An efficient and facile synthesis of inhibitors for hepatitis C viral and anti-SARS agents: 4-aryl-5-cyano-1,6-dihydro-2-thiouracils

Article abstract of DOI:10.1007/s11164-011-0434-4

One-pot, multicomponent reaction for the synthesis of 4-aryl-5-cyano-1,6- dihydro-2-thiouracils via three-component from aromatic aldehydes, ethyl 2-cyanoacetate and S-benzylisothiourea hydrochloride (methyl carbamimidothioate sulfate) under methanol is d

Full text of DOI:10.1007/s11164-011-0434-4

Res Chem Intermed (2012) 38:983–994
DOI 10.1007/s11164-011-0434-4
An efficient and facile synthesis of inhibitors
for hepatitis C viral and anti-SARS agents:
4-aryl-5-cyano-1,6-dihydro-2-thiouracils
•
Liangce Rong Shan Yin Sheng Xia Shimin Tao
•
•
•
•
Yanhui Shi Shujiang Tu
Received: 26 August 2011 / Accepted: 28 October 2011 / Published online: 12 November 2011
Ó Springer Science+Business Media B.V. 2011
Abstract One-pot, multicomponent reaction for the synthesis of 4-aryl-5-cyano-
1,6-dihydro-2-thiouracils via three-component from aromatic aldehydes, ethyl
2-cyanoacetate and S-benzylisothiourea hydrochloride (methyl carbamimidothioate
sulfate) under methanol is described. These compounds have many drug activities,
such as anti-hepatitis C viral, anti-Severe acute respiratory syndrome and anti-
HIV-1 integrese activity. The advantages of this procedure include the short reac-
tion time, mild reaction conditions and excellent yields.
Keywords Thiouracils Á Three-component reaction Á Heterocyclic compound Á
Cycloaddition Á Drug activity
Introduction
It is well known that pyrimidione is an important intermediate in heterocyclic
synthesis, and its skeleton exists in many natural or synthetic biologically active
materials. Its derivatives are applied in various pharmaceutical and biochemical
fields [1, 2]. Dihydropyrimidiones, the important derivatives of pyrimidione, are
found in a wide range of biological activities such as anticancer [3], anti-HIV [4],
antibacterial [5], antimalarial [6], antihypertensive [7], sedative hypnotics [8],
anticonvulsant [9], antithyroid [10], antihistaminic agents [11] and antibiotics [12].
Thiouracils (thiopimidiones) are the contained sulfur atoms derivatives of dihydro-
pyrimidiones [13]. According to the reported literature, thiouracils (thiopimidiones)
derivatives have many medical and biological properties. They not only inhibit
L. Rong (&) Á S. Yin Á S. Xia Á S. Tao Á Y. Shi Á S. Tu
Jiangsu Key Laboratory of Green Synthetic Chemistry For Functional Materials,
College of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou 221116, Jiangsu, People’s Republic of China
e-mail: lcrong2005@yahoo.com
123

984
L. Rong et al.
nucleic acid metabolism [14, 15] but also inhibit the formation of thyroid hormones,
and they were also used for the treatment of hyperthyroidism and Basedow’s disease
[16]. Furthermore, a recent study revealed that thiopimidiones (thiouracils)
derivatives could be applied as inhibitors for hepatitis C viral (anti-HCV) [17],
and another paper reported that it has anti-HIV-1 integrese activity [18].
Ramajayam et al. [19] reported these compounds could be used as anti-severe
acute respiratory syndrome agents. Taking into account their wide applicability,
it is therefore very necessary to find effective methods for the synthesis of these
compounds.
Multicomponent reactions (MCRs) [20–22], which can produce various com-
pounds, provide one of the most efficient methods for the synthesis of structurally
diverse organic compounds. Recently, this synthetic method was the preferred method
for chemists to prepare organic compounds. Here, we report a facile and efficient
multicomponent reaction to synthesize these active materials: 4-aryl-5-cyano-1,
6-dihydro-2-thiouracils.
Results and discussion
Ding [17] has reported the preparation of thiouracils derivatives. He first
synthesized intermediate products: 5-cyano-4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahy-
dro-pyrimidine derivatives, then reacted intermediate products with benzyl
bromides to give thiouracils derivatives. This total reaction time exceeded 20 h,
but the main problem in this procedure was the by-products, i.e. S and N
disubstituted pyrimidine derivatives could also be obtained. Chen [23] has reported
synthesizing four similar compounds using two-step reaction procedures; however,
the total reaction time was too long (more than 30 h) and the yields of products were
too low (28–43%). So, we hope to discover a new procedure for synthesis of these
compounds. In order to improve the yields of compounds, we design a one-pot,
multicomponent reaction to prepare target products using aromatic aldehydes, ethyl
2-cyanoacetate, and S-benzylisothiorea hydrochloride as starting reactants.
In our study, at first, we want to find a suitable synthesis condition to carry out
this synthesis. 4-fluorobenzaldehyde 1a, ethyl 2-cyanoacetate 2, and S-benzyl-
isothiourea hydrochloride 3 were chosen as the starting materials for the model
reaction. The three reagents were reacted in the different solvents and used different
catalysts. In our research, we found: when CH3CN was used as solvent and Et3N,
C5H11N, K2CO3, Na2CO3, KOH, NaOH were used as catalysts, the reaction would
not work. When CH3OH or EtOH were used as solvents, the reactions could be
brought out with different results. The results could be summarized as follows:
when organic catalysts (Et3N, C5H11N) were used, the reaction also would not work,
but when weak inorganic base (K2CO3, Na2CO3) was used as catalyst, the reaction
could be brought out with low yields. However, when a strong inorganic base such
NaOH or KOH was used, the reaction could be carried out smoothly with high
yields. Take into account the cost, toxicity and availability of catalysts and solvents,
we chose NaOH and CH3OH as the ideal catalyst and solvent to carry out theses
synthesis. The optimized reaction results are listed in Table 1.
123

Synthesis of inhibitors for hepatitis C viral and anti-SARS agents
985
Table 1 Synthesis of 4a in the presence of different catalysts and solvents
Entry
Solvent
Catalyst (1 mmol)
Yields (%)
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
EtOH
K2CO3
Na2CO3
Et3N
0
0
2
3
0
4
C5H11
N
0
5
NaOH
KOH
0
6
0
7
K2CO3
Na2CO3
Et3N
25
20
0
8
9
10
11
12
13
14
15
16
17
18
C5H11
N
0
NaOH
KOH
89
83
17
13
0
K2CO3
Na2CO3
Et3N
EtOH
EtOH
EtOH
C5H11
N
0
EtOH
NaOH
KOH
75
70
EtOH
Reagents and conditions: 4-fluorobenzaldehyde 1a (1 mmol), ethyl 2-cyanoacetate 2 (1 mmol), S-ben-
zylisothiourea hydrochloride 3 (1 mmol), NaOH (1 mmol) and solvent (10 mL)
Bold indicates the optimized reaction condition
R
CHO
CN
NH
NH2
NaOH
CN
O
+
HCl
+
O
methanol
PhH2CS
R
N
C2H5O
N
H
PhH2CS
1
2
3
4
Scheme 1 Synthesis of 2-(benzylthio)-6-oxo-1,6-dihydropyrimidine
Using this optimized reaction condition, we used different aromatic aldehydes to
react with ethyl 2-cyanoacetate and S-benzylisothiourea hydrochloride, and a series
of 2-(benzylthio)-6-oxo-1,6-dihydropyrimidines could be gained with high yields
(Scheme 1). The results of reactions are summarized in Table 2. As shown in Table 2,
both electron-withdrawing (such as F, Cl, Br) or electron-donating substitute groups
(CH3–, CH3O–) on aromatic aldehydes could give ideal results. We tried to use
heterocyclic atom aldehydes, such as picolinaldehyde and isonicotinaldehyde, in this
procedure, and we found that they were both suitable for synthesis of 2-(benzylthio)-6-
oxo-1,6-dihydropyrimidines with good yields (4n, 4o).
123

986
L. Rong et al.
Yields (%)
Table 2 Synthesis of
2-(benzylthio)-6-oxo-1,6-
dihydropyrimidine
Entry
R
Products
1
4-F
4a
4b
4c
4d
4e
4f
89
90
96
91
91
90
90
89
87
94
92
89
95
88
90
2
3-Cl
8
2,4-Cl2
9
3,4-Cl2
3
4-Br
7
H
4
4-CH3
4g
4h
4i
5
4-CH3O
2-CH3O
3,4-(CH3)2
3,4-(CH3O)2
2,5-(CH3O)2
3,4,5-(CH3O)3
2-Pyridyl
4-Pyridyl
6
10
11
12
13
14
15
4j
4k
4l
4m
4n
4o
R
CHO
CN
NH
NaOH
methanol
CN
H2SO4
NH2
+
H3CS
+
O
R
N
C2H5O
2
H3CS
N
O
1
2
5
H
6
Scheme 2 Synthesis of 2-(methylthio)-6-oxo-1,6-dihydropyrimidines
In order to expand this synthesis under similar conditions, methyl carbamim-
idothioate sulfate was used to replace S-benzylisothiourea hydrochloride to react
with aromatic aldehydes and ethyl 2-cyanoacetate (Scheme 2). To our delight, we
also found that all the reactions were carried out smoothly, and corresponding
products 4-aryl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile could
be obtained with good yields. The results are summarized in Table 3. From
Table 3, we can find that the reactions have very good applicability, and aromatic
aldehydes with different substituent groups can give efficient results. Investigating
the above reactions, we can come to the conclusion that CH3OH and NaOH are the
efficient conditions for the synthesis of these compounds under a multicomponent
reaction. In these procedures, the reaction time was no more than 30 min.
The structures of all the products were confirmed on the basis of spectroscopic
1
data, particularly H NMR analysis and HRMS spectra. We take 4g and 6f as
examples to analyze their structures. In 4g 1H NMR, its spectrum revealed a singlet
signal at d = 2.41(3H), 4.54 (2H) ppm due to CH3 and PhCH2 protons. The triplet
123

Synthesis of inhibitors for hepatitis C viral and anti-SARS agents
Table 3 Synthesis of
987
Entry
R
Products
Yields (%)
2-(methylthio)-6-oxo-
1,6-dihydropyrimidines
1
2
3
4
5
6
7
8
4-F
6a
6b
6c
6d
6e
6f
86
80
88
90
92
90
89
87
3-Cl
4-Cl
3-Br
4-Br
4-CH3
4-CH3O
3,4-(CH3)2
6g
6h
signal at d = 7.27 (1H, J = 7.2 Hz), 7.33 (2H, J = 7.6 Hz) ppm and doublet
signals at 7.39 (2H, J = 8.0 Hz), 7.42 (2H, J = 8.0 Hz) and 7.87 (2H, J =
8.4 Hz ppm were due to nine phenyl protons. In HRMS spectrum, the calculated
m/z [C19H15N3OS (M ? Na)?] of 4g is 356.0834, and the m/z found is 356.0831.
The error value is only 0.82 ppm.
In 6f 1H NMR, its spectrum revealed a singlet signal at d = 2.41(3H), 2.61 (3H)
ppm due to CH3 and SCH3 protons. The doublet signals at 7.39 (2H, J = 8.0 Hz),
7.90 (2H, J = 8.0 Hz) were due to four phenyl protons. In the HRMS spectrum, the
calculated m/z (C13H11N3OS [M ? Na]?) of 6f is 280.0521, and the m/z found is
280.0531. The error value is only 3.57 ppm. Although we have not found chemical
1
shift of active H on nitrogen atoms in 4 or 6 H NMR, we can see it in IR (about
3,400 cm-1). This phenomenon can also be found in the literature [22].
Conclusions
In conclusion, we have expanded a facile and high efficiency one-pot reaction
for the synthesis of 4-aryl-5-cyano-1,6-dihydro-2-thiouracils via the reaction of
different aromatic aldehydes, ethyl 2-cyanoacetate and S-benzylisothiourea
hydrochloride (methyl carbamimidothioate sulfate). Due to employing a one-pot,
multicomponent reaction, this method offers several advantages including easy
experimental work-up procedure and lower cost, and especially high yield of
products in a short reaction time.
Experimental
Melting points were determined on XT-5 microscopic melting-point apparatus and
were uncorrected. IR spectra were recorded on a FT Bruker Tensor 27 spectrometer.
1H NMR spectra were obtained from solution in DMSO-d6 with Me4Si as internal
standard using a Bruker-400 spectrometer. Microanalyses were carried out using
a Perkin-Elmer 2400 II analyzer. HRMS spectra were obtained with a Bruker
microTOF-Q 134 instrument.
123

988
L. Rong et al.
General procedure for the synthesis of 4-aryl-5-cyano-1,6-dihydro-2-thiouracils
The mixture of aromatic aldehydes 1 (1 mmol), ethyl 2-cyanoacetate 2 (1 mmol),
S-benzylisothiorea hydrochloride 3 or methyl carbamimidothioate sulfate 5
(1 mmol), CH3OH (10 mL) and NaOH (1 mmol) was put in a reaction flask at
70 °C about 30 min. After completion, the reaction mixture was poured into water,
filtered, and then washed with water thoroughly. The products were dried and
recrystallized from 95% ethanol.
2-(Benzylthio)-4-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4a)
Melting point 193–194 °C; IR (KBr) m: 3,421, 2,220, 1,734, 1,660, 1,604, 1,539,
1
1,506, 1,473, 1,376, 1,243, 1,161, 1,000, 848, 784 cm-1; H NMR (400 MHz,
DMSO-d6) d: 4.55 (2H, s, PhCH2–), 7.27 (1H, t, J = 7.2 Hz, ArH), 7.31–7.35 (2H,
m, ArH), 7.41–7.46 (4H, m, ArH), 8.03 (2H, dd, J = 5.6 Hz, J = 8.8 Hz, ArH);
Anal. Calcd. for C18H12FN3OS: C 64.08, H 3.59, N 12.46. Found: C 63.96, H 3.60,
N 12.41.
HRMS m/z calculated for C18H12FN3OS [M ? Na]?: 360.0583, found: 360.0585.
2-(Benzylthio)-4-(3-chlorophenyl)- 6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4b)
Melting pioint 219–220 °C; IR (KBr) m: 3,430, 2,221, 1,731, 1,714, 1,694, 1,682,
1
1,652, 1,614, 1,583, 1,567, 1,519, 1,505, 1,455, 1,362 cm-1; H NMR (400 MHz,
DMSO-d6) d: 4.54 (2H, s, PhCH2–), 7.28 (1H, t, J = 7.2 Hz, ArH), 7.34 (2H, t,
J = 7.2 Hz, ArH), 7.43 (2H, d, J = 8.4 Hz, ArH), 7.62 (1H, t, J = 8.0 Hz, ArH),
7.70 (1H, d, J = 8.4 Hz, ArH), 7.88–7.91 (2H, m, ArH); Anal. Calcd. for
C18H12ClN3OS: C 61.10, H 3.42, N 11.88. Found: C 61.01, H 3.40, N 11.92.
HRMS m/z calculated for C18H12ClN3OS [M ? H]?: 354.0468, found:
354.0474.
2-(Benzylthio)-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile
(4c)
Melting point 184–185 °C; IR (KBr) m: 3,416, 2,226, 1,678, 1,638, 1,586, 1,528,
1
1,474, 1,389, 1,365, 1,257, 1,107, 1,057, 1,002, 866, 781, 699 cm-1; H NMR
(400 MHz, DMSO-d6) d: 4.43 (2H, s, PhCH2–), 7.25–7.32 (3H, m, ArH), 7.37 (2H,
dd, J = 2.0 Hz, J = 8.4 Hz, ArH), 7.62 (1H, d, J = 8.4 Hz, ArH), 7.68 (1H, d,
J = 8.4 Hz, ArH), 7.89 (1H, d, J = 2.0 Hz, ArH); Anal. Calcd. for C18H11
Cl2N3OS: C 55.68, H 2.86, N 10.82. Found: C 55.75, H 2.88, N 10.78.
HRMS m/z calculated for C18H11Cl2N3OS [M ? H]?: 388.0078, found: 388.0077.
2-(Benzylthio)-4-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile
(4d)
Melting point 192–193 °C; IR (KBr) m: 3,440, 1,760, 1,666, 1,537, 1,531, 1,471,
1
1,255, 1,209 cm-1; H NMR (400 MHz, DMSO-d6) d: 4.53 (2H, s, PhCH2–), 7.27
123

Synthesis of inhibitors for hepatitis C viral and anti-SARS agents
989
(1H, t, J = 7.2 Hz, ArH), 7.34 (2H, t, J = 7.6 Hz, ArH), 7.42 (2H, d, J = 6.8 Hz,
ArH), 7.87 (1H, d, J = 8.4 Hz, ArH), 7.92 (1H, dd, J = 2.0 Hz, J = 8.4 Hz, ArH),
8.09 (1H, d, J = 1.6 Hz, ArH); Anal. Calcd. for C18H11Cl2N3OS: C 55.68, H 2.86,
N 10.82. Found: C 55.74, H 2.87, N 10.80.
HRMS m/z calculated for C18H11Cl2N3OS [M ? Na]?: 409.9898, found:
409.9887.
2-(Benzylthio)-4-(4-bromophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4e)
Melting point 243–245 °C; IR (KBr) m: 3,435, 1,769, 1,650, 1,539, 1,521, 1,469,
1
1,369, 1,254, 1,210, 1,187, 1,119, 1,074, 998 cm-1; H NMR (400 MHz, DMSO-
d6) d: 4.54 (2H, s, PhCH2–), 7.27 (1H, t, J = 7.2 Hz, ArH), 7.33 (2H, t, J = 7.2 Hz,
ArH), 7.42 (2H, d, J = 7.2 Hz, ArH), 7.81 (2H, d, J = 8.4 Hz, ArH), 7.89 (2H, d,
J = 8.8 Hz); Anal. Calcd. for C18H12BrN3OS: C 54.28, H 3.04, N 10.55. Found: C
54.19, H 3.06, N 10.59.
HRMS m/z calculated for C18H12BrN3OS [M ? Na]?: 419.9782, found: 419.9774.
2-(Benzylthio)-4-phenyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4f)
Melting point 191–193 °C (lit.[18] 202–204 °C); IR (KBr) m: 3,420, 2,220, 1,653,
1
1,539, 1,495, 1,474, 1,262, 1,213, 1,119, 1,002, 694 cm-1; H NMR (400 MHz,
DMSO-d6) d: 4.55 (2H, s, PhCH2–), 7.27 (1H, t, J = 7.2 Hz, ArH), 7.32 (2H, t,
J = 6.8 Hz, ArH), 7.43 (2H, t, J = 6.8 Hz, ArH), 7.57–7.63 (3H, m, ArH), 7.95
(2H, d, J = 6.8 Hz, ArH); Anal. Calcd. for C18H13N3OS: C 67.69, H 4.10, N 13.16.
Found: C 67.59, H 4.12, N 13.18.
HRMS m/z calculated for C18H13N3OS [M ? H]?: 320.0858, found: 320.0855.
2-(Benzylthio)-6-oxo-4-p-tolyl-1,6-dihydropyrimidine-5-carbonitrile (4g)
Melting point 224–225 °C (lit.[18] 229–232 °C); IR (KBr) m: 3,423, 2,221, 1,735,
1,639, 1,542, 1,471, 1,373, 1,225, 1,191, 1,140, 1,116, 998, 781, 703, 566 cm-1; 1H
NMR (400 MHz, DMSO-d6) d: 2.41 (3H, s, CH3), 4.54 (2H, s, PhCH2–), 7.27 (1H,
t, J = 7.2 Hz, ArH), 7.33 (2H, t, J = 7.6 Hz, ArH), 7.39 (2H, d, J = 8.0 Hz, ArH),
7.42 (2H, d, J = 8.0 Hz, ArH), 7.87 (2H, d, J = 8.4 Hz, ArH); Anal. Calcd. for
C19H15N3OS: C 68.45, H 4.53, N 12.60. Found: C 68.54, H 4.51, N 12.64.
HRMS m/z calculated for C19H15N3OS [M ? Na]?: 356.0834, found: 356.0831.
2-(Benzylthio)-4-(4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile
(4h)
Melting point 242–243 °C (lit.[18] 248–250 °C); IR (KBr) m: 3,421, 2,216, 1,747,
1,650, 1,601, 1,539, 1,507, 1,473, 1,370, 1,303, 1,262, 1,216, 1,180, 1,141, 1,024,
1
998 cm-1; H NMR (400 MHz, DMSO-d6) d: 3.86 (3H, s, CH3O), 4.55 (2H, s,
PhCH2–), 7.13 (2H, d, J = 8.8 Hz, ArH), 7.27 (1H, t, J = 7.2 Hz, ArH), 7.33 (2H,
t, J = 7.6 Hz, ArH), 7.43 (2H, d, J = 7.2 Hz, ArH), 8.03 (2H, d, J = 8.8 Hz, ArH);
123

990
L. Rong et al.
Anal. Calcd. for C19H15N3O2S: C 65.31, H 4.33, N 12.03. Found: C 65.40, H 4.32,
N 11.99.
HRMS m/z calculated for C19H15N3O2S [M ? H]?: 350.0963, found: 350.0947.
2-(Benzylthio)-4-(2-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile
(4i)
Melting point 189–190 °C; IR (KBr) m: 3,066, 2,221, 1,648, 1,601, 1,525, 1,491,
1
1,468, 1,253 cm-1; H NMR (400 MHz, DMSO-d6) d: 3.85 (3H, S, CH3O), 4.45
(2H, s, PhCH2–), 7.09–7.13 (1H, m, ArH), 7.22 (1H, d, J = 8.0 Hz, ArH),
7.27–7.34 (3H, m, ArH), 7.39–7.44 (3H, m, ArH), 7.53–7.57 (1H, m, ArH); Anal.
Calcd. for C19H15N3O2S: C 65.31, H 4.33, N 12.03. Found: C 65.41, H 4.32, N
12.00.
HRMS m/z calculated for C19H15N3O2S [M ? Na]?: 372.0783, found: 372.0802.
2-(Benzylthio)-4-(3,4-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile
(4j)
Melting point 186–188 °C; IR (KBr) m: 3,430, 2,220, 1,790, 1,769, 1,747, 1,715,
1,681, 1,668, 1,651, 1,538, 1,505, 1,373, 1,249 cm-1; 1H NMR (400 MHz, DMSO-
d6) d: 2.30 (3H, s, CH3), 2.32 (3H, s, CH3), 4.54 (2H, s, PhCH2–), 7.28 (1H, t,
J = 7.2 Hz, ArH), 7.33 (3H, t, J = 7.2 Hz, ArH), 7.43 (2H, d, J = 7.2 Hz, ArH),
7.70 (2H, d, J = 4.4 Hz, ArH); Anal. Calcd. for C20H17N3OS: C 69.14, H 4.93, N
12.09. Found: C 69.38, H 4.90, N 12.13.
HRMS m/z calculated for C20H17N3OS [M ? H]?: 348.1171, found: 348.1143.
2-(Benzylthio)-4-(3,4-dimethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-
5-carbonitrile (4k)
Melting point 217–219 °C; IR (KBr) m: 3,000, 2,223, 1,735, 1,702, 1,686, 1,664,
1
1,543, 1,364, 1,271, 1,207 cm-1; H NMR (400 MHz, DMSO-d6) d: 3.76 (3H, s,
CH3O), 3.86 (3H, s, CH3O), 4.58 (2H, s, PhCH2–), 7.17 (1H, d, J = 8.4 Hz, ArH),
7.27 (1H, t, J = 7.2 Hz, ArH), 7.33 (2H, t, J = 7.6 Hz, ArH), 7.45 (2H, d,
J = 6.8 Hz, ArH), 7.60 (1H, d, J = 2.0 Hz, ArH), 7.71 (1H, dd, J = 2.0 Hz, ArH);
Anal. Calcd. for C20H17N3O3S: C 63.31, H 4.52, N 11.07. Found: C 63.25, H 4.50,
N 11.09.
HRMS m/z calculated for C20H17N3O3S [M ? H]?: 380.1069, found: 380.1062.
2-(Benzylthio)-4-(2,5-dimethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-
5-carbonitrile (4l)
Melting point 208–209 °C; IR (KBr) m: 3,447, 2,226, 1,697, 1,656, 1,541, 1,499,
1,473, 1,412, 1,297, 1,265, 1,228, 1,187, 1,040, 1,012, 863, 816, 736, 694,
1
668 cm-1; H NMR (400 MHz, DMSO-d6) d: 3.74 (3H, s, CH3O), 3.80 (3H, s,
CH3O), 4.47 (2H, s, PhCH2–), 7.01 (1H, d, J = 2.4 Hz, ArH), 7.10–7.17 (2H, m,
123

Synthesis of inhibitors for hepatitis C viral and anti-SARS agents
991
ArH), 7.27–7.33 (3H, m, ArH), 7.41 (2H, d, J = 7.2 Hz, ArH); Anal. Calcd. for
C20H17N3O3S: C 63.31, H 4.52, N 11.07. Found: C 63.25, H 4.54, N 11.09.
HRMS m/z calculated for C20H17N3O3S [M ? H]?: 380.1069, found: 380.1079.
2-(Benzylthio)-4-(3,4,5-trimethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-
5-carbonitrile (4m)
Melting point 237–238 °C; IR (KBr) m: 3,445, 2,212, 1,656, 1,560, 1,505, 1,478,
1,467, 1,409, 1,366, 1,310, 1,271, 1,132, 1,123, 1,016, 1,004, 950, 781, 673 cm-1
;
1H NMR (400 MHz, DMSO-d6) d: 3.76 (3H, s, CH3O), 3.80 (6H, s, 2XCH3O), 4.59
(2H, s, PhCH2–), 7.27 (1H, t, J = 7.2 Hz, ArH), 7.31–7.34 (4H, m, ArH), 7.45 (2H,
d, J = 6.8 Hz, ArH); Anal. Calcd. for C21H19N3O4S: C 61.60, H 4.68, N 10.26.
Found: C 61.68, H 4.69, N 10.24.
HRMS m/z calculated for C21H19N3O4S [M ? Na]?: 432.0994, found: 432.0995.
2-(Benzylthio)-4-(pyridin-2-yl)-6-oxo-1,6-dihydro pyrimidine-5-carbonitrile (4n)
Melting point 211–213 °C; IR (KBr) m: 3,422, 2,217, 1,718, 1,671, 1,536, 1,480,
1,380, 1,321, 1,266, 1,242, 1,163, 1,118, 1,001, 774, 705 cm-1 1H NMR
;
(400 MHz, DMSO-d6) d: 4.62 (2H, s, PhCH2–), 7.27 (1H, t, J = 7.2 Hz, ArH),
7.34 (2H, t, J = 7.2 Hz, ArH), 7.47 (2H, t, J = 6.8 Hz, ArH), 7.63–7.67 (1H, m,
ArH), 8.05–8.09 (1H, m, ArH), 8.26 (1H, d, J = 8.0 Hz, ArH), 8.76–8.78 (1H, m,
ArH); Anal. Calcd. for C17H12N4OS: C 63.73, H 3.78, N 17.49. Found: C 63.67, H
3.79, N 17.51.
HRMS m/z calculated for C17H12N4OS [M ? Na]?: 343.0630, found: 343.0641.
2-(Benzylthio)-6-oxo-4-(pyridin-4-yl)-1,6-dihydro pyrimidine-5-carbonitrile (4o)
Melting point 257–258 °C; IR (KBr) m: 3,432, 2,230, 1,701, 1,655, 1,561, 1,527,
1
1,498, 1,468, 1,266, 872, 714, 670, 659 cm-1; H NMR (400 MHz, DMSO-d6) d:
4.55 (2H, s, PhCH2–), 7.27 (1H, t, J = 7.2 Hz, ArH), 7.33 (2H, t, J = 7.6 Hz, ArH),
7.41 (2H, d, J = 7.6 Hz, ArH), 7.97 (2H, dd, J = 1.6 Hz, J = 1.6 Hz, ArH), 8.90
(2H, dd, J = 1.2 Hz, J = 1.6 Hz, ArH); Anal. Calcd. for C17H12N4OS: C 63.73, H
3.78, N 17.49. Found: C 63.68, H 3.77, N 17.53.
HRMS m/z calculated for C17H12N4OS [M ? H]?: 321.0810, found: 321.0801.
4-(4-Fluorophenyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (6a)
Melting point [ 280 °C; IR (KBr) m: 3,565, 2,851, 2,755, 2,224, 1,652, 1,602,
1,540, 1,505, 1,473, 1,382, 1,258, 1,228, 1,162, 1,002, 850, 786, 569, 700 cm-1; 1H
NMR (400 MHz, DMSO-d6) d: 2.62 (3H, s, SCH3), 7.43 (2H, t, J = 8.8 Hz, ArH),
8.06 (2H, dd, J = 5.6 Hz, J = 8.8 Hz, ArH); Anal. Calcd. for C12H8FN3OS: C
55.16, H 3.09, N 16.08. Found: C 55.27, H 3.11, N 16.15.
HRMS m/z calculated for C12H8FN3OS [M ? Na]?: 284.0270, found: 284.0271.
123

992
L. Rong et al.
4-(3-Chlorophenyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (6b)
Melting point 263–265 °C; IR (KBr) m: 3,444, 3,072, 3,024, 2,943, 2,714, 2,225,
1,653, 1,544, 1,526, 1,475, 1,382, 1,254, 1,216, 1,011, 895, 803, 783, 704,
1
679 cm-1; H NMR (400 MHz, DMSO-d6) d: 2.61 (3H, s, SCH3), 7.62 (1H, t,
J = 8.0 Hz, ArH), 7.70 (1H, d, J = 7.2 Hz, ArH), 7.92 (1H, d, J = 8.0 Hz, ArH),
7.96 (1H, s, ArH); Anal. Calcd. for C12H8ClN3OS: C 51.90, H 2.90, N 15.13.
Found: C 51.77, H 2.89, N 15.16.
HRMS m/z calculated for C12H8ClN3OS [M ? Na]?: 299.9974, found: 299.9980.
4-(4-Chlorophenyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (6c)
Melting point [ 300 °C; IR (KBr) m: 3,461, 3,089, 2,869, 2,759, 2,221, 1,664,
1,597, 1,547, 1,471, 1,435, 1,400, 1,381, 1,283, 1,254, 1,213, 1,186, 1,093, 1,003,
784, 687 cm-1; 1H NMR (400 MHz, DMSO-d6) d: 2.61 (3H, s, SCH3), 7.67 (2H, d,
J = 8.8 Hz, ArH), 7.99 (2H, d, J = 8.4 Hz, ArH); Anal. Calcd. for C12H8ClN3OS:
C 51.90, H 2.90, N 15.13. Found: C 51.81, H 2.91, N 15.18.
HRMS m/z calculated for C12H8ClN3OS [M ? Na]?: 299.9974, found: 299.9982.
4-(3-Bromophenyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (6d)
Melting point 252–254 °C; IR (KBr) m: 3,410, 3,076, 3,025, 2,940, 2,765, 2,713,
2,224, 1,653, 1,543, 1,524, 1,473, 1,380, 1,252, 1,213, 1,116, 1,009, 883, 801, 782,
1
699, 663, 568 cm-1; H NMR (400 MHz, DMSO-d6) d: 2.61 (3H, s, SCH3), 7.55
(1H, t, J = 8.0 Hz, ArH), 7.83 (1H, dd, J = 0.8 Hz, J = 8.4 Hz, ArH), 7.95 (1H, d,
J = 8.0 Hz, ArH), 8.09 (1H, s, ArH); Anal. Calcd. for C12H8BrN3OS: C 44.74, H
2.50, N 13.04. Found: C 44.82, H 2.52; N 13.10.
HRMS m/z calculated for C12H8BrN3OS [M ? Na]?: 343.9469, found: 343.9460.
4-(4-Bromophenyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (6e)
Melting point [ 300 °C; IR (KBr) m: 3,435, 3,011, 2,930, 2,873, 2,756, 2,226,
1,667, 1,540, 1,462, 1,455, 1,395, 1,380, 1,252, 1,212, 1,184, 1,119, 1,075, 1,012,
1,002, 826, 784 cm-1; 1H NMR (400 MHz, DMSO-d6) d: 2.61 (3H, s, SCH3), 7.80
(2H, d, J = 8.8 Hz, ArH), 7.91 (2H, d, J = 8.4 Hz, ArH); Anal. Calcd. for
C12H8BrN3OS: C 44.74, H 2.50, N 13.04. Found: C 44.80, H 2.54, N 13.11.
HRMS m/z calculated for C12H8BrN3OS [M ? Na]?: 343.9469, found: 343.9463.
2-(Methylthio)-6-oxo-4-p-tolyl-1,6-dihydropyrimidine-5-carbonitrile (6f)
Melting point [ 290 °C; IR (KBr) m: 3,068, 2,935, 2,845, 2,752, 2,220, 1,651, 1,608,
1,573, 1,531, 1,505, 1,472, 1,456, 1,434, 1,417, 1,380, 1,257, 1,220, 1,187, 1,116,
1,001, 782 cm-1; 1H NMR (400 MHz, DMSO-d6) d: 2.41 (3H, s, CH3), 2.61 (3H, s,
SCH3), 7.39 (2H, d, J = 8.0 Hz, ArH), 7.90 (2H, d, J = 8.0 Hz, ArH); Anal. Calcd.
for C13H11N3OS: C 60.68, H 4.31, N 16.33. Found: C 60.80, H 4.34, N 16.36.
HRMS m/z calculated for C13H11N3OS [M ? Na]?: 280.0521, found: 280.0531.
123

Synthesis of inhibitors for hepatitis C viral and anti-SARS agents
993
4-(4-Methoxyphenyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile
(6g)
Melting point [ 300 °C; IR (KBr) m: 3,444, 2,842, 2,754, 2,226, 1,651, 1,607,
1,575, 1,540, 1,506, 1,471, 1,456, 1,417, 1,382, 1,313, 1,258, 1,219, 1,177, 1,025,
1
998, 843, 786 cm-1; H NMR (400 MHz, DMSO-d6) d: 2.62 (3H, s, SCH3), 3.86
(3H, s, OCH3), 7.13 (2H, d, J = 9.2 Hz, ArH), 8.04 (2H, d, J = 8.8 Hz, ArH);
Anal. Calcd. for C13H11N3O2S: C 57.13, H 4.06, N 15.37. Found: C 57.24, H 4.09,
N 15.41.
HRMS m/z calculated for C13H11N3O2S [M ? Na]?: 296.0470, found: 296.0475.
4-(3,4-Dimethylphenyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile
(6h)
Melting point 266–268 °C; IR (KBr) m: 3,451, 3,022, 2,942, 2,864, 2,757, 2,220,
1,641, 1,546, 1,523, 1,472, 1,386, 1,257, 1,215, 1,186, 1,118, 1,022, 994, 931, 901,
1
837, 787, 680, 667, 568 cm-1; H NMR (400 MHz, DMSO-d6) d: 2.30 (3H, s,
CH3), 2.31 (3H, s, CH3), 2.61 (3H, s, SCH3), 7.33 (1H, d, J = 8.0 Hz, ArH), 7.71
(1H, d, J = 8.0 Hz, ArH), 7.75 (1H, s, ArH); Anal. Calcd. for C14H13N3OS: C
61.97, H 4.83, N 15.49. Found: C 61.85, H 4.87, N 15.44.
HRMS m/z calculated for C14H13N3OS [M ? Na]?: 294.0677, found: 294.0675.
Acknowledgments We are grateful to the National Natural Science Foundation of China (NSFC)
(21172188) and Foundation of Xuzhou Normal University (10XLS02) for financial support.
References
1. K.S. Atwal, G.C. Rovnyak, B.C. O’Reilly, J. Schwartz, J. Org. Chem. 54, 5898 (1989)
2. C.O. Kappe, W.M.F. Fabian, M.A. Semones, Tetrahedron 53, 2803 (1997)
3. E.C. Taylor, B. Liu, J. Org. Chem. 68, 9938 (2003)
4. P. Herdewijn, J. Balzarini, M. Baba, R. Pauwels, A.V. Aerschot, G. Janssen, E.D. Clercq, J. Med.
Chem. 31, 2040 (1988)
5. J. Matsumoto, S. Minami, J. Med. Chem. 18, 74 (1975)
6. A. Agarwal, K. Srivastava, S.K. Puri, P.M.S. Chauhan, Bioor. Med. Chem. Lett. 15, 3130 (2005)
7. H. Maeda, T. Akaike, Y. Miyamoto, M. Yoshida, European patent No. EP07959298, 1997
8. K.S. Jain, T.S. Chitre, P.B. Miniyar, M.K. Kathiravan, V.S. Bendre, V.S. Veer, S.R. Shahane,
C.J. Shishoo, Curr. Sci. 90, 793 (2006)
9. A.K.G. Sanjay, H.P. Kayath, S. Ajit, S. Geete, K.C. Mishra, Indian J. Pharma. 26, 227 (1994)
10. J.F. Lagorce, F. Comby, A. Rousseau, J. Buxeraud, C. Raby, Chem. Pharma. Bull. 41, 1258 (1993)
11. V. Alagarsamy, V.R. Solomon, M. Murugan, Bioorg. Med. Chem. 15, 4009 (2007)
12. R.L. Tolman, R.K. Robins, L.B. Townsend, J. Am. Chem. Soc. 90, 524 (1968)
13. Z.L. Shen, X.P. Xu, S.J. Ji, J. Org. Chem. 75, 1162 (2010)
14. P.T. Cardeilhac, Proc. Soc. Exp. Biol. Med. 125, 692 (1967)
15. J.A. Nelson, J.W. Carpenter, L.M. Rose, D.J. Adamson, Cancer Res. 35, 2872 (1975)
16. D.J. Hurst, The Chemistry and biochemistry of pyrimidines (Purines and Pteridines, Wiley, 1980)
17. Y.L. Ding, J.L. Girarde, K.L. Smith, G. Larson, B. Prigaro, J.Z. Wu, N.H. Yao, Bioorg. Chem. 34, 26
(2006)
18. R. Ramajayam, N.B. Mahera, N. Neamati, M.R. Yadav, R. Giridhar, Arch. Pharm. Chem. Life Sci.
342, 710 (2009)
19. R. Ramajayam, K.P. Tan, H.G. Liu, P.H. Liang, Bioorg. Med. Chem. Lett. 20, 3569 (2010)
123

994
L. Rong et al.
20. G. Vasuki, K. Kumaravel, Tetrahedron Lett. 49, 5636 (2008)
21. M.B. Madhusudana Reddy, V.P. Jayashankarara, M.A. Pasha, Synth. Commun. 40, 2930 (2010)
22. T.H. Babu, P.T. Perumal, Synlett 3, 341 (2011)
23. W.X. Chen, Y.J. Huang, S.R. Gundala, H. Yang, M. Li, P.C. Tai, B. Wang, Bioorg. Med. Chem. 38,
1617 (2010)
123