Ultrasound-assisted synthesis of 6-methyl-1,2,3,4-tetrahydro-N-aryl-2-oxo/ thio-4-arylpyrimidine-5-carboxamides catalyzed by uranyl nitrate hexahydrate

Article abstract of DOI:10.1002/jccs.201300380

An efficient and simple method developed for the synthesis of 6-methyl-1,2,3,4-tetrahydro-N-aryl-2-oxo/thio-4-arylpyrimidine-5-carboxamide derivatives (4a-o) using UO₂(NO₃)₂.6H ₂O catalyst under conventional and

Full text of DOI:10.1002/jccs.201300380

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Ultrasound-Assisted Synthesis of 6-Methyl-1,2,3,4-tetrahydro-N-aryl-2-oxo/thio-4-
arylpyrimidine-5-carboxamides Catalyzed by Uranyl Nitrate Hexahydrate
K. Venkatesan, V. S. V. Satyanarayana* and A. Sivakumar*
Chemistry Division, School of Advanced Sciences, VIT University, Vellore – 632014, Tamilnadu, India
(Received: Jul. 26, 2013; Accepted: Nov. 2, 2013; Published Online: ??; DOI: 10.1002/jccs.201300380)
An efficient and simple method developed for the synthesis of 6-methyl-1,2,3,4-tetrahydro-N-aryl-2-
2 3 2 2
oxo/thio-4-arylpyrimidine-5-carboxamide derivatives (4a-o) using UO (NO ) .6H O catalyst under con-
ventional and ultrasonic conditions. The ultrasound irradiation synthesis had shown several advantages
such as milder conditions, shorter reaction times and higher yields. The structures of all the newly synthe-
1 13
sized compounds have been confirmed by FT-IR, H NMR, C NMR and mass spectra.
Keywords: Ultrasonic irradiation; UO
INTRODUCTION
2
(NO
3
)
2
.6H
2
O; Spectral characterization.
However, insipte of their potential utility, many of
these methods require the use of expensive reagents,
stoichiometric amounts of catalysts, strongly acidic condi-
tions in combination with bronsted acids, such as hydro-
The dihydropyrimidinone (DHPM) is the most im-
portant ring system in the synthesis of different pharmaco-
logically active agents such as antihypertensive agents, cal-
cium channel blockers, neuropeptide Y (NPY) antagonists,
a-1a-antagonists, antiviral, antitumor, antibacterial and
5
6-59
chloric acid and acetic acid
as additives, long reaction
times, high temperatures and unsatisfactory yields. There-
fore, to avoid these limitations, the development of a mild,
efficient and cost effective catalyst with high catalytic ac-
tivity, short reaction time with simple work-up procedure
for the preparation of dihydropyrimidinones is of prime in-
terest and would extend the scope of pyrimidinone chemis-
try.
1
-7
anti-inflammatory drugs. In addition, the batzelladine al-
kaloids containing the DHPM core unit inhibit the binding
of HIV envelope protein gp-120 to human CD
4
cells and
8
-10
therefore, are potential new leads for AIDS therapy.
Hence synthesis of dihydropyrimidinones (DHPMs) has
always been of great interest to the organic chemists.
The synthetic strategies used to generate DHPMs
have been well documented and have typically involved
Ultrasound has increasingly been employed in or-
ganic synthesis for decades with varied success. Chemical
applications extend to such varied areas as organic and
organometallic chemistry, materials science, aerogels, food
11-14
variations of the original Biginelli reaction.
The one-
pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones was
first reported by Biginelli in 1893, often involves unsatis-
factory yields (20–60%), harsh reaction conditions and
6
0-62
chemistry and medicinal research.
Ultrasound is con-
sidered as non-conventional energy source when used to
perform chemical reactions and they are regarded as having
very interesting results compared to the conventional heat-
ing sources. Ultrasonic acceleration effects on chemical
1
5-17
long reaction times.
Apart from subtle modifications
from the original design, the Biginelli reaction takes place
by mixing different substituted aldehydes, urea or thiourea,
and an active 1,3-dicarbonyl compound in combination
processes are widely used both in laboratory and industrial
61,63
1
8
19
23
27
with different catalytic systems such as AcOH,
12
, InCl
H
2
SO
4
3
,
,
practice.
Sonication mostly affects reaction rates,
2
lanthanide triflate, KSF clay, LiClO
0
21
22
, LaCl
4
3
yields, and in some cases the ratios of reaction products.
In continuation of our interest on the ultrasonic accel-
2
4
25
26
PPE,
Mn(OAc)
tetrafluoroborate, SiO
CdCl
2
,
BF
3
.OEt
2
,
ion-exchange resin,
2
8
29
3
,
InBr
3
,
1-n-butyl-3-methyl imidazolium
erated reactions and uranyl nitrate hexahydrate (UO
64,65
2
(NO
3 2
) ×
3
0
31
32
35
41
47
2
/NaHSO
4
,
ytterbium triflates,
2
6H O) catalyst,
we wish to report a simple, efficient
3
3
34
FeCl
3
,
MgBr
37
2
,
Ceric ammonium nitrate (CAN),
40
and practical approach for the synthesis of 6-methyl-
36
, ZrCl
38 39
, LiBr, AlCl
BiCl
3
4
, Cu(OTf)
43
2
3
44-46
.H
2
O, p-TSA,
1,2,3,4-tetrahydro-N-aryl-2-oxo/thio-4-arylpyrimidine-5-
4
, NaCl, alkaline phosphates
2
Pb(NO
3
)
2
and sulphates
2 3 2 2
carboxamide derivatives catalyzed by UO (NO ) .6H O
4
8,49
50-53
under classical reflux,
microwave
or ultrasound ir-
using conventional and ultrasonic irradiation methods. The
characterization of all the synthesized compounds through
5
radiation and solvent-free conditions.
4
20,30,55
*
Corresponding author. E-mail: vsvsatyanarayana@yahoo.co.in, svkmr7627@gmail.com
J. Chin. Chem. Soc. 2014, 61, 000-000
© 2014 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Article
Venkatesan et al.
1 13
IR, H NMR, C NMR and mass spectra is also described.
Table 2. Effect of different catalysts on the formation of
compound 4k in the presence of acetonitrile under
ultrasonic irradiation
RESULTS AND DISCUSSION
Catalyst
Yield
b
(%)
The one-pot there-component reaction for the synthe-
sis of 5-carboxamide-DHPMs was carried out by the reac-
tion between different substituted aldehydes, urea or thio-
urea and substituted acetoacetanilides using uranyl nitrate
hexahydrate catalyst under conventional heating and ultra-
Entry
Catalyst
RuCl .2H
Time (min.)
(
mol %)
1
2
3
4
5
6
3
2
O
5
10
30
30
67
65
65
88
88
87
65
RuCl .2H O
3
2
RuCl
.2H
O
20
30
3
2
UO
UO
UO
(NO
(NO
(NO
)
)
)
.6H
.6H
.6H
O
O
O
5
21
2
2
2
3
3
3
2
2
2
2
2
2
sonic irradiation conditions (Scheme 1). UO
2
(NO
3
)
2
.6H
2
O
10
21
15
21
is relatively cost effective catalyst for the synthesis of 5-
carboxamide-DHPMs compared with the other lewis acid
catalysts reported for the same in the literature. In order to
optimize the reaction conditions, the condensation of benz-
aldehyde, urea and acetoacetanilide in the presence of cata-
a
7
Conc. HCl
1 mL
18 h
a
Reaction carried out under reflux condition.
Isolated yields.
b
lytic amounts of UO
ultrasound conditions using different solvent systems
chloroform, dichloromethane, ethanol, methanol, aceto-
2 3 2 2
(NO ) .6H O under conventional and
2 3 2 2
UO (NO ) .6H O was found to be about 5 mol%. Larger
amounts of the catalyst (Entries 5 and 6, Table 2) did not
improve the yield, while lowering the amount of catalyst
did not have much effect on the yield. After optimizing the
conditions, this method was tried out for synthesis of
Beginelli type dihydropyrimidinones by using different
heterocyclic and aryl aldehydes with a variety of substitu-
tions at ortho-, meta-, para-positions, urea or thiourea and
different substituted acetoacetanilide under conventional
heating and ultrasonic irradiation conditions to establish
(
nitrile) was examined as a model reaction (Table 1 & 2).
Scheme 1
The results show that the reaction proceeded more ef-
ficiently under ultrasonic irradiation as compared to con-
ventional heating. The reaction was completed within 21
min to furnish the desired 6-methyl-1,2,3,4-tetrahydro-N-
phenyl-2-oxo-4-(4-hydroxy-3-methoxyphenyl)pyrimi-
dine-5-carboxamide in 88% yield at 16 kHz operating fre-
quency of ultrasonic irradiation in the presence of 5 mol%
2 3 2 2
the catalytic importance of UO (NO ) .6H O for this reac-
tion (Table 3). Generally, the synthetic procedure involves
stirring the mixture of aldehyde (1 mmol), acetoacetanilide
(1 mmol), urea or thiourea (1.2 mmol) and UO
2 3 2
(NO ) .
6H O (5 mol%) for 360 and 21 min in the presence of
2
acetonitrile at reflux temperature and ultrasonic irradiation,
respectively. The corresponding results are summarized in
Table 3.
UO
2 3 2 2
(NO ) .6H O under acetonitrile solvent (Entry 4, Ta-
ble 1).
Moreover, reaction work-up is simple and the catalyst
can be easily separated from the product. After completion
of the reaction, the reaction mixture was cooled to room
Furthermore, effect of quantity of catalyst loading
was examined. The optimum catalyst loading for
Table 1. Effect of the solvent for the synthesis of 6-methyl-1,2,3,4-tetrahydro-N-phenyl-2-oxo-4-(4-hydroxy-3-methoxy-
phenyl)pyrimidine-5-carboxamide (4k) catalyzed by UO (NO ) .6H O
2
3 2
2
b
Catalyst (mol %)
Time (min.)
Yield (%)
Entry
Solvents
a
a
RuCl3
UO (NO ) .6H O
2
RuCl3
UO (NO ) .6H O
2
RuCl3
UO (NO ) .6H O
2 3 2 2
3 2
2
3 2
2
1
2
3
4
5
a
Chloroform
Dichloromethane
Ethanol
5
5
5
5
5
5
900
900
600/30
600/30
420/21
420/21
420/21
20
19
43/31
41/28
68/71
76/78
85/88
5
5
5
5
900
57
Methanol
900
61
a
Acetonitrile
900/30
65/67
Under conventional and ultrasonic heating.
Isolated yield of product from conventional and ultrasonic heating reaction.
b
2
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J. Chin. Chem. Soc. 2014, 61, 000-000

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Ultrasound-assisted Synthesis of DPHMs
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)
a
Reaction time (min.)
Yield (%)
Compd.
R
R1
X
M.P. (°C)
US
Conv.
US
Conv.
4
4
1
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
a
b
c
d
e
f
H
H
Ph H
Ph H
O
S
21
21
24
24
21
21
24
21
21
24
21
21
24
24
21
450
450
480
480
480
480
480
420
420
450
420
480
480
480
420
87
85
83
81
83
80
81
83
79
84
88
82
84
82
83
82
83
80
78
79
75
76
77
75
80
85
79
78
75
77
225-228
214-217
253-256
242-245
206-209
188-191
123-126
192-195
201-204
235-238
230-233
205-208
248-251
228-230
239-242
1
H
Ph 3-OEt-4-OH
Ph 3-OEt-4-OH
Ph 2,4-Cl
O
S
H
H
O
S
H
Ph 2,4-Cl
g
h
i
H
Ph 4-OEt-3-OMe
2-C H S
S
H
O
S
4
3
H
2-C H S
4 3
j
H
Ph 4-OEt
Ph 4-OH-3-OMe
Ph 2,4-Cl
O
O
O
O
S
k
l
H
4-Cl
4-Cl
4-Cl
4-Cl
m
n
o
Ph 4-OEt
Ph 4-OEt
2-C H S
4
O
3
Isolated yields; US = Ultrasonic irradiation; Conv. = Conventional heating; C H S = Thiophene.
4
3
temperature and diluted with ice cold water and kept aside
overnight. The separated solid was suction filtered and
washed with large amount of water. The catalyst which is
highly soluble in water could be easily removed by wash-
ing with excess amount of cold water through suction fil-
tration.
2 3 2 2
presence of UO (NO ) .6H O as catalyst produces an open
chain ureide which subsequently undergo cyclization and
dehydration to afford the corresponding 6-methyl-1,2,3,4-
tetrahydro-N-aryl-2-thio/oxo-4-arylpyrimidine-5-carbox-
amide 4a-o.
The efficiency of UO
with that of other catalyst, RuCl
in the synthesis of 6-methyl-1,2,3,4-tetrahydro-N-phenyl-
-oxo-4-(4-hydroxy-3-methoxyphenyl)pyrimidine-5-car-
2
(NO
3 2 2
) .6H O was compared
Plausible reaction mechanism of Biginelli condensa-
tion via formation of acyliminium ion intermediate is pre-
sented in Scheme 2, this intermediate is formed by the reac-
tion of the different substituted carbaldehyde 2 and urea or
3
reported as a new catalyst
2
boxamide by one-pot three-component condensation of 4-
hydroxy-3-methoxy benzaldehyde, urea and acetoacetani-
lide in the presence of different solvent systems under re-
flux and ultrasonic irradiation conditions (Table 1 & 2).
2 3 2 2
thiourea 3 and then stabilized by UO (NO ) .6H O through
a coordinate bond owing to its empty orbital. Subsequent
addition of the acyliminium ion to acetoacetanilide 1 in the
3
The data listed in Table 2 show that RuCl can also act as a
Scheme 2
suitable catalyst for this reaction at different catalytic
amounts under ultrasonic irradiation conditions.
In conclusion, we have developed a simple and effi-
cient procedure for the synthesis of 6-methyl-1,2,3,4-tetra-
hydro-N-aryl-2-oxo/thio-4-arylpyrimidine-5-carboxamide
derivatives by one-pot three-component condensation of
different substituted aldehydes, urea or thiourea and substi-
tuted acetoacetanilides under conventional heating and ul-
2 3 2 2
trasonic irradiation conditions using UO (NO ) .6H O as
catalyst. The key advantages of this process are mild reac-
tion conditions, shorter reaction times, cost effectiveness
of catalyst, easy work-up and high yields. In order to im-
prove the selectivity and yield, the effects of solvents and
J. Chin. Chem. Soc. 2014, 61, 000-000
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3

Article
Venkatesan et al.
mole proportion of catalyst are investigated with
4-(3-ethoxy-4-hydroxyphenyl)-6-methyl-2-oxo-N-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (4c): mp. 253-256
ºC; IR (KBr) nmax: 3542, 3259, 2977, 2931, 1701, 1660, 1609,
1591, 1581, 1518, 1491, 1478, 1436, 1411, 1371, 1336, 1281,
2 3 2 2 3
UO (NO ) .6H O and RuCl catalysts. The structures of
the synthesized compounds have been confirmed through
1
spectral characterization such as IR, H NMR, and mass
-
1 1
spectra.
1225, 1212, 1155, 1121, 1093, 1062, 1041 cm ; H NMR (300
MHz, DMSO-d , ppm), d = 9.10 (s, 1H, CONH), 8.86 (s, 2H, NH
& 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, OCH ), 2.48 (s, 3H, CH ),
); C NMR (125 MHz, DMSO-d , ppm),
= 164.53, 163.35, 152.70, 152.57, 146.86, 146.76, 146.58,
6
H
EXPERIMENTAL
1
General: The H NMR spectra were obtained on BRUKER
2
3
1
3
AV-(500, 400 and 300) MHz spectrometer with DMSO-d
6
as the
1.18–1.32 (m, 3H, CH
3
6
solvent using tetramethylsilane (TMS) as the internal standard.
Infrared (IR) spectra were recorded at room temperature from
d
C
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+]
-
1
-1
000 cm to 400 cm with KBr pellets at a resolution of 4 cm ,
-1
4
using Avatar 330 equipped with DTGS detector. All reagents
were purchased from Aldrich, SD fine Chemicals and Qualigens
and used without further purification. Mass spectra were obtained
by using HRMS. The melting points were determined by open
capillaries and are uncorrected. Sonication was performed in a
SONICS, Vibra Cell, VC 130, ultrasonic processor equipped with
a 3 mm wide and 140 mm long probe, which was immersed di-
rectly into the reaction mixture. The operating frequency was 20
kHz and the output power was 0-130 Watt through manual adjust-
ment.
21 3 4
calcd. for C20H N O : 367.1532; found: 367.1531. 4-(3-ethoxy-
4-hydroxyphenyl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (4d): mp. 242-245 ºC; IR
(KBr) nmax: 3349, 3192, 2975, 2931, 1672, 1625, 1595, 1571,
1512, 1467, 1435, 1400, 1283, 1234, 1217, 1189, 1149, 1120,
-
1 1
1108, 1084, 1039, 1012 cm ; H NMR (300 MHz, DMSO-d
ppm), d = 10.29 (s, 1H, CONH), 9.52 (s, 1H, NH), 8.87–8.94
(split peak, 2H, NH & OH), 6.36–7.26 (m, 8H, ArH of phenyl
ring), 5.25 (s, 1H, CH proton), 3.56–3.95 (m, 2H, OCH ), 2.45 (s,
3H, CH ), 1.18–1.35 (m, 3H, CH ); HRMS (EI): m/z [M+] calcd.
S: 383.1304; found: 383.1302. 4-(2,4-dichloro-
6
,
H
2
General procedure for the preparation of compound 6-
methyl-1,2,3,4-tetrahydro-N-aryl-2-thio/oxo-4-arylpyrimi-
dine-5-carboxamide (4a-o): Conventional method: A mixture
of aldehyde (1 mmol), acetoaetanilide (1 mmol), urea or thiourea
3
3
21 3 3
for C20H N O
phenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimi-
dine-5-carboxamide (4e): mp. 206-209 ºC; IR (KBr) nmax: 3397,
3265, 3168, 3084, 3006, 1669, 1626,1595, 1563, 1525, 1498,
1478, 1436, 1380, 1331, 1236, 1179, 1140, 1101, 1075, 1045
(
2 3 2 2
1.2 mmol), UO (NO ) .6H O (5 mol%), and 20 mL acetonitrile
was refluxed for the appropriate time mentioned in Table 3. After
completion of the reaction as indicated by TLC, the reaction mix-
ture 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.
-
1 1
6 H
cm ; H NMR (500 MHz, DMSO-d , ppm), d =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¢ & 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 =
7.2 Hz, p-ArH of phenyl ring), 5.75 (d, 1H, J = 2.0 Hz, CH pro-
Ultrasonic irradiation: A mixture of aldehyde (1 mmol),
acetoaetanilide (1 mmol), urea or thiourea (1.2 mmol) and
1
3
ton), 2.02 (s, 3H, CH
ppm), d = 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,
2 3 2
16.20; HRMS (EI): m/z [M+] calcd. For C18 15Cl N O :
3 6
proton); C NMR (100 MHz, DMSO-d ,
UO
2
(NO
3
)
2
.6H
2
O (5 mol%) in 20 mL acetonitrile was subjected
C
to ultrasonic irradiation using ultrasonic processor equipped with
a 3 mm wide and 140 mm long probe, which was immersed di-
rectly into the reaction mixture varying time periods as shown in
Table 3. The operating frequency was 16 kHz and the output
power was 104 Watts through manual adjustment. The progress of
the reaction was monitored by TLC (ethyl acetate: hexane, 7:3).
The reaction mixture was poured into crushed ice, stirred for
H
375.0541; found: 375.0541. 4-(2,4-dichlorophenyl)-1,2,3,4-
tetrahydro-6-methyl-N-phenyl-2-thioxopyrimidine-5-carboxa
mide (4f): mp. 188-191 ºC; IR (KBr) nmax: 3397, 3276, 3088,
2360, 2342, 1672, 1654, 1629, 1598, 1560, 1540, 1523, 1498,
-
1473, 1438, 1329, 1234,1202, 1180, 1143, 1101, 1076, 1046 cm ;
1
1
1
5-20 min and left overnight. The solid separated was filtered
6 H
H NMR (500 MHz, DMSO-d , ppm), d =10.13 (s, 1H, CONH),
through a funnel and washed with ice-cold water and then recrys-
tallized from hot methanol to afford pure compounds 4a-o and
their physical data is given in Table 3.
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¢ & m¢-ArH of phenyl
ring), 7.39 (d, 1H, J = 8.5 Hz, o¢-ArH of phenyl ring), 7.26 (t, 2H,
4
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Ultrasound-assisted Synthesis of DPHMs
1
3
J = 8.0 Hz, m,m¢-ArH of phenyl ring), 7.02 (t, 1H, J = 7.2 Hz,
p-ArH of phenyl ring), 5.75 (d, 1H, J = 2.5 Hz, CH proton), 2.03
3 6 C
(t, 3H, J = 6.9 Hz, CH ); C NMR (100 MHz, DMSO-d , ppm), d
= 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,
(
s, 3H, CH
3
proton); HRMS (EI): m/z [M+] calcd. for
C
18
H
15Cl
2
N
3
OS: 391.0313; found: 391.0312. 4-(4-ethoxy-3-
21 3 3
16.98, 14.60; HRMS (EI): m/z [M+] calcd. for C20H N O :
methoxyphenyl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-tetrahy-
351.1583; found: 351.1582. 4-(4-hydroxy-3-methoxyphenyl)-6-
methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydropyrimidine-5-car-
boxamide (4k): mp. 230-233 ºC; IR (KBr) nmax: 3411, 3285,
2363, 2341, 1683, 1653, 1628, 1597, 1539, 1521, 1487, 1442,
dropyrimidine-5-carboxamide (4g): mp. 123-126 ºC; IR (KBr)
n
max: 3349, 3291, 3175, 3094, 2977, 2361, 1680, 1635, 1596,
1
561, 1513, 1482, 1439, 1394, 1334, 1264, 1229, 1197, 1180,
-
139, 1029 cm ; H NMR (500 MHz, DMSO-d
1
1
-1 1
1386, 1330, 1262, 1241, 1164, 1124, 1074, 1034 cm ; H NMR
1
6
, ppm), d
H
= 9.95
(
s, 1H, CONH), 9.72 (s, 1H, NH), 9.38 (s, 1H, NH), 7.54 (d, 2H, J
(300 MHz, DMSO-d , ppm), d = 9.53 (s, 1H, CONH), 8.93 (s,
6
H
=
8.5 Hz, o,o¢-ArH of phenyl ring), 7.26 (t, 2H, J = 7.2 Hz,
1H, OH), 8.67 (s, 1H, NH), 7.55 (d, 3H, J = 7.8 Hz, NH & o,o¢-
ArH of phenyl ring), 7.25 (t, 2H, J = 7.8 Hz, m,m¢-ArH of phenyl
ring), 7.00 (t, 1H, J = 7.35 Hz, p-ArH of phenyl ring), 6.82 (s, 2H,
o,m¢-ArH of phenyl ring), 6.71 (s, 1H, o¢-ArH of phenyl ring),
m,m¢-ArH of phenyl ring), 7.02 (t, 1H, J = 7.2 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
1
3
phenyl ring), 5.36 (s, 1H, CH proton), 3.96 (q, 2H, J = 6.7 Hz,
5.34 (s, 1H, CH), 3.67 (s, 3H, OCH
3
), 2.07 (s, 3H, CH
3
); C NMR
OCH
Hz, CH
97.1460; found: 397.1459. 6-methyl-2-oxo-N-phenyl-4-(thio-
2
), 3.67 (s, 3H, OCH
3
), 2.07 (s, 3H, CH
3
), 1.29 (t, 3H, J = 6.7
(100 MHz, DMSO-d , ppm), d
6
C
= 165.46, 152.51, 147.32, 145.80,
3
); HRMS (EI): m/z [M+] calcd. for C21
H
23
N
3
O
3
S:
139.19, 137.88, 135.18, 128.47, 123.04, 119.52, 118.47, 115.21,
3
110.71, 105.56, 55.46, 54.75, 16.95; HRMS (EI): m/z [M+] calcd.
phen-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4h):
mp. 192-195 ºC; IR (KBr) nmax: 3249, 2362, 1697, 1640, 1592,
for C19
H
19
N
3
O
4
: 353.1376; found: 353.1374. N-(4-chlorophen-
yl)-4-(2,4-dichlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxamide (4l): mp. 205-208 ºC; IR (KBr) nmax
3397, 3195, 1673, 1630,1596, 1565, 1530, 1469, 1439, 1383,
1
1
509, 1492, 1452, 1396, 1307, 1286, 1251, 1208, 1148, 1089,
-
:
1 1
H
040, 1012 cm ; H NMR (500 MHz, DMSO-d6, ppm), d = 9.57
-
1 1
1235, 1202, 1102, 1046 cm ; H NMR (500 MHz, DMSO-d
(
s, 1H, CONH), 8.85 (s, IH, NH), 7.80 (s, 1H, NH), 7.58 (d, 2H, J
6
,
=
8.0 Hz, o,o¢-ArH of phenyl ring), 6.93–7.38 (m, 6H, ArH of
ppm), d = 9.84 (s, 1H, CONH), 8.88 (s, 1H, NH), 7.58 (s, 1H,
H
phenyl & thiophene ring), 5.59 (d, 1H, J = 3.0 Hz, CH), 2.06 (s,
NH), 7.52–7.55 (m, 3H, o,o¢ & 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¢ & m¢-ArH of phenyl ring), 5.75 (d, 1H, J = 2.0 Hz, CH),
3
3
H, CH
3 15 3 2
); HRMS (EI): m/z [M+] calcd. For C16H N O S:
13.0885; found: 313.0884. 6-methyl-N-phenyl-4-(thiophen-2-
yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4i):
mp. 201-204 ºC; IR (KBr) nmax: 3368, 3284, 1679, 1635, 1566,
3
2.02 (s, 3H, CH ); HRMS (EI): m/z [M+] calcd. for
C
18
H
14Cl
3
N
3
O
2
: 409.0152; found: 409.0151. N-(4-chlorophen-
yl)-4-(4-ethoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyr-
imidine-5-carboxamide (4m): mp. 248-251 ºC; IR (KBr) nmax
1
1
548, 1523, 1499, 1477, 1439, 1360, 1328, 1232, 188, 1117,
-1 1
076, 1037 cm ; H NMR (500 MHz, DMSO-d
6
, ppm), d
H
=10.14
:
(
s, 1H, CONH), 9.73 (s, 1H, NH), 9.62 (s, 1H, NH), 6.95–7.68 (m,
3293, 2981, 2926, 1702, 1659, 1618, 1585, 1513, 1492, 1477,
1412, 1396, 1376, 1341, 1303, 1272, 1241, 1177, 1137, 1115,
-1 1
8
H, ArH of phenyl & thiophene ring), 5.67 (d, 1H, J = 3.0 Hz,
13
); C NMR (100 MHz, DMSO-d
CH), 2.10 (s, 3H, CH
3
6
, ppm), d
C
6 H
1093, 1049 cm ; H NMR (500 MHz, DMSO-d , ppm), d = 9.16
=
174.19, 164.53, 146.91, 138.94, 136.61, 128.54, 126.78,
25.67, 124.29, 123.34, 119.74, 107.07, 50.36, 16.55; HRMS
EI): m/z [M+] calcd. for C16 OS : 329.0657; found:
29.0656. 4-(4-ethoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,2,3,4-
(d, 1H, CONH), 7.60 (t, 1H, J = 2.2 Hz, NH), 7.30 (q, 2H, J = 7.0
Hz, NH, m-ArH of phenyl ring), 7.12 (q, 2H, J = 7.0 Hz, o,o¢-ArH
of phenyl ring), 7.04 (q, 2H, J = 6.5 Hz, m,m¢-ArH of phenyl ring),
6.63–6.85 (m, 3H, ArH phenyl ring), 5.13–5.29 (split peak, 1H,
1
(
H
15
N
3
2
3
tetrahydropyrimidine-5-carboxamide (4j): mp. 235-238 ºC; IR
KBr) nmax: 3249, 3114, 2981, 2927, 2597, 1736, 1666, 1628,
CH proton), 3.95–4.03 (m, 2H, OCH
1.29–1.35 (m, 3H, CH ); HRMS (EI): m/z [M+] calcd. for
: 385.1193; found: 385.1192. N-(4-chlorophenyl)-
4-(4-ethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyr-
imidine-5-carboxamide (4n): mp. 228-230 ºC; IR (KBr) nmax
2 3
), 2.46–2.51 (m, 3H, CH ),
(
3
1
1
611, 1597, 1516, 1440, 1392, 1358, 1328, 1267, 1247, 1176,
20 3 3
C H20ClN O
-1 1
170, 1074, 1048, 1008 cm ; H NMR (300 MHz, DMSO-d
6
,
ppm), d
H
= 9.52 (s, 1H, CONH), 8.70 (s, 1H, NH proton), 7.55 (d,
:
3
H, J = 7.5 Hz, NH & o,o¢-ArH of phenyl ring), 7.17-7.26 (m, 4H,
3199, 2978, 2925, 1673, 1616, 1560, 1512, 1492, 1464, 1411,
1395, 1338, 1304, 1252, 1197, 1182, 1162, 1111, 1092, 1047,
ArH of phenyl ring), 6.99 (t, 1H, J = 7.2 Hz, p-ArH of phenyl
ring), 6.86 (d, 2H, J = 8.4 Hz, m,m¢-ArH of phenyl ring), 5.36 (s,
-1 1
1014 cm ; H NMR (500 MHz, DMSO-d
6 H
, ppm), d = 10.35 (s,
1
2 3
H, CH), 3.98 (t, 2H, J = 6.9 Hz, OCH ), 2.04 (s, 3H, CH ), 1.28
1H, CONH), 9.51 (s, 1H, NH), 7.31–7.33 (split peak, 1H, NH),
J. Chin. Chem. Soc. 2014, 61, 000-000
© 2014 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
5

Article
Venkatesan et al.
1
1
1
4. Falsone, F. S.; Kappe, C. O. Arkivoc 2001, (ii), 122.
7
.12–7.14 (split peak, 2H, o,o¢-ArH of phenyl ring), 7.00 (d, 2H, J
5. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
6. Folkers, K.; Harwood, H. J.; Johnson, T. B. J. Am. Chem.
Soc. 1932, 54, 3751.
=
3.5 Hz, m,m¢-ArH of phenyl ring), 6.81-6.87 (m, 2H, ArH of
phenyl ring), 6.64 (d, 3H, J = 9.0 Hz, ArH of phenyl ring),
3
.94–4.04 (m, 2H, OCH
CH ); HRMS (EI): m/z [M+] calcd. for C20
01.0965; found: 401.0964. N-(4-chlorophenyl)-6-methyl-2-
2
), 2.16 (s, 3H, CH
3
), 1.30–1.35 (m, 3H,
1
1
7. Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1934, 56,
3
3 2
H20ClN O
S:
1180.
4
8. Mamedov, V. A.; Mustakimova, L. V.; Gubaidullin, A. T.;
Vdovina, S. V.; Litvinov, I. A.; Reznik, V. S. Chem. Hetero-
cycl. Comp. 2006, 42, 1229.
oxo-4-(thiophen-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carbox-
amide (4o): mp. 239-224 ºC; IR (KBr) nmax: 3245, 3103, 1664,
1
2
2
9. Akbar, M.; Zendehdel, M.; Nasab, M. H.; Fard, M. A. B.
Hetetocycl. Commun. 2009, 15, 451.
1
1
1
594, 1529, 1491, 1427, 1398, 1307, 1240, 1187, 1091, 1042,
-1 1
012 cm ; H NMR (500 MHz, DMSO-d
6 H
, ppm), d = 10.12 (s,
0. Ma, Y.; Qian. C.; Wang, L.; Yang, M. J. Org. Chem. 2000,
H, CONH), 8.95 (s, 1H, NH), 7.95 (s, 1H, NH), 7.63–7.65 (split
6
5, 3864.
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
1. Bigi, F.; Carloni, S.; Frulanti, B.; Maggi, R.; Sartori, G. Tet-
rahedron Lett. 1999, 40, 3465.
ring), 5.73 (d, 1H, J = 3.0 Hz, CH), 2.08 (s, 3H, CH
3
); HRMS (EI):
22. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
270.
3. Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron Lett.
000, 41, 9075.
4. Kappe, C. O.; Falsone, S. F. Synlett. 1998, 7, 718.
6
3 2
m/z [M+] calcd. for C16H14ClN O S: 347.0495; found: 347.0494.
2
2
2
ACKNOWLEDGEMENTS
Authors gratefully acknowledge the management of
VIT University, Vellore for encouraging and providing
necessary facilities for carrying out this work and SAIF IIT
Chennai for spectral analysis.
25. Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999, 10,
1799.
2
2
6. Bussolari, J. C.; McDonnell, P. A. J. Org. Chem. 2000, 65,
777.
7. Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem. 1998,
3, 3454.
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