Efficient Synthesis of 5-Carboxanilide-Dihydropyrimidinones Using Cobalt(II) Nitrate Hexahydrate

Article abstract of DOI:10.1002/jccs.201600841

5-Carboxanilide-dihydropyrimidinone derivatives were synthesized in good yield in a three-component and efficient process by the condensation reaction of acetoacetanilide, aldehyde and urea/thiourea in the presence of cobalt(II) nitrate hexahydrate as cat

Full text of DOI:10.1002/jccs.201600841

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Efficient Synthesis of 5-Carboxanilide-Dihydropyrimidinones Using Cobalt(II) Nitrate
Hexahydrate
*
*
Mehrnoush Kangan, Nourallah Hazeri, Afshin Yazdani-Elah-Abadi
and Malek-Taher Maghsoodlou
Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, Zahedan 98135-674, Iran
(Received: December 13, 2016; Accepted: February 25, 2017; DOI: 10.1002/jccs.201600841)
5-Carboxanilide-dihydropyrimidinone derivatives were synthesized in good yield in a three-
component and efficient process by the condensation reaction of acetoacetanilide, aldehyde and
urea/thiourea in the presence of cobalt(II) nitrate hexahydrate as catalyst in ethanol at ambient
condition.
Keywords: 5-Carboxanilide-dihydropyrimidinones; Acetoacetanilide; Cobalt(II) nitrate
hexahydrate.
INTRODUCTION
Pyrimidines exhibit a broad range of biological effects
carboxanilide-dihydropyrimidinones using cobalt(II) nitrate
hexahydrate as catalyst in ethanol at ambient condition
(Scheme 1).
including antiviral, antitumor, antibacterial, antihypertensive,1
anti-inflammatory,2 neuropeptide Y (NPY) antagonistic
activity,3 cardiovascular calcium,4 and channel blocking.5 In
1893, Biginelli reported the synthesis of dihydropyrimidinones
via the reaction of benzaldehyde, ethyl acetoacetate, and urea
in ethanol under strongly acidic conditions.6 However, this
method suffers from drawbacks such as low yields of the
desired products, particularly in the case of substituted alde-
hydes, and loss of acid-sensitive functional groups during the
reaction. This has led to multistep synthetic strategies that pro-
duce somewhat better yields but lack the simplicity of the origi-
nal one-pot Biginelli protocol.7 Many synthetic methods for
preparing of pyrimidines have been developed to improve and
modify this reaction by using Lewis acid catalysts as well as
protic acids, including TaBr5,8 lanthanide triflate,9 HCOOH,10
VCl3,11 Sr(OTf )2,12 PPh3,13 indium(III) halides,14 LiBr,15 silica
sulfuric acid,16 Mn(OAc)3ꢀ2H2O,17 Y(NO3)3ꢀ6H2O,18
In(OTf )3,19 FeCl3ꢀ6H2O, NiCl2ꢀ6H2O,20 Ce(NO3)3ꢀ6H2O,21
silica chloride,22 H3BO3,23 SrCl2ꢀ6H2O–HCl,24 Yb(OTf )3,25
Bi(NO3)3ꢀ5H2O,26 tungstate sulfuric acid,27 and HClO4–
SiO2.28 In addition, ionic liquids,29 microwave irradiation,30
ultrasound irradiation,31 and etidronic acid32 were also utilized
as the catalytic agent. However, many of these methods suffer
from long reaction times, expensive reagents, and strong acidic
conditions. In continuation of our research on multicomponent
reactions,33–35 here we report an efficient synthesis of 5-
RESULTS AND DISCUSSION
Because of the biological importance of dihydropyri-
midinones and to develop methods of the synthesis of new
derivatives of pyrimidinones, we have chosen the reaction
of acetoacetanilide (1.0 mmol), 4-nitrobenzaldehyde
(1.0 mmol), and urea/thiourea (1.5 mmol) used as starting
materials. The reaction was initially carried out in EtOH in
the presence of different catalysts (Table 1). As seen in
Table 1, cobalt(II) nitrate hexahydrate (10 mol%) was
found to be the most effective catalyst for the reaction at
room temperature. The reaction was performed in various
solvents, and EtOH was found to be the best solvent in
respect to the time and yield of the reaction (Table 2).
According to the obtained optimum conditions, we
decided to synthesize new derivatives using various aro-
matic aldehydes in the present of urea/thiourea and a cata-
lytic amount of cobalt(II) nitrate hexahydrate. The
corresponding desired products were isolated in excellent
yield, and the results are summarized in Table 3.
The proposed mechanism for the synthesis of 5-car-
boxanilide-dihydropyrimidinones in the presence of
cobalt(II) nitrate hexahydrate as catalyst is shown in
Scheme 2.
*Corresponding authors. Email: mehrnooshkangani@gmail.com; nhazeri@chem.usb.ac.ir
J. Chin. Chem. Soc. 2017
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Article
Kangan et al.
R
instrument using CDCl3 and DMSO, with TMS as
internal standard, at 300 and 75 MHz, respectively.
The mass spectra were recorded on a Shimadzu
GCMS-QP5050A mass spectrometer operating at an
ionization potential of 70 eV. All reagents and solvents
were obtained from Aldrich and Merck and used with-
out further purification.
O
R
H
X
O
O
O
EtOH,Co(NO3)2.6H2O
r.t
+
+
H2N
NH2
S
N
NH
H
N
H
N
H
4
X
X= O,
1
2
3
Scheme
1. Synthesis
of
5-carboxanilide-
dihydropyrimidinones in the presence
of cobalt(II) nitrate hexahydrate as cat-
alyst in ethanol at ambient conditions.
General procedure for the synthesis of 5-carboxanilide-
dihydropyrimidinones
Table 1. Optimization of the reaction conditions for the
synthesis of 4a1
Cobalt(II) nitrate hexahydrate (10 mol%) was
added to a mixture of aromatic aldehyde (1.0 mmol),
acetoacetanile (1.0 mmol), and urea or thiourea
(1.5 mmol) in EtOH (2 mL) at ambient temperature.
The progress of reaction was monitored by thin-layer
chromatography (TLC). After completion of the reac-
tion, the products were isolated by filtration and
washed with EtOH (3 × 2 mL) to afford pure products
in good to high yields (85–90).
Isolated
Entry Catalyst (mol%)
Solvent Time
Yield (%)
1
2
3
4
5
6
7
8
TiO2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
5 h
24 h
7 h
11 h
8 h
10 h
5 h
20
45
40
20
30
46
50
65
Zn(SO4)2Á7H2O
Zr(NO3)4
ZrCl4
HClO4–SiO2
KHSO4
NH4HSO4
Co(NO3)2.6H2O
(5 mol%)
2 h
Characterization of compounds
9
Co(NO3)2.6H2O
(10 mol%)
Co(NO3)2.6H2O
(15 mol%)
EtOH
EtOH
40 min
40 min
85
85
1,2,3,4-Tetrahydro-6-methyl-4-(4-nitrophenyl)-2-oxo-N-phenyl-
pyrimidine-5-carboxamide (4a)
IR (KBr, cm−1): 3375,
10
3268, 3106, 2931, 1723, 1667. 1H NMR (300 MHz,
DMSO) δ (ppm): 2.07 (s, 3H,CH3), 5.51(s, 1H, CH),
7.01 (t, J = 6.0 Hz, 1H), 7.26 (t, J = 6.0 Hz, 2H), 7.54
(d, J = 6.0 Hz, 2H), 7.756 (d, J = 6.0 Hz, 2H), 7.77 (s,
br, 1H, NH), 8.23 (d, J = 6.0 Hz, 2H), 8.91 (s, 1H,
NH), 9.65 (s, 1H, NH). 13C NMR (75 MHz, DMSO) δ
(ppm) : 17.54, 55.06, 104.84, 120.03, 123.72, 124.35,
128.05, 129.03, 139.39, 139.49, 139.72, 139.82, 147.24,
151.90, 152.73, 152.79, 152.84, 165.41, MS (EI, 70 eV)
m/z (%): 352 (M+, 16), 324 (10), 307 (14), 283 (16),
262 (100), 234 (25), 214 (8), 199 (5), 179 (16), 163 (16),
135 (50), 91 (53), 69 (50), 41 (80).
1
Amounts of material in all reactions: aldehyde (1.0 mmol),
urea/thio urea (1.5 mmol), and acetoacetanilide (1.0 mmol).
Table 2. Synthesis of 4a1 in the presence of different solvents
Entry
Solvent
Time
Isolated Yield (%)*
1
2
3
4
5
EtOH, r.t.
MeOH, r.t.
CH3CN, r.t.
CHCL3, r.t.
H2O, r.t.
40 min
1 h
5 h
10 h
24
24
85
65
40
50
Trace
Trace
6
1
Solvent-free
Amounts of material in all reactions: aldehyde (1.0 mmol),
urea/thio urea (1.5 mmol), acetoacetanilide (1.0 mmol),
Co(NO3)2.6H2O (10 mol%), solvent (2 mL).
1,2,3,4-Tetrahydro-6-methyl-4-(2-chlorophenyl)-2-oxo-N-phe-
nylpyrimidine-5-carboxamide (4b)
IR (KBr, cm−1):
3409, 3225, 3102, 2966, 1698, 1662. 1H NMR
(300 MHz, CDCl3) δ (ppm): 2.38 (s, 3H, CH3), 5.86 (s,
1H, CH), 5.88 (s, 1H, NH), 6.98–7.51 (m, 10H, Ar,
NH), 8.34 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): δ
(ppm): 18.05, 52.98, 102.74, 120.12 (2C), 124.41,
126.71, 128.28 (2C), 128.95, 130.32, 132.45, 137.61,
138.03, 142.95, 153.17, 164.16. MS (EI, 70 eV) m/z (%):
343 (M + 2, 16), 341 (M+, 33), 306 (25), 249 (100),
EXPERIMENTAL
Physical methods
IR spectra were recorded on a JASCO FT-IR
460 plus spectrophotometer. Melting points of all com-
pounds were measured on an Electro Thermal 9100
apparatus. The 1H and 13C-NMR spectra were
recorded on
a
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JOURNAL OF THE CHINESE
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5-Carboxanilide-Dihydropyrimidinones
Table 3. Synthesis of 5-carboxanilide-dihydropyrimidinones
Entry
1
Ar
Product
Time (min)
40
Isolated yields (%)
85
M.p. (ꢁC)
4a
287–288
2
4b
60
80
185–186
3
4
4c
4d
60
60
90
80
230–233
223–225
5
4e
40
90
183–184
6
4f
40
90
215–218
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Article
Kangan et al.
Scheme 2. Proposed mechanism for the synthesis of 5-carboxanilide-dihydropyrimidinones in the presence of cobalt(II)
nitrate hexahydrate as catalyst.
223 (9), 206 (45), 185 (16), 166 (25), 137 (19), 111(9),
93 (50),65 (30), 42 (45).
55.57, 107.84, 114.41 (2C), 119.98, 120.08 (2C), 123.79,
128.19 (2C), 129.04 (2C), 135.67, 139.35, 159.27,
165.44, 174.08. MS (EI, 70 eV) m/z (%): 353(M+, 66),
335 (6), 261 (100), 233 (29), 202 (33), 178 (37), 161 (54),
133 (8), 115 (8), 94 (4), 77 (29), 59 (4), 42 (29).
1,2,3,4-Tetrahydro-6-methyl-4-(thiophen-2-yl)-2-oxo-N-phenyl-
pyrimidine-5-carboxamide (4c)
IR (KBr, cm−1): 3406,
3278, 3121, 2959, 1715, 1674. 1H NMR (300 MHz,
DMSO) δ (ppm): 2.072 (s, 3H, CH3), 5.68 (s, 1H,
CH), 6.93–7.59 (m, 8H, Ar), 7.82 (s, 1H, NH), 8.88 (s,
1H, NH), 9.59 (s, 1H, NH). 13C NMR (75 MHz,
DMSO): δ (ppm): 17.54, 50.91, 105.77, 120.09, 123.58,
124.04, 125.44, 127.18, 128.99 (2C), 139.61, 139.85,
139.95, 149.12, 152.85, 165.30. MS (EI, 70 eV) m/z
(%): 313 (M+, 9), 299 (50), 278 (9), 252 (60),
221 (100), 186 (33), 161 (9), 138 (65), 121 (20), 93 (65),
65 (50), 45 (80).
1,2,3,4-Tetrahydro-6-methyl-4-(2,3-methoxyphenyl)-2-thio-oxo-
N-phenylpyrimidine-5-carboxamide
(4f)
IR
(KBr,
cm−1): 3444, 3374, 3231, 2333, 1700, 1671. H NMR
(300 MHz, DMSO) δ (ppm): 2.05 (s, 3H, CH3), 3.71 (s,
3H, OCH3), 3.76 (s, 3H, OCH3), 5.69 (s, 1H, CH),
6.85–7.59 (m, 8H, Ar), 9.22 (s, 1H, NH), 9.72 (s, 1H,
NH), 9.95 (s, 1H, NH). 13C NMR (75 MHz, DMSO):
δ (ppm): 16.83, 50.77, 56.11, 60.85, 107.71, 112.74,
119.92, 120.23 (2C), 123.62, 124.55, 129.01 (2C),
135.57, 136.94, 139.64, 145.89, 152.72, 165.23, 174.73.
MS (EI, 70 eV) m/z (%): 383(M+, 58), 352 (33),
291 (100), 263 (33), 232 (29), 208 (20), 191 (8), 173 (33),
155 (16), 137 (16), 120 (15), 93 (45), 65 (37), 42 (45).
1
1,2,3,4-Tetrahydro-6-methyl-4-(2-chlorophenyl)-2-thio-oxo-N-
phenylpyrimidine-5-carboxamide (4d)
IR (KBr, cm−1):
3403, 3205, 3212, 3020, 1717, 1678. 1H NMR
(300 MHz, DMSO) δ (ppm): 2.07 (s, 3H, CH3), 5.39 (s,
1H, CH), 7.012–7.56 (m, 9H, Ar), 9.49 (s, 1H, NH),
9.77 (s, 1H, NH), 10.09 (s, 1H, NH). 13C NMR
(75 MHz, DMSO): δ (ppm): 16.93, 54.82, 107.22,
120.05, 120.15, 123.89, 128.76, 129.08 (2C), 129.12,
132.80, 136.19, 136.29, 139.23, 139.34, 142.35, 165.18,
174.53. MS (EI, 70 eV) m/z (%): 359 (M + 2, 25),
357 (M+, 83), 334 (4), 291 (6), 265 (100), 237 (25),
206 (50), 165 (70), 137 (20), 120 (18), 93 (75),
65 (45), 42 (50).
CONCLUSIONS
In this study, an efficient synthesis method for the
preparation of 5-carboxanilide-dihydropyrimidinones at
ambient conditions was described. The high yields of
products, easy work-up, and short reaction times are
the advantages of this method.
1,2,3,4-Tetrahydro-6-methyl-4-(4-methoxyphenyl)-2-thio-oxo-
ACKNOWLEDGMENTS
This work was supported financially by the
University of Sistan and Baluchestan.
N-phenylpyrimidine-5-carboxamide
(4e)
IR
(KBr,
cm−1): 3383, 3278, 3190, 2836, 1737, 1677. H NMR
(300 MHz, DMSO) δ (ppm): 2.07 (s, 1H, CH3), 3.72 (s,
3H, OCH3), 5.35 (s, 1H, C, H), 6.90–7.56 (m, 9H, Ar),
9.40 (s, 1H, NH), 9.71 (s, 1H, NH), 9.97 (s, 1H, NH).
13C NMR (75 MHz, DMSO): δ (ppm): 16.88, 54.92,
1
Supporting information
Additional supporting information is available in
the online version of this article.
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5-Carboxanilide-Dihydropyrimidinones
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