One-pot three-component synthesis of 4-aryl-3,4-dihydro-pyrimidin- 2(1H)-thiones catalyzed by Ni loaded SiO2

Article abstract of DOI:10.4314/bcse.v26i1.13

A simple and efficient method has been developed for the synthesis of 4-aryl-3,4- dihydropyrimidin-2(1H)-thiones from methyl 3-oxopentanoate, aldehydes and thiourea in the presence of a catalytic amount of Ni loaded SiO₂ at room temperature.

Full text of DOI:10.4314/bcse.v26i1.13

Bull. Chem. Soc. Ethiop. 2012, 26(1), 121-126.
Printed in Ethiopia
DOI: http://dx.doi.org/10.4314/bcse.v26i1.13
ISSN 1011-3924
 2012 Chemical Society of Ethiopia
ONE-POT THREE-COMPONENT SYNTHESIS OF 4-ARYL-3,4-DIHYDRO-
PYRIMIDIN-2(1H)-THIONES CATALYZED BY Ni LOADED SiO2
Suresh Maddila and Sreekanth B. Jonnalagadda*
School of Chemistry, University of KwaZulu-Natal, Westville Campus, Chiltern Hills, Private
Bag 54001, Durban-4000, South Africa
(Received June 7, 2011; revised August 5, 2011)
ABSTRACT. A simple and efficient method has been developed for the synthesis of 4-aryl-3,4-
dihydropyrimidin-2(1H)-thiones from methyl 3-oxopentanoate, aldehydes and thiourea in the presence of a
catalytic amount of Ni loaded SiO2 at room temperature.
KEY WORDS: Ni loaded SiO2, 4-Aryl-3,4-dihydropyrimidin-2(1H)-thiones, One-pot three-component
synthesis, Methyl 3-oxopentanoate, Aldehydes, Thiourea
INTRODUCTION
In recent years, dihydropyrimidinones (DHPMs) and their derivatives have occupied an
important position in natural and synthetic organic chemistry because of their wide range of
biological activities, such as calcium channel blockers, antiviral, antihypertensive, antifilarial,
antibacterial [1-4], and antagonists [5]. Several alkaloids which contain the dihydropyrimidine
core unit that have been isolated from marine sources also showed interesting biological
properties. Most notable among these are the batzelladine alkaloids, which were found to be
potent as HIV gp-120-CD4 inhibitors [6].
In 1893, Biginelli reported the first synthesis of DHPM by a simple one-pot condensation
reaction of ethyl acetoacetate, benzaldehyde, and thiourea [7]. However, this method often
suffers from drawbacks such as harsh conditions, long reaction times and low yields,
particularly when aliphatic and substituted aromatic aldehydes are used. Recently, several
synthetic procedures for preparing of DHPMs have been reported, such as the use of a number
of Lewis acid catalysts as well as protic acids including Y(NO3)3.6H2O [8], Cu(BF4)2 [9],
KAl(SO4)2.12H2O [10], Mg(ClO4)2 [11], triphenylphosphine [12], Ca(NO3)2 [13], and H3BO3
[14]. In addition, microwave irradiation [15], ultrasound irradiation [16], and ionic liquid [17]
have also been utilized to improve and modify this reaction. As part of our current studies on
the development of new catalysts [18, 19], herein, we report an efficient and environmentally
friendly method for the synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones catalyzed by Ni
on SiO2 at room temperature (Scheme 1).
R
S
O
O
Ni - SiO2
EtOH, r.t
CHO
+
H3COOC
C2H5
+
NH2
NH
H2N
C2H5
OMe
R
N
H
S
3
2
1
4
Scheme 1. The synthetic route of 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones.
__________
*Corresponding author. E-mail: Jonnalagaddas@ukzn.ac.za

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Suresh Maddila and Sreekanth B. Jonnalagadda
We studied the possibility to synthesize 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones by the
Biginelli reaction using methyl 3-oxopentanoate, aldehydes and thiourea using Ni-SiO2 as the
catalyst (Scheme 1). Here, an efficient and simple method for the synthesis of target compounds
is described and the synthesis of some compounds has been reported in our previous studies
[20, 21].
EXPERIMENTAL
All reagents and solvents were purchased and used without further purification. Melting points
were determined on a Fisher–Johns melting point apparatus were uncorrected. Crude products
were purified by column chromatography on silica gel of 60–120 mesh. The NMR spectra were
recorded on a Varian 300 MHz spectrometer for 1H NMR. The chemical shifts were reported as
ppm down field using TMS as an internal standard. LC–MS Mass spectra were recorded on a
MASPEC low resolution mass spectrometer operating at 70 eV.
To conclude, we have shown that the Ni loaded SiO2 is a highly active catalyst for the
synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones. General procedure for the preparation
of 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones: A mixture of thiourea (1 mmol), substituted
benzaldehyde (1 mmol) and methyl 3-oxopentanoate (1.5 mmol) with Ni loaded SiO2 (20
mol%) in EtOH (1 mL) was stirred at ambient temperature for an appropriate time (Table 1).
After completion of the reaction as indicated by TLC, the Ni–SiO2 was filtered and washed with
50% EtOH (2 × 10 mL). The crude product was purified by recrystallization from diethyl ether
(solid products) or by chromatography using silica gel and mixtures of hexane/ethyl acetate of
1
increasing polarity. The physical data (mp, IR, H NMR, LCMS) of known compounds were
found to be identical with those reported in the literature [20, 21]. Some selected product
characterization data.
RESULTS AND DISCUSSION
Methyl 3-oxopentanoate, aldehydes and thiourea were selected as the model reaction to examine
catalytic activity of Ni on SiO2 at ambient temperature. We observed that the model reaction did
not proceed in the absence of SiO2 even after 24 h (Table 1, entry 1). When using catalytic
amount of 10 mol% Ni SiO2, the reaction gave a 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones
with 70% yield in 1.5 h in EtOH (Table 1, entry 3), and further lowering the catalyst loading up
to 5 mol% led to lower yield of 55% in 1.5 h (Table 1, entry 2). In the presence of 20 mol%
catalyst the reaction affords the corresponding 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones in
98% yield within 1.5 h (Table 1, entry 4), and Ni SiO2 (25 mol%) also gives 98% yield in 1.5 h
(Table 1, entry 5). The solvents examined were trichloromethane, acetonitrile and ethanol,
among which ethanol is shown to be the best (Table 1). Accordingly, 20 mol% Ni-SiO2 catalyst
loading in EtOH is considered optimal for the synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-
thiones.
We prepared a range of 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones under the optimized
conditions (Table 2). Methyl 3-oxopentanoate, different aldehydes were coupled with thiourea
under these reaction conditions. The reactions are clean and highly selective affording
exclusively 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones in high yields in a short reaction time.
The reaction of methyl 3-oxopentanoate, thiourea with with 2,4-dimethoxy, 3-hydroxy-4-
methoxy and 3-nitro-4-ethyl benzaldehyde is completed within 1.5 h with 98%, 96% and 94%
yield, respectively (Table 2, entries 1 and 3). Similarly, the reaction of methyl 3-oxopentanoate
and thiourea with o-methoxy, o-ethoxy and o-nitro benzaldehydes produce the corresponding
products in excellent yields of 93, 89 and 98% in 1.5, 2.0 and 1.5 h, respectively (Table 2,
entries 4–6). This method is equally effective with electron-withdrawing o-chloro, m-chloro, o-
fluoro, m-bromo p-bromo and 2-hydroxy-5-bromobenzaldehydes (Table 2, entries 7–12). The
Bull. Chem. Soc. Ethiop. 2012, 26(1)

Synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones catalyzed by Ni loaded SiO2
123
reaction of methyl 3-oxopentanoate and thiourea with o-methyl, m-methyl and m,p-dimethyl
benzaldehyde produce the corresponding products in 84%, 82% and 86% yields, respectively,
with ‘longer’ reaction time (3 h) (Table 2, entries 13 and 15).
Table 1. Three-component synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones under various
conditionsa.
Entry Catalyst (%)
Time (h)
24
Yieldb (%)
1
2
3
4
5
6
7
No catalyst
0
5
1.5
55
70
98
98
86c
90d
10
20
25
20
20
1.5
1.5
1.5
2
2.5
aNi-SiO2 was added to a mixture of 1.5 mmol of methyl 3-oxopentanoate, 1 mmol of aldehyde and 1 mmol of
thiourea. bIsolated yield. cIn the presence of CHCl3. dIn the presence of CH3CN.
Table 2. Preparation of various 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones in the presence of Ni-SiO2 in
EtOH at room temperaturea.
Product
R
2-OCH3, 4-OCH3
3-OH, 4-OCH3
3-NO2, 4-C2H5
2-OCH3
2-OC2H5
2-NO2
Time (h)
Yield (%)
98
1
2
1.5
1.5
1.5
1.5
2
96
3
94
4
93
5
89
6
1.5
1.5
1.5
2
98
7
2-Cl
92
8
3-Cl
93]
91
9
2-F
10
11
12
13
14
15
3-Br
2
94
4-Br
2
90
2-OH, 5-Br
2-CH3
1.5
3
92
84
4-CH3
3
82
3-CH3, 4-CH3
3
86
aReaction conditions: thiourea (1 mmol), substituted benzaldehyde (1 mmol), ethyl 3-oxopentanoate (1.5 mmol),
Ni-SiO2 (20 mol%), room temperature, EtOH.
6-Ethyl-4-(2,4-dimethoxyphenyl)–5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (1).
Mp 189–191 °C; 1H NMR: δ = 1.10 (t, 3H, CH3), 2.45 (m, 2H, CH2), 3.58 (s, 3H, OCH3), 3.72
(s, 6H, Ar-2OCH3), 4.80 (d, 1H, CH), 6.40–6.65 (m, 2H, C6H3), 9.45 (s, 1H, NH), 9.85 (s, 1H,
NH); IR (KBr): 3315, 3180, 3120, 2980, 1662, 1571, 1460, 1435, 1348, 1282, 1199, 1180,
1121, 765 cm-1; MS (70 eV, EI): m/z (%): 337 (M+1); Anal. calcd for C16H20N2O4S: C, 57.31;
H, 5.74; N, 8.37. Found: C, 57.16; H, 5.64; N, 8.45.
6-Ethyl-4-(3-hydroxy-4-methoxyphenyl)–5-(methoxycarbonyl)-3,4-dihydro-pyrimidin-2(1H)-
1
thione (2). Mp 159-161 °C; H NMR: δ = 1.14 (t, 3H, CH3), 2.55-3.00 (m, 2H, CH2), 3.58 (s,
3H, OCH3), 3.79 (s, 3H, Ar-OCH3), 5.42 (d, 1H, CH), 6.55–6.95 (m, 3H, C6H3), 9.05 (s, 1H,
OH), 9.65 (s, 1H, NH), 10.25 (s, 1H, NH); IR (KBr): 3318, 3190, 3120, 2990, 1667, 1583,
Bull. Chem. Soc. Ethiop. 2012, 26(1)

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Suresh Maddila and Sreekanth B. Jonnalagadda
1471, 1431, 1345, 1292, 1201, 1184, 1121, 762 cm-1; MS (70 eV, EI): m/z (%): 322 (M+); Anal.
calcd for C15H18N2O4S: C, 55.88; H, 5.65; N, 8.70. Found: C, 55.98; H, 5.51; N, 8.93.
6-Ethyl-4-(4-ethyl-3-nitrophenyl)–5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (3).
1
Mp 190-191 °C; H NMR: δ = 1.10-1.21 (t, 6H, 2CH3), 2.45–2.85 (m, 4H, CH2), 3.54 (s, 3H,
OCH3), 5.40 (d, 1H, CH), 7.55–8.10 (m, 3H, C6H3), 9.75 (s, 1H, NH), 10.32 (s, 1H, NH); IR
(KBr): 3293, 3181, 3101, 2979, 2921, 1729, 1678, 1571, 1549, 1476, 1439, 1349, 1322, 1281,
1194, 1164, 1109, 755 cm-1; MS (70 eV, EI): m/z (%): 349 (M+); Anal. calcd for C16H19N3O4S:
C, 55.10; H, 5.25; N, 12.14. Found: C, 55.38; H, 5.64; N, 12.01.
6-Ethyl-4-(2-methoxyphenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (4). Mp
231 °C, lit.20 234–236 °C; 1H NMR: δ = 1.11 (t, 3H, CH3), 2.45–3.00 (m, 2H, CH2), 3.54 (s, 3H,
Ar-OCH3), 3.78 (s, 3H, OCH3), 5.55 (d, 1H, CH), 6.48–7.95 (m, 4H, C6H4), 9.28 (s, 1H, NH),
10.30 (s, 1H, NH); IR (KBr): 3201, 2978, 2944, 1721, 1668, 1585, 1492, 1478, 1433, 1284,
1258, 1179, 1141, 1105, 760 cm-1; MS (70 eV, EI): m/z (%): 306 (M+).
6-Ethyl-4-(2-ethoxyphenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (5). Mp
1
204–206 °C; H NMR: δ = 1.08 (t, 3H, CH3), 1.42 (t, 3H, Ar-CH3), 2.51–2.74 (m, 2H, CH2),
3.45 (s, 3H, OCH3), 3.85–4.10 (m, 2H, Ar-OCH2), 5.43 (d, 1H, CH), 6.68–7.38 (m, 4H, C6H4),
9.21 (s, 1H, NH), 10.27 (s, 1H, NH); IR (KBr): 3315, 3181, 3118, 2975, 2942, 1719, 1655,
1585, 1482, 1431, 1328, 1299, 1261, 1236, 1186, 1131, 1101, 1008, 758 cm-1; MS (70 eV, EI):
m/z (%): 320 (M+); Anal. calcd for C16H20N2O3S: C, 59.98; H, 6.29; N, 8.74. Found: C, 59.32;
H, 6.81; N, 8.64.
6-Ethyl-4-(2-nitrophenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (6). Mp
158–160 °C; 1H NMR: δ = 1.12 (t, 3H, CH3), 2.58–2.95 (m, 2H, CH2), 3.45 (s, 3H, OCH3), 5.58
(d, 1H, CH), 7.35–7.64 (m, 4H, C6H4), 9.64 (s, 1H, NH), 10.50 (s, 1H, NH); IR (KBr): 3274,
3173, 2974, 2949, 1718, 1654, 1558, 1523, 1470, 1438, 1351, 1309, 1270, 1200, 1180, 1127,
1101, 750 cm-1; MS (70 eV, EI): m/z (%): 322 (M+1); Anal. calcd for C14H15N3O4S: C, 52.33;
H, 4.71; N, 13.07. Found: C, 52.87; H, 4.74; N, 12.99.
6-Ethyl–4-(2-chlorophenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (7). Mp
1
183–184 °C, lit.21 196–198 °C; H NMR: δ = 1.10 (t, 3H, CH3), 2.38–2.95 (m, 2H, CH2), 3.45
(s, 3H, OCH3), 5.61 (d, 1H, CH), 7.15–7.55 (m, 4H, C6H4), 9.60 (s, 1H, NH), 10.40 (s, 1H,
NH); IR (KBr): 3265, 3170, 3012, 2945, 1707, 1640, 1592, 1468, 1433, 1314, 1269, 1187,
1137, 1105, 774 cm-1; MS (70 eV, EI): m/z (%): 311 (M+1).
6-Ethyl–4-(3-chlorophenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (8). Mp
1
169–170 °C, lit.21 175-177 °C; H NMR: δ = 1.09 (t, 3H, CH3), 2.42–2.84 (m, 2H, CH2), 3.51
(s, 3H, OCH3), 5.24 (d, 1H, CH), 7.10-7.45 (m, 4H, C6H4), 9.58 (s, 1H, NH), 10.45 (s, 1H, NH);
IR (KBr): 3321, 3184, 3110, 2994, 1684, 1574, 1442, 1280, 1191, 1109, 762 cm-1; MS (70 eV,
EI): m/z (%): 311 (M+1).
6-Ethyl-4-(2-fluorophenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (9). Mp
183–185 °C; 1H NMR: δ = 1.10 (t, 3H, CH3), 2.67–2.73 (m, 2H, CH2), 3.49 (s, 3H, OCH3), 5.43
(d, 1H, CH), 7.14–7.22 (m, 4H, C6H4), 9.56 (s, 1H, NH), 10.39 (s, 1H, NH); IR (KBr): 3265,
3179, 2934, 1699, 1642, 1576, 1485, 1462, 1436, 1313, 1273, 1225, 1189, 1149, 1132, 1105,
759 cm-1; MS (70 eV, EI): m/z (%): 294 (M+); Anal. calcd for C14H15N2O2SF: C, 57.13; H, 5.14;
N, 9.52. Found: C, 56.59; H, 4.47; N, 9.47.
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Synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones catalyzed by Ni loaded SiO2
125
6-Ethyl–4-(3-bromophenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (10). Mp
1
185–187 °C, lit.21 195–197 °C; H NMR: δ = 1.10 (t, 3H, CH3), 2.45–3.00 (m, 2H, CH2), 3.48
(s, 3H, OCH3), 5.24 (s, 1H, CH), 7.15–7.60 (m, 4H, C6H4), 9.64 (d, 1H, NH), 10.45 (s, 1H,
NH); IR (KBr): 3320, 3177, 3121, 2991, 2936, 1672, 1588, 1471, 1438, 1368, 1291, 1194,
1175, 1132, 779 cm-1; MS (70 eV, EI): m/z (%): 358 (M+2).
6-Ethyl-4-(4-bromophenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (11). Mp
1
181–183 °C, lit.21 178–179 °C; H NMR: δ = 1.09 (t, 3H, CH3), 2.36–2.95 (m, 2H, CH2), 3.52
(s, 3H, OCH3), 5.20 (d, 1H, CH), 7.20–7.60 (m, 4H, C6H4), 9.70 (s, 1H, NH), 10.45 (s, 1H,
NH); IR (KBr): 3172, 2984, 1681, 1582, 1468, 1441, 1351, 1279, 1199, 1110, 764 cm-1; MS
(70 eV, EI): m/z (%): 358 (M+2).
6-Ethyl-4-(5-bromo-2-hydroxyphenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione
1
(12). Mp 207–209 °C; H NMR: δ = 1.04 (t, 3H, CH3), 1.86–2.48 (m, 2H, CH2), 3.38 (s, 3H,
OCH3), 3.64 (s, H, OH), 4.74 (s, 1H, CH), 6.76–7.49 (m, 3H, C6H3), 9.12 (s, 1H, NH), 10.15 (s,
1H, NH); IR (KBr): 3315, 3183, 3121, 2979, 2943, 1724, 1655, 1585, 1479, 1446, 1329, 1301,
1262, 1238, 1187, 1141, 1112, 986, 760 cm-1; MS (70 eV, EI): m/z (%): 374 (M+2), 372 (M+);
Anal. calcd for C14H16N2O3SBr: C, 45.17; H, 4.33; N, 7.52. Found: C, 45.59; H, 4.46; N, 7.59.
6-Ethyl-4-(2-methylphenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (13). Mp
181–183 °C, lit.20 192–193 °C; 1H NMR: δ = 1.12 (t, 3H, CH3), 2.40 (s, 3H, Ar-CH3), 2.48-2.75
(m, 2H, CH2), 3.48 (s, 3H, OCH3), 5.30 (d, 1H, CH), 7.10-7.35 (m, 4H, C6H4), 9.50 (s, 1H,
NH), 10.30 (s, 1H, NH); IR (KBr): 3270, 3169, 3009, 2972, 1690, 1631, 1580, 1461, 1434,
1311, 1187, 1136, 1101, 755 cm-1; MS (70 eV, EI): m/z (%): 290 (M+).
6-Ethyl-4-(4-methylphenyl)-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (14). Mp
1
177–179 °C; H NMR: δ = 1.10 (t, 3H, CH3), 2.15 (s, 3H, Ar-CH3), 2.45–2.75 (m, 2H, CH2),
3.51 (s, 3H, OCH3), 5.25 (d, 1H, CH), 6.90–7.24 (m, 4H, C6H4), 9.60 (s, 1H, NH), 10.35 (s, 1H,
NH); IR (KBr): 3188, 2988, 1679, 1651, 1592, 1518, 1473, 1349, 1282, 1199, 1121, 765 cm-1;
MS (70 eV, EI): m/z (%): 290 (M+). Anal. calcd for C15H18N2O2S: C, 62.04; H, 6.24; N, 9.64.
Found: C, 62.31; H, 6.19; N, 9.47.
6-Ethyl-4-(3,4-dimethylphenyl)–5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione (15).
Mp 145-147 °C; 1H NMR: δ = 1.07 (t, 3H, CH3), 2.20-2.30 (s, 6H, Ar-2CH3), 2.60-2.72 (m, 2H,
CH2), 3.51 (s, 3H, OCH3), 5.12 (d, 1H, CH), 7.02–7.15 (m, 3H, C6H3), 9.65 (s, 1H, NH), 10.35
(s, 1H, NH); IR (KBr): 3170, 3018, 2995, 1674, 1652, 1599, 1518, 1468, 1430, 1348, 1290,
1150, 1110, 761 cm-1; MS (70 eV, EI): m/z (%): 305 (M+1); Anal. calcd for C16H20N2O2S: C,
63.15; H, 6.60; N, 9.20. Found: C, 63.28; H, 6.49; N, 9.10.
CONCLUSIONS
In conclusion, we have developed a novel and highly efficient method for the synthesis of 4-
aryl-3,4-dihydropyrimidin-2(1H)-thiones by treatment of methyl 3-oxopentanoate, aldehydes
and thiourea with Ni loaded silica as catalyst, which acts an effective Lewis acid. The
significant advantages of this method are good yields, short reaction times and simple workup
procedure, plus easy preparation and handling of the catalyst. This methodology may find wide
uses in organic synthesis for preparation of the 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones.
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Suresh Maddila and Sreekanth B. Jonnalagadda
ACKNOWLEDGEMENTS
The authors are thankful to the authorities of School of Chemistry, University of KwaZulu-
Natal, Westville campus, Durban, South Africa for the facilities and encouragement.
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