One-step synthesis of 2,4,5-trisubstituted pyrimidines

Article abstract of DOI:10.1002/jhet.606

A simple and straightforward methodology towards the synthesis of 2,4,5-trisubstituted pyrimidines has been developed by one-step reaction of isoflavones with thiourea or guanidine. Ten 2-mercapto-4,5-diphenylpyrimidines and eight 2-amino-4,5-diphenylpyri

Full text of DOI:10.1002/jhet.606

September 2011
One-Step Synthesis of 2,4,5-Trisubstituted Pyrimidines
1073
Chuang-Jun Zhang, Wen-Yong Han, Mi-Xiang Gao,
Fei-Fei Xu, and Zun-Ting Zhang*
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, Xi’an 710062, People’s Republic of China
*E-mail: zhangzt@snnu.edu.cn
Received April 21, 2010
DOI 10.1002/jhet.606
Published online 18 May 2011 in Wiley Online Library (wileyonlinelibrary.com).
A simple and straightforward methodology towards the synthesis of 2,4,5-trisubstituted pyrimidines
has been developed by one-step reaction of isoflavones with thiourea or guanidine. Ten 2-mercapto-4,5-
diphenylpyrimidines and eight 2-amino-4,5-diphenylpyrimidines were reported. All of them were char-
acterized by FT-IR, NMR, and elemental analysis. A variety of substrates can participate in the process
with good yields and high purities, making this methodology suitable for library synthesis in drug
discovery.
J. Heterocyclic Chem., 48, 1073 (2011).
INTRODUCTION
dines. The use of combinatorial approaches to the high-
throughput synthesis of this druglike scaffold would be
a powerful advance in helping to speed up drug dis-
covery. Recently, we have reported the high-throughput
synthesis of 3,4-diarylpyrazoles, 4,5-diphenyl-2-pyrimi-
dinylguanidine and 2,3-diarylpyrimido[1,2-a]benzimida-
zole by using a one-pot reaction of hydrazine [29], bis-
guanidine [30] and 2-aminobenzimidazole [31] with iso-
flavones. Herein, we report a strategy for the preparation
of 2-mercapto-4,5-diphenylpyrimidines and 2-amino-4,5-
diphenylpyrimidines by the cyclocondensation of isofla-
vones (1) with thiourea (2a) or guanidine (2b) (Table 1).
Pyrimidines are well-known and widely investigated
six-membered nitrogen-containing heterocyclic com-
pounds that exhibit important biological activity [1–4].
Specifically, 2,4,5-trisubstituted and 2,4,6-trisubstituted
pyrimidines have shown potent anticancer activity as
BEL-7402 inhibitors [5], CDK inhibitors [6], PI-3 kinase
inhibitors [7], cytokines inhibitors [8], and Akt kinase
inhibitors [9]. Recently, it was reported that pyrimidine
derivatives bearing mercapto and amino moieties as new
candidates for the antagonism at the P2Y12 receptors
(Scheme 1) [10].
It is convenient to synthesize substituted pyrimidines
by reaction of amidines or guanidines with a, b-unsatu-
rated ketones [11,12], b-diketones [13,14], b-alkoxy and
b-aminovinyl ketones [15–18], and N-arylacetyleneic
imines [19,20]. Natural isoflavones display a wide range
of biological activities [21]. For instance, soybean isofla-
vones (daidzein and genistein) have shown pharmaco-
logical effects as antidysrhythmic [22], antioxidant [23],
and anticardio-cerebral vascular disease [24]. Ipriflavone
has been reported to be efficient for preventing and
treating osteoporosis [25]. It was reported that the chro-
mone fragment present in isoflavones can generate a
1,3-diketone equivalent which readily reacts with ami-
dines [26], guanidine [5], carbamide [27], and thioureas
[28] to form the corresponding 2-substituted pyrimi-
RESULTS AND DISCUSSION
We turned our attention to optimize the condition of
the cyclocondensations of isoflavones (1) with thiourea
(2a) and designed a process by the cyclocondensation of
40,5,7-trimethoxylisoflavone (1a) with thiourea (2a) as a
model substrate (Table 2). As shown in Table 2, we
used NaOMe as base and 3a yield was 35% (Table 2,
entry 1). It was also found that K2CO3 and triethylamine
(TEA) was ineffective in providing the desired conden-
sation product (Table 2, entries 2 and 3). A comparative
reactivity study of bases in the reaction showed that
NaOH proved to be more effective for this cycloconden-
sation (Table 2, entry 4). As it was shown, solvents
C
V
2011 HeteroCorporation

1074
C.-J. Zhang, W.-Y. Han, M.-X. Gao, F.-F. Xu, and Z.-T. Zhang
Vol 48
Scheme 1
equivalency of NaOH, it was found that that 3 equiva-
lency of NaOH gave the best results (Table 2, entry 13).
Similarly, the cyclocondensations of isoflavone 1a with
guanidine 2b (Table 3). It was demonstrated that the con-
ditions of the cyclocondensation of 1a with 2b were
NaOH 3 equiv, the ratio of 1a:2b (1:3), 95% EtOH as
solvent which gave best result (Table 3, entry 12).
MeOH, EtOH, THF, MeCN, and DMF have been
attempted, EtOH gave expected result (Table 2, entry 5).
Further study the ratio of 1a and 2a, the ratio of 1a: 2a
(1:4), the yield of 3a was good for the cyclocondensation
reaction (Table 2, entry 10). Finally, under different
With the optimized reaction conditions and proven
results in hand, the condensation of variety of structur-
ally divergent isoflavones (1) and thiourea (2a) or
Table 1
Synthesis of 2-mercapto-4,5-diphenylpyrimidine (3) and 2-amino-4,5-diphenylpyrimidine (4) by the
cyclocondensations of various isoflavones with thiourea (2a) or guanidine (2b) in EtOH.
Entry
Substrate
R1
R2
R3
R4
R5
R6
Product
Time (h)
Yield (%)a
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
OiPr
OiPr
OMe
OMe
OMe
OH
H
H
H
OMe
H
H
H
H
H
OMe
OMe
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
4.0
4.0
4.2
3.0
3.0
5.5
5.2
6.5
6.0
8.0
4.0
4.0
3.2
6.8
7.0
4.0
10.0
8.5
89
83
80
82
93
85
78
70
76
56
92
86
89
77
72
82
68
60
2
3
4
H
H
H
H
5
6
OMe
H
OMe
H
H
OMe
OMe
OH
OMe
OH
OH
iPr
H
7
8
H
H
H
H
H
9
OMe
OH
H
H
H
H
iPr
H
10
11
12
13
14
15
16
17
18
1j
3j
1a
1b
1e
1g
1h
1k
1l
OMe
OMe
OMe
OMe
OH
H
OMe
H
OMe
H
H
OMe
OMe
OMe
OH
OMe
H
4a
4b
4e
4g
4h
4k
4l
H
OMe
H
H
H
H
H
H
H
OMe
OMe
OH
H
H
Me
OH
H
H
H
iPr
OMe
OH
1m
H
4n
For details, see Experimental.
a Isolated yield after silica chromatography.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
One-Step Synthesis of 2,4,5-Trisubstituted Pyrimidines
1075
Table 2
Optimization of cyclocondensation of 40,5,7-trimethoxylisoflavone
directly dependant on the number of free hydroxyl
group present on the engaged isoflavone. Because the
hydroxyls of isoflavone 1 under basic condition would
be oxygen ions, which possess stronger electron donabil-
ity than alkoxy groups of the isoflavone, it is not favor-
able to the condensation reaction.
1a with thiourea 2a.a
To explain the mechanism for the formation of 2,4,5-tri-
substituted pyrimidines (3 or 4) by the cyclocondensation
of isoflavones (1) with thiourea (2a) or guanidine (2b) in
the presence of NaOH, a postulated reaction course was
illustrated in Scheme 2. As it was reported that isoflavone
may undergo ring opening reaction when refluxing in the
presence of alkali to form a b-diketone intermediate 5 [32].
Subsequent, attack of the primary amine group from the
sulfocarbamide (2a) or guanidine (2b) on the aldehyde car-
bon in 5, followed by ring closure reaction between sec-
ondary amine and the carbonyl carbon to produce 3 or 4.
Meanwhile, intermediate 5 at high concentration of base
may eliminate HCOOH to generate byproduct 6 [32].
Molar ratios
1a/2a/base
Yield
(%)b 3a
Entry
Solvent
Base
1
2
MeOH
MeOH
MeOH
MeOH
EtOH
THF
NaOMe
K2CO3
TEA
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
1:3:1
1:4:1
1:5:1
1:4:2
1:4:3
1:4:4
35
23
NRc
46
3
4
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
5
6
55
NRc
trace
31
7
MeCN
DMF
8
9
CONCLUSIONS
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
63
72
73
81
89
85
10
11
12
13
14
Concluding, we have developed a simple, efficient,
one-step method for the synthesis of functionalized
Table 3
Optimization of cyclocondensation of 40,5,7-trimethoxylisoflavone
1a with guanidine 2b.a
a All reaction were carried out in the appropriate solvent (15 mL) using
40,5,7-trimethoxylisoflavone (1a, 1mmol), thiourea (2a) and base until
complete disappearance of 1a ( refluxing for 4 h, TLC check).
b Isolated yield after silica chromatography.
c No reaction.
guanidine (2b) were studied to illustrate this concise and
general method for the synthesis of 2-mercapto-4,5-di-
phenylpyrimidine and 2-amino-4,5-diphenylpyrimidine.
All substrates smoothly reacted to give the correspond-
ing 2,4,5-trisubstituted pyrimidines in 3–10 h in good to
excellent yields, and the results were summarized in Ta-
Molar ratios
1a/2b/base
Yield
(%)b 5a
Entry
Solvent
Base
1
1
2
3
4
5
MeOH
MeOH
MeOH
MeOH
EtOH
EtOH
MeCN
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
NaOMe
K2CO3
TEA
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
1:3:1
1:4:1
1:3:2
1:3:3
1:3:4
39
26
NRc
50
55
61
12
26
73
67
85
92
87
ble 1. All products were characterized by IR, H-NMR,
13C-NMR , and elemental analysis.
The reaction has a general character that isoflavone 1
with various substituent such as alkoxy and alkyl groups
gave 3 or 4 in high yield. In contrast, the presence of
the more hydroxyl groups, the lower the yields. In Table
3, isoflavones 1a-1f and 1k (Table 1, entries 1–6, entries
11–13 and entry 16), which do not contain hydroxyl
groups, gave yields of 3 and 4 about 85%. Isoflavone
with one hydroxyl group, 1g–1i and 1l (Table 1, entries
7–9, entries 14–15, and entry 17) only gave yields of 3
and 4 about 75% while those with two free hydroxyls 1j
and 1m (Table 1, entry 10 and entry 18) gave yields
roughly 60%. Condensation of trihydroxyisofalvone ge-
nistein (4’,5,7-trihydroxyisoflavone) with 2a or 2b failed
to produce product 3 or 4. The yields of 3 and 4 are
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
d
6
7
8
9
10
d
d
d
11
12
d
d
13
a All reaction were carried out in the appropriate solvent (15 mL) using
40,5,7-trimethoxylisoflavone (1a, 1mmol), guanidine (2b) and base
until complete disappearance of 1a (refluxing for 4 h, TLC check).
b Isolated yield after silica chromatography.
c No reaction.
d The reaction with 95% EtOH as solvent.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1076
C.-J. Zhang, W.-Y. Han, M.-X. Gao, F.-F. Xu, and Z.-T. Zhang
Vol 48
Scheme 2. Proposed mechanism for the formation of 3a (aR ¼ ASH or NH2).
General procedure for the preparation of 2-amino-4,5-
diphenylpyrimidine (Table 1, entries 11–18). The corre-
sponding isoflavones 1 (1 mmol), guanidine hydrochloride 2b
(3 mmol) and sodium hydroxide (3, 4, and 5 mmol were used
for 0, 1, and 2 free hydroxyl of 1, respectively) was refluxed
in 95% ethanol (15 mL) for 3–10 h. All reactions were moni-
tored by TLC, which showed the disappearance of 1 that was
indicative of the reaction being complete. The reaction mixture
was added into water (30 mL) and adjusted to neutrality with
the solution of 5% HCl. A yellow precipitate appeared and
was filtered. The yellow precipitate was dissolved in a solution
of 10% HCl (15 mL) and filtered. The mother liquid was neu-
tralized with sodium hydroxide until crude product was com-
pletely precipitated. The crude product was filtered and puri-
fied by column chromatography on silica gel using chloro-
form-methanol (4:1) to give the corresponding pure product.
2-Mercapto-4-(2-hydroxy-4,6-dimethoxyphenyl)-5-(4-methox-
yphenyl)pyrimidine (3a). Yellow solid. mp 264.6–266.0ꢀC. IR
(KBr), m (cmꢁ1): 3440, 3066, 2926, 1612, 1572, 1513, 1345,
2,4,5-trisubstituted pyrimidines by the cyclocondensa-
tions of natural isoflavone and its derives with thiourea
or guanidine in good to high yield. These compounds
present a privileged core from a biological point of
view. Efforts to expand the scope of the method in com-
bination with its application to the synthesis of pharma-
ceutical molecules are ongoing in our laboratory.
EXPERIMENTAL
All other commercially obtained reagents were used as
received. The silica gel (size 200–300 mesh) used for the col-
umn chromatography was purchased from Qingdao Haiyang
Chemistry Plant (China). Thin-Layer chromatography (TLC):
silica gel 60 GF254 plate; and the eluant of column chromatog-
raphy was the mixture of chloroform and methanol. Thiourea,
guanidine, ipriflavone, daiazein, genistein, formonone, and 5-
methyl-7-methoxylisoflavone without further purification. Sub-
strate 1a and 1l are derived from genistein. Substrate 1b, 1f,
1g, 1i, and 1m are derived from daiazein. Substrates 1d is
derived from ipriflavone. Substrate 1e is derived from irisoli-
done (4’,6-dialkoxy-5,7-dihydroxyisoflavone), which was sepa-
rated from the flower of pueraria lobata by one of the authors.
Melting points were measured on X-5 micromelting point ap-
paratus and were uncorrected. IR spectra were recorded on
1
1245, 1106, 1070, 1033, 831. H-NMR (300 MHz, DMSO-d6),
d 3.70 (s, 9H), 6.00 (d, 2H), 6.82 (d, J ¼ 7.5 Hz, 2H), 7.06 (d,
J ¼ 8.1 Hz, 2H), 8.51 (s, 1H), 9.97 (s, 1H), 13.78 (s, 1H);
13C-NMR (75 MHz, DMSO-d6), d 55.1, 55.4, 55.5, 89.8, 93.4,
104.6, 113.6, 126.5, 128.9, 129.2, 133.1, 155.8, 158.7, 161.3,
162.2, 165.3, 178.1. Anal. Calcd for C19H18N2O4S: C, 61.61;
H, 4.90; N, 7.56. found C, 61.50; H, 4.72; N, 7.80.
1
2-Mercapto-4-(2-hydroxy-4-methoxyphenyl)-5-(4-methoxy-
phenyl)pyrimidine (3b). Yellow solid. mp 246.2–247.8ꢀC. IR
(KBr), m (cmꢁ1): 3441, 2923, 2838, 1600, 1537, 1453, 1322,
Fourier transform Infrared Spectrometer using KBr pellets. H-
and 13C-NMR spectra were recorded on a Bruker DRX-300
Avance spectrometer at 300 MHz in DMSO-d6 or CDCl3 with
TMS as internal standard (chemical shifts in ppm). The ele-
mental analyses were performed with an Elementar Analysen-
systeme GmbH Vario EL III.
1
1249, 1178, 833, 659, 560, 403. H-NMR (300 MHz, DMSO-
d6), d 3.72 (s, 3H), 3.76 (s, 3H), 6.21 (d, 1H), 6.38 (s, 1H),
6.95 (d, J ¼ 7.8 Hz, 3H), 7.20 (d, J ¼ 7.6 Hz, 2H), 7.80 (s,
1H), 13.40 (s, 1H), 14.02 (s, 1H); 13C-NMR (75 MHz,
DMSO- d6), d 55.1, 55.3, 101.5, 105.3, 111.9, 116.5, 121.2,
127.4, 129.7, 132.0, 156.6, 158.9, 161.6, 163.2, 164.3, 177.3.
Anal. Calcd for C18H16N2O3S: C, 63.51; H, 4.74; N, 8.23.
found C, 63.36; H, 4.71; N, 8.50.
2-Mercapto-4-(2-hydroxy-4-isopropxyphenyl)-5-phenylpyr-
imidine (3c). Yellow solid. mp 236.8–238.5ꢀC. IR (KBr), m
(cmꢁ1): 3442, 2977, 2925, 2362, 1597, 1531, 1456, 1378,
1318, 1274, 1164, 1104, 850, 551. 1H-NMR (300 MHz,
DMSO-d6), d 1.23 (d, J ¼ 5.9 Hz, 6H), 4.58 (m, 1H), 6.16 (d,
J ¼ 8.1 Hz, 1H), 6.34 (s, 1H), 6.88 (d, J ¼ 8.9 Hz, 1H), 7.27–
7.35 (m, 5H), 7.97 (s, 1H), 13.31 (s, 1H), 14.04 (s, 1H); 13C-
NMR (75 MHz, DMSO-d6), d 21.7, 69.6, 102.8, 106.7, 111.4,
General procedure for the preparation of 2-mercapto-
4,5-diphenylpyrimidine (Table 1, entries 1–10). The corre-
sponding isoflavones 1 (1 mmol), thiourea 2a (4 mmol) and
sodium hydroxide (3, 4 and 5 mmol were used for 0, 1, and 2
free hydroxyl of 1, respectively) was refluxed in ethanol (15
mL) for 3–8 h. All reactions were monitored by TLC, which
showed the disappearance of 1 that was indicative of the reac-
tion being complete. The reaction mixture was added into 5%
HCl (40 mL). A yellow precipitate appeared and was filtered.
The yellow precipitate was neutralized by washing with water
and purified by column chromatography on silica gel using
chloroform-methanol (5:1) to give the corresponding pure
product.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
One-Step Synthesis of 2,4,5-Trisubstituted Pyrimidines
1077
116.4, 121.4, 127.8, 128.5, 132.2, 156.7, 158.6, 161.4, 162.3,
164.2, 177.3. Anal. Calcd for C19H18N2O2S: C, 67.43; H,
5.36; N, 8.28. found C, 67.15; H, 5.29; N, 8.61.
22.7, 25.9, 55.3, 101.3, 105.3, 115.5, 123.3, 125.8, 131.7,
135.4, 157.0, 158.4, 160.8, 162.2, 164.5, 176.6. Anal. Calcd
for C23H26N2O3S: C, 67.29; H, 6.38; N, 6.82. found C, 67.01;
H, 6.57; N, 6.99.
2-Mercapto-4-(2-hydroxy-3-bromo-4-isopropxyphenyl)-5-
phenylpyrimidine (3d). Yellow solid. mp 236.8–238.2ꢀC. IR
(KBr), m (cmꢁ1): 3341, 2979, 2923, 1597, 1555, 1427, 1384,
2-Mercapto-4-(2,4-dihydroxyphenyl)-5-(4-hydroxyphenyl)pyri-
midine (3j). Yellow solid. mp 282.6–284.0ꢀC. IR (KBr), m
(cmꢁ1): 3837, 3793, 3646, 3395, 2914, 1608, 1552, 1389,
1241, 1163, 1044, 834. 1H-NMR (300 MHz, DMSO-d6), d
6.06 (s, 1H), 6.25 (s, 1H,), 6.87 (d, J ¼ 8.0 Hz, 2H), 7.06 (s,
1H), 7.18 (d, J ¼ 9.0 Hz, 2H), 7.85 (s, 1H); 13C-NMR (75
MHz, DMSO-d6), d 103.2, 106.9, 114.5, 115.4, 126.7, 129.5,
130.8, 131.7, 157.1, 158.4, 160.1, 163.4, 164.5, 176.2. Anal.
Calcd for C16H12N2O3S: C, 61.53; H, 3.87; N, 8.97. found C,
61.32; H, 4.02; N, 8.72.
2-Amino-4-(2-hydroxy-4,6-dimethoxyphenyl)-5-(4-methoxy-
phenyl)pyrimidine (4a). Yellow solid. mp 150.1–150.9ꢀC. IR
(KBr), m (cmꢁ1): 3458, 3367, 2970, 2933, 1632, 1540, 1455,
1346, 1236, 1188, 1150, 1092, 830, 758, 612, 575. 1H-NMR
(300 MHz, DMSO-d6), d 3.45 (s, 3H), 3.68 (s, 3H) , 3.69 (s,
3H), 5.96 (s, 1H), 5.99 (s, 1H), 6.55 (s, 2H), 6.77 (d, J ¼ 7.5
Hz, 2H), 7.03 (s, J ¼ 7.6 Hz, 2H), 8.13 (s, 1H), 9.50 (s, 1H);
13C-NMR (75 MHz, DMSO-d6), d 55.2, 55.5, 55.9, 89.6, 93.5,
108.4, 113.3, 124.7, 128.8, 129.9, 156.1, 157.5, 157.9, 158.1,
160.6, 161.4, 162.2. Anal. Calcd for C19H19N3O4: C, 64.58; H,
5.42; N, 11.89. found C, 64.26; H, 5.27; N, 12.09.
1
1326, 1265, 1158, 1105, 702. H-NMR (300 MHz, DMSO-d6),
d 1.27 (d, J ¼ 3.5 Hz, 6H), 4.63 (m, 1H), 6.51 (s, 1H), 7.13
(s, 1H), 7.28–7.38 (m, 5H), 8.00 (s, 1H), 13.26 (s, 1H), 13.43
(s, 1H); 13C-NMR (75 MHz, DMSO-d6), d 21.7, 69.5, 102.8,
106.7, 111.4, 116.4, 121.4, 127.8, 128.5, 132.2, 156.9, 158.7,
161.4 , 162.2 , 164.4, 181.2. Anal. Calcd for C19H17BrN2O2S:
C, 54.68; H, 4.11; N, 6.71. found C, 54.81; H, 4.02; N, 6.54.
2-Mercapto-4-(2-hydroxy-4,5,6-trimethoxyphenyl)-5-(4-methox-
yphenyl)pyrimidine (3e). Yellow solid. mp 278.7–279.8ꢀC. IR
(KBr), m (cmꢁ1): 3453, 3138, 2960, 2869, 1621, 1563, 1461,
1386, 1286, 1187, 1102, 945, 847, 787, 710, 565, 491. 1H-
NMR (300 MHz, DMSO- d6), d 3.76 (s, 12H), 6.03 (s, 1H),
7.07 (d, J ¼ 8.4 Hz, 2H), 7.13 (d, J ¼ 8.3 Hz, 2H), 8.48 (s,
1H); 13C-NMR (75 MHz, DMSO-d6), d 55.0, 55.2, 55.8, 56.0,
90.3, 93.7, 105.6, 114.1, 127.1, 128.0, 129.6, 132.0, 156.0,
158.8, 161.8, 162.8, 165.8, 176.9. Anal. Calcd for
C20H20N2O5S: C, 59.99; H, 5.03; N, 7.00. found C, 60.31; H,
5.13; N, 6.72.
2-Mercapto-4-(2-hydroxy-4-methoxyphenyl)-5-(3,5-diisopropyl-
4-methoxyphenyl)pyrimidine (3f). Yellow solid. mp 238.6–
240.0ꢀC. IR (KBr), m (cmꢁ1): 3739, 3436, 2960, 2922, 1641,
1591, 1435, 1296, 1205, 1160, 1024, 841. 1H-NMR (300
MHz, DMSO-d6), d 1.02 (d, J ¼ 4.3 Hz, 12H), 3.22 (m, 2H),
3.77 (s, 3H), 3.83 (s, 3H), 6.23 (d, J ¼ 6.9 Hz, 1H), 6.64 (s,
1H), 6.84 (s, 2H), 6.95 (d, J ¼ 7.7 Hz, 1H), 7.96 (s, 1H); 13C-
NMR (75 MHz, DMSO- d6), d 22.8, 26.0, 55.1, 55.3, 101.5,
105.6, 112.0, 114.2, 121.4, 127.6, 129.7, 132.0, 157.3, 158.9,
162.1, 163.6, 164.9, 178.2. Anal. Calcd for C24H28N2O3S: C,
67.90; H, 6.65; N, 6.60. found C, 67.60; H, 6.46; N, 6.83.
2-Mercapto-4-(2-hydroxy-4-methoxyphenyl)-5-(4-hydroxyphe-
nyl)pyrimidine (3g). Yellow solid. mp 248.6–249.8ꢀC. IR (KBr),
m (cmꢁ1): 3411, 3250, 3151, 2937, 2833, 1596, 1462, 1496,
2-Amino-4-(2-hydroxy-4-methoxyphenyl)-5-(4-methoxyphe-
nyl)pyrimidine (4b). Yellow solid. mp 156.5–157.2ꢀC. IR
(KBr), m (cmꢁ1): 3410, 3318, 3192, 2924, 1629, 1616, 1589,
1
1485, 1442, 1382, 1247, 1181, 1156, 679, 614, 558. H-NMR
(300 MHz, DMSO- d6), d 3.70 (s, 3H), 3.76 (s, 3H), 6.14 (d, J
¼ 8.7 Hz, 1H), 6.37 (s, 1H), 6.85-6.92 (m, 5H), 7.11 (d, 2H, J
¼ 8.4 Hz), 8.22 (s, 1H), 12.29 (s, 1H); 13C-NMR (75 MHz,
DMSO-d6), d 55.0, 55.7, 101.6, 104.8, 114.1, 121.3, 129.7,
129.8, 131.6, 158.2, 159.0, 160.1, 160.5, 161.3, 161.9. Calcd
for C18H17N3O3: C, 66.86; H, 5.30; N, 13.00. found C, 67.09;
H, 5.16; N, 13.35.
2-Amino-4-(2-hydroxy-4,5,6-trimethoxyphenyl)-5-(4-methoxy-
phenyl)pyrimidine (4e). Yellow solid. mp 234.5–235.6ꢀC. IR
(KBr), m (cmꢁ1): 3485, 3341, 2985, 2937, 2832, 1615, 1584,
1469, 1459, 1250, 1203, 1183, 1117, 1038, 992, 942, 845,
1
1248, 1095, 817, 557. H-NMR (300 MHz, DMSO-d6), d 3.73
(s, 3H), 6.24 (d, J ¼ 7.0 Hz, 1H), 6.39 (s, 1H), 6.74 (d, J ¼ 7.7
Hz, 2H), 6.97 (d, J ¼ 8.4 Hz, 1H,), 7.04 (d, J ¼ 7.4 Hz, 2H),
7.83 (s, 1H); 13C-NMR (75 MHz, DMSO-d6), d 55.1, 101.5,
105.5, 111.9, 115.6, 121.7, 125.6, 129.7, 132.1, 157.0, 158.4,
160.8, 163.0, 164.6, 176.8. Anal. Calcd for C17H14N2O3S: C,
62.56; H, 4.32; N, 8.58. found C, 62.85; H, 4.53; N, 8.37.
1
833. H-NMR (300 MHz, DMSO-d6), d 3.43 (s, 3H), 3.57 (s,
3H), 3.69 (s, 3H), 3.71 (s, 3H), 6.21 (s, 1H), 6.56 (s, 2H), 6.78
(d, J ¼ 8.3 Hz, 2H), 7.10 (d, J ¼ 8.3 Hz, 2H), 8.19 (s, 1H),
9.21 (s, 1H); 13C-NMR (75 MHz, DMSO-d6), d 54.9, 55.2,
55.5, 60.3, 95.5, 113.4, 124.3, 129.1, 129.5, 134.1, 150.7,
150.8, 153.2, 157.5, 158.0, 161.1, 162.2. Calcd for
C20H21N3O5: C, 62.65; H, 5.52; N, 10.96. found C, 62.86; H,
5.31; N, 10.67.
2-Mercapto-4-(2,4-dihydroxyphenyl)-5-(4-methoxyphenyl)pyr-
imidine (3h). Yellow solid. mp 259.7–261.5ꢀC. IR (KBr), m
(cmꢁ1): 3307, 2923, 2841, 1600, 1555, 1516, 1389, 1248, 1179,
1
856, 831, 792, 557. H-NMR (300 MHz, DMSO-d6), d 3.76 (s,
2-Amino-4-(2-hydroxy-4-methoxyphenyl)-5-(4-hydroxyphenyl)-
pyrimidine (4g). Yellow solid. mp 293.3–294.4ꢀC. IR (KBr), m
(cmꢁ1): 3474, 3366, 2924, 1638, 1587, 1539, 1479, 1435,
1378, 1265, 1243, 1206, 1135, 835. 1H-NMR (300 MHz,
DMSO-d6), d 3.70 (s, 3H), 6.13 (d, J ¼ 8.6 Hz, 1H), 6.37 (s,
1H), 6.73 (d, J ¼ 8.0 Hz, 2H), 6.87–7.00 (m, 5H), 8.14 (s,
3H), 6.14 (d, 1H), 6.28 (s, 1H), 6.91 (d, 1H), 6.94 (d, 2H), 7.16
(d, 2H), 7.80 (s, 1H); 13C-NMR (75 MHz, DMSO- d6), d 55.3,
101.5, 105.6, 112.4, 115.5, 125.7, 129.7, 132.1, 157.0, 158.3,
160.9, 163.0, 164.8, 176.8. Anal. Calcd for C17H14N2O3S: C,
62.56; H, 4.32; N, 8.58. found C, 62.32; H, 4.17; N, 8.80.
2-Mercapto-4-(2-hydroxy-4-methoxyphenyl)-5-(3,5-diisopropyl-
4-hydroxyphenyl)pyrimidine (3i). Yellow solid. mp 241.3–
242.8ꢀC. IR (KBr), m (cmꢁ1): 3436, 2962, 1651, 1568, 1462,
1290, 1188, 1046, 831, 783, 712, 478. 1H-NMR (300 MHz,
DMSO-d6), d 1.09 (d, 12H), 3.21 (m, 2H), 3.70 (s, 3H), 6.24
(d, J ¼ 6.0 Hz, 1H), 6.38 (s, 1H), 6.83 (s, 2H), 6.93 (d, J ¼
8.1 Hz, 1H), 7.94 (s, 1H); 13C-NMR (75 MHz, DMSO-d6), d
1
1H), 9.44 (s, 1H), 12.56 (s, 1H); H-NMR (300 MHz, DMSO-
d6 þ D2O), d 3.71 (s, 3H), 6.18 (d, J ¼ 8.7 Hz, 1H), 6.38 (s,
1H), 6.75 (d, J ¼ 8.2 Hz, 2H), 6.90 (d, J ¼ 8.7 Hz, 1H), 6.99
(d, J ¼ 8.1 Hz, 2H), 8.15 (s, 1H); 13C-NMR (75 MHz,
DMSO-d6 þ D2O), d 55.0, 101.5, 104.8, 113.9, 115.5, 121.5,
128.2, 129.9, 131.6, 156.0, 159.1, 160.1, 160.3, 161.3, 161.8.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1078
C.-J. Zhang, W.-Y. Han, M.-X. Gao, F.-F. Xu, and Z.-T. Zhang
Vol 48
[4] Musonda, C. C.; Whitlock, G. A.; Witty, M. J.; Brun, R.;
Kaiser, M. Bioorg Med Chem Lett 2009, 19, 401.
Calcd for C17H15N3O3: C, 66.01; H, 4.89; N, 13.58. found C,
65.83; H, 5.05; N, 13.25.
[5] Xie, F. C.; Zhao, H. B.; Zhao, L. Z.; Lou, L. G.; Hu, Y. H.
Bioorg Med Chem Lett 2009, 19, 275.
2-Amino-4-(2,4-dihydroxyphenyl)-5-(4-methoxyphenyl)pyri-
midine (4h). Yellow solid. mp 297.3–298.5ꢀC. IR (KBr), m
(cmꢁ1): 3441, 3337, 1629, 1577, 1540, 1455, 1395, 1336,
[6] Georg, D.; Frank, H.; Helmut, W.; Alexander, P.; Anthony
S. P.; Bernd, K.; Gisela, S.; Martin, S.; Martin, L.; Andreas, S.; Stef-
fen, S.; Walter, S. PCT Int Appl, WO 2003032997 A1, 2003.
[7] Martin, P. PCT Int Appl WO 2006005918 A1, 2006.
[8] Srinivas, A. S. S. V.; Tadiparthi, R.; Sharma, G. V. R.;
Thirunavukkarasu, S.; Bhakiaraj, D. P.; Kachhadia, V.; Narsimhan, K.;
Thara, S. N.; Rajagopal, S.; Reddy, G.; Narayanan, S.; Parameswaran,
V.; Janarthanam, V. US 20070167413 A1, 2007.
1
1287, 1247, 1207, 1178, 1037, 829, 799. H-NMR (300 MHz,
DMSO-d6), d 3.76 (s, 3H), 5.95 (d, J ¼ 8.3 Hz, 1H), 6.21 (s,
1H), 6.75 (d, J ¼ 8.6 Hz, 1H), 6.89–6.92 (m, 4H), 7.11 (d, J
¼ 8.2 Hz, 2H), 8.13 (s, 1H), 9.66 (s, 1H), 12.27 (s, 1H); 13C-
NMR (75 MHz, DMSO-d6), d 55.0, 103.2, 106.1, 111.9,
114.1, 120.5, 129.9, 130.3, 131.8, 158.2, 159.9, 160.0, 160.5,
160.6, 161.8. Calcd for C17H15N3O3: C, 66.01; H, 4.89; N,
13.58. found C, 66.27; H, 4.62; N, 13.39.
[9] Bilodeau, M. T.; Chua, P. C.; Cosford, N. D. P.; Hoffman,
J. M.; Nagasawa, J. PCT Int Appl,WO 2005100344 A1, 2005.
[10] Crepaldi, P.; Cacciari, B.; Bonache, M. C.; Spalluto, G.;
Varani, K.; Borea, P. A.; Ku¨gelgen, I. von; Hoffmann, K.; Pugliano,
M.; Razzari, C.; Cattaneo, M. Bioorg Med Chem 2009, 17, 4612.
[11] Funabiki, K.; Nakamura, H.; Matsui, M.; Shibata, K. Synlett
1999, 756.
2-Amino-4-(2-hydroxy-4-methoxy-6-methylphenyl)-5-phenyl-
pyrimidine (4k). White solid. mp 148.2–149.1ꢀC. IR (KBr), m
(cmꢁ1): 3474, 3275, 3126, 2958, 2920, 1625, 1581, 1536, 1460,
1
1340, 1195, 1147, 1036, 843, 812, 761, 700, 625, 555. H-NMR
(300 MHz, DMSO-d6), d 1.81 (s, 3H), 3.64 (s, 3H), 6.16 (s,
1H), 6.18 (s, 1H), 6.65 (s, 2H), 7.15-7.18 (m, 5H), 8.23 (s, 1H),
9.29 (s, 1H); 13C-NMR (75 MHz, DMSO-d6), d 19.4, 54.7,
98.3, 105.7, 115.9, 119.2, 124.6, 126.9, 127.6, 128.3, 136.7,
155.2, 157.8, 159.3, 162.3, 163.9. Calcd for C18H17N3O2: C,
70.34; H, 5.58; N, 13.67. found C, 70.62; H, 5.85; N, 13.31.
2-Amino-4-(2,6-dihydroxy-4-methoxyphenyl)-5-(4-methoxy-
phenyl)pyrimidine (4l). Red solid. mp 136.5–137.2ꢀC. IR
(KBr), m (cmꢁ1): 3496, 3372, 3219, 1621, 1541, 1464, 1437,
[12] Karpov, A. S.; Merkul, E.; Rominger, F.; Mu¨ller, T. J. J.
Angew Chem Int Ed 2005, 44, 6951.
[13] Bellur, E.; Langer, P. Tetrahedron 2006, 62, 5426.
[14] Sevenard, D. V.; Khomutov, O. G.; Koryakova, O. V.; Sat-
tarova, V. V.; Kodess, M. I.; Stelten, J.; Loop, I.; Lork, E.; Pashke-
¨
vich, K. I.; Roschenthaler, G.-V. Synthesis 2000, 1738.
[15] Zanatta, N.; Cortelini, M. de F. M.; Carpes, M. J. S.; Bona-
corso, H. G.; Martins, M. A. P. J Heterocycl Chem 1997, 34, 509.
[16] Madruga, C. da C.; Clerici, E.; Martins, M. A. P.; Zanatta,
N. J Heterocycl Chem 1995, 32, 735.
1
1362, 1285, 1247, 1181, 1156, 1056, 830, 816, 556. H-NMR
(300 MHz, CDCl3), d 3.72 (s, 3H), 3.75 (s, 3H), 5.14 (s, 2H),
5.95 (s, 2H), 6.80 (d, J ¼ 8.2 Hz, 2H), 7.12 (d, J ¼ 8.2 Hz,
2H), 8.24 (s, 1H); 13C-NMR (75 MHz, CDCl3), d 54.7, 57.9,
94.6, 103.9, 113.8, 124.2, 128.2, 128.9, 156.3, 158.5, 159.6,
160.0, 160.4, 162.4. Calcd for C18H17N3O4: C, 63.71; H, 5.05;
N, 12.38. found C, 63.49; H, 5.32; N, 12.57.
2-Amino-4-(2,4-dihydroxyphenyl)-5-(3,5-diisopropyl-4-hydrox-
yphenyl)pyrimidine (4m). Yellow solid. mp 297.8–298.9ꢀC. IR
(KBr), m (cmꢁ1): 3564, 3471, 3354, 3230, 2962, 2600, 1635,
1595, 1576, 1542, 1490, 1456, 1405, 1351, 1252, 1286, 1271,
1202, 984, 880, 833, 814. 1H-NMR (300 MHz, DMSO-d6), d
1.06 (d, J ¼ 6.7 Hz, 12H), 3.26 (m, 2H), 5.92 (d, J ¼ 8.0 Hz,
1H), 6.21 (s, 1H), 6.73 (d, J ¼ 8.6 Hz, 1H), 6.80 (s, 2H), 6.86
(s, 2H), 8.07 (s, 1H), 8.17 (s, 1H), 9.62 (s, 1H), 12.32 (s, 1H);
13C-NMR (75 MHz, DMSO-d6), d 22.8, 26.0, 103.1, 105.8,
112.1, 121.5, 123.6, 128.9, 131.7, 135.4, 149.6, 159.8, 159.9,
160.2, 160.3, 161.7. Calcd for C22H25N3O3: C, 69.64; H, 6.64;
N, 11.07. found C, 69.88; H, 6.42; N, 11.29.
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Bonacorso, H. G.; Martins, M. A. P. J Heterocycl Chem 1998, 35, 451.
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Remesy, C.; Chap, H.; Payrastre, B. Biochem Pharmacol 1997, 53, 1649;
(b) Wang, I. K.; Lin-Shiau, S. Y.; Lin, J. K. Eur J Cancer 1999, 35, 1517.
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Pharmacol Sin 1985, 20, 647.
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Adletcteutr, H. Proc Natl Acad Sci USA 1998, 95, 3106; (b) Record,
I. R.; Dreosti, I. E.; McInerney, J. K. J Nutr Biochem 1995, 6, 481.
[24] (a) Potter, S. M. J Nutr 1995, 125, 606; (b) Sirtori, C. R.; Lovati,
M. R.; Manzoni, C.; Monetti, M.; Pazzucconi, F.; Gatti, E. J Nutr 1995,
125, 598; (c) Adlercreutz, H.; Goldin, B. R.; Gorbach, S. L.; Hockerstedt,
K. A. V.; Watanabe, S.; Hamalainen, E. K.; Markkanen, M. H.; Makela, T.
H.; Wahala, K. T.; Hase, T. A.; Fotsis, T. J Nutr 1995, 125, 757; (d) Ozaki,
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Acknowledgments. This research was supported by the National
Natural Science Foundation of China (No. 20772076) and the
Fundamental Research Funds for Central Universities (No.
GK200901010).
[26] Xie, F. C.; Li, S. K.; Bai, D. L.; Lou, L. G.; Hu, Y. H.
J Comb Chem 2007, 9, 12.
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Crosby, D. G.; Berthold, R. V.; Johnson, H. E. Org Synth 1963, 43, 68.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet