E. Nope et al.
Catalysis Today 372 (2021) 126–135
media. There are few investigations reporting on the use of basic cata-
lysts and in all cases the reaction is carried out under solvent conditions.
Conventional catalysts such as NaOH in ethanol [27], K2CO3 in DMF or
ethanol [16,28], and anhydrous acetic acid [29] have been reported
with good yields but longer reaction times and with auxiliary processes
for compound separation. The use of microwaves using K2CO3 in ethanol
[30] has recently been reported, although auxiliary substances such as
acetic acid for extraction of the product are required. Therefore the
search for environmentally friendly protocols is a requirement in the
synthesis of these compounds. The basic properties of hydrotalcites can
be modulated with the incorporation of other divalent or trivalent cat-
ions in the structure of brucite. Several examples have been described in
Knoevenagel condensation and Michael addition using these basic solids
[31,32]. However, the synthesis of uracil derivatives via the Biginelli
multicomponent reaction, which may involve these reactions, has not
been explored using hydrotalcites, in part because this type of reaction
requires acidic sites, excess of solvent, and prolonged reaction times. In
view of the advantages of these materials and considering that the
Knoevenagel reaction and Michael addition are typical basic reactions,
in this work we present a simple solvent-free protocol for the multi-
component synthesis of uracil derivatives, with excellent yields and
good green parameters, using hydrotalcites with double divalent cation
as materials that present high basicity due to the incorporation of
another Me2+ in the brucite layer, which improves their basic and
structural properties.
thiourea (1 mmol), and the selected catalyst (the amount of catalyst,
which depended on the test performed, is specified in each of the tables
of the results obtained), in solvent-free conditions, was thoroughly
mixed and then heated at 80 ◦C for 6 h. The reaction was monitored by
TLC using chloroform: methanol 9:1 mixture as the elution phase, to
verify the reaction end point. On cooling, 3 mL acetone was added to the
solid residue.
The reaction mixture was filtered to separate the catalyst, acetone
was evaporated in a rotatory evaporator, and the crude product of 2,4-
dioxo-6-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile was dried
under vacuum up to constant weight. The crude product was recrys-
tallized from a water:ethanol mixture (ratio depending on the product)
to give the pure uracil derivatives.
2.5. Catalyst reutilization
The reusability of the catalyst was examined by running five
consecutive tests, under the same reaction conditions (aldehyde (1
mmol); ethyl cyanoacetate (1 mmol); urea/thiourea (1 mmol); solvent-
free; catalyst (LDH-MgCo, 50 mg); temperature, 80 ◦C; time, 6 h.; stir-
ring). After each experiment, the catalyst was filtered (3 mL of acetone
was previously added), washed with more acetone (2 × 2 mL), dried
under vacuum (25 ◦C), and then reused.
2.6. 1 H NMR and 13 C NMR spectra of selected synthesized compounds
2. Experimental
2,4-Dioxo-6-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (1)
1H RMN (400 Hz, DMSO-d6), δ (ppm) 7.43 (3H, m), 7.69 (2H, m),
10.11 (2H, s).
2.1. General
13C RMN (100 Hz, DMSO-d6), δ (ppm) 78.80, 120.56, 128.25,
128.49, 130, 139.35, 159.08, 165.36, 179.53.
6-(4-Chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-car-
bonitrile (2)
Organic substrates and reagents were purchased from Aldrich, and
used without further purification. The reaction yields were obtained
from crystallized products. All the products were identified by com-
parison of analytical, thin layer chromatography (TLC) and nuclear
magnetic resonance (1H and 13C NMR) data with those reported.
1H RMN (400 Hz, DMSO-d6), δ (ppm) 7.53ꢀ 7.47 (2H, m), 7.75ꢀ 7.68
(2H, m), 10.14 (1H, s).
13C RMN (100 Hz, DMSO-d6), δ (ppm) 78.76, 120.37, 128.36,
130.31, 134.69, 138.09, 158.92, 166.18, 171.19.
6-(2-Chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-car-
bonitrile (3)
2.2. Synthesis of hydrotalcites
Layered double hydroxides (LDH) with a Mg/Al ratio of 3 were
synthesized by co-precipitation method [6]. The hydrolysis was per-
formed at 120 ◦C for 16 h, then the pH was adjusted at 9.8, and the
mixture was subjected to an aging process for 24 h at 120 ◦C with
constant agitation. The precipitate obtained was washed several times
with deionized water and dried at 80 ◦C for 12 h. The solid obtained was
called LDH–Mg. The incorporation of Ni2+ and Co2+ was performed
applying the same methodology, using 1.53 g of Mg(NO3)2∙6H2O, 0.712
g of Al(NO3)3∙9H2O, 1.71 g of Ni(NO3)2∙6H2O or 1.71 g of Co
(NO3)2∙6H2O as precursor salts with a 3 Me2+:Al3+ ratio. The materials
1H RMN (400 Hz, DMSO-d6), δ (ppm) 7.32ꢀ 7.29 (1H, m), 7.44ꢀ 7.34
(3H, m), 7.52ꢀ 7.46 (1H, dd, J = 7.52, J = 1.72 Hz), 10.10 (2H, s).
13C RMN (100 Hz, DMSO-d6), δ (ppm) 81.15, 119.31, 127.35,
129.66, 129.84, 130.28, 130.88, 139.13, 159.07, 165.38.
6-(2,3-Dichlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-
carbonitrile (4)
1H RMN (400 Hz, DMSO-d6), δ (ppm) 7.26 (1H, m), 7.75 (2H, s),
10.12 (2H, s).
13C RMN (100 Hz, DMSO-d6), δ (ppm) 78.68, 120.53, 130.78,
130.85, 135.65, 135.68, 145.96, 158.93, 166.27.
6-(3-Nitrophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-car-
bonitrile (5)
can be described as [(MgNi)2+
Al3+x(OH)2]x+ and [(MgCo)2+
Al3+x(OH)2]x+, and were labelled1a-xs LDH-MgNi and LDH-MgCo.
1-x
1H RMN (400 Hz, DMSO-d6), δ (ppm) 7.79ꢀ 7.73 (1H, t, J = 7.98 Hz),
8.22ꢀ 8.16 (1H, d, J = 7.76, J = 1.36 Hz), 8.35ꢀ 8.29 (1H, dd, J = 8.21,
J=2.53 Hz), 8.51 (1H, s), 10.24 (2H, s).
2.3. Characterization of hydrotalcite
The solids were characterized by X-ray diffraction (XRD), N2-phys-
isorption at 77 K, temperature programmed desorption of CO2 (CO2-
TPD), Fourier-transform infrared (FTIR) spectra, and basicity by titra-
tion of benzoic acid. The equipment and methodologies of the distinct
characterization techniques have been reported in previous works [6].
The morphology of samples was observed using a Philips-505 scanning
electron microscope (SEM).
13C RMN (100 Hz, DMSO-d6), δ (ppm) 78.91, 120.11, 123.13,
124.77, 130.10, 130.15, 134.89, 147.90, 158.90, 165.05, 169.82.
4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbon-
itrile (6)
1H RMN (400 Hz, DMSO-d6), δ (ppm) 7.48 (3H, m), 7.73 (2H, m),
11.61 (2H, s).
13C RMN (100 Hz, DMSO-d6), δ (ppm) 85.57, 119.38, 128.43,
128.66, 130.51, 138.16, 162.99, 167.81, 184.35.
4-Oxo-2-thioxo-6-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carbon-
itrile (7)
2.4. General procedure for the synthesis of uracil derivatives
All the reactions were performed in a reaction test tube, which was
equipped with a condenser and immersed in an oil bath. A mixture of
ethyl cyanoacetate (1 mmol), benzaldehyde (1 mmol), and urea or
1H RMN (400 Hz, DMSO-d6), δ (ppm) 3.82 (3H, s), 7.02 (2H, m), 7.78
(2H, m), 11.50 (2H, s).
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