One-step synthesis of diarylpyrazolo[3,4- b]pyridines from isoflavones

Article abstract of DOI:10.1021/cc1000506

A new concise, facile, and efficient method for the synthesis of 3-hydroxy-5,6-diphenylpyrazolo[3,4-b]pyridine derivatives has been described. The cyclocondensation of isoflavones with 3-amino-5-hydroxypyrazole in the presence of sodium methoxide gave fused heteroaromatic 3-hydroxy-5,6- diphenylpyrazolo[3,4-b]pyridines in moderate to good yields.

Full text of DOI:10.1021/cc1000506

600
J. Comb. Chem. 2010, 12, 600–603
One-Step Synthesis of Diarylpyrazolo[3,4-b]pyridines from Isoflavones
Zun-Ting Zhang,* Yong Liang, Yu-Qing Ma, Dong Xue, and Jun-Ling Yang
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, P.R.China
ReceiVed March 24, 2010
A new concise, facile, and efficient method for the synthesis of 3-hydroxy-5,6-diphenylpyrazolo[3,4-b]pyridine
derivatives has been described. The cyclocondensation of isoflavones with 3-amino-5-hydroxypyrazole in
the presence of sodium methoxide gave fused heteroaromatic 3-hydroxy-5,6-diphenylpyrazolo[3,4-b]pyridines
in moderate to good yields.
Introduction
b]pyridines obtained by treating 3-amino-5-hydroxypyrazole
and varied isoflavones under basic condition.
Fused heteroaromatic compounds containing ring-junction
nitrogen atoms are important for the preparation of biologically
active molecules.1,2 One such heteroaromatic class of com-
pounds is an important pharmaceutical target (Scheme 1).3 The
structural diversity and biological importance of substituted
pyridines have made them attractive targets for synthesis for
many years.4 The 4,5-dihydropyrazolo[3,4-b]pyridine systems
are also convenient models for investigating the reactivity,
chemical stability, and tautomerism of partially hydrogenated
azoloazines. As a result, these compounds have become
interesting substances for the preparation of novel analogues
of new fused or substituted derivatives.5
Results and Discussion
On the basis of our previous results,17-19 we envisioned
the synthesis of 2-hydroxy-6-phenyl-7-(2-hydroxy-4-isopro-
poxy)pyrazolo[1,5-a]pyrimidine 3a by the condensation of
1a (4-isopropoxyisoflavone, 1.0 equiv) with 3-amino-5-
hydroxypyrazole 2 (1.1 equiv) under basic conditions
(Scheme 2). Surprisingly, the unexpected compound 4a (3-
hydroxy-5-phenyl-6-(2-hydroxy-4-isopropoxy)pyrazolo[3,4-
b]pyridine) was obtained and elucidated by spectroscopic
analyses (1H- and 13C NMR, IR) and elemental analysis.
These results prompted us to turn our attention to optimiz-
ing the conditions for the efficient formation of 4a (Table
1). When NaOH (5 M) was used as base, 4a was obtained
in 40% yield (entry 1). It was found that Et3N was ineffective
in providing the desired product (entry 2). Examination of
the effects of the other bases on yield showed NaOMe to be
the most effective for the condensation (entries 1-3). Further
studies with varying amounts of NaOMe revealed that 4.0
equiv of base are necessary to obtain a high yield of 4a
(entries 3-6). MeOH was an ideal solvent, since reactions
in tetrahydrofuran (THF), N,N-dimethylformamide (DMF),
or EtOH gave lower yields with higher temperature (entries
6-8). The best condition to obtain the maximum yield (81%)
was using NaOMe (4.0 equiv) as base in methanol with 1:1.2
as the ratio of 1a/2.
One of the most common approaches used for the syntheses
of the pyrazolo[3,4-b]pyridine core has been with the annulation
of the pyridine ring onto appropriately substituted pyrazole, or
its reverse.6 The described bicyclic core was also prepared by
the cyclocondensation of 5-aminopyrazole with 1,3-dicarbonyl
compounds7-9 or their ethoxymetylene derivatives.10 Moreover,
a one-pot synthesis of 1H-pyrazolo[3,4-b]pyridines by conden-
sation of dihydropyrazolone, ethyl acetoacetate, and a conve-
nient aldehyde was also described.11 The promising Diels-Alder
cycloaddition of pyrazolylimine as diene with nitroalkene was
recently reported.12
Natural isoflavones display a wide range of biological
activities.13,14 It was reported that the chromone fragment
present in isoflavones can generate a 1,3-diketone equivalent
in the presence of alkali, which readily reacts with
amidines,15 guanidine,16 and hydrazine17 to form the corre-
sponding 2-substituted pyrimidines and diarylpyrazoles.
Recently, we have reported the high-throughput synthesis
of 3,4-diarylpyrazoles, 4,5-biphenyl-2-pyrimidinylguanidine,
and 2,3-diarylpyrimido[1,2-a]benzimidazole via a one-pot
reaction of hydrazine,17 bisguanidine,18 or 2-aminobenzimi-
dazole19 with isoflavones. Herein, we now report an effective,
concise, and facile synthesis of 5,6-diphenylpyrazolo[3,4-
Having the optimized conditions, the scope of the reaction
was examined and summarized in Table 2. All products were
1
characterized by IR, H NMR, 13C NMR, mass spectrometry
(MS), and elemental analysis. Also single crystal X-ray dif-
Scheme 1. Pyrazolo[3,4-b]pyridine as a Raf Kinases
Inhibitor
* To whom correspondence should be addressed. E-mail: zhangzt@
snnu.edu.cn. Phone: 86-29-85303940. Fax: 86-29-85303774.
10.1021/cc1000506  2010 American Chemical Society
Published on Web 06/04/2010

Synthesis of Diarylpyrazolo[3,4-b]pyridines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 601
Scheme 2. Designed Synthetic Route for the Synthesis of 3a
Table 1. Optimization of the Reaction Conditionsa
entry
solventb
base
molar ratios 1a/2/base
4a yield/%c
1
2
3
4
5
6
7
8
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
1/1.1/4
1/1.1/4
1/1.2/4
1/1.3/4
1/1.4/4
1/1.5/4
40
0
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
58
66
72
45
38
34
82
81
80
78
DMFd
MeOH
MeOH
MeOH
MeOH
9
10
11
12
a All reactions were carried out with isoflavone 1a (2 mmol), 3-amino-5-hydroxypyrazole 2, and varying bases in indicated solvents (20 mL) for
24 h. b Reactions with EtOH, MeOH, and THF as solvent were carried out at reflux. c Isolated yield based on isoflavone (1a). d Carried out at 100 °C.
fraction analysis was realized on 4d (Figure 1). As shown in
the Table 2, the yield decreases as the number of hydroxyl
groups on the aryl rings of the isoflavones increase. For
example, isoflavones 1a, 1b, 1d, 1f, 1i, 1k, 1l, 1m, 1p, 1q, and
1s, (Table 2, entries 1, 2, 4, 6, 9, 10-13, 16, 17, and 19) lacking
a hydroxyl group, afforded 4 in near 80% yield. Isoflavones
with one hydroxyl group, 1c, 1e, 1j, and 1o (entries 3, 5, 10,
and 15) afforded 4 in about 65% yield while isoflavones with
two hydroxyl groups such as 1g, 1h, and 1s (entries 7, 8, and
18) gave desired products in about 60%. It is even more difficult
for Genistein (4′,5,7-trihydroxyisoflavone, entry 14) to produce
4 (39%). It seems possible that the hydroxyl groups of the
isoflavones can deprotonate under basic reaction conditions,
increasing the electron-donating ability of the hydroxyisofla-
vones more than the corresponding alkoxy and benzoxyisofla-
vones, preventing condensation with 2.
Figure 1. Single-crystal X-ray structural analysis of 4d.
Further experimental and mechanistic studies are required
to fully understand the differences of chemoselective con-
densation of isoflavone 1 with pyrazole 2. As reported,20
isoflavone may undergo ring-opening reaction in the presence
of alkali to form an R,ꢀ-unsaturated ketone intermediate 6

602 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Zhang et al.
Table 2. Synthesis of 3-Hydroxy-5,6-diphenylpyrazolo[3,4-b]pyridines 4a
b
entry
substrate
R1
R2
R3
R4
R5
R6
R7
product
yield
time/h
1
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
i-OPr
OMe
OH
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
82
77
66
78
60
81
56
64
76
70
84
73
84
39
77
76
78
52
85
14
16
25
19
24
14
36
38
16
27
15
20
19
48
31
27
16
38
17
2
H
H
Me
H
H
H
H
3
H
OMe
OMe
H
OMe
OH
OH
H
OH
H
OMe
OMe
OH
OH
OMe
OMe
OH
OMe
H
4
OMe
OH
H
OMe
H
H
H
5
H
H
H
6
OMe
OH
OH
OMe
OMe
i -OPr
OMe
OMe
OH
H
H
H
H
7
H
H
H
H
8
H
H
i-Pr
H
i -Pr
H
9
H
H
10
11
12
13
14
15
16
17
18
19
H
H
H
H
H
H
H
H
H
H
i-Pr
H
i -Pr
H
OMe
H
OMe
OH
H
H
H
OMe
OMe
OMe
OH
H
i-Pr
i -Pr
H
i -Pr
i -Pr
H
H
OMe
H
H
H
H
H
H
H
NO2
H
OBn
H
a Isoflavones 1 (2 mmol), 2 (2.4 mmol), NaOCH3 (8, 10, 12, and 14 mmol were used for 0, 1, 2, and 3 hydroxyl groups in 1, respectively), in
methanol. b Isolated yield.
Scheme 3. Proposed Mechanism for the Formation of 4
(Scheme 3). If the primary amine group of the 3-amino-5-
hydroxylpyrazole 2 attacks the ꢀ-carbon of 6, followed by
ring closure, 3 is formed. However, if C4 of the 3-amino-
5-hydroxypyrazole 2 attacks the ꢀ-carbon in 6, followed by
ring closure between the primary amine and the carbonyl
carbon in the intermediate of 5 would give 4. The intermedi-
ate 5n was successfully isolated from the crude reaction
mixture of 2 and genistein 1n. The 5-hydroxy group of
pyrazole 2 would become an oxyanion in basic condition,
enhancing the electrophilic substitution reaction at the
ꢀ-carbon of 6 with C4 of 2 leading to different chemose-
lectivity of the cyclocondensation between 1 and 2. Ad-
ditionally, the concentration of base is important for the
cyclocondensations. Intermediate 6 would convert to ketone

Synthesis of Diarylpyrazolo[3,4-b]pyridines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 603
7 at high concentration of base by elimination of HC(OMe)3.
However, it would be too difficult for isoflavones to produce
the intermediate 6 in low base concentration.
Acknowledgment. This research was supported by the
National Natural Science Foundation of China (No: 20772076),
the Fundamental Research Funds for the Central Universities
(No: GK200901010), and the Science and Innovation Funds
of Graduate Programs of Shaanxi Normal University (No:
2009CXS013).
Conclusions
An efficient, concise one-step synthesis of the functionalized
3-hydroxy-5,6-diphenylpyrazolo[3,4-b]pyridines is described.
The method employs a moderate heating of isoflavones with
3-amino-5-hydroxypyrazole in the presence of strong base to
afford the fused 3-hydroxy-5,6-diphenylpyrazolo[3,4-b]pyridines
biological core chemoselectively. The 5-hydroxyl group of
3-amino-5-hydroxypyrazole is probably one of the key factors
that will affect the results of the reaction.
Note Added after ASAP Publication. There were errors
in the structures of Table 1 and Schemes 3 and 4 in the
version of this paper published ASAP June 4, 2010; the
correct version published on June 9, 2010.
Supporting Information Available. Synthetic procedures;
characterization data, copies of 1H and 13C NMR spectra of
all compounds; crystal and structure refinement data for 4d.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
General Procedure. The corresponding isoflavone 1 (2
mmol), 1H-3-amine-5-hydroxypyrazol 2 (2.4 mmol), and
sodium methoxide (8 mmol) were refluxed in methanol (20 mL)
for 16-48 h. All reactions were monitored by thin-layer
chromatography (TLC), which showed the disappearance of 1
that was indicative of the reaction being complete. The reaction
mixture was concentrated to 5 mL by a rotary evaporator. The
condensate was poured into ice water (20 mL) and adjusted to
neutrality with the solution of 5% HCl. A yellow precipitate
appeared and was filtered after 15 minutes. Then the precipitate
was dissolved and dried over MgSO4, then concentrated under
reduced pressure, and purified by column chromatography on
silica gel column, using chloroform-methanol (15:1) to give
the corresponding pure product 4.
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CC1000506