Polycyclic Aromatic Compounds
ISSN: 1040-6638 (Print) 1563-5333 (Online) Journal homepage: http://www.tandfonline.com/loi/gpol20
Amino Functionalized Nano Fe3O4@SiO2 as a
Magnetically Green Catalyst for the One-Pot
Synthesis of Spirooxindoles Under Mild Conditions
Fatemeh Alemi-Tameh, Javad Safaei-Ghomi, Mohammad MahmoudiHashemi & Majid Monajjemi
To cite this article: Fatemeh Alemi-Tameh, Javad Safaei-Ghomi, Mohammad Mahmoudi-Hashemi
& Majid Monajjemi (2016): Amino Functionalized Nano Fe3O4@SiO2 as a Magnetically Green
Catalyst for the One-Pot Synthesis of Spirooxindoles Under Mild Conditions, Polycyclic Aromatic
Compounds, DOI: 10.1080/10406638.2016.1179650
To link to this article: http://dx.doi.org/10.1080/10406638.2016.1179650
Published online: 12 Dec 2016.
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Date: 23 February 2017, At: 18:21
POLYCYCLIC AROMATIC COMPOUNDS
http://dx.doi.org/./..
Amino Functionalized Nano Fe O @SiO as a Magnetically
Green Catalyst for the One-Pot Synthesis of Spirooxindoles
Under Mild Conditions
Fatemeh Alemi-Tameh, Javad Safaei-Ghomi , Mohammad Mahmoudi-Hashemi,
and Majid Monajjemi
Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran
ABSTRACT
ARTICLE HISTORY
(3-Aminopropyl)-triethoxysilane attached to Fe3 O4 @SiO2 nanoparticles
has been characterized by powder X-ray diffraction, vibrating sample
magnetometer, scanning electronic microscope, transmission electron
microscope, energy dispersive X-ray, thermal gravimetric analysis, and
Fourier transform infrared spectroscopy. The prepared nanoparticles
employed as a heterogeneous catalyst in the synthesis of spirooxindoles derivatives in one-pot four-component reactions of isatin, methyl
cyanoacetate or malononitrile, hydrazine hydrate, and ethyl acetoacetate. Amino-functionalized magnetic nanoparticles showed high catalytic activity in mild reaction conditions and excellent yields of products in short reaction times. Also, this nanocatalyst can be easily recovered by a magnet and reused for subsequent reactions for at least
5 times without noticeable loss in catalytic activity.
Received  December 
Accepted  April 
KEYWORDS
Core–shell;
Fe O @SiO –NH ;
multicomponent reactions;
one-pot synthesis;
spirooxindoles
Introduction
Today, nanoscale materials have attracted tremendous attention due to their properties which
differ greatly from their bulk counterparts (1). They have been used extensively in chemistry
(2), physics (3), biology (4), as well as catalytic synthesis (5). Recently, magnetic nanostructures have received considerable attention because of their unique magnetic properties. Most
solid catalysts have problems in recovering and reusing, whereas magnetic nanostructures can
be easily retrieved under the influence of a magnetic field and can be used in subsequent reactions (6–13). Surface coating of magnetic nanoparticles and core–shell structure nanoparticles
are very important because of their difficulty in dispersion and aggregation in organic media.
Thus, the use of magnetic core–shell structure composites as catalysts has been mentioned
in literature, due to their special properties (14, 15). Magnetic core–shell structure composites have been developed in many applications, such as drug delivery (16), cancer treatment
through hyperthermia (17), magnetic resonance imaging (MRI) (18), and as adsorbent for
aqueous heavy metals (19). Therefore, in recent years, much attention has been focused on
the synthesis of magnetic metal oxide structures by coating a silica shell around preformed
nanoparticles (20–22).
CONTACT Javad Safaei-Ghomi
[email protected]
Department of Chemistry, Science and Research Branch, Islamic
Azad University, Tehran, Iran.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpol.
©  Taylor & Francis Group, LLC
2
F. ALEMI-TAMEH ET AL.
Figure . Some biologically important molecules containing spirooxindole motif.
Newly multicomponent reactions (MCRs) have been applied in designing diverse procedures to produce biologically active compounds that lead to an important area of research
in organic, combinatorial, and medicinal chemistry (23–26). MCRs have been paid much
attention, owing to excellent synthetic efficiency, inherent atom economy, procedural simplicity, and environmental friendliness (27–29). Heterocyclic MCR methods have created the
research strategies for creating novel desired structures through the combination of small heterocyclic molecules (30, 31). Spirooxindoles as heterocyclic compounds exist both in nature
and in biologically active molecules. These compounds show a wide range of pharmaceutical
activities such as antitumour (32), antimalarial (33), antiviral (34), and antifungal (35) properties. Also lately, they have attracted great attention in a number of publications (36–38).
Some of these spirooxindole compounds have been considered as candidates for drug discovery. The spirooxindole system is the core structure of many biologically active molecules such
as NITD609 and MDM2-P53, Elacomine and Horsfline (Figure 1) (39).
Due to their extensive biological activities, producing novel spirooxindole derivatives is an
interesting subject in medicinal chemistry. A number of methods have been developed for the
preparation of spirooxindole derivatives in the presence of various catalysts such as 4-DMAP
(40), TEBA (41), TBAF (42), EDDA (43), piperidine (44, 45), Meglumine (46). However, some
of the reported methods tolerate disadvantages including long reaction times, harsh reaction
conditions, consumption of large amounts of catalyst, and use of toxic and non-reusable catalyst. Therefore, to avoid these limitations, the exploration of an efficient, easily available catalyst with high catalytic activity and short reaction time for the preparation of spirooxindoles
is still favored. The chemical synthesis productivity can be enhanced by nanosized catalysts
because of small size and high surface to volume ratios. Expansion of new catalytic transformations with simple separation and recyclability of the catalyst is an essential task in chemical
synthesis. To overcome the separation problems of the nanocatalysts, magnetic materials have
emerged as recoverable catalysts. Separation of magnetic nanoparticles is simple, convenient,
economical, and environmentally benign. In this paper, we wish to report a method for preparation of amino-functionalized magnetic nanoparticles (Fe3 O4 @SiO2 –NH2 ) and its application on the synthesis of spirooxindole derivatives in one-pot four-component reactions of
isatin, methyl cyanoacetate or malononitrile, hydrazine hydrate, and ethyl acetoacetate under
mild conditions (Scheme 1).
Experimental
Chemicals and apparatus
All materials were purchased from Sigma–Aldrich and Merck and used without further
purifications. All melting points were determined in capillary tubes on a Boetius melting
POLYCYCLIC AROMATIC COMPOUNDS
3
Scheme . One-pot four-component reaction for the synthesis of spirooxindole derivatives.
point microscope. 1 H NMR and 13 C NMR spectra were characterized, respectively, at 400
and 100 MHz on Bruker Avance 400-MHz spectrometers. Spectral data were recorded at the
presence of DMSO-d6 as solvents. The elemental analysis (C, H, and N) were obtained by
means of a Carlo ERBA Model EA 1108 analyzer. Fourier transform infrared (FT-IR) spectra were recorded on WQF-510, spectrometer 550 Nicolet in the range of 400–4000 cm−1
using KBr pellets. The energy-dispersive X-ray spectroscopy (EDS) measurements were performed by SAMX analyzer. Powder X-ray diffraction (XRD) measurements were carried out
on a Philips diffractometer of X’pert Company with monochromatized Cu Kα radiation
(λ = 1.54056 nm). A TGAQ5 thermogravimetric analyzer was used to study the thermal properties of the compounds under an inert N2 atmosphere at 20 mL min−1 and heating rate of
10°C min−1 . Transmission electron microscopy (TEM) was performed on Philips CM30. SEM
images were taken by MIRA3-TESCAN. The magnetic properties of Fe3 O4 , Fe3 O4 @SiO2 ,
and Fe3 O4 @SiO2 –NH2 nanoparticles were measured with a vibrating sample magnetometer
(VSM, PPMS-9T) at 300 K in Kashan University, Iran.
Preparation of Fe3 O4 nanoparticles
The Fe3 O4 nanoparticles were synthesized by co-precipitation method. FeCl3 .6H2 O (11.68 g)
and FeCl2 .4H2 O (4.30 g) were dissolved in 200 mL deionized water, then 15 mL NH3 .H2 O
(25%) was added to the solution drop wise under nitrogen atmosphere and vigorous stirring in
70–75°C. The magnetic nanoparticles were separated from solution by an external magnetic
decantation and washed several times by deionized water.
Preparation of Fe3 O4 @SiO2 nanoparticles
1 g of magnetic nanoparticles was dispersed in 20 mL ethanol in ultrasonic bath for 30 min
at room temperature. Then, 6 mL aqueous NH3 (25%) and 2 ml tetraethyl orthosilicate
(TEOS) was added to the solution. The resulting solution was stirred at 35–40°C for 24 h.
The Fe3 O4 @SiO2 NPs were separated from solution by an external magnetic decantation and
washed with ethanol (3 × 15 mL) and dried at room temperature.
4
F. ALEMI-TAMEH ET AL.
Scheme . Preparation routes of Fe O @SiO –NH nanoparticles.
Preparation of Fe3 O4 @SiO2 –NH2 nanoparticles
1 g of Fe3 O4 @SiO2 nanoparticles dispersed in 25 mL of dry toluene in ultrasonic bath for
15 min. Then, 2.2 mL 3-(aminopropyl)-triethoxysilane (APTES) was added to the solution
drop wise and the mixture was refluxed under nitrogen atmosphere with vigorous stirring for
20 h. Finally, Fe3 O4 @SiO2 –NH2 nanoparticles were separated from solution by an external
magnetic decantation and washed several times with (20 mL ethanol) and dried at room temperature (Scheme 2). The APTES content in Fe3 O4 @SiO2 NPs is 2.84 mmol/g, which agree
well with the content of nitrogen element in Fe3 O4 @SiO2 –NH2 NPs evaluated by elemental
analysis.
General procedure for the Fe3 O4 @SiO2 –NH2 NPs catalyzed multicomponent synthesis
of spiro [indoline-3, 4´-pyrano [2,3- c] pyrazole] derivatives
A mixture of isatin 1 (1 mmol), hydrazine 4 (1.1 mmol), methyl cyanoacetate 2 (1 mmol) or
malononitrile 2 (1.1 mmol), ethyl acetoacetate 3 (1 mmol), and Fe3 O4 @SiO2 –NH2 nanoparticles (0.035 g) were heated in EtOH (10 mL) at 60°C. The completion of the reaction was
monitored by TLC and the catalyst was separated from reaction before work-up by an external magnet field. Then the mixture was poured into cold water; the obtained precipitate was
filtered and recrystallized twice by (EtOAc/n-hexane 3:1). Afterward, the products were characterized by 1 H NMR, FT-IR, 13 C NMR spectroscopy. Products 5a, 5b, 5c, and 5d (Figure 2)
were characterized by spectroscopic data.
POLYCYCLIC AROMATIC COMPOUNDS
5
Figure . Structures of products 5a, 5b, 5c and 5d.
Characterization of compounds
6´-Amino-3´-methyl-2-oxo-2´ H-Spiro [indoline-3,4´ -pyro [2,3- c] Pyrazole]-5´-methoxylate
(5a): White solid; m.p.: 268–272°C; IR (KBr): V¯(cm−1 ) = 3492 and 3388(stretch NH),
3253(stretch NH), 1716(stretch CO), 1624(stretch CO), 1602(bend NH), 1439(aromatic
C=C), 1394, 1093, 930 and 758; 1 H NMR (400 MHz, DMSO-d6 ): δ = 1.65 (s, 3H, CH3 ), 3.03
(s, 3H, OCH3 ), 7.12–7.13 (m, 1H, CH, ArH), 6.92–6.93 (m, 1H, CH, ArH), 6.88–6.90 (m, 1H,
CH, ArH), 6.85–6.86 (m, 1H, CH, ArH), 7.87 (br s, 2H, H2 N), 9.97 (s, 1H, HN), 11.87 (s,
1H, HN) ppm; 13 C NMR (100 MHz, DMSO-d6 ): δ = 10.10, 49.00, 58.70, 79.00, 97.80, 111.50,
121.00, 125.00, 126.00, 131.00, 134.00, 137.00, 143.00, 156.80, 164.93, 173.74 ppm. Anal. calcd.
for C16 H14 N4 O4 : C, 58.89; H, 4.32; N, 17.17.; found: C, 58.77; H, 4.38; N, 17.20.
6´-Amino-3´-methyl-2-oxo-5-Cloro- 2´ H-spiro [indoline-3,4´ -pyro [2,3- c] pyrazole]-5´methoxylate (5b): White solid; m.p.: 270–275°C; IR (KBr): V¯ (cm−1 ) = 3404 and 3283(stretch
NH), 3180 (stretch NH), 1698 (stretch CO), 1670 (stretch CO), 1601 (bend NH), 1550 and
1469 (aromatic C=C), 1207, 806, 769. 1 H NMR (400 MHz, DMSO-d6 ): δ = 1.76 (s, 3H, CH3 ),
3.35 (s, 3H, OCH3 ), 7.15 (d d, 3 J = 8.4 Hz, 4 J = 2.0 Hz, 1H, HC, ArH), 6.97 (d, J = 8.4 Hz, 1H,
HC, ArH), 6.89 (d, J = 2.0 Hz, 1H, HC, ArH), 7.74 (br s, 2H, H2 N), 9.54 (s, 1H, HN), 11.41 (s,
1H, HN) ppm; 13 C NMR (100 MHz, DMSO-d6 ): δ = 10.14, 49.10, 56.10, 74.90, 96.04, 113.09,
120.13, 126.00, 128.63, 130.70, 136.00, 137.10, 141.33, 157.00, 164.34, 172.13 ppm. Anal. calcd.
for C16 H13 ClN4 O4 : C, 53.27; H, 3.63; N, 15.53; found: C, 53.20; H, 3. 69; N, 15.47.
6´-Amino-3´-methyl-2-oxo-5-Bromo- 2´ H-spiro [indoline-3,4´ -pyro [2,3- c] pyrazole]-5´methoxylate (5c): Yellow solid; m.p.: 250–255°C; IR (KBr): V¯ (cm−1 ) = 3377 and 3294
(stretch NH), 3143 (stretch NH), 1732 (stretch CO), 1676 (stretch CO), 1612 (bend NH),
1550 and 1473 (aromatic C=C), 1207, 818, 660. 1 H NMR (400 MHz, DMSO-d6 ): δ = 1.58 (s,
3H, CH3 ), 3.25 (s, 3H, OCH3 ), 6.94 (d, J = 8.0 Hz, 1H, HC, ArH), 7.00 (s, 1H, HC, ArH), 7.30
(d, J = 8.0 Hz, 1H, HC, ArH), 8.03 (s, 2H, H2 N), 10.54 (s, 1H, HN), 12.22 (s, 1H, HN) ppm;
13
C NMR (100 MHz, DMSO-d6 ): δ = 10.13, 48.80, 58.70, 77.70, 96.80, 111.51, 120.30, 124.51,
6
F. ALEMI-TAMEH ET AL.
126.00, 130.74, 133.93, 136.70, 142.60, 156.70, 163.74, 174.33 ppm. Anal. calcd for C16 H13 Br
N4 O4 : C, 47.43; H, 3.23; N, 13.83; found: C, 47.30; H, 3.10; N, 13.90.
6´-Amino-3´-methyl-2-oxo-5-Nitro- 2´ H-spiro [indoline-3,4´ -pyro [2,3- c] pyrazole]-5´methoxylate (5d): Yellow solid; m.p.: 268–270°C; IR (KBr): V¯(cm−1 ) = 3398 and 3300
(stretch NH), 3145 (stretch NH), 1736 (stretch CO), 1670 (stretch CO), 1622 (bend NH), 1498
and 1338 (stretch NO), 1292, 694. 1 H NMR (400 MHz, DMSO-d6 ): δ = 1.58 (s, 3H, CH3 ),
3.25 (s, 3H, OCH3 ), 8.00 (d, J = 8.0 Hz, 1H, HC, ArH), 7.52 (s, 1H, HC, ArH), 7.03 (d, J =
8.0 Hz, 1H, HC, ArH), 8.14 (s, 2H, HN2 ), 11.15 (s, 1H, HN), 12.29 (s, 1H, HN) ppm; 13 C NMR
(100 MHz, DMSO-d6 ): δ = 10.11, 48.83, 52.20, 74.80, 96.90, 111.04, 119.41, 126.71, 137.25,
137.61, 138.51, 144.20, 148.90, 156.00, 164.02, 173.20 ppm. Anal. Calcd. for C16 H13 N5 O6 : C,
51.76; H, 3.53; N, 18.86; Found: C, 51.70; H, 3.50; N, 18.77.
Results and discussion
Characterization of Fe3 O4 @SiO2 –NH2 nanoparticles
The particle size and morphology of synthesized Fe3 O4 , Fe3 O4 @SiO2 , and Fe3 O4 @SiO2 –NH2
nanoparticles were determined by Scanning Electronic Microscopy (SEM). The SEM images
of samples show that the nanoparticles have uniform size, spherical shape, and disordered
mesophere. The statistic results from SEM image clearly demonstrate that Fe3 O4 @SiO2 –NH2
NPs have a mean diameter of about 25–31 nanometer (Figure 3).
TEM was applied to observe core–shell structure of Fe3 O4 @SiO2 –NH2 nanoparticles. The
TEM image revealed that the Fe3 O4 @SiO2 –NH2 nanoparticles have a core–shell structure.
These nanoparticles have dark Core of Fe3 O4 and light shell of amino-silica shell, indicating
that hydrophilic Fe3 O4 nanoparticles are coated by amino-silica shell (Figure 3).
Figure 4a shows the powder XRD spectrum. The characteristic peaks in the spectrum
are in accordance with the standard Fe3 O4 (cubic phase) XRD spectrum. The same peaks
were observed in the both of Fe3 O4 and Fe3 O4 @SiO2 –NH2 patterns, showing retention of
the crystalline spinel ferrite core structure during the attachment of APTES process. A weak
bond near 2θ = 19° in Fe3 O4 @SiO2 –NH2 patterns could be associated with the silica shell
coated on Fe3 O4 NPs. The crystallite size diameter (D) of the Fe3 O4 @SiO2 –NH2 NPs has
been calculated by Debye–Scherer equation (D = Kλ/βcosθ), where λ is the X-ray wavelength (1.54 Å for Cu Kα), θ is the Bragg angle of the maximum of diffraction peak, K is
called shape factor which usually takes a constant value of about 0.9, and β is full-width at halfmaximum (FWHM). The crystallite size of Fe3 O4 @SiO2 –NH2 NPs calculated by the Debye–
Scherer equation is about 31 nm, in good agreement with the result obtained by SEM. The
elemental composition of Fe3 O4 @SiO2 –NH2 NPs was shown by EDS spectrum (Figure 4b).
The elemental analysis of Fe3 O4 @SiO2 –NH2 NPs indicated that the amounts of oxygen, carbon, iron, silicon, and nitrogen were about 46.83, 10.87, 26.26, 12.00, and 4.04 wt%, respectively. The results proved that amine groups were successfully coated onto the surface of
MNPs.
Magnetic measurements of Fe3 O4 , Fe3 O4 @SiO2 , and Fe3 O4 @SiO2 –NH2 nanoparticles
were investigated with VSM. Room temperature specific magnetization (M) versus applied
magnetic field (H) curve measurements for Fe3 O4 , Fe3 O4 @SiO2 , and Fe3 O4 @SiO2 –NH2 are
illustrated in Figure 5. The results demonstrate that all 3 samples are superparamagnetic and
the highest saturation magnetization is 59.1 emu/g, which belongs to bare MNPs (Fe3 O4 NPs).
As illustrated in Figure 5, the amounts of saturation magnetization for Fe3 O4 @SiO2 NPs and
POLYCYCLIC AROMATIC COMPOUNDS
7
Figure . SEM image of (a) Fe O NPs, (b) Fe O @SiO NPs and (c) Fe O @SiO –NH NPs (d) TEM image of
Fe O @SiO –NH .
Figure . (a) The XRD pattern of Fe O NPs and Fe O @SiO –NH NPs. (b) EDS spectrum of Fe O @SiO –NH
NPs.
8
F. ALEMI-TAMEH ET AL.
Figure . The VSM curve of Fe O , Fe O @SiO and Fe O @SiO –NH .
Fe3 O4 @SiO2 –NH2 are 39.7 and 31.7 emu/g, respectively. The lower saturation magnetization of Fe3 O4 @SiO2 –NH2 than that of Fe3 O4 @SiO2 NPs is attributed to the extra layer coated
onto MNPs. These results demonstrate that the magnetization property decreases by coating
and functionalization. However, it is still high enough to be separated by a magnet. These
results prove that the catalysts can be easily separated and recovered by an external magnetic
field.
Thermogravimetric analysis (TGA) evaluates the thermal stability of the Fe3 O4 @SiO2 –
NH2 NPs. These nanoparticles show suitable thermal stability without significant decrease in
weight. 1.9% decrease in weight between 30 and 250°C is attributed to the removal of surface
hydroxyl groups and physically adsorbed solvent molecules trapped in SiO2 layer. Organic
groups desorbed at temperatures above 250°C, therefore, 4.8% decreasing in weight between
250 and 600°C was resulted from the decomposition of aminopropyl group grafted to the
silica surface. These results prove that the catalyst is stable up to 200°C and can be used in
organic reactions (Figure 6).
Figure 7 illustrates FT-IR spectra of Fe3 O4 , Fe3 O4 @SiO2 , and Fe3 O4 @SiO2 –NH2 NPs. In
all three spectra, the revealed peaks of Fe3 O4 were observed at 559–584 cm−1 , which could
be attributed to the characteristic absorption of Fe–O bond. These peaks confirm the presence of Fe3 O4 nanoparticles. In Fe3 O4 @SiO2 spectrum and Fe3 O4 @SiO2 –NH2 spectrum, the
Figure . TGA curve of Fe O @SiO –NH NPs.
POLYCYCLIC AROMATIC COMPOUNDS
9
Figure . FT- IR spectrum of Fe O , Fe O @SiO , Fe O @SiO –NH NPs.
intense peak at 1089, 1070 cm−1 was derived from the Si–O–Si stretching vibrations. These
peaks proved that SiO2 has coated the surface of Fe3 O4 . In Fe3 O4 @SiO2 –NH2 spectrum, the
characterized peaks at 1630, 1547 cm−1 could be attributed to the C–N stretching vibrations
and NH2 bending vibration; moreover, the peak at 2925 cm−1 is related to bending vibration
of CH2 and CH3 in the NPs and the peak at 3987 cm−1 is assigned to the N–H stretching
vibration. These described peaks confirmed that Fe3 O4 @SiO2 –NH2 NPs are prepared.
Catalytic behaviors of Fe3 O4 @SiO2 –NH2 nanoparticles
After preparation and characterization of Fe3 O4 @SiO2 –NH2 nanoparticles, its catalytic activity was evaluated in an MCR between malononitrile, hydrazine hydrate, ethyl acetoacetate,
and isatin as a model reaction. Initially, we selected various catalysts such as 4-DMAP, Meglumine, Piperidin, and Fe3 O4 @SiO2 –NH2 NPs for the model reaction to get high yield of the
desired product with the best catalyst. We examined the model reaction without catalyst. In
the absence of nanocatalysts, the products were obtained in very low yield after prolonged
reaction time. Moreover, the quantity of the catalyst is optimized for the formation of the
desired product. The results summarized in Table 1, clearly reveal that an enhancement in
catalyst loading from 0.01 to 0.035 g improved the yield of the desired product to a great
Table . Synthesis of spirooxindole e by different catalysts.
Entry










a Isolated yield.
Amount of catalyst
Time (min)
Yielda (%) [ref]
—
Piperidine (. mmol)
-DMAP (. mmol)
Meglumine ( mol%)
Fe O @SiO –NH (. g)
Fe O @SiO –NH (. g)
Fe O @SiO –NH (. g)
Fe O @SiO –NH (. g)
Fe O @SiO –NH (. g)
Fe O @SiO –NH (. g)











 ()
 ()
 ()






10
F. ALEMI-TAMEH ET AL.
Table . Fe O @SiO –NH nanoparticles catalyzed synthesis of spirooxindole in various solvents in model
reaction.
Solvent
Time (min)
Yielda (%)
H O
EtOH
MeOH
CH Cl
EtOH/H O(:)










Entry





a Isolated yields.
extent. The best result in terms of yield (94%) was achieved within 20 min with the catalyst
loading of 0.035 g (Entry 8).
In another effort, the model reaction was carried out in different solvents such as H2 O,
EtOH, MeOH, CH2 Cl2 , EtOH/H2 O (1:1) and the results are listed in Table 2. It is observed
that the reaction progress was appropriate in “EtOH” and it was selected as the best solvent
(Entry 2).
Afterward, a series of spirooxindole derivatives were synthesized in one-pot fourcomponent reaction of various isatin derivatives, malononitrile or methyl cyanoacetate, 1,3dicarbonyl compounds, hydrazine hydrate, at optimized conditions of catalyst and solvent
(Table 3). The results show that istain having either electron-donating (alkyl) or electronwithdrawing groups (halides, nitro) obtained higher yield than istain without substituent.
Also, the reaction with malononitrile obtained higher yield than methyl cyanoacetate, which
was certainly due to the higher reactivity of malononitrile.
Mechanistic aspects
Scheme 3 shows a proposed mechanism for this reaction in the presence of Fe3 O4 @SiO2 –
NH2 NPs. The catalytic active site in the Fe3 O4 @SiO2 NPs is Fe+3 and Fe+2 , which behaves as
a Lewis acid and attaches to carbonyl groups of ethyl acetoacetate, isatin, and nitriles to accelerate the conjugate and direct additions of nucleophiles to corresponding substrates. Another
rule of the catalyst is related to basic (−NH2 ) properties of functionalized Fe3 O4 , which plays
a crucial catalytic role in the described transformation. Initially hydrazine hydrate is reacted
with 1, 3-dicarbonyl compound to form intermediate (I) via condensation reaction. Then,
Table . One-pot synthesis of spirooxindoles catalyzed by Fe O @SiO –NH a NPs.
Entry
R
R
R
Product
Time (min)
Yieldb %
Mp(°C) Found
Mp(°C) Reported [Ref]









H
H
H
H
H
H
H
H
H
H
Cl
Br
NO
H
Cl
Br
NO
CH
CO Me
CO Me
CO Me
CO Me
CN
CN
CN
CN
CN
a
b
c
d
e
f
g
h
i


















–
–
–
–
–
–
–
–
–
—
—
—
—
– ()
– ()
– ()
– ()
– ()
a Reaction conditions: isatin derivatives ( mmol), ethyl acetoacetate (. mmol), methyl cyanoacetate or malononitrile
( mmol), hydrazine hydrate (. mmol), and Fe O @SiO –NH NPs (.) g.
b Isolated yields.
POLYCYCLIC AROMATIC COMPOUNDS
11
Scheme . Proposed reaction pathway for the synthesis of spirooxindoles using Fe O @SiO –NH NPs as
catalyst.
intermediate (I), in the presence of Fe3 O4 @SiO2 –NH2 NPs, is condensed with isatin derivatives to form intermediate (II) via Knoevenagel condensation reaction. In the next step, malononitrile or methyl cyanoacetate reacts with intermediate (II) through Michael addition.
Lastly, the final product is formed by intra-molecular cyclization reactions. This proposed
mechanism has also been supported by literature (40, 45).
Figure . Recycling of Fe O @SiO –NH NPs catalyst for the preparation of 5b.
12
F. ALEMI-TAMEH ET AL.
Recycling of the catalyst
After the reaction was completed, the catalyst was separated by external magnetic field.
Fe3 O4 @SiO–NH2 NPs were washed for 3 to 4 times with ethanol and dried at room temperature for 5 h. The separated catalyst can be reused for 5 times. As shown in Figure 8, the
product yields reduced to a small extent on each reuse (run 1, 87%; run 2, 87%; run 3, 86%;
run 4, 85%; run 5, 84%).
Conclusion
A green and efficient method for the synthesis of spirooxindoles has been developed by
Fe3 O4 @SiO2 –NH2 NPs as nanocatalyst in one-pot four-component reaction. The products
were obtained in excellent yields in short reaction times compared to using traditional base
catalysts such as Et3 N or piperidine. Also, using this catalyst is more cost-effective compared
to recently reported catalysts such as Meglumine. The procedure offers several advantages
including short reaction times, a simple procedure, high atom economy, excellent yields,
reusability of the catalyst, and little catalyst loading.
Acknowledgments
The authors are grateful to the Department of Chemistry, Science and Research Branch, Islamic Azad
University, Tehran, Iran for supporting this work.
ORCID
Javad Safaei-Ghomi
http://orcid.org/0000-0002-9837-4478
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