Efficient one-pot synthesis of novel spirooxindole derivatives via three-component reaction in aqueous medium

Article abstract of DOI:10.1021/cc100056p

A novel and efficient one-pot synthesis of spiro[indoline-3,4′- pyrazolo[3,4-b]quinoline]dione, spiro[furo[3,4-e]pyrazolo[3,4-b]pyridine-4, 3′-indoline]dione, and spiro[indeno[2,1-e]pyrazolo[3,4-b]pyridine-4, 3′-indoline]dione derivatives via three-component reaction of isatin, 5-amino-3-methylpyrazole, and 1,3-dicarbonyl compounds in aqueous medium is described. The advantages of this method include high efficiency, mild reaction conditions, convenient operation, and environmentally benign conditions.

Full text of DOI:10.1021/cc100056p

J. Comb. Chem. 2010, 12, 571–576
571
Efficient One-Pot Synthesis of Novel Spirooxindole Derivatives via
Three-Component Reaction in Aqueous Medium
Hui Chen and Daqing Shi*
Key Laboratory of Organic Synthesis of Jiangsu ProVince, College of Chemistry, Chemical Engineering
and Materials Science, Soochow UniVersity, Suzhou, Jiangsu 215123, P.R. China
ReceiVed March 31, 2010
A novel and efficient one-pot synthesis of spiro[indoline-3,4′-pyrazolo[3,4-b]quinoline]dione, spiro[furo-
[3,4-e]pyrazolo[3,4-b]pyridine-4,3′-indoline]dione, and spiro[indeno[2,1-e]pyrazolo[3,4-b]pyridine-4,3′-in-
doline]dione derivatives via three-component reaction of isatin, 5-amino-3-methylpyrazole, and 1,3-dicarbonyl
compounds in aqueous medium is described. The advantages of this method include high efficiency, mild
reaction conditions, convenient operation, and environmentally benign conditions.
Introduction
this kind of compounds have been reported, such as a potent
cyclin dependent kinase 1 (CDK1) inhibitor,19 human
immunodeficiency virus (HIV) reverse transcriptase inhibi-
tors,20 CCR1 antagonists,21 protein kinase inhibitors,22 and
inhibitors of cGMP degradation, together with studies of
several herbicidal and fungicidal activities.23 Numerous
methods for the synthesis of pyrazolopyridines in the past
20 years have been reported with respect to their different
structures.24
The development of organic reactions in water has become
highly desirable in recent years to meet environmental
considerations.25,26 The unique properties of water in aqueous
medium like high dielectric constant and cohesive energy
density showed an extraordinary effect on reaction rates.
Moreover, its cost-effectiveness, high abundance, non-
inflammability and non-toxic nature increased its applicabil-
ity.27
Multicomponent reactions (MCRs)1 are special types of
synthetically useful organic reactions in which three or more
different starting materials react to give a final product in a
one-pot procedure. Such reactions are one of the best tools
in modern organic synthesis to generate compound libraries
for screening purposes because of their productivity, simple
procedures, convergence, and facile execution.2 This meth-
odology allows molecular complexity and diversity to be
created by the facile formation of several new covalent bonds
in a one-pot transformation quite closely approaching the
concept of an ideal synthesis, and it is particularly well
adapted for combinatorial synthesis.3
The indole nucleus is probably the most well-known het-
erocycle, a common and important feature of a variety of natural
products and medicinal agents.4 Compounds carrying the indole
moiety exhibit antibacterial and antifungal activities.5 Further-
more, it has been reported that sharing of the indole 3-carbon
atom in the formation of spiroindoline derivatives highly
enhances biological activity.6-8 The spirocyclic oxindole core
is featured in a number of natural alkaloids as well as
medicinally relevant compounds.9-14 For example, spirot-
ryprostatin B, a natural alkaloid isolated from the fermentation
broth of Aspergillus fumigatus, has been identified as a novel
inhibitor of microtubule assembly,10 and pteropodine and
isopteropodine have been shown to modulate the function of
muscarinic serotonin receptors (Figure 1).12 Therefore, a number
of methods have been reported for the preparation of spiroox-
indole derivatives.15-17
However, to the best of our knowledge, there have been
few reports about the synthesis of spirooxindole derivatives
in aqueous medium lately.28-31 As a part of our research
program, which aims to develop new selective and environ-
mentally friendly methodologies for the preparation of
Heterocycles containing the pyrazole ring are important
targets in synthetic and medicinal chemistry because this
fragment is a key moiety in numerous biologically active
compounds,18 among them such prominent drug molecules
as Viagra, Celebrex, Analginum, and many others. On the
other hand, pyrazolopyridines have received more and more
attention in the recent years. Pharmaceutical researches of
Figure 1. Naturally occurring and biologically active spirocyclic
oxindoles.
* To whom correspondence should be addressed. E-mail: dqshi@
suda.edu.cn.
10.1021/cc100056p  2010 American Chemical Society
Published on Web 06/01/2010

572 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Scheme 1. Model Reaction
Chen and Shi
Table 1. Optimization of Reaction Conditions
Table 2. Synthesis of Compound 4 in Aqueous Medium
temperature
time
(h)
yield
(%)
time
(h)
yield
(%)
entry
solvent
(°C)
catalyst
entry
R1
X
R2
R3
products
1
2
3
4
5
6
7
8
water
water
water
water
water
water
water
water
AcOH
CH3CN
THF
DMF
EtOH
water
water
water
80
80
80
80
80
80
80
r.t.
95
80
65
90
80
80
80
80
24
8
8
8
8
8
8
24
8
8
8
8
8
8
8
8
<20
69
73
87
54
31
29
23
82
79
75
77
80
72
86
88
1
2
3
4
5
6
7
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
H
H
H
H
H
CH3
H
CH3
CH3
CH3
CH3
CH3
CH3
H
4a
4b
4c
4d
4e
4f
8
10
12
6
8
9
87
87
88
85
86
82
85
HCl (10%)
5-CH3
5-Br
5-F
H
H
H
p-TSA (10%)
CAN (10%)
FeCl3 (10%)
CoCl2 (10%)
Cu(OAc)2 (10%)
CAN (10%)
CAN (10%)
CAN (10%)
CAN (10%)
CAN (10%)
CAN (10%)
CAN (5%)
CH3
4g
10
4). Performing the reaction in the presence of CAN at room
temperature led to low conversion of 4a in 23% yield even
with prolonged time (Table 1, entry 8). Subsequently, we
further turned to testing the effect of solvents. AcOH,
CH3CN, tetrahydrofuran (THF), N,N-dimethylformamide
(DMF), or EtOH showed no superiority to water (Table 1,
entry 9-13) as solvents.
9
10
11
12
13
14
15
16
CAN (15%)
CAN (20%)
We also evaluated the amount of CAN required for this
reaction. It was found that when increasing the amount of
CAN from 5 mol % to 10, 15, and 20 mol %, the yields
increased from 72% to 87, 86, and 88%, respectively (Table
1, entries 14-16). Using 10 mol % CAN in water is
sufficient to push this reaction forward. More amounts of
the catalyst did not improve the yields.
Under the optimized reaction conditions, a series of
spiro[indoline-3,4′-pyrazolo[3,4-b]quinoline]dione derivatives
4 were synthesized (Scheme 2). The results are summarized
in Table 2.
To further expand the scope of the present method, we
investigated one-pot reactions involving tetronic acid 5 and
1,3-indanedione 7. To our delight, under the above optimized
conditions, the reactions proceeded smoothly, and a variety
of the desired spirooxindoles products 6 and 8 were obtained
in good yields (Scheme 3 and Table 3).
As shown in Tables 2 and 3, it was found that this method
works with a wide variety of substrates. A series of different
position substituted isatins including either electron-with-
drawing or electron-donating groups and different 1,3-
dicarbonyl compounds were used in this reaction. However,
the yield of 5-amino-1,3-dimethylpyrazole with 4-chloroisatin
and tetronic acid (Table 3, Entry 10) was relatively low,
which is probably due to the low reactivity of the carbonyl
in 4-chloroisatin.
heterocyclic compounds,32 herein, we investigated a three-
component reaction of isatin, 5-amino-3-methylpyrazole, and
1,3-dicarbonyl compounds to afford a series of spiro[indo-
line-3,4′-pyrazolo[3,4-b]quinoline]dione, spiro[furo[3,4-e]pyra-
zolo[3,4-b]pyridine-4,3′-indoline]dione, and spiro[indeno-
[2,1-e]pyrazolo[3,4-b]pyridine-4,3′-indoline]dione derivatives
in water catalyzed by CAN (Ceric Ammonium Nitrate).
Results and Discussion
Initially, to get spiro[indoline-3,4′-pyrazolo[3,4-b]quino-
line]dione derivatives 4a, we tested the reaction of 5-amino-
1-phenyl-3-methylpyrazole 1a, isatin 2a, dimedone 3 as a
simple model substrate in various reaction conditions (Scheme
1). The results are shown in Table 1.
It was found that when the reaction was carried out without
any catalysts the yield of product was very low (Table 1,
<20%, entry 1) even after 24 h. To improve the yields, we
examined this reaction using different Brønsted and Lewis
acids (Table 1, entries 2-7). Some Brønsted acids such as
HCl and p-TSA (p-toluenesulfonic acid) can catalyze this
reaction with moderate yields (Table 1, entries 2-3).
However, the use of some Lewis acids, for example, FeCl3,
CoCl2, Cu(OAc)2 led to low product formation (Table 1,
entries 5-7). Finally, CAN was identified as the optimal
catalyst, with 4a being isolated in 87% yield (Table 1, entry
Scheme 2. Synthesis of Spiro[indoline-3,4′-pyrazolo[3,4-b]quinoline]dione Derivatives 4

Spirooxindole Derivatives via Three-Component Reaction
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 573
Scheme 3. Synthesis of Spirooxindole Derivatives 6 and 8
Table 3. Synthesis of Compound 6 and 8 in Aqueous Medium
The structures of the products 4a-g, 6a-k, 8a-c, 13,
1
and 14a,b were characterized by IR, H NMR, 13C NMR
time
(h)
yield
(%)
entry
R1
X
R2
products
spectra as well as high resolution mass spectrometry
(HRMS). The structure of 14a was further confirmed by
X-ray diffraction analysis. The molecular structure 14a is
shown in Figure 2.
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
C6H5
CH3
H
H
H
H
CH3
H
H
H
H
H
H
CH3
H
H
H
6a
6b
6c
6d
6e
6f
6g
6h
6i
6
8
6
10
8
12
12
8
10
12
6
6
8
86
87
88
85
86
89
85
86
81
57
88
91
90
88
5-F
5-CH3
H
H
In summary, we have described a simple one-pot three
component reaction involving isatin, 5-amino-3-methylpyra-
zole, and 1,3-dicarbonyl compounds for the synthesis of
spiro[indoline-3,4′-pyrazolo[3,4-b]quinoline]dione, spiro-
[furo[3,4-e]pyrazolo[3,4-b] pyridine-4,3′-indoline]dione, and
spiro[indeno[2,1-e]pyrazolo[3,4-b]pyridine-4,3′- indoline]di-
one derivatives in water. Particularly, valuable features of
this method include the good yields of the products, broader
substrate scope, mild reaction conditions, reduced environ-
mental impact, and the straightforwardness of the procedure,
which make it a useful and attractive process for the synthesis
of these important compounds.
5-Br
5-Cl
5-F
5-CH3
4-Cl
H
H
5-F
H
9
10
11
12
13
14
6j
6k
8a
8b
8c
6
According to the literature,33 we proposed the plausible
mechanism for the formation of spirooxindole derivatives
4. The first step involves the formation of 3-(5-amino-3-
methyl-1-phenyl-1H-pyrazol-4-yl)-3-hydroxyindolin-2-one 9
by the nucleophilic addition of 1-phenyl-3-methyl-5-pyra-
zolone 1 to isatin 2 as a key intermediate, which lost a water
to afford 10. Then, 10 is attacked via Michael addition of
dimedone 3 to give the intermediate 11 followed by
cycloaddition and dehydration to form the desired product
4 (Scheme 4).
To prove the mechanism, when the reaction of 5-amino-
1-phenyl-3-methylpyrazole 1, isatin 2a, dimedone 3 was
carried out for 1 h, the intermediate 3-(5-amino-3-methyl-
1-phenyl-1H-pyrazol-4-yl)-3-hydroxyindolin-2-one 9 was
isolated and characterized by spectroscopic methods. We
were pleased to find that the reaction of intermediate 9 with
dimedone 3 in the presence of CAN under the same reaction
conditions proceeded smoothly giving the 3′,7′,7′-trimethyl-
1′-phenyl-6′,7′,8′,9′-tetrahydrospiro[indoline-3,4′-pyrazolo-
[3,4-b]quinoline]-2,5′(1′H)-dione 4a in 84% yield. (Scheme
5).
Experimental Section
Melting points were determined in open capillaries and
uncorrected. IR spectra were recorded on a Varian F-1000
spectrometer in KBr pellet. 1H NMR and 13C NMR spectra
were obtained from a solution in DMSO-d6 with Me4Si as
internal standard using Varian Inova-400 MHz or Inova-300
MHz spectrometer. HRMS analyses were carried out using
time-of-flight mass spectrometry (TOF-MS) or GCT-TOF
instrument.
General Procedure for the Synthesis of 4, 6, and 8. A
mixture of 5-amino-3-methylpyrazole (1 mmol), isatin (1
mmol), 1,3-dicarbonyl compounds (1 mmol), and CAN (10
mol %) in H2O (5 mL) was stirred at 80 °C for 6-12 h.
After completion of the reaction confirmed by thin-layer
chromatography (TLC; eluent acetone/petroleum ether, 1:2),
the reaction mixture was cooled to room temperature. Then,
the precipitated product was filtered, dried, and recrystallized
from DMF and ethanol to afford the pure 4, 6, or 8 as a
white powder.
Finally, to further explore the potential of this protocol
for synthesis of spiro-heterocyclic compounds, we investi-
gated the reaction involving acenaphthylene-1,2-dione 12 and
obtained 1′,3′,7′,7′-tetramethyl-6′,7′,8′,9′-tetrahydro-2H-
spiro[acenaphthylene-1,4′-pyrazolo[3,4-b]quinoline]-2,5′(1′H)-
dione 13 and spiro[acenaphthylene-1,4′-furo[3,4-e]pyrazo-
lo[3,4-b]pyridine]dione derivatives 14 in good yields (Scheme
6).
3′,7′,7′-Trimethyl-1′-phenyl-6′,7′,8′,9′-tetrahydrospiro[in-
doline-3,4′-pyrazolo[3,4-b]quinoline]-2,5′(1′H)-dione (4a).
M.p.: >300 °C. IR (KBr) ν: 3284, 3157, 2955, 1710, 1618,
1532, 1467, 1366, 1123, 751, 684 cm-1. 1H NMR (300 MHz,
DMSO-d6): δH 0.97 (s, 3H, CH3), 1.01 (s, 3H, CH3), 1.55

574 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Chen and Shi
Scheme 4. Proposed Mechanism for the Synthesis of Spirooxindole Derivatives 4
Scheme 5. Two-Step Synthesis of Spirooxindole 4a
Scheme 6. Synthesis of Spirocyclic Acenaphthyleneones 13 and 14
(s, 3H, CH3), 1.97 (d, J ) 15.9 Hz, 1H, CH2), 2.08 (d, J )
15.9 Hz, 1H, CH2), 2.56 (s, 2H, CH2), 6.79 (d, J ) 7.5 Hz,
1H, ArH), 6.84 (d, J ) 3.6 Hz, 2H, ArH), 7.06-7.12 (m,
1H, ArH), 7.40-7.43 (m, 1H, ArH), 7.48-7.56 (m, 4H,
ArH), 9.68 (s, 1H, NH), 10.32 (s, 1H, NH). 13C NMR (75
MHz, DMSO-d6): δC 12.0, 27.6, 28.9, 32.8, 41.6, 49.4, 51.0,
102.3, 108.6, 109.2, 122.1, 123.8, 124.1, 127.9, 127.9, 130.1,
137.3, 137.7, 138.5, 142.4, 145.7, 153.7, 180.3, 194.0. HRMS
(ESI): m/z calcd for C26H24N4O2: 425.1972 [M+H]+, found:
425.1972.
1′,3-Dimethyl-1-phenyl-7,8-dihydrospiro[furo[3,4-e]pyra-
zolo[3,4-b]pyridine-4,3′-indoline]-2′,5(1H)-dione (6d).
M.p.: >300 °C. IR (KBr) ν: 3189, 3052, 2940, 1704, 1651,
1549, 1475, 1363, 1118, 1019, 753, 689 cm-1. 1H NMR (300

Spirooxindole Derivatives via Three-Component Reaction
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 575
CH3), 7.10 (d, J ) 6.0 Hz, 1H, ArH), 7.54 (t, J ) 6.8 Hz,
1H, ArH), 7.76-7.82 (m, 2H, ArH), 7.87 (d, J ) 6.8 Hz,
1H, ArH), 8.18 (d, J ) 7.6 Hz, 1H, ArH), 9.99 (s, 1H, NH).
HRMS (ESI): m/z calcd for C25H23N3O2: 398.1863 [M+H]+,
found: 398.1863.
3′-Methyl-1′-phenyl-7′,8′-dihydro-2H-spiro[acenaphth-
ylene-1,4′-furo[3,4-e]pyrazolo[3,4-b]pyridine]-2,5′(1′H)-di-
one (14b). M.p.: >300 °C. IR (KBr) ν: 3190, 3053, 2948,
1750, 1699, 1651, 1541, 1472, 1332, 1120, 1027, 786, 658
cm-1. 1H NMR (300 MHz, DMSO-d6): δH 0.99 (s, 3H, CH3),
4.99 (s, 2H, CH2), 7.40-7.47 (m, 2H, ArH), 7.53-7.60 (m,
4H, ArH), 7.71 (t, J ) 7.8 Hz, 1H, ArH), 7.89 (t, J ) 7.8
Hz, 1H, ArH), 8.00 (d, J ) 8.4 Hz, 1H, ArH), 8.06 (d, J )
6.9 Hz, 1H, ArH), 8.35 (d, J ) 8.1 Hz, 1H, ArH), 10.71 (s,
1H, NH). 13C NMR (75 MHz, DMSO-d6): δC 12.5, 52.3,
66.6, 99.2, 102.9, 122.2, 123.0, 124.0, 125.4, 128.3, 129.5,
130.0, 130.3, 132.5, 132.8, 138.2, 139.1, 141.6, 143.0, 145.9,
160.6, 171.1, 204.4. HRMS (ESI): m/z calcd for C26H17N3O3:
420.1343 [M+H]+, found: 420.1329.
Figure 2. Crystal structure of 14a.
MHz, DMSO-d6): δH 1.42 (s, 3H, CH3), 3.22 (s, 3H, CH3),
4.94 (s, 2H, CH2), 7.02 (t, J ) 7.5 Hz, 1H, ArH), 7.08 (d, J
) 8.1 Hz, 2H, ArH), 7.31 (t, J ) 7.5 Hz, 1H, ArH),
7.41-7.46 (m, 1H, ArH), 7.51-7.59 (m, 4H, ArH), 10.67
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δC 10.7, 25.8,
45.8, 65.2, 96.7, 100.5, 107.7, 122.3, 122.7, 123.8, 127.0,
128.1, 129.1, 132.8, 136.9, 137.8, 142.3, 144.7, 159.3, 169.4,
175.5. HRMS [Found: m/z 398.1379 (M+), calcd for
C23H18N4O3: M, 398.1379].
1,3-Dimethyl-1H-spiro[indeno[2,1-e]pyrazolo[3,4-b]py-
ridine-4,3′-indoline]-2′,5(10H)-dione (8c). M.p.: >300 °C.
IR (KBr) ν: 3361, 3196, 3125, 3059, 2932, 1693, 1602, 1540,
1505, 1340, 1229, 1189, 863, 757, 720, 632 cm-1. 1H NMR
(400 MHz, DMSO-d6): δH 1.44 (s, 3H, CH3), 3.80 (s, 3H,
CH3), 6.85-6.88 (m, 2H, ArH), 6.92 (d, J ) 6.8 Hz, 1H,
ArH), 7.15-7.21 (m, 2H, ArH), 7.36 (t, J ) 7.2 Hz, 1H,
ArH), 7.50 (t, J ) 7.6 Hz, 1H, ArH), 7.73 (d, J ) 7.2 Hz,
1H, ArH), 10.54 (s, 1H, NH), 11.05 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): δC 16.8, 41.0, 52.6, 107.2, 111.1,
114.7, 125.3, 125.9, 127.5, 129.9, 133.7, 136.1, 137.3, 139.6,
140.8, 141.9, 144.2, 147.2, 148.7, 162.0, 184.2, 194.7. HRMS
[Found: m/z 368.1273 (M+), calcd for C22H16N4O2: M,
368.1273].
General Procedure for the Synthesis of 13 and 14. A
mixture of 5-amino-3-methylpyrazole (1 mmol), acenaph-
thylene-1,2-dione (1 mmol), dimedone or tetronic acid (1
mmol), and CAN (10 mol %) in H2O (5 mL) was stirred at
80 °C for 6-12 h. After completion of the reaction confirmed
by TLC (eluent acetone/petroleum ether, 1:2), the reaction
mixture was cooled to room temperature. Then, the precipi-
tated product was filtered, dried and recrystallizated from
DMF and ethanol to afford the pure 13 or 14 as a yellow
powder.
1′,3′,7′,7′-Tetramethyl-6′,7′,8′,9′-tetrahydro-2H-spiro[ace-
naphthylene-1,4′-pyrazolo[3,4-b]quinoline]-2,5′(1′H)-dione (13).
M.p.: >300 °C. IR (KBr) ν: 3280, 3183, 3047, 2949, 1720,
1603, 1544, 1465, 1366, 1251, 1149, 1042, 989, 781 cm-1.
1H NMR (400 MHz, DMSO-d6): δH 0.78 (s, 3H, CH3), 1.01
(s, 3H, CH3), 1.03 (s, 3H, CH3), 1.90 (d, J ) 16.4 Hz, 1H,
CH2), 2.00 (d, J ) 16.0 Hz, 1H, CH2), 2.54 (d, J ) 17.2
Hz, 1H, CH2), 2.61 (d, J ) 16.8 Hz, 1H, CH2), 3.64 (s, 3H,
Acknowledgment. We are grateful to the foundation of
Key Laboratory of Organic Synthesis of Jiangsu Province
for financial support.
Supporting Information Available. Representative ex-
perimental procedures, spectral data of compounds 4a-g,
6a-k, 8a-c, 9, 13, and 14a,b, and crystal data for 14a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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