H3PW12O40: An efficient catalyst for the synthesis of spirooxindoles under ultrasound irradiation

Article abstract of DOI:10.14233/ajchem.2013.14390

A simple and efficient one-pot three-component synthesis of the biologically important spirooxindoles scaffold was carried out by the reaction of isatin, malononitrile and 1,3-dicarbonyl compounds in presence of tungstophosphoric acid as a catalyst. This

Full text of DOI:10.14233/ajchem.2013.14390

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Asian Journal of Chemistry; Vol. 25, No. 12 (2013), 6619-6621
http://dx.doi.org/10.14233/ajchem.2013.14390
H3PW12O40: An Efficient Catalyst for the Synthesis of Spirooxindoles Under Ultrasound Irradiation
MARJANEH SAMADIZADEH
Department of Chemistry, Islamic Azad University, Central Tehran Branch, Tehran 19379-58814, Iran
Corresponding author: E-mail: mar.samadizadeh@iauctb.ac.ir
(Received: 3 August 2012;
Accepted: 22 May 2013)
AJC-13534
A simple and efficient one-pot three-component synthesis of the biologically important spirooxindoles scaffold was carried out by the
reaction of isatin, malononitrile and 1,3-dicarbonyl compounds in presence of tungstophosphoric acid as a catalyst. This method is of
great value because of high yield processing and easy handling.
Key Words: Spirooxindole, Heteropoly acids, Ultrasound irradiation, Reusability.
applied with success, milder reaction condition and higher
yields in comparison to the classical methods21,22. Ultrasound-
promoted syntheses has attracted much attention during the
past few decades. As part of our endeavor development
methodology for synthesis spirooxindoles, we investigated a
three-component reaction involving isatin 1 with malononitrile
and 1,3-dicarbonyl compounds 2 catalyzed with heteropoly
acids and silica supported heteropoly acids under Ultrasound
(Scheme-I).
INTRODUCTION
The indole nucleus is probably the most well-known
heterocycle, a common and important feature of a variety of
natural products and medicinal agents1. Compounds carrying
the indole moiety exhibit antibacterial and antifungal activities2.
Furthermore, it has been reported that sharing of the indole 3-
carbon atom in the formation of spiroindoline derivatives
highly enhances biological activity3-5. The spirooxindole
system is the core structure of many pharmacological agents
and natural alkaloids6-9. For example, spirotryprostatin A, a
natural alkaloid isolated from the fermentation broth of
Aspergillus fumigatus, has been identified as a novel inhibitor
of microtubule assembly10 and pteropodine and isopteropodine
have been shown to modulate the function of muscarinic
serotonin receptors. Due to these properties spirooxindoles
have been attention and many procedures have been reported
R''
R''
O
NH2
CN
O
O
O
CN
CN
O
H3PW12O40@SiO2
)))), EtOH
R
O
O
N
R
N
R''
R''
R'
R'
1
2
3
for synthesis of various spirooxindoles11-15
.
Scheme-I:Reaction of isatins, 1,3-cyclohexadione and malononitrile in the
presence of silica supported of tungstophosphoric acid under
ultrasound irradiation
Heteropolyacids, catalyze a wide variety of reactions in
homogeneous or heterogeneous (liquid-solid, gas-solid or
liquid-liquid biphasic) systems, offering strong options for
more efficient and cleaner processing compared to conven-
tional mineral acids16-18. A major disadvantage of bulk
heteropolyacids lies in their low specific surface area, less than
10 m2 g-1 that can be improved by supporting on oxidic carriers
especially SiO2 which is an inexpensive and noncorrosive
neutral solid19,20. The support provides an opportunity to spread
HPAs over a large surface area, which generally increases cata-
lytic activity.
EXPERIMENTAL
All starting materials were purchased from Merck or
Fluka. Substituted N-methylisatins were synthesized according
to a literature procedure23. The supported H3PW12O40 catalyst
was prepared by the incipient wetness method according to
literature24.
General procedure for the synthesis of spirooxindoles:
A mixture of isatin (1 mmol), malononitrile (1 mmol), cyclo-
hexane-1,3-dione (1 mmol) and H3PW12O40@SiO2 (8 mol %)
in EtOH (5 mL) was irradiated by ultrasonics irradiation for
given time in Table-2. Upon completion, monitored by TLC,
Ultrasound irradiation, an efficient and innocuous
technique for reagent activation in the synthesis of organic
compounds and in particular heterocyclic compounds, has been

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6620 Samadizadeh
Asian J. Chem.
TABLE-1
OPTIMIZATION OF REACTION CONDITION IN
THE SYNTHESIS OF SPIROOXINDOLE 3a
TABLE-2
SYNTHESIS OF SPIROOXINDOLES 3a-g
Entry
3a
R
H
R’
H
R’’
H
Time (min) Yield (%)a
Amouts of catalyst
(mmol)
Time
(min)
Yield
(%)a
6
10
6
86
81
79
76
84
75
79
Entry
Solvent
H
H
Me
H
3b
3c
1
2
3
4
5
6
7
8
H3PMo12O40(20)
10
10
20
10
10
10
10
10
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
THF
74
86
70
86
86
78
75
70
4-Br
4-Br
6-Br
H
H
H3PW12O40(20)
H
Me
Me
Me
Me
8
3d
3e
H7SiW9V3O40(20)
H3PW12O40@SiO2(9)
H3PW12O40@SiO2(8)
H3PW12O40@SiO2(7)
H3PW12O40@SiO2(8)
H3PW12O40@SiO2(8)
H
10
6
Me
CH2Ph
3f
H
6
3g
aIsolated yields.
aIsolated yields.
The structures of compounds 3a-g were deduced from
1
their elemental analysis, IR and high-field H and 13C NMR
spectra. The IR spectrum of compound 3a showed absorption
bands due to the NH2 and NH groups at 3372, 3287, 3133 and
the CH at 2955 and the CN group at 2191and C=O group at
1698 cm-1. The 1H NMR spectrum of 3a showed two singlet
for NH and NH2 group (δ = 10.39 and 7.21), three multiplet
for CH2 groups (δ = 2.63-2.67, 2.30-2.37 and 1.90-1.93) and
the aromatic moieties gave rise to multiplets in the aromatic
region of the spectrum (δ = 6.77-7.13 ppm). The 1H decoupled
13C NMR spectrum of 3 showed 17 distinct resonances in agree-
ment with the suggested structure. As shown in Table-2, it
was found that this method works with a wide variety of
substrates. A series of different position substituted isatins
including either electron-withdrawing or electron-donating
groups and different substituted 1,3-cyclohexanedione were
used in this reaction.
the catalyst was separated by filteration. The solvent was
evaporated and the residue was recrystallized from dioxane/
EtOH (1:1) to afford the pure product in 86 % yield. This
procedure was followed for the synthesis of all the
spirooxindoles (3a-g) (Table-1).
1
(3a): Yield: 86 %; m.p. >300 ºC; H NMR (DMSO-d6,
400 MHZ) δ: 10.39 (s, 1H), 7.21 (br s, 2H,), 7.13 (t, 1H, J =
7.6 Hz), 7.01 (d, 1H, J = 7.6 Hz), 6.88 (t, 1H, J = 7.6 Hz), 6.77
(d, 1H, J = 8.0 Hz), 2.63-2.67 (m, 2H), 2.30-2.37 (m, 2H),
1.90-1.93 (m, 2H); 13C NMR (DMSO-d6, 100 MHZ) δ: 195.1,
178.2, 166.1, 158.7, 142.0, 134.6, 128.2, 123.3, 121.8, 117.4,
111.9, 109.2, 57.6, 46.9, 36.4, 26.8, 19.8; FT IR (KBr, νmax
,
cm-1): 3372, 3287, 3133, 2955, 2191, 1698, 1613, 1466, 1350,
1211, 1011, 933, 764, 679.
(3b):Yield: 81 %; m.p. 289-290 ºC; 1H NMR (DMSO-d6,
400 MHZ) δ: 10.37 (s, 1H), 7.20 (br s, 2H), 7.14 (t, 1H, J =
10.0 Hz), 6.97 (d, 1H, J = 9.6 Hz), 6.88 (t, 1H, J = 10.0 Hz),
6.78 (d, 1H, J = 10.0 Hz), 2.56 (d, 2H, J = 7.2 Hz), 2.18 (d,
1H, J = 21.2 Hz), 2.08 (d, 1H, J = 21.6 Hz), 1.03 (s, 3H), 1.00
(s, 3H); 13C NMR (DMSO-d6, 100 MHZ) δ: 194.9, 178.1,
164.2, 158.9, 142.1, 134.5, 128.2, 123.1, 121.8, 117.4, 110.9,
109.3, 57.5, 50.1, 46.9, 40.0, 32.0, 27.7, 27.1; FT IR (KBr,
νmax, cm-1): 3380, 3310, 3141, 2963, 2192, 1721, 1659, 1605,
1466, 1350, 1219, 1057, 903, 748, 679, 556.
Proposed mechanism for the synthesis of spiro derivative
3 was described in Scheme-II. The process represents a typical
cascade reaction in which the isatin 1 first condenses with
malononitrile to afford isatylidene malononitrile derivative 4
in the presence of heteropolyacids in EtOH. This step was
regarded as a fast Knoevenagel condensation. Then, 4 is attacked
via Michael addition of dimedone 2 to give the intermediate 5
followed by the cycloaddition of hydroxyl group to the cyano
moiety to form the desired product 3 (Scheme-II).
1
(3c): Yield: 79 %; m.p. >300 ºC; H NMR (DMSO-d6,
OH
400 MHZ) δ: 10.66 (s, 1H,), 7.33 (br s, 2H), 7.11 (t, 1H, J =
7.2 Hz), 7.03 (d, 1H, J = 8.0 Hz), 6.81 (d, 1H, J = 7.6 Hz),
2.62-2.67 (m, 2H), 2.25- 2.32 (m, 2H), 1.94-1.96 (m, 2H); 13C
NMR (DMSO-d6, 100 MHZ) δ: 195.3, 177.9, 166.7, 158.8,
141.4, 137.0, 130.9, 126.2, 117.3, 113.4, 111.2, 56.9, 47.2,
36.4, 26.8, 19.8; FT IR (KBr, νmax, cm-1): 3357, 3271, 3156,
2963, 2192, 1728, 1651, 1450, 1350, 1219, 1011, 910, 733,
656.
NC
CN
O
OH
O
N
O
H3PW12O40@SiO2
CN
CN
N
O
O
O
N
H
N
H
N
H
1
5
4
O
O
NH2
CN
NH
O
O
CN
O
O
N
H
N
H
RESULTS AND DISCUSSION
3
Scheme-II: Proposed mechanism for synthesis of spirooxindoles
Initially, evaluation of various catalysts and solvent
systems was carried out for the synthesis of spirooxindole with
fused chromenes.After systematic screening, silica supported
of H3PW12O40 (H3PW12O40@SiO2) and ethanol were found to
be the best (entry 5).
Conclusion
We have described a simple one-pot three component
reaction involving isatin, malononitrile reagent and 1,3-
dicarbonyl compounds for the synthesis of a series of
spirooxindoles derivatives in presence of heteropolyacids.
Particularly, valuable features of this method include the higher
yields of the products, broader substrate scope, mild reaction
conditions, catalyst recyclable and the straight forwardness of
Encouraged by this success, we extended this reaction of
different isatin 1 and 1,3-dicarbonyl compound in the
presence of malononitrile. The corresponding products 3a-g
was synthesized in high yield (74-85 %) and the results are
summarized in Table-2.

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H3PW12O40: An Efficient Catalyst for the Synthesis of Spirooxindoles Under Ultrasound Irradiation 6621
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