A clean and expedient synthesis of spirooxindoles in aqueous media catalyzed over nanocrystalline MgO

Article abstract of DOI:10.1016/j.tetlet.2012.07.030

An efficient and eco-friendly method for the synthesis of spirooxindoles with fused tetrahydrochromenes has been demonstrated using basic nanocrystalline MgO catalyst in aqueous condition. The method has been applied for the synthesis of a range of compou

Full text of DOI:10.1016/j.tetlet.2012.07.030

Tetrahedron Letters 53 (2012) 5004–5007
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Tetrahedron Letters
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A clean and expedient synthesis of spirooxindoles in aqueous media
catalyzed over nanocrystalline MgO
Bikash Karmakar a,c, Anupam Nayak b, Julie Banerji c,
⇑
a Gobardanga Hindu College, Department of Chemistry, Khantura, North 24, Parganas 743273, India
b Bagnan College, Department of Chemistry, Bagnan, Howrah 711303, India
c Centre of Advances Studies on Natural products including Organic Synthesis, Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and eco-friendly method for the synthesis of spirooxindoles with fused tetrahydrochromenes
has been demonstrated using basic nanocrystalline MgO catalyst in aqueous condition. The method has
been applied for the synthesis of a range of compounds with variable functionalities in excellent yield and
selectivity.
Received 25 April 2012
Revised 7 July 2012
Accepted 9 July 2012
Available online 15 July 2012
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent synthesis
Spirooxindoles
4H-Chromene
Nanocrystalline MgO
Water chemistry
In the last few years, considerable effort is being made on the
advancement of green chemistry using protocols having less envi-
ronmental impact, maintaining higher atom-economy and recycla-
bility. Multicomponent reactions have become popular for
constructing complex molecules involving atom-economic way.1
The green effect becomes more enhanced when the reactions are
performed in water and over reusable heterogeneous catalysts.
The importance of indoles and their derivatives is well recognized
by the synthetic as well as natural product chemists due to their
profound medicinal implications. As a result there has been an urge
to prepare a variety of indole skeletons following easy and effective
methodology.2 Spiro compounds represent a distinguished class of
molecules which are present in many naturally occurring sub-
stances.3 Indoles being involved in these spiro nuclei enhance the
biological activity to a significant extent. Examples that include this
class are some cytostatic alkaloids like spirotryprostatins and pter-
opodines. They are effective inhibitors of microtubule activity and
modulators of the function of muscarinic serotonin receptors.4
Among the spirooxindole compounds those with substituted fused
4H chromenes have immense importance due to their spasmolitic,
diuretic, anticoagulant, anticancer, and antinaphylactic activities.5
Especially the nitrile substituted 4H chromenes are significant as
they are effective drugs in human neurodegenerative disorders.6
In view of these important implications, our current focus has been
targeted on the facile synthesis of these moieties in a green
pathway.
There have been several reports available in the literature on
the multicomponent synthesis of fused spirochromenes. The con-
ventional procedure constitutes the three component condensa-
tion of isatin, active methylene component, and 1,3-dicarbonyl
compound. The methodology involves the use of InCl3 in refluxing
acetonitrile or InCl3/SiO2 composite in microwave,7 applying the
use of electrogenerated base8 or the water mediated surfactant cat-
alyzed synthesis.9 However, most of the reported methods are
associated with drawbacks like the use of carcinogenic organic sol-
vents, applying high temperatures, use of expensive, and sometime
non-commercially available catalysts. Those methods involving
water mediated synthesis, lack the reusability property of the cat-
alyst. A very recent method has been published on the synthesis
over nanoparticular ZnS catalyst in water.10 However, keeping in
mind their own merits of the reported methods, we believe that
there is scope for further development on the environmental and
economical impact of the reaction.
Nanocrystalline metal oxides find excellent application as ac-
tive adsorbent for gases, for destruction of hazardous chemicals,11
and as catalyst in various organic reactions.12 In continuation of
our efforts for the development of synthetic methodologies for
the production of various biologically important moieties using
mesoporous heterogeneous and reusable catalysts,13 we wish to
report for the first time the use of nanocrystalline MgO catalyzed
one-pot three-component synthesis of spirooxindoles with fused
⇑
Corresponding author. Tel.: +91 33 2350 8386; fax: +91 33 2351 9755.
E-mail address: juliebanerji47@gmail.com (J. Banerji).
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.030

B. Karmakar et al. / Tetrahedron Letters 53 (2012) 5004–5007
5005
O
O
O
O
O
Nano MgO
H2O, 80 oC
+
+
NC
X
NH2
N
H
O
X
N
H
O
Scheme 1. Multicomponent synthesis of spirooxindoles.
chromenes in water with excellent yields (Scheme 1).14 Our main
focus in this work was to develop a methodology which would in-
volve inexpensive and easily available reagent, fast and high yield
reaction, and clean and eco friendly pathway.
of spirooxindole gradually improved at 40 and 60 °C and reached a
maximum at 80 °C. With further rise in temperature the yield did
not improve.
On obtaining the optimized condition, a series of spirooxindoles
with fused tetrahydro chromene derivatives were synthesized by
combining isatin, different nitrilo active methylene components,
and 1,3 dicarbonyl compounds in order to delineate the approach.
In Table 3 the detailed study following the results has been given.
This method is compatible with a wide variety of substrates. Three
different cyano containing active methylene components viz., mal-
ononitrile, ethyl cyanoacetate, and cyano acetamide were used
(2a–c). Similarly, a variety of 1,3 dicarbonyl compounds (both cyc-
lic and acyclic) were used in the reactions (3a–f). In all the cases
high yield of the products were observed in short reaction time.
Meanwhile, 4-hydroxycoumarin (3g) was used instead of 1,3 dicar-
bonyl compounds to utilize its nucleophilic center and also here
the corresponding spirooxindole derivative was generated in
excellent yield. In all the cases the products were characterized
by 1H NMR, 13C NMR, IR spectroscopy, and elemental analysis
and correlated with authentic data.
Recyclability of nanocrystalline MgO was examined through the
reaction of isatin, malononitrile, and cyclohexane-1,3-dione in
water. After completion of the reaction, the crude solid reaction
mixture was filtered. It was then dissolved in hot methanol and fil-
tered to separate the catalyst. The recovered MgO was washed
with methanol several times and dried in an oven at 80 °C before
being reused with a fresh batch of reactants. A comparison of mor-
phology as well as internal chemical structure of the reused MgO
with the fresh batch have been performed with SEM analysis and
X-ray diffraction study.15 The study revealed that the similar
spongy porous structure and same crystal planes were still re-
tained after reuse which is a major concern in retaining similar cat-
alytic activity. Thus it was found that MgO could be recycled three
times without much significant loss of activity. The reusability test
has been shown in Table 4. The gradual reduction in activity might
be exclaimed due to agglomeration of small particles.
MgO has a three-dimensional polyhedral structure, which hav-
ing the presence of high surface concentrations of edge/corner and
various exposed crystal planes (such as 200, 100 and 111) leads to
inherently high surface reactivity per unit area.15 Besides this, the
NC MgO has a Lewis acid site Mg2+, Lewis basic sites O2À and OÀ,
lattice bound and isolated Bronsted hydroxyls, and anionic and
cationic vacancies. A cascade reaction mechanism follows in the
synthesis of spirooxindoles. Initial step involves a Knoevenagel
condensation between isatin and malononitrile. The intermediate
isatylidene malononitrile then undergoes Michael reaction via
the enolic nucleophilic center of 1,3-dicarbonyl compound. Both
these steps are known to be promoted by bases. Therefore the sur-
face hydroxyls and oxide anions (basic sites) are expected to play
their roles here. The final step is supposed to be catalyzed by Lewis
acid site Mg2+ which involves the cyclization of hydroxyl group to
cyano function affording the spirooxindole with fused tetrahydro
chromene.
At the outset of our study, we investigated the three-
component reaction between isatin, malononitrile, and cyclohex-
ane-1,3-dione in equimolar ratio as a model reaction in water at
80 °C, both in the absence and presence of catalysts as additives.
The results have been shown in Table 1. We obtained a poor result
in the absence of any catalyst even after 10 h of the reaction (entry
1, Table 1). Considering the reaction being base catalyzed, a variety
of basic catalysts were employed under the same condition. Easily
available and cheap bases like NaHCO3, K2CO3, and MgCO3 were
found to promote the reaction in shorter reaction time along with
moderate yield of the product (entry 2–4). Being encouraged with
this result, we decided to go on with the surface active heteroge-
neous catalyst, viz., nanocrystalline MgO (5 mol %). Interestingly,
it afforded an improved yield of 84% of the spirooxindole derivative
within 2 h of the reaction (entry 5). A further better result was
obtained with an increase in catalyst loading (entry 6–7). We wish
to mention here that bulk MgO did not prove to be as efficient as its
nano counterpart (entry 8). Finally the reaction condition was
optimized with 15 mol % nanocrystalline MgO in water at 80 °C.
In a separate study we examined the probe reaction with a var-
iation of temperature. At room temperature (25 °C) fruitful amount
of conversion was not observed. However the productivity in-
creased by raising the temperature. As shown in Table 2, the yield
Table 1
Evaluation of catalysts in the synthesis of spirooxindole by combining isatin,
malononitrile and cyclohexane-1,3-dionea
Entry
Catalyst (mol%)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
None
10
6
6
6
2
2
2
2
33
57
61
67
84
88
93
78
NaHCO3 (10)
K2CO3 (10)
MgCO3 (10)
NC MgO (5)
NC MgO (10)
NC MgO (15)
bulk MgO (15)
a
Reaction condition: Isatin: malononitrile: cyclohexane-1,3-dione = 1:1:1, H2O,
80 °C; Isolated yield; NC stands for nanocrystalline.
Table 2
Effect of temperature in the synthesis of spirooxindole by combining isatin,
malononitrile and cyclohexane-1,3-dionea
Entry
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
25
40
60
80
12
6
2
27
51
87
93
2
a
In conclusion, we have described a novel and highly efficient
green protocol for the synthesis of diverse spirooxindole
Reaction condition: Isatin: malononitrile: cyclohexane-1,3-dione = 1:1:1, H2O,
15 mol % NC MgO; Isolated yield.

5006
B. Karmakar et al. / Tetrahedron Letters 53 (2012) 5004–5007
Table 3
Synthesis of spirooxindoles with varying reaction components in water over nanocrystalline MgOa
O
O
O
O
O
Nano MgO
H2O, 80 C
+
+
NC
X
NH2
N
H
O
o
X
N
H
O
2
3
4
1
NC
CO2Et
NC
O
CONH2
NC
O
CN
2a
2b
2c
O
O
O
O
O
O
O
O
HN
NH
OEt
OMe
O
O
3a
3b
3c
3d
3e
OH
O
O
O
Ph
Ph
3f
3g
Entry
2
3
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2c
2c
2c
3a
3b
3c
3d
3e
3f
3g
3a
3b
3d
3f
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
2
2
1.5
2
2
2.5
1.2
2
93
95
88
87
84
83
91
90
92
85
80
88
84
85
80
9
2
10
11
12
13
14
15
2.5
3.0
1.5
2.5
2
3g
3a
3b
3d
3.0
a
Reaction condition: All three reactants in equimolar ratio, H2O, 80 °C; 15 mol % NC MgO; Isolated yield.
Supplementary data
Table 4
Reusability study of NC MgO in the synthesis of spirooxindole by combining isatin,
malononitrile and cyclohexane-1,3-dionea
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
07.030.
Entry
Yielda (%)
1
2
3
4
93
92
85
83
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Acknowledgements
This work was financially supported by UGC, New Delhi and J.B.
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14. (i) Procedure for the synthesis of nanocrystalline Mgo: The catalyst was
prepared by non-hydrothermal sol-gel approach. Anhydrous MgCO3 was
used as the Mg source. Triethanolamine was used as
a surfactant and
structure directing template. MgCO3 was dissolved in triethanolamine with
stirring at room temperature. Deionised water was added to form a gel. Then
another co-surfactant triethyl ammonium hydroxide was added dropwise to
the mixture to maintain a pH 12. This was aged at room temperature for 24 h
to obtain a white gel. The gel was dried at 120 °C for another 24 h and finally
the cake was calcined at 600 °C for 6 h to obtain a fine white powder. The
material has been characterized by SEM, TEM, and X-ray diffraction study
(Supplementary data).
(ii) Typical Procedure for the synthesis of spirooxindoles: A mixture of isatin,
malononitrile, and cyclohexane-1,3-dione in equimolar ratio was heated
(5 mL) in water at 80 °C. After completion of the reaction a precipitate was
observed which was filtered. The solid thus obtained was dissolved in hot
methanol to separate the catalyst. Pure product was obtained by
recrystallization of the filtrate. The products were characterized by 1H NMR,
13C NMR, IR spectroscopy, and elemental analysis. The characteristic
spectroscopic data have been provided in the Supplementary data.
13. (a) Karmakar, B.; Nayak, A.; Chowdhury, B.; Banerji, J. Arkivoc 2009, XII, 209; (b)
Postole, G.; Chowdhury, B.; Karmakar, B.; Pinki, K.; Banerji, J.; Auroux, A. J.
Catal. 2010, 269, 110; (c) Karmakar, B.; Chowdhury, B.; Banerji, J. Catal.
15. The comparison studies have been shown in Supplementary data.