Silica-ZnCl2: An efficient and reusable solid catalyst for one pot synthesis of 5-methyl mercaptothiocarbonyl-4-aryl-3- dihydropyrimidin-2(1H)-ones under solvent-free conditions

Article abstract of DOI:10.1002/bkcs.10606

Synthetic application of Silica-ZnCl₂, as an efficient and eco-friendly catalyst for the synthesis of a small library of dihydropyrimidinones is described in this report. The reaction involves a one pot, multicomponent reaction of β-oxodithioca

Full text of DOI:10.1002/bkcs.10606

Article
DOI: 10.1002/bkcs.10606
BULLETIN OF THE
L. R. Devi et al.
KOREAN CHEMICAL SOCIETY
Silica–ZnCl2: An Efficient and Reusable Solid Catalyst for One
Pot Synthesis of 5-Methyl Mercaptothiocarbonyl-4-aryl-3-
dihydropyrimidin-2(1H)-ones Under Solvent-Free Conditions
Laishram Ronibala Devi,† Leimajam Vartima Chanu,‡ Hojune Choi,§ Dahyun Lee,§
§,
Okram Mukherjee Singh,‡, and Sang-Gyeong Lee
*
*
†Department of Basic Science and Humanities, National Institute of Technology, Langol 795004, India
‡Department of Chemistry, Manipur University, Canchipur 795003, India.
*E-mail: ok_mukherjee@yahoo.co.in
§Department of Chemistry, Research Institute of Natural Science (RINS), Graudate School for Molecular
Materials and Nanochemistry, Gyeongsang National University, Jinju 660-701, Korea.
*E-mail: leesang@gnu.ac.kr
Received June 29, 2015, Accepted October 31, 2015, Published online November 30, 2015
Synthetic application of Silica–ZnCl2, as an efficient and eco-friendly catalyst for the synthesis of a small
library of dihydropyrimidinones is described in this report. The reaction involves a one pot, multicomponent
reaction of β-oxodithiocarboxylates, aldehydes, and urea under solvent-free conditions. The experimental pro-
cedure is simple, environmental benign, tolerated with many functional groups, and results in good to excellent
yield of the products.
Keywords: Dihydropyrimidinones, β-Oxodithiocarbonates, Solvent-free, Silica–ZnCl2
Introduction
under strongly acidic conditions.1,2,19,20 Since then, many
improved protocols have been reported from time-to-
time,21–28 some of them still suffer from drawbacks such as
unsatisfactory yields, cumbersome product isolation proce-
dures, and environmental pollution.29–37 We are reporting
herein the application of silica–ZnCl2 as an effective catalyst
in multicomponent reactions under solvent-free conditions for
the synthesis of a small library of 5-methylmercaptothiocarbo-
nyl-4-aryl-3-dihydropyrimidin-2(1H)-ones in good to excel-
lent yields.
Heterogeneous catalysts are advantageous over homogeneous
catalysts as theycan beeasily recovered from thereaction mix-
ture by simple filtration and reusable after activation, thereby
making the process economically viable. Granite, quartz, and
silica catalysts were reported also as efficient heterogeneous
catalysts for Biginelli reaction.1 Among of heterogeneous cat-
alysts, silica gel is one of the more extensively used surface
material supports for different chemical transformations in
organic synthesis.2 Among the heterogeneous catalysts,
solid-based catalyst, silica–ZnCl2, attracted much attention
in recent years as catalyst for organic synthesis due to eco-
nomic and environmental friendly considerations.3–6 It’s
surface is both thermally and chemically stable during the
reaction process, and it is also an abundant and inexpensive
material. We are using this catalytic system for the first time
in the synthesis of dihydropyrimidines from a multicompo-
nent reaction of β-oxodithiocarboxylates, aldehydes, and urea
(Schemes 1 and 2).
Dihydropyrimidinones(DHPMs)arewell-knownbioactive
heterocycles exhibiting a wide spectrum of biological activ-
ities. They show remarkable pharmacological properties such
as calcium channel blockers, mitotic kinesin Eg5 motor pro-
tein inhibitors, as well as potent HIV gp-120-CD4
inhibitors.7–14 They are also reported as potential antifungal,
antiviral, antitumor, antibacterial, and anti-inflammatory
agents.15–18 Synthesis of polyfunctionalized dihydropyrimi-
dine was first reported by Biginelli in 1893, involving a
one-pot condensation of an aldehyde, β-ketoester, and urea
Experimental
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on FT-NMR spectrometer using CDCl3. Chemical
shifts δ are measured in parts per million (ppm) with either
CDCl3 as solvent and are relative to tetramethylsilane
(TMS) as the internal reference. Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = tri-
plet, m = multiplet, br = broad) and coupling constants (J)
in Hertz. The FT-IR spectra were recorded on a **Perkin-
Elmer FT-IR spectrometer (KBr). Elemental analyses were
recorded using Perkin-Elmer 2400 analytical instrument.
Mass spectra (ESI-MS) were recorded at **Waters, Q-TOF
LC-MS spectrometer. Melting points were determined on a
“Veego” capillary melting point apparatus and are uncor-
rected. Silica gel 60 was used for column separations. Chem-
ical yields refer to the pure isolated substances.
Preparation of SiO2–ZnCl2. A mixture of activated SiO2
(10 g) and anhydrous ZnCl2 (3 g) was refluxed in
Bull. Korean Chem. Soc. 2015, Vol. 36, 2915–2919
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
2915

Article
BULLETIN OF THE
ISSN (Print) 0253-2964 | (Online) 1229-5949
KOREAN CHEMICAL SOCIETY
S
O
S
O
NaH/DMF
0-25 oC
+
R1
Me S
S Me
R1
SMe
3a-e
1
2a-e
Scheme 1. Synthesis of β-oxodithiocarbonates.
S
R2
O
S
O
Me S
NH
Silica-ZnCl2
R1
SMe
R2CHO
4a-c
H2N
NH2
+
+
solvent-free, 90°C
3a-e
R1
N
H
O
5
6a-o
R1 = C6H5, 4-MeOC6H5, 4-ClC6H5, 4-MeC6H5, CH3
R2 = C6H5, 4-ClC6H4, 4-MeOC6H4
Yield= 70-82%
Scheme 2. Synthesis of dihydropyrimidines.
dichloromethane (30 mL) for 10 h. SiO2-ZnCl2 was obtained
as a free-flowing powder after filtration under reduced pres-
sure and dried over P2O5.
Preparation of β-Oxodithioester 3a-e. β-Oxodithioesters
3a–e were prepared according to our earlier reported
methods.38–40
CDCl3) δ 2.31 (s, 3H), 3.79 (s, 3H), 5.83 (d, J = 2.1
Hz, 1H), 6.17 (s, 1H, NH), 6.83 (d, J = 8.4 Hz, 2H), 7.31
(d, J = 8.4 Hz, 2H), 7.37–7.46 (m, 5H), 8.07 (s, 1H, NH);
13C NMR (75.5 MHz, CDCl3) δ 20.4, 55.2, 60.4, 113.9,
119.6, 128.2, 128.4, 128.8, 129.8, 134.1, 134.6, 136.2,
152.7, 159.3, 227.2; IR (KBr) (νmax, cm−1) 1244, 1610,
1691, 3095, 3213; MS (ESI): m/z = 370 (M)+. Anal. Calcd
for C19H18N2O2S2: C, 61.60; H, 4.90; N, 7.56. Found: C,
61.50; H, 4.84; N, 7.53.
General Procedure for Synthesis of 5-Methylmercap-
tothiocarbonyl-4-aryl-3-dihydropyrimidin-2(1H)-ones
(6a–o). A mixture of β-oxodithioester 3 (5 mmol), aldehyde
4 (5 mmol), urea 5 (5 mmol), and silica–ZnCl2 (100 mg) was
5-Methylmercaptothiocarbonyl-4-(4-chlorophenyl)-6-
phenyl-3,4-dihydropyrimidin-2(1H)-one (6c): Yellow
ꢀ
heatedinapreheatedoilbathat90 Cwithstirringfor1 h. The
1
ꢀ
progress of the reaction was monitored by TLC (hexane/
EtOAc, 8:2). After cooling, EtOAc (30 mL) was added and
silica–ZnCl2 was filtered. The organic phase was washed with
H2O (2 × 50 mL) and extracted with EtOAc (2 × 30 mL). The
organic layer was dried over anhydrous Na2SO4. The solvent
was evaporated under reducedpressure and the resulting crude
residue was subjected to column chromatography on SiO2
(gradient elution using EtOAc/hexanes as the eluent). All
the compounds were characterized by spectroscopy, mass
spectrometry, and elemental analysis.
powder. mp 230–231 C. H NMR (300 MHz, CDCl3) δ
2.30 (s, 3H), 5.45 (s, 1H, NH), 5.93 (d, J = 1.8 Hz, 1H),
6.46 (s, 1H, NH), 7.28–7.41 (m, 9H); 13C NMR (75.5
MHz, CDCl3) δ 20.4, 60.8, 119.6, 127.1, 128.2, 128.7,
128.9, 129.7, 132.7, 135.3, 135.8, 141.5, 153.1, 226.8; IR
(KBr) (νmax, cm−1): 1256, 1614, 1695, 3086; MS:
m/z = 374.5 (M)+. Anal. Calcd for C18H15N2OS2Cl: C,
57.67; H, 4.03; N, 7.47. Found: C, 57.60; H, 4.14; N, 7.43.
5-Methylmercaptothiocarbonyl-4-phenyl-6-(4-methox-
yphenyl)-3,4-dihydropyrimidin-2(1H)-ones (6d): Yellow
1
ꢀ
5-Methylmercaptothiocarbonyl-4,6-diphenyl-3,4-dihy-
dropyrimidin-2(1H)-one (6a): Bright yellow powder. mp
powder. mp 188–189 C. H NMR (300 MHz, CDCl3) δ
2.31 (s, 3H), 3.83 (s, 3H), 5.60 (s, 1H, NH), 5.90 (d, J = 2.1
Hz, 1H), 6.72 (s, 1H, NH), 6.87 (d, J = 6.6 Hz, 2H),
7.26–7.39 (m, 7H); 13C NMR (75.5 MHz, CDCl3) δ 20.5,
55.4, 60.9, 119.1, 127.1, 128.0, 128.1, 128.6, 129.4, 131.6,
136.7, 140.1, 141.7, 152.6, 227.1; IR (KBr) (νmax, cm−1):
1253, 1610, 1695, 3086, 3211; MS (ESI): m/z = 370 (M)+.
Anal. Calcd for C19H18 N2O2S2: C, 61.60; H, 4.90; N, 7.56.
Found: C, 61.59; H, 4.93; N, 7.53.
1
ꢀ
198–200 C. H NMR (300 MHz, CDCl3) δ 2.30 (s, 3H),
5.87 (d, J = 2.7 Hz, 1H), 6.32 (s, 1H, NH), 7.28–7.44 (m,
10H), 7.61 (s, 1H, NH); 13C NMR (75.5 MHz, CDCl3) δ
20.5, 60.9, 119.4, 127.2, 128.1, 128.2, 128.7, 128.8, 129.9,
134.6, 136.5, 141.7, 152.6, 227.0; IR (KBr) (νmax, cm−1)
1226, 1629, 1700, 3084, 3198; MS (ESI): m/z = 340 (M)+.
Anal. Calcd for C18H16N2OS2: C, 63.50; H, 4.74; N, 8.23.
Found: C, 63.58; H, 4.79; N, 8.30.
5-Methylmercaptothiocarbonyl-4-(4-methoxyphenyl)-
6-(4-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-ones
5-Methylmercaptothiocarbonyl-4-(4-methoxyphenyl)-
6-phenyl-3,4-dihydropyrimidin-2(1H)-one (6b): Bright
1
ꢀ
(6e): Yellow powder. mp 207–208 C. H NMR (300 MHz,
CDCl3) δ 2.31 (s, 3H), 3.78 (s, 3H), 3.82 (s, 3H) 5.48 (s, 1H,
yellow powder. mp 182–183 C. 1H NMR (300 MHz,
ꢀ
Bull. Korean Chem. Soc. 2015, Vol. 36, 2915–2919
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2916

BULLETIN OF THE
Article
Synthesis of Pyrimidin-2(1H)-ones Derivatives under Solvent-Free
KOREAN CHEMICAL SOCIETY
NH), 5.85 (s, 1H), 6.61(s, 1H, NH), 6.82 (d, J = 6.3 Hz, 2H),
6.85–6.89 (m, 2H), 7.26–7.30 (m, 2H), 7.36 (d, J = 6.3 Hz,
2H); 13C NMR (75.5 MHz, CDCl3) δ 20.5, 60.9, 60.11,
119.1, 127.1, 128.0, 128.1, 128.6, 129.4, 131.6, 136.7,
140.1, 141.7, 152.6, 227.1; MS (ESI): m/z = 400 (M)+. Anal.
Calcd for C20H20 N2O3S2: C, 59.98; H, 5.03; N, 6.99.
Found: C, 59.95; H, 5.07; N, 6.97.
(75.5 MHz, CDCl3) δ 20.5, 21.4, 60.9, 119.1, 127.1, 128.0,
128.1, 128.6, 129.4, 131.6, 136.7, 140.1, 141.7, 152.6,
227.1; IR (KBr) (νmax, cm−1): 1259, 1619, 1697, 3083,
3210; MS (ESI): m/z = 354 (M)+. Anal. Calcd for
C19H18N2OS2: C, 64.38; H, 5.12 N, 7.90. Found: C,
64.35; H, 5.15; N, 7.95.
5-Methylmercaptothiocarbonyl-4-(4-methoxyphenyl)-
6-(4-methylphenyl)-3,4-dihydropyrimidin-2(1H)-ones
5-Methylmercaptothiocarbonyl-4-(4-chlorophenyl)-6-
(4-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-ones
1
ꢀ
(6k): Yellow powder. mp 228–229 C. H NMR (300 MHz,
CDCl3) δ 2.17 (s, 3H), 2.32 (s, 3H), 3.82 (s, 3H), 5.58 (s, 1H,
NH), 5.90 (d, J = 1.8 Hz, 1H), 6.62 (s, 1H, NH), 6.88 (d, J = 6.6
Hz, 2H), 7.25–7.31 (m, 2H), 7.32–7.38 (m, 4H); 13C NMR
(75.5 MHz, CDCl3) δ 20.6, 21.5, 56.1, 60.9, 119.1, 127.1,
128.0, 128.1, 128.6, 129.4, 131.6, 136.7, 140.1, 141.7,
152.6, 227.1; MS (ESI): m/z = 384 (M)+. Anal. Calcd for
C20H20N2O2S2: C, 62.47; H, 5.24; N, 7.29. Found: C,
62.45; H, 5.27; N, 7.26.
1
ꢀ
(6f ): Yellow powder. mp 194–195 C. H NMR (300 MHz,
CDCl3) δ 2.31 (s, 3H), 3.78 (s, 3H), 5.43 (s, 1H, NH), 5.91 (s,
1H), 6.59 (s, 1H, NH), 6.89 (d, J = 6.9 Hz, 2H), 7.22–7.31 (m,
4H), 7.38 (d, J = 6.6 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ
20.8, 55.8, 60.9, 119.1, 127.1, 128.0, 128.1, 128.6, 129.4,
131.6, 136.7, 140.1, 141.7, 153.6, 227.8; MS (ESI):
m/z = 404 (M)+. Anal. Calcd for C19H17 N2O2S2Cl: C,
56.36; H, 4.23; N, 6.92. Found: C, 56.33; H, 4.25; N, 6.95.
5-Methylmercaptothiocarbonyl-4-phenyl-6-(4-chloro-
phenyl)-3,4-dihydropyrimidin-2(1H)-ones (6g): Yellow
5-Methylmercaptothiocarbonyl-4-(4-chlorophenyl)-6-
(4-methylphenyl)-3,4-dihydropyrimidin-2(1H)-ones (6l):
1
powder. mp 224–225 C. H NMR (300 MHz, CDCl3) δ
2.30 (s, 3H), 5.52 (s, 1H, NH), 5.89 (d, J = 1.8 Hz, 1H),
6.79 (s, 1H, NH), 7.26–7.35 (m, 5H), 7.37–7.41 (m, 4H);
13C NMR (75.5 MHz, CDCl3) δ 20.4, 60.8, 119.6, 127.1,
128.2, 128.7, 128.9, 129.7, 132.7, 135.3, 135.8, 141.5,
153.1, 226.8; MS: m/z = 374 (M)+. Anal. Calcd for
C18H15N2O S2Cl: C, 57.67; H, 4.03; N, 7.47. Found: C,
57.65; H, 4.05; N, 7.49.
Yellow powder. mp 197–198 C. 1H NMR (300 MHz,
ꢀ
ꢀ
CDCl3) δ 2.17 (s, 3H), 2.30 (s, 3H), 5.43 (s, 1H, NH), 5.90
(d, J = 1.8 Hz,1H), 6.59 (s, 1H, NH), 7.26–7.35 (m, 4H),
7.36–4.41 (m, 4H); 13C NMR (75.5 MHz, CDCl3) δ 20.5,
21.4, 60.9, 119.1, 127.1, 128.0, 128.1, 128.6, 129.4, 131.6,
136.7, 140.1, 141.7, 152.6, 227.2; MS (ESI): m/z = 388
(M)+. Anal. Calcd for C19H17N2OS2Cl: C, 58.67; H,
4.41; N, 7.20. Found: C, 58.65; H, 4.43; N, 7.24.
5-Methylmercaptothiocarbonyl-4-(4-methoxyphenyl)-
6-(4-chlorophenyl)-3,4-dihydropyrimidin-2(1H)-ones
5-Methylmercaptothiocarbonyl-4-phenyl-6-methyl-
3,4-dihydropyrimidin-2(1H)-ones (6m): Yellow powder.
1
1
ꢀ
ꢀ
(6h): Yellow powder. mp 195–196 C. H NMR (300 MHz,
CDCl3) δ 2.31 (s, 3H), 3.78 (s, 3H), 5.77 (d, J = 2.1 Hz, 1H),
6.32 (s, 1H, NH), 6.82 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz,
2H), 7.28–7.37 (m, 5H), 8.07 (s, 1H, NH); 13C NMR (75.5
MHz, CDCl3) δ 20.5, 21.4, 60.9, 119.1, 127.1, 128.0,
128.1, 128.6, 129.4, 131.6, 136.7, 140.1, 141.7, 152.6,
227.1; IR (KBr) (νmax, cm−1): 1253, 1610, 1695, 3086,
3211; MS (ESI): m/z = 404 (M)+. Anal. Calcd for C19H17
N2O2S2Cl: C, 56.36; H, 4.23; N, 6.92. Found: C, 56.39; H,
4.21; N, 6.95.
mp 150–151 C. H NMR (300 MHz, CDCl3) δ 2.31 (s,
3H), 2.40 (s, 3H), 5.67 (s, 1H, NH), 5.77 (d, J = 2.1
Hz, 1H), 6.32 (s, 1H, NH), 7.29–7.32 (m, 3H), 7.37–7.40
(m, 2H); 13C NMR (75.5 MHz, CDCl3) δ 20.4, 24.4,
60.9, 119.6, 126.2, 127.6, 128.5, 143.2, 145.2, 153.1,
226.5; MS (ESI): m/z = 278 (M)+. Anal. Calcd for
C13H14N2OS2: C, 56.09; H, 5.07; N, 10.06. Found: C,
56.07; H, 5.09; N, 10.09.
5-Methylmercaptothiocarbonyl-4-(4-methoxyphenyl)-
6-methyl-3,4-dihydropyrimidin-2(1H)-ones (6n): Yellow
1
ꢀ
5-Methylmercaptothiocarbonyl-4-(4-chlorophenyl)-6-
(4-chlorophenyl)-3,4-dihydropyrimidin-2(1H)-ones (6i):
powder. mp 153–155 C. H NMR (300 MHz, CDCl3) δ
2.32 (s, 3H), 2.41 (s, 3H), 3.76 (s, 3H), 5.68 (s, 1H, NH),
5.79 (d, J = 2.1 Hz, 1H), 6.33 (s, 1H, NH), 7.29–7.31 (m,
2H), 7.38–7.40 (m, 2H); 13C NMR (75.5 MHz, CDCl3) δ
20.4, 24.4, 55.1, 60.9, 119.6, 126.2, 127.6, 128.5, 143.2,
145.2, 153.1, 226.5; MS (ESI): m/z = 308 (M)+. Anal. Calcd
for C14H16N2O2S2: C, 54.42; H, 5.99; N, 7.68. Found: C,
54.43; H, 5.97; N, 7.70.
Yellow powder. mp 226–227 C. 1H NMR (300 MHz,
ꢀ
CDCl3) δ 2.31 (s, 3H), 5.5 (s, 1H, NH), 5.96 (d, J = 2.1 Hz,
1H), 6.64 (s, 1H, NH), 7.25–7.34 (m, 4H), 7.37–7.39 (m,
4H); 13C NMR (75.5 MHz, CDCl3) δ 20.5, 21.4, 60.9,
119.1, 127.1, 128.0, 128.1, 128.6, 129.4, 131.6, 136.7,
140.1, 141.7, 152.6, 227.1; IR (KBr) (νmax, cm−1): 1256,
1617, 1695, 3086, 3210; MS (ESI): m/z = 407 (M)+. Anal.
Calcd for C18H14N2OS2Cl2: C, 52.81; H, 3.45; N, 6.84.
Found: C, 52.85; H, 3.41; N, 6.85.
Methylmercaptothiocarbonyl-4-(4-chlorophenyl)-6-
methyl-3,4-dihydropyrimidin-2(1H)-ones (6o): Yellow
1
ꢀ
powder. mp 147–149 C. H NMR (300 MHz, CDCl3) δ
2.31 (s, 3H), 2.43 (s, 3H), 5.69 (s, 1H, NH), 5.78 (d, J = 2.1
Hz, 1H), 6.32 (s, 1H, NH), 7.29–7.31 (m, 2H), 7.37–7.40
(m, 2H); 13C NMR (75.5 MHz, CDCl3) δ 20.7, 24.5, 60.7,
119.5, 126.1, 127.7, 128.5, 143.1, 145.2, 153.3, 226.7; MS
(ESI): m/z = 342 (M)+. Anal. Calcd for C13H13ClN2OS2: C,
49.91; H, 4.19; N, 8.95. Found: C, 49.90; H, 4.17; N, 8.97.
5-Methylmercaptothiocarbonyl-4-phenyl-6-(4-methyl-
phenyl)-3,4-dihydropyrimidin-2(1H)-ones (6j): Yellow
1
ꢀ
powder. mp 203–205 C. H NMR (300 MHz, CDCl3) δ
2.30 (s, 3H), 2.37 (s, 3H), 5.43 (s, 1H, NH), 5.92 (d, J = 2.1
Hz, 1H), 6.44 (s, 1H, NH), 7.18 (d, J = 5.8 Hz, 2H),
7.26–7.35 (m, 5H), 7.37 (d, J = 5.8 Hz, 2H); 13C NMR
Bull. Korean Chem. Soc. 2015, Vol. 36, 2915–2919
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2917

BULLETIN OF THE
Article
Synthesis of Pyrimidin-2(1H)-ones Derivatives under Solvent-Free
Results and Discussion
KOREAN CHEMICAL SOCIETY
3b–e. Several substituents such as p-OMe, p-Me, p-Cl, p-
Br, and p-F on the phenyl were tolerated. Thus, using the opti-
mized reaction conditions, a library of compounds 3a–m was
synthesized in good yields (Table 2). The structures of the pro-
ducts were confirmed based on their analytical and spectral
data (Table 2).
We initiated our investigation by heating equimolar amounts
of aldehyde 1a, β-oxodithiocarbonate 2a, and urea 3 in the
presence of 100 mg of silica–ZnCl2, using various solvent
such as EtOH, MeOH, acetonitrile, and THF. The desired
dihydropytrimidines product 4a was obtained with 40–56%
yields as shown in Table 1. Then we ꢀattempted the reaction
without any solvent by heating at 90 C, but no satisfactory
yield was obtained after 1 h as we have done with other sol-
vents. The heating was kept longer (7 h) and slight improve-
ment in the yield (60%) was observed under solvent-free
condition. In order to get the optimum condition, we increased
the catalytic amount from 100 to 150 mg under solvent-free
condition, we get satisfactory yield of 76% after 1 h
(Table 1, entry 6). Increasing the catalytic amount to
200 mg or the prolong heating could not bring any changes
in the yield. Thus, we optimized the reaction condition at
An advantage of the solid-supported catalyst is its recycla-
bility. In view of development of eco-friendly methodologies,
recovery and reuse of the catalyst are highly preferable. Silica-
supported ZnCl2 was easily separated from the reaction
medium by adding EtOAc (5 mL), washed with dry and warm
ethanol, and reused in the subsequent reactions. The recovered
catalyst can be reused in subsequent reactions without signif-
icant loss in its efficiency (Table 3).
Conclusion
In summary, we have developed an efficient and mild
method for synthesis of 5-methylmercaptothiocarbonyl-4-
aryl-3dihydropyrimidin-2(1H)-ones by the reaction of
β-oxodithiocarboxylates, aldehyde, and urea in the presence
of silica-supported ZnCl2 under solvent-free conditions. The
use of an inexpensive reagent under mild reaction conditions,
ꢀ
90 C for 1 h under solvent-free condition using 150 mg of
silica–ZnCl2.
After optimizing the reaction conditions, we evaluated the
generality and scope of the condensation reaction by using dif-
ferent aromatic aldehydes 2b–c and β-oxodithiocarbonates
Table 1. Optimization of the reaction conditions using silica–ZnCl2.a
Entry
Amount of silica–ZnCl2 (mg)
Solvents
Temperature (ꢀC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
a
100
100
100
100
100
150
200
EtOH
MeOH
Acetonitrile
THF
Reflux
Reflux
Reflux
Reflux
90
7
7
7
7
7
1
1
40
45
47
56
60
76
70
—
—
90
90
—
Reaction conditions: 3 (2 mmol), 4 (2 mmol), 5 (2 mmol), solvent (5 mL), and silica–ZnCl2.
b
Isolated yields.
Table 2. Silica–ZnCl2 catalyzed preparation of dihydropyrimidines.a
Entry
R1
R2
Yield (%)b
Product
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
4-CH3OC6H4
4-ClC6H4
Ph
4-CH3OC6H4
4-ClC6H4
Ph
4-CH3OC6H4
4-ClC6H4
Ph
4-CH3OC6H4
4-ClC6H4
Ph
76
75
71
74
73
80
75
82
76
70
70
73
72
6a
6b
6c
6d
6e
6f
6g
6h
6i
4-CH3OC6H5
4-CH3OC6H5
4-CH3OC6H5
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
CH3
9
10
11
12
13
a
6j
6k
6l
6m
ꢀ
Reaction conditions: 3 (2.0 mmol), 4 (2.0 mmol), 5 (2.0 mmol), silica–ZnCl2 (150 mg), 90 C, 1.0 h.
b
Isolated yields.
Bull. Korean Chem. Soc. 2015, Vol. 36, 2915–2919
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2918

BULLETIN OF THE
Article
Synthesis of Pyrimidin-2(1H)-ones Derivatives under Solvent-Free
KOREAN CHEMICAL SOCIETY
13. C. O. Kappe, Eur. J. Med. Chem. 2000, 35, 1043.
Table 3. Reusability of silica–ZnCl2 catalyst on the reaction.
14. O. Alam, S. A. Khan, N. Siddiqui, W. Ahsan, S. P. Verma,
S. J. Gilani, Eur. J. Med. Chem. 2010, 45, 5113.
15. O. M. Singh, S. J. Singh, M. B. Devi, L. N. Devi, N. I. Singh,
S. G. Lee, Bioorg. Med. Chem. Lett. 2008, 18, 6462.
16. N. Kaur, K. Kaur, T. Raj, G. Kaur, A. Singh, T. Aree, J. Park,
T. Kim, N. Singh, D. O. Jang, Tetrahedron 2015, 71, 332.
17. S. Chitra, D. Devanathan, K. Pandiarajan, Eur. J. Med. Chem.
2010, 45, 367.
Run
Cycle
Yield (%)
1
2
3
4
0
1
2
3
88
86
84
83
18. S. N. Mokale, S. S. Shinde, R. D. Elgire,
J. N. Sangshetti, D. B. Shinde, Bioorg. Med. Chem. Lett.
2010, 20, 4424.
and with short reaction times and good yields makes this an
attractive addition to existing procedures.
19. C. O. Kappe, Tetrahedron 1993, 49, 6937.
20. P. Biginelli, Gazz. Chim. Ital. 1893, 23, 360.
21. E. H. Hu, D. R. Sidler, U. H. Dolling, J. Org. Chem. 1998,
63, 3454.
22. J. Lu, H. R. Ma, Synlett 2000, 63.
23. N. Y. Fu, Y. F. Yuan, Z. Cao, S. W. Wang, J. T. Wang, C. Peppe,
Tetrahedron 2002, 58, 4801.
Acknowledgments. O. M. S. is thankful to DBT, India
(BT/278/NE/TBP/2011) for financial assistance. This rea-
search was supported by Basic Science Reasearch Program
through the National Reasearch Foundation of Korea (NRF)
funded by the ministry of Education, Science and Technology
(Grant Number: 2015032802). Laishram Ronibala Devi and
Hojune Choi are equally contributed for this study.
24. G. Maiti, P. Kundu, C. Guin, Tetrahedron Lett. 2003,
44, 2757.
25. Q. Sun, Y. Wang, Z. Ge, T. Cheng, R. Li, Synthesis
2004, 1047.
References
26. K. Ramalinga, P. Vijayalakshmi, T. N. B. Kaimal, Synlett
2001, 863.
27. M. I. Lannou, F. Helion, J. L. Namy, Synlett 2008, 105.
28. B. C. Ranu, A. Hajra, U. Jana, J. Org. Chem. 2000, 65, 6270.
29. A. S. Paraskar, G. K. Dewker, A. Sudalai, Tetrahedron Lett.
2003, 44, 3305.
1. A. M. Elmaghraby, I. A. Mousa, A. A. Harb, M. Y. Mahgoub,
ISRN Org. Chem. 2015, 706, 437.
2. H. N. Karade, M. Sathe, M. P. Kaushik, Molecules 2007,
12, 1341.
3. D. Das, J.-F. Lee, S. Cheng, Chem. Commun. 2001, 21, 2178.
4. B.Karimi, M. Khalkhali, J. Mol. Catal. A:Chem. 2005, 232, 113.
5. S. Shylesh, S. Sharma, S. P. Mirajkar, A. P. Singh, J. Mol. Catal.
A: Chem. 2004, 212, 219.
6. K. Wilson, A. F. Lee, D. J. Macquarrie, J. H. Clark, Appl. Catal.
A Gen. 2002, 228, 127.
7. K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd,
S. Moreland, A. Hedberg, B. C. O’Reilly, J. Med. Chem.
1991, 34, 806.
8. A. Dondoni, A. Massi, S. Sabbatini, Tetrahedron Lett. 2002,
43, 5913.
9. T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King,
S. L. Schreiber, T. J. Mitchison, Science 1999, 286, 971.
10. A. D. Patil, N. V. Kumar, W. C. Kokke, M. F. Bean, A. J. Freyer,
C. De Brosse, S. Mai, A. Truneh, D. J. Faulkner, B. Carte,
A. L. Breen, R. P. Hertzberg, R. K. Johnson, J. W. Westley,
B. C. M. Ports, J. Org. Chem. 1995, 60, 1182.
11. G. C. Rovynak, S. C. Kimball, B. Beyer, G. Cucinotta, J. D.
Dimarco, J. Gougoutas, A. Hedberg, M. Malley, J. P. McCarthy,
R. Zhang, S. Moreland, J. Med. Chem. 1995, 38, 119.
12. S. J. Haggarty, T. U. Mayer, D. T. Miyamoto, R. Fathi,
R. W. King, T. J. Mitchison, S. L. Schreiber, Chem. Biol.
2000, 7, 275.
30. Y. Ma, C. Qian, L. Wang, M. Yang, J. Org. Chem. 2000,
65, 3864.
31. C. V. Reddy, M. Mahesh, P. V. K. Raju, T. R. Babu,
V. V. N. Reddy, Tetrahedron Lett. 2002, 43, 2657.
32. A. Dondoni, A. Massi, Tetrahedron Lett. 2001, 42, 7975.
33. J. S. Yadav, B. V. Subba Reddy, R. Srinivas, C. Venugopal,
T. Ramalingam, Synthesis 2001, 1341.
34. S. K. De, R. A. Gibbs, Synthesis 2005, 1748.
35. X. Han, F. Xu, Y. Luo, Q. Shen, Eur. J. Org. Chem. 2005,
8, 1500.
36. W. Su, J. Li, Z. Zheng, Y. Shen, Tetrahedron Lett. 2005,
46, 6037.
37. Y. Huang, F. Yang, C. Zhu, J. Am. Chem. Soc. 2005, 127,
16386.
38. N. S. Devi, S. J. Singh, L. R. Devi, O. M. Singh, Tetrahedron
Lett. 2013, 54, 183.
39. T. P. Singh, S. Bhattacharya, O. M. Singh, Org. Lett. 2013,
15, 1974.
40. K. A. Devi, L. G. Chanu, I. H. Chanu, O. M. Singh, Lett. Org.
Chem. 2014, 11, 743.
Bull. Korean Chem. Soc. 2015, Vol. 36, 2915–2919
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2919