Synthesis of pyrimidine carboxamide derivatives catalyzed by uranyl nitrate hexa hydrate with their antibacterial and antioxidant studies

Article abstract of DOI:10.4314/bcse.v30i1.11

An efficient and simple method was developed for the synthesis pyrimidine-5-carboxamides using UO₂(NO₃)₂.6H₂O catalyst under conventional and microwave irradiation. The synthesis of dihydropyrimidine using urany

Full text of DOI:10.4314/bcse.v30i1.11

Bull. Chem. Soc. Ethiop. 2016, 30(1), 119-128.
Printed in Ethiopia
DOI: http://dx.doi.org/10.4314/bcse.v30i1.11
ISSN 1011-3924
 2016 Chemical Society of Ethiopia
SYNTHESIS OF PYRIMIDINE CARBOXAMIDE DERIVATIVES CATALYZED BY
URANYL NITRATE HEXA HYDRATE WITH THEIR ANTIBACTERIAL AND
ANTIOXIDANT STUDIES
K. Venkatesan1,2*, V.S.V. Satyanarayana2 and A. Sivakumar2
1Department of Humanities and Sciences, CVR College of Engineering, Hyderabad,
Telangana –501510, India
2Chemistry Division, School of Advanced Sciences, VIT University, Vellore – 632 014, India
(Received September 2, 2014; revised January 1, 2016)
ABSTRACT. An efficient and simple method was developed for the synthesis pyrimidine-5-carboxamides using
UO2(NO3)2.6H2O catalyst under conventional and microwave irradiation. The synthesis of dihydropyrimidine
using uranyl nitrate had shown many advantages such as easy work up, shorter reaction times and higher yields
1
using acetonitrile as a solvent. The structures of the synthesized compounds were confirmed by FT-IR, H NMR,
13C NMR and mass spectral data. All the synthesized compounds screened for in vitro antioxidant and
antibacterial activity and the results are reported.
KEY WORDS: Microwave, Uranyl nitrate, Antioxidant, Antibacterial
INTRODUCTION
Nitrogen based heterocycles provides broad range of biological activities; the lone pair present
in the nitrogen atoms acts as donor facilitating the construction of various supramolecular
blocks. Multi-component reactions (MCRs) are an important class of organic reactions, which is
widely used to construct different target molecules in one pot reaction using three or more
numbered starting materials. In 1893 an Italian chemist Pietro Biginelli has reported the
synthesis of dihydropyrimidines by a simple one-pot cyclocondensation reaction of ethyl
acetoacetate, benzaldehyde and urea [1]. The literature reveals that Human kinesin Eg5, plays a
crucial role in mitosis by establishing the bipolar spindle, which has been proved to be an
interesting drug target for the development of cancer chemotherapeutics. In a similar way,
monastrol, the first Biginelli compound, exhibited good anticancer property. Batzelladine A and
B compounds of DHPMs derived [2] from natural marine sources, were the first low molecular
weight natural products showing promising anti HIV activity and hence considered as potential
molecules for treatment of AIDS.
The limited availability of the natural products renders them to be attractive targets for total
synthesis [3]. The dihydropyrimidinone (DHPM) is the most important core structure in the
synthesis of different medicinally and pharmacologically valuable agents such as antibacterial
[4], antiviral [5], antitumor [6], antihypertensive agents [7], calcium channel blockers [8],
neuropeptide Y (NPY) antagonists [9], α-1a-antagonists [10] and anti-inflammatory drugs [11].
In addition, the batzelladine alkaloids containing the DHPM ring structure inhibit the binding of
HIV envelope protein gp-120 to human CD4 cells and there are potential of new molecule for
AIDS treatment [12-13]. Therefore, dihydropyrimidinones (DHPMs) synthesis always shows
the attraction to organic chemists.
Biginelli reaction takes place by mixing different substituted aldehydes, urea or thiourea,
and an active 1,3-dicarbonyl compound in combination with different catalytic systems such as
AcOH [14], ZrCl4 [15], Cu(OTf)2 [16], SiO2/H2SO4 [17], La(OTf)3 [18], CdCl2 [19], 1-n-butyl-3-
methyl imidazolium tetrafluoroborate [20], SiO2/NaHSO4 [21], Pb(NO3)2 [22], NaCl [23], KSF
__________
*Corresponding author. E-mail: venkippk@gmail.com

120
K. Venkatesan et al.
clay [24], FeCl3 [25], BiCl3 [26], ion-exchange resin [27], LiBr [28], AlCl3.H2O [29], p-TSA
[30], MgBr2 [31], (NH4)2Ce(NO3)6 [32], Mn(OAc)3 [33], InBr3 [ 34], microwave [35-38] or
ultrasound irradiation [39] and solvent-free conditions [40], Co(NO3)2.6H2O [41], ZnCl2/TBAB
[42]. In the last two decades microwave mediated reactions have been of great interest in
organic synthesis because of their shorter reaction times and high yields of products with good
selectivity.
EXPERIMENTAL
General
All the reagents were purchased from Aldrich, SD Fine Chemicals and Qualigens and used
without further purification. The 1H NMR spectra were obtained on Bruker AV-500 MHz
spectrometer with DMSO-d6 as the solvent using tetramethylsilane (TMS) as the internal
standard. Infrared (IR) spectra were recorded at room temperature from 4000-400 cm-1 with KBr
pellets at a resolution of 4 cm-1, using Avatar 330 equipped with DTGS detector. The
microwave irradiation experiments were carried out using conventional (unmodified) household
microwave oven equipped with a turntable was used (LG, MG-395 WA, 760 W) and operating
at 2450 MHz. Mass spectra were obtained using HRMS (JEOL 1600 HRMS). Melting points
were determined by open capillaries and are uncorrected.
General procedure for the preparation of compound 6-methyl-1,2,3,4-tetrahydro-N-aryl-2-
thio/oxo-4-arylpyrimidine-5-carboxamide (4a-o)
Conventional method. A mixture of aldehyde (1 mmol), acetoaetanilide (1 mmol), urea or
thiourea (1.2 mmol), UO2(NO3)2.6H2O (5 mol%) and 20 mL acetonitrile was refluxed as per
duration time mentioned in Table 3. After completion of the reaction as indicated by TLC, the
reaction mixture was poured into crushed ice, stirred for 15-20 min. and left overnight. The solid
separated was filtered through a funnel, washed with ice-cold water and then recrystallized from
hot methanol to afford pure compounds 4a-o.
Microwave irradiation. A mixture of aldehyde (1 mmol), acetoaetanilide (1 mmol), urea or
thiourea (1.2 mmol), UO2(NO3)2.6H2O (5 mol%) and acetonitrile (5 mL) were taken in a small
beaker and then the reaction mixture was subjected to microwave irradiation at an interval of 3
min at 160 W for about 15-18 min; varying time periods as shown in Table 3. The completion of
the reaction was monitored by TLC. After the completion of the reaction, the mixture was
poured into ice cold water stirred well and the solid separated was filtered, dried and then
recrystallized from hot methanol to afford pure compounds 4a-o.
4-(3-Ethoxy-4-hydroxyphenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (4c). M.p. 253-256 ºC; IR (KBr) νmax: 3542, 3259, 2977, 2931, 1701, 1660, 1609,
1591, 1581, 1518, 1491, 1478, 1436, 1411, 1371, 1336, 1281, 1225, 1212, 1155, 1121, 1093,
1
1062, 1041 cm-1; H NMR (300 MHz, DMSO-d6, ppm), δH = 9.10 (s, 1H, CONH), 8.86 (s, 2H,
NH and OH), 7.53 (s, 1H, NH), 6.37–7.28 (m, 8H, ArH of phenyl ring), 5.23 (s, 1H, CH), 3.77-
3.84 (m, 2H, OCH2), 2.48 (s, 3H, CH3), 1.18–1.32 (m, 3H, CH3); 13C NMR (125.757 MHz,
DMSO-d6, ppm), δC = 164.53, 163.35, 152.70, 152.57, 146.86, 146.76, 146.58, 146.49, 143.16,
142.04, 135.98, 132.26, 128.72, 127.35, 126.03, 125.54, 119.30, 118.02, 115.74, 115.59,
112.66, 102.58, 64.27, 64.17, 63.86, 53.17, 38.83, 15.26, 15.20; HRMS (EI): m/z [M+] calcd. for
C20H21N3O4: 367.1532; found: 367.1531.
4-(3-Ethoxy-4-hydroxyphenyl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (4d). M.p. 242-245 ºC; IR (KBr) νmax: 3349, 3192, 2975, 2931, 1672, 1625, 1595,
1571, 1512, 1467, 1435, 1400, 1283, 1234, 1217, 1189, 1149, 1120, 1108, 1084, 1039, 1012 cm-
1; 1H NMR (300 MHz, DMSO-d6, ppm), δH = 10.29 (s, 1H, CONH), 9.52 (s, 1H, NH), 8.87–8.94
Bull. Chem. Soc. Ethiop. 2016, 30(1)

Synthesis of pyrimidine carboxamide derivatives catalyzed by uranyl nitrate hexa hydrate 121
(split peak, 2H, NH and OH), 6.36-7.26 (m, 8H, ArH of phenyl ring), 5.25 (s, 1H, CH), 3.56-
3.95 (m, 2H, OCH2), 2.45 (s, 3H, CH3), 1.18-1.35 (m, 3H, CH3); HRMS (EI): m/z [M+] calcd.
for C20H21N3O3S: 383.1304; found: 383.1302.
4-(2,4-Dichlorophenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide
(4e). M.p. 206-209 ºC; IR (KBr) νmax: 3397, 3265, 3168, 3084, 3006, 1669, 1626,1595, 1563,
1
1525, 1498, 1478, 1436, 1380, 1331, 1236, 1179, 1140, 1101, 1075, 1045 cm-1; H NMR (400
MHz, DMSO-d6, ppm), δH =10.11 (s, 1H, CONH), 9.86 (s, 1H, NH), 9.36 (s, 1H, NH), 7.56 (d,
1H, J = 2.5 Hz, m-ArH of phenyl ring), 7.50 (d, 3H, J = 7.5 Hz, o,o' and m'-ArH of phenyl
ring), 7.38 (d, 1H, J = 8.5 Hz, o'-ArH of phenyl ring), 7.25 (t, 2H, J = 8.0 Hz, m,m'-ArH of
phenyl ring), 7.02 (t, 1H, J = 7.25 Hz, p-ArH of phenyl ring), 5.75 (d, 1H, J = 2.0 Hz, CH), 2.02
(s, 3H, CH3); 13C NMR (100.612 MHz, DMSO-d6, ppm), δC = 174.12, 164.36, 139.35, 138.77,
135.03, 133.08, 132.16, 130.83, 128.86, 128.02, 123.37, 119.47, 106.37, 52.42, 16.20; HRMS
(EI): m/z [M+] calcd. For C18H15Cl2N3O2: 375.0541; found: 375.0541.
4-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydro-6-methyl-N-phenyl-2-thioxopyrimidine-5-
carboxamide (4f). M.p. 188-191 ºC; IR (KBr) νmax: 3397, 3276, 3088, 2360, 2342, 1672, 1654,
1629, 1598, 1560, 1540, 1523, 1498, 1473, 1438, 1329, 1234,1202, 1180, 1143, 1101, 1076,
1
1046 cm-1; H NMR (500 MHz, DMSO-d6, ppm), δH =10.13 (s, 1H, CONH), 9.87 (s, 1H, NH),
9.37 (s, 1H, NH), 7.56 (d, 1H, J = 2.0 Hz, m-ArH of phenyl ring), 7.51 (d, 3H, J = 8.5 Hz, o,o'
and m'-ArH of phenyl ring), 7.39 (d, 1H, J = 8.5 Hz, o'- ArH of phenyl ring), 7.26 (t, 2H, J = 8.0
Hz, m,m'-ArH of phenyl ring), 7.02 (t, 1H, J = 7.25 Hz, p-ArH of phenyl ring), 5.75 (d, 1H, J =
2.5 Hz, CH), 2.03 (s, 3H, CH3); HRMS (EI): m/z [M+] calcd. for C18H15Cl2N3OS: 391.0313;
found: 391.0312.
4-(4-Ethoxy-3-methoxyphenyl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (4g). M.p. 123-126 ºC; IR (KBr) νmax: 3349, 3291, 3175, 3094, 2977, 2361, 1680,
1635, 1596, 1561, 1513, 1482, 1439, 1394, 1334, 1264, 1229, 1197, 1180, 1139, 1029 cm-1; 1H
NMR (500 MHz, DMSO-d6, ppm), δH = 9.95 (s, 1H, CONH), 9.72 (s, 1H, NH), 9.38 (s, 1H,
NH), 7.54 (d, 2H, J = 8.5 Hz, o,o'-ArH of phenyl ring), 7.26 (t, 2H, J = 7.25 Hz, m,m'-ArH of
phenyl ring), 7.02 (t, 1H, J = 7.25 Hz, p-ArH of phenyl ring), 6.91 (d, 1H, J = 8.0 Hz, o-ArH of
phenyl ring), 6.85 (s, 1H, m’-ArH of phenyl ring), 6.78 (d, 1H, J = 8.0 Hz, o'-ArH of phenyl
ring), 5.36 (s, 1H, CH), 3.96 (q, 2H, J = 6.75 Hz, OCH2), 3.67 (s, 3H, OCH3), 2.07 (s, 3H, CH3),
1.29 (t, 3H, J = 6.75 Hz, CH3); HRMS (EI): m/z [M+] calcd. for C21H23N3O3S: 397.1460; found:
397.1459.
6-Methyl-2-oxo-N-phenyl-4-(thiophen-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4h).
M.p. 192-195 ºC; IR (KBr) νmax: 3249, 2362, 1697, 1640, 1592, 1509, 1492, 1452, 1396, 1307,
1286, 1251, 1208, 1148, 1089, 1040, 1012 cm-1; 1H NMR (500 MHz, DMSO-d6, ppm), δH = 9.57
(s, 1H, CONH), 8.85 (s, IH, NH), 7.80 (s, 1H, NH), 7.58 (d, 2H, J = 8.0 Hz, o,o'-ArH of phenyl
ring), 6.93–7.38 (m, 6H, ArH of phenyl and thiophene ring), 5.59 (d, 1H, J = 3.0 Hz, CH), 2.06
(s, 3H, CH3); HRMS (EI): m/z [M+] calcd. For C16H15N3O2S: 313.0885; found: 313.0884.
6-Methyl-N-phenyl-4-(thiophen-2-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
(4i). M.p. 201-204 ºC; IR (KBr) νmax: 3368, 3284, 1679,1635, 1566, 1548, 1523, 1499, 1477,
1439, 1360, 1328, 1232, 188, 1117, 1076, 1037 cm-1; 1H NMR (400 MHz, DMSO-d6, ppm), δH
=10.14 (s, 1H, CONH), 9.73 (s, 1H, NH), 9.62 (s, 1H, NH), 6.95-7.68 (m, 8H, ArH of phenyl
and thiophene ring), 5.67 (d, 1H, J = 3.0 Hz, CH), 2.10 (s, 3H, CH3); 13C NMR (100.612 MHz,
DMSO-d6, ppm), δC = 174.19, 164.53, 146.91, 138.94, 136.61, 128.54, 126.78, 125.67, 124.29,
123.34, 119.74, 107.07, 50.36, 16.55; HRMS (EI): m/z [M+] calcd. for C16H15N3OS2: 329.0657;
found: 329.0656.
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K. Venkatesan et al.
4-(4-Ethoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4j).
M.p. 235-238 ºC; IR (KBr) νmax: 3249, 3114, 2981, 2927, 2597, 1736, 1666, 1628, 1611, 1597,
1
1516, 1440, 1392, 1358, 1328, 1267, 1247, 1176, 1170, 1074, 1048, 1008 cm-1; H NMR (300
MHz, DMSO-d6, ppm), δH = 9.52 (s, 1H, CONH), 8.70 (s, 1H, NH proton), 6.84-7.55 (m, 10H,
NH and ArH of phenyl ring), 5.36 (s, 1H, CH), 3.98 (t, J = 6.90 Hz, 2H, OCH2), 2.04 (s, 3H,
CH3), 1.28 (t, 3H, J = 6.90 Hz, CH3); 13C NMR (100.612 MHz, DMSO-d6, ppm), δC = 172.04,
165.31, 157.75, 152.49, 139.21, 138.15, 136.27, 128.46, 127.47, 123.00, 119.50, 114.19,
105.58, 62.91, 54.46, 16.98, 14.60; HRMS (EI): m/z [M+] calcd. for C20H21N3O3: 351.1583;
found: 351.1582.
4-(4-Hydroxy-3-methoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (4k). M.p. 230-233 ºC; IR (KBr) νmax: 3411, 3285, 2363, 2341, 1683, 1653, 1628,
1597, 1539, 1521, 1487, 1442, 1386, 1330, 1262, 1241, 1164, 1124, 1074, 1034 cm-1; 1H NMR
(300 MHz, DMSO-d6, ppm), δH = 9.53 (s, 1H, CONH), 8.93 (s, 1H, OH), 8.67 (s, 1H, NH),
6.71–7.56 (m, 9H, NH and ArH of phenyl ring), 5.34 (s, 1H, CH), 3.67 (s, 3H, OCH3), 2.07 (s,
3H, CH3); 13C NMR (100.612 MHz, DMSO-d6, ppm), δC = 165.46, 152.51, 147.32, 145.80,
139.19, 137.88, 135.18, 128.47, 123.04, 119.52, 118.47, 115.21, 110.71, 105.56, 55.46, 54.75,
16.95; HRMS (EI): m/z [M+] calcd. for C19H19N3O4: 353.1376; found: 353.1374.
N-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (4l). M.p. 205-208 ºC; IR (KBr) νmax: 3397, 3195, 1673, 1630,1596, 1565, 1530,
1
1469, 1439, 1383, 1235, 1202, 1102, 1046 cm-1; H NMR (500 MHz, DMSO-d6, ppm), δH =
9.84 (s, 1H, CONH), 8.88 (s, 1H, NH), 7.58 (s, 1H, NH), 7.52-7.55 (m, 3H, o,o' and m-ArH of
phenyl ring), 7.45 (d, 2H, J = 2.0 Hz, m,m'-ArH of phenyl ring), 7.28-7.30 (split peak, 2H, o'
and m'-ArH of phenyl ring), 5.75 (d, 1H, J = 2.0 Hz, CH), 2.02 (s, 3H, CH3); HRMS (EI): m/z
[M+] calcd. for C18H14Cl3N3O2: 409.0152; found: 409.0151.
N-(4-Chlorophenyl)-4-(4-ethoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (4m). M.p. 248-251 ºC; IR (KBr) νmax: 3293, 2981, 2926, 1702, 1659, 1618, 1585,
1513, 1492, 1477, 1412, 1396, 1376, 1341, 1303, 1272, 1241, 1177, 1137, 1115, 1093, 1049 cm-
1
;
1H NMR (500 MHz, DMSO-d6, ppm), δH = 9.16 (d, 1H, CONH), 7.60 (t, 1H, J = 2.25 Hz,
NH), 6.63-7.31 (m, ArH and NH protons), 5.13-5.29 (split peak, 1H, CH), 3.95-4.03 (m, 2H,
OCH2), 2.46-2.51 (m, 3H, CH3), 1.29-1.35 (m, 3H, CH3); HRMS (EI): m/z [M+] calcd. for
C20H20ClN3O3: 385.1193; found: 385.1192.
N-(4-Chlorophenyl)-4-(4-ethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (4n). M.p. 228-230 ºC; IR (KBr) νmax: 3199, 2978, 2925, 1673, 1616, 1560, 1512,
1
1492, 1464, 1411, 1395, 1338, 1304, 1252, 1197, 1182, 1162, 1111, 1092, 1047, 1014 cm-1; H
NMR (500 MHz, DMSO-d6, ppm), δH = 10.35 (s, 1H, CONH), 9.51 (s, 1H, NH), 7.31-7.33
(split peak, 1H, NH), 7.12-7.14 (split peak, 2H, o,o'-ArH of phenyl ring), 7.00 (d, 2H, J = 3.5
Hz, m,m'-ArH of phenyl ring), 6.81-6.87 (m, 2H, ArH of phenyl ring), 6.64 (d, 2H, J = 9.0 Hz,
ArH of phenyl ring), 5.62 (s, 1H, CH), 3.94–4.04 (m, 2H, OCH2), 2.16 (s, 3H, CH3), 1.30-1.35
(m, 3H, CH3); HRMS (EI): m/z [M+] calcd. for C20H20ClN3O2S: 401.0965; found: 401.0964.
N-(4-Chlorophenyl)-6-methyl-2-oxo-4-(thiophen-2-yl)-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (4o). M.p. 239-224 ºC; IR (KBr) νmax: 3245, 3103, 1664, 1594, 1529, 1491, 1427,
1
1398, 1307, 1240, 1187, 1091, 1042, 1012 cm-1; H NMR (500 MHz, DMSO-d6, ppm), δH =
10.12 (s, 1H, CONH), 8.95 (s, 1H, NH), 7.95 (s, 1H, NH), 7.63–7.65 (split peak, 2H, o,o'-ArH
of phenyl ring), 7.51-7.59 (split peak, 2H, m,m'-ArH of phenyl ring), 6.95-7.42 (m, 3H, ArH of
thiophene ring), 5.73 (d, 1H, J = 3.0 Hz, CH), 2.08 (s, 3H, CH3); HRMS (EI): m/z [M+] calcd.
for C16H14ClN3O2S: 347.0495; found: 347.0494.
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Synthesis of pyrimidine carboxamide derivatives catalyzed by uranyl nitrate hexa hydrate 123
Screening of antioxidant activity
The radical-scavenging activity of synthesized compound was evaluated and compared to that of
butylated hydroxyl toluene (BHT) and ascorbic acid using the DPPH radical scavenging assay.
This assay is based on the measurements of the scavenging ability of compounds towards the
stable radical DPPH. The disappearance of absorption of this commercially available radical is
measured spectrophotometrically at 517 nm in a dimethyl sulphoxide (DMSO) solution using a
UV/Vis-spectrophotometer under thermo-static conditions at 25 ºC. DPPH has an odd electron
and hence has a strong absorption band at 517 nm. When this electron becomes paired off, the
absorption decreases stoichiometrically with respect to the number of electrons or hydrogen
atoms taken up. Such a change in the absorbance by this reaction has been extensively adopted
to test the capacity of several molecules to act as free radical scavengers. Hence, faster is the
decrease of absorbance; more pronounced is the antioxidant activity of the compound.
3.0 mL of a freshly prepared DPPH solution of 6.02 x 10-5 M in DMSO was placed in a test
tube and 100 μL of a DMSO solution of each test compound added. After that the solution was
kept at room temperature for 30 min in dark and the absorbance was measured at 517 nm. The
control contained all the reaction reagents except the synthetic compound or positive control
substance. The experiment was carried out in triplicate and average values are reported. The
DPPH scavenging activity was expressed as the inhibition of free radical DPPH in percent (I %)
as described by Tepe et al. [43].
Inhibition (%) = [(control OD–sample OD)/control OD] x 100.
Screening of antibacterial activity
The in vitro antibacterial studies were carried out against three “Gram +ve” bacterial strains,
Staphylococcus aureus (MTCC 3381), Pseudomonas aeruginosa (MTCC 2295) and Bacillus
cereus (MTCC 8372) and two “Gram -ve” bacterial strains, Escherichia coli (MTCC 1302),
Klebsiella pneumonia (MTCC 3384) by agar well diffusion method using Muller Hinton agar as
the medium [44]. A number of antimicrobial discs were placed on the agar for the sole purpose
of producing zones of inhibition in the bacterial lawn. 20 mL of agar media was poured into
each Petri dish. Excess of suspension was decanted and plates were dried by placing them in an
incubator at 37 oC for an hour. Using a punch, wells were made on these seeded agar plates and
different concentrations of the test compounds in dimethylsulfoxide (DMSO) were added into
each labeled well. A control was also prepared for the plates in the same way using DMSO as
solvent. All the plates were incubated at 37 oC for 24 h. The degree of effectiveness was
measured by determining the diameters of the zone of inhibition produced by the compounds.
Activity of each compound was compared with standard drug ampicillin available in the market.
Minimum inhibitory concentration (MIC) was calculated as the lowest concentration of the
sample at which there is no visible growth of the bacteria.
RESULTS AND DISCUSSION
In the present work a simple, efficient and practical approach for the synthesis of 4-aryl
pyrimidine-5-carboxamide by reacting actoacetanilide, urea or thiourea with substituted
benzaldehyde using UO2(NO3)2.6H2O under conventional and microwave irradiation methods
are reported (Scheme 1). UO2(NO3)2.6H2O is a cost effective catalyst for the synthesis of 5-
carboxamide-DHPM compounds compared to the other Lewis acid catalysts reported in the
literature.
The optimized reaction condition was developed using condensation of benzaldehyde, urea
and acetoacetanilide in the presence of catalytic amounts of UO2(NO3)2.6H2O under
conventional and microwave irradiations using different solvent system such as chloroform,
Bull. Chem. Soc. Ethiop. 2016, 30(1)

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K. Venkatesan et al.
dichloromethane, ethanol, methanol, acetonitrile and different catalytic mole percent was also
examined and the results are reported (Table 1 and 2).
R = H, Cl, X = O, S; R1 = 2,4-dichlorophenyl, 4-ethoxyphenyl, 3-ethoxy-4-hydroxylphenyl, 3-
methoxy-4-hydroxylphenyl, 2-thiophene
Scheme 1. Facile one pot synthesis of 6-methyl-1,2,3,4-tetrahydro-N-aryl-2-oxo-4-aryl
pyrimidine-5-carboxamide derivatives (4a-o) catalyzed by UO2(NO3)2.6H2O.
Table 1. Effect of solventa..
S. No.
Solvents
Chloroform
Dichloromethane
Ethanol
Methanol
Acetonitrile
Catalyst (mol %)
Time (min)
Yield (%)
1
2
3
4
5
5
5
5
5
5
25
25
16
16
15
33
29
75
73
91
aAldehyde (1 mmol), acetoaetanilide (1 mmol), urea or thiourea (1.2 mmol), UO2(NO3)2.6H2O (5 mol%), 800 W.
Table 1 indicates that polar solvents such as methanol, ethanol and acetonitrile, gave better
yields when compared to non polar ones, which indicate that acetonitrile is the best solvent for
this conversion.
Table 2. Effect of catalysts loadinga.
S. No
Catalyst
Catalyst (mol %)
Time (min)
Yield (%)
1
2
3
4
UO2(NO3)2.6H2O
UO2(NO3)2.6H2O
UO2(NO3)2.6H2O
Conc. HCl
5
10
15
15
15
15
91
91
91
63
1 mL
16 h
The results are shown that the reaction proceed more efficiently under microwave irradiation
when compared to conventional heating. Furthermore, effect of catalyst loading was studied.
The optimum catalyst mole percent was found to be 5 mol %, when we increasing the catalyst
mole percent (1 and 2, Table 2) did not show any improvement in the yield percent. After
optimization of the reaction conditions, this method was used for synthesis of DHPM using
different substituted aldehydes, urea or thiourea and substituted acetoacetanilide under
conventional heating and microwave irradiation conditions to synthesis of new DHPM
derivatives by using UO2(NO3)2.6H2O as a catalyst for this reaction (Table 3).
The catalyst which is highly soluble in water could be easily removed by washing with
excess amount of cold water through suction filtration. All the synthesized compounds
characterized through IR, 1H NMR and HRMS mass spectra.
Antioxidant activity
Antioxidant activities of all the newly synthesized compounds 4a-o was carried out using DPPH
free radical scavenging assay method. The antioxidant studies revealed that compound 4c, 4d, 4f
and 4g show reasonable free radical scavenging activity (70.88, 71.45, 76.34, and 72.60℅,
respectively) compared to that of BHT (butylated hydroxyl toluene) and ascorbic acid (100%),
while that compound 4e, 4k and 4o shows good activity, while that compounds 4a, 4b, 4h, 4i,
Bull. Chem. Soc. Ethiop. 2016, 30(1)

Synthesis of pyrimidine carboxamide derivatives catalyzed by uranyl nitrate hexa hydrate 125
4j, 4l, and 4m do not show antioxidant activity at 100 µg/mL concentration at 1 hour incubation
time. Compound 4c and 4d having phenolic OH in their substitution this have contributed to
better antioxidant activity.
Table 3. Experimental results and physical data of 6-methyl-1,2,3,4-tetrahydro-N-aryl-2-oxo/thio-4-
arylpyrimidine-5-carboxamide derivatives 4a-o.
Reaction time (min)
Yield (%)a
Compound
R
H
R1
X
O
m.p. (°C)
MW
15
Conv.
MW
Conv.
4a
450
91
90
82
225-228 [41]
4b
4c
H
H
S
16
17
450
480
83
80
214-217 [41]
253-256
O
86
83
O
O
OH
4d
H
S
18
480
78
242-245
OH
Cl
Cl
4e
4f
H
H
H
O
S
S
18
19
19
480
480
480
85
83
83
79
75
76
206-209
188-191
123-126
Cl
Cl
O
4g
O
4h
4i
H
H
O
S
18
18
420
420
86
82
77
75
192-195
201-204
S
S
4j
4k
4l
H
H
O
O
O
19
19
17
450
420
480
87
89
88
80
85
79
235-238
230-233
205-208
O
O
OH
Cl
Cl
4-Cl
4m
4-Cl
O
17
480
89
78
248-251
O
Bull. Chem. Soc. Ethiop. 2016, 30(1)

126
K. Venkatesan et al.
4n
4o
4-Cl
4-Cl
S
18
18
480
85
88
75
77
228-230
239-242
O
O
420
S
aAldehyde (1 mmol), acetoaetanilide (1 mmol), urea or thiourea (1.2 mmol), 5 mL acetonitrile.
Figure 1. Comparsion of antioxidant activity of compounds 4a-o, BHT and ascorbic acid using
DPPH radical scavenging method after 30 min and 1 h incubation.
Free radical scavenging capacities of the synthesized compounds 4a-o, BHT and ascorbic
acid at 100 μg/mL concentration after half an hour and 1 hour incubation time in dark at room
temperature are shown in Figure 1. The radical scavenging activity (RSA) for methanolic
solutions of synthesized compounds 4a-o are presented in (Table 4) and compared with those of
standards BHT and ascorbic acid.
Table 4. Antioxidant activity of compounds 4a-o using DPPH radical scavenging method.
After 30 min incubation*
Compound Absorbance % Antioxidant activity Compound Absorbance % Antioxidant activity
After 1 h incubation
4c
4d
4e
4f
4g
2.03
1.99
2.58
1.65
1.91
2.45
2.50
7.00
70.88
71.45
63.02
76.34
72.60
64.86
64.23
4c
4d
4e
4f
4g
4k
4o
1.92
1.74
2.25
1.41
1.50
1.92
2.14
72.47
75.13
67.81
79.77
78.53
72.48
69.33
4k
4o
Control**
*BHT and ascorbic acid was used as a standard antioxidant. ** DPPH in DMSO.
Antibacterial activity
Antibacterial activity screening of all the synthesized compounds 4a-o against different “Gram
+ve” bacterial strains S. aureus (MTCC 3381), P. aeruginosa (MTCC 2295) and B. cereus
(MTCC 8372) and two “Gram -ve” bacterial strains E. coli (MTCC 1302), K. pneumonia
(MTCC 3384) organisms by zone inhibition method.
The compounds 4c, 4g, 4h and 4k shows highest activity against S. aureus, P. aeruginosa,
Bull. Chem. Soc. Ethiop. 2016, 30(1)

Synthesis of pyrimidine carboxamide derivatives catalyzed by uranyl nitrate hexa hydrate 127
E. coli and K. pneumonia and moderate activity against B. cereus while compounds 4d and 4j
showed good activity against B. cereus and moderate activity against other bacterial strains.
The compounds 4d and 4o show moderate activity against P. aeruginosa and K. pneumonia and
least activity against other organisms. Compounds 4a, 4b, 4e, 4f, 4i, 4j, 4l and 4n show least
activity against all the micro organisms screened. The data on the antibacterial activity of these
compounds is given in Table 5.
Table 5. Antibacterial activities of the synthesized compounds 4a-o.
Compound
Zone of bacterial inhibition ina (mm)
K. pneumonia B. cereus P. aeruginosa
25 µg/mL 50 µg/mL 25 µg/mL 50 µg/mL 25 µg/mL 50 µg/mL 25 µg/mL 50 µg/mL 25 µg/mL 50 µg/mL
E. coli
S. aureus
4a
4b
4c
4d
4e
9
10
12
15
14
13
8
10
11
13
13
11
10
11
10
12
14
12
10
12
11
15
14
13
9
11
11
14
14
13
10
13
12
11
9
8
9
10
12
11
10
10
11
9
10
12
10
11
11
12
4f
4g
9
13
11
16
9
11
10
14
9
10
12
13
10
13
11
15
10
12
11
15
4h
4i
12
10
10
11
8
13
12
12
15
10
10
9
14
11
11
14
9
8
11
12
13
13
9
10
9
13
12
11
15
12
9
11
8
13
14
10
14
11
10
11
11
8
4j
4k
4l
9
10
13
10
12
7
11
9
4m
4n
10
9
13
11
9
10
12
11
11
10
12
13
12
11
14
13
9
10
11
12
4o
11
13
12
13
10
12
12
14
9
11
Ampicilinb
19
17
16
18
16
aZone of inhibition in mm. bStandard antibacterial drug (25 µg/mL)
.
CONCLUSION
A simple and efficient procedure for the synthesis of 6-methyl-1,2,3,4-tetrahydro-N-aryl-2-
oxo/thio-4-arylpyrimidine-5-carboxamide derivatives by one-pot three-component condensation
of different substituted aldehydes, urea or thiourea and substituted acetoacetanilides under
conventional heating and microwave irradiation conditions using UO2(NO3)2.6H2O as catalyst
has been presented. The main advantages of this process such as mild reaction conditions,
shorter reaction times, cost effective catalyst, easy work-up and high yields. The synthesized
compounds 4a-o were screened for their in vitro antioxidant activity using DPPH free radical
scavenging method. The compound 4e, 4k and 4o shows good antioxidant activity when
compared to other synthesized compounds. Antibacterial activity of the synthesized compounds
also carried out and it was observed that compounds 4c, 4g, 4h and 4k showed highest activity
against S. aureus, P. aeruginosa, E. coli and K. pneumonia remaining compound showed
moderate activity in comparison with standard drug.
ACKNOWLEDGMENTS
Authors gratefully acknowledge the management of VIT University, Vellore for encouraging
and providing necessary facilities for carrying out this work and SAIF IIT Madras for recording
spectral analysis.
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