An Efficient and Facile Synthesis of 5-(Thiophene-2-carbonyl)-6-(trifluoromethyl)-tetrahydro-pyrimidin-2(1H)-one and 6-(Thiophen-2-yl)-4,5-dihydropyrimidin-2(1H)-one from Same Substrates Under Different Conditions

Article abstract of DOI:10.1002/jhet.2299

(Chemical Equation Presented) A series of 5-(thiophene-2-carbonyl)-6-(trifluoromethyl)-tetrahydropyrimidin-2(1H)-one and 6-(thiophen-2-yl)-4,5-dihydropyrimidin-2(1H)-one derivatives have been synthesized from the reactions of aromatic aldehydes, 4,4,4-tri

Full text of DOI:10.1002/jhet.2299

Month 2014
An Efficient and Facile Synthesis of 5-(Thiophene-2-carbonyl)-6-
(trifluoromethyl)-tetrahydro-pyrimidin-2(1H)-one and 6-(Thiophen-2-yl)-4,5-
dihydropyrimidin-2(1H)-one from Same Substrates Under Different Conditions
a
a
a
a
a
b
*
*
Rong Liang-Ce, Yunyun Zha, Sheng Xia, Linlin Ji, Jing Zhang, and Peijun Cai
aCollege of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, 221116,
Jiangsu, People’s Republic of China
bSchool of Chemical Engineering and Technology, China University of Mining and Technology, Xuzhou, 221006,
Jiangsu, People’s Republic of China
E-mail: lcrong2005@yahoo.com; caipj@163.com
Received March 28, 2014
*
DOI 10.1002/jhet.2299
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A
series of 5-(thiophene-2-carbonyl)-6-(trifluoromethyl)-tetrahydropyrimidin-2(1H)-one and 6-
(thiophen-2-yl)-4,5-dihydropyrimidin-2(1H)-one derivatives have been synthesized from the reactions
of aromatic aldehydes, 4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-dione and urea under the different
conditions with high yields. In this research, it was found that the p-toluenesulfonic acid was an
efficient catalyst for obtaining 5-(thiophene-2-carbonyl)-6-(trifluoromethyl)-tetrahydropyrimidin-2(1H)-
one derivative. At the same time, solvent-free and NaOH were the preferred conditions for the synthesis
of 6-(thiophen-2-yl)-4,5-dihydropyrimidin-2(1H)-one derivative. Moreover, because of short reaction
time, excellent yields, simple setup, this research offered an efficient process for preparing these kind
compounds.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
RESULTS AND DISCUSSION
In 1893, Biginelli reported the first synthesis of 3,
4-dihydropyrimidones (DHPMs) by a simple one-pot
condensation reaction of ethyl acetoacetate, benzalde-
hyde, and urea [1]. Because of the wide range of biological
activities, such as calcium channel blockers, antihyperten-
sive agents, a1a adrenergic antagonists, and neuropeptide
Y antagonists [2], this kind of compound has been extended
into many DHPMs-type products by using various 1,3-
dicarbonyl compound building blocks, for instance,
deuterogenic ethyl acetoacetate [3], cyclic 1,3-dicarbonyl com-
pounds (cyclopentane-1,3-dione, dimedone) [4], heterocyclic
compounds (tetronic acid, barbituric acid) [5], 1-tetralone [6],
acetophenone [7], 2,4-dioxopentane [8], and so on.
In recent years, we have designed and synthesized some
kinds heterocyclic compounds [9], herein, we reported an
efficient method for the synthesis of DHPMs-type com-
pounds by the reactions of aromatic aldehyde, 4,4,4-
trifluoro-1-(thien-2-yl)butane-1,3-dione, and urea under
mild conditions.
In order to carry out our project, we began to explore the
reaction about 4-methylbenzaldehyde 1d (1.0 mmol), 4,4,
4-trifluoro-1-(thien-2-yl)butane-1,3-dione 2 (1.0 mmol), and
urea 3 (1.0 mmol) to determine the best promoter. Different
catalysts or promoters such as HCl[1], FeCl3[6b],
polyphosphate ester [10], ZrCl4 [11], heteropoly acids [12],
InBr3 [13], NH2SO3H [14], and Cu(OTf)2 [15], which were
already used as catalysts for Biginelli or Biginelli-type
reactions, were applied in this reaction, but no products
were observed. However, a satisfactory result (87%) was
obtained when the reaction was carried out in the presence
of p-toluenesulfonic acid (0.5 mmol) in CH3CN (10 mL)
under reflux condition (Scheme 1). The product was
characterized by H NMR and IR. In its H NMR, the
singlet at delta 2.15 ppm with three protons is methyl
group (CH3–). Two doublets at 4.25 (1H, d, J = 11.2 Hz),
4.90 (1H, d, J = 11.2 Hz) with same coupling constant are
possible with protons of C-4 and C-5 of pyrimidine ring.
In its IR, the wave numbers of more than 3000 cmÀ1
1
1
© 2014 HeteroCorporation

R. Liang-Ce, Y. Zha, S. Xia, L. Ji, J. Zhang, and P. Cai
Vol 000
Scheme 1. Synthesis of 6-hydroxy-5-(thiophene-2-carbonyl)-4-p-tolyl-6-(trifluoromethyl)- tetrahydropyrimidin-2(1H)-onea.
(3438, 3361, 3210, 3113 cmÀ1) might be hydroxy (–OH)
and imino groups (–NH–). Fortunately, we obtained the
crystal of this product, and the X-ray of it certified its
absolute structure. It was a DHPMs-type product (4d)
6-hydroxy-4-(4-methoxyphenyl)-5-(thiophene-2-carbonyl)-
6-(trifluoromethyl)tetrahydropyrimidin-2(1H)-one. Then, we
investigated the background of this kind compound, and
we found that only one literature has reported one
compound of this structure as its intermediate [3b]. So, this
DHPMs-type product has not been effectively reported, and
we went to prepare this kind of compound under our
reaction conditions.
Then, the different aromatic aldehydes with various
substituted groups have been chosen to react with 4,4,
4-trifluoro-1-(thien-2-yl)butane-1,3-dione and urea under
screening conditions and a series of DHPMs-type products
have been obtained with high yields. The results showed that
either electron-withdrawing groups (such as –F, –Cl, and –Br)
or electron-donating groups (such as CH3–, CH3O–) had no
effect on these syntheses, so all the reactions could be carried
out smoothly. The results were listed in Table 1.
many advantages, such as high efficiency and selectivity,
easy separation and purification, mild reaction conditions,
and this benefit industry as well as the environment. In
our research, we also went to test this reaction under
solvent-free condition.
We also began the reaction about 4-methylbenzaldehyde
1d (1.0 mmol), 4,4,4-trifluoro-1-(thien-2-yl)butane-1,
3-dione 2 (1.0 mmol), and urea 3 (1.0 mmol) in the
presence of p-toluenesulfonic acid (0.5 mmol) under 70°C
about 0.5 h. However, the result exceeded our expectations
and no product was gained under this condition. Under
screening, we found that other acetic acid catalysts, such as
ZrCl4 [11], InBr3 [12], NH2SO3H [14], and Cu(OTf)2 [15]
also had no effect on this solvent-free reaction. The
inorganic alkali, NaOH, was often used in solvent-free
organic synthesis, and we wanted to test this reaction in
the presence of NaOH (0.5 mmol). To our delight, we
found that the reaction could be operated very well, and
high yield could be given about 92% (Scheme 2). Then,
1
the product was characterized by IR and H NMR. In its
IR, the wave number of more than 3000 cmÀ1 was only
3324 cmÀ1, and this is different from compound 4d. In its
1H NMR, a singlet at delta 2.36 ppm with three protons
Solvent-free organic synthesis has garnered much
attention from organic chemists [16]. This method has
Journal of Heterocyclic Chemistry
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Synthesis of Pyrimidin-2(1H)-One
Table 1
might be a methyl group (–CH3). However, the chemical
shifts at 4.25 ppm and 4.90 ppm were not found in this
compoud. In addition, a singlet at delta 11.86 ppm was
not found in 4d 1H NMR. These information could
give conclusion that this compound was different from
compound 4d.
Synthesis of 5-(thiophene-2-carbonyl)-6-(trifluoromethyl)-
tetrahydropyrimidin-2(1H)-one derivativea.
Luckily, when 3-methoxybenzaldehyde was used in this
synthesis, the crystal of the product was obtained. With
the help of X-ray analysis, the structure of the product
was confirmed and it was 4-(thiophen-2-yl)-6-p-
tolylpyrimidin-2(1H)-one. Studying on the product, it
could be found that the trifluoromethyl in this reaction
was lost. Therefore, it was really different from the
aforementioned products.
Under investigation, we found that Jainey P. [17] has
reported to synthesize the similar compounds from the
reaction of 3-Aryl-1-(thiophen-2-yl)prop-2-en-1-one and
urea in reflux EtOH about 16–22 h with moderate yields.
However, in our method, the process was very simple
and the reaction time was about 0.5 h. So, we decided to
use our method to prepare more products. Many aromatic
aldehydes with different substituted groups have been used
in the reactions, and the 4-(thiophen-2-yl)-6-arylpyrimidin-
2(1H)-one derivative was obtained with excellent yields.
The results were summarized in Table 2.
Entry
Ar
Product
Yieldsb (%)
1
2
3
4
5
6
7
8
9
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
84
82
79
87
93
90
88
80
83
90
4-FC6H4
4-BrC6H4
4-CH3C6H4
3,4-(CH3)2C6H3
3-CH3OC6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
3,4-OCH2OC6H3
10
4j
aReagents and conditions: aromatic aldehydes 1 (1.0 mmol), 4,4,4-trifluoro-1-
(thien-2-yl)butane-1,3-dione 2 (1.0 mmol), urea 3 (1.0 mmol), and p-toluenesulfonic
acid (0.5 mmol), CH3CN (10 mL), reflux.
bIsolated yields.
Scheme 2. Synthesis of 4-(thiophen-2-yl)-6-p-tolylpyrimidin-2(1H)-onea.
Journal of Heterocyclic Chemistry
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R. Liang-Ce, Y. Zha, S. Xia, L. Ji, J. Zhang, and P. Cai
Vol 000
Table 2
Synthesis of 6-(thiophen-2-yl)-4,5-dihydropyrimidin-2(1H)-one
derivativea.
Entry
Ar
Product
Yieldsb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
C6H5
3-FC6H4
4-FC6H4
3,4-Cl2C6H3
4-CH3C6H4
3,4-(CH3)2C6H3
2-CH3OC6H4
3-CH3OC6H4
4-CH3OC6H4
2,5-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
4-CF3C6H4
3,4-OCH2OC6H3
2-pyridyl
4-pyridyl
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
92
78
83
82
92
83
88
90
93
90
85
78
86
77
79
Figure 1. The crystal structure of 4d.
aReagents and conditions: aromatic aldehydes 1 (1.0mmol), 4,4,4-trifluoro-
1-(thien-2-yl)butane-1,3-dione 2 (1.0mmol), urea 3 (1.0mmol), and NaOH
(0.5 mmol), 70°C.
bIsolated yields.
The structures of all the products were confirmed on the
1
basis of spectroscopic data, particularly H NMR analysis
and HRMS spectra. The structures of 4d and 5h were
additionally confirmed by X-ray single crystal analysis.
The crystal structures of 4d and 5h were shown in Figures 1
[18] and 2 [19]. The possible reaction mechanisms of 4
and 5 were given in Figures 3 and 4. In Figure 3, first, a
Knoevenagel condensation reaction was operated between
1 and 2 to give 6. Then, the reaction intermediate 7 was
obtained from the reaction of urea 3 and intermediate 6.
Compound 4 was achieved after the selective intramolecular
cyclization and proton transfer. In Figure 4, initially, a
condensation intermediate 6 was produced by reactions 1
and 2. Under alkaline condition, the OHÀ attacked the
trifluoromethyl carbonyl to lose TFA, and β-unsaturated
carbonyl compound 10 was gained. Then, urea 3 reacted
with 10 to give 11. Compound 5 was formed by sequential
intramolecular cyclization, dehydration, and oxidation
reaction.
Figure 2. The crystal structure of 5h.
methods have been reported for the synthesis of these products.
In this research, it was found that the p-toluenesulfonic
acid was an efficient catalyst for obtaining 5-(thiophene-2-
carbonyl)-6-(trifluoromethyl)-tetrahydropyrimidin-2(1H)-
one derivative. At the same time, solvent-free and NaOH
were the preferred conditions for the synthesis of
6-(thiophen-2-yl)-4,5-dihydropyrimidin-2(1H)-one deriv-
atives. Moreover, because of short reaction time, excellent
yields, and simple setup, this research offered an efficient
process for preparing these two kinds of compounds.
EXPERIMENTAL
Melting points were determined on XT-5 microscopic melting
point apparatus and were uncorrected. IR spectra were recorded
on an FT Bruker Tensor 27 spectrometer (Bruker, Germany).
1H NMR and 13C NMR spectra were obtained from a solution
in DMSO-d6 with Me4Si as an internal standard using a Bruker-
400 spectrometer. HRMS spectra were obtained with a Bruker
microTOF-Q 134 instrument. X-ray diffractions were recorded
on a Siemens P4 or Simart-1000 diffractometer.
In conclusion, a series of 5-(thiophene-2-carbonyl)-6-
(trifluoromethyl)-tetrahydropyrimidin-2(1H)-one and 6-(thiophen-
2-yl)-4,5-dihydropyrimidin-2(1H)-one derivatives have
been synthesized from the reactions of aromatic aldehydes,
4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-dione and urea under
different conditions with high yields. Under investigation, few
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Month 2014
Synthesis of Pyrimidin-2(1H)-One
Figure 3. Possible reaction mechanism of compound 4.
Figure 4. Possible reaction mechanism of compound 5.
General procedure for the synthesis of 5-(thiophene-2-
6-Hydroxy-4-phenyl-5-(thiophene-2-carbonyl)-6-(trifluoromethyl)-
carbonyl)-6-(trifluoromethyl)- tetrahydropyrimidin-2(1H)-one
tetrahydropyrimidin-2(1H)-one (4a).
m.p. 242–243°C; IR
derivative.
The mixture of aromatic aldehydes 1 (1.0mmol),
(KBr, ν, cmÀ1): 3351, 2360, 2341, 1668, 1516, 1456, 1416,
4,4,4-trifluoro-1-(thien-2-yl) butane-1,3-dione 2 (1.0 mmol), urea
3 (1 mmol), and p-toluenesulfonic acid (0.5 mmol) was put in a
reaction flask with CH3CN (10 ml) and let them under reflux
conditions about 3 h (monitored by TLC). After completing the
reaction, the precipitation was precipitated from CH3CN solution,
then filtered, dried, and bottled.
1360, 1258, 1207, 1184, 1071, 771, 726, 702, 669, 653,
530 cmÀ1 1H NMR (400 MHz, DMSO-d6), (δ, ppm): 4.38
;
(1H, d, J = 11.2 Hz, CH), 4.83 (1H, d, J = 10.8 Hz, CH), 7.05
(1H, t, J = 4.4 Hz, ArH), 7.13-7.21 (5H, m, ArH), 7.38 (2H, d,
J = 7.2 Hz, ArH), 7.82 (1H, br, OH),7.86 (1H, s, NH), 7.95 (1H,
s, NH); HRMS m/z calculated for C16H13F3N2O3S [M]+:
370.0599. Found: 370.0570.
General procedure for the synthesis of 6-(thiophen-2-yl)-
4,5-dihydropyrimidin-2(1H)-one derivative. The mixture of
aromatic aldehydes 1 (1.0 mmol), 4,4,4-trifluoro-1-(thien-2-yl)
butane-1,3-dione 2 (1.0 mmol), urea 3 (1 mmol), and NaOH
(0.5 mmol) was put in a reaction flask and let them under
solvent-free conditions. The reactions were operated under 70°C
about 0.5 h (monitored by TLC). After completing the reaction,
the mixture was put into 15 ml H2O, and the precipitation was
precipitated from H2O solution, then filtered, recrystallized from
95% EtOH, dried, and bottled.
4-(4-Fluorophenyl)-6-hydroxy-5-(thiophene-2-carbonyl)-6-
(trifluoromethyl)-tetrahydropyrimidin-2(1H)-one (4b). m.p.
236–237°C; IR (KBr, ν, cmÀ1): 3401, 3222, 3097, 2906, 2361,
2342, 1672, 1608, 1513, 1491, 1417, 1361, 1252, 1232, 1202,
1178, 1110, 1072, 1017, 935, 883, 838, 729, 634, 536 cmÀ1
;
1H NMR (400 MHz, DMSO-d6), (δ, ppm): 4.29 (1H, d,
J = 11.2 Hz, CH), 4.94 (1H, d, J = 10.8 Hz, CH), 7.02 (2H, t,
J = 8.8 Hz, ArH), 7.08 (1H, t, J = 4.4 Hz, ArH), 7.27 (1H, s,
ArH), 7.34 (1H, s, ArH), 7.45 (2H, t, J = 6.4 Hz, ArH),
Journal of Heterocyclic Chemistry
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R. Liang-Ce, Y. Zha, S. Xia, L. Ji, J. Zhang, and P. Cai
Vol 000
7.86(1H, br, OH), 7.88 (1H, s, NH), 7.89 (1H, s, NH); HRMS
m/z calculated for C16H12F4N2O3S [M]+: 388.0505. Found:
388.0486.
2839, 2360, 2341, 1694, 1626, 1517, 1463, 1412, 1360, 1250,
1195, 1141, 1024, 855, 769, 744, 733, 719, 648, 621,
1
545 cmÀ1; H NMR (400 MHz, DMSO-d6), (δ, ppm): 3.62 (3H,
4-(4-Bromophenyl)-6-hydroxy-5-(thiophene-2-carbonyl)-6-
(trifluoromethyl)-tetrahydropyrimidin-2(1H)-one (4c). m.p.
220–221°C; IR (KBr, ν, cmÀ1): 3438, 3358, 3213, 3107,
2907, 2361, 2342, 1686, 1645, 1489, 1412, 1340, 1273, 1248,
s, OCH3), 3.70 (3H, s, OCH3), 4.40 (1H, d, J = 10.4 Hz, CH),
4.90 (1H, d, J = 10.4 Hz, CH), 6.72 (1H, d, J = 8.4 Hz, ArH),
6.79 (1H, s, ArH), 7.09 (1H, t, J = 4.0 Hz, ArH), 7.14–7.19 (2H,
m, ArH), 7.31 (1H, s, ArH), 7.87 (1H, s, OH), 7.99 (1H, s,
NH), 8.00 (1H, s, NH); HRMS m/z calculated for
C18H17F3N2O5S [M]+: 430.0810. Found: 430.0782.
1198, 1107, 1073, 1012, 831, 752, 727, 635, 531 cmÀ1 1H
;
NMR (400 MHz, DMSO-d6), (δ, ppm): 4.31 (1H, d,
J = 10.8 Hz, CH), 4.93 (1H, d, J = 11.2 Hz, CH), 7.08 (1H, t,
J = 4.0 Hz, ArH), 7.35–7.47 (6H, m, ArH), 7.88 (1H, s, NH),
7.89 (1H, s, NH), 8.00 (1H, br, OH); HRMS m/z calculated
for C16H12BrF3N2O3S [M À H]À: 446.9626. Found: 446.9600.
6-Hydroxy-5-(thiophene-2-carbonyl)-4-p-tolyl-6-(trifluoromethyl)-
6-Hydroxy-5-(thiophene-2-carbonyl)-6-(trifluoromethyl)-4-
(3,4,5-trimethoxyphenyl)-tetrahydropyrimidin-2(1H)-one (4i). m.p.
212–213°C; IR (KBr, ν, cmÀ1): 3285, 3215, 3102, 2942,
2836, 2361, 2342, 1695, 1638, 1598, 1499, 1412, 1331,
1242, 1179, 1128, 998, 836, 786, 732, 655, 626, 545 cmÀ1
;
tetrahydropyrimidin-2(1H)-one (4d).
m.p. 240–241°C; IR
1H NMR (400 MHz, DMSO-d6), (δ, ppm): 3.49 (3H, s,
OCH3), 3.69 (6H, s, 2 × OCH3), 4.38 (1H, d, J = 11.2 Hz,
CH), 4.88 (1H, d, J = 11.2 Hz, CH), 6.69 (2H, s, ArH), 7.09
(1H, t, J = 4.0 Hz, ArH), 7.14 (1H, s, ArH), 7.30 (1H, s,
ArH), 7.88 (1H, s, NH), 7.90 (1H, s, NH),7.98 (1H, s, OH);
HRMS m/z calculated for C19H19F3N2O6S [M]+: 460.0916.
Found: 460.0881.
(KBr, ν, cmÀ1): 3438, 3361, 3210, 3113, 3087, 2900, 2361,
2342, 1920, 1683, 1643, 1518, 1483, 1412, 1308, 1248, 1200,
1186, 1112, 1072, 1027, 998, 827, 812, 770, 751, 719, 681, 656,
1
636, 533 cmÀ1; H NMR (400 MHz, DMSO-d6), (δ, ppm): 2.15
(3H, s, CH3), 4.25 (1H, d, J = 11.2 Hz, CH), 4.90 (1H, d,
J = 11.2 Hz, CH), 7.00 (2H, d, J = 8.0 Hz, ArH), 7.07 (1H, t,
J = 4.0 Hz, ArH), 7.22 (2H, s, ArH), 7.27 (2H, d, J = 8.0 Hz,
ArH), 7.78 (1H, br, OH), 7.85 (1H, s, NH), 7.87 (1H, s, NH);
HRMS m/z calculated for C17H15F3N2O3S [M À H]À: 383.0677.
Found: 383.0649.
4-(Benzo[d][1,3]dioxol-5-yl)-6-hydroxy-5-(thiophene-2-
carbonyl)-6-(trifluoromethyl)-tetrahydropyrimidin-2(1H)-one
(4j). m.p. 260–261°C; IR (KBr, ν, cmÀ1): 3370, 3210, 3090,
2911, 2361, 2342, 1687, 1646, 1490, 1448, 1416, 1361, 1314,
1246, 1209, 1111, 1035, 920, 870, 819, 724, 682, 636, 558,
4-(3,4-Dimethylphenyl)-6-hydroxy-5-(thiophene-2-carbonyl)-
6-(trifluoromethyl)-tetrahydropyrimidin-2(1H)-one (4e). m.p.
198–199°C; IR (KBr, ν, cmÀ1): 3433, 3216, 3095, 2923, 2361,
2343, 1686, 1543, 1491, 1414, 1361, 1324, 1250, 1183, 1110.
546 cmÀ1 1H NMR (400 MHz, DMSO-d6), (δ, ppm): 4.29
;
(1H, d, J = 11.2 Hz, CH), 4.86 (1H, d, J = 11.2 Hz, CH), 5.89
(2H, d, J = 4.0 Hz, CH2), 6.70 (1H, d, J = 8.0 Hz, ArH), 6.77
(1H, d, J = 8.0 Hz, ArH), 7.12 (3H, d, J = 4.4 Hz, ArH), 7.27
(1H, s, ArH), 7.82 (1H, s, NH), 7.90 (1H, s, NH), 7.93 (1H,
br, OH); HRMS m/z calculated for C17H13F3N2O5S
[M À H]À: 413.0419. Found: 413.0395.
830, 750, 716, 680, 635, 549 cmÀ1 1H NMR (400 MHz,
;
DMSO-d6), (δ, ppm): 2.06 (3H, s, CH3), 2.11 (3H, s, CH3), 4.25
(1H, d, J = 11.2Hz, CH), 4.85 (1H, d, J = 11.2 Hz, CH), 6.94 (1H,
d, J = 7.6Hz, ArH), 7.08 (1H, s, ArH), 7.09–7.20 (4H, m, ArH),
7.74 (1H, br, OH), 7.87 (2H, s, 2NH); HRMS m/z calculated for
C18H17F3N2O3S [M À H]À: 397.0834. Found: 397.0807.
6-Phenyl-4-(thiophen-2-yl)pyrimidin-2(1H)-one (5a). m.p.
257–258°C; IR (KBr, ν, cmÀ1): 3309, 3220, 3077, 3034, 2947,
2361, 2342, 1869, 1793, 1634, 1575, 1532, 1497, 1439, 1422,
1393, 1349, 1327, 1261, 1194, 1161, 1089, 1076, 1051, 987,
6-Hydroxy-4-(3-methoxyphenyl)-5-(thiophene-2-carbonyl)-
6-(trifluoromethyl)-tetrahydropyrimidin-2(1H)-one (4f).
m.p.
194–195°C; IR (KBr, ν, cmÀ1): 3444, 3360, 3207, 3093, 2908,
2831, 2361, 2342, 1686, 1657, 1610, 1588, 1489, 1414, 1362,
1321, 1267, 1194, 1182, 1101, 1073, 1042, 869, 785, 728, 700,
858, 765, 685, 612, 578 cmÀ1; H NMR (400 MHz, DMSO-d6),
1
(δ, ppm): 7.27 (1H, t, J = 4.0 Hz, ArH), 7.56–7.62 (4H, m,
ArH), 7.88 (1H, d, J = 5.2 Hz, ArH), 8.05 (2H, d, J = 6.8 Hz,
ArH), 8.23 (1H, d, J = 3.6 Hz, ArH), 12.02 (1H, s, NH); HRMS
m/z calculated for C14H10N2OS [M]+: 254.0514. Found:
254.0492.
1
641, 584, 548cmÀ1; H NMR (400MHz, DMSO-d6), (δ, ppm):
3.67 (3H, s, OCH3), 4.33 (1H, d, J = 11.2 Hz, CH), 4.92 (1H, d,
J= 11.2 Hz, CH), 6.69 (1H, d, J= 6.8 Hz, ArH), 6.90 (1H, d,
J= 7.6 Hz, ArH), 7.02 (1H, s, ArH), 7.07 (1H, s, ArH), 7.10 (1H, d,
J= 8.4 Hz, ArH), 7.21 (1H, s, ArH), 7.32 (1H, s, ArH), 7.85 (1H, s,
NH), 7.87 (1H, s, NH), 7.92 (1H, s, OH); HRMS m/z calculated for
C17H15F3N2O4S [MÀ H]À: 399.0626. Found: 399.0601.
6-(3-Fluorophenyl)-4-(thiophen-2-yl)pyrimidin-2(1H)-one
(5b). m.p. 277–278°C; IR (KBr, ν, cmÀ1): 3318, 3107, 3069,
3013, 2912, 2361, 2342, 1869, 1829, 1772, 1717, 1621, 1586,
1540, 1523, 1489, 1445, 1422, 1395, 1346, 1262, 1189, 1167,
1092, 1078, 1045, 1001, 950, 871, 850, 786, 757, 714, 697,
6-Hydroxy-4-(4-methoxyphenyl)-5-(thiophene-2-carbonyl)-
1
6-(trifluoromethyl)-tetrahydropyrimidin-2(1H)-one (4g).
m.p.
660, 640, 613, 594, 524 cmÀ1; H NMR (400 MHz, DMSO-d6),
238–239°C; IR (KBr, ν, cmÀ1): 3436, 3376, 3208, 3103, 2903,
2841, 2359, 2340, 1688, 1636, 1587, 1518, 1412, 1371, 1345,
1308, 1255, 1203, 1181, 1112, 1071, 1040, 996, 837, 820, 768,
(δ, ppm): 7.28 (1H, t, J = 4.0 Hz, ArH), 7.42–7.47 (1H, m,
ArH), 7.59–7.64 (1H, m, ArH), 7.71 (1H, s, ArH), 7.88 (1H, d,
J = 4.8 Hz, ArH), 7.96 (2H, d, J = 8.4 Hz, ArH), 8.25 (1H, d,
J = 3.6 Hz, ArH), 11.96 (1H, s, NH); HRMS m/z calculated for
C14H9FN2OS [M À H]À: 271.0342. Found: 271.0328.
751, 719, 681, 657, 635, 541 cmÀ1 1H NMR (400 MHz,
;
DMSO-d6), (δ, ppm): 3.62 (3H, s, OCH3), 4.27 (1H, d,
J = 11.2Hz, CH), 4.90 (1H, d, J = 11.2 Hz, CH), 6.74 (2H, d,
J = 8.4 Hz,ArH), 7.07 (1H, t, J = 4.0 Hz, ArH), 7.25 (1H, s, ArH),
7.32 (3H, m, ArH), 7.86 (1H, s, OH), 7.87 (1H, s, NH), 7.89
(1H, s, NH); HRMS m/z calculated for C17H15F3N2O4S [M]+:
400.0705. Found: 400.0675.
4-(3,4-Dimethoxyphenyl)-6-hydroxy-5-(thiophene-2-carbonyl)-
6-(trifluoromethyl)-tetrahydropyrimidin-2(1H)-one (4h). m.p.
233–234°C; IR (KBr, ν, cmÀ1): 3336, 3211, 3080, 2961, 2935,
6-(4-Fluorophenyl)-4-(thiophen-2-yl)pyrimidin-2(1H)-one
(5c). m.p. 245–246°C; IR (KBr, ν, cmÀ1): 3299, 3115, 3083,
2934, 2361, 2343, 1869, 1845, 1830, 1793, 1772, 1749, 1734,
1717, 1637, 1611, 1587, 1560, 1540, 1523, 1509, 1474, 1444,
1431, 1389, 1350, 1340, 1309, 1260, 1237, 1165, 1104, 1089,
1075, 1050, 1015, 987, 864, 834, 767, 722, 635, 623, 584, 562,
1
509 cmÀ1; H NMR (400 MHz, DMSO-d6), (δ, ppm): 7.24 (1H,
m, ArH), 7.38 (2H, t, J = 8.8 Hz, ArH), 7.58 (1H, s, ArH), 7.84
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Pyrimidin-2(1H)-One
(1H, d, J = 4.8 Hz, ArH), 8.12 (2H, t, J = 7.6 Hz, J = 6.0 Hz, ArH),
8.19 (1H, d, J = 4.8 Hz, ArH), 11.93 (1H, s, NH); HRMS m/z
calculated for C14H9FN2OS [M]+: 272.0420. Found: 272.0399.
6-(3,4-Dichlorophenyl)-4-(thiophen-2-yl)pyrimidin-2(1H)-one
(5d). m.p. 232–233°C; IR (KBr, ν, cmÀ1): 3311, 2955, 2361,
2343, 1869, 1845, 1793, 1749, 1717, 1698, 1647, 1638, 1608,
1559, 1541, 1508, 1475, 1438, 1427, 1375, 1339, 1255, 1144,
(400 MHz, DMSO-d6), (δ, ppm): 3.86 (3H, s, OCH3), 7.11
(2H, d, J = 8.8 Hz, ArH), 7.27 (1H, s, ArH), 7.48 (1H, s, ArH),
7.86 (2H, d, J = 3.6 Hz, ArH), 8.06 (1H, d, J = 7.6 Hz, ArH),
8.21 (1H, s, ArH), 11.85 (1H, s, NH); HRMS m/z calculated
for C15H12N2O2S [M]+: 284.0619. Found: 284.0599.
6-(2,5-Dimethoxyphenyl)-4-(thiophen-2-yl)pyrimidin-2(1H)-
one (5j).
m.p. 257–258°C; IR (KBr, ν, cmÀ1): 3319, 3072,
1086, 1031, 934, 864, 828, 724, 670, 622 cmÀ1
;
1H NMR
2835, 2362, 2343, 1668, 1621, 1601, 1542, 1506, 1458, 1429,
(400 MHz, DMSO-d6), (δ, ppm): 7.23 (1H, s, ArH), 7.76 (2H, d,
J = 7.6 Hz, ArH), 7.82 (1H, d, J = 4.4 Hz, ArH), 8.07 (1H, d,
J = 8.4 Hz, ArH), 8.21 (1H, s, ArH), 8.36 (1H, s, ArH), 12.23
(1H, s, NH); HRMS m/z calculated for C14H8Cl2N2OS
[M À H]À: 320.9656. Found: 320.9672.
1386, 1355, 1296, 1267, 1236, 1180, 1135, 1075, 1036, 957,
884, 812, 737, 717, 671, 636, 600, 552 cmÀ1 1H NMR
;
(400 MHz, DMSO-d6), (δ, ppm): 3.74 (3H, s, OCH3), 3.76
(3H, s, OCH3), 7.08 (2H, t, J = 2.8 Hz, ArH), 7.12 (2H, d,
J = 2.8 Hz, ArH), 7.20 (1H, t, J = 4.0 Hz, J = 4.8 Hz, ArH), 7.84
(1H, d, J = 4.4 Hz, ArH), 8.04 (1H, d, J = 3.2 Hz, ArH), 11.71
(1H, s, NH); HRMS m/z calculated for C16H14N2O3S
[M À H]À: 313.0647. Found: 313.0652.
4-(Thiophen-2-yl)-6-p-tolylpyrimidin-2(1H)-one (5e). m.p.
222–223°C; IR (KBr, ν, cmÀ1): 3324, 2911, 2365, 2345, 1869,
1845, 1793, 1749, 1717, 1684, 1624, 1571, 1542, 1523, 1509,
1460, 1474, 1449, 1430, 1390, 1352, 1340, 1255, 1187, 1090,
4-(Thiophen-2-yl)-6-(3,4,5-trimethoxyphenyl)pyrimidin-2
1
1073, 985, 906, 858, 808, 761, 705, 626, 590 cmÀ1; H NMR
(1H)-one (5k).
m.p. 228–229°C; IR (KBr, ν, cmÀ1): 3290,
(400 MHz, DMSO-d6), (δ, ppm): 2.36 (3H, s, CH3), 7.23 (1H, t,
J = 4.0 Hz, ArH), 7.34 (2H, d, J = 8.0 Hz, ArH), 7.48 (1H, s,
ArH), 7.83 (1H, d, J = 4.8 Hz, ArH), 7.93 (2H, d, J = 7.6 Hz,
ArH), 8.18 (1H, d, J = 3.6 Hz, ArH), 11.86 (1H, s, NH); HRMS
m/z calculated for C15H12N2OS [M À H]À: 267.0592. Found:
267.0602.
2946, 2839, 2361, 2342, 1671, 1654, 1611, 1582, 1542, 1507,
1455, 1432, 1389, 1346, 1301, 1245, 1175, 1128, 1083, 1045,
1006, 952, 915, 854, 795, 751, 703, 669, 636, 619, 598,
1
518 cmÀ1; H NMR (400 MHz, DMSO-d6), (δ, ppm): 3.71 (3H,
s, OCH3), 3.88 (6H, s, 2 × OCH3), 7.25 (1H, m, ArH), 7.31
(2H, s, ArH), 7.47 (1H, s, ArH), 7.85 (1H, t, J = 5.2 Hz,
J = 6.0 Hz, ArH), 8.22 (1H, d, J = 4.4 Hz, ArH), 11.90 (1H, s,
NH); HRMS m/z calculated for C17H16N2O4S [M À H]À:
343.0753. Found: 343.0772.
6-(3,4-Dimethylphenyl)-4-(thiophen-2-yl)pyrimidin-2(1H)-
one (5f). m.p. 167–168°C; IR (KBr, ν, cmÀ1): 3315, 2915,
2361, 2342, 1845, 1793, 1749, 1698, 1624, 1575, 1559,
1541, 1523, 1507, 1490, 1449, 1429, 1386, 1350, 1336,
1257, 1089, 1074, 990, 903, 879, 808, 762, 703, 625,
4-(Thiophen-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-2
(1H)-one (5l). m.p. >280°C; IR (KBr, ν, cmÀ1): 3305, 3115,
1084, 3030, 2913, 2361, 2342, 1869, 1845, 1772, 1575, 1522,
1474, 1445, 1412, 1390, 1343, 1256, 1244, 1168, 1136, 1119,
1067, 1018, 986, 901, 860, 838, 788, 760, 728, 669, 620,
590 cmÀ1 1H NMR (400 MHz, DMSO-d6), (δ, ppm): 2.26
;
(3H, s, CH3), 2.28 (3H, s, CH3), 7.23 (1H, t, J = 3.6 Hz,
ArH), 7.27 (1H, d, J = 8.0 Hz, ArH), 7.45 (1H, s, ArH), 7.75
(1H, d, J = 7.6 Hz, ArH), 7.83 (2H, s, ArH), 8.18 (1H, s,
ArH), 11.81 (1H, s, NH); HRMS m/z calculated for
C16H14N2OS [M À H]À: 281.0749. Found: 281.0756.
582 cmÀ1 1H NMR (400 MHz, DMSO-d6), (δ, ppm): 7.28
;
(1H, t, J = 4.0 Hz, ArH), 7.77 (1H, s, ArH), 7.88 (1H, d,
J = 5.2 Hz, ArH), 7.93 (2H, d, J = 8.4 Hz, ArH), 8.24 (1H, d,
J = 4.0 Hz, ArH), 8.30 (2H, d, J = 8.0 Hz, ArH), 12.15 (1H, s,
NH); HRMS m/z calculated for C15H9F3N2OS [M]+:
322.0388. Found: 322.0397.
6-(2-Methoxyphenyl)-4-(thiophen-2-yl)pyrimidin-2(1H)-one
(5g). m.p. 224–225°C; IR (KBr, ν, cmÀ1): 3401, 3015, 2362,
2343, 1685, 1671, 1654, 1636, 1577, 1542, 1498, 1458, 1438,
1419, 1340, 1256, 1067, 983, 925, 811, 738, 669, 616, 588,
6-(Benzo[d][1,3]dioxol-5-yl)-4-(thiophen-2-yl)pyrimidin-2
(1H)-one (5m). m.p. >280°C; IR (KBr, ν, cmÀ1): 3280, 3096,
2905, 2361, 2342, 1869, 1845, 1793, 1749, 1717, 1698, 1625,
1539, 1523, 1504, 1490, 1448, 1425, 1399, 1339, 1259, 1232,
1159, 1118, 1095, 1077, 1040, 991, 935, 884, 853, 839, 801,
569 cmÀ1 1H NMR (400 MHz, DMSO-d6), (δ, ppm): 3.81
;
(3H, s, OCH3), 7.06 (1H, t, J = 7.2 Hz, ArH), 7.10 (1H, s,
ArH), 7.16 (1H, d, J = 8.4 Hz, ArH), 7.20 (1H, t, J = 4.4 Hz,
ArH), 7.48–7.53 (2H, m, ArH), 7.84 (1H, d, J = 4.8 Hz,
ArH), 8.04 (1H, d, J = 3.6 Hz, ArH), 11.73 (1H, s, NH);
HRMS m/z calculated for C15H12N2O2S [M]+: 284.0619.
Found: 284.0601.
773, 704, 668, 623, 601, 563 cmÀ1 1H NMR (400 MHz,
;
DMSO-d6), (δ, ppm): 6.15 (2H, s, CH2), 7.10 (1H, d, J = 8.4 Hz,
ArH), 7.27 (1H, t, J = 4.4 Hz, ArH), 7.52 (1H, s, ArH), 7.68
(2H, s, ArH), 7.86 (1H, d, J = 5.2 Hz, ArH), 8.22 (1H, d,
J = 3.6 Hz, ArH), 11.84 (1H, s, NH); HRMS m/z calculated for
C15H10N2O3S [M + Na]+: 321.0310. Found: 321.0334.
6-(3-Methoxyphenyl)-4-(thiophen-2-yl)pyrimidin-2(1H)-one
(5h). m.p. 215–216°C; IR (KBr, ν, cmÀ1): 3331, 3094, 2995,
2906, 2361, 1342, 1909, 1869, 1772, 1734, 1698, 1626, 1611,
1540, 1508, 1456, 1421, 1392, 1352, 1287, 1274, 1220, 1088,
1042, 995, 947, 917, 872, 842, 781, 757, 724, 694, 669, 635,
6-(Pyridin-2-yl)-4-(thiophen-2-yl)pyrimidin-2(1H)-one (5n). m.p.
167–168°C; IR (KBr, ν, cmÀ1): 3289, 3075, 2361, 2342, 1793,
1772, 1934, 1698, 1683, 1647, 1617, 1577, 1541, 1490, 1457,
1429, 1374, 1340, 1262, 1073, 990, 863, 823, 669, 656, 623,
618, 596, 546 cmÀ1 1H NMR (400 MHz, DMSO-d6), (δ,
;
ppm): 3.87 (3H, s, OCH3), 7.16 (1H, d, J = 8.0 Hz, ArH), 7.27
(1H, s, ArH), 7.47 (1H, t, J = 8.0 Hz, ArH), 7.55 (1H, s, ArH),
7.63 (2H, t, J = 7.6 Hz, ArH), 7.88 (1H, s, ArH), 8.24 (1H, s,
ArH), 11.96 (1H, s, NH); HRMS m/z calculated for
C15H12N2O2S [M]+: 284.0619. Found: 284.0604.
1
586 cmÀ1; H NMR (400 MHz, DMSO-d6), (δ, ppm): 7.25 (1H,
s, ArH), 7.82 (1H, s, ArH), 7.85 (1H, d, J = 4.0 Hz, ArH), 8.03
(2H, d, J = 4.0 Hz, ArH), 8.22 (1H, s, ArH), 8.76 (2H, d,
J = 4.0 Hz, ArH), 12.13 (1H, s, NH); HRMS m/z calculated for
C13H9N3OS [M]+: 255.0466. Found: 255.0446.
6-(Pyridin-4-yl)-4-(thiophen-2-yl)pyrimidin-2(1H)-one (5o). m.p.
238–239°C; IR (KBr, ν, cmÀ1): 3301, 3085, 2910, 2360, 2341,
1868, 1844, 1792, 1772, 1716, 1645, 1637, 1616, 1593, 1553,
1539, 1508, 1473, 1427, 1396, 1373, 1341, 1263, 1090, 863,
6-(4-Methoxyphenyl)-4-(thiophen-2-yl)pyrimidin-2(1H)-one
(5i). m.p. 237–238°C; IR (KBr, ν, cmÀ1): 3295, 3066, 2995,
2912, 2837, 2357, 2330, 1619, 1606, 1572, 1538, 1511, 1475,
1448, 1430, 1392, 1352, 1340, 1298, 1256, 1218, 1178, 1090,
1033, 984, 902, 857, 820, 788, 723, 625 cmÀ1 1H NMR
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Liang-Ce, Y. Zha, S. Xia, L. Ji, J. Zhang, and P. Cai
Vol 000
1
822, 731, 613 cmÀ1; H NMR (400 MHz, DMSO-d6), (δ, ppm):
[8] (a) Zhu, A. L.; Li, Q. Q.; Li, L. J.; Wang, J. J Catal Lett
2013, 143, 463; (b) Safari, J.; Zarnegar, Z. RSC Adv 2013, 3, 17962;
(c) Wang, D. C.; Guo, H. M.; Qu, G. R. Synth Commun 2010, 40, 1115.
[9] (a) Rong, L. C.; Ji, H. L.; Xia, S.; Yin, S.; Shi, Y. H.; Tu, S. J.
J Heterocyclic Chem 2012, 49, 696; (b) Gao, L. J.; Ji, H. L.; Rong, L. C.;
Tang, D.; Zha, Y. Y.; Shi, Y. H.; Tu, S. J. J Heterocyclic Chem 2011, 48,
957; (c) Rong, L. C.; Xia, S.; Yin, S.; Tao, S. M.; Zha, Y. Y.; Tu, S.
J Res Chem Intermed 2013, 39, 3699.
7.29 (1H, t, J = 4.4 Hz, ArH), 7.85 (1H, s, ArH), 7.89 (1H, d,
J = 4.8 Hz, ArH), 8.06 (2H, d, J = 5.6 Hz, ArH), 8.25 (1H, d,
J = 3.6 Hz, ArH), 8.80 (2H, d, J = 5.2 Hz, ArH), 12.18 (1H, s,
NH); HRMS m/z calculated for C13H9N3OS [M]+: 255.0466.
Found: 255.0458.
[10] Kappe, C. O.; Falsone, S. F. Synlett 1998, 718.
[11] Reddy, C. V.; Mahesh, M.; Raju, K.; Babu, T. R.;
Reddy, V. V. N. Tetrahedron Lett 2002, 43, 2657.
[12] Rafiee, E.; Jafari, H. Bioor Med Chem Lett 2006, 16 2463.
[13] Ramalinga, K.; Vijayalaxmi, P.; Kaimal, T. N. B. Synlett
2001, 863.
Acknowledgements. We are grateful to the National Natural Science
Foundation of China (NSFC) (No. 51174201), the Open Foundation
of Southwest University of Science and Technology (No. 11zxjk10),
and the Priority Academic Program Development of Jiangsu
Higher Education Institutions for financial support.
[14] Li, J. T.; Hu, J. F.; Liu, T. S. Ultrason Sonochem 2003,
10, 119.
[15] Paraskar, A. S.; Dewkar, G. K.; Sudalai, A. Tetrahedron Lett
2003, 44, 3305.
REFERENCES AND NOTES
[16] (a) Tanaka, T.; Toda, F. Chem Rev 2000, 100, 1025;
(b) Cave, G. W. V.; Raston, C. L. T. Chem Commun 2000, 2199;
(c) Babak Kaboudin, B.; Karimi, M. Bioorg Med Chem Lett 2006, 16, 5324.
[17] Jainey, P. J.; Ishwar, K.; B Indian J Heterocyclic Chem 2011,
20, 309.
[1] Biginelli, P. Gazz Chim Ital 1893, 23, 360.
[2] (a) Kappe, C. O.; Stadler, A. Org React 2004, 63, 1; (b) Kappe,
C. O. QSAR Comb Sci 2003, 22, 630; (c) Kappe, C. O. Acc Chem Res
2000, 33, 879; (d) Kappe, C. O. Eur J Med Chem 2000, 35, 1043;
(e) Kappe, C. O. Tetrahedron 1993, 49, 6937.
[3] (a) Sabitha, G.; Reddy, K. B.; Yadav, J. S.; Shailajab, D.; Sivudu,
K. S. Tetrahedron Lett 2005, 46, 8221; (b) Ma, Y.; Qian, C.; Wang, L.;
Yan, M. J Org Chem 2000, 65, 3864; (c) Pisani, L.; Prokopcová, H.;
Kremsner, J. M.; Kappe, C. O. J Comb Chem 2007, 9, 415.
[4] (a) Yarım, M.; Sarac, S.; Kilic, F. S.; Erol, K. Il Farmaco 2003,
58, 17; (b) Evans, C. G. E. Gestwicki, J. Org Lett 2009, 11, 2957.
[5] Byk, G.; Gottlieb, H. E.; Herscovici, J.; Mirkin, F. J Comb
Chem 2000, 2, 732.
[18] X-ray crystallography for 4d: empirical formula
C17H14F3N2O3S, Fw = 383.36, T = 296(2) K, monoclinic, space group P2
(1)/n, a = 6.5804 (5) Ǻ, b = 21.9201 (17) Ǻ, c = 15.0638 (12) Ǻ, α = 90°,
β = 100.032 (5)°, γ = 90°, V = 2139.6 (3) Ǻ3, Z= 4, Dcalcd. = 1.190Mg/m3,
λ (MoKα) = 0.71073 Ǻ, μ = 0.192 mmÀ1, F(000) = 788. 1.66° < θ < 27.61°,
R = 0.2601, wR = 0.6380. s = 1.043. Largest diff. peak and hole: 6.903 and
À0.987 e. ǺÀ3
.
[19] X-ray crystallography for 5h: empirical formula C15H12
N2O2S, Fw = 284.33, T = 296(2) K, monoclinic, space group C2/c,
a = 13.802 (2) Ǻ, b = 7.3026(12) Ǻ, c = 13.111(2) Ǻ, α = 90°, β = 94.604
(2)°, γ = 90°, V = 1317.8 (4) Ǻ3, Z = 4, Dcalcd. = 1.433 Mg/m3,
λ (MoKα) = 0.71073 Ǻ, μ = 0.248mmÀ1, F(000) =592. 3.16° < θ <25.20°,
R = 0.0406, wR = 0.1167. s = 1.059. Largest diff. peak and hole: 0.277
[6] Gao, L.; Ji, H.; Rong, L.; Han, H.; Shi, Y.; Tu, S. J Heterocyclic
Chem 2010, 47, 358.
[7] Wang, Z. T.; Xu, L. W.; Xia, C. G.; Wang, H. Q. Tetrahedron
Lett 2004, 45, 7951.
and À0.256 e. ǺÀ3
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet