An efficient synthesis of pyrazolo[3,4-b]pyridine-4-spiroindolinones by a three-component reaction of 5-aminopyrazoles, isatin, and cyclic β-diketones

Article abstract of DOI:10.1016/j.tetlet.2011.03.067

Novel pyrazolopyridine-spiroindolinones were prepared by the three-component reaction of 5-aminopyrazoles, isatin, and cyclic β-diketones in aqueous media and catalyzed by p-TSA. This protocol provides a simple one-step procedure with the advantages of ea

Full text of DOI:10.1016/j.tetlet.2011.03.067

Tetrahedron Letters 52 (2011) 2664–2666
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An efficient synthesis of pyrazolo[3,4-b]pyridine-4-spiroindolinones by a
three-component reaction of 5-aminopyrazoles, isatin, and cyclic b-diketones
Jairo Quiroga a, , Sandra Portillo a, Alfredo Pérez b, Jaime Gálvez a, Rodrigo Abonia a, Braulio Insuasty a
⇑
a Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A.A. 25360 Cali, Colombia
b Grupo de Investigación en Compuestos Heterocíclicos, Programa de Química, Universidad del Atlántico, Km 7 vía antigua Puerto Colombia, Barranquilla, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel pyrazolopyridine-spiroindolinones were prepared by the three-component reaction of 5-aminopy-
razoles, isatin, and cyclic b-diketones in aqueous media and catalyzed by p-TSA. This protocol provides a
simple one-step procedure with the advantages of easy work-up, mild reaction conditions and environ-
mentally benign.
Received 14 February 2011
Revised 10 March 2011
Accepted 14 March 2011
Available online 21 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazolopyridine-spiroindolinone
Isatin
5-Aminopyrazoles
Cyclic b-diketones
Compounds with spiro skeletons not only constitute subunits in
numerous alkaloids, but are also templates for drug discovery and
have been used as scaffolds for combinatorial libraries.1 Synthesis
of some spiro-derivatives has been performed by conventional
methods and procedures based on three-component one-pot
approaches.2
mentally friendly methodologies for the preparation of these com-
pounds, herein we report a three-component reaction between 5-
amino-3-methyl-1-phenylpyrazole 5a, b-diketones 3 and isatin 6
in aqueous media and catalytic p-TSA, leading to the formation of
several
pyrazolopyridine-spiroindolinone
derivatives
7a–g
(Scheme 2, Table 1).10
Isatin is a privileged lead molecule for designing potential bio-
active agents, and its derivatives have been shown to possess a
broad spectrum of bioactivity, as many of which have been as-
sessed as anti-HIV,3 anti-viral,4 anti-tumor,5 anti-fungal,6 and
anti-convulsants7 agents. These interesting properties have
prompted many efforts toward the synthesis and pharmacological
screening of isatin derivatives.
In our interest in the development of synthetic strategies to
obtain functionalized heterocycles,8 we have concentrated much
of our recent efforts in the preparation of such bioactive nitro-
gen-containing heterocycles, and have already reported simple
and efficient procedures to reach interesting molecules such as
pyrazolo[3,4-b]pyridines with biological properties.9
O
O
3
O
2
N
Ar
O
N
N
H
N
1
N
N
H
H
O
Ar
4
Scheme 1.
Recently, we have described the three-component reaction be-
tween 5-(4-R-benzylamino)pyrazoles 1, paraformaldehyde 2, and
cyclic b-diketones 3 by conventional heating or by microwave irra-
diation to obtain pyrazolo[3,4-b]pyridine-5-spirocycloalkane-
dione (Scheme 1).2e
H
N
O
O
O
O
N
PTSA
80 0C
NH2
N
N
O
N
As part of our program on the synthesis of spiro-heterocyclic
compounds and the development of newselective and environ-
N
H
N
O
3
H
6
5a
7a-g
⇑
Corresponding author. Fax: +57 2 33392440.
E-mail address: jaiquir@univalle.edu.co (J. Quiroga).
Scheme 2.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.067

J. Quiroga et al. / Tetrahedron Letters 52 (2011) 2664–2666
2665
Table 1
In order to evaluate the versatility and regiochemistry of this
procedure we performed the three-component reaction, under
the same reaction conditions,10 between 5-amino-1H-pyrazoles
5b and 5c, b-diketones 3 and isatin 6. The presence of a third nucle-
ophilic center in the 1-NH-aminopyrazoles 5b,c, could lead to the
formation of spiro-pyrazolo[3,4-b]pyridines 8 or spiro-pyrazol-
o[1,5-a]pyrimidines 9 (Scheme 3).
Pyrazolopyridine-spiroindolinone derivatives 7a–g
Entry
b-Diketone
Product
Mp (°C)
Yield (%)
m/z
O
H
N
O
O
N
O
a
241–243
75
424
N
N
H
Table 2
Pyrazolopyridine-spiroindolinone derivatives 8a–j
O
O
H
N
Entry Pyrazole b-Diketone
Product
Mp °C Yield m/z
O
(%)
O
N
O
H
N
b
c
d
e
f
315–318
304–305
335–337
>350
78
45
72
77
70
52
396
430
382
412
458
445
N
N
N
N
N
N
N
O
N
O
H
320–
322
a
b
c
5b
5b
5b
78
348
306
336
O
N
N
O
O
H
N
H
H
O
O
H
O
N
O
N
O
N
O
>350 65
N
H
N
N
H
H
O
O
H
N
O
H
N
HN
O
N
O
N
O
O
>350 96
N
H
O
O
NH
N
N
N
H
N
O
H
H
H
O
H
N
O
H
N
O
N
O
333–
75
HN
OH
d
5b
382
O
O
N
335
O
O
N
H
O
N
N
O
NH
H
H
O
O
N
H
N
H
O
H
N
O
O
N
323–
67
O
H
N
O
e
f
5b
5c
5c
5c
5c
5c
268
410
368
416
398
330
325
O
O
O
N
N
N
H
H
O
O
304–307
298–300
O
H
O
O
N
N
H
O
O
O
O
>350 60
O
N
N
N
N
N
H
N
N
H
N
H
O
N
O
H
N
N
H
NH
g
O
O
N
H
g
h
i
>350 68
O
N
H
N
H
O
H
N
O
O
318–
49
H
N
320
O
N
H
N
O
O
O
R
N
H
O
H
N
N
H
O
N
H
HN
R
O
O
3
8a-j
>350 92
N
H
O
O
N
NH
NH2
N
H
H
N
H
N
H
N
N
O
O
H
5b: R = CH3
5c: R = C6H5
O
O
O
H
O
N
N
O
N
H
N
R
O
X
N
H
6
O
j
>350 75
O
O
9
N
H
N
H
Scheme 3.

2666
J. Quiroga et al. / Tetrahedron Letters 52 (2011) 2664–2666
H
N
O
O
O
O
O
-H2O
R
5a-c
O
O
7a-e, 8a-j
O
O
N
N
H
NH2
N
6
3
N
H
O
11
R1
10
R = CH3, C6H5
R1 = C6H5, H
Scheme 4.
4. Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.;
Tuntland, T.; Zhang, K.; Karanewsky, D.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16,
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8. (a) Quiroga, J.; Trilleras, J.; Insuasty, B.; Abonía, R.; Nogueras, M.; Cobo, J.
Tetrahedron Lett. 2008, 49, 2689–2691; (b) Quiroga, J.; Trilleras, J.; Insuasty, B.;
Abonía, R.; Nogueras, M.; Marchal, A.; Cobo, J. Tetrahedron Lett. 2008, 49, 3257–
3259; (c) Quiroga, J.; Insuasty, B.; Insuasty, H.; Abonía, R.; Ortíz, A. J.; Sánchez,
A.; Nogueras, M. J. Heterocycl. Chem. 2001, 38, 339–341; (d) Quiroga, J.;
Hormaza, A.; Insuasty, B.; Ortíz, A. J.; Sánchez, A.; Nogueras, M. J. Heterocycl.
Chem. 1998, 35, 231–233; (e) Quiroga, J.; Hormaza, A.; Insuasty, B.; Saitz, C.;
Jullian, C. J. Heterocycl. Chem. 1998, 35, 575–578; (f) Quiroga, J.; Mejía, D.;
Insuasty, B.; Abonía, R.; Nogueras, M.; Sánchez, A.; Cobo, J.; Low, J. N.
Tetrahedron 2001, 57, 6947–6953.
9. (a) Quiroga, J.; Cruz, S.; Insuasty, B.; Abonía, R.; Hernandez, P.; Bolaños, A.;
Moreno, R. J. Heterocycl. Chem. 1998, 35, 333–338; Orlov, V. D.; Quiroga, J.;
Kolos, N. N. Khim. Geterosikl. Soedin. 1987, 1247–1251. CA: 88, 167373; (c)
Quiroga, J.; Portilla, J.; Serrano, H.; Abonía, R.; Insuasty, B.; Nogueras, M.; Cobo,
J. Tetrahedron Lett. 2007, 48, 1987–1990; (d) Quiroga, J.; Cobo, D.; Insuasty, B.;
Abonía, R.; Cruz, S.; Nogueras, M.; Cobo, J. J. Heterocycl. Chem. 2008, 45, 155–
159; (e) Quiroga, J.; Trilleras, J.; Sánchez, A. I.; Insuasty, B.; Abonía, R.;
Nogueras, M.; Cobo, J. Lett. Org. Chem. 2009, 6, 381–383.
The reaction showed a high regioselectivity. In all cases only a
sole regioisomer 8 was obtained and in good yields (60–96%) (only
one product, pyrazolo[3,4-b]pyridine-spiroindolinones 8a–j)
(Table 2). We consider that the formation of the pyrazolepyridine
isomer 8 is due to the higher nucleophilicity of the C-4 over the
N-1 in the aminopyrazole 5b,c. This orientation has been observed
by us in the reaction of NH-5-aminopyrazoles with dimedone and
other carbonyl compounds.8e,f
The structures of all new compounds were determined on the
basis of their analytical techniques, 1D and 2D NMR, and MS, spec-
troscopic data which agree with the proposed structures.
A possible mechanism for the established three-component
reaction is outlined in Scheme 4. We consider that the b-diketone
iniatilly reacts with isatin to give the condensation product 10,
which undergoes a Michel-type addition of 5-aminopyrazole 5a–c
followed by the cyclocondensation of the intermediate adduct 11
to give the corresponding products 7a–g and 8a–j.
In summary, the described three component synthesis in aque-
ous media is a simple, practical, environmentally friendly and very
regioselective method for the preparation of some novel heterocy-
clic compound containing spiropyrazolopyridine system, with the
advantages of easy work-up and mild reaction conditions. The bio-
logical and fluorescent properties of the new compounds obtained
in this research are under investigation.
10. General procedure for the preparation of pyrazolopyridine-spiroindolinones 7a–g
and 8a–j.
A solution of 5-aminopyrazole 5a–c (0.1 mmol), b-diketone 3
(0.1 mmol) and isatin 6 (0.1 mmol) in H2O/EtOH [5:1 (v/v))] and a catalytic
amounts of PTSA (0.1 g) was heated at 80 °C (water bath) for 6–12 h. Then, the
reaction mixture was filtered hot and the resulting solid products were washed
with ethanol, dried in air and recrystallized from ethanol.
Acknowledgements
Data
for
( )-3,7,7-trimethyl-1-phenyl-6,7,8,9-tetrahydrospiro[pyrazolo[3,4-
b]quinoline-4,30-indoline]-20,5(1H)-dione 7a: Beige solid, yield 75%, 241–
243 °C. 1H NMR (400 MHz DMSO-d6) d: 1.00 (s, 3H, CH3-7), 1.03 (s, 3H, CH3-
7), 1.57 (s, 3H, CH3-3), 2.00 (d, 1H, H-6 J = 16.0 Hz), 2.11 (d, 1H, H-6 J = 16.0 Hz),
2.58 (s, 2H, H-8), 6.81 (d, 1H, H-70), 6.85–6.87 (m, 2H, H-40, H-50), 7.09–7.13 (m,
1H, H-60), 7.40–7.44 (m, 1H, Hp), 7.51–7.57 (m, 4H, Hm, Ho), 9.68 (s, 1H, H-9),
10.32 (s, 1H, H-10). 13C NMR (100 MHz DMSO-d6) d: 11.8 (CH3-3), 27.4 (CH3-7),
28.6 (CH3-7), 32.6 (C-7), 41.4 (C-8), 49.2 (Cspiro), 50.9 (CH2-6), 102.1 (C-3a),
108.4 (C-4a), 109.0 (C-70), 121.9 (C-50), 123.6 (C-40), 123.9 (Co), 127.6 (Cp),
127.7 (C-60), 129.9 (Cm), 137.1 (C-3a0), 137.5 (Ci), 138.3 (C-9a), 142.2 (C-7a0),
145.5 (C-3), 153.5 (C-8a), 180.0 (C-20), 193.8 (C-5). IE EM: m/z: 424 (M+, 7), 380
(8), 340 (100), 312 (19). Anal. Calcd for C26H24N4O2.H2O: C, 70.57; H, 5.92; N,
12.66; found: C, 70.81; H, 5.99; N, 12.70.
Data for ( )-3,7,7-trimethyl-6,7,8,9-tetrahydrospiro[pyrazolo[3,4-b]quinoline-
4,3’-indoline]-20,5(1H)-dione 8a: Beige solid, yield 78%, 320–322 °C. 1H NMR
(400 MHz DMSO-d6) d: 1.00 (s, 3H, CH3-7), 1.03 (s, 3H, CH3-7), 1.58 (s, 3H, CH3-
3), 1.94 (d, 1H, H-6 J = 16.00 Hz), 2.06 (d, 1H, H-6 J = 16.0 Hz), 2.44 (s, 1H, H-8
J = 16.0 Hz), 2.51 (s, 1H, H-8 J = 16.0 Hz), 6.73–6.81 (m, 3H, H-70, H-40, H-50),
7.05 (dd, 1H, H-60), 9.94 (s, 1H, H-9), 10.16 (s, 1H, H-10), 11.89 (s, 1H, H-1). 13C
NMR (100 MHz DMSO-d6) d: 9.1 (CH3-3), 27.5 (CH3-7), 28.7 (CH3-7), 32,5 (C-7),
41.8 (C-8), 48.7 (Cspiro), 50.9 (C-6), 101.9 (C-3a), 105.7 (C-4a), 108.8 (C-70),
121.7 (C-50), 123.0 (C-40), 127.2 (C-60), 134.9 (C-9a), 138.1 (C-3a0), 142.1 (C-7a0),
146.5 (C-3), 154.6 (C-8a),180.2 (C-20), 192,6 (C-5). IE EM: m/z: 348 (M+, 20),
304 (10), 264 (100), 236 (15). Anal. Calcd for C20H20N4O2: C, 68.95; H, 5.79; N,
16.08; found: C, 68.97; H, 5.75; N, 16.09.
Authors wish to thank COLCIENCIAS, Universidad del Atlántico
and Universidad del Valle for financial support.
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