Magnetic, acidic, ionic liquid-catalyzed one-pot synthesis of spirooxindoles

Article abstract of DOI:10.1021/co400080z

Magnetic, supported, acidic ionic liquid was synthesized and identified as an efficient catalyst for the one-pot synthesis of novel spirooxindole derivatives at mild conditions and in good yields. Three component reaction of wide variety of substituted isatins, 1,3-dimethyl-2-amino uracil, and barbituric acid, thiobarbituric acid, and dimedon as 1,3-dicarbonyl compounds gives the target compounds. Operational simplicity, low cost, high yields, environmental friendliness, wide applicability and reusability and easy recovery of the catalyst using an external magnet are the key features of this methodology.

Full text of DOI:10.1021/co400080z

Research Article
pubs.acs.org/acscombsci
Magnetic, Acidic, Ionic Liquid-Catalyzed One-Pot Synthesis of
Spirooxindoles
Ali Khalafi-Nezhad* and Somayeh Mohammadi
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
*
S Supporting Information
ABSTRACT: Magnetic, supported, acidic ionic liquid was synthesized and identified as an efficient catalyst for the one-pot
synthesis of novel spirooxindole derivatives at mild conditions and in good yields. Three component reaction of wide variety of
substituted isatins, 1,3-dimethyl-2-amino uracil, and barbituric acid, thiobarbituric acid, and dimedon as 1,3-dicarbonyl
compounds gives the target compounds. Operational simplicity, low cost, high yields, environmental friendliness, wide
applicability and reusability and easy recovery of the catalyst using an external magnet are the key features of this methodology.
KEYWORDS: multicomponent reaction, spirooxindole, magnetic catalyst, supported acidic ionic liquid
1
. INTRODUCTION
of the wide-ranging biological activity associated with them
such as antibacterial, antifungal, antiinflammatory, and anti-
In recent years, there has been considerable growth of interest
in the synthesis of spirooxindole derivatives (Figure 1) because
1
pyretic activities. On the other hand, a large number of
pyrimidine derivatives consist of barbituric acid and 2-amino-
uracil have attracted great interest for their biological activities
2
and applications in medicine and therapeutics. In this context,
the synthesis of this important ring system fused with
spirooxindole remains a topic of current interest. Various
methods for the preparation of spirooxindole derivatives have
3,4
been reported. However, to the best of our knowledge, some
of these methods suffer from tedious synthetic routes, long
reaction time, drastic reaction conditions, toxicity, corrosive-
ness, cost, as well as unreusability of catalyst. Therefore, there is
still a need for versatile, simple, and environmentally friendly
processes.
Recently, ionic liquids (IL), especially acidic types, have
attracted increasing interest in organic synthesis, because they
5
can provide green and efficient media for organic reactions. In
Received: June 17, 2013
Revised: August 2, 2013
Figure 1. Representatives of spirooxindole-containing compounds.
©
XXXX American Chemical Society
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Research Article
Scheme 1. Various Synthesized Spirooxindoles in the
Presence of MSAIL
group transformations as a catalyst in green processes.
Therefore, in continuation with our interest in developing
efficient and environmental benign synthetic methodologies,
13
we focused our attention on a simple, green, and efficient
method for synthesis of biological active spirooxindole
derivatives from a wide variety of isatin, 1,3-dimethyl-2-amino
uracil, and different 1,3-dicarbonyl compounds in high yields
and short reaction time (Scheme 1). Lower cost, operational
simplicity, high yields, and the possibility of easy recovering of
the catalyst are the most advantages of this method. To the best
of our knowledge, this is the first report on the synthesis of
these spiro pyrimido pyrimidine derivatives in the presence of
magnetic ionic liquid.
14
However, very recently, Das et al. have reported a PEG-
OSO H mediated one-pot three-component domino coupling
3
of 1,3-diketo compounds, 6-aminouracil/4-aminocoumarin, and
isatin/5-bromoisatin under thermal conditions to afford highly
substituted uracil and coumarin fused spirooxindole derivatives.
But the set of reactants used in this method is quite small (only
isatin and 5-bromo isatin) and in contrast to the easy separation
of a magnetic, supported catalyst by a magnetic force, the
separation of PEG-OSO H catalyst from the product needs
3
parallel with the use of ILs in organic transformations, they also
have been used as reaction medium for multicomponent
reactions (MCRs). The MCRs are an attractive synthetic
filtration and H O evaporation under reduced pressure.
2
6
2
. RESULTS AND DISCUSSION
strategy, because the complex products are formed in single
step and diversity can be achieved simply by varying the
Catalyst Preparation. New MSAIL as a catalyst was
7
reaction components.
prepared based on the following procedure (Scheme 2, see the
Supporting Information). The magnetic catalyst was charac-
terized using some different microscopic and spectroscopic
techniques such as transmission electron microscopy (TEM),
scanning electron microscopy (SEM), and FT-IR. The number
On the other hand, heterogeneous catalysis is generally
preferred to homogeneous catalysis mainly because of the easy
recovering and possible recycling of the catalyst, simple
experimental procedures, and minimization of chemical wastes
as compared to the liquid phase counterparts. It seems that
magnetic nanoparticles (MNP) can be a good candidate as a
support material for heterogeneous catalysts, because of easy
synthesis, high surface area, facile separation by magnetic forces,
+
of H site of MSAIL determined by acid−base titration was
1
0.85 ± 0.05 mequiv·g. (see the Supporting Information,
Figures 1−3).
Optimization of Reaction. To show the merit of MSAIL
as a catalyst in organic synthesis, we first applied this catalyst for
multicomponent reaction. The reaction of isatin, 1,3-dimethyl-
2-amino uracil, and barbituric acid affording spirooxindole was
examined in the presence of different catalysts and solvents.
The results of the optimized conditions are summarized in
Table 1.
8
and low toxicity and cost. According to these attractive
properties, many MNP supported catalysts have been designed
and widely applied as novel magnetically separated catalysts in
9
,10
11
traditional metal catalysis,
organocatalysis, and even
1
2
enzyme catalysis. In this work, for combining the benefits
of ILs and heterogeneous magnetic catalysts, we reveal a new
nanometer scale, magnetic, supported, acidic ionic liquid
During our optimization studies, when the reaction was
carried out in the absence of catalyst the reaction was
(MSAIL), which can be used for different organic functional
a
Scheme 2. Different Steps for the Synthesis of MSAIL
a
(
i) toluene, reflux, 24 h; (ii) toluene, rt, 8h; (iii) ethanol, 30 min.
B
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Table 1. Combined Effects of Solvents and Catalysts on the Multicomponent Reaction between Isatin, Barbituric Acid, and 1,3-
a
Dimethyl-2-amino Uracil
a
b
c
entry
condition
cat.
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
EtOH (reflux)
EtOH (reflux)
MeCN (reflux)
MeCN (reflux)
24
24
24
24
13
10
10
24
24
12
8
trace
39
CH COOH
3
FeCl3
45
AlCl3
50
H O (reflux)
2
p-TSA
SSA
75
H O (reflux)
2
75
EtOH (reflux)
H PMo O
70
3
12 40
H O (reflux)
2
nano-Fe O4
trace
trace
65
3
H O (reflux)
2
nano-Fe O .SiO
2
3
4
10
11
12
13
14
15
EtOH (reflux)
EtOH (reflux)
MeOH(reflux)
DMF (reflux)
[MIMPSA][HSO4]
nano-MSAIL
nano-MSAIL
nano-MSAIL
nano-MSAIL
nano-MSAIL
75
8
75
10
5
75
H O (reflux)
2
75
H O (rt)
2
5
89
a
b
c
Reaction conditions: isatin(1 mmol), barbituric acid (1 mmol), 1,3-dimethyl-2-amino uracil (1 mmol). 1.5 mol % of catalysts was used. Isolated
yield.
Table 2. Effect of Catalyst Amount on the Reaction between
a
Isatin, Barbituric Acid, and 1,3-Dimethyl-2-amino Uracil
entry
amount of cat. (mg)
yield (%)
1
2
3
4
5
40
45
50
55
60
38
65
89
89
90
a
Reaction conditions: isatin (1 mmol), barbituric acid (1 mmol), 1,3-
dimethyl-2-amino uracil (1 mmol), H O (1 mL), catalyst (MSAIL), rt,
2
5
h.
incomplete even after 24h under reflux in ethanol and nearly no
product was obtained (Table 1, entry 1). When different solid
catalysts such as FeCl , AlCl , p-TSA, SSA, and H PMo O
3
3
3
12 40
were used, their effect was only moderate (Table 1, entries 3−
7
). By using a typical acidic IL [MIMPSA][HSO ] 65% yields
4
of the product were obtained after 12h, respectively (Table 1,
entry 10). In comparison with [MIMPSA][HSO ], MSAIL
4
increased the yield to 75% in a shorter reaction time (Table 1,
entry 11). This is presumed to occur due to the adsorption of
reactants on the surface of the nanomagnetic support,
increasing the local concentration of reactants around the
active sites of the MSAIL and effectively promoting the
reaction. Decreasing the reaction temperature to ambient
increased the yield to 89% after 5h.
The efficiency of the supported catalyst was found to be
solvent dependent with water being the best. The catalyst
concentration, which afforded the best yields, was 1.5 mol %
(
Table 2). Increasing the amount of catalyst did not change the
Figure 2. Diversity of reagents.
yield dramatically, whereas reducing it significantly decreased
the product yield.
C
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Figure 3. Synthesized spirooxindoles in the presence of MSAIL.
The methodology was evaluated by using 1,3-dimethyl 2-
amino uracil, isatin derivatives, and different 1,3-dicarbonyl
groups such as barbituric acid, thiobarbituric acid and dimedon
as nucleophiles (Scheme 1, Figure 2), under similar conditions
subsequent step a molecule of barbituric acid would suffer a
conjugated addition over I rendering intermediate II, which
after condensation would afford main product.
To shed light on the above proposed mechanism, when the
reaction of 2-amino-uracil with isatin was carried out for 1 h,
the intermediate 6-imino-1,3-dimethyl-5-(2-oxo-1,2-dihydro-
indol-3-ylidene) dihydro-pyrimidine-2,4-dione (I) was isolated
and characterized by spectroscopic methods. Then, the
intermediate (I) was converted to intermediate 5-[3-(6-
amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro pyrimidin-5-
yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2,4,6-trione (II) after at-
tacking enolate of nucleophileand followed by cyclization
afforded the corresponding spiro-compound (Scheme 3).
To show an additional advantage of our developed catalytic
system we explored the recycling of catalyst MSAIL, which was
able to be recycled simply via attaching an external magnet after
completion the reaction and washed with ethyl acetate, dried
under vacuum and reused in a subsequent reaction. Nearly
quantitative catalyst (up to 98%) could be recovered from each
(
50 mg MSAIL, H O, room temp.) to explore the scope of the
2
procedure reported in Figure 3.
The reactions proceeded smoothly and the desired
spirooxindole products from a diverse set of substrates were
obtained in good yields (Figures 2 and 3). Isatins with electron-
withdrawing groups as well as electron-donating substituents
underwent this one-pot conversion to give the corresponding
spirooxindols in good yield (Figure 3); however, the reaction
time of isatins with electron-rich groups was longer than those
of with electorn-withdrowing group, which is probably because
of the lower reactivity of the isatins with electron-rich groups.
The structure of final adducts are compatible with the
mechanistic proposal depicted in Scheme 3 in which after the
protonation of isatin by our catalyst, a molecule of uracil would
be added affording intermediate I after dehydratation. In a
D
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ACS Combinatorial Science
Research Article
Scheme 3. Proposed Mechanism for the Multicomponent Reaction Using MSAIL Catalyst
readily separated by use of a magnetic force and reused without
any significant loss of catalytic activity after five runs. Besides
the synthesis of spirooxindole derivatives, such an environ-
mentally benign catalyst should find a wider application in
various acid-catalyzed reactions, which is an ongoing project.
4
. EXPERIMENTAL PROCEDURES
General Considerations. All chemicals were purchased
from Fluka, Merck, and Aldrich chemical companies. For
1
recorded H NMR spectra we used a Bruker (250 MHz) Avanc
DRX in pure deuterated DMSO-d and CDCl solvents with
6
3
Figure 4. Catalytic recovery times of MSAIL catalyst for fifth runs.
tetramethyl silane (TMS) as the internal standard. Mass spectra
were recorded on a FINNIGAN-MAT 8430 mass spectrometer
operating at 70 eV. FT-IR spectroscopy (Shimadzu FT-IR 8300
spectrophotometer), was employed for characterization of the
compounds. The scanning electron micrograph for MSAIL
catalyst was obtained by SEM instrumentation (SEM, XL-30
FEG SEM, Philips, at 20 kV). Melting points were determined
in open capillary tubes in a Barnstead Electrothermal 9100 BZ
circulating oil melting point apparatus. The reaction monitoring
was accomplished via TLC on silica gel PolyGram SILG/
UV254 plates.
run. In a test of five cycles, the catalyst could be reused without
any significant loss of catalytic activity (Figure 4).
When using a supported catalyst, there is a possibility that
the active species might migrate from the solid support to the
liquid phase, since the leached active ones become responsible
for the good catalytic activity. To explore the catalyst leaching,
the reaction of isatin (2 mmol), 1,3 dimethyl-2-amino uracil (2
mmol) and dimedone (2 mmol) catalyzed by MSAIL was
carried out at room temperature. When the reaction time
reached 2.5h, hot ethanol (20 mL) was added and the MSAIL
was easily removed using a magnetic force. The solution was
averagely divided into two parts (P1 and P2). The
corresponding product of P1 was obtained with a 40% yield.
Moreover, the solution of P2 was reacted under the above
conditions for another 2.5h to afford the product in 41% yield,
which was similar to P1 and less than normal (82%, Figure 3,
entry 15). Therefore, these above results convinced us that the
leaching of MSAIL was negligible in the catalytic process.
General Procedure for the Synthesis of Spirooxin-
doles Derivatives from Isatin Using MSAIL. An equimolar
mixture of isatin (1 mmol), 1,3-dimethyl-2-amino uracil (1
mmol), barbituric acid (1 mmol) and 1.5 mol % MSAIL in H O
2
(
1 mL) was stirred at room temperature. Completion of the
reaction was monitored by TLC. All the reactions were
invariably complete in 4−8 h. Upon completion of the reaction,
5 mL of ethyl acetate was added to the reaction mixture. The
spirooxindole derivatives were dissolved in ethyl acetate and the
catalyst was separated magnetically from the product solution,
washed with ethyl acetate, and used for subsequent cycles after
drying under vacuum. Pure products were afforded by
evaporation of the solvent, followed by recrystallization from
ethanol or by column chromatography on silica gel using ethyl
acetate/hexane as the eluent.
3
. CONCLUSION
In conclusion, we successfully developed a novel MNP
supported acidic IL and used it in a one-pot three-component
condensation of isatin with 1,3-dimethyl-2-amino uracil and
1
,3-dicarbonyl compounds to prepare spirooxindole derivatives
in excellent yields (up to 90%). Moreover, the catalyst could be
E
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ACS Combinatorial Science
′,3′-Dimethyl-1′H-spiro[indoline-3,5′-pyrido-
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9
6%); mp >300 °C. IR (solid film, cm ): 3754, 3286, 3109,
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1
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+
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ASSOCIATED CONTENT
Supporting Information
■
*
S
(
Experimental procedures, characterization data of catalyst and
1
13
+
−
product, and copies of H NMR and C NMR spectra of all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
ionic liquid [Bmim ][BF ]: Reactions of arylaldehyde, 3-arylamino-
4
5,5-dimethylcyclohex-2-enone, and active methylene compounds.
Tetrahedron 2007, 63, 4439−4449. (b) Dabiri, M.; Arvin-Nezhad,
H.; Khavasi, H. R.; Bazgir, A. A novel and efficient synthesis of
pyrimido[4,5-d]pyrimidine-2,4,7-trione and pyrido[2,3-d:6,5-d] dipyr-
imidine-2,4,6,8-tetrone derivatives. Tetrahedron 2007, 63, 1770−1774.
AUTHOR INFORMATION
Corresponding Author
E-mail: khalafi@chem.susc.ac.ir.
■
(
c) Li, Y.; Yu, Z.; Alper, H. Palladium-catalyzed synthesis of highly
*
substituted endocyclic enol lactones via a three-component coupling
reaction in an ionic liquid. Org. Lett. 2007, 9, 1647−1649. (d) Maiti,
B.; Chanda, K.; Sun, C. M. Traceless synthesis of hydantoin fused
tetrahydro-β-carboline on ionic liquid support in green media. Org.
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Azizian Kohan, S. Sulfonic acid functionalized ionic liquid in
combinatorial approach, a recyclable and water tolerant-acidic catalyst
for one-pot friedlander quinoline synthesis. J. Comb. Chem. 2010, 12,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge Shiraz University for partial support of this
work.
■
1
37−140. (f) Hasaninejad, A.; Zare, A.; Shekouhy, M.; Ameri Rad, J.
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dx.doi.org/10.1021/co400080z | ACS Comb. Sci. XXXX, XXX, XXX−XXX