One-pot three-component synthesis of spiro[pyrazolo[3,4-b]pyridine-4, 3′-indoline] derivatives catalyzed by melamine trisulfonic acid

Article abstract of DOI:10.1002/jccs.201200046

Novel spiro[pyrazolo[3,4-b]pyridine-4,3′-indoline] derivatives were prepared by the three-component reaction of isatins 3-methyl-1-phenyl-1H- pyrazol-5-amine and Meldrum's acid in the presence of a catalytic amount of melamine trisulfonic acid. This protocol provides a simple one-step procedure with the advantages of easy work-up, mild reaction conditions and environmentally benign.

Full text of DOI:10.1002/jccs.201200046

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
One-pot Three-component Synthesis of Spiro[pyrazolo[3,4-b]pyridine-4,3¢-indoline]
Derivatives Catalyzed by Melamine Trisulfonic Acid
Li-Min Yang, Peng-Li Sun and Li-Qiang Wu*
School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P. R. China
(Received: Feb. 1, 2012; Accepted: May 28, 2012; Published Online: ??; DOI: 10.1002/jccs.201200046)
Novel spiro[pyrazolo[3,4-b]pyridine-4,3¢-indoline] derivatives were prepared by the three-component re-
action of isatins 3-methyl-1-phenyl-1H-pyrazol-5-amine and Meldrum’s acid in the presence of a catalytic
amount of melamine trisulfonic acid. This protocol provides a simple one-step procedure with the advan-
tages of easy work-up, mild reaction conditions and environmentally benign.
Keywords: Spiro[pyrazolo[3,4-b]pyridine-4,3¢-indoline]; Melamine trisulfonic acid; Catalysis;
Green chemistry.
INTRODUCTION
Multi-component reactions (MCRs), in which multi-
MTSA as a solid acid catalyst is prepared from reaction of
melamine with neat chlorosulfonic acid at room tempera-
ture.13
ple reactions are combined into the synthetic operation
have been used extensively to form carbon-carbon bonds in
the synthetic chemistry.1 Such reactions offer a wide range
of possibilities for the efficient constrution of highly com-
plex molecules in a single procedure, thus avoiding the
complicated purification operations and allowing savings
of both solvents and reagents. In the past decade, there has
been tremendous development in three- and four-compo-
nent reactions, and great efforts continue to be made to de-
velop new MCRs.2
Herein, we describe a simple and efficient protocol
for rapid preparation of spiro[pyrazolo[3,4-b]pyridine-
4,3¢-indoline] derivatives using a catalytic amount of recy-
clable MTSA in water (Scheme I). To the best of our
knowledge, it is probably the first example of synthesizing
spiro[pyrazolo[3,4-b]pyridine-4,3¢-indoline] derivatives
using MTSA as catalyst in aqueous media. This process
provides an opportunity to use water and avoids environ-
mentally harmful conventional organic solvents.
Indole moiety is probably the most well-known het-
erocycle and a common and important feature of a variety
of natural products and medicinal agents.3 Furthermore, it
has been reported that sharing of the indole 3-carbon atom
in the formation of spiroindoline derivatives highly en-
hances biological activity.4 The spirooxindole system is the
core structure of many pharmacological agents and natural
alkaloids.5 Pyrazolo[3,4-b]pyridines have been studied for
over a century due to a variety of chemical and biological
significance. They have been reported as antibacterial,6
antimicrobial,7 antiviral,8 oncogenic Ras inhibiting9 and
cyclooxygenase inhibiting activities.10
Scheme I
EXPERIMENTAL
1H NMR spectra were determined on Bruker AV-400
spectrometer at room temperature using tetramethylsilane
(TMS) as an internal standard (DMSO-d6 solution), cou-
pling constants (J) were measured in Hz; Elemental analy-
sis were performed by a Vario-III elemental analyzer; Melt-
ing points were determined on a XT-4 binocular micro-
scope and were uncorrected; Commercially available re-
agents were used throughout without further purification
unless otherwise stated.
Recently, melamine trisulfonic acid (MTSA) has
emerged as a promising solid acid catalyst for acid-cata-
lyzed reactions, such as acetylation of alcohols, phenols,
and amines,11 oxathioacetalyzation of aldehydes,12 the
nitrosation of secondary amines and oxidation of ura-
zoles.13 This catalyst is safe, easy to handle, and environ-
mentally benign, and presents fewer disposal problems.
* Corresponding author. Tel: +086-373-3029879; Fax: +086-373-3029879; E-mail: wliq870@163.com
J. Chin. Chem. Soc. 2012, 59, 000-000
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1

Article
Yang et al.
3,5¢-Dimethyl-1-phenyl-1,5-dihydro-spiro[pyrazolo[3,4-
b]pyridine-4,3¢-indoline]-2¢,6(7H)-dione (4c)
Preparation of MTSA catalyst
A 250 mL suction flask charged with 5 mL chloro-
sulfonic acid (75.2 mmol) was equipped with a gas inlet
tube for conducting HCl gas over an adsorbing solution.
Melamine (3.16 g, 25.07 mmol) was added in small por-
tions over a period of 30 min at room temperature. HCl gas
evolved from the reaction vessel immediately. After com-
pletion of the addition of melamine, the mixture was
shaken for 30 min; meanwhile, the residual HCl was re-
moved by suction. Melamine trisulfonic acid (7.7 g, 85%)
was obtained as a white solid.
Orange power, m.p. 234-235 oC; 1H NMR (400 MHz,
DMSO-d6) d: 10.70 (s, 1H, NH), 10.54 (s, 1H, NH), 7.55-
7.45 (m, 4H, Ar-H), 7.37-7.36 (m, 1H, Ar-H), 7.07-7.02
(m, 2H, Ar-H), 6.86-6.81 (m, 1H, Ar-H), 2.90 (d, 1H, J =
15.6 Hz, CH2), 2.65 (d, 1H, J = 15.6 Hz, CH2), 2.23 (s, 3H,
CH3), 1.53 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6)
d: 178.7, 169.5, 144.6, 140.7, 139.4, 138.2, 131.9, 131.5,
129.7, 129.5, 127.5, 124.7, 123.4, 110.2, 101.0, 46.2, 30.9,
21.1, 12.3; Anal. calcd for C21H18N4O2: C 70.38, H 5.06, N
15.63; found: C 70.33, H 4.99, N 15.56.
General procedure for the preparation of 4
5¢-Fluoro-3-methyl-1-phenyl-1,5-dihydro-spiro[pyra-
zolo[3,4-b]pyridine-4,3¢-indoline]-2¢,6(7H)-dione (4d)
Orange power, m.p. 144-145 oC; 1H NMR (400 MHz,
DMSO-d6) d: 10.71 (s, 1H, NH), 10.64 (s, 1H, NH), 7.50-
7.38 (m, 4H, Ar-H), 7.37-7.35 (m, 1H, Ar-H), 7.21-7.19
(m, 1H, Ar-H), 7.13-6.93. (m, 1H, Ar-H), 6.92-6.91 (m,
1H, Ar-H), 3.11 (d, 1H, J = 16 Hz, CH2), 2.63 (d, 1H, J =
15.6 Hz, CH2), 1.52 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) d: 178.7, 169.3, 157.5, 144.5, 140.8, 138.4,
133.4, 133.3, 129.7, 127.6, 123.4, 115.8, 112.3, 111.3,
100.3, 46.7, 30.9, 12.3; Anal. calcd for C20H15FN4O2: C
66.29, H 4.17, N 15.46; found: C 66.32, H 4.09, N 15.52.
5¢-Bromo-3-methyl-1-phenyl-1,5-dihydro-spiro[pyra-
zolo[3,4-b]pyridine-4,3¢-indoline]-2¢,6(7H)-dione (4e)
Orange power, m.p. 198-200 oC; 1H NMR (400 MHz,
DMSO-d6) d: 10.78 (s, 1H, NH), 10.71 (s, 1H, NH), 7.50-
7.44 (m, 6H, Ar-H), 7.39-7.36 (m, 1H, Ar-H), 6.91-6.89
(m, 1H, Ar-H), 3.07 (d, 1H, J = 15.6 Hz, CH2), 2.69 (d, 1H,
J = 15.6 Hz, CH2), 1.53 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) d: 178.3, 169.3, 144.4, 141.4, 140.8, 138.1,
134.2, 132.0, 129.7, 127.6, 127.1, 123.7, 123.4, 114.2,
112.4, 100.3, 46.4, 30.9, 12.3; Anal. calcd for
C20H15BrN4O2: C 56.75, H 3.57, N 13.24; found: C 56.71,
H 3.49, N 13.32.
A mixture of isatins (1 mmol), 3-methyl-1-phenyl-
1H-pyrazol-5-amine (1 mmol), Meldrum’s acid (1 mmol)
and MTSA (0.05 mmol) in water (5 mL) was heated at re-
flux for an appropriate time (TLC). After completion of the
reaction, the reaction mixture was cooled to room tempera-
ture. Then, the precipitated product was filtered and washed
with water and cooled ethanol to afford the products. The
filtrate was evaporated under reduced pressure, after re-
moval of the water, MTSA was recovered. The recovering
washed with CH2Cl2, dried in an oven at 100 °C for 30 min
prior to use.
3-Methyl-1-phenyl-1,5-dihydro-spiro[pyrazolo[3,4-b]-
pyridine-4,3¢-indoline]-2¢,6(7H)-dione (4a)
Yellow power, m.p. 236-237 oC; 1H NMR (400 MHz,
DMSO-d6) d: 10.71 (s, 1H, NH), 10.63 (s, 1H, NH), 7.50-
7.46 (m, 4H, Ar-H), 7.37-7.22 (m, 3H, Ar-H), 7.02-6.92
(m, 2H, Ar-H), 2.99 (d, 1H, J = 15.6 Hz, CH2), 2.65 (d, 1H,
J = 15.6 Hz, CH2), 1.50 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) d: 178.7, 169.5, 144.6, 142.0, 140.8, 138.2,
131.7, 129.7, 129.3, 127.5, 124.3, 123.4, 122.6, 110.4,
100.8, 46.2, 30.7, 12.2; Anal. calcd for C20H16N4O2: C
69.76 H 4.68, N 16.27; found: C 69.60, H 4.72, N 16.20.
5¢-Chloro-3-methyl-1-phenyl-1,5-dihydro-spiro[pyra-
zolo[3,4-b]pyridine-4,3¢-indoline]-2¢,6(7H)-dione (4b)
Orange red power, m.p. 181-183 oC; 1H NMR (400
MHz, DMSO-d6) d: 10.77 (s, 1H, NH), 10.71 (s, 1H, NH),
7.60-7.47 (m, 4H, Ar-H), 7.38-7.31 (m, 3H, Ar-H), 6.95-
6.86 (m, 1H, Ar-H), 3.08 (d, 1H, J = 16 Hz, CH2), 2.68 (d,
1H, J = 15.6 Hz, CH2), 1.53 (s, 3H, CH3); 13C NMR (100
MHz, DMSO-d6) d: 178.4, 169.3, 144.4, 141.0, 140.9,
138.1, 133.8, 129.7, 129.2, 127.6, 126.6, 124.5, 123.4,
111.9, 100.2, 46.5, 30.9, 12.3; Anal. calcd for
C20H15ClN4O2: C 63.41, H 3.99, N 14.79; found: C 63.36,
H 4.05, N 14.85.
1¢,3-Dimethyl-1-phenyl-1,5-dihydro-spiro[pyrazolo[3,4-
b]pyridine-4,3¢-indoline]-2¢,6(7H)-dione (4f)
o
1
Blackish green power, m.p. 110-112 C; H NMR
(400 MHz, DMSO-d6) d: 10.75 (s, 1H, NH), 7.50-7.46 (m,
4H, Ar-H), 7.39-7.28 (m, 3H, Ar-H), 7.13-7.07 (m, 2H,
Ar-H), 3.18 (s, 3H, CH3), 3.04 (d, 1H, J = 16 Hz, CH2), 2.67
(d, 1H, J = 16 Hz, CH2), 1.44 (s, 3H, CH3); 13C NMR (100
MHz, DMSO-d6) d: 176.8, 169.4, 144.5, 143.6, 140.8,
138.2, 130.9, 129.7, 129.4, 127.5, 123.9, 123.4, 123.2,
109.5, 100.6, 45.8, 30.9, 26.7, 12.2; Anal. calcd for
C21H18N4O2: C 70.38, H 5.06, N 15.63; found: C 70.40, H
2
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Synthesis of Spiro[pyrazolo[3,4-b]pyridine-4,3¢-indoline]
Table 2. Preparation of spiro[pyrazolo[3,4-b]pyridine-4,3'-indo-
lines][a]
5.02, N 15.50.
Entry
R1
R2
Time/h
Product
Yield/%[b]
RESULTS AND DISCUSSION
The choice of an appropriate reaction media is of cru-
cial importance for successful synthesis. Initially, the
three-component reaction of isatin (1a), 3-methyl-1-phen-
yl-1H-pyrazol-5-amine (2) and Meldrum’s acid (3) as a
simple model substrate was investigated to establish the
feasibility of the strategy and optimize the reaction condi-
tions (Table 1). Different solvents and catalysts were
screened in the model reaction. As could be seen in Table 1,
the best result was obtained with a 5 mol% of MTSA as the
catalyst in refluxing water and the desired product, 3-meth-
yl-1-phenyl-1,5-dihydro-spiro[pyrazolo[3,4-b]pyridine-
4,3¢-indoline]-2¢,6(7H)-dione 4a, is obtained in good yield
(entry 5). Using lower amount of catalyst resulted in lower
yields, while higher amount of catalyst did not affect reac-
tion times and yields (Table 1). When this reaction was car-
ried out without any catalyst, TLC and 1H NMR spectra of
the reaction mixture showed a combination of starting ma-
terials and numerous products, the yield of the expected
product was very poor (Table 1, entry 1).
1
2
3
4
5
6
H
H
H
Cl
Me
F
4
3
4a
4b
4c
4d
4e
4f
94 (90, 89, 85 )[c]
91
88
92
93
87
H
5
H
3
H
Br
H
2.5
3.5
Me
a Reaction conditions: isatins (1 mmol); 3-methyl-1-phenyl-1H-
pyrazol-5-amine (1 mmol); Meldrum's acid (1 mmol); MTSA
(0.05 mmol); H2O (5 mL); reflux.
b Isolated yield.
c The catalyst was reused for four runs.
10.63 (D2O exchangeable) due to –NH, two double at d
2.99 and 2.65 due to –CH2 and aromatic protons in the
range d 6.92–7.50. Resonances at d 46.2 (spiro carbon), d
169.5 (–C=O group) and d 178.7 (isatin –C=O group) were
observed in the 13C NMR spectrum.
The reusability of the catalyst was tested in the syn-
thesis of 4a. The catalyst was recovered after each run,
washed with CH2Cl2, dried in an oven at 100 °C for 30 min
prior to use, and tested for its activity in the subsequent run
with no fresh catalyst added. The catalyst was tested for
four runs. It was seen that the catalyst displayed very good
reusability (Table 2, entry 1).
After optimizing the reaction conditions, a variety of
isatins were employed under similar circumstances to eval-
uate the substrate scope of this reaction. The results are
shown in Table 2. As anticipated from our original results,
these reactions proceeded very cleanly at refluxing water
and no undesirable side reactions were observed. The 1H
NMR spectrum of 4a exhibited two singlet at d 10.71 and
The formation of products 4a–4f can be rationalized by
initial formation of heterodiene 5 by standard Knoevenagel
condensation of Meldrum’s acid 3 and isatins 1 in the pres-
ence of a catalytic amount of MTSA. Subsequent Michael-
type addition of 3-methyl-1-phenyl-1H-pyrazol-5-amine 2
to the heterodienes 5 followed by cyclization, removing
CO2 and acetone afford the corresponding products 4a–4f
(Scheme II).
Table 1. Optimization of reaction conditions for synthesis of 4a[a]
Yield/
[b]
%
Entry
Conditions
Catalyst
Time/h
1
H2O (reflux)
H2O (reflux)
H2O (reflux)
H2O (reflux)
H2O (reflux)
H2O (reflux)
H2O (reflux)
H2O (reflux)
H2O (reflux)
-
12
5
5
4
4
4
4
8
7
8
9
5
6
trace
69
78
86
94
93
93
35
68
72
42
63
70
2
MTSA (2 mol%)
MTSA (3 mol%)
MTSA (4 mol%)
MTSA (5 mol%)
MTSA (6 mol%)
MTSA (7 mol%)
H2SO4 (5 mol%)
p-TsOH (5 mol%)
3
Scheme II
4
5
6
7
8
9
10
11
12
13
H2O (reflux) NH2SO3H (5 mol%)
H2O (reflux)
FeCl3 (5 mol%)
MTSA (5 mol%)
EtOH (reflux)
CH3CN (reflux) MTSA (5 mol%)
a Reaction conditions: isatin (1 mmol); 3-methyl-1-phenyl-1H-
pyrazol-5-amine (1 mmol); Meldrum's acid (1 mmol).
b Isolated yield.
J. Chin. Chem. Soc. 2012, 59, 000-000
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3

Article
Yang et al.
New York, 1996.
CONCLUSIONS
4. (a) Da-Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz.
Chem. Soc. 2001, 12, 273. (b) Abdel-Rahman, A. H.; Keshk,
E. M.; Hanna, M. A.; El-Bady, Sh. M. Bioorg. Med. Chem.
2006, 12, 2483.
In conclusion, we have demonstrated a simple and en-
vironmental friendly protocol for the synthesis of spiro-
[pyrazolo[3,4-b]pyridine-4,3¢-indoline] derivatives using
MTSAas a catalyst in aqueous media. The method employs
inexpensive, non-toxic, and an easily available catalyst and
eliminates the use of hazardous organic solvents. Further
studies to delineate the scope and limitations of the present
methodology are underway.
5. (a) Kang, T.-H.; Matsumoto, K.; Murakami, Y.; Takayama,
H.; Kitajima, M.; Aimi, N.; Watanabe, H. Eur. J. Pharmacol.
2002, 444, 39. (b) Usui, T.; Kondoh, M.; Cui, C.-B.;
Mayumi, T.; Osada, H. Biochem. J. 1998, 333, 543.
6. Thakor, S. F.; Patel, Dinesh, M.; Patel, M. P.; Patel, R. G.
Saudi. Pharma. J. 2007, 15, 48.
7. (a) Amin, M. A.-S.; Ismail, M. M.; Barakat, S. E.-S.; Ab-
dul-Rahman, A. A. A.; Bayomi, A. H.; El-Gamal, K. M. A.
Bull. Pharm. Sci. Assiut Univ. 2004, 27, 237. (b) El-Sayed,
O. A.; Aboul-Enein, H. Y. Arch. Pharm. 2001, 334, 117.
8. Radl, S.; Zikan, V.; Smejkal, F. Collect. Czech. Chem.
Commun. 1985, 50, 1057.
ACKNOWLEDGEMENTS
We are pleased to acknowledge the financial support
from Xinxiang Medical University.
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J. Chin. Chem. Soc. 2012, 59, 000-000