One-step synthesis of 1-(4,5-diphenylpyrimidin-2-yl)thiourea

Article abstract of DOI:10.1002/hlca.200900438

A simple and straightforward methodology toward the synthesis of novel 1-(4,5-diphenylpyrimidin-2-yl)thiourea has been developed by a one-step reaction of isoflavones with amidinothiourea. A series of 16 new compounds was synthesized. All compounds were characterized by FT-IR, NMR, and elemental analysis. The structure of a typical compound was established by X-ray diffraction. Avariety of substrates can participate in the process with good yields and high purities, making this methodology suitable for library synthesis in drug discovery.

Full text of DOI:10.1002/hlca.200900438

Helvetica Chimica Acta – Vol. 93 (2010)
1641
One-Step Synthesis of 1-(4,5-Diphenylpyrimidin-2-yl)thiourea
by Wen-Yong Hana), Zun-Ting Zhang*a), Ying-Chun Zhangb), Dong Xuea), and Gang Lia)
a) Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical
Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in
Northwest of China, and School of Chemistry and Materials Science, Shaanxi Normal University,
Xiꢀan 710062, P. R. China
(phone: þ 86-29-85303940; fax: þ 86-29-85307774; e-mail: zhangzt@snnu.edu.cn)
b) Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Jinan Central
Hospital, Affiliated Hospital of Shandong University, Jinan 250013, P. R. China
A simple and straightforward methodology toward the synthesis of novel 1-(4,5-diphenylpyrimidin-
2-yl)thiourea has been developed by a one-step reaction of isoflavones with amidinothiourea. A series of
16 new compounds was synthesized. All compounds were characterized by FT-IR, NMR, and elemental
analysis. The structure of a typical compound was established by X-ray diffraction. Avariety of substrates
can participate in the process with good yields and high purities, making this methodology suitable for
library synthesis in drug discovery.
Introduction. – Pyrimidines are well-known and widely investigated six-membered
N-containing heterocyclic compounds that exhibit important biological activities [1 –
4]. Thiourea and their related analogs have become the focus of interest in recent
past on account of their pharmacological activities such as anti-HIV [5], antinocicep-
tive [6], antibacterial [7], antiviral [8], and anticancer [8]. It is convenient to synthesize
substituted pyrimidines by reaction of amidines or guanidines with a,b-unsaturated
ketones [9][10], b-diketones [11][12], b-alkoxy- and b-aminovinyl ketones [13 – 16],
and N-arylacetylenic imines [17][18]. Natural isoflavones display a wide range of
biological activities [19]. For instance, soybean isoflavones (daidzein and genistein)
have shown pharmacological effects such as antidysrhythmic [20], antioxidant [21], and
anticardio-cerebral vascular disease activities [22]. Ipriflavone (¼ 7-(1-methylethoxy)-
3-phenyl-4H-benzopyran-4-one) has been reported to be efficient in preventing and
treating osteoporosis [23]. It was reported that the chromone fragment present in
isoflavones can generate a 1,3-diketone equivalent which readily react with amidines
[24], guanidine [2], carbamide [25], and sulfocarbamides [26] to form the correspond-
ing 2-substituted pyrimidines. The use of combinatorial approaches for the high-
throughput synthesis of this drug-like scaffold would be a powerful advance in helping
to speed up drug discovery. Recently, we have reported the high-throughput synthesis
of 3,4-diarylpyrazoles and 4,5-diphenylpyrimidin-2-ylguanidine by a one-pot reaction
of hydrazine [27] or bisguanidine [28] with isoflavones. To the best of our knowledge,
using isoflavone as starting material to synthesize the pyrimidinylthioureas has not
been reported so far. Herein, we report a new way for the preparation of the unknown
class of 1-(4,5-diphenylpyrimidin-2-yl)thiourea by the cyclocondensation of isoflavones
(1) with amidinothiourea (2; Table 1).
ꢁ 2010 Verlag Helvetica Chimica Acta AG, Zꢂrich

1642
Helvetica Chimica Acta – Vol. 93 (2010)
Table 1. Synthesis of 1-(4,5-Diphenylpyrimidin-2-yl)thiourea by Reaction of Various isoflavones with
Amidinothiourea in MeOH (for details, see Exper. Part)
Entry Substrate R1 R2
R3
R4
R5 R6
R7
Time [h] Yield of 3 [%]a)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
H
H
H
H
H
H
iPrO
MeO
MeO
MeO
H
H
H
H
H
MeO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3.0
2.5
2.5
3.0
2.0
3.5
2.5
2.5
3.0
3.5
3.5
4.0
4.5
69
72
80
67
72
65
73
76
68
87b)
74
53
60
57
54
–c)
MeO
MeO
H
MeO
H
H
MeO
BnO
H
MeO MeO MeO
MeO
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
Br iPrO
H
H
H
H
H
H
H
H
H
EtO
BnO
MeO
MeO
MeO
MeO
MeO
iPr MeO iPr
MeO iPr MeO iPr
H
H
H
H
H
H
OH
iPr OH
OH
Br OH
MeO
H
iPr
NO2 4.0
Br
H
H
MeO Br
OH
5.0
24
H
H
a) Yield of product after recrystallization from EtOH. b) Yield of product after chromatography on silica
gel. c) Target compound 3p was not obtained.
Results and Discussion. – We turned our attention to optimize the condition of the
cyclocondensations of isoflavones 1 with amidinothiourea (2) and designed a process
based on the cyclocondensation of ipriflavone (1a) with amidinothiourea (2) as a model
substrate (Table 2). As shown in Table 2, we used NaOH as base, and 3a was obtained
in 36% yield (Entry 1). It was also found that K2CO3 was ineffective in providing the
desired condensation product (Entry 2). A comparative reactivity study of bases in the
reaction showed that MeONa proved to be more effective for this cyclocondensation
(Entry 3). From the solvents tried, MeOH, EtOH, THF, MeCN, BuOH, and DMF,
MeOH gave the expected result (Entry 3). Further study with varying MeONa
equivalents revealed that 3.0 equiv. of base is necessary to obtain a high yield of the
condensation product (Entry 10). Finally, the ratio 1a/2 was also evaluated. In the case
of a ratio 1a/2 of 1:3, the yield of 3a was high for the cyclocondensation reaction
(Entry 13).
With the optimized reaction conditions and results in hand, the condensation of a
variety of structurally divergent isoflavones (1) and amidinothiourea (2) were studied

Helvetica Chimica Acta – Vol. 93 (2010)
1643
Table 2. Optimization of Cyclocondensation of Ipriflavone (1a) with Amidinothiourea (2)a)
Entry
Solvent
Base
Molar ratio 1a/2/base
Yield of 3a [%]b)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
MeOH
MeOH
MeOH
EtOH
THF
MeCN
BuOH
DMF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
NaOH
K2CO3
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 1
1 : 1 : 2
1 : 1 : 3
1 : 1 : 4
1 : 2 : 3
1 : 3 : 3
1 : 4 : 3
36
29
61
52
trace
38
30
28
72
79
66
85
93
91
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
a) All reactions were carried out in the appropriate solvent (15 ml) using ipriflavone (1a),
amidinothiourea (2), and base until complete disappearance of 1a (reflux for 3 h, TLC check). b) Yield
of product after chromatography on silica gel.
to illustrate this concise and general method for the synthesis of 1-(4,5-diphenylpyr-
imidin-2-yl)thiourea. All substrates smoothly reacted for 2 – 5 h to give the corre-
sponding 1-(4,5-diphenylpyrimidin-2-yl)thiourea in good-to-excellent yields, and the
1
results are summarized in Table 1. All products were characterized by IR, H- and
13C-NMR spectroscopy, and elemental analysis. Single-crystal X-ray diffraction analysis
of 3a (Fig.) was used to corroborate the postulated structures unequivocally, which
added clear evidence for the structure.
In general, isoflavone 1 substituted with RO and BnO groups gave high yields. In
contrast, the presence of OH groups led to lower yields. As shown in Table 1,
isoflavones 1a – 1k (Entries 1 – 11), which do not contain OH groups, gave 3 in ca. 70%
yields. Isoflavones with one OH group at C(4’), 1l – 1o (R6 ¼ OH, Entries 12 – 15) gave
3 in only ca. 55% yields. However, when one free OH group in engaged on the
benzopyranone ring, at C(7), it would be the Oꢀ part under basic condition which
possessed stronger electron-donor quality than RO and BnO groups of the isoflavone,
and it was not favorable for the condensation of 1 with 2. Using 1p as starting material,
2-amino-4-(2,4-dihydroxyphenyl)-5-(4-methoxyphenyl)pyrimidine was obtained in-
stead of the expected product 3p (Entry 16). In a longer reaction time, 3p was
hydrolyzed, lost thioureido fragment, and was converted to 2-amino-4-(2,4-dihydroxy-
phenyl)-5-(4-methoxyphenyl)pyrimidine.

1644
Helvetica Chimica Acta – Vol. 93 (2010)
Figure. Single-crystal X-ray structure of 3a. Displacement ellipsoids are shown at the 30%-probability
level. In the case of 3a, one iPrO group is disordered.
To rationalize the mechanism of the formation of 1-(4,5-diphenylpyrimidin-2-
yl)thiourea 3 by the cyclocondensation of isoflavones 1 with amidinothiourea (2) in the
presence of MeONa, a postulated reaction course is illustrated in the Scheme. As it has
been already reported, isoflavone may undergo ring-opening reaction, when refluxing
in the presence of alkali, to form a a,b-unsaturated ketone intermediate 4 [29].
Subsequent attack of the primary amine group of the amidinothiourea (2) at the b-C-
atom of 4, followed by ring-closure reaction between secondary amine and the C¼O C-
atom, led to 3. Meanwhile, intermediate 4 at a high concentration of base may eliminate
HC(OMe)3 to generate a by-product 5 [29].
Conclusions. – In summary, a convenient method for the synthesis of substituted
pyrimidines bearing thiourea moiety at C(2) was described. The protocol was
applicable to a variety of isoflavones and amidinothiourea as starting materials and
gave 1-(4,5-biphenylpyrimidin-2-yl)thiourea in good-to-excellent yields. Efforts to
extend the scope of the method in combination with its application to the synthesis of
pharmaceutically relevant molecules are ongoing in our laboratory.
Experimental Part
General. TLC: silica-gel 60 GF254 plates (SiO2); visualization under UV light (254 nm). M.p.: X-5
Macro melting point tester; uncorrected. IR Spectra: Nicolet 170SX FT-IR spectrophotometer in KBr
pellets; n˜ in cmꢀ1. 1H- and 13C-NMR spectra: Bruker Avance 300 at 300 and 75 MHz, resp., in (D6)DMSO
unless otherwise indicated; d in ppm rel. to Me4Si as internal standard, J in Hz. X-Ray crystallography:
Bruker Smart-1000 CCD diffractometer.
General Procedure for the Synthesis of 3a – 3o (Table 1, Entries 1 – 15). The mixture of corresponding
isoflavones 1 (1 mmol), amidinothiourea 2 (3 mmol), and MeONa (3 mmol) was refluxed in MeOH

Helvetica Chimica Acta – Vol. 93 (2010)
1645
Scheme. Proposed Mechanism for the Formation of 3
(15 ml) for 2 – 5 h. All reactions were monitored by TLC, which showed the disappearance of 1 that was
indicative of the completion of the reaction. The mixture was poured into a soln. of 10% aq. HCl (40 ml),
and a yellow precipitate formed. The precipitate was filtered and washed with dist. H2O until neutrality.
The crude product was recrystallized from EtOH or purified by column chromatography (CC) on
SiO2 with CHCl3/MeOH 20 :1 to give the corresponding pure product. With 1p as starting material, 2-
amino-4-(2,4-dihydroxyphenyl)-5-(4-methoxyphenyl)pyrimidine was obtained instead of 3p (Table 1,
Entry 16).
1-{4-[2-Hydroxy-4-(1-methylethoxy)phenyl]-5-phenylpyrimidin-2-yl}thiourea (3a). Yellow solid.
M.p. 247.2 – 248.58. IR: 3370, 3188, 2978, 1623, 1571, 1526, 1422, 1357, 1324, 1262, 1194, 1110, 992, 850,
700. 1H-NMR: 1.23 (d, J ¼ 5.4, 6 H); 4.53 (m, 1 H); 6.26 (d, J ¼ 8.4, 1 H); 6.33 (s, 1 H); 6.92 (d, J ¼ 8.4,
1 H); 7.23 – 7.31 (m, 5 H); 8.60 (s, 1 H); 9.18 (s, 1 H); 10.09 (s, 1 H); 10.32 (s, 1 H); 10.89 (s, 1 H).
1H-NMR ((D6)DMSO/D2O): 1.18 (d, J ¼ 5.2, 6 H); 4.47 (m, 1 H); 6.25 (s, 1 H); 6.28 (s, 1 H); 6.88 (s,
1 H); 7.17 – 7.27 (m, 5 H); 8.55 (s, 1 H). 13C-NMR ((D6)DMSO/D2O): 21.6; 69.5; 102.9; 106.5; 115.7;
127.6; 127.9; 128.4; 129.3; 131.8; 135.9; 155.4; 156.6; 158.5; 159.8; 162.8; 180.2. Anal. calc. for C20H20N4O2S
(380.46): C 63.14, H 5.30, N 14.73; found: C 63.40, H 5.03, N 14.34.
Suitable crystals for an X-ray crystal-structure determination were obtained from EtOH.
1-[4-(2-Hydroxy-4,6-dimethoxyphenyl)-5-(4-methoxyphenyl)pyrimidin-2-yl]thiourea (3b). Yellow
solid. M.p. 238.6 – 239.38. IR: 3385, 3186, 3004, 2838, 1622, 1577, 1522, 1426, 1340, 1214, 1160, 1110,
1037, 835, 633, 565. 1H-NMR: 3.42 (s, 3 H); 3.70 (s, 3 H); 3.71 (s, 3 H); 6.01 (s, 1 H); 6.03 (s, 1 H); 6.85 (d,
J ¼ 8.4, 2 H); 7.11 (d, J ¼ 8.4, 2 H); 8.61(s, 1 H); 9.09 (s, 1 H); 9.61 (s, 1 H); 10.30 (s, 1 H); 10.66 (s, 1 H).
13C-NMR: 55.0; 55.3; 89.9; 93.8; 107.1; 113.6; 128.1; 129.1; 129.9; 156.0; 156.2; 157.6; 158.1; 158.6; 161.0;
161.4; 180.8. Anal. calc. for C20H20N4O4S (412.46): C 58.24, H 4.89, N 13.58; found: C 58.53, H 4.70, N
13.32.

1646
Helvetica Chimica Acta – Vol. 93 (2010)
1-[4-(2-Hydroxy-4-methoxyphenyl)-5-(4-methoxyphenyl)pyrimidin-2-yl]thiourea (3c). Yellow solid.
M.p. 268.1 – 269.68. IR: 3370, 3189, 2840, 1621, 1572, 1523, 1427, 1356, 1273, 1211, 1081, 1043, 843, 796, 644,
562. 1H-NMR: 3.70 (s, 3 H); 3.74 (s, 3 H); 6.32 (d, J ¼ 8.1, 1 H); 6.37 (s, 1 H); 6.89 (d, J ¼ 7.5, 2 H); 6.97 (d,
J ¼ 8.1, 1 H); 7.15 (d, J ¼ 7.5, 2 H); 8.58 (s, 1 H); 9.16 (s, 1 H); 10.10 (s, 1 H); 10.31 (s, 1 H); 10.85 (s, 1 H).
13C-NMR: 55.0; 101.7; 105.2; 114.0; 115.9; 127.3; 128.4; 129.7; 131.7; 155.5; 157.2; 158.5; 158.6; 161.5;
162.5; 180.8. Anal. calc. for C19H18N4O3S (382.44): C 59.67, H 4.74, N 14.65; found: C 59.34, H 4.92, N
14.88.
1-[4-(2-Hydroxy-4-methoxyphenyl)-5-phenylpyrimidin-2-yl]thiourea (3d). White solid. M.p. 254.8 –
255.78. IR: 3376, 3189, 2839, 1624, 1582, 1527, 1422, 1268, 1212, 1130, 1080, 1024, 963, 851, 796, 703.
1H-NMR: 3.68 (s, 3 H); 6.27 (d, J ¼ 7.9, 1 H); 6.36 (s, 1 H); 6.93 (d, J ¼ 8.2, 1 H); 7.14 – 7.29 (m, 5 H); 8.58
(s, 1 H); 9.11 (s, 1 H); 10.08 (s, 1 H); 10.28 (s, 1 H); 10.79 (s, 1 H). 13C-NMR: 55.6; 102.1; 105.7; 116.3;
126.9; 127.9; 128.0; 129.0; 132.3; 136.8; 156.2; 157.7; 159.1; 162.1; 163.1; 181.3. Anal. calc. for C18H16N4O2S
(352.41): C 61.35, H 4.58, N 15.90; found: C 61.17, H 4.76, N 15.67.
1-[4-(2-Hydroxy-4,5,6-trimethoxyphenyl)-5-(4-methoxyphenyl)pyrimidin-2-yl]thiourea (3e). White
solid. M.p. 233.8 – 234.78. IR: 3393, 3192, 2999, 2835, 1614, 1568, 1424, 1244, 1110, 1022, 834, 736.
1H-NMR: 3.43 (s, 3 H); 3.58 (s, 3 H); 3.72 (s, 3 H); 3.74 (s, 3 H); 6.25 (s, 1 H); 6.87 (d, J ¼ 8.3, 2 H); 7.19
(d, J ¼ 8.3, 2 H); 8.66 (s, 1 H); 9.13 (s, 1 H); 9.46 (s, 1 H); 10.30 (s, 1 H); 10.73 (s, 1 H). 13C-NMR: 55.1;
55.5; 60.4; 60.5; 95.7; 111.4; 113.7; 127.7; 129.4; 129.5; 134.0; 150.7; 150.8; 154.1; 155.9; 157.6; 158.8; 160.8;
180.8. Anal. calc. for C21H22N4O5S (442.49): C 57.00, H 5.01, N 12.66; found: C 57.21, H 4.79, N 12.43.
1-[4-(2-Hydroxy-4-methoxy-6-methylphenyl)-5-phenylpyrimidin-2-yl]thiourea (3f). White solid.
M.p. 289.8 – 290.78. IR: 3233, 2839, 1617, 1587, 1563, 1512, 1427, 1306, 1271, 1157, 1047, 822, 765, 702,
558. 1H-NMR: 1.83 (s, 3 H); 3.65 (s, 3 H); 6.19 (s, 1 H); 6.21 (s, 1 H); 7.19 – 7.25 (m, 5 H); 8.67 (s, 1 H);
9.08 (s, 1 H); 9.47 (s, 1 H); 10.26 (s, 1 H); 10.67 (s, 1 H). 13C-NMR: 20.0; 55.3; 99.2; 106.7; 118.3; 128.1;
128.7; 130.1; 135.9; 137.5; 156.1; 157.0; 158.7; 160.6; 164.0; 181.4. Anal. calc. for C19H18N4O2S (366.44): C
62.28, H 4.95, N 15.29; found: C 62.51, H 4.60, N 15.08.
1-{4-[3-Bromo-2-hydroxy-4-(1-methylethoxy)phenyl]-5-phenylpyrimidin-2-yl}thiourea (3g). Yellow
solid. M.p. 249.7 – 251.88. IR: 3380, 3187, 2981, 1618, 1576, 1523, 1419, 1348, 1264, 1196, 1106, 1048, 845,
700, 641. 1H-NMR: 1.28 (d, J ¼ 4.6, 6 H); 4.56 (m, 1 H); 6.52 (s, 1 H); 7.23 – 7.34 (m, 6 H); 8.62 (s, 1 H);
9.17 (s, 1 H); 10.08 (s, 1 H); 10.25 (s, 1 H); 10.31 (s, 1 H); 10.89 (s, 1 H). 13C-NMR: 22.1; 22.2; 71.7; 101.1;
103.4; 117.3; 128.1; 129.0; 132.6; 134.9; 136.5; 156.1; 156.3; 157.1; 159.1; 161.9; 181.3. Anal. calc. for
C20H19BrN4O2S (459.36): C 52.29, H 4.17, N 12.20; found: C 52.53, H 4.02, N 11.97.
1-[4-(4-Ethoxy-2-hydroxyphenyl)-5-(4-methoxyphenyl)pyrimidin-2-yl]thiourea (3h). Yellow solid.
M.p. 262.5 – 263.68. IR: 3388, 3195, 1623, 1567, 1524, 1426, 1355, 1272, 1244, 1209, 1041, 850, 800, 614.
1H-NMR: 1.29 (t, J ¼ 6.0, 3 H); 3.75 (s, 3 H); 3.97 (d, J ¼ 6.5, 2 H); 6.29 (d, J ¼ 8.0, 1 H); 6.36 (s, 1 H); 6.89
(d, J ¼ 7.7, 2 H); 6.95 (d, J ¼ 8.7, 1 H); 7.15 (d, J ¼ 7.7, 2 H); 8.57 (s, 1 H); 9.10 (s, 1 H); 10.30 (s, 1 H); 10.75
(s, 1 H). 13C-NMR: 15.0; 55.5; 63.5; 102.6; 106.0; 114.5; 116.3; 127.8; 128.9; 130.2; 132.2; 156.0; 157.8;
159.0; 159.1; 161.3; 163.0; 181.3. Anal. calc. for C20H20N4O3S (396.46): C 60.59, H 5.08, N 14.13; found: C
60.41, H 5.39, N 13.97.
1-{4-[4-(Benzyloxy)-2-hydroxyphenyl]-5-[4-(benzyloxy)phenyl]pyrimidin-2-yl}thiourea (3i). Yel-
low solid. M.p. 200.5 – 201.68. IR: 3383, 3198, 3027, 1621, 1568, 1516, 1423, 1241, 1019, 835, 735, 697.
1H-NMR: 5.05 (s, 2 H); 5.08 (s, 2 H); 6.41 (d, J ¼ 8.5, 1 H); 6.47 (s, 1 H); 6.98 (d, J ¼ 8.1, 1 H); 7.16 (d, J ¼
6.5, 2 H); 7.37 – 7.42 (m, 12 H); 8.58 (s, 1 H); 9.17 (s, 1 H); 10.12 (s, 1 H); 10.32 (s, 1 H); 10.85 (s, 1 H).
13C-NMR: 69.2; 102.6; 105.9; 114.8; 116.2; 127.3; 127.7; 127.9; 128.4; 128.6; 129.8; 131.7; 136.7; 136.9;
155.5; 157.1; 157.8; 158.5; 160.6; 162.4; 180.8. Anal. calc. for C31H26N4O3S (534.63): C 69.64, H 4.90, N
10.48; found: C 69.87, H 4.66, N 10.42.
1-{4-(2-Hydroxy-4-methoxyphenyl)-5-[4-methoxy-3,5-bis(1-methylethyl)phenyl]pyrimidin-2-yl}thio-
urea (3j). Yellow solid. M.p. 229.4 – 230.68. IR: 3446, 3239, 2963, 1623, 1574, 1522, 1419, 1212, 1076, 1010,
1
791. H-NMR: 1.05 (d, J ¼ 4.5, 12 H); 3.18 (m, 2 H); 3.65 (s, 3 H); 3.69 (s, 3 H); 6.34 – 6.40 (m, 2 H);
6.93 – 6.97 (m, 3 H); 8.68 (s, 1 H); 9.16 (s, 1 H); 9.97 (s, 1 H); 10.33 (s, 1 H); 10.80 (s, 1 H). 13C-NMR:
23.6; 25.8; 55.1; 61.9; 101.6; 105.1; 116.4; 124.4; 127.8; 131.3; 131.6; 141.0; 153.5; 155.6; 156.8; 158.2; 161.5;
162.8; 180.8. Anal. calc. for C25H30N4O3S (466.60): C 64.35, H 6.48, N 12.01; found: C 64.56, H 6.29, N
12.29.

Helvetica Chimica Acta – Vol. 93 (2010)
1647
1-{4-(2-Hydroxy-4,6-dimethoxyphenyl)-5-[4-methoxy-3,5-bis(1-methylethyl)phenyl]pyrimidin-2-
yl}thiourea (3k). White solid. M.p. 263.8 – 264.78. IR: 3393, 3278, 3138, 2960, 1618, 1587, 1513, 1219, 1153,
1106, 1067, 1039, 1011, 946, 818. 1H-NMR: 1.05 (s, 12 H); 3.16 (s, 2 H); 3.25 (s, 3 H); 3.62 (s, 3 H); 3.67 (s,
3 H); 5.96 (s, 1 H); 6.12 (s, 1 H); 6.92 (s, 2 H); 8.68 (s, 1 H); 9.10 (s, 1 H); 9.71 (s, 1 H); 10.33 (s, 1 H);
10.64 (s, 1 H). 13C-NMR: 23.6; 25.7; 55.1; 55.2; 61.9; 90.0; 94.0; 107.1; 123.8; 129.9; 131.6; 140.6; 153.5;
156.0; 156.5; 157.3; 157.8; 161.2; 161.7; 180.8. Anal. calc. for C26H32N4O4S (496.62): C 62.88, H 6.49, N
11.28; found: C 62.63, H 6.76, N 11.02.
1-[4-(2-Hydroxy-4-methoxyphenyl)-5-(4-hydroxyphenyl)pyrimidin-2-yl]thiourea (3l). Yellow solid.
M.p. 255.4 – 256.68. IR: 3373, 3160, 1623, 1568, 1531, 1424, 1358, 1263, 1082, 960, 795, 613. 1H-NMR: 3.71
(s, 3 H); 6.31 (d, J ¼ 8.4, 1 H); 6.39 (s, 1 H); 6.71 (d, J ¼ 5.3, 2 H); 6.96 (d, J ¼ 8.6, 1 H); 7.02 (d, J ¼ 8.0,
2 H); 8.55 (s, 1 H); 9.15 (s, 1 H); 9.55 (s, 1 H); 10.15 (s, 1 H); 10.31 (s, 1 H); 10.84 (s, 1 H). 13C-NMR:
55.1; 101.7; 105.1; 115.4; 115.9; 126.7; 127.6; 129.7; 131.7; 155.3; 156.9; 157.3; 158.4; 161.5; 162.4; 180.8.
Anal. calc. for C18H16N4O3S (368.41): C 58.68, H 4.38, N 15.21; found: C 58.47, H 4.53, N 15.48.
1-{4-(2-Hydroxy-4-methoxyphenyl)-5-[4-hydroxy-3,5-bis(1-methylethyl)pyrimidin-2-yl}thiourea
(3m). Yellow solid. M.p. 145.5 – 146.68. IR: 3228, 2960, 1622, 1569, 1519, 1209, 1150, 1077, 844, 796, 768.
1H-NMR: 1.01 (d, J ¼ 6.6, 12 H); 3.20 – 3.26 (m, 2 H); 3.69 (s, 3 H); 6.33 (d, J ¼ 8.5, 1 H); 6.40 (s, 1 H);
6.85 (s, 2 H); 6.93 (d, J ¼ 8.5, 1 H); 8.17 (s, 1 H); 8.65 (s, 1 H); 9.12 (s, 1 H); 9.98 (s, 1 H); 10.33 (s, 1 H);
10.76 (s, 1 H). 13C-NMR: 22.7; 25.9; 55.1; 101.6; 105.0; 116.6; 123.4; 126.8; 128.3; 131.3; 135.1; 150.2;
155.3; 156.9; 158.1; 161.4; 162.5; 180.8. Anal. calc. for C24H28N4O3S (452.57): C 63.69, H 6.24, N 12.38;
found: C 63.91, H 6.02, N 12.03.
1-[4-(2-Hydroxy-4-methoxyphenyl)-5-(4-hydroxy-3-nitrophenyl)pyrimidin-2-yl]thiourea (3n). Yel-
low solid. M.p. 254.7 – 255.98. IR: 3455, 3160, 2999, 1626, 1578, 1520, 1429, 1288, 1149, 1074, 1017, 788.
1H-NMR: 3.71 (s, 3 H); 6.35 (s, 1 H); 6.42 (d, J ¼ 8.0, 1 H); 7.04 (d, J ¼ 8.4, 1 H); 7.10 (d, J ¼ 8.4, 1 H); 7.30
(d, J ¼ 8.0, 1 H); 7.79 (s, 1 H); 8.65 (s, 1 H); 9.18 (s, 1 H); 9.96 (s, 1 H); 10.30 (s, 1 H); 10.82 (s, 1 H); 11.09
(s, 1 H). 13C-NMR: 55.1; 101.6; 105.5; 116.0; 119.1; 124.8; 125.8; 127.5; 131.7; 135.2; 136.7; 151.4; 156.0;
156.5; 158.4; 161.7; 162.7; 180.8. Anal. calc. for C18H15N5O5S (413.41): C 52.30, H 3.66, N 16.94; found: C
52.03, H 3.87, N 16.74.
1-[4-(5-Bromo-2-hydroxy-4-methoxyphenyl)-5-(3,5-dibromo-4-hydroxyphenyl)pyrimidin-2-yl]th-
iourea (3o). Yellow solid. M.p. 228.4 – 229.78. IR: 3423, 3301, 3227, 1608, 1576, 1512, 1417, 1307, 1260,
1211, 1046, 878, 739. 1H-NMR: 3.80 (s, 3 H); 6.49 (s, 1 H); 7.38 – 7.45 (m, 3 H); 8.64 (s, 1 H); 9.18 (s, 1 H);
10.08 (d, 2 H); 10.23 (s, 1 H); 10.86 (s, 1 H). 13C-NMR: 56.2; 99.5; 100.8; 111.7; 117.2; 125.4; 130.3; 132.1;
134.1; 150.1; 156.0; 156.1; 157.3; 158.3; 161.4; 180.8. Anal. calc. for C18H13Br3N4O3S (605.10): C 35.73, H
2.17, N 9.26; found: C 35.97, H 2.01, N 9.57.
2-Amino-4-(2,4-dihydroxyphenyl)-5-(4-methoxyphenyl)pyrimidine. Yellow solid. M.p. 208.7 – 209.58.
IR: 3474, 3366, 2925, 2361, 1587, 1539, 1435, 1206, 1169, 1135, 835. 1H-NMR: 3.76 (s, 3 H); 5.95 (d, 1 H);
6.21(s, 1 H); 6.74 – 6.92 (m, 5 H); 7.11 (d, 2 H); 8.13 (s, 1 H); 9.66 (s, 1 H); 12.27 (s, 1 H). 13C-NMR: 55.0;
103.2; 106.1; 111.9; 114.1; 120.5; 129.9; 130.3; 131.8; 158.2; 160.0; 160.5; 160.6; 161.8. Anal. calc. for
C17H15N3O3 (309.32): C 66.01, H 4.89, N 13.58; found: C 66.31, H 4.53, N 13.37.
X-Ray Crystal Structure of 3a (see Table 3 and Fig.)1). Diffraction data were collected on a Bruker
Smart-1000 CCD diffractometer with graphite-monochromated MoKa radiation (l 0.71073 ꢃ) using the
(w ꢀ 2q) scan technique. The structure was solved by direct methods and refined on F2 by full matrix
least-squares with the SHELXL-97 program. All non-H-atoms were refined anisotropically. All H-atoms
were treated using a riding model. The crystal used for the diffraction study showed no decomposition
i
during data collection. In the crystal structure of 3a, an PrO group (C(19), C(20), C(19’), C(20’)) was
disordered 0.50 and 0.50 occupied positions, so the bond lengths C(19)ꢀC(20) and C(19’)ꢀC(20’) were
restrained in the refinement.
1
)
The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as
deposition No. CCDC-757075. Copies of the data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/data_request/cif.

1648
Helvetica Chimica Acta – Vol. 93 (2010)
Table 3. Crystallographic Data of Compound 3a
Crystallized from
Empirical formula
Mr [g/mol]
EtOH
C20H20N4O2S
380.46
Crystal color, shape
Crystal dimensions [mm]
Temp. [K]
colorless, block
0.38 ꢁ 0.26 ꢁ 0.14
296(2)
Crystal system
Space group
Z
monoclinic
P21/c
4
Unit cell parameters:
a [ꢃ]
b [ꢃ]
14.406(3)
16.114(3)
8.6911(18)
106.674(4)
1932.7(7)
1.342
c [ꢃ]
b [8]
V [ꢃ3]
Dx [g cmꢀ3
]
Absorption coefficient [mmꢀ1
]
0.192
q Range for data collection [8]
Limiting indices
Reflections collected
2.53 – 25.04
ꢀ 10 ꢂ h ꢂ 17; ꢀ 19 ꢂ k ꢂ 17; ꢀ 10 ꢂ l ꢂ 10
9540
Independent reflections
Absorption correction
3391 [R(int) ¼ 0.0580]
none
Completeness to qmax
98.9%
Data/restraints/parameters
Goodness-of-fit on F2
3391/0/264
1.010
Final R indices [I > 2s(I)]
R indices (all data)
Largest difference peak and hole [e ꢃꢀ3
R1 ¼ 0.0507, wR2 ¼ 0.1158
R1 ¼ 0.1179, wR2 ¼ 0.1285
0.204, ꢀ 0.196
]
We thank the National Natural Science Foundation of China (No. 20772076) and the Science and
Technology Key Project of Xiꢀan of Shaanxi Province (No. CXY08019).
REFERENCES
ˇ
ˇ
ˇ
´
´
[1] T. Gazivoda, M. Sokcevic, M. Kralj, L. Suman, K. Pavelic, E. D. Clercq, G. Andrei, R. Snoeck, J.
´
´
Balzarini, M. Mintas, S. Raic-Malic, J. Med. Chem. 2007, 50, 4105.
[2] F. Xie, H. Zhao, L. Zhao, L. Lou, Y. Hu, Bioorg. Med. Chem. Lett. 2009, 19, 275.
[3] M. B. Deshmukh, S. M. Salunkhe, D. R. Patil, P. V. Anbhule, Eur. J. Med. Chem. 2009, 44, 2651.
[4] C. C. Musonda, G. A. Whitlock, M. J. Witty, R. Brun, M. Kaiser, Bioorg. Med. Chem. Lett. 2009, 19,
401.
[5] I.-J. Kang, L.-W. Wang, C.-C. Lee, Y.-C. Lee, Y.-S. Chao, T.-A. Hsu, J.-H. Chern, Bioorg. Med. Chem.
Lett. 2009, 19, 1950.
ˆ
[6] L. dos Santos, L. A. Lima, V. Cechinel-Filho, R. Correa, F. de C. Buzzi, R. J. Nunes, Bioorg. Med.
Chem. Lett. 2008, 16, 8526.
[7] S. A. Khan, N. Singh, K. Saleem, Eur. J. Med. Chem. 2008, 43, 2272.
:
[8] S. Karakus¸, S¸. G. KꢂÅꢂkgꢂzel, I. KꢂÅꢂkgꢂzel, E. De. Clercq, C. Pannecouque, G. Andrei, R. Snoeck,
F. S¸ahin, ꢄ. F. Bayrak, Eur. J. Med. Chem. 2009, 44, 3591.
[9] K. Funabiki, H. Nakamura, M. Matsui, K. Shibata, Synlett 1999, 756.
[10] A. S. Karpov, E. Merkul, F. Rominger, T. J. J. Mꢂller, Angew. Chem., Int. Ed. 2005, 44, 6951.

Helvetica Chimica Acta – Vol. 93 (2010)
[11] E. Bellur, P. Langer, Tetrahedron 2006, 62, 5426.
1649
[12] D. V. Sevenard, O. G. Khomutov, O. V. Koryakova, V. V. Sattarova, M. I. Kodess, J. Stelten, I. Loop,
E. Lork, K. I. Pashkevich, G.-V. Rçschenthaler, Synthesis 2000, 1738.
[13] N. Zanatta, M. de F. M. Cortelini, M. J. S. Carpes, H. G. Bonacorso, M. A. P. Martins, J. Heterocycl.
Chem. 1997, 34, 509.
[14] C. da C. Madruga, E. Clerici, M. A. P. Martins, N. Zanatta, J. Heterocycl. Chem. 1995, 32, 735.
[15] N. Zanatta, M. B. Fagundes, R. Ellensohn, M. Marques, H. G. Bonacorso, M. A. P. Martins, J.
Heterocycl. Chem. 1998, 35, 451.
[16] M. Soufyane, S. van den Broek, L. Khamliche, C. Mirand, Heterocycles 1999, 51, 2445.
[17] H.-B. Yu, W.-Y. Huang, J. Fluorine Chem. 1997, 84, 65.
[18] H.-B. Yu, W.-Y. Huang, J. Fluorine Chem. 1998, 87, 69.
´
´
[19] G. Agullo, L. Gamet-Payrastre, S. Manenti, C. Viala, C. Remesy, H. Chap, B. Payrastre, Biochem.
Pharmacol. 1997, 53, 1649; I. K. Wang, S. Y. Lin-Shiau, J.-K. Lin, Eur. J. Cancer 1999, 35, 1517.
[20] L. L. Fan, D. H. Zhao, M. Q. Zhao, G. Y. Zeng, Acta Pharm. Sin. 1985, 20, 647.
[21] M. J. Tikkanen, K. Wꢅhꢅlꢅ, S. Ojala, V. Vihma, H. Adlercreutz, Proc. Natl. Acad. Sci. U.S.A. 1998,
95, 3106; I. R. Record, I. E. Dreosti, J. K. McInerney, J. Nutr. Biochem. 1995, 6, 481.
[22] S. M. Potter, J. Nutr. 1995, 125, 606S; C. R. Sirtori, M. R. Lovati, C. Manzoni, M. Monetti, F.
Pazzucconi, E. Gatti, J. Nutr. 1995, 125, 598; C. Herman, H. Adlercreutz, B. R. Goldin, S. L.
Gorbach, K. A. V. Hçckerstedt, S. Watanabe, E. K. Hꢅmꢅlꢅinen, M. H. Markkanen, T. H. Mꢅkelꢅ,
K. T. Wꢅhꢅlꢅ, T. A. Hase, T. Fotsis, J. Nutr. 1995, 125, 757; Y. Ozaki, Y. Yatomi, Y. Jinnai, S. Kume,
Biochem. Pharmacol. 1993, 46, 395.
[23] J.-Y. L. Reginster, Bone Miner. 1993, 23, 223; P. C. Ruenitz, Curr. Med. Chem. 1995, 2, 791.
[24] F. Xie, S. Li, D. Bai, L. Lou, Y. Hu, J. Comb. Chem. 2007, 9, 12.
[25] W. R. Sherman, J. E. C. Taylor, Org. Synth. 1957, 37, 15.
[26] H. M. Foster, H. R. Snyder, Org. Synth. 1955, 35, 80; D. G. Crosby, R. V. Berthold, H. E. Johnson,
Org. Synth. 1963, 43, 68.
[27] Z.-T. Zhang, D.-J. Tan, D. Xue, HeIv. Chim. Acta 2007, 90, 2096.
[28] Z.-T. Zhang, F.-F. Xu, M.-X. Gao, L. Qiu, J. Comb. Chem. 2009, 11, 880.
´
[29] V. Szabo, M. Zsuga, React. Kinet. Catal. Lett. 1976, 5, 229.
Received December 5, 2009