Microwave-Assisted Catalyst Free Three Component Synthesis of Mono and Bis Spiro Pyrazolopyridines in Solvent Free Reaction

Article abstract of DOI:10.1002/jhet.2124

Multicomponent synthesis of mono and bis-spiro pyrazolopyridines from isatin derivatives, indanedione, and 3-methyl-5-aminopyrazole under microwave irradiation in the absence of any catalyst or solvent with high yield and short reaction time is reported.

Full text of DOI:10.1002/jhet.2124

Month 2014
Microwave-Assisted Catalyst Free Three Component Synthesis of
Mono and Bis Spiro Pyrazolopyridines in Solvent Free Reaction
a
b
a
*
Mohammad Nikpassand, Leila Zare Fekri, and Neda Jamshidi
aDepartment of Chemistry, Rasht Branch, Islamic Azad University, Rasht, Iran
bDepartment of Chemistry, Payame Noor University, Tehran, Iran
*
E-mail: nikpassand@iaurasht.ac.ir
Received June 28, 2013
DOI 10.1002/jhet.2124
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Multicomponent synthesis of mono and bis-spiro pyrazolopyridines from isatin derivatives, indanedione,
and 3-methyl-5-aminopyrazole under microwave irradiation in the absence of any catalyst or solvent with
high yield and short reaction time is reported.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
Recently, the application of microwaves in organic syn-
thesis is very popular, because they often proceed much
faster and deliver products in higher yield and higher
purity. It has been demonstrated that the use of microwave
irradiation can allow precise control of reaction parameters.
The energy of the microwave is directly transferred to the
molecules of the reaction mixture via dielectric heating,
which is relatively faster and more efficient than conven-
tional heating procedure. Because this heating caused by
dipolar polarization.
The pyrazolopyridine ring system represents the core
skeleton of a pharmaceutically important class of hetero-
cyclic compounds possessing a broad range of biological
activities, such as potent cyclin kinase 1(CDK1) inhibitor
[1], HIV reverse transcriptase inhibitor [2], chemokine
receptor 1 antagonists [3], protein kinase inhibitors [4],
inhibitors of cyclic guanosine monophosphate degradation
[5], inhibitors of xantine oxidases [6], antiviral [7], potent
antimalarial agents [8] vasodilator,[9] antimicrobial [10],
anti-inflammatory [11], anxiolytic [12], hypoglycemic [13],
and antitumor agents [14].
RESULT AND DISCUSSION
Compounds with spiro skeleton not only constitute sub-
units in numerous alkaloids but also are templates for drug
discovery and have been used as scaffolds for combinato-
rial libraries [15]. On the other hand, isatin is a privileged
lead molecule for designing potential bioactive agents, and
its derivatives have been shown to possess a broad range
of bioactivity as many of which have been assessed as
anti-HIV [16], antiviral [17], antifungal [18], antitumor
[19], and anticonvulsant agents [20]. In order to enhance
the activity of isatin, it is a hot topic to construct isatin
containing pyrazolopyridine moiety in green, efficient,
and simple condition.
In our interest for the development of green synthetic
strategies to obtain heterocyclic pharmaceutical compounds
[21–25], we have concentrated on to report the first micro-
wave- assisted catalyst free multicomponent synthesis of
spiropyrazolopyridines via 5-aminopyrazole, isatin deriva-
tives, and indane-1,3-dione. Furthermore, to improve the
pharmaceutical properties of pyrazolopyridines, we were
triggered to prepare novel bis spiropyrazolopyridines.
Initially, the reaction of isatin (1a), indan-1,3-dione (4),
and 5-aminopyrazole (5) was studied (i) at reflux condition
and (ii) under microwave condition. As expected, the
© 2014 HeteroCorporation

M. Nikpassand, L. Zare Fekri, and N. Jamshidi
Vol 000
reaction at 140°C under microwave irradiation proceeded
in higher yield and shorter reaction time without any unde-
sirable by-product. Further optimization of the reaction
was performed by checking the solvent such as EtOH,
CH3CN, DMF, and H2O. On the contrary, the reaction
worked well under solvent free conditions (Table 1).
To investigate the scope of this synthesis, different
synthesized bis isatin and mono isatins were reacted with
indane1,3-dione and aminopyrazole under microwave
reactor condition, and the results were listed in Table 2.
All of synthesized compounds were prepared in racemic
mixture.
of execution. This simple process makes this procedure
economic, benign, and a waste-free chemical process for
the synthesis of pyrazolopyridines.
EXPERIMENTAL
Infrared spectra were determined on a Shimadzo IR-470
spectrometer (Japan). 1H nmr and 13C nmr spectra were recorded
on a 500 MHz Bruker DRX-500 (Germany) in CDCl3 as solvent
and tetramethylslane as internal standard. Chemicals were pur-
chased from Merck and Fluka. Elemental analyses were
performed on a Carlo-Erba EA1110CNNO-S analyzer (China)
and agreed with the calculated values. All microwave-assisted re-
actions were performed using a Discover single mode cavity mi-
crowave synthesizer (CEM Corp., India). All solvents used were
dried and distilled according to standard procedures.
All of synthesized compound are new and were charac-
terized by ir, nmr, and elemental analysis.
General procedure for the synthesis of mono and bis
CONCLUSION
spiropyrazolopyridines.
A mixture of isatin derivatives
(1 mmol), indandione (2 mmol), and 3-methyl-5-aminopyrazole
(1 mmol) was irradiated with microwave (300 W) for required
reaction time (2–4 min) at 140°C. After completion of the
reaction, the mixture was washed with water and filtered to
separate the product as pure crystalline products from EtOH in
92–98% yields.
3-Methyl-1H-spiro[indeno[2,1-e]pyrazolo[3,4-b]pyridine-4,3′-
indoline]-2′,5(10H)-dione, (6a). mp. 267°C dec; as a red solid;
ir (KBr): 3430, 2925, 1685, 1540, 1367; 1H nmr (DMSO-d6,
400 MHz): δH 1.56 (s, 3H), 7.25–7.29 (m, 4H), 7.47 (m, 2H),
7.53 (m, 2H), 11.58 (s, 2H); 13C nmr (DMSO-d6, 100 MHz):
δC 27.83, 30.32, 105.13, 118.94, 133.17, 135.48, 135.97, 136.76,
140.03, 140.63, 141.06, 143.51, 143.87, 144.87, 146.57, 147.00,
147.94, 149.20, 149.23, 175.65, 189.24; Anal. Calcd. for
C21H14N4O2: C, 71.18; H, 3.98; N, 15.81. Found: C, 71.27;
H, 3.88; N, 15.79.
Finally, we develop an efficient and convenient procedure
for the synthesis of mono and bis spiro pyrazolopyridines
through three component synthesis of bis isatin derivatives,
indan-1,3-dione, and aminopyrazole in the absence of cata-
lyst under microwave condition (Scheme 1). This procedure
offers advantages such as reduced reaction time, mild
reaction condition, productivity and higher yield, and ease
Table 1
Optimization of reaction and solvent on the model reaction.
Reaction
condition
Time
(min)
Yield
(%)
Entry
Solvent
EtOH
EtOH
CH3CN
DMF
5′-Chloro-3-methyl-1H-spiro[indeno[2,1-e]pyrazolo[3,4-b]
pyridine-4,3′-indoline]-2′,5(10H)-dione, (6b). mp. 253°C dec;
1
2
3
4
5
6
Reflux
120
7
7
9
5
75
78
74
80
85
97
Microwave
Microwave
Microwave
Microwave
Microwave
1
as a red solid; ir (KBr): 3450, 2965, 1687, 1611 1560, 1379; H
nmr (DMSO-d6, 400MHz): δH 1.53 (s, 3H), 7.20–7.26 (m, 4H),
7.77 (m, 2H), 8.53 (m, 1H), 11.58 (s, 2H); 13C nmr (DMSO-d6,
100 MHz): δC 28.00, 32.78, 107.90, 117.43, 123.45, 123.78,
132.11, 133.87, 135.79, 136.96, 140.57, 141.65, 142.08, 142.63,
143.44, 142.85, 145.15, 157.91, 159.98, 175.01, 188.51; Anal.
Calcd. for C21H13ClN4O2: C, 64.87; H, 3.37; N, 14.41. Found: C,
64.76; H, 3.28; N, 14.49.
H2O
Solvent free
2
EtOH, ethanol; DMF, dimethylformamide.
Table 2
5′-Bromo-3-methyl-1H-spiro[indeno[2,1-e]pyrazolo[3,4-b]
Synthesis of fused mono, bis spiro pyrazolopyridine derivatives.
pyridine-4,3′-indoline]-2′,5(10H)-dione, (6c).
mp. 289°C
dec; as a red solid; ir (KBr): 3445, 2975, 1685, 1617, 1550,
1375; 1H nmr (DMSO-d6, 400 MHz): δH 1.52 (m, 3H), 7.29–7.35
(m, 4H), 7.43 (m, 2H), 7.47 (m, 1H), 11.58 (s, 2H); 13C nmr
(DMSO-d6, 100 MHz): δC 27.65, 29.08, 103.67, 105.17, 107.96,
111.20, 111.75, 113.00, 115.23, 115.65, 117.19, 121.09, 121.78,
123.76, 145.14, 145.46, 145.98, 149.00, 150.11, 153.20, 175.45,
189.33; Anal. Calcd. for C21H13BrN4O2; C, 58.22; H, 3.02;
N, 12.93. Found: C, 58.23; H, 3.14; N, 12.89.
Entry
Product
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
6a
6b
6c
7a
7b
7c
7d
7e
7f
2
3
4
3
2
4
3
3
4
2
3
2
97
95
93
94
97
92
98
95
93
96
94
97
1,1′-(Hexane-1,6-diyl(bis(3-methyl-1H-spiro[indeno[1,2-b]
pyrazolo[3,4-e] pyridine-4,3΄-indoline]-2́,5 (10H)-dione, (7a).
9
mp. 267°C dec; as a brown solid; ir (KBr): 3446, 2925, 1685,
1
10
11
12
7g
7h
7i
1558, 1614, 1375; H nmr (DMSO-d6, 400 MHz): δH 1.48 (m,
14H), 3.75 (m, 4H), 6.95 (s, 4H), 7.09–7.16 (m, 4H), 7.25 (m,
2H), 7.32 (m, 2H), 7.43 (m, 2H), 7.53 (d, 2H, J = 6.8 Hz),
11.58 (s, 2H), 12.30 (s, 2H); 13C nmr (DMSO-d6, 100 MHz):
aYield after crystallization from EtOH.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Bis Spiro Pyrazolopyridines
Scheme 1. Synthesis of mono and bis spiropyrazolopyridines.
δC 20.94, 25.43, 27.12, 30.11, 45.51, 101.13, 118.10, 118.94,
130.07, 135.09, 135.87, 135.97, 136.01, 136.43, 136.72,
140.03, 140.63, 140.96, 143.51, 143.87, 144.23, 145.64,
151.43, 158.43, 175.45, 189.33; Anal. Calcd. for C48H38N8O4:
C, 72.90; H, 4.84; N, 14.17. Found: C, 72.87; H, 4.74; N, 14.23.
1,1′-(Pentane-1,5-diyl(bis(3-methyl-1H-spiro[indeno[1,2-b]
(d,2H, J = 8.4 Hz), 7.12 (d,2H, J = 8.0 Hz), 7.34 (m, 4H), 7.47
(m, 4H), 7.92 (m, 2H); 13C nmr (DMSO-d6, 100 MHz): δC 19.88,
23.42, 27.55, 30.33, 47.37, 103.15, 105.71, 107.19, 117.45,
117.82, 119.53, 123.02, 127.46, 127.48, 135.14, 137.92, 141.36,
145.43, 147.26, 147.38, 149.25, 151.43, 155.98, 173.82, 190.14;
Anal. Calcd. for C48H36Cl2N8O4: C, 67.06; H, 4.22; N, 13.03.
Found: C, 67.14; H, 4.26; N, 13.05.
pyrazolo[3,4-e] pyridine-4,3΄-indoline]-2,́ 5 (10H)-dione, (7b).mp.
295°C dec; as a brown solid; ir (KBr): 3045, 2927, 1679, 1571,
1608, 1352; 1H nmr (DMSO-d6, 400MHz): δH 1.53 (s, 6H), 1.78
(s, 6H), 3.76 (s, 4H), 6.92–6.99 (m, 4H), 7.11–7.14 (m, 2H), 7.19
(d, 2H, J = 6.8 Hz), 7.21–7.26 (m, 2H), 7.36 (t, 2H, J = 7.4 Hz),
7.46 (t, 2H, J = 7.4Hz), 7.71–7.77 (d, 2H, J = 6.4 Hz),11.59
(s, 2H),12.31 (s, 2H); 13C nmr (DMSO-d6, 100 MHz): δC 18.83,
23.42, 26.94, 29.31, 48.42, 103.18, 103.54, 107.83, 109.11,
113.17, 113.89, 117.01, 123.45, 123.85, 127.24, 129.83, 131.52,
131.83, 140.05, 143.85, 145.36, 147.15, 153.64, 177.43, 190.23;
Anal. Calcd. for C47H36N8O4: C, 72.67; H, 4.67; N, 14.42.
Found: C, 72.66; H, 4.63; N, 14.38.
1,1′-(Pentane-1,5-diyl(bis(5΄-chloro-3-methyl-1H-spiro[indeno
[1,2-b]pyrazolo[3,4-e]pyridine-4,3΄-indoline]-2́,5 (10H)-dione,
(7e). mp. 308°C dec; as a red solid; ir (KBr): 3074, 2925, 1712
(C═O), 1606, 1568, 1342; 1H nmr (DMSO-d6, 400MHz):
δ
H 1.54 (s, 6H), 1.73 (s, 6H), 3.74 (s, 4H), 7.04 (s, 2H),7.15–7.21
(m, 4H), 7.28 (t, 2H, J = 7.2 Hz), 7.38 (t, 3H, J = 7.0 Hz), 7.47
(t, 2H, J = 6.8 Hz), 7.75 (d, 2H, J = 6.8Hz), 11.65 (s, 2H),
12.37 (s, 2H); 13C nmr (DMSO-d6, 100MHz): δC 23.82, 27.02,
27.08, 29.32, 46.72, 102.03, 120.08, 120.42, 124.52, 127.05,
128.40, 131.08, 131.86, 135.02, 135.89, 136.06, 136.58, 136.64,
136.92, 141.80, 147.74, 158.40, 176.96, 188.94; Anal. Calcd. for
C47H34Cl2N8O4: C, 66.75; H, 4.05; N, 13.25. Found: C, 66.74; H,
4.09; N, 13.21.
1,1′-(Butane-1,4-diyl(bis(3-methyl-1H-spiro[indeno[1,2-b]
pyrazolo[3,4-e] pyridine-4,3΄-indoline]-2́,5 (10H)-dione, (7c).
mp. 297°C dec; as a brown solid; ir (KBr): 3062, 2931, 1685,
1,1′-(Butane-1,4-diyl(bis(5΄-chloro-3-methyl-1H-spiro[indeno
1
1558, 1608, 1363; H nmr (DMSO-d6, 400 MHz): δH 1.51 (m,
[1,2-b]pyrazolo[3,4-e]pyridine-4,3΄-indoline]-2́,5 (10H)-dione,
4H), 1.85 (s, 6H), 3.83 (s, 4H), 6.90–6.95 (m, 4H), 7.14–7.23
(m, 6H), 7.32 (t, 2H, J = 6.8 Hz), 7.36 (t, 2H, J = 7.2 Hz),
7.71 (d, 2H, J = 6.8 Hz) 11.58 (s, 2H), 12.29 (s, 2H); 13C
nmr (DMSO-d6, 100 MHz): δC 15.53, 25.43, 27.94, 50.12,
105.17, 105.71, 107.98, 108.03, 110.11, 115.00, 117.19,
117.83, 123.51, 123.83, 130.07, 130.51, 130.83, 137.41,
141.01, 145.23, 147.20, 147.45, 176.43, 190.11; Anal.
Calcd. for C46H34N8O4: C, 72.43; H, 4.49; N, 14.69.
Found: C, 72.55; H, 4.58; N, 14.61.
(7f). mp. 305°C dec; as a light brown solid; ir (KBr): 3070,
1
2927, 1683, 1577, 1606, 1342; H nmr (DMSO-d6, 400 MHz):
δH 1.51 (m, 4H), 1.85 (s, 6H), 3.83 (s, 4H), 6.90–6.95 (m, 4H),
7.14–7.23 (m, 6H), 7.32 (t, 2H, J = 6.8 Hz), 7.36 (t, 2H,
J = 7.2Hz), 7.71 (d, 2H, J = 6.8 Hz) 11.58 (s, 2H), 12.29 (s, 2H);
13C nmr (DMSO-d6, 100MHz): δC 15.46, 23.12, 25.66, 47.31,
107.17, 108.00, 111.23, 115.47, 115.87, 117.05, 123.43, 125.41,
125.93, 127.07, 135.44, 135.82, 135.93, 143.01, 145.11, 147.33,
147.36, 147.48, 151.20, 175.14, 189.00; Anal. Calcd. for
C46H32Cl2N8O4: C, 66.43; H, 3.88; N, 13.47. Found: C, 66.37;
H, 3.84; N, 13.42.
1,1′-(Hexane-1,6-diyl(bis(5΄-chloro-3-methyl-1H-spiro[indeno
[1,2-b]pyrazolo[3,4-e]pyridine-4,3΄-indoline]-2́,5 (10H)-dione,
(7d). mp. 308°C dec; as a brown solid; ir (KBr): 3068, 2933,
1,1′-(Pentane-1,4-diyl(bis(5΄-bromo-3-methyl-1H-spiro[indeno
1
1710 (C═O), 1577, 1602, 1346; H nmr (DMSO-d6, 400 MHz):
[1,2-b]pyrazolo[3,4-e]pyridine-4,3΄-indoline]-2́,5 (10H)-dione,
δH 1.10 (m, 4H), 1.18 (m, 4H), 1.35 (s, 6H), 3.34 (m, 4H), 6.83
(7g). mp. 305°C dec; as a brown solid; ir (KBr): 3749, 2929,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Nikpassand, L. Zare Fekri, and N. Jamshidi
Vol 000
1
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1733 (C═O), 1564, 1608, 1344; H nmr (DMSO-d6, 400 MHz):
δH 1.57–1.90 (m, 12H), 3.85 (m, 4H), 7.15–7.87 (m, 14H), 11.67
(s, 2H), 12.39 (s, 2H); 13C nmr (DMSO-d6, 100 MHz): δC 21.83,
26.53, 27.17, 30.11, 49.51, 101.51, 103.11, 103.55, 105.23,
107.07, 113.15, 113.89, 117.23, 123.47, 127.01, 129.32,
131.11,131.51,131.66, 137.15, 141.81, 143.75, 147.81, 169.17,
188.42; Anal. Calcd. for C47H34Br2N8O4: C, 60.40; H, 3.67;
N, 11.99. Found: C, 60.48; H, 3.54; N, 11.67.
1,1′-(Butane-1,4-diyl(bis(5′-bromo-3-methyl-1H-spiro[indeno
[1,2-b]pyrazolo[3,4-e]pyridine-4,3′-indoline]-2
(7h). mp. 311°C dec; as a orange solid; ir (KBr): 3080,
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́,5 (10H)-dione,
2929, 1716 (C═O), 1577, 1606, 1342; 1H -MR (DMSO-d6,
400 MHz): δH 1.54 (s, 4H), 1.79 (s, 6H), 3.82 (s, 4H), 7.13–7.15
(m, 6H),7.28–7.46 (m, 6H), 7.74 (s, 2H), 11.68 (s, 2H), 12.38
(s, 2H); 13C nmr (DMSO-d6, 100 MHz): δC 14.51, 17.83, 27.01,
27.36, 45.94, 111.36, 113.07, 113.83, 115.87, 117.23, 123.44,
127.07, 127.35, 127.91, 129.53, 131.13, 131.37, 134.43, 137.82,
139.51, 147.81, 149.24, 171.46, 187.36; Anal. Calcd. for
C46H32Br2N8O4: C, 60.01; H, 3.50; N, 12.17. Found: C, 60.11;
H, 3.65; N, 12.14.
1,1′-(1,4-Phenylenebis (methylene) di (3-methyl-1H-spiro
[indeno[1,2-b]pyrazolo 3,4-e]pyridine-4,3′-indoline]-2́,5 (10H)-
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dione, (7i). mp. 288°C dec; as a brown solid; ir (KBr): 3068,
2925, 1730 (C═O), 1558,1610, 1348; 1H nmr (DMSO-d6,
400 MHz): δH 1.53 (s, 6H), 5.12 (s, 4H), 6.91–6.98 (m, 4H),
7.09–7.23 (m, 4H), 7.37 (d, 2H, J= 7.8 Hz), 7.46 (m, 2H), 7.55–7.58
(m, 2H),7.74 (m, 2H), 11.62 (s, 2H), 12.43 (s, 2H); 13C nmr
(DMSO-d6, 100 MHz): δC 27.13, 29.21, 45.18, 103.75, 105.51,
107.36, 109.21, 111.13, 111.17, 113.51, 113.91, 115.07, 115.72,
117.23, 119.14, 123.25, 123.64, 125.27, 130.17, 130.84, 135.36,
137.41, 147.32, 177.23, 192.45; Anal. Calcd. for C50H34N8O4:
C, 74.26; H, 4.53; N, 13.82. Found: C, 74.32; H, 4.57; N, 13.79.
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Acknowledgments. We thank the Research Committee of Islamic
Azad University of Rasht Branch for partial support given to
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