Regioselective three-component synthesis of indolylpyrazolo[3, 4-b]pyridines induced by microwave and under solvent-free conditions

Article abstract of DOI:10.2174/157017809788681284

New 4-(1H-indol-3-yl)-6-arylpyrazolo[3, 4-b]pyridines 7 have been prepared in a solvent-free three-component reaction induced by microwave from 5-aminopyrazole 1, benzaldehydes 2 and 3-indolyl-3-oxopropanenitrile 5. These compounds were also obtained by means of the reaction of aminopyrazole 1 with benzylidene-derivatives of 3-(1H-indol-3-yl)-3-oxopropanenitrile 6, prepared in the reaction of 3-(1H-indol-3-yl)-3-oxopropanenitrile and aldehydes. 2009 Bentham Science Publishers Ltd.

Full text of DOI:10.2174/157017809788681284

Letters in Organic Chemistry, 2009, 6, 381-383
381
Regioselective Three-Component Synthesis of Indolylpyrazolo[3,4-
b]pyridines Induced by Microwave and under Solvent-Free Conditions
Jairo Quiroga*,a, Jorge Trillerasa, Ana Isabel Sáncheza, Braulio Insuastya, Rodrigo Aboníaa,
Manuel Noguerasb and Justo Cobob
aHeterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A.A. 25360 Cali,
Colombia
bDepartment of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
Received December 13, 2007: Revised June 04, 2009: Accepted June 04, 2009
Abstract: New 4-(1H-indol-3-yl)-6-arylpyrazolo[3,4-b]pyridines 7 have been prepared in a solvent-free three-component
reaction induced by microwave from 5-aminopyrazole 1, benzaldehydes 2 and 3-indolyl-3-oxopropanenitrile 5. These
compounds were also obtained by means of the reaction of aminopyrazole 1 with benzylidene-derivatives of 3-(1H-indol-
3-yl)-3-oxopropanenitrile 6, prepared in the reaction of 3-(1H-indol-3-yl)-3-oxopropanenitrile and aldehydes.
Keywords: 5-Aminopyrazole, 3-(1H-indol-3-yl)-3-oxopropanenitrile, Benzaldehyde, Indolylpyrazolo[3,4-b]pyridine, Three-
component reaction, Solvent-free procedure, Microwave.
Microwave-assisted solvent-free reactions have received
much attention due to their enhanced reaction rates as well as
higher yields and purities. These methods are regarded as
environmentally benign and easy to perform, paving the way
to the development of “Green Chemistry” protocols [1].
Multi-component reactions, an important class of organic
tandem reactions, are one-pot processes with at least three
components to form a single product, which incorporates
most or even all of the starting materials [2], and particularly
under solvent-free conditions enhance the reaction
efficiency, and simplicity and lessen environmental impact.
Multi-component reactions (MCRs) have been oriented
during the last years towards developing combinatorial
chemistry procedures, because of their high efficiency and
convenience in comparison with multistage procedures.
Hence, most of the scientific efforts have been focused on
the development of multi-component procedures to prepare
diverse heterocyclic compound libraries and to afford new
and effective MCRs [2b].
In our search for multicomponent procedure to prepare
fused heterocyclic systems such pyrazolo[3,4-b]pyridine
derivatives, well known for their wide range of biological
and pharmacological activities [5], we have already reported
several approximations. For example, three-component, one-
pot condensation synthesis of 4-aryl-5-cyano-6-phenyl-4,7-
dihydropyrazolo-[3,4-b]pyridine
4
(Scheme 1) using
microwave irradiation, a process that is adaptable for the
assembly of a library of compounds has recently gained
much attention in pharmaceutical research [6,7],
R
O
Ar
R
CN
ArCH=O
+
N
CN
Ph
Ph
N
2
3
NH2
N
R'
O
1
or
N
N
H
CN
R'
4
Ph
Ar
Simple nitrogen containing heteroaromatic compounds
have received much attention in the literature over the years.
They are, among other things, pharmacophores of paramount
importance, which have exciting biological properties in
their own right and also serve as important synthetic building
blocks in drug discovery.
Scheme 1.
In this way, we have planned the regioselective synthesis
of a new family of pyrazolo[3,4-b]pyridines bearing a
indolyl residue and a versatile functional group, such as
cyanide that can give a higher diversity potential to this
family. Thus a new series of pyrazolo[3,4-b]pyridines 7
through three-component microwave-assisted reaction of 5-
aminopyrazole 1 with 3-(1H-indol-3-yl)-3-oxopropanenitrile
5 and aromatic aldehydes 3 is described here.
Indole is essential both in nature as well as for
commercial drug development. Indole moieties are present in
many natural compounds and many drugs, participating in
vital biological processes [3]. On the synthetic point of view,
it is known that cyanoacetic acid can serve as a building
block in various reactions like cyclizations or syntheses of
coumarins and others heterocycles [4].
In the first attempt to afford the pyrazolo[3,4-b]pyridine
derivatives 7, a two-component classical reaction was carried
out, where 1-(1H-indol-3-yl)-3-aryl-2-cyano-1-propenones 6
was prepared through a simple solvent-free reaction of
equimolar amounts of benzaldehydes 3 and 3-(1H-indol-3-
yl)-3-oxopropanenitrile 5 (Scheme 2), using a focused
microwave reactor (CEM Discover TM) [8].
*Address correspondence to this author at the Heterocyclic Research Group,
Department of Chemistry, Universidad del Valle, A.A 25360, Cali,
Colombia; Fax: +57 2 33392440; E-mail: jaiquir@univalle.edu.co
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

382 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
Quiroga et al.
CN
O
O
Ar
CN
MW
ArCH=O
+
6 min.
N
N
H
H
MW
Method A
9 min.
5
3
6a-m
1
O
Ar
H3C
H3C
ArCH=O
4
CN
5
6
3
N
1
CN
3
+
2
N
NH2
N
N
N
7
MW 9 min.
Method B
N
Ph
Ph
H
NH
1
5
7a-m
Scheme 2.
Then, to afford the pyrazolo[3,4-b]pyridine derivatives 7
aminopyrazoles 1 and 1-(1H-indol-3-yl)-3-aryl-2-cyano-1-
propenone 6 were reacted by induction with microwave
irradiation with isolated yields never exceeding 35 %
(method A, Scheme 2 and Table 1) [9]. A three-component
one-pot cyclocondensation was then tried in a similar fashion
to a previously reported method using 5-aminopyrazole 1,
aromatic aldehydes 3 and 3-(1H-indol-3-yl)-3-oxopropan-
enitrile 5 rendering compounds 7 with good to excellent
yields (51-98%, method B, Scheme 2, and Table 1) [9].
The structures of all indolyl-chalcone analogs 6 and
indolylpyrazolo[3,4-b]pyridines 7 were appropriately estab-
1
lished by IR, H NMR, 13C NMR and MS spectra. Single
crystal X-ray diffraction analysis of compounds 7c, 7f and
7k was used to corroborate the postulated structures [10].
We can conclude that the reported one-step procedure is
efficient, simple and very regioselective alternative for the
preparation of indolylpyrazolo[3,4-b]pyridines via a three-
component cyclocondensation reaction of 5-aminopyrazole,
aromatic aldehydes and 3-(1H-indol-3-yl)-3-oxopropan-
enitrile in solvent-free conditions under microwave
irradiation. The best results were obtained with a three-
component cyclocondensation reaction, compared to the
two-component cyclocondensation reaction and conventional
We have also studied different reaction conditions
concluded that when reactions were carried out under
conventional heating conditions (reflux in ethanol and/or
DMF) the expected products were not obtained.
Table 1. Synthesis of 1-(1H-indol-3-yl)-3-aryl-2-cyano-1-propenone 6 and Indolylpyrazolo[3,4-b]pyridine 7 in Solvent-Free
Conditions Induced by Microwave for 6 and 9 min Respectively
Entry
Ar
Compound 6
Compound 7
M.p. ºC
Yield (%)
M.p. ºC
*Yield (%)
a
b
c
d
e
f
4-ClC6H4
4-NO2C6H4
4-OCH3C6H4
C6H5
253-255
246-248
212-214
231-233
221-223
204-206
244-246
201-203
215-217
237-239
167-169
214-216
259-261
70
87
71
93
88
83
81
83
82
77
87
88
72
286-288
300-302
270-272
288-290
306-308
273-275
338-340
288-289
296-298
278-280
273-275
297-299
318-320
61
59
85
62
72
89
98
87
53
75
89
51
70
4-BrC6H4
4-CH3C6H4
4-FC6H4
g
h
i
2-CF3C6H4
2-FC6H4
j
3,4-OCH2OC6H3
3,4,5-tri-CH3OC6H2
3-piridil
k
l
m
C6H5-CH=CH-CHO
*The reported yield were obtain by method B. By the Method A the isolated yields never exceeded 35 %.

Regioselective Three-Component Synthesis of Indolylpyrazolo[3,4-b]pyridines
Letters in Organic Chemistry, 2009, Vol. 6, No. 5
383
experiment was carried out using a focused microwave reactor
(CEM Discover TM). The 3-(1H-indol-3-yl)-3-oxopropanenitrile 5
(0.5 mmol) was mixed with equimolar amounts of aromatic
aldehydes 2 (0.5 mmol). The mixture was exposed to microwave
radiation at a 200 ºC with a maximum power of 300 W for 6 min.
The solid was dissolved in hot ethanol-DMF solution (2:1). After
cooling, the solid product was filtrated and washed with ethanol
and ether to afford the pure product. Selective spectral and
physical/chemical data for compound 6k: 1-(1H-indol-3-yl)-3-
(3,4,5-trimethoxyphenyl)-2-cyano-1-propenone. Brown dark solid.
heating conditions. Prominent advantages of this new
method are operational simplicity, good yields, short
reaction times and easy workup. The readily obtainable 3-
functionally substituted indole has shown to be an excellent
precursor to obtain heterocycle fused systems.
ACKNOWLEDGEMENTS
1
m.p. 167-169 ºC, yield 87 %. H NMR: ꢀ = 3.79 (s, 3H, OCH3);
The authors wish to thank COLCIENCIAS, Universidad
del Valle, the Spanish ‘Consejería de Innovación, Ciencia y
Empresa, Junta de Andalucía’ and Servicios Técnicos de
Investigación de la Universidad de Jaén for financial
support. We also thank professor Fabio Zuluaga for
reviewing this manuscript.
3.85 (s, 6H, OCH3); 7.27-7.35 (m, 2H, H-5 and H-6); 7.51 (s, 2H,
Ho); 7.56 (d, 1H, H-7); 8.19 (d, 1H, H-4); 8.21 (s, 1H, H-10); 8.45
(s, 1H, H-2); 12.28 (s, 1H, NH). 13C NMR: ꢀ = 56.0 (OCH3); 60.3
(OCH3); 108.3 (Co trimethoxyphenyl); 110.0 (C-9); 112.4 (C-7);
113.6 (C-3); 118.1 (CN); 121.3 (C-4); 122.3 (C-5); 123.5 (C-6);
126.1 (C-7a); 127.6 (Ci trimethoxyphenyl); 135.4 (C-2); 136.6 (C-
3a); 141.1 (Cp Ph); 152.2 (C-10); 152.8 (Cm Ph); 181.3 (C=O). The
mass spectrum shows the following peaks: MS (70 eV) m/z (%):
362(28, M+), 144(100), 116(35), 89(27), 44(18), 43(26), 41(27),
40(19). HR-MS (EI): C21H18N2O4 calcd 362.1267, found 362.1263.
General procedure for the preparation of 6-(1H-indol-3-yl)-3-
methyl-1-phenyl-4-aryl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
7 under microwave irradiation. Microwave experiment was carried
out a focused microwave reactor (CEM Discover TM). Method A.
The 5-aminopyrazole 1 and 1-(1H-indol-3-yl)-3-aryl-2-cyano-1-
propenone 6 was exposed to microwave radiation at 200 °C with a
maximum power of 300 W for 9 min. The reaction mixture was
dissolved in hot ethanol-DMF solution (2:1) and solid product was
filtrated and washed with ethanol and diethyl ether to afford the
pure products 6 in lower yields than 35%. Method B. The 5-
aminopyrazole 1 (0.5 mmol) was mixed with equimolar amounts of
3-(1H-indol-3-yl)-3-oxopropanenitrile 5 (0.5 mmol) and aromatic
aldehydes 3 (0.5 mmol); and the mixture exposed to microwave
radiation at 200 °C with a maximum power of 300 W for 9 min.
The reaction mixture was dissolved in hot ethanol-DMF solution
(2:1) and solid product was filtrated and washed with ethanol and
diethyl ether to afford the pure products 7 in goods yields. Selective
spectral and physical/chemical data for compound 7k: 6-(1H-indol-
3-yl)-4-(3,4,5-trimethoxyphenyl)-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-carbonitrile. Yellow crystalline solid
m.p. 273-275 ºC, yield 89 %. 1H NMR: ꢀ = 2.14 (s, 3H, CH3);3.82
(s, 3H, OCH3); 3.86 (s, 6H, OCH3); 7.02 (s, 2H, Ho
trimethoxyphenyl); 7.19 (t, 1H, H-5´); 7.27 (t, 1H, H-6´); 7.41 (t,
1H, Hp of Ph); 7.57 (d, 1H, H-7´); 7.60 (t, 2H, Hm of Ph); 8.28 (d,
2H, Ho of Ph); 8.44 (s, 1H, H-2´); 8.47 (d, 1H, H-4´); 11.89 (s, 1H,
NH). 13C NMR: ꢀ = 14.4 (CH3); 56.2 (OCH3); 60.22 (OCH3); 99.2
(C-5); 106.8 (Co trimethoxyphenyl); 111.7 (C-3a); 112.2 (C-7´);
112.8 (C-3´); 118.7 (CN); 120.9 (C-5´); 121.1 (Co Ph); 121.4 (C-
2´); 122.6 (C-6´); 126.0 (Ci trimethoxyphenyl); 126.4 (Cp Ph);
129.1 (Cm Ph); 129.2 (Cp trimethoxyphenyl); 129.4 (C-4´); 136.4
(C-7´a); 138.3 (C-3´a); 138.4 (Ci Ph); 144.0 (C-3); 150.1 (C-6a);
152.6 (C-4); 152.8 (Cm trimethoxyphenyl); 155.4 (C-6). The mass
spectrum shows the following peaks: MS (70eV) m/z (%) = 515
(100, M+), 484 (23), 414 (8), 258 (10), 77 (31), 51 (13). HR-MS
(EI): C31H25N5O3 calcd 515.1957 found 515.1967.
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