An efficient one-pot synthesis of diarylpyrazolo[1,5-a]pyrimidine from isoflavones

Article abstract of DOI:10.1002/jhet.546

Direct synthetic methods of 6,7-diphenylpyrazolo[1,5-a]pyrimidine derivatives have been developed. Cyclocondensation of isoflavones with 3-aminopyrazole in the presence of sodium methoxide as alkali promoter gave 6,7-diphenylpyrazolo[1,5-a]pyrimidines in

Full text of DOI:10.1002/jhet.546

March 2011
An Efficient One-Pot Synthesis of Diarylpyrazolo
[1,5-a]pyrimidine from Isoflavones
279
Zun-Ting Zhang,* Yu-Qing Ma, Yong Liang, Dong Xue, and Qing He
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 January 20, 2010
DOI 10.1002/jhet.546
Published online 19 November 2010 in Wiley Online Library (wileyonlinelibrary.com).
Direct synthetic methods of 6,7-diphenylpyrazolo[1,5-a]pyrimidine derivatives have been developed.
Cyclocondensation of isoflavones with 3-aminopyrazole in the presence of sodium methoxide as alkali
promoter gave 6,7-diphenylpyrazolo[1,5-a]pyrimidines in moderate to good yields.
J. Heterocyclic Chem., 48, 279 (2011).
INTRODUCTION
RESULTS AND DISCUSSION
Pyrazolo[1,5-a]pyrimidine, although virtually unknown
as natural products, are an important pharmaceutical tar-
gets (Scheme 1) [1]. They and related fused heterocycles
are of interest as potential bioactive molecules. Pyra-
zolo[1,5-a]pyrimidines exhibited biological activities,
such as cSRC kinase inhibitors involved with ischemic
brain pathology [2], cyclin dependent kinase 1 inhibitor
[3], HIV reverse transcriptase inhibitors [4], CCR1 antag-
onists [5], protein kinase inhibitors [6], cGMP degrada-
tion inhibitors, or herbicidal and fungicidal activities [7].
Numerous methods for the synthesis of pyrazolo[1,5-
a]pyrimidine have been reported in the last 20 years, which
involved the reaction between aminopyrazoles and 1,3-bise-
lectrophilic compounds, such as b-dicarbonyl, alkoxymeth-
ylene-b-dicarbonyl [8], and b-enaminone compounds [9]. It
was reported that the chromone fragment present in isofla-
vones can generate a 1,3-diketone equivalent which readily
react with amidines [10], guanidine [11], sulfocarbamides
[12], and hydrazine [13] to form the corresponding 2-substi-
tuted pyrimidines and diarylpyrazoles. Recently, we have
reported the high-throughput synthesis of 3,4-diarylpyra-
zoles, 4,5-biphenyl-2-pyrimidinylguanidine and 2, 3-diary-
lpyrimido[1,2-a] benzimidazole by using one-step reaction
of hydrazine [14], biguanidine [15], and 2-aminobenzimi-
dazole [16] with isoflavones respectively. Herein, we report
a new strategy for the preparation of the unknown class of
6,7-diphenylpyrazolo [1,5-a]pyrimidines from isoflavones.
We designed the cyclocondensation of isoflavone 1,
which can generate a 1,3-dicarbonal equivalent in the
presence of alkali, with 3-aminopyrazoles 2 to synthe-
size 6,7-diphenylpyrazolo[1,5-a]pyrimidines 3 (Scheme
2). Thus, treatment of ipriflavone (7-isopropoxyisofla-
vone) 1a with 3-aminopyrazole 2 (1.1 equiv) in refluxed
ethanol in the presence of sodium hydroxide (3 equiv)
for 12 h afforded 6-phenyl-7-(2-hydroxy-4-isopropoxy-
phenyl) pyrazolo[1,5-a]pyrimidine 3a [38%] (Table 1,
entry 1). We then turned our attention to optimize the
conditions of the cyclocondensations between isoflavone
1a and 3-aminopyrazole 2 (Table 1). Thus when NaOH
(5M) was used as base, 3a obtained in 38% yield (entry
1). It was also found that Et3N was ineffective in provid-
ing the desired condensation product (entry 2). A compar-
ative reactivity study of bases in the reaction showed that
NaOMe proved to be most effective for the cycloconden-
sation (entry 3). Further study with varying NaOMe
equivalents revealed that 3.0 equiv of base is necessary
to obtain a high yield of 3a (entries 3–6). MeOH was a
solvent of choice, since reactions in THF, DMF, or EtOH
gave lower yields (entries 6–10). Compound 3a was
obtained in high yield when ratio of 1a:2 (1:1.3) were
used (entry 12).
Next, the condensation of a variety of structurally di-
vergent isoflavones 1 with 2 were performed to illustrate
this concise and general method for the synthesis of 3.
C
V
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280
Z.-T. Zhang, Y.-Q. Ma, Y. Liang, D. Xue, and Q. He
Vol 48
Scheme 1
reported [17], isoflavone may undergo ring opening
reaction in the presence of alkali to form a a,b-unsatu-
rated ketone intermediate 5 (Scheme 3). Attack of the
primary amine group from the 3-aminoprazole 2 on the
b-carbon in 5, followed by the ring closure reaction
between produce 3. Additionally, the choice of base is
very important for the cyclocondensations of aminopyra-
zoles with isoflavone. Intermediate 5 was showed to
undergo conversion to ketone 6 [18] at high concentra-
tion of base by elimination of HC(OMe)3 molecule. On
the other hand, the isoflavone ring would be hard to
open and produce intermediate 5 in the lower concentra-
tion of base.
The wide range of isoflavones (1a–1t) reacted efficiently
with 2 under the basic conditions to afford the respec-
tive products 3 (12–45 h) in moderate to excellent yields
(Table 2). All products were characterized by IR,
1H-NMR, 13C-NMR, MS, and elemental analysis. Single
crystal X-ray diffraction analysis of 3a (Fig. 1) was
used to corroborate the postulated structures unequivo-
cally, which added additional evidence for the structures
identification. The reaction has a general character and
isoflavone 1 with various substituent on the both aryl
rings (e.g. alkoxy groups) gave 3 in high yields (Table
2). The yields, however, decrease when the number of
the hydroxyl group on the aryl rings increase. For exam-
ple, isoflavones, 1a, 1b, 1d, 1f, 1i, 1k, 1l, 1m, 1q, and
1t (Table 2, entries 1, 2, 4, 6, 9, 11–13, 17, 20), which
do not contain hydroxyl group gave 3 in about 80%
yields. Isoflavone with one hydroxyl group, 1c, 1e, 1j,
1o, and 1s ( Table 2, entries 3, 5, 10, 15, 19) afforded 3
in about 65% yield while isoflavone with two free
hydroxyl groups such as 1g and 1h (Table 2, entries 7,
8) gave desired products in about 60% yields. Consider-
ation of Genistein (40,5,7-trihydroxyisoflavon) (Table 2,
entry 14 ) with 2 produced 3n (45%) was well but in
lower yield.
CONCLUSIONS
In summary, we have developed a useful method for
the construction of fused 6,7-diphenylpyrazolo[1,5-a] pyr-
imidines derivatives by the cyclocondensation of 3-ami-
nopyrazole with isoflavone in methanol and the presence
of sodium methoxide. It is an efficient and regioselective
approach toward the synthesis 6,7-diphenylpyrazolo[1,5-
a]pyrimidines. The yields of pyrazolo[1,5-a] pyrimidine
derivatives are excellent, most between 70–80%. On the
basis of the present investigation, we are now carrying
out research on the applications of 6,7-diphenylpyra-
zolo[1,5-a] pyrimidines in pharmacology.
EXPERIMENTAL
Melting points were measured on X-5 micro melting point
apparatus, which is uncorrected. IR spectra were recorded on
1
Fourier transform Infrared Spectrometer. The H-NMR spectra
were recorded at 300.00 MHz on Bruker DRX-300 Advance
spectrometer; chemical shifts (d scale) are reported in parts per
million (ppm) downfield from Me4Si which was used as the
internal standard for all NMR spectra. 1H-NMR spectra are
reported in order: multiplicity and approximate coupling con-
stant (J value) in hertz (Hz), number of protons; signals were
characterized as s (singlet), d (doublet), t (triplet), m (multip-
let), and br s (broad signal). The 13C-NMR spectra were
recorded at 75.00 MHz; chemical shifts (d scale) are reported
in parts per million (ppm). The MS instrument is LTQ ESI-
MS. The elemental analyses were performed with an Elemen-
tar Analysensyteme GmbH Vario EL III. All the products are
The yields of 3 are directly dependant on the number
of free hydroxyl group present on the engaged isofla-
vone. Because the hydroxyls at isoflavones 1 under the
basic conditions would be oxyanions, which possess
stronger electron donability than alkoxy and benzyoxyl
groups, they might prevent condensation of the reaction.
Further experimentation and mechanistic studies are
required to fully understand the regioselective of the
cyclocondensation of isoflavone 1 with pyrazoles 2. As
Scheme 2. The designed cyclocondensation route of isoflavones 1 with aminopyrazoles 2.
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An Efficient One-Pot Synthesis of Diarylpyrazolo[1,5-a]pyrimidine from Isoflavones
281
Table 1
Optimization of cyclocondensation of isoflavone 1a with 3-aminepyrazole 2a.
Entry
Solvent
Base
Molar ratios (eq.) 1a/2/base
3a Yield/%b
1c
2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
NaOH
Et3N
1/1.1/3
1/1.1/3
1/1.1/2
1/1.1/3
1/1.1/4
1/1.1/5
1/1.1/3
1/1.1/3
1/1.2/3
1/1.3/3
1/1.4/3
1/1.5/3
38
0
3
4
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
53
70
64
45
30
25
75
88
85
89
5
6
7
8d
9
DMF
MeOH
MeOH
MeOH
MeOH
10
11
12
a All reactions were carried out with isoflavone 1a (2 mmol) and 3-aminopyrazole 2 and different kind of base until the formation in appropriate
solvents (20 mL) was completed as monitored by TLC(24 h, refluxing).
b Isolated yield based on isoflavone.
c Reactions with EtOH, MeOH, and THF as solvent were carried out under the boiling point.
d The reaction with DMF as solvent was carried at 100ꢀC.
new compounds, which were characterized by IR, 1H-NMR,
and 13C-NMR spectra. X-Ray crystallography dates were given
by Bruker Smart-1000 CCD diffactometer. All other commer-
cially obtained reagents were used as received. Thin-layer
chromatography (TLC): silica gel 60 GF254 plate; and the
eluant of column chromatography is the mixture of petroleum
ether and ethyl acetate at volume ratio of 1:1.
(s, 1H), 8.61 (s, 1H), 9.73 (s, 1H); 13C-NMR [75 MHz,
DMSO-d6/TMS, d (ppm)]: 21.8, 69.3, 96.1, 102.7, 106.2,
110.3, 122.1, 127.3, 128.2, 129.3, 131.6, 135.3, 142.6, 144.3,
147.7, 150.5, 156.9, 159.7. ESI-MS: m/z (rel intensity) 368
(MþNa, 52), 346 (M þ 1, 100). Anal. Calcd for C21H19N3O2:
C, 73.03; H, 5.54; N, 12.17. Found C, 73.10; H, 5.58; N,
12.20.
General procedure for the synthesis of diarylpyra-
zolo[1,5-a]pyrimidine 3. The isoflavone 1a–1t (2 mmol), 3-
aminepyrazol 2 (2.6 mmol), and sodium methoxide (6, 8, 10,
and 12 mmol were used for 0, 1, 2, and 3 free hydroxyl group
of 1) were refluxed in methanol (40 mL) for 12–45 h. All
reactions were monitored by TLC, which showed the disap-
pearances of the starting materials. The reaction mixture was
then concentrated to 10 mL by using rotary evaporator, the
condensate was poured into a 10% HCl (15 mL) and a light
yellow precipitate formed. This precipitate was collected by
filtration and washed with distilled water until the pH value of
the filtrate was 7. Finally, the precipitate was recrystallized
from absolute ethanol or purified on silica gel column chroma-
tography (CHCl3:CH3OH ¼ 20:1), 3 were obtained.
6-Phenyl-7-(2-hydroxyl-4-methoxy-6-methyphenyl)pyra-
zolo[1,5-a]pyrimidine (3b). m. p. 242.0–242.2ꢀC; IR (KBr),
m (cmꢁ1): 3489, 3240, 3172, 3056, 2997, 1595, 1513, 1453,
1335, 1283, 1197, 1160, 1132, 1039, 831; 1H-NMR [300
MHz, DMSO-d6/TMS, d (ppm)]: 1.71 (s, 3H), 3.72 (s, 3H),
6.28 (s, 2H), 6.81 (d, J ¼ 1.9 Hz, 1H), 7.32 (s, 5H), 8.13 (d,
J ¼ 1.9 Hz, 1H), 8.63 (s, 1H), 9.71 (s, 1H); 13C-NMR [75 MHz,
DMSO-d6/TMS, d (ppm)]: 19.0, 54.9, 96.1, 98.7, 106.2, 110.7,
122.6, 127.6, 128.2, 128.8, 135.3, 138.2, 141.9, 144.4, 147.7,
150.4, 156.6, 160.9. EIMS: m/z (rel intensity) 354 (MþNa, 38),
332 (M þ 1, 100). Anal. Calcd for C20H17N3O2: C, 72.49; H,
5.173; N, 12.68; Found C, 72.55; H, 5.21; N, 12.72.
6-(4-Methoxyphenyl)-7-(2,4-dihydroxylphenyl)pyrazolo[1,5-
a]pyrimidine (3c). m. p. 245.0–245.7ꢀC; IR (KBr), m (cmꢁ1):
3142, 2958, 2836, 1709, 1605, 1506, 1458, 1209, 1238, 1179,
836; 1H-NMR [300 MHz, DMSO-d6/TMS, d (ppm)]: 3.73 (s,
3H,), 6.22 (d, J ¼ 8.2 Hz, 2H), 6.35 (s, 1H), 6.76 (s, 1H), 6.86
(d, 2H), 7.22 (d, J ¼ 8.2Hz, 2H), 8.10 (s, 1H), 8.57 (s, 1H),
6-Phenyl-7-(2-hydroxyl-4-isopropoxyphenyl)pyrazolo[1,5-
a]pyrimidine(3a). m. p. 248–250ꢀC; IR (KBr), m (cmꢁ1):
3314, 2977, 1684, 1610, 1519, 1423, 1386, 1235, 1113, 993,
1
837, 796, 699; H-NMR [300 MHz, DMSO-d6/TMS, d (ppm)]:
1.26 (d, 6H), 4.53 (m, 1H), 6.35 (d, J ¼ 8.4 Hz, 1H), 6.40 (s,
9.54 (s, 1H), 9.56 (s, 1H); 13C-NMR [75 MHz, DMSO-d6
/
1H), 6.80 (s, 1H), 6.96 (d, J ¼ 8.4 Hz, 1H), 7.31 (s, 5H), 8.14
TMS, d (ppm)]: 55.5, 96.5, 103.1, 107.1, 109.6, 114.2, 122.2,
Journal of Heterocyclic Chemistry
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Z.-T. Zhang, Y.-Q. Ma, Y. Liang, D. Xue, and Q. He
Vol 48
Table 2
Synthesis of 6,7-diphenylpyrazolo[1,5-a]pyrimidines 3 by the cyclocondensations of aminopyrazoles 2 with isoflavones 1a.
Product/yieldb/time
Entry
Substrate
R1
R2
R3
R4
R5
R6
R7
3
1
2
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
Br
H
H
H
i-OPr
OMe
OH
OMe
OH
H
H
H
Me
H
OMe
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
88
12
13
24
15
20
12
32
35
13
22
14
16
18
42
28
18
15
45
26
13
79
65
86
61
82
58
62
76
74
82
77
86
45
80
76
77
48
70
83
3
4
H
H
H
H
OMe
OMe
H
H
H
5
H
H
H
6
7
OMe
OH
OH
OMe
OMe
i-OPr
OMe
OMe
OH
H
H
H
H
H
H
OMe
OH
OH
H
H
H
8
9
H
H
H
H
i-Pr
H
i-Pr
H
10
11
12
13
14
15
16
17
18
19
20
H
H
H
H
H
H
OH
H
H
H
H
H
i-Pr
H
H
OMe
OMe
OH
OH
OMe
OMe
OH
OH
OMe
i-Pr
H
H
OMe
H
OMe
OH
H
OMe
H
OMe
OMe
OMe
OH
H
H
i-Pr
i-Pr
H
i-Pr
Br
H
i-Pr
i-Pr
H
i-Pr
Br
H
H
H
OH
H
OMe
OEt
H
1t
H
H
3t
a
Reaction conditions. For a detailed experimental operation, see Experimental section. 1 (2 mmol), 2 (2.6 mmol), NaOCH3 (3: 6, 8, 10, and 12
mmol were used for 0, 1, 2, and 3 free hydroxyl group of 1), 70ꢀC.
b Isolated yield after silica gel chromatography.
128.0, 131.0, 131.9, 143.2, 144.5, 148.1, 151.2, 157.3, 159.0,
160.2; ESI-MS: m/z (rel intensity) 437 (95), 356 (M þ Na,
40), 437.12 (51), 334 (M þ 1, 100), 318 (13), 274 (25). Anal.
Calcd for C19H15N3O3: C, 68.46; H, 4.54; N, 12.61; Found
C, 68.52; H, 4.61; N, 12.71.
(ppm)]: 6.23 (s, 1H), 6.37 (d, J ¼ 7.4 Hz, 1H), 6.78 (s, 1H),
6.86 (d, J ¼ 7.4 Hz, 1H), 7.25 (m, 5H), 8.12 (s, 1H), 8.60 (s,
1H), 9.58 (s, 2H); 13C-NMR [75 MHz, DMSO-d6/TMS, d
(ppm)]: 160.3, 157.3, 151.0, 148.5, 135.9, 132.0, 129.8, 128.7,
127.7, 126.7, 125.1, 122.5, 108.8, 107.1, 103.1, 96.5. ESI-MS:
m/z (rel intensity) 388 (63), 365 (40), 346 (63), 330 (M þ Na,
11), 304 (M þ 1, 26), 274(52). Anal Calcd for C18H13N3O2:
C, 71.28; H, 4.32; N, 13.85; Found C, 71.21; H, 4.26;
N, 13.77.
6-(4-Methoxyphenyl)-7-(2-hydroxyl-4,6-dimethoxyphenyl)-
pyrazolo[1,5-a]pyrimidine (3d). m. p. 248.6–249.3ꢀC; IR
(KBr), m (cmꢁ1): 3129, 3011, 2955, 2837, 1605, 1509, 1462,
1
1370, 1201, 1167, 1114, 1029, 935, 825; H-NMR [300 MHz,
DMSO-d6/TMS, d (ppm)]: 3.51 (s, 3H), 3.69(s, 3H), 3.73 (s,
3H), 6.06 (s, 1H), 6.11(s, 1H), 6.75 (s, 1H), 6.89 (d, J ¼ 8.3
Hz, 2H), 7.24 (d, J ¼ 8.3 Hz, 2H), 8.07 (s, 1H), 8.56 (s, 1H),
9.69 (s, 1H); 13C-NMR [75 MHz, DMSO-d6/TMS, d (ppm)]:
55.0, 55.5, 89.9, 93.7, 95.8, 100.3, 113.6, 123.0, 127.6, 129.8,
139.9, 143.9, 147.6, 150.3, 156.8, 158.7, 158.9, 162.2; ESI-
MS: m/z (rel intensity) 400 (M þ Na, 68), 378 (M þ 1, 100),
274 (22). Anal. Calcd for C21H19N3O4: C, 66.83; H, 5.07;
N, 11.13; Found C, 66.86; H, 5.12; N, 11.18.
6-Phenyl-7-(2,4-dihydroxylphenyl)pyrazolo[1,5-a]pyrimi-
dine (3e). m.p. 240.7–242.5ꢀC; IR (KBr), m (cmꢁ1): 3132,
2971, 1611, 1536, 1456, 1264, 1168, 1521, 1447, 1247, 1203,
1100, 1021, 834; 1H-NMR [300 MHz, DMSO-d6/TMS, d
6-(4-Methoxyphenyl)-7-(2-hydroxyl-4-methoxyphenyl)pyr-
azolo[1,5-a]pyrimidine (3f). m. p. 247.8–248.5ꢀC; IR (KBr),
m (cmꢁ1): 3142, 2962, 2889, 1614, 1504, 1449, 1319, 1250,
1202, 1087, 1034, 833; 1H-NMR [300 MHz, DMSO-d6/TMS,
d (ppm)]: 3.73 (s, 6H), 6.38–6.45 (m, 2H), 6.78 (s, 1H), 6.88
(d, J ¼ 8.6 Hz, 2H), 7.00 (d, 1H), 7.23 (d, J ¼ 8.6 Hz, 2H),
8.11 (s, 1H), 8.60 (s, 1H), 9.82 (s, 1H); 13C-NMR [75 MHz,
DMSO-d6/TMS, d (ppm)]: 55.0, 96.1, 101.2, 104.8, 110.7,
113.7, 121.8, 127.3, 130.5, 131.5, 142.2, 144.1, 147.6, 150.7,
156.8, 158.5, 161.3; ESI-MS: m/z (rel intensity) 370 (MþNa,
60), 348 (M þ 1, 100). Anal. Calcd for C20H17N3O3:
C, 69.15; H, 4.93; N, 12.10; Found C, 66.09; H, 4.81; N,
11.89.
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283
1H), 9.49–9.55 (d, 2H); 13C-NMR [75 MHz, DMSO-d6/TMS,
d (ppm)]: 159.4, 156.7, 150.6, 149.8, 147.2, 143.9, 142.5,
134.9, 130.9, 126.1, 124.2, 122.5, 109.7, 106.5, 102.3, 95.8,
25.9, 22.7; ESI-MS: m/z (rel intensity) 477 (22), 437 (12), 426
(9), 404 (Mþ1, 100), 274 (20). Anal. Calcd for C24H25N3O3:
C, 71.44; H, 6.25; N, 10.41; Found C, 71.39; H, 6.19; N,
10.37.
6-Phenyl-7-(2-hydroxyl-4-methoxyphenyl)pyrazolo[1,5-a]-
pyrimidine (3i). m. p. 240.3–240.8ꢀC; IR (KBr), m (cmꢁ1):
3135, 2959, 1615, 1537, 1497, 1273, 1200, 1164, 1112, 829;
1H-NMR [300 MHz, DMSO-d6/TMS, d (ppm)]: 3.67 (s, 3H),
6.42 (m, 2H), 6.80 (s, 1H), 7.12 (d, J ¼ 7.5 Hz, 1H), 7.25 (m,
5H), 8.12 (s, 1H), 8.60 (s, 1H), 9.81 (s, 1H); 13C-NMR [75
MHz, DMSO-d6/TMS, d (ppm)]: 55.5, 96.6, 101.6, 105.3,
110.8, 122.6, 127.8, 128.7, 129.8, 132.1, 135.7, 143.1, 144.7,
148.5, 151.0, 157.5, 161.9; ESI-MS: m/z (rel intensity) 444
(100), 437 (50), 424 (30), 402 (76), 360 (38), 318(M þ 1, 44),
274(19). Anal. Calcd for C19H15N3O2: C, 71.91; H, 4.76; N,
13.24; Found C, 72.00; H, 4.82; N, 13.41.
6-(4-Hydroxyphenyl)-7-(2-hydroxy-4-methoxyphenyl)-
pyrazolo[1,5-a]pyrimidine (3j). m. p. 242.2–244.2ꢀC; IR (KBr),
m (cmꢁ1): 3272, 3118, 2936, 2665, 1596, 1495, 1442, 1382,
1
1316, 1235, 1204, 1172, 829; H-NMR [300 MHz, DMSO-d6/
Figure 1. Single-crystal X-ray structural analysis of 3a.
TMS, d (ppm)]: 3.74 (s, 3H), 6.42 (m, 2H), 6.69 (d, J ¼ 8.3
Hz, 2H), 6.77 (s, 1H), 6.97 (d, 1H), 7.11 (d, J ¼ 8.3 Hz, 2H),
8.10 (s, 1H), 8.57 (s, 1H), 9.53 (s, 1H), 9.77 (s, 1H); 13C-
NMR [75 MHz, DMSO-d6/TMS, d (ppm)]: 55.0, 96.0, 101.2,
104.8, 110.9, 115.1, 122.2, 125.6, 130.0, 130.5, 131.5, 142.1,
143.9, 147.5, 150.8, 156.8, 161.3; ESI-MS: m/z (rel intensity)
437 (39), 432 (22), 356 (M þ Na, 34), 334 (M þ 1, 100), 318
(26), 276 (68), 274 (43) . Anal. Calcd for C19H15N3O3: C,
68.46; H, 4.54; N, 12.61; Found C, 68.53; H, 4.61; N, 12.70.
6-Phenyl-7-(2-hydroxyl-3-bromo-4-isopropoxyphenyl)pyr-
azolo[1,5-a]pyrimidine (3k). m. p. 210.2–210.9ꢀC; IR (KBr),
m (cmꢁ1): 3140, 2980, 2901, 1607, 1486, 1445, 1403, 1323,
1258, 1192, 1105, 1102, 971, 839; 1H-NMR [300 MHz,
DMSO-d6/TMS, d (ppm)]: 1.06 (s, 12H), 3.12–3.20 (m, 2H),
3.64 (s, 3H), 3.71 (s, 3H), 6.41 (d, J ¼ 8.0 Hz, 1H), 6.49 (s,
1H), 6.76 (s, 1H), 6.94 (d, J ¼ 8.0 Hz, 1H), 7.07 (s, 2H) 8.09
(s, 1H), 8.67 (s, 1H), 9.71 (s, 1H); 13C-NMR [75 MHz,
DMSO-d6/TMS, d (ppm)]: 162.0, 157.5, 153.9, 151.0, 148.1,
144.6, 142.8, 141.3, 131.7, 131.2, 125.7, 122.5, 111.7, 105.4,
101.8, 96.5, 62.3, 55.6, 26.3, 24.2; ESI-MS: m/z (rel intensity)
437 (M þ Na, 57), 424 (M ꢁ 1, 19), 368 (38), 346 (100), 274
6-(4-Hydroxylphenyl)-7-(2,4-dihydroxylphenyl)pyrazolo[1,5-
a]pyrimidine (3g). m. p. 240.6–240.8ꢀC; IR (KBr), m (cmꢁ1):
3138, 2923, 1611, 1545, 1505, 1455, 1251, 1179, 1110, 837;
1H-NMR [300 MHz, DMSO-d6/TMS, d (ppm)]: 6.21(d, J ¼
8.0 Hz, 1H), 6.63 (s, 1H), 6.68 (d, J ¼ 7.6 Hz, 2H), 6.75 (s,
1H), 6.83 (d, J ¼ 8.0 Hz, 1H), 6.96 (s, 1H), 7.09 (d, J ¼ 7.6
Hz, 2H), 8.09 (s, 1H), 8.55 (s, 1H), 9.73 (bs, 3H); 13C-NMR
[75 MHz, DMSO-d6/TMS, d (ppm)]: 160.1, 157.3, 157.2,
151.2, 148.0, 144.4, 143.0, 131.9, 130.9, 126.3, 122.6, 115.6,
109.7, 107.0, 103.0, 96.4; ESI-MS: m/z (rel intensity) 437
(100), 346 (M þ Na, 22), 319 (M þ 1, 73), 274 (60), 267
(43). Anal. Calcd for C18H13N3O3: C, 67.71; H, 4.10; N,
13.16; Found C, 67.69; H, 3.99; N, 13.01.
6-(3,5-Diisopropyl-4-hydroxylphenyl)-7-(2,4-dihydroyphe-
nyl)pyrazolo[1,5-a]pyrimidine (3h). m. p. 244.2–245.9ꢀC; IR
(KBr), m (cmꢁ1): 3140, 2956, 2869, 2833, 1622, 1496, 1306,
1251, 1190, 1156, 955, 788; 1H-NMR [300 MHz, DMSO-d6/
TMS, d (ppm)]: 1.20 (m, 12H), 3.2 (m, 2H), 6.19 (s, 1H), 6.37
(s, 1H), 6.74 (s, 1H), 6.95 (s, 2H), 8.06–8.10 (m, 2H), 8.64 (s,
Scheme 3. Proposed mechanism for the formation of 3.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

284
Z.-T. Zhang, Y.-Q. Ma, Y. Liang, D. Xue, and Q. He
Vol 48
(19). Anal. Calcd for C21H18BrN3O2: C, 59.45; H, 4.28; N,
9.90; Found C, 59.41; H, 4.22; N, 9.84.
9.54 (s, 1H); 13C-NMR [75 MHz, DMSO-d6/TMS, d (ppm)]:
162.4, 158.5, 157.1, 153.4, 150.0, 147.5, 143.9, 140.7, 140.1,
131.1, 124.8, 124.5, 123.9, 123.1, 95.8, 94.9, 93.8, 90.0, 61.9,
55.4, 55.2, 25.9, 24.7, 23.6; ESI-MS: m/z (rel intensity) 488
(38), 484 (M þ Na, 60), 462 (M þ 1, 100).Anal. Calcd for
C27H31N3O4: C, 70.26; H, 6.77; N, 9.10; Found C, 70.12; H,
6.47; N, 8.95.
6-(3,5-Diisopropyl-4-methoxylphenyl)-7-(2-hydroxy-4-methoxy-
phenyl)pyrazolo[1,5-a] pyrimidine(3l). m. p. 204.3–206.8ꢀC; IR
(KBr), m (cmꢁ1): 3452, 3140, 2956, 2873, 1642, 1623, 1496,
1468, 1306, 1078, 1014, 971, 892; 1H-NMR [300 MHz,
DMSO-d6/TMS, d (ppm)]: 1.06 (s, 12H), 3.16 (m, 2H), 3.64
(s, 3H), 3.71 (s, 3H,), 6.41 (d, J ¼ 8.0 Hz, 1H), 6.49 (s, 1H),
6.76 (s, 1H), 6.94 (d, J ¼ 8.0 Hz, 1H), 7.07 (s, 2H), 8.09 (s,
1H), 8.67 (s, 1H), 9.71 (s, 1H); 13C-NMR [75 MHz, DMSO-
d6/TMS, d (ppm)]: 162.0, 157.5, 153.9, 151.0, 148.1, 144.6,
142.8, 141.3, 131.7, 131.2, 125.7, 122.5, 111.7, 105.4, 101.8,
96.5, 62.3, 55.6, 26.3, 24.2; ESI-MS: m/z (rel intensity) 454
(MþNa, 34), 432 (M þ 1, 100). Anal. Calcd for C26H29N3O3:
C, 72.37; H, 6.77; N, 9.74; Found C, 71.20; H, 6.52; N, 9.49.
6-(4-Methoxyphenyl)-7-(2-hydroxyl-4,5,6-trimethoxyphe-
nyl)pyrazolo[1,5-a]pyrimidine (3m). m. p. 240.2–241ꢀC; IR
(KBr), m (cmꢁ1): 3136, 2976, 2930, 1616, 1509, 1429, 1296,
6-(4-Methoxyphenyl)-7-(2-hydroxyl-3-bromo-4-methoxyphe-
nyl)pyrazolo[1,5-a] pyrimidine (3q). m. p. 202.8–204.3ꢀC; IR
(KBr), m (cmꢁ1): 3488, 2940, 1600, 1490, 1451, 1396, 1250,
1
1205, 1049, 829, 787; H-NMR [300 MHz, DMSO-d6/TMS, d
(ppm)]: 3.86 (d, 6H), 6.80 (s, 1H), 6.52 (s, 1H), 6.90 (s, 1H, J
¼ 8.4 Hz), 7.08 (s, 1H), 7.24 (s, 1H, J ¼ 8.4 Hz), 7.36–7.48
(d, 2H), 8.13 (s, 1H,), 8.59 (s, 1H), 10.15 (d, 1H); 13C-NMR
[75 MHz, DMSO-d6/TMS, d (ppm)]: 56.6, 96.7, 96.9, 100.9,
112.8, 114.3, 122.5, 130.4, 131.0, 134.0, 134.4, 144.7, 145.0,
151.0, 151.3, 157.0; ESI-MS: m/z (rel intensity) 505 (22), 453
(27), 426 (M þ 1, 100). Anal. Calcd for C20H16BrN3O3: C,
56.35; H, 3.78; N, 9.86; Found C, 56.41; H, 3.84; N, 9.97.
6-(3,5-Diisopropyl-4-hydroxylphenyl)-7-(2,4,6-trihydroxyl-
phenyl)pyrazolo[1,5-a]pyrimidine (3r). m. p. 248.4–249.6ꢀC;
IR (KBr), m (cmꢁ1): 3207, 2962, 1876, 1648, 1565, 1443,
1295, 1191, 1158, 833; 1H-NMR [300 MHz, DMSO-d6/TMS,
d (ppm)]: 1.15 (d, 12H, J ¼ 6.2 Hz), 3.30 (m, 2H), 6.00 (s,
1H), 6.09 (s, 1H), 6.62 (s, 1H), 7.21 (s, 2H), 7.87 (s, 1H), 8.01
(s, 1H), 8.07 (s, 1H), 10.30 (s, 1H), 13.32 (s, 1H), 15.03 (s,
1H); 13C-NMR[75 MHz, DMSO-d6/TMS, d (ppm)]: 179.4,
163.7, 162.5, 150.1, 148.5, 142.7, 141.1, 134.7, 131.1, 125.1,
123.7, 119.9, 107.1, 101.9, 98.0, 91.6, 26.2, 23.0. ESI-MS: m/z
(rel intensity) 462 (32), 442 (M þ Na, 44), 420 (M þ 1, 100),
346 (50). Anal. Calcd for C24H25N3O4: C, 68.72; H, 6.01; N,
10.02; Found C, 68.81; H, 6.21; N, 10.15.
6-(4-Hydroxyl-3,5-dibromophenyl)-7-(2-hydroxyl-4-methoxy-
phenyl)pyrazolo[1,5-a]pyrimidine (3s). m. p.185.1–189.5ꢀC; IR
(KBr), m (cmꢁ1): 3466, 2922, 1601, 1543, 1466, 1299, 877,
785; 1H-NMR [300 MHz, DMSO-d6/TMS, d (ppm)]: 3.84 (s,
3H), 6.46 (d, 1H, J ¼ 7.8 Hz), 6.80 (s, 1H), 7.09 (s, 1H, J ¼
7.8 Hz), 7.48 (d, 2H), 8.14 (s, 1H,), 8.63 (s, 1H), 9.98 (t, 2H);
13C-NMR [75 MHz, DMSO-d6/TMS, d (ppm)]: 55.0, 96.3,
100.3, 101.1, 105.5, 111.4, 119.8, 129.1, 131.5, 132.9, 134.0,
140.8, 142.5, 144.4, 147.7, 150.2, 156.6, 161.6; ESI-MS: m/z
(rel intensity) 491 (M þ 1, 19), 477 (100), 431 (40). Anal.
Calcd for C19H13Br2N3O3: C, 46.46; H, 2.67; N, 8.56; Found
C, 46.52; H, 2.71; N, 8.84.
6-(4-Methoxyphenyl)-7-(2-hydroy-4-ethoxyphenyl)pyra-
zolo[1,5-a]pyrimidin (3t). m. p. 240.2–241ꢀC; IR (KBr), m
(cmꢁ1): 3136, 2976, 2930, 1616, 1509, 1429, 1296, 1249,
1185, 1115, 1032, 830; 1H-NMR [300 MHz, DMSO-d6/TMS,
d (ppm)]: 1.33 (t, J ¼ 6.9 Hz, 3H), 3.74 (s, 3H), 4.00 (q, J ¼
6.9 Hz, 3H), 6.40 (m, 2H), 6.76 (s, 1H), 6.88 (d, J ¼ 8.6 Hz,
2H), 6.98 (d, J ¼ 8.4 Hz), 7.23 (d, J ¼ 8.6 Hz, 2H), 8.09 (s,
1H), 8.57 (s, 1H), 9.64 (s, 1H); 13C-NMR [75 MHz, DMSO-
d6/TMS, d (ppm)]: 15.1, 55.6, 63.5, 96.5, 102.3, 105.9, 111.2,
114.3, 122.3, 127.9, 131.0, 132.0, 142.8, 144.5, 148.1, 151.2,
157.3, 159.1, 161.2; ESI-MS: m/z (rel intensity) 437 (19),
390(35), 384 (M þ Na, 80), 362(M þ 1, 100). Anal. Calcd for
C21H19N3O3: C, 69.79; H, 5.30; N, 11.63; Found C, 71.01; H,
5.06; N, 11.59.
1
1249, 1185, 1115, 1032, 830; H-NMR [300 MHz, DMSO-d6/
TMS, d (ppm)]: 1.33 (t, J ¼ 6.9 Hz, 3H), 3.74 (s, 3H), 4.00
(q, J ¼ 6.9 Hz, 3H), 6.40 (m, 2H), 6.76 (s, 1H), 6.88 (d, J ¼
8.6 Hz, 2H), 6.98 (s, 1H), 7.23 (d, J ¼ 8.6 Hz, 2H), 8.09 (s,
1H), 8.57 (s, 1H), 9.64 (s, 1H); 13C-NMR [75 MHz, DMSO-
d6/TMS, d (ppm)]: 15.1, 55.6, 63.5, 96.5, 102.3, 105.9, 111.2,
114.3, 122.3, 127.9, 131.0, 132.0, 142.8, 144.5, 148.1, 151.2,
157.3, 159.1, 161.2 ESI-MS: m/z (rel intensity) 437 (19),
390(35), 384 (M þ Na, 80), 362(M þ 1, 100). Anal. Calcd for
C21H19N3O3: C, 69.79; H, 5.30; N, 11.63; Found C, 71.01; H,
5.06; N, 11.59.
6-(4-Hydroxylphenyl)-7-(2,4,6-trihydroxylphenyl)pyra-
zolo[1,5-a]pyrimidine (3n). m. p. 204.2–210.9ꢀC; IR (KBr),
m (cmꢁ1): 3143, 2936, 2838, 1613, 1509, 1467, 1366, 1256,
1185, 1096, 1034, 994, 826; 1H-NMR [300 MHz, DMSO-d6/
TMS, d (ppm)]: 3.43 (s, 3H), 3.71 (m, 9H), 6.32 (d, J ¼ 9.1
Hz, 1H), 6.91 (m, 2H), 7.28–7.33 (m, 2H), 8.12 (d, 1H, J ¼ 9.1
Hz), 8.61 (s, 1H), 9.58 (s, 1H); 13C-NMR [75 MHz, DMSO-d6/
TMS, d (ppm)]: 158.8, 154.9, 151.6, 151.2, 150.4, 147.5, 143.9,
139.4, 134.0, 130.0, 127.3, 122.6, 113.7, 104.3, 96.0, 95.5, 60.4,
60.1, 55.6, 55.0; ESI-MS: m/z (rel intensity) 430(MþNa, 76),
408 (M þ 1, 100). Anal. Calcd for C22H21N3O5: C, 64.86; H,
5.20; N, 10.31; Found C, 64.79; H, 5.00; N, 10.22.
6-(3,5-Diisopropyl-4-hydroxylphenyl)-7-(2-hydroxy-4-methox-
yphenyl)pyrazolo[1,5-a]pyrimidine (3o). m. p. 246.5–247.2ꢀC;
IR (KBr), m (cmꢁ1): 3546, 3133, 2962, 2580, 1612, 1535,
1467, 1312, 1238, 1202, 1105, 1025, 788; 1H-NMR [300
MHz, DMSO-d6/TMS, d (ppm)]: 1.05 (s, 12H), 3.23 (m, 2H),
3.71 (s, 3H), 6.45 (d, 1H, J ¼ 8.5 Hz), 6.50 (s, 1H), 6.76 s,
1H), 6.93 (m, 3H), 8.08 (s, 1H), 8.13 (s, 1H), 8.68 (s, 1H),
9.81 (s, 1H); 13C-NMR [75 MHz, DMSO-d6/TMS, d (ppm)]:
161.4, 157.0, 150.7, 150.1, 147.4, 143.9, 141.9, 134.9, 131.2,
126.0, 124.2, 122.6, 111.4, 104.9, 101.3, 95.8, 55.1, 26.0, 22.7;
ESI-MS: m/z (rel intensity) 440 (M þ Na, 22), 418 (M þ 1,
100). Anal. Calcd for C25H27N3O3: C, 71.92; H, 6.52; N,
10.06; Found C, 71.89; H, 649; N, 9.98.
6-(3,5-Diisopropyl-4-methoxyphenyl)-7-(2-hydroxyl-4,6-dime-
thoxyphenl)pyrazolo[1,5-a]pyrimidine (3p). m. p. 242.0–
243.7ꢀC; IR (KBr), m (cmꢁ1): 3148, 2962, 2872, 1627, 1502,
1
1463, 1356, 1304, 1249, 1196, 1159, 1004, 939, 808; H-NMR
[300 MHz, DMSO-d6/TMS, d (ppm)]: 0.85 (s, 12H), 2.96 (m,
2H), 3.24 (s, 3H), 3.49 (s, 3H), 3.57 (s, 3H), 5.86 (s, 1H), 5.89
(s, 1H), 6.53 (s, 1H), 6.83 (s, 2H), 7.86 (s, 1H), 8.41 (s, 1H),
Acknowledgments. This research was supported by the
National Natural Science Foundation of China (No: 20772076),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
An Efficient One-Pot Synthesis of Diarylpyrazolo[1,5-a]pyrimidine from Isoflavones
285
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the Fundamental Research Funds for the Central Universities
(No: GK200901010) and Science and Technology Key Project
of Xi’an of Shaanxi province (No: CXY08019).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet