidinthiones are in
demand.
1.1 Preparation of the Fe3O4 NPs
The Fe3O4 NPs were prepared as reported in the literature
[23]. Typically, to prepare Fe3O4 NPs 5.2 g of FeCl3 and 2.0 g
of FeCl2 were successively dissolved in 25 ml of distilled water
containing 0.85 ml of 12.1 mol/L HCl. The resulting solution
was added dropwise into 250 ml of a 1.5 mol/L NaOH solution
under vigorous stirring. The last step generated an instant black
precipitate. The precipitate was isolated in a magnetic field and
the supernatant was removed from the precipitate by decanta-
tion.
1.2 Synthesis of 3,4-dihydropyrimidin-2(1H)-ones
All the chemicals were purchased from Merck, Fluka and
Sigma-Aldrich. The reactions were monitored by thin layer
chromatography (TLC). The products were isolated and iden-
tified by comparing their physical and spectral data with au-
thentic samples. Infrared (IR) spectra were recorded on FT-IR
1
Recently, the application of nanoparticles (NPs) as catalysts
has attracted worldwide attention because of their high cata-
lytic activity and improved selectivity [17]. Although the
nanocatalysts have several advantages over conventional
catalyst systems the isolation and recovery of these nanocata-
lysts is difficult. To overcome this problem the use of mag-
netically recoverable nanocatalysts is of interest [18]. This type
of nanocatalyst can be easily separated from the reaction
mixture using an external magnetic field. Fe3O4 NPs have been
used as an efficient and magnetically recoverable nanocatalyst
in the three-component coupling of an aldehyde, an alkyne, and
an amine [19]. Also, the application of Fe3O4 NPs as nano-
catalysts in a C-C coupling reaction by the Sonoga-
shira-Hagihara reaction has been investigated [20].
JASCO-680, H-NMR spectra were obtained on a Bruker
DPX-300 MHz and melting points were determined on a
Barnstead Electrothermal (BI 9300) apparatus.
In
a
typical procedure for the preparation of
5-(ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-one (7a), a mixture of benzaldehyde (1 mmol), ethy-
lacetoacetate (1 mmol), urea (1.5 mmol), and Fe3O4 NPs (0.046
g) was stirred at 80 °C for 16 min. After the completion of the
reaction as determined by TLC, 5 ml of ethanol was added to
the reaction mixture, stirred and heated for 5 min. The reaction
mixture was filtered and washed with hot ethanol. The hot
filtrate was poured onto crushed ice and the solid product
collected by filtration and washed with cold ethanol and a
mixture of ethanol-water. The solid product was recrystallized
from ethanol. The products were characterized by IR, 1H NMR,
and by a comparison of their melting points with the reported
melting points.
Because of their inherent properties like environmental
friendliness, greater selectivity, operational simplicity,
non-corrosive nature, moisture insensitivity, and ease of isola-
tion, it is of interest to determine the behavior of this catalytic
system for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones
(thiones).
5-Ethoxycarbonyl-6-methyl-4-(2-chloro-6-flourophenyl)-3,
4-dihydropyrimidin-2(1H)-one (7g). mp: 246–248 °C; Rf =
0.33 (n-hexane:ethyl acetate = 2:1); IR (KBr, cm–1): 3349, 3122,
1
Following our interest in producing 3,4-dihydropyrimidine-
2(1H)-ones [21,22], a study to revisit this reaction in a parallel
combinatorial fashion using the Fe3O4 NPs solvent-free syn-
thesis approach was initiated (Scheme 2).
2983, 1698, 1636, 1520, 1454, 1230; H NMR (400 MHz,
CDCl3): G 0.95 (t, 3H, J = 7.0 Hz), 2.19 (s, 3H), 3.88 (q, 2H, J =
6.8 Hz), 5.86 (s, 1H), 7.16 (dd, J = 8.2 and J = 21.6 Hz, 1H), 7.3
(m, 2H), 7.63 (s, 1H), 9.3 (s, 1H); Anal. Calcd. for
C14H14ClFN2O3: C, 53.77; H, 4.51; Cl, 11.34; F, 6.08; N, 8.96;
O, 15.35; Found: C, 53.8; H, 4.6; N, 9.0.
R2
R1
O
X
H2N NH2
X = O, S
6
H
O
O
R2
5-Ethoxycarbonyl-6-methyl-4-(2-hydroxy-3-methoxypheny
l)-3,4-dihydropyrimidin-2(1H)-one (7k). mp: 221–223 °C; Rf =
0.3 (n-hexane:ethyl acetate = 2:1). IR (KBr, cm–1): 3450, 3352,
Fe3O4 NPs
N
1
+
R CHO
+
solvent-free
80 oC
X
Me
N
Me
H
7
4
1
5
2938, 1677, 1625, 1529, 1479, 1274. H NMR (500 MHz,
Scheme 2. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones (thiones)
CDCl3): G 1.34 (t, J = 7.1 Hz, 3H), 2.01 (s, 3H), 3.19 (s, 1H),
3.89 (s, 3H), 4.28 (q, J = 7.1 Hz, 2H), 4.66 (s, 1H), 5.7 (s, 1H),
using Fe3O4 NPs.