Manganese ferrite nanoparticle catalyzed tandem and green synthesis of spirooxindoles

Article abstract of DOI:10.1039/c4ra05756b

An environmentally benign and efficient method for the synthesis of spirooxindoles has been developed via a one-pot and three-component reaction of isatins, malononitrile, and anilinolactones in the presence of a catalytic amount of manganese ferrite nanoparticles in PEG-400, as a nontoxic, green, and reusable solvent. The significant advantages of this protocol are; the use of a magnetically recoverable and reusable catalyst, high to excellent product yields, operational simplicity and the use of PEG-400 as an environmentally-friendly solvent. This journal is

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PAPER
Manganese ferrite nanoparticles catalyzed tandem and green synthesis
of spirooxindoles
Ramin Ghahremanzadeh,a Zahra Rashid,b Amir-Hassan Zarnanic and Hossein Naeimi b*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An environmentally benign and efficient method for the synthesis of spirooxindoles has been developed via a oneꢀpot and threeꢀ
component reaction of isatins, malononitrile, and anilinolactones in the presence of catalytic amount of manganese ferrite nanoparticles
in PEGꢀ400, as a nontoxic, green, and reusable solvent. The significant advantages of this protocol are; the use of magnetically
recoverable and reusable catalyst, high to excellent product yields, operational simplicity and the use of PEGꢀ400 as an environmentꢀ
10 friendly solvent.
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
Introduction
Multicomponent reactions (MCRs) are special types of
synthetically important organic reactions in which three or more
15 different starting materials come together in a single reaction
vessel to produce a final product containing diverse substituents
from all the reactants.1 Such strategies are excellent tools in
modern organic synthesis and medicinal chemistry due to the
product diversity, operational simplicity, reduction in reaction
20 steps and workꢀups, less time and energy consumption and a high
degree of atom economy.2,3 In the last decade, with increasing
environmental concerns, the design of new MCRs with ecoꢀ
friendly, green procedures has drawn significant attention,
especially in the fields of drug discovery, organic synthesis, and
25 material science.4,5 The use of polyethylene glycol (PEG), as a
green solvent for organic synthesis has attracted extensive
attention recently, due to its many pros such as; water solubility,
50
Spirooxindole cores are an important constituent in many
natural and synthetic biologically active compounds, as well as in
many drug molecules,12 in which an indole system is joined to
varied heterocyclic motifs at the Cꢀ3 position through a spiro
carbon atom. Molecules containing the spirooxindole moiety are
55 widely found in
a number of natural products such as
Spirotryprostatin A, Horsfiline, and Elacomine (Figure 1).13
These natural products have been shown to possess a variety of
important biological activities such as; antiꢀtumor,14 antiꢀ
tuberculosis,15 antiꢀmicrobial,16 antiꢀmycobacterium,17 antiꢀ
60 fungus,18 antiꢀmalaria,19 and antiꢀoxidation.20 Consequently,
looking for efficient, new and concise synthetic methods to
prepare spirooxindole fused heterocycles is a major challenge and
a popular field in chemistry 21ꢀ23 In recent years several methods
using a variety of reagents and catalysts have been reported for
65 the promoting preparation of spirooxindoles. One of an
interesting catalysts for the synthesis of spiirooxindole
derivatives is magnetic nanoparticles.24, 25
thermal stability over
a
wide range of temperatures,
recoverability, nonꢀvolatility, nonꢀexplosiveness, commercial
30 availability, and low toxicity.6 A number of organic reactions
have been reported using PEG as a solvent medium or support for
various organic transformations.7ꢀ9 Therefore, additional MCRs
has become a critical and demanding research area in organic
chemistry for the synthesis of molecular complexity and
35 heterocyclic compounds such as spirooxindoles.10,11.
O
H
N
N
O
H3C
NH
N
70
H
O
H3CO
O
Notes and references
O
N
aNanobiotechnology Research Center, Avicenna Research Institute,
ACECR, Tehran, Iran. Fax+ 98-02122432021; Tel: +98-02122432020;
40 E-mail: r.ghahremanzadeh@avicenna.ac.ir
H
HO
H3CO
N
H
N
H
Spirotryprostatin A
Horsfiline
Elacomine
bDepartment of Organic Chemistry, Faculty of Chemistry, University of
Kashan, Kashan, 87317, I.R. Iran. Fax: +98-03615511121; Tel: +98-
03615912388; E-mail: Naeimi@kashanu.ac.ir
75
Figure 1. Selected spirooxindole natural products
cReproductive Immunology Research Center, Avicenna Research Institute,
45 ACECR, Tehran, Iran. Fax+ 98-02122432021; Tel: +98-02122432020 E-
mail: zarnania@gmail.com.
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appropriate time. After completion of the reaction as indicated by
60 TLC, the mixture was magnetically concentrated with the aid of
an external magnet to separate the catalyst. The separated catalyst
washed with acetone several times followed by EtOH, then dried
under vacuum and reutilized four times for the same reaction.
After separation of the catalyst, H2O (10 ml) was added to the
65 reaction mixture and was shaken for a few minutes to dissolve
PEG and precipitate the product. The crude product (insoluble in
water) was filtered and reꢀcrystallized by ethanol for more
purification. The desired pure product was identified as white
powder (Yield: 83%). mp>300ºC. IR (KBr) (νmax/ cm–1): 3454,
Magnetic nanoparticles are a group of nanostructured
materials of considerable interest, largely due to their advanced
technological and medical applications, envisioned or
realized.26,27.In recent years they have emerged as a suitable
group of heterogeneous catalysts because of their extremely small
size, large surface to volume ratio, and because they can achieve
many of the goals of green chemistry. Magnetic nanoparticles
open up new opportunities to come up with an amazing and
efficient system to facilitate catalyst recovery in organic
10 reactions, because the magnetic nature of these particles allows
for simple recovery and recycling of the catalysts by an external
magnet, and magnetic separation is an attractive alternative to
filtration or centrifugation as it prevents the loss of catalyst and
increases reusability.28,29
5
1
70 2185, 1721, 1682. H NMR (DMSOꢀd6, 400 MHz): δppm: 2.37
(3H, s, CH3), 4.47ꢀ4.64 (2H, m, OCH2) 5.99 (2H, s, NH2), 6.82ꢀ
7.44 (8H, m, ArH), 10.48 (1H, s, NH). 13C NMR (DMSOꢀd6, 100
MHz): δppm: 21.2, 48.2, 60.0, 66.1, 99.0, 109.8, 119.5, 122.5,
125.3, 128.9, 129.3, 131.2, 131.7, 134.3, 140.3, 141.8, 152.8,
75 159.6, 170.1, 178.0. Anal. Calcd for C22H16N4O3: C, 68.74; H,
4.20; N, 14.58%;. Found C,68.69; H, 4.24; N, 14.53%. MS: m/z
384.
15
In this research we report an environmentally benign
synthetic method to uncover a green protocol for oneꢀpot threeꢀ
component synthesis of 2ꢀaminoꢀ2',5ꢀdioxoꢀ1ꢀphenylꢀ5,7ꢀ
dihydroꢀ1Hꢀspiro[furo[3,4ꢀb]pyridineꢀ4,3'ꢀindoline]ꢀ3ꢀ
Results and discussion
carbonitrile derivatives. This reaction was carried out by using
Due to the unique properties of spirooxindole compounds and in
80 continuation of our research for the efficient preparation of
spirooxindole heterocycles 31ꢀ33 via a simple and environmentally
benign synthetic method, a three component synthesis was
planned based on foreseeing a oneꢀpot reaction among isatins 1,
malononitrile 2, and anilinolactones 3 for the synthesis of
85 spirooxindoles (Scheme 1).
20 manganese ferrite nanoparticles as an efficient, reusable, and
recoverable catalyst in PEGꢀ400, as a safe, inexpensive, reusable,
and biodegradable polymeric solvent.
Experimental
The chemicals used in this work were obtained from Fluka and
25 Merck and were used without purification. Melting points were
measured on an Electrothermal 9200 apparatus. IR spectra were
recorded as KBr pellets on a PerkinꢀElmer 781 spectrophotometer
RN
O
O
O
X
1
and an Impact 400 Nicolet FTꢀIR spectrophotometer. H NMR
O
O
O
NC
H2N
and 13C NMR spectra were recorded in DMSO–d6 solvents on a
30 Bruker DRXꢀ400 spectrometer with tetramethylsilane as internal
reference. The elemental analyses (C, H, N) were obtained from a
Carlo ERBA Model EA 1108 analyzer. Nanostructures were
characterized using a Holland Philips Xpert Xꢀray powder
diffraction (XRD) diffractometer (Cu K, radiation, k = 0.154056
35 nm), at a scanning speed of 2°/min from 10° to 100° /(2θ).
Scanning electron microscope (SEM) was performed on a FEI
Quanta 200 SEM operated at a 20 kV accelerating voltage. The
purity determination of the substrates and reaction monitoring
were accomplished by TLC on silicaꢀgel polygram SILG/UV 254
40 plates (from Merck Company).
X
CN
CN
HN
+
+
O
N
N
R
1
2
3
R1
R1
Scheme 1 Oneꢀpot synthesis of spirooxindoles.
Anilinolactones are versatile synthetic intermediates in
organic synthesis that combine the nucleophilicity of an enamine
90 and the electrophilicity of an enone. They are commonly applied
34,35
in the preparation of heterocyclic compounds.
As shown in
Scheme 2, when tetronic acid was reacted with an equimolar
amount of various anilines in 1,4ꢀdioxane at room temperature,
the corresponding products were obtained in excellent yields and
95 purity. 36
Typical experimental procedure for the preparation of
catalyst
MnFe2O4 nanoparticles have been prepared following the
reported standard protocol by coꢀprecipitation of MnCl2 and
45 FeCl3 in water in the presence of sodium hydroxide. Briefly,
MnCl2·4H2O and FeCl3·6H2O were taken in molar ratio of Mn2+:
Fe3+= 1:2 to prepare 0.3 mol·Lꢀ1 metal ion solution of 100 mL
containing 0.1 mol·Lꢀ1 Mn2+ and 0.2 mol·Lꢀ1 Fe3+. Then, it was
slowly dropped into 100 mL NaOH solution of 3 mol·Lꢀ1 at the
50 preheated temperature of 95°C. After aging for 2 h with
continuous stirring, the mixture was filtered, washed and dried at
60°C for 12 h. 30
Scheme 2. Synthetic rout of anilinolactones.
Typical procedure for the preparation of 2-amino-2',5-dioxo-
1-p-tolyl-5,7-dihydro-1H-spiro[furo[3,4-b]pyridine-4,3'-
55 indoline]-3-carbonitrile (5b): A mixture of isatin 1a (1 mmol),
malononitrile 2 (1 mmol), 4ꢀ(4ꢀmethylphenylamino) furanꢀ2(3H)ꢀ
one 3b (1 mmol), and MnFe2O4 (5 mol%) were taken in PEGꢀ400
(1 mL). The resulting mixture was stirred at 90°C for an
100
2
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Recent studies on the preparation of spirooxindoles
revealed that one of the usual conditions for their synthesis uses
water as a solvent in the presence of pꢀtoluenesulfonic acid (pꢀ
Although the detailed mechanism of the above reaction has
not yet been clarified, we proposed the possible pathway to form
the spiro product 4 via domino reactions. As shown in Scheme 4,
TSA) as an economical, nonꢀtoxic catalyst under reflux 40 compound 4 could be synthesized via sequential condensation,
5
conditions. 37ꢀ40 Hence, the reaction of isatin 1a, malononitrile 2,
and 4ꢀ(4ꢀmethylphenylamino) furanꢀ2(3H)ꢀone 3b in a 1:1:1
molar ratio as a model substrate was refluxed for 8 hr in water
with pꢀTSA (20%). After completion and workꢀup of the reaction
a powdery product was obtained and purified.
addition, hydrolysis, cyclization and tautomerization. The
reaction may proceed in a stepwise manner, in which the isatin 1a
can be firstly condensed with malononitrile 3 to afford isatylidene
malononitrile 6 in the presence of pꢀTSA in water. This step was
45 regarded as a fast Knoevenagel condensation reaction. Then,
compound 6 is attacked by a Michael type addition with 4ꢀ(4ꢀ
methylphenylamino) furanꢀ2(3H)ꢀone 3b to produce the
intermediate 7. We suspect in the presence of pꢀTSA as a
Bronsted acid and water, the iminium group in the intermediate 7,
50 was hydrolyzed followed by an intramolecular cyclization and
tautomerizationto afford product 4 (Scheme 4). In the proposed
mechanism, pꢀTSA may be able to catalyze the reaction steps due
to its acidic nature.
10
HN
O
O
O
NC
H2N
N
O
O
O
5b
CN
CN
O
+
+
p-TSA
H2O, reflux
CH3
N
HN
H
NH2
CH3
1 a
2
3b
HN
O
O
O
+
NC
C
N
NC
O
O
CH3
CN
H2N
O
O
CN
2
NH
CH3
N
4
ꢀ H2O
H
6
3b
Scheme 3. The reaction leading to the synthesis of
spirooxindoles.
HN
O
O
O
O
O
1a
NC
N
H
C
NH
H
15
Product structure was characterized based on Mass, 1H
NMR, and 13C NMR spectra. In the 1H NMR spectrum of product
(as shown in Figure 2), the signal at δ= 10.70 ppm indicates the
presence of –NH proton of oxindole ring (D2O exchangeable), the
NH2 protons resonated at δ= 7.70 ppm with two integral values
N
7
HN
O
CH3
O
O
NC
NH2
20 (exchangeable with D2O), the aromatic protons exhibited
multiplets in the region δ= 6.85–7.26 ppm with four integral
values, the signals around δ= 5.06ꢀ5.21 ppm with two integral
values are assigned to the protons of OCH2 of tetronic acid. The
13C NMR spectrum showed 15 distinct signals; also the mass
25 spectrum of product displayed the molecular ion peak at m/z: 295.
Surprisingly, the reaction did not proceed according to
expectation and spectral data were inconsistent with the expected
structure 5b. Indeed, the data were in good agreement with the
structure of an unprecedented product, and showed the structure
30 of the unexpected product 4. Also, the structure of the identity of
the obtained product was confirmed by comparing its melting
point with that of this previously. 41
C
N
HO
CH3
HN
HN
O
O
O
O
O
O
NC
NC
HN
O
H2N
O
4
55
Scheme 4. Proposed mechanism for the formation of compound 4
In order to produce the expected product 5, we continued to
60 explore different catalysts and media on the model reaction
(Scheme 5). The results are summarized in Table 1. As shown in
this table, when we tested on the model reaction in PEG 400 or in
ionic liquids (IL) with magnetic nanoparticles as the catalyst, the
product 5b was obtained (Table 1, entries 10ꢀ14). PEGꢀ400 in the
65 presence of MnFe2O4 as the catalyst proved to be the best system
tested based on its reaction rate as well as yield while under other
conditions as seen in Table 1, compound 4 was produced.
70
35
Figure 2. The 1H NMR spectrum of 2ꢀaminoꢀ2',5ꢀdioxoꢀ5,7ꢀ
dihydrospiro[furo[3,4ꢀb]pyranꢀ4,3'ꢀindoline]ꢀ3ꢀcarbonitrile 4
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diameter of about 30ꢀ35 nm (Figure 4). The magnetization curve
for MnFe2O4 nanoparticles is shown in Figure 5. It is of great
importance that a catalyst should possess sufficient magnetic and
super paramagnetic properties for its practical application.
25 Magnetic hysteresis measurements on MnFe2O4 were conducted
in an applied magnetic field at room temperature, with the field
sweeping from ꢀ10000 to +10000 Oersted. As shown in Figure 5,
the hysteresis loop for the sample was completely reversible
confirming its super paramagnetic nature. The catalyst showed
30 high permeability in magnetization and high reversibility in the
hysteresis loop.
HN
O
O
O
O
O
O
NC
H2N
CN
CN
HN
O
+
+
N
N
H
1a
2
3b
5b
Me
Me
Scheme 5. Model reaction for the synthesis of 2ꢀAminoꢀ2',5ꢀdioxoꢀ1ꢀpꢀ
tolylꢀ5,7ꢀdihydroꢀ1Hꢀspiro[furo[3,4ꢀb]pyridineꢀ4,3'ꢀindoline]ꢀ3
carbonitrile 5b.
5
Table 1. Screening on the various reaction conditions for the synthesis of 5b
Entry
Medium
Catalyst
Product
Time (h) Yield (%)b
1
H2O(90°C)
pꢀTSA
4
4
8
12
12
12
4
75
68
69
48
70
73
62
51
83
70
46
54
51
ꢀ
2
H2O(90°C)
Alum
3
EtOH(70°C)
pꢀTSA
4
4
CH3CN(70°C)
[Bmim]Br(90°C)
[Bmim]PF6(90°C)
PEGꢀ400(100°C)
PEGꢀ400(100°C)
pꢀTSA
4
5
pꢀTSA
4
35 Figure 3. The Xꢀray diffraction patterns of calcinated MnFe2O4.
6
pꢀTSA
4
4
7
pꢀTSA
4
6
8
CH3COOH
4
6
9
PEGꢀ400(100°C) Nano MnFe2O4
PEGꢀ400(100°C) Nano CuFe2O4
PEGꢀ400(100°C) Nano Fe3O4
[Bmim]PF6(90°C) Nano MnFe2O4
[Bmim]PF6(90°C) Nano CuFe2O4
5b
5b
5b
5b
5b
-
6
10
11
12
13
14
15
16
6
8
8
8
PEGꢀ400(100°C)
H2O(90°C)
ꢀ
ꢀ
ꢀ
6
-
12
ꢀ
ꢀ
[Bmim]PF6(90°C)
-
Figure 4. The SEM image of MnFe2O4 before the reaction
aReaction conditions isatin 1a (1 mmol), malononitrile 2 (1 mmol), 4ꢀ(4
methylphenylamino) furanꢀ2(3H)ꢀone 3b (1 mmol).
40
bIsolated yields.
60
40
20
0
Characterization of the catalyst
10 The manganese ferrite nanoparticles were prepared by coꢀ
precipitation of MnCl2 and FeCl3 in basic solution at 95°C using
the previous reported method. The synthesized MnFe2O4 was
characterized by Xꢀray diffraction (XRD), scanning electron
microscope (SEM), and vibrating sample magnetometer (VSM).
15 The position and relative intensities of all peaks were confirmed
as well as with standard XRD pattern of MnFe2O4 (JCPDS card
No. 73ꢀ1964). The calcined manganese ferrite at 800°C present a
particle size of 33 nm, calculated from the broadening of the peak
at 2Ө = 35.31 using the Scherer equation (Figure 3). The SEM
20 image revealed that manganese ferrite nanoparticles have a mean
-20
-40
-60
-10000 -8000 -6000 -4000 -2000
0
2000 4000 6000 8000 10000
Applied Field(Oe)
Figure 5. The vibrating sample magnetometer curve of
synthesizedMnFe2O4 nanoparticles.
45
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In the next step, in order to optimize the more suitable
83
81
78
73
81
reaction conditions, we evaluated the amount of catalyst required,
and the effect of temperature for this transformation. Our
optimization studies revealed that when the model reaction was
carried out in the presence of 2 mol% of catalyst, 62% yield is
obtained. It was found that catalyst loadings above 5 mol% did
not improve the reaction rate of yield. Thus 5 mol% of catalyst
was chosen as the maximum quantity of the catalyst for the
reaction (Table 2, Entry 2). Also, the effect of temperature was
50
100%
50%
0%
5
55
1
2
3
4
5
10 studied by carrying out the model reaction in PEGꢀ400 at
different temperatures in the presence of 5 mol% of catalyst. As
shown in Table 2, when the reaction temperature was 25°C or
40°C (Table 2, Entries 5, 6), the reaction was proceeded, but the
obtained yield remained low even after longer reaction time until
15 24 hr. However, at elevated temperature (40–90°C) using PEGꢀ
400 gave better results in terms of yield and reaction time. It was
realized that when temperature increased up further to 110°C
(Table 2, Entry 8), there was no significant improvement of the
rate as well as yield of the reaction. Thus, the temperature of
20 90°C was found to be the most suitable reaction temperature for
an optimum yield of desired product (Table 2, Entry 2).
Runs
60
65
Figure 6. Catalyst recyclability study on the synthesis of 2ꢀaminoꢀ2',5ꢀ
dioxoꢀ1ꢀpꢀtolylꢀ5,7ꢀdihydroꢀ1Hꢀspiro[furo[3,4ꢀb]pyridineꢀ4,3'ꢀindoline]ꢀ
3ꢀcarbonitrile 5b
Finally, we examined the recyclability of the PEG after
the extraction of the product. In order to prove that the use of
polyethylene glycol as environmentally benign solvent is also
practical; it must be conveniently recycled with minimum loss
70 and decomposition. In this procedure, after completion of the
reaction, the crude product (insoluble in water) was filtered and
recrystallized from ethanol for further purification. In order to
recover the PEG, H2O was evaporated under reduced pressure,
and the result was washed with diethyl ether, and dried under
75 reduced pressure. The recycled PEG does not change in its
reactivity but approximately 5% weight loss of PEG was
observed from cycle to cycle (Table 3).
Table 2 Evaluation of different amounts of the MnFe2O4 nanoparticles
as catalyst and effect of temperature on the model reactiona.
Entry
Catalyst (mol%)
Temperature/°
Time (h)
Yield (%)b
62
1
2
90
8
2
3
4
5
6
7
8
5
10
20
5
90
90
6
8
83
83
Table 3. Evaluation of different amounts of the MnFe2O4 nanoparticles as
catalyst and effect of temperature on the model reactiona.
90
8
84
8
0
No. of cycles
Product yield (%)b
Time (h)
Fresh
83
Run 1
82
Run 2
80
Run 3
80
25
24
24
10
6
<50
<50
72
5
40
6
6
6
6
5
70
aReaction conditions: Isatin 1a (1 mmol), malononitrile 2 (1 mmol), 4ꢀ(4
methylphenylamino) furanꢀ2(3H)ꢀone 3a (1 mmol), MnFe2O4 (5 mol%), PEGꢀ400
5
110
83
(1 mL), 90°C.
bIsolated
25 aReaction conditions: isatin 1a (1 mmol), malononitrile 2 (1 mmol), 4ꢀ(4
methylphenylamino) furanꢀ2(3H)ꢀone 3b (1 mmol), PEGꢀ400 (1 mL).
We have not established an exact mechanism for the formation
of 5b, however, a reasonable possibility based on literatures
bIsolated yields.
42, 43
is shown in Scheme 6. Compound 5b could be synthesized via
85 sequential
condensation,
addition,
cyclization
and
Most remarkably, we were also able to recycle the
30 catalyst for five times with almost the same catalytic activity as
illustrated in Figure 5. The catalyst was recovered in excellent
yield (96–98%) after each of the new set of reaction. Isatin,
malononitrile, and 4ꢀ(4ꢀmethylphenylamino) furanꢀ2(3H)ꢀone
were also employed as the reactants of the model reaction for the
35 reusability study of the catalyst at 90°C in PEGꢀ400. In this
procedure, after completion of the reaction, the catalyst could be
magnetically recovered by an external magnetic field and the
retained catalyst was washed with acetone to remove the residual
product. After being dried, catalyst was subjected to other
40 reaction runs. After separation of the catalyst, water (10 ml) was
added to the reaction mixture and was shaken for a few minutes
to dissolve PEG and precipitated the product. The crude product
(insoluble in water) was filtered and washed with ethanol for
further purification. The procedure was repeated and the results
45 indicated that in five consecutive runs. The isolated yields were
remained similar with no detectable loss (Figure 6).
tautomerization. The process represents a typical domino reaction
in which the activated isatin 1, may be firstly condensed with
malononitrile 2 to afford isatylidene malononitrile 6 in the
presence of manganese ferrite nanoparticles as a catalyst in PEGꢀ
90 400. This step was regarded as a fast Knoevenagel condensation.
Then, compound 6 is attacked by Michael addition of 4ꢀ(4ꢀ
methylphenylamino) furanꢀ2(3H)ꢀone 3b to give the intermediate
7, followed by intraꢀmolecular cyclization and tautomerization to
afford the target product 5b. The manganese ferrite nanoparticles
95 as a Lewis acid probably can catalyze the reaction steps.
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NC
C
N
O
O
In order to generalize the optimum conditions and check the
feasibility of this protocol, different derivatives of 2ꢀaminoꢀ2',5
dioxoꢀ1ꢀphenylꢀ5,7ꢀdihydroꢀ1Hꢀspiro[furo[3,4ꢀb]pyridineꢀ4,3'
indoline]ꢀ3ꢀcarbonitrile 5a-l were prepared from the oneꢀpot
reaction mixture of isatins 1a-e, malononitrile 2, and
anilinolactones 3a-g in the presence of a catalytic amount of
CN
CN
O
5
N
NH
3b
CH3
ꢀ H2O
2
H
6
O
HN
O
O
O
O
NC
N
H
1a
+
C
HN
NH
H+
10 MnFe2O4 (5 mol%) in PEGꢀ400 at 90°C. The results are
HN
summarized in Table 4. Compounds 5a–l are stable solids and the
7
O
C
1
structures of which were determined by IR, Mass, H and 13C
H
O
CH3
: Manganese ferrite nanoparticles
NC
O
NMR spectroscopy, and elemental analysis.
N
NH
To determine the percent leaching of the manganese ferrite
15 nanoparticles, the model reaction was carried out in the presence
of catalyst for 1h, and at that point the catalyst was separated by
external magnet. The residue was then allowed to react, but no
significant progress was observed after 24h. Also, it was
determined the amount of Fe and Mn metals in product 4a as a
20 model reaction by atomic absorption in that the quantity of the
residue of Fe and Mn metals was not detectable.
CH3
HN
O
O
O
NC
C
N
HN
CH3
HN
HN
O
O
O
O
O
NC
H
Tautomerization
O
NC
HN
N
H2N
N
25
5b
CH3
CH3
Scheme 6. Proposed mechanism for the synthesis of 5b.
Table 4. Synthesis of spiroꢀfuroꢀpyridineꢀindolineꢀcarbonitrile via oneꢀpot three component reaction catalyzed by manganese ferrite nanoparticles in PEGꢀ
400a
30
RN
O
O
X
O
O
O
O
NC
H2N
X
CN
CN
HN
Nano MnFe2O4 (5 mol%)
PEGꢀ400
+
+
O
N
N
R
1a-e
2
3a-g
5a-l
35
R1
R1
Entry
Isatin 1
Anilinolactone 3
O
Product 5
HN
Time (h)
Yield(%)b
O
O
O
O
O
NC
H2N
HN
1
5
79
O
N
N
H
5a
RN
O
O
O
O
O
O
NC
HN
2
5
83
H2N
N
O
N
H
CH3
CH3
5b
6
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HN
O
O
O
O
O
NC
HN
O
3
5
80
O
H2N
N
N
H
Cl
Cl
5c
HN
O
O
O
O
O
O
NC
HN
4
5
77
O
H2N
N
N
H
Cl
Cl
5d
RN
O
O
O
O
O
O
NC
HN
5
80
5
O
H2N
N
CH3
N
H
CH3
5e
HN
O
O
O
O
NC
O
HN
O
6
5
79
O
Cl
H2N
N
N
H
Cl
Cl
Cl
5f
HN
O
O
O
O
O
NC
HN
O
7
5
75
O
H2N
N
N
H
Br
Br
5g
HN
O
O
O
Br
O
O
O
Br
NC
O
HN
8
4
73
N
H2N
N
H
5h
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O
O
HN
O
Br
O
O
O
Br
NC
O
HN
HN
HN
4
76
9
H2N
N
N
CH3
H
CH3
5i
HN
O
O
NO2
O
O
O
O
O2N
NC
O
10
3
81
N
H
H2N
N
5j
O
O
HN
NO2
O
O
O
O
NC
O2N
O
11
3
84
H2N
N
N
H
Br
Br
5k
O
O
HN
O
NO2
O
O
O
O2N
NC
O
HN
12
3
75
H2N
N
N
H
Cl
Cl
5l
aReaction conditions: isatin 1a-e (1 mmol), malononitrile
2
(1 mmol), anilinolactones 3a-g (1 mmol), MnFe2O4 (5 mol%), PEGꢀ400 (1 mL), 90°C.
bIsolated yields.
Avicenna Research Institute. And also, we are thankful from
University of Kashan for supporting this work by grant number
159148/15.
5
Conclusions
In conclusion, we have developed an efficient and more
environmentally friendly protocol for the oneꢀpot synthesis of
spirooxindoles via a threeꢀcomponent condensation reaction of
isatins, malononitrile, and anilinolactones by using manganese
10 ferrite nanoparticles as a powerful catalyst in PEGꢀ400. The
notable features of this procedure are mild and green reaction
conditions, convenient workup, recyclability and reusability of
the magnetic catalyst, high to excellent product yields, and
recyclability of PEG.
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