Synthesis of Biginelli compounds using cobalt hydrogen sulfate

Article abstract of DOI:10.1002/jccs.201190016

Efficient synthesis of various 2-oxo(thioxo)-1,2,3,4-tetrahydropyrimidines containing acetyl, carboethoxy, carbomethoxy and carboxamide groups on 5-position of the M-substituted and ATL-unsubstituted heterocyclic ring was achieved using cobalt hydrogen su

Full text of DOI:10.1002/jccs.201190016

522
Journal of the Chinese Chemical Society, 2011, 58, 522-527
Synthesis of Biginelli Compounds Using Cobalt Hydrogen Sulfate
Hamid Reza Memarian* and Mahnaz Ranjbar
Catalysis Division, Department of Chemistry, University of Isfahan, 81746-73441 Isfahan, I. R. Iran
Received February 6, 2011; Accepted March 24, 2011; Published Online April 6, 2011
Efficient synthesis of various 2-oxo(thioxo)-1,2,3,4-tetrahydropyrimidines containing acetyl, carbo-
ethoxy, carbomethoxy and carboxamide groups on 5-position of the N1-substituted and N1-unsubstituted
heterocyclic ring was achieved using cobalt hydrogen sulfate Co(HSO4)2 under thermal conditions. Good
to high yield, shorter reaction times, easy work up and simple preparation of Co(HSO4)2 are the advan-
tages using this synthetic method.
Keywords: Biginelli reaction; Cobalt hydrogen sulfate; Condensation; Lewis acid;
2-Oxo-1,2,3,4-tetrahydropyrimidines.
INTRODUCTION
The Biginelli reaction, a three components condensa-
Here, we wish to introduce cobalt hydrogen sulfate
Co(HSO4)2 as an efficient catalyst for the synthesis of vari-
ous N1-methyl substituted and unsubstituted 5-acetyl-,
5-carboethoxy-5-carbomethoxy- and 5-carboxamido-2-
oxo(thioxo)-1,2,3,4-tetrahydropyrimidines.
tion reaction between an aldehyde, urea and an easily
enolizable dicarbonyl compound in the presence of Brønsted
acid under formation of 2-oxo-1,2,3,4-tetrahydropyrimi-
dines (THPMs) was originally described by Italian chemist
Pietro Biginelli in 1893.1 The THPMs and their derivatives
have shown a wide scope of important pharmacological
and biological properties including antibacterial, antifun-
gal, antiviral, antitubercular, anticancer and anti-malarial
properties.2-5 Due to the biological importance of THPMs,
several new and improved procedures by applying micro-
wave,6 ultrasound6 or UV irradiations7 in the presence of
various catalysts have been reported. Although many of
these methods gave pure tetrahydropyrimidinones in good
to excellent yields, but in most cases urea and ethyl aceto-
acetate were only used as reactants for the synthesis of
5-carboethoxy-2-oxo-1,2,3,4-tetrahydropyrimidines.8-10
Therefore, introducing a suitable and efficient catalyst to
facilitate the synthesis of various 1,2,3,4-tetrahydropyr-
imidines is highly interesting.
RESULTS AND DISCUSSION
For the optimization of the reaction condition, the
synthesis of compound 1 as model substrate has been car-
ried out in 0.2 mL of acetonitrile, ethanol and water in the
presence of 0.3 mmol of Co(HSO4)2 (Table 1). These re-
sults and also the data of the optimization of the amount of
the catalyst indicated that the best solvent for this synthesis
is ethanol in the presence of 0.3 mmol of the catalyst (Table
2). It is noteworthy that by carrying the reaction with 1
mmol of 1,3-dicarbonyl compound or by using 0.1 and 0.2
mmol of catalyst, the formation of trace amount of two side
products was observed and also by using of more than 0.2
mL ethanol, the yield of reaction was drastically decreased.
The latter observation is possibly due to deactivation of the
catalyst by the coordination of the ethanol oxygen lone pair
to the empty orbital of the catalyst instead of coordination
to the oxygen of the carbonyl compound to activate this
group for the nucleophilic attack of urea.
Much effort has been done to the use of inorganic re-
agents in organic transformation, because these reagents
often provide milder reaction conditions and easier work
up than reactions using organic reagents. Metal hydrogen
sulfates (MHSs) have been used as an efficient reagent and
heterogeneous catalyst in many organic reactions such as
deprotection, oxidation, bond formation and bond cleav-
age.11 Due to stability, cheapness and mild reaction condi-
tions many works are devoted to the usage of MHSs.
In an optimized reaction condition various 2-oxo-
(thioxo)-1,2,3,4-tetrahydropyrimidines were synthesized
in the presence of 0.3 mmol of the catalyst in ethanol under
thermal conditions (Scheme I and Table 3).
A comparison of the results obtained in the present
study with those reported in other works indicates that the

Synthesis of Biginelli Compounds
J. Chin. Chem. Soc., Vol. 58, No. 4, 2011 523
Table 1. Solvent effect on the synthesis of 1 at reflux conditions
Scheme I
Solventa
Time (h)
Yield (%)b
2
O
H R
X
O
O
Co(HSO4)2
C2H5OH ,
R3
N
H
R2CHO
+
1
H3C
R3 R HN
NH2
Acetonitrile
Ethanol
2.5
2.5
4.5
70
95
51
+
D
H3C
N
X
R1
Water
a The mole ratio of aldehyde : dicarbonyl compound : urea is 1:
Scheme II
1.2 : 2.
b Isolated yield.
X
H
H
+ H+, H2O
O
X
or
N
I
NHR1
+
Co (I)
R2
R2
H
R1HN
NH2
Co (II), H2O
Table 2. Optimization of the amount of Co(HSO4)2 for the
synthesis of 1 in ethanol
Catalyst (mmol)a
Conversion (%)b
H
H
H+ or Co (II)
O
O
O
O
O
O
or
R3
R3
R3
0.1
0.2
0.3
0.4
~ 60
~ 80
100
100
H3C
H3C
H3C
O
II
III
R2
N
O
H
H R2
N
R3
H
H
X
HNR1
R3
H2O
a The mole ratio of aldehyde: dicarbonyl compound: urea is
1: 1.2 : 2.
b Conversion after 2.5 h under thermal conditions.
I + II or III
H3C
O
H3C
N
X
R1
H
or
Co (I)
R2
O
H
R1NH
use of Co(HSO4)2 which is simultaneously a Lewis acid
and also a Brønsted acid facilitates smooth condensation of
urea, thiourea or their methyl-substituted derivatives with
aldehyde under formation of the imino-intermediate I
(Scheme II). This is indicated by the effect of the nature of
the aryl or alkyl group in the aldehyde molecule on the
yield and time of reaction. On the other hand, the results in-
dicated that the reaction with thiourea is slower than with
urea. It seems that the nitrogen lone pair in the thiourea
molecule is possibly delocalized to the sulfur d-orbitals,
which causes a decrease of nucleophilic character of its ni-
trogen towards the aldehyde carbonyl group. It should be
noted that by increasing the amount of the catalyst, the
yield of the reaction with thiourea did not change too much.
This explains the above suggestion and not the complex
formation between the catalyst and soft sulfur atom in
thiourea molecule. The reactions with N-methylurea or
N-methylthiourea are also in many cases slower than those
with urea or thiourea. It is clear that the presence of the
methyl group increases the electron density on the nitrogen
atom, which is expected to be a better nucleophilic species,
but due to increasing the steric hindrance and also the fail-
ure of the possible elimination of water from the N-methyl-
ammonium intermediate IV, a slower reaction with N-meth-
ylurea or N-methylthiourea has been observed. This sug-
gestion is supported by the formation of N1-methyl substi-
tuted 2-oxo(thioxo)-1,2,3,4-tetrahydropyrimidines and
NH2
X
IV
also by the failure of the reaction with N,N¢-dimethylurea.
This catalyst is especially suitable for the synthesis of
THPM-5-carboxamides. Whereas the THPM-amides (en-
tries 35-39) were synthesized using ZrCl4 in 43-66% after
10-12 hours heating,12 the same compounds were obtained
in higher yield (72-92%) and shorter reaction time (1-4.5
hours) using Co(HSO4)2. This catalyst is also used for the
synthesis of 4-alkyl-THPMs and 2-thioxo-1,2,3,4-tetra-
hydropyrimidines. This is the advantage of Co(HSO4)2
compared to Bi(NO3)3 and other catalysts which are not
suitable for the synthesis of these derivatives.8 The catalyst
Co(HSO4)2 is easily prepared by the reaction of CoCl2 with
concentrated sulfuric acid. After completion of THPM syn-
thesis, the catalyst and the excess of b-dicarbonyl com-
pounds were easily removed by addition of water and small
amount of ethanol. Recently CoCl2 alone13 or in combina-
tion with HCl14 have been used for the synthesis of 2-oxo-
1,2,3,4-tetrahydropyrimidines. The advantages of Co(HSO4)2
over these catalysts are that CoCl2 is also soluble in ethanol,
which hinders purification of the product and also the pres-
ence of HCl may cause hydrolysis of the b-ketoesters or
b-ketoamides in the presence of formed water under reflux
conditions. All these decrease the yield of reaction.

524 J. Chin. Chem. Soc., Vol. 58, No. 4, 2011
Memarian and Ranjbar
Table 3. Synthesis of various Biginelli compounds in ethanol under thermal conditions
Entry
R1
R2
R3
X
Time (h)a Yield (%)b
1
H
H
C6H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OCH3
OCH3
OCH3
OCH3
OCH3
OC2H5
OC2H5
OCH3
OCH3
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OCH3
OCH3
OC2H5
OCH3
CH3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
2.5
2.75
3
95
79
84
95
78
78
75
43
71
74
84
87
90
82
70
40
77
47
87
86
81
47
61
92
77
73
74
83
82
88
71
78
74
75
91
77
72
86
92
80
54
2
4-BrC6H4
4-FC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-NO2C6H4
2-Pyridyl
2-Thienyl
C6H5
3
H
4
H
2.5
3.5
2
5
H
6
H
7
H
3
8
H
0.75
6
9
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
H
2
H
4-BrC6H4
4-FC6H4
4-MeOC6H4
4-NO2C6H4
C6H5
3.75
5.5
2.5
4.5
6.5
8
H
H
H
H
H
4-BrC6H4
C6H5
S
H
S
6.5
8
H
4-BrC6H4
C6H5
S
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
O
O
O
O
O
O
O
S
3.5
3
4-BrC6H4
4-FC6H4
4-MeOC6H4
4-NO2C6H4
4-BrC6H4
4-FC6H4
C6H5
2.5
4
7.5
3
6
8
C6H5
S
8.5
1
C6H5
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
2-BrC6H4
4-BrC6H4
4-FC6H4
4-MeOC6H4
4-NO2C6H4
C6H5
CH3
1.5
1.5
1
H
CH3
H
CH3
H
CH3
3
H
CH3
2.5
4.5
4
H
C6H5
H
C6H5
2-ClC6H4NH
4-MeOC6H4NH
PhCH2NH
H
C6H5
2
H
C6H5
2.25
1
H
C6H5
4-ClC6H4NH
2-ClC6H4NH
2-ClC6H4NH
OC2H5
H
4-MeOC6H4
C6H5
4.5
2.75
3
CH3
H
n-Pr
a The times are given after maximum progression of the reaction.
b Isolated yield.
EXPERIMENTAL
cooled to room temperature and water was added. Stirring
was continued for several minutes for dissolving the cata-
lyst and the excess of urea or thiourea. The solid products
were filtered and washed with water. The pure products
were obtained by recrystallization from ethanol. The prod-
ucts have been characterized by comparison of their physi-
cal and spectroscopic data with those of the authentic sam-
ples. The physical and spectroscopic data of the new com-
General procedure for the synthesis of THPMs under
reflux conditions
Amixture of aldehyde (1 mmol), 1,3-dicarbonyl com-
pound (1.2 mmol), urea or thiourea (2 mmol) and Co(HSO4)2
(0.3 mmol) in EtOH (0.2 mL) was heated at 85 ºC for ap-
propriate time. After completion of the reaction indicated
by TLC (n-hexane : ethyl acetate, 3:1), the mixture was

Synthesis of Biginelli Compounds
J. Chin. Chem. Soc., Vol. 58, No. 4, 2011 525
pounds are reported below.
–CH3OH]+, 203 (24) [M –CH3OCO]+, 185 (100) [M –Ph]+,
153 (87) [M –Ph, –S]+, 126 (63) [M –Ph, –CH3OCO]+, 115
(53), 103 (41), 86 (34), 84 (36), 77 (47) [Ph]+, 59 (22).
Methyl 4-(4¢-bromophenyl)-6-methyl-2-thioxo-1,2,3,4-
tetrahydropyrimidin-5-carboxylate (18)
Ethyl 6-methyl-2-oxo-4-(2¢-pyridyl)-1,2,3,4-tetrahydro-
pyrimidin-5-carboxylate (8)
Mp 204-205 oC; IR (KBr): n = 3228, 3109, 2981,
2931, 1709, 1670, 1593 cm-1; 1H NMR (300 MHz, [D6]-
DMSO): d = 1.06 (t, 3J = 7.1 Hz, 3H, OCH2CH3), 2.24 (s,
3H, 6-CH3), 3.96 (q, 3J = 7.1 Hz, 2H, OCH2CH3), 5.23 (d,
3J = 2.9 Hz, 1H, 4-H), 7.24 (mc, 2H, 3¢-H, 5¢-H), 7.70 (mc,
2H, 4¢-H, 6¢-H), 8.50 (mc, 1H, N1-H), 9.20 (s, 1H, N3-H)
ppm; 13C NMR (75.47 MHz, [D6]-DMSO): d = 14.50
(OCH2CH3), 18.30 (6-CH3), 56.13 (C-4), 59.54 (OCH2CH3),
98.47, 121.37, 123.05, 137.01, 149.40, 149.76, 152.93,
162.74 (5-C=O), 165.80 (2-C=O) ppm; MS (EI, 70 eV):
m/z (%) = 261 (47) [M]+, 216 (18) [M –C2H5O]+, 188 (19)
[M –C2H5OCO]+, 183 (100) [M –C5H4N]+, 173 (17) [M
–C2H5OCO, –CH3]+, 155 (64) [M –C5H4N, –C2H4]+, 110
(12) [M –C2H5OCO, –C5H4N]+, 78 (71) [C5H4N]+, 67 (36),
52 (37).
o
Mp 177-179 C; IR (KBr): n = 3174, 2997, 1714,
1651, 1585 cm-1; 1H NMR (300 MHz, [D6]-DMSO): d =
2.30 (s, 3H, 6-CH3), 3.55 (s, 3H, OCH3), 5.16 (d, 3J = 3.2
Hz, 1H, 4-H), 7.17 (d, 3J = 8.3 Hz, 2H, 2¢-H, 6¢-H), 7.56 (d,
3J = 8.3 Hz, 2H, 3¢-H, 5¢-H), 9.71 (s, 1H, N1-H), 10.44 (s,
1H, N3-H) ppm; 13C NMR (75.47 MHz, [D6]-DMSO): d =
17.71 (6-CH3), 51.64 (C-4), 53.83 (OCH3), 100.40, 121.35,
129.06, 132.04, 143.03, 146.14, 165.96 (5-C=O), 174.71
(C=S) ppm; MS (EI, 70 eV): m/z (%) = 342 (20) [M 81Br]+,
340 (19) [M 79Br]+, 283 (24) [M 81Br –CH3OCO]+, 281 (25)
[M79Br –CH3OCO]+, 185 (100) [M –p-BrC6H4]+, 153 (27)
[M –p-BrC6H4, –CH3OH]+, 126 (12) [M –p-BrC6H4,
–CH3OCO]+, 102 (18), 86 (17), 75 (43), 59 (20).
Methyl 4-(4¢-bromophenyl)-6-methyl-2-oxo-1,2,3,4-
Ethyl 4-(4¢-bromophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidin-5-carboxylate (11)
tetrahydropyrimidin-5-carboxylate (20)
Mp 150-152 oC; IR (KBr): n = 3215, 3087, 2933,
1711, 1680, 1628 cm-1; 1H NMR (300 MHz, [D6]-DMSO):
Mp 222-225 oC; IR (KBr): n = 3365, 3222, 3109,
2947, 1725, 1689, 1635, 1489 cm-1; 1H NMR (300 MHz,
[D6]-DMSO): d = 2.29 (s, 3H, 6-CH3), 3.53 (s, 3H, OCH3),
5.18 (s, 1H, 4-H), 7.22 (d, 3J = 7.1 Hz, 2H, 2¢-H, 6¢-H), 7.51
(d, 3J = 7.1 Hz, 2H, 3¢-H, 5¢-H), 7.87 (s, 1H, N1-H), 9.36 (s,
1H, N3-H) ppm; 13C NMR (75.47 MHz, [D6]-DMSO): d =
18.36 (6-CH3), 51.26 (C-4), 53.89 (OCH3), 99.06, 120.90,
128.96, 131.81, 144.44, 149.43, 152.63 (5-C=O), 166.55
(2-C=O) ppm; MS (EI, 70 eV): m/z (%) = 326 (7) [M 81Br]+,
324 (7) [M 79Br]+, 311 (10) [M 81Br –CH3]+, 309 (10) [M
79Br –CH3]+, 294 (2) [M 81Br –CH3OH]+, 292 (2) [M 79Br
–CH3OH]+, 267 (10) [M 81Br –CH3OCO]+, 265 (13) [M
79Br –CH3OCO]+, 184 (8), 169 (100) [M –p-BrC6H4]+, 137
(45) [M –p-BrC6H4, –CH3OH]+, 110 (12) [M –p-BrC6H4,
–CH3OCO]+, 94 (7) [M –p-BrC6H5, –CH3OCOCH3]+, 59
(15) [CH3OCO]+.
3
d = 1.11 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.49 (s, 3H, 6-
3
CH3), 3.10 (s, 3H, N-CH3), 4.03 (q, J = 7 Hz, 2H,
OCH2CH3), 5.15 (d, 3J = 3.4 Hz, 1H, 4-H), 7.18 (d, 3J = 8.3
Hz, 2H, 2¢-H, 6¢-H), 7.52 (d, 3J = 8.3 Hz, 2H, 3¢-H, 5¢-H),
8.03 (d, 3J = 3.6 Hz, 1H, N-H) ppm; 13C NMR (75.47 MHz,
[D6]-DMSO): d = 14.50 (OCH2CH3), 16.50 (6-CH3), 30.20
(N-CH3), 52.37 (C-4), 60.06 (OCH2CH3), 102.33, 120.87,
128.83, 131.82, 143.87, 151.49, 153.34 (5-C=O), 165.89
(2-C=O) ppm; MS (EI, 70 eV): m/z (%) = 354 (5) [M 81Br]+,
352 (5) [M 79Br]+, 339 (4) [M 81Br –CH3]+, 337 (4) [M 79Br
–CH3]+, 325 (12) [M 81Br –C2H5]+, 323 (11) [M 79Br
–C2H5]+, 281 (4) [M 81Br –C2H5OCO]+, 279 (4) [M 79Br
–C2H5OCO]+, 197 (100) [M –p-BrC6H4]+, 169 (37) [M
–p-BrC6H4, –C2H4]+, 152 (3) [M –p-BrC6H4, –C2H5O]+,
151 (23) [M –p-BrC6H4, –C2H5OH]+, 124 (3) [M –p-
BrC6H4, –C2H5OCO]+, 56 (78).
Methyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydro-
pyrimidin-5-carboxylate (17)
o
Mp 223-226 C; IR (KBr): n = 3319, 3186, 2997,
Ethyl 4-(4¢-fluorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
1665, 1579 cm-1; 1H NMR (300 MHz, [D6]-DMSO): d =
2.32 (s, 3H, 6-CH3), 3.51 (s, 3H, OCH3), 5.24 (s, 1H, 4-H),
7.27 (brd s, 5H, Ar-H), 9.70 (s, 1H, N1-H), 10.39 (s, 1H,
N3-H) ppm; 13C NMR (75.47 MHz, [D6]-DMSO): d =
17.73 (6-CH3), 51.47 (C-4), 54.49 (OCH3), 100.95, 126.83,
128.15, 129.03, 145.77, 143.78, 166.08 (5-C=O), 174.75
(C=S) ppm; MS (EI, 70 eV): m/z (%) = 262 (96) [M]+, 247
(48) [M –CH3]+, 231 (7) [M –CH3O]+, 230 (11) [M
tetrahydropyrimidin-5-carboxylate (21)
o
Mp 124-125 C; IR (KBr): n = 3226, 3109, 2979,
1725, 1687, 1616 cm-1; 1H NMR (300 MHz, [D6]-DMSO):
d = 1.10 (brd s, 3H, OCH2CH3), 2.50 (s, 3H, 6-CH3), 3.11
(s, 3H, N-CH3), 4.02 (brd s, 2H, OCH2CH3), 5.2 (s, 1H,
4-H), 7.19 (m, 4H, Ar-H), 8.03 (s, 1H, N-H) ppm; 13C NMR
(75.47 MHz, [D6]-DMSO): d = 14.40 (OCH2CH3), 16.42
(6-CH3), 30.10 (N-CH3), 52.33 (C-4), 59.97 (OCH2CH3),

526 J. Chin. Chem. Soc., Vol. 58, No. 4, 2011
Memarian and Ranjbar
102.73, 115.58 (d, 2J = 21.28 Hz, C-3¢, C-5¢), 128.56 (d, 3J
= 8.15 Hz, C-2¢, C-6¢), 140.78 (C-1¢), 151.22 (C-6), 153.41
(5-C=O), 161.84 (d, 1J = 243.28 Hz, C¢-4), 165.93 (2-C=O)
ppm; MS (EI, 70 eV): m/z (%) = 292 (12) [M]+, 291 (4) [M
–H]+, 277 (13) [M –CH3]+, 263 (50) [M –C2H5]+, 219 (16)
[M –C2H5OCO]+, 197 (29) [M – p-FC6H4]+, 169 (44) [M
–p-FC6H4, –C2H4]+, 151 (52) [M –p-FC6H5, – C2H5O]+,
124 (12) [M –p-FC6H5, –C2H5OCO]+, 95 (17) [p-FC6H4]+,
84 (9), 56 (100).
1682, 1622 cm-1; 1H NMR (300 MHz, [D6]-DMSO): d =
2.51 (s, 3H, 6-CH3), 3.11 (s, 3H, N-CH3), 3.56 (s, 3H,
OCH3), 5.21 (s, 1H, 4-H), 7.12 (brd s, 2H, 3¢-H, 5¢-H), 7.29
(brd s, 2H, 2¢-H, 6¢-H), 8.05 (s, 1H, N-H) ppm; 13C NMR
(75.47 MHz, [D6]-DMSO): d = 16.45 (6-CH3), 30.12
(N-CH3), 51.44 (C-4), 52.15 (OCH3), 102.46, 115.62 (d, 2J
= 21.20 Hz, C-3¢, C-5¢), 128.51 (d, 3j = 8.07 Hz, C-2¢, C-6¢),
1
140.60, 151.55, 153.54 (5-C=O), 161.87 (d, J = 243.36
Hz, C-4¢), 166.45 (2-C=O) ppm; MS (EI, 70 eV): m/z (%) =
278 (8) [M]+, 263 (23) [M –CH3]+, 247 (3) [M –CH3O]+,
219 (35) [M –CH3OCO]+, 183 (100) [M –p-FC6H4]+, 152
(9) [M –p-FC6H4, –CH3O]+, 151 (73) [M –p-FC6H4,
–CH3OH]+, 96 (4) [p-FC6H5]+, 95 (13) [p-FC6H4]+, 56 (92).
Methyl 1,6-dimethyl-4-phenyl-2-thioxo-1,2,3,4-tetra-
hydropyrimidin-5-carboxylate (27)
Ethyl 4-(4¢-methoxyphenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidin-5-carboxylate (22)
o
Mp 136-139 C; IR (KBr): n = 3221, 3091, 2983,
1725, 1682, 1635 cm-1; 1H NMR (300 MHz, [D6]-DMSO):
d = 1.12 (brd s, 3H, OCH2CH3), 2.48 (s, 3H, 6-CH3), 3.10
(s, 3H, N-CH3), 3.71 (s, 3H, OCH3), 4.01 (brd s, 2H,
OCH2CH3), 5.11 (s, 1H, 4-H), 6.88 (brd s, 2H, 3¢-H, 5¢-H),
o
Mp 160-162 C; IR (KBr): n = 3215, 2972, 2947,
7.12 (brd s, 2H, 2¢-H, 6¢-H), 7.93 (s, 1H, N-H) ppm; 13
C
1684, 1639 cm-1; 1H NMR (300 MHz, [D6]-DMSO): d =
2.53 (s, 3H, 6-CH3), 3.49 (s, 3H, N-CH3), 3.62 (s, 3H,
OCH3), 5.25 (d, 3J = 3.9 Hz, 1H, 4-H), 7.29 (mc, 5H, Ph),
9.93 (d, 3J = 3.9 Hz, 1H, N-H) ppm; 13C NMR (75.47 MHz,
[D6]-DMSO): d = 16.74 (6-CH3), 36.67 (N-CH3), 51.4
(C-4), 52.6 (OCH3), 105.53, 126.48, 128.17, 129.12,
142.47, 148.78, 166.21 (5-C=O), 178.54 (C=S) ppm; MS
(EI, 70 eV): m/z (%) = 276 (61) [M]+, 261 (39) [M –CH3]+,
245 (5) [M –CH3O]+, 243 (8) [M –CH3OH, –H]+, 217 (56)
[M –CH3OCO]+, 199 (85) [M –Ph]+, 167 (42) [M –Ph,
–CH3OH]+, 140 (6) [M –Ph, –CH3OCO]+, 91 (20) [C7H7]+,
77 (61) [Ph]+, 56 (100).
NMR (75.47 MHz, [D6]-DMSO): d = 14.52 (OCH2CH3),
16.45 (6-CH3), 30.12 (N-CH3), 52.25 (C-4), 55.46 (OCH3),
59.94 (OCH2CH3), 103.19 (C-5), 114.18, 127.68, 136.63,
153.57, 150.71, 158.92 (5-C=O), 166.07 (2-C=O) ppm;
MS (EI, 70 eV): m/z (%) = 304 (39) [M]+, 303 (15) [M
–H]+, 289 (27) [M –CH3]+, 275 (100) [M –C2H5]+, 231 (64)
[M –C2H5OCO]+, 197 (36) [M –p-CH3OC6H4]+, 169 (47)
[M –p-CH3OC6H4, –C2H4]+, 151 (66) [M –p-CH3OC6H5,
–C2H5O]+, 124 (36) [M –p-CH3OC6H4, –C2H5OCO]+, 84
(37), 77 (17) [Ph]+, 56 (78).
Methyl 4-(4¢-bromophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidin-5-carboxylate (24)
5-Benzoyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-
Mp 157-159 oC; IR (KBr): n = 3195, 3087, 2947,
1725, 1685 cm-1; 1H NMR (300 MHz, [D6]-DMSO): d =
2.51 (s, 3H, 6-CH3), 3.11 (s, 3H, N-CH3), 3.57 (s, 3H,
O-CH3), 5.17 (s, 1H, 4-H), 7.20 (d, 3J = 7.5 Hz, 2H, 2¢-H,
6¢-H), 7.52 (d, 3J = 7.3 Hz, 2H, 3¢-H, 5¢-H), 8.07 (s, 1-H,
N-H) ppm; 13C NMR (75.47 MHz, [D6]-DMSO): d = 16.54
(6-CH3), 30.23 (N-CH3), 51.56 (C-4), 52.23 (OCH3),
102.08, 120.94, 128.79, 131.85, 143.69, 151.79, 153.40
(5-C=O), 166.39 (2-C=O) ppm; MS (EI, 70 eV): m/z (%) =
340 (17) [M 81Br]+, 338 (19) [M 79Br]+, 325 (38) [M
81Br–CH3]+, 323 (39) [M 79Br –CH3]+, 309 (5) [M 81Br
–CH3O]+, 307 (9) [M 79Br –CH3O]+, 281 (36) [M 81Br
–CH3OCO]+, 279 (41) [M79Br –CH3OCO]+, 183 (93) [M
–p-BrC6H4]+, 151 (58) [M –p-BrC6H4, –CH3OH]+, 124
(13) [M –p-BrC6H4, –CH3OCO]+, 56 (100).
pyrimidine (34)
Mp 208-210 oC, (lit. [43] mp 203-204 oC); IR (KBr):
n = 3300, 3109, 2924, 1705, 1647, 1595 cm-1; MS (EI, 70
eV): m/z (%) = 292 (48) [M]+, 277 (21) [M –CH3]+, 215
(72) [M –Ph]+, 187 (76) [M –PhCO]+, 105 (65) [PhCO]+,
77 (100) [Ph]+.
1,6-Dimethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimi-
din-5-(2-chlorophenylcarboxamide) (40)
o
Mp 205-207 C; IR (KBr): n = 3234, 3099, 2924,
1695, 1630 cm-1; 1H NMR (300 MHz, [D6]-DMSO): d =
2.29 (s, 3H, 6-CH3), 3.09 (s, 3H, N-CH3), 5.31 (s, 1H, 4-H),
7.29 (mc, 9H, Ar-H), 7.81 (s, 1H, N-H), 9.43 (5-NH-amide)
ppm; 13C NMR (75.47 MHz, [D6]-DMSO): d = 17.16
(6-CH3), 29.87 (N-CH3), 54.37 (C-4), 108.68, 126.72,
127.22, 127.74, 127.79, 127.90, 128.67, 128.98, 129.90,
135.49, 141.13, 143.94, 153.93 (5-C=O), 166.44 (2-C=O)
ppm; MS (EI, 70 eV): m/z (%) = 355 (4) [M]+, 340 (6) [M
–CH3]+, 229 (76) [M –C6H4ClNH]+, 228 (8) [M
Methyl 4-(4¢-fluorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidin-5-carboxylate (25)
Mp 132-134 oC; IR (KBr): n = 3221, 3103, 2927,

Synthesis of Biginelli Compounds
J. Chin. Chem. Soc., Vol. 58, No. 4, 2011 527
–C6H4ClNH2]+, 201 (31) [M –C6H4ClNHCO]+, 186 (20)
[M –C6H4ClNHCOCH3]+, 151 (7), 132 (12), 77 (35) [Ph]+,
56 (100).
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ACKNOWLEDGMENTS
We are thankful to the Center of Excellence (Chemis-
try), Research Council and Office of Graduate Studies of
the University of Isfahan for their financial support.
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K. V. Green Chem. 2001, 3, 305.
10. Lin, H.; Ding, J.; Chen, X.; Zhng, Z. Molecules 2000, 5,
1240.
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