KAl(SO4)212H2O as a recyclable lewis acid catalyst for synthesis of spirooxindoles in aqueous media

Article abstract of DOI:10.1080/00397911.2010.517895

A simple and efficient procedure for the synthesis of spirooxindole has been described that employs a three-component condensation reaction in one pot using isatin, active methylene reagent, and 1,3-dicarbonyl compounds in an aqueous medium.

Full text of DOI:10.1080/00397911.2010.517895

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KAl(SO4)2 · 12H2O as a Recyclable
Lewis Acid Catalyst for Synthesis of
Spirooxindoles in Aqueous Media
Hossein A. Oskooie a , Majid M. Heravi a , Narges Karimi a & Hoda
Hamidi a
a Department of Chemistry, School of Science, Alzahra University,
Vanak, Tehran, Iran
To cite this article: Hossein A. Oskooie , Majid M. Heravi , Narges Karimi & Hoda Hamidi (2011)
KAl(SO4)2 · 12H2O as a Recyclable Lewis Acid Catalyst for Synthesis of Spirooxindoles in Aqueous
Media, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 41:22, 3344-3350, DOI: 10.1080/00397911.2010.517895
To link to this article: http://dx.doi.org/10.1080/00397911.2010.517895
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Synthetic Communications1, 41: 3344–3350, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517895
KAl(SO4)2 ꢀ 12H2O AS A RECYCLABLE LEWIS ACID
CATALYST FOR SYNTHESIS OF SPIROOXINDOLES
IN AQUEOUS MEDIA
Hossein A. Oskooie, Majid M. Heravi, Narges Karimi, and
Hoda Hamidi
Department of Chemistry, School of Science, Alzahra University, Vanak,
Tehran, Iran
GRAPHICAL ABSTRACT
Abstract A simple and efficient procedure for the synthesis of spirooxindole has been
described that employs a three-component condensation reaction in one pot using isatin,
active methylene reagent, and 1,3-dicarbonyl compounds in an aqueous medium.
Keywords Alum; spirooxindole; water
INTRODUCTION
Multicomponent reactions (MCRs), an important subclass of tandem
reactions,[1] are one-pot processes in which three or four easily accessible components
react to form a single product, which incorporates essentially all the carbon atoms of
the starting materials.[2] MCRs are a promising and vital field of chemistry because
the synthesis of complicated molecules can be achieved in a very fast, efficient, and
time-saving manner without the isolation of any intermediate.[3] Recently, great
attention has been focused on the use of water as a green solvent in organic transfor-
mations. Water is a desirable solvent for chemical reactions because it is safe,
nontoxic, environmentally friendly, readily available, and inexpensive compared to
organic solvents.[4–6] Since the pioneering studies by Breslow[7,8] on Diels–Alder reac-
tions, there has been an increasing recognition that organic reactions can proceed well
Received June 9, 2010.
Address correspondence to Majid M. Heravi, Department of Chemistry, School of Science,
Alzahra University, Vanak, Tehran, Iran. E-mail: mmh1331@yahoo.com
3344

SPIROOXINDOLE SYNTHESIS IN WATER
3345
in aqueous media, offering key advantages over organic solvents such as rate
enhancement and insolubility of the final products, which facilitates their isolation.
The indole nucleus is probably the most well-known heterocycle, a common and
important feature of a variety of natural products and medicinal agents.[9] Com-
pounds carrying the indole moiety exhibit antibacterial and antifungal activities.[10]
Furthermore, it has been reported that sharing the indole 3-carbon atom in the
formation of spiroindoline derivatives highly enhances biological activity.[11,12] The
spirooxindole system is the core structure of some pharmacological agents and
natural alkaloids.[13–15]
RESULTS AND DISCUSSION
We first investigated the catalytic activities of various catalysts, which promoted
the model reaction of isatin (1 mmol), malononitrile (1 mmol), and 5,5-dimethyl-1,3-
cyclohexanedione (1 mmol) in water (Scheme 1).
In the course of this study, we found that KAl(SO4)2 ꢀ 12H2O was the most
effective catalyst, producing spirooxindole in greater yields than other catalysts,
which furnished the product in lesser yields (60–80%). We also studied the model
reaction catalyzed by KAl(SO4)2 ꢀ 12H2O (0.35 mmol) at different temperatures.
The reaction rate was increased as the reaction temperature was raised. When it
was carried out at 80 ꢁC, the maximum yield was obtained in a short reaction period
(Table 1, entry 4).
To evaluate the effect of catalyst concentration, the model reaction was carried
out in the presence of different amounts of catalyst (0.15, 0.25, and 0.35 mmol) at
80 ꢁC. The results showed that 0.35 mmol of catalyst was sufficient to achieve a fairly
good yield. With 0.15 mmol of KAl(SO4)2 ꢀ 12H2O, a lower yield was observed under
the same reaction period. This encouraged us to study the scope of the reaction
under the optimized reaction parameters in the presence of 0.35 mmol of catalyst
at 80 ꢁC. The results of using KAl(SO4)2 ꢀ 12H2O as a catalyst in the multicomponent
reaction of isatin, malononitrile, and 5,5-dimethyl-1,3-cyclohexanedione are
summarized in Table 2.
As shown in Table 2, the reaction times of methyl cyanoacetate with isatins and
1,3-dicarbonyl compounds was longer than those of malononitrile, which is prob-
ably because of the lower reactivities of the cyanoacetates.
The plausible mechanism of this reaction (Scheme 2) includes a fast Knoevenagel
condensation between isatin and CH-acidic cyanoacetic ester derivatives in the
Scheme 1. Synthesis of spirooxindoles from dimedone.

3346
H. A. OSKOOIE ET AL.
Table 1. Catalytic activity of various catalysts for the reaction of isatin, malononi-
trile, and 5,5-dimethyl-1,3-cyclohexanedione
Entry
Catalyst
Temperature (ꢁC)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
DABCO (0.35 mmol)
Glycin (0.35 mmol)
CA-SiO2 (0.35 mmol)
Alum (0.35 mmol)
Alum (0.15 mmol)
Alum (0.25 mmol)
Alum (0.35 mmol)
Alum (0.35 mmol)
80
80
80
80
80
80
50
90
240
90
35
25
50
40
45
40
60
75
80
90
75
83
85
88
aIsolated yields.
Table 2. Synthesis of compound 4
Entry
R
R1
R2
X
Time (min)
Yielda (%)
Mp (lit.) (ꢁC)
4a
4b
4c
4d
H
H
H
H
H
CH3
CH3
CH3
CH3
CN
25
35
90
88
87
82
282–285 (289–290)[16]
257–260 (255–256)[16]
>300 (>300)[16]
H
CO2CH3
CN
CO2CH3
6-Br
6-Br
60
125
275–277 (271–273)[16]
aIsolated yields.
Scheme 2. Plausible mechanism for the synthesis of spirooxindoles.

SPIROOXINDOLE SYNTHESIS IN WATER
3347
Scheme 3. Synthesis of spirooxindoles from 4-hydroxy coumarin.
presence of alum in water in the first step and a Michael addition of diketones to the
unsaturated nitrile, the product of Knovenagel condensation, in the second stage,
followed by cycloaddition of the hydroxyl group to the cyano moiety to from the
desired product.[16]
To further expand the scope of this approach, we examined one-pot reactions
involving 4-hydroxy coumarin and barbituric acid instead of 5,5-dimethyl-1,3-cyclo-
hexanedione. Under these conditions, a variety of desired spirooxindoles products 6
and 8 were obtained in good yields (Schemes 3 and 4 and Table 3).
The isolated KAl(SO4)2 ꢀ 12H2O catalyst from the crude mixture was reutilized
two times, and yields were comparable with the first run (with the yields of the
product 4a being 90%, 88%, and 87%, respectively).
All the products obtained were fully characterized by spectroscopic methods
such as infrared (IR), 1H NMR, gas chromatography (GC)–mass spectrometry
and also by comparison of their spectra data with those reported.
Scheme 4. Synthesis of spirooxindoles from barbituric acid.
Table 3. Synthesis of compounds 6 and 8
Entry
R
R1
X
Time (min)
Yielda (%)
Mp (lit) (ꢁC)
6a
6b
6c
6d
8a
8b
H
6-Br
H
H
H
CN
CN
30
45
40
50
80
55
80
78
79
76
75
73
288–290 (292–294)[16]
>300 (>300)[16]
287–290 (287–288)[16]
270–272 (275–277)[16]
248–250 (245–247)[16]
238–240 (232–234)[16]
CH3
H
CN
H
CO2CH3
CO2CH3
CN
H
6-Br
CH3
H
aIsolated yields.

3348
H. A. OSKOOIE ET AL.
CONCLUSION
In conclusion, we demonstrated a simple procedure for synthesis of spirooxin-
doles in water using KAl(SO4)2 ꢀ 12H2O, an inexpensive, efficient, and recyclable cata-
lyst. Good yields and simple workup procedure are some advantages of this protocol.
EXPERIMENTAL
Chemicals and Apparatus
All the chemicals were purchased from Merck Company. Melting points were
measured using a Barnstead Electrothermal instrument (GC)-mass analysis was per-
formed using an Agilent 6890 GC system Hp-5 capillary 30 m ꢂ 530 mm ꢂ 1.5 mm
nominal. IR spectra were recorded as KBr discs on a Brucker Tensor 27 Fourier
transform (FT)–IR spectrometer. 1H NMR spectra were recorded on a Bruker
AQS Avance 300-MHz spectrometer using tetramethylsilane (TMS) as an internal
standard. Elemental analyses were performed using a Heracus CHN-O-Rapid
analyzer.
General Procedure for Preparation of 2-Amino-5-oxo-spiro[(4H)-5,6,
7,8-tetrahydrochromene-4,3’-(3’H)-indol]-(1’H)-2’-one-3-carbonitrile (4a)
A mixture of isatin (1 mmol), malononitrile (1 mmol), 5,5-dimethyl-1,3-cyclo-
hexanedione (1 mmol), KAl(SO4)2 ꢀ 12H2O (0.35 mmol), and water (10 mL) were
mixed at 80 ꢁC for the appropriate time (Table 2). After completion of the reaction,
the crude product obtained was filtered to yield a solid. For further purification, it
was crystallized from ethanol to afford the pure product.
General Procedure for Recovery of the Catalyst
The catalyst in the aqueous phase can be recovered by removing the water
under vacuum, then washing it with acetone and ethanol (25 ml) and drying at room
temperature.
Spectral Data for Selected Compounds
2-Amino-5-oxo-spiro[(4H)-5,6,7,8-tetrahydrochromene-4,3’-(3’H)-indol]-
(1’H)-2’-one-3-carbonitrile (4a). White solid; mp 282–285 ꢁC; IR (KBr): 3375,
3317, 2903, 2187, 1718, 1653, 1219 cmꢃ1;1H NMR (300 MHz, CDCl3) d: 0.96 (s,
3H, CH3), 1.01 (s, 3H, CH3), 2.05 (d, J ¼ 16.2 Hz, 1H), 2.15 (d, J ¼ 15.9 Hz, 1H),
2.50 (m, 2H, CH2), 6.73–7.12 (m, 4H), 7.20 (m, 2H, NH2), 10.38 (s, 1H, NH). Anal.
calcd. for C17H13N3O3: C, 66.44; H, 4.26; N, 13.67. Found: C, 66.21; H, 4.39; N,
13.86.
2-Amino-5-oxo-spiro[(3’H)-indol-3,4-4(H)-pyrano(3,2-c)chromen]-(1’H)-
2’-one-3-carbonitrile (6a). White solid; mp 288–290 ꢁC; IR (KBr): 3353, 3300,
1
2951, 2187, 1721, 1663, 1223, 968, 862, 743 cmꢃ1; H NMR (300 MHz, CDCl3) d:
6.82 (d, 1H, J ¼ 7.9 Hz, ArH), 6.90 (t, 1H, J ¼ 7.3 Hz, ArH), 7.20 (t, J ¼ 7.3 Hz,

SPIROOXINDOLE SYNTHESIS IN WATER
3349
2H, ArH), 7.47 (d, J ¼ 8.2 Hz, 1H, ArH), 7.55 (t, 1H, J ¼ 7.3 Hz, ArH), 7.63 (br, s,
2H, NH2), 7.74 (t, 1H, J ¼ 7.3 Hz, ArH), 7.92(d, 1H, J ¼ 7.8 Hz, ArH), 10.65 (s, 1H,
NH). Anal. calcd. for C20H11N3O4: C, 67.23; H, 3.10; N, 11.76. Found: C, 67.31; H,
3.14; N, 11.67.
Methy2-amino-5,7-dioxo-spiro[1’-methy-(3’H)-indol-3’,4,4(H)-5,6,7,8-
tetrahydropyrano(2,3-d)pyramidine-(1’H)-2’-one-3-carboxylate (8a). White
solid; mp 248–250 ꢁC; IR (KBr): 3505, 3423, 3317, 2205, 16693, 1658, 1463, 1342,
1
1130, 913, 825, 743 cmꢃ1; H NMR (300 MHz, DMSO-d6) d: 3 (s, 3H, CH3), 3.19
(s, 3H, CH3), 6.8–6.88 (m, 2H, ArH), 6.95 (d, 1H, J ¼ 10.2 Hz, ArH), 7. 12 (t, 1H,
J ¼ 10.1 Hz, ArH), 7.85 (br, s, 2H, NH2), 10.9 (br, s, 1H, NH), 12 (br, s, 1H, NH)
12.5 (br, s, 1H, NH). Anal. calcd. for C17H14N4O6: C, 55.14; H, 3.81; N, 15.13.
Found: C, 55.26; H, 3.70; N, 15.11.
ACKNOWLEDGMENTS
We are grateful to Alzahra University Research Council for partial support of
this work.
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