Chitosan/ionic liquid forms a renewable and reusable catalyst system used for the synthesis of highly functionalized spiro derivatives

Article abstract of DOI:10.1039/c3nj01545a

Chitosan, a reusable heterogeneous catalyst, can be combined with an ionic liquid as a green solvent to generate a highly efficient catalyst system for our densely functionalised and diversified target molecule. The reaction is completed with a good to ex

Full text of DOI:10.1039/c3nj01545a

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Chitosan/ionic liquid forms a renewable and
reusable catalyst system used for the synthesis of
highly functionalized spiro derivatives†
Cite this: New J. Chem., 2014,
38, 3181
Pratibha Rai,a Madhulika Srivastava,a Jaya Singhb and Jagdamba Singh*a
Received (in Porto Alegre, Brazil)
7th December 2013,
Accepted 10th March 2014
Chitosan, a reusable heterogeneous catalyst, can be combined with an ionic liquid as a green solvent to
generate a highly efficient catalyst system for our densely functionalised and diversified target molecule.
The reaction is completed with a good to excellent yield. This procedure demonstrates an eco-friendly
catalyst system and eliminates the use of toxic transition metal catalysts, bases and volatile organic
solvents, which adversely affect the environment and human beings.
DOI: 10.1039/c3nj01545a
www.rsc.org/njc
liquids as environmentally friendly solvents, e.g. hydrogena-
tion, the Suzuki reaction, Aldol condensation, Diels–Alder
Introduction
Creating a highly efficient, selective, eco-friendly, and reusable reactions, alkylation, Michael addition and the Schmidt reac-
catalyst is an interesting target in synthetic chemistry. Catalysis tion.4 Room temperature ionic liquids have found particular
is at the centre of many chemical procedures. Catalysts are not application in materials science, electrochemistry and separa-
only required in organic syntheses, but are also used in fine tion technology.7 Since the use of the first ionic liquid as a
chemical industries. The chemical nature and form of a catalyst reaction medium for organic synthesis, researchers have mostly
play an important role in a reaction. A strong relationship concentrated on homogeneous catalysis in ionic liquids.8 How-
between heterogeneous catalysis and the practices and princi- ever, homogeneous catalysis has many drawbacks, such as
ples of eco-friendly synthesis could potentially result in an multistep separation of the catalyst by extraction, distillation,
environmentally benign society.1 Replacement or elimination chromatography etc., costly metal complexes and the extraction
of toxic reagents or volatile organic solvents in chemical of metal ions, which involves a difficult procedure.9 Hetero-
processes is one of the main goals of green chemistry.2 During geneous catalysis, on the other hand, produces less waste, thus
the past ten years, room temperature ionic liquids have been making the procedure easier, results in less adulteration of the
described as very efficient green reaction media to replace products with the active catalytic species, allows reuse and
traditional volatile organic solvents.3 They display many advan- separation of the catalysts, and does not involve the use of
tages, such as excellent ability to dissolve organic compounds, toxic solvents.10,11 The crisis of the reduction in non-renewable
negligible vapour pressure, ease of separation from products resources has created and encouraged chemists to use biomass,
and recyclability.4 Additionally, one of the most important such as polymers present in nature, in place of fossil resources.
features of ionic liquids is their tendency to form solvophobic For instance, polysaccharides, which exist widely in nature, have
interactions that generate an internal pressure, encouraging been used as supports in heterogeneous catalytic systems.12
better involvement of the reactants in a reaction medium and
In recent years, the application of small synthetic or natural
promoting multicomponent reactions more efficiently, as com- organic scaffolds has provided an interesting substitute for
pared to traditional solvents.5 Their broad liquid range and conventional metal-catalyzed reactions in some asymmetric
solvating ability also establish them as suitable reaction media syntheses. In this respect, chitosan can play an important role
for multi component processes.6 During the last decade, a as a renewable, biocompatible, natural polymer which is physio-
number of organic syntheses have been performed using ionic logically inert and stable to air and moisture.13 In fact, chitosan
is a polysaccharide obtained from chitin, which is present in
a Department of Chemistry, University of Allahabad, Allahabad, Uttar Pradesh,
India. E-mail: rpp599@gmail.com, madhulikasrivastava8@gmail.com,
dr.jdsau@gmail.com
nature (Fig. 1). It is a linear polyamine and a polar biopolymer,
which is available in ample amounts in nature throughout the
world.14 It is insoluble in most organic compounds. Chemists
have described the greater performance of chitosan than that of
chitin in many areas of industry that involve heterogeneous
catalysis. Since chitosan has both amino and hydroxyl groups,
b Department of Chemistry, LRPG College, Sahibabad, Uttar Pradesh, India.
E-mail: nimesh.singh@in.abb.com
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3nj01545a
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concerns and the important features of dihydropyrano[2,3-c]-
pyrazoles and spiro moieties, we wish to demonstrate the combi-
nation of an ionic liquid as a green reaction medium and
chitosan as a reusable heterogeneous catalyst for this protocol
(Scheme 1).
Results and discussion
A number of protocols have been demonstrated for the syn-
thesis of dihydropyrano[2,3-c]pyrazole and its related derivatives.
These transformations involve a base- or an acid-catalyzed
reaction between a hydrazine, a b-ketoester, an isatin and an
active methylene compound. Several methods have been
reported for the synthesis of dihydropyrano[2,3-c]pyrazole,
involving the application of L-proline,22 Aspergillus niger,23
ultrasound waves,24 triethylamine (TEA)25 and meglumine.26
Previously examined methods have long reaction times and
multistep work-up procedures, and use catalysts and toxic
solvents. Keeping these aspects in mind, we tried to develop
an eco-friendly approach for the synthesis of our target mole-
cule. We selected ethylacetoacetate (1a), phenylhydrazine (2a),
isatin (3a) and malononitrile (4a) as reactants, based on the
disconnection approach (Fig. 3).
Fig. 1 Applications of chitosan in different fields.
it can be altered chemically into different forms and can take
part in various types of reactions as an appropriate support for
various catalytic species.15 Hence, chitosan, as a natural poly-
glucosamine, can be examined as a heterogeneous catalyst in
organic transformation.16,17 The indole nucleus is a highly
versatile heterocyclic scaffold present in different types of med-
icinal agents and natural products. Molecules with indole nuclei
display antifungal and antibacterial activities.18 Moreover, it has
been reported that C-3 spiroindoline derivatives have high
biological activity.19 The oxindole moiety is the core structure
of various natural alkaloids and pharmacological agents.20
Dihydropyrano[2,3-c]pyrazoles also play an important role in
biologically active molecular scaffolds, and hence are an attrac-
tive moiety in medicinal chemistry. They have been broadly
applied as medicinal intermediates because of their important
biological and pharmaceutical properties. They are an attractive
synthetic moiety with a high level of bioactivity that involves anti-
inflammatory and antimicrobial properties. Fig. 2 shows some
important bioactive spiro moieties.21 Due to environmental
A
series of spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-
carbonitriles were prepared using ethylacetoacetate (1 mmol),
phenylhydrazine (1 mmol), malononitrile (1 mmol) and isatin
(1 mmol) in the absence of a catalyst.
We discovered that only trace amounts of the products were
formed after a long time. In order to optimize the reaction
conditions, test reactions were performed using model reac-
tants under different reaction conditions to investigate the
effect of different solvents and varying amounts of catalyst in
terms of the amount of product and the reaction time. We
observed that commonly used bases (entries 2–5 of Table 1)
Fig. 2 Some important bioactive molecules containing a spiro-oxindole
moiety.
Fig. 3 Disconnection approach for the target molecule (5a).
Table 1 Optimization of the catalyst
Entry
Catalyst
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
None
NaOH
KOH
DEA
TEA
SDS
CTAB
Chitosan
3
3
3
3
3
3
3
3
Trace
40
42
45
48
50
60
76
Reaction conditions: ethylacetoacetate (1 mmol), phenylhydrazine
(1 mmol), malononitrile (1 mmol) and isatin (1 mmol). a Yield of product.
Scheme 1 General reaction scheme.
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Table 3 Optimization of the ionic liquid
could catalyze the reaction, with a moderate yield (40–50%) of
the product. In addition, a number of by-products were formed.
In the next step, we used surfactants, for example SDS (sodium
dodecyl sulfate) and CTAB (cetyltrimethylammonium bromide)
to carry out this protocol, but again, the yield of the product
was not satisfactory (entries 6 and 7 of Table 1). In order to
develop an eco-efficient approach and in continuation of our
Entry
Ionic liquid
Time (h)
Yielda (%)
1
2
3
4
5
(Bmim)BF4
(Hmim)HSO4
(Hmim)H2PO4
(Bmim)PF6
3
3
3
3
3
Trace
25
28
65
92
(Bmim)OH
previous work27 on the development of a green protocol, we Reaction conditions: ethylacetoacetate (1 mmol), phenylhydrazine
a
(1 mmol), malononitrile (1 mmol) and isatin (1 mmol). Yield of
examined the potential of chitosan by performing the model
reaction with it. The reaction proceeded smoothly, resulting in
product.
the formation of the corresponding products in good yields and
in different types of ionic liquid, such as (Bmim)BF4,
(Hmim)HSO4, (Hmim)H2PO4 and (Bmim)PF6 (Table 3). The
interaction of the ionic liquid with chitosan results in enhance-
ment of the basicity of the medium, thereby increasing the rate
of the reaction. This catalyst system increases the yield of the
product when the reaction is carried out at room temperature.
The recyclability of the catalyst system using chitosan
(20 mol%) and (Bmim)OH (5 ml) was also examined for the
test reaction. After completion of the reaction, the reaction
medium, products and reactants were separated from the
reaction mixture by extraction with ethylacetate and water.
The mixture of chitosan catalyst and ionic liquid reaction
medium was then washed several times with water and further
applied in the conversion under similar conditions to those
used in the first run. It was observed that the catalyst and
solvent system could be reused six times. In the first three
cycles, the system did not show a significant decrease in
catalyst activity (Table 4).
After optimization of the reaction conditions, the method
was evaluated using different types of b-ketoesters (1), hydra-
zines (2), isatins (3) and active methylene compounds (4). Two
ethylacetoacetates (1), four substituted hydrazines (2), two
malononitriles (4) and many substituted isatins (3) were used
for the synthesis of a library of 60-amino-30-methyl-2-oxo-10-
phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-
carbonitriles in good yields at room temperature in the
presence of chitosan as a catalyst and an ionic liquid as a
reaction medium. The results are shown in Table 5. From
Table 5, it is obvious that this protocol works with a broad
range of reactants.
reaching completion within 3 hours. Chitosan has a high
concentration of both primary and secondary hydroxyl groups
and amino groups. Hence, it can increase the activity of the
nucleophilic and electrophilic centres of the reactants during
the reaction via lone pairs and hydrogen bonding. The activity
of the chitosan catalyst was optimized for the synthesis of the
desired product. The results showed that when we increased
the amount of chitosan to 20 mol%, the yield of the product
continuously increased from 76 to 85% (entry 3 of Table 2).
Using amounts of chitosan less than 20 mol% (5 mol%,
10 mol% and 15 mol%), the desired product was obtained in a
moderate yield with a longer reaction time, while with a further
increase in the amount of chitosan, there was no increase in the
yield of the target molecule (entries 4 and 5 of Table 2). From this
result, we concluded that 20 mol% chitosan is the optimum
amount for obtaining the desired product. Corma and co-
workers previously demonstrated that the reaction rate of the
Knoevenagel condensation, in which solid catalysts are used,
decreased in a non-polar reaction medium, and a higher yield
was obtained on increasing the polarity of the solvents.28 Gascon
and co-workers reported a similar result, in which polar solvents
increased the reaction rate of the heterogeneous Knoevenagel
condensation, and the reaction was completed with difficulty in
non-polar solvents.29 A literature survey showed that ionic
liquids can act as a substitute reaction medium, connecting
various types of polymers that are present in nature and result-
ing in an improvement in their reusability. In order to increase
the basicity of the catalyst, we used ionic liquids. We found that
ionic liquids form good combinations with chitosan. After
examining chitosan-catalyzed reactions in the presence of an
ionic liquid as a reaction medium, there are a number of points
that need to be discussed.
A plausible mechanism for the reaction is shown in
Scheme 2. In the first step, the hydroxyl group of chitosan
activates the carbonyl group of the b-ketoester (1), which
undergoes a condensation reaction with the hydrazine (2),
In the next step, we investigated the effect of various types of
ionic liquids on the model reaction, using chitosan as a reaction
promoter. The reaction was performed using 20 mol% chitosan
Table 4 Reusability of the catalyst system
Table 2 Optimization of the amount of catalyst
Entry
Cycle
Catalyst system
Yielda (%)
Entry
Amount of chitosan (mol%)
Time (h)
Yielda (%)
1
2
3
4
5
6
1
2
3
4
5
6
Catalyst system
Catalyst system
Catalyst system
Catalyst system
Catalyst system
Catalyst system
92
80
70
65
58
56
1
2
3
4
5
10
15
20
30
40
3
3
3
3
3
65
76
85
85
85
Reaction conditions: ethylacetoacetate (1 mmol), phenylhydrazine
(1 mmol), malononitrile (1 mmol) and isatin (1 mmol). a Yield of product.
Reaction conditions: ethylacetoacetate (1 mmol), phenylhydrazine
(1 mmol), malononitrile (1 mmol) and isatin (1 mmol). a Yield of product.
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Table 5 Synthesis of compound (5a–5o) by using diversified b-ketoester (1), hydrazine (2), isatin (3) and active methylene compounds (4)a
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Ethylacetoacetate (1)
Hydrazine (2)
Isatin (3)
Active methylene compound (4)
Yieldb (%)
Time (h)
3
92
NH2–NH2
NH2–NH2
89
86
4
5
NH2–NH2
85
4.5
NH2–NH2
NH2–NH2
NH2–NH2
87
87
86
4.5
5
6
88
91
91
93
4
NH2–NH2
3
2.5
2.5
93
89
2.5
3.5
NH2–NH2
90
91
3.5
3
a
b
Reaction conditions: Stoichiometric amount of b-ketoester, hydrazines, isatin and active methylene compound. Yield of product.
leading to the formation of intermediate (A). A Knoevenagel higher reactivity towards malononitrile as compared to isatins
condensation between the isatin (3) and the active methylene with electron donating groups. Here, we demonstrate an eco-
compound (4), leading to the formation of intermediate (B), is friendly and efficient protocol for a four-component synthesis
facilitated by the amine group of chitosan. Finally, Michael of pyrano[2,3-c]pyrazoles in ionic liquids in the presence of
addition between intermediate (A) and intermediate (B) occurs chitosan as a catalyst. The chitosan as reaction promoter and
to form intermediate (C), which undergoes intramolecular the ionic liquid as reaction medium could be reused in their
cyclization followed by tautomerization to form the desired original pure forms after being used in the model reaction.
product (5). Isatins with electron withdrawing groups show Both the reaction medium and the catalyst could be recycled
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were added to the reaction mixture in a separating funnel. The
chitosan and the ionic liquid separated from the organic layer.
The chitosan was recovered after centrifugation of the water
layer, and was used in further reactions. Recovery of the ionic
liquid was also investigated. The water layer was dried under
vacuum at 90 1C to afford (Bmim)OH, which was used in
subsequent runs without purification.
Acknowledgements
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing micro-analysis spectra and also UGC, New Delhi, for
awarding a Junior Research Fellowship (JRF) to Pratibha Rai
and a SRF to Madhulika Srivastava.
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1
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