Novel organometallic nanomagnetic catalyst for multicomponent synthesis of spiroindoline derivatives

Article abstract of DOI:10.1007/s11164-017-3228-5

A novel, green, reusable polyaniline (PANI)/Fe₃O₄/carbon nanotube (CNT) nanomagnetic catalyst has been prepared, characterized by Fourier-transform infrared (FT-IR) spectroscopy, transmission electron microscopy (TEM), and X-ray diff

Full text of DOI:10.1007/s11164-017-3228-5

Res Chem Intermed
https://doi.org/10.1007/s11164-017-3228-5
Novel organometallic nanomagnetic catalyst
for multicomponent synthesis of spiroindoline
derivatives
Seyedeh Fatemeh Hojati1 · Amirhassan Amiri1 · Sakineh Mohamadi1 ·
Nasrin MoeiniEghbali1
Received: 10 October 2017 / Accepted: 4 December 2017
© Springer Science+Business Media B.V., part of Springer Nature 2017
Abstract A novel, green, reusable polyaniline (PANI)/Fe3O4/carbon nanotube
(CNT) nanomagnetic catalyst has been prepared, characterized by Fourier-trans-
form infrared (FT-IR) spectroscopy, transmission electron microscopy (TEM),
and X-ray difraction (XRD) analysis, and applied for four-component synthesis
of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives from isatin, hydrazine
hydrate or phenylhydrazine, ethyl acetoacetate, and malononitrile or ethyl cyanoac-
etate in aqueous medium at room temperature. Use of water as safe and environmen-
tally benign solvent, short reaction time, high product yield, easy workup procedure,
and easy separation and reusability of the catalyst are noteworthy advantages of this
approach.
Keywords Spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] · PANI/Fe3O4/CNT
nanocomposite · Multicomponent reaction · Aqueous medium
Introduction
Multicomponent reaction strategies have attracted a great deal of interest from
chemists and biochemists because of their signifcant advantages over conventional
linear-type syntheses. Multicomponent reactions leading to formation of multifunc-
tional heterocycles are applied in the pharmaceutical and agrochemical industries
and synthetic chemistry [1, 2]. Spiro[indoline-3,4′-pyrano[2,3-c]pyrazoles] repre-
sent a substantial category of natural alkaloids that exhibit a wide range of biological
and pharmacological activities and can be prepared by multicomponent reactions.
*
Seyedeh Fatemeh Hojati
sf.hojati@hsu.ac.ir; hojatee@yahoo.com
1
Department of Chemistry, Hakim Sabzevari University, Sabzevar, Iran
1 3

S. F. Hojati et al.
Antidysplasia, antiallergic, hypoglycemic [3], antimicrobial [4], antifungal [5],
antiinfammatory [6], antibacterial [7], and anticancer [8] efects have been found
for these heterocycles. Furthermore, they have been used in agriculture as insecti-
cides, acaricides, herbicides [9], and fungicides [10]. Due to their extensive range
of pharmacological activities and industrial and synthetic applications, a number of
methods have been developed for preparation of spiro[indoline-3,4′-pyrano[2,3-c]
pyrazole] derivatives. Although some reported procedures are useful, most of them
sufer from disadvantages such as prolonged reaction time, moderate product yield,
and use of expensive, toxic or nonreusable catalysts such as InCl3 [11], 4-(dimeth-
ylamino)pyridine (4-DMAP) [3], NaHCO3 [12], I2 [13], Et3N [14], piperidine [8],
and C17H35COONa [15]. Furthermore, most of these reactions were performed in
organic solvents, which can lead to environmental pollution, while the fact that
some MCRs can be carried out in aqueous medium is another attractive feature for
use in organic chemistry. There is therefore still a need to develop new methods
for preparation of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives in presence
of highly efcient and reusable catalysts in aqueous medium via multicomponent
reactions. After the pioneering works of Breslow on the Diels–Alder reaction, much
attention has been paid to development of organic reactions in aqueous medium [16,
17]. Recent investigations have shown that use of aqueous medium in organic trans-
formations can reduce the number of reaction steps and thereby the reaction time,
pollution, and byproduct formation, while also increasing the selectivity and prod-
uct yield. Furthermore, the absence of volatile organic solvents provides economical
and environmental benefts. Furthermore, water is cheap, safe, easily available, and
environmentally benign.
Recently, magnetic nanoparticles have attracted special attention as a new class
of heterogeneous catalyst due to their high surface area and easy separation using an
external magnet. The dominant characteristics of magnetic nanoparticles and exten-
sive biological applications of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] motivated
us to perform four-component synthesis of these valuable heterocycles using a novel
polyaniline (PANI)/Fe3O4/CNT magnetic nanocatalyst (Scheme 1).
Experimental
Materials
All chemicals were purchased from Merck, Aldrich, and Fluka. IR spectra were
obtained using a Shimadzu 435-U-04 spectrophotometer from KBr pellets. Melting
1
points were taken using an Electrothermal 9100 apparatus and are uncorrected. H
nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AVANCE
300-MHz spectrometer in dimethylsulfoxide (d6) (DMSO) as solvent. Transmission
electron microscopy (TEM) was carried out using a Leo 912 AB. The X-ray difrac-
tion (XRD) pattern of the catalyst was taken using Philips PW 1730 apparatus.
1 3

Novel organometallic nanomagnetic catalyst for multicomponent…
O
R3
N
R2
O
O
N
NC
X
NH2
N
R1
PANI/Fe3O4/CNT
H2O, rt
(2)
Me
(1)
(3)
R2
+
X
O
O
O
H2N NHR3
N
Me
OEt
R1
(4)
(5a-t)
k) R1=H, R2=Br, R3=H, X=COOEt
l) R1=Bn, R2=H, R3=H, X=COOEt
m) R1=H, R2=H, R3=Ph, X=CN
n) R1=H, R2=Cl, R3=Ph, X=CN
p) R1=H, R2=NO2, R3=Ph, X=CN
q) R1=Me, R2=H, R3=Ph, X=CN
r) R1=H, R2=Br, R3=Ph, X=CN
t)R1=Bn, R2=H, R3=Ph, X=CN
a) R1=H, R2=H, R3=H, X=CN
b) R1=H, R2=Cl, R3=H, X=CN
c) R1=H, R2=NO2, R3=H, X=CN
d) R1=Me, R2=H, R3=H, X=CN
e) R1=H, R2=Br, R3=H, X=CN
f) R1=Bn, R2=H, R3=H, X=CN
g) R1=H, R2=H, R3=H, X=COOEt
h) R1=H, R2=Cl, R3=H, X=COOEt
j) R1=Me, R2=H, R3=H, X=COOEt
Scheme 1 Synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives using PANI/Fe3O4/CNT
magnetic nanocatalyst
Catalyst preparation
PANI/Fe3O4/CNT nanocomposite was synthesized in three steps according to litera-
ture method [18, 19]. In the frst step, carbon nanotubes (CNTs) were oxidized with
acid treatment by refux. Briefy, carbon nanotubes (0.2 g) were added to 50 mL
HNO3 (60%) solution and sonicated in a bath for 30 min and stirred for 24 h at
refux. The oxidized carbon nanotubes were fltered through a 0.22-μm membrane
and washed with excess distilled water until the pH of the fltrate was 7.0. Then,
the oxidized carbon nanotubes were dried in vacuum oven at 60 °C. In the second
step, magnetic nanoparticles were synthesized by a simple coprecipitation method.
In this case, 4.3 g ferrous chloride tetrahydrate and 11.68 g ferric chloride hexahy-
drate were dissolved in 400 mL deionized water under nitrogen atmosphere. After-
ward, 20 mL ammonia solution (30% w/w) was added, and the mixture was stirred
at 60 °C for 60 min. The precipitate was isolated from the solution by applying an
external magnet, washed with deionized water, and fnally dried in vacuum oven at
60 °C for 24 h.
In the fnal step, PANI/Fe3O4/CNT nanocomposite was synthesized via oxidative
polymerization of aniline monomers in presence of Fe3O4 nanoparticles and CNTs
(as charge-balancing dopant in the polymer) using potassium persulfate as oxidant.
Briefy, 250 mg dried Fe3O4 NPs and 50 mg carbon nanotubes –COOH were added
to 50 mL deionized water under stirring for 5 min, then 0.5 mL aniline monomers
was added and stirred for 20 min. Nitrogen gas was bubbled through the reaction
mixture for 10 min under stirring to remove oxygen. Subsequently, 2.7 g potassium
1 3

S. F. Hojati et al.
persulfate was added to the mixture. After addition of oxidant, the mixture was
stirred for 16 h at room temperature. The resultant PANI/Fe3O4/CNT nanocompos-
ite was collected using a magnet and washed with deionized water, tetrahydrofuran,
and methanol several times to remove unreacted materials, then dried at 60 °C under
vacuum for 12 h. The nanocomposite was characterized by FT-IR spectroscopy,
TEM, and XRD analysis [18, 19].
Physical and spectral data of products
6′‑Amino‑3′‑methyl‑2‑oxo‑1′H‑spiro[indoline‑3,4′‑pyrano[2,3‑c]
pyrazole]‑5′‑carbonitrile (5a) IR (KBr, cm−1): 3378, 3338, 3131, 2691, 1711,
1
1641. H NMR (300 MHz, DMSO-d6, ppm): 1.54 (s, 3H, CH3), 6.90–7.26 (m, 4H,
Ar), 7.23 (s, 2H, NH2), 10.59 (s, 1H, NH), 12.28 (s, 1H, NH).
6′‑Amino‑3′‑methyl‑2‑oxo‑1′H‑spiro[5‑chloro‑indoline‑3,4′‑pyrano‑[2,3‑c]
pyrazole]‑5′‑carbonitrile (5b) IR (KBr, cm−1): 3396, 3136, 2182, 1714, 1644.
1H NMR (300 MHz, DMSO-d6, ppm): 1.58 (s, 3H, CH3), 6.92–6.93 (m, 1H, Ar),
7.23–7.24 (m, 1H, Ar), 7.29–7.31 (m, 3H, Ar, NH2), 10.76 (s, 1H, NH), 12.35 (s,
1H, NH).
6′‑Amino‑3′‑methyl‑2‑oxo‑1′H‑spiro[5‑nitroindoline‑3,4′‑pyrano[2,3‑c]
1
pyrazole]‑5′‑carbonitrile (5c) IR (KBr, cm−1): 3450, 3322, 2193, 1731, 1644. H
NMR (300 MHz, DMSO-d6, ppm): 1.58 (s, 3H, CH3), 7.13–7.15 (m, 1H, Ar), 7.43
(s, 2H, NH2), 7.91–7.92 (m, 1H, Ar), 8.23–8.25 (m, 1H, Ar), 11.37 (s, 1H, NH),
12.41 (s, 1H, NH).
6′‑Amino‑1,3′‑dimethyl‑2‑oxo‑1′H‑spiro[indoline‑3,4′‑pyrano[2,3‑c]
1
pyrazole]‑5′‑carbonitrile (5d) IR (KBr, cm−1): 3196, 3136, 2682, 1714, 1644. H
NMR (300 MHz, DMSO-d6, ppm): 1.45 (s, 3H, CH3), 3.20 (3H, s, CH3), 7.06–7.14
(4H, m, Ar), 7.25 (2H, s, NH2), 7.31–7.41 (1H, m, Ar), 12.29 (s, 1H, NH).
6′‑Amino‑3′‑methyl‑2‑oxo‑1′H‑spiro[5‑bromoindoline‑3,4′‑pyrano‑[2,3‑c]
1
pyrazole]‑5′‑carbonitrile (5e) IR (KBr, cm−1): 3391, 3138, 2181, 1713, 1642. H
NMR (300 MHz, DMSO-d6, ppm): 1.58 (3H, s, CH3), 6.87–6.89 (m, 1H, Ar), 7.23–
7.24 (m, 1H, Ar), 7.32 (s, 2H, NH2), 7.42–7.44 (m, 1H, Ar), 10.78 (s, 1H, NH),
12.35 (s, 1H, NH).
6′‑Amino‑1‑benzyl‑3′‑methyl‑2‑oxo‑1′H‑spiro[indoline‑3,4′‑pyrano[2,3‑c]
pyrazole]‑5′‑carbonitrile (5f) IR (KBr, cm−1): 31876, 3140, 2182, 1714, 1644. 1H
NMR (300 MHz, DMSO-d6, ppm): 1.35 (s, 3H, CH3), 4.91 (d, 1H, J = 15.6 Hz,
CH2Ph), 5.00 (d, 1H, J = 15.6 Hz, CH2Ph), 7.00–7.14 (m, 3H, Ar), 7.23–7.36 (m,
6H, Ar, NH2), 7.37–7.44 (m, 2H, Ar), 12.30 (s, 1H, NH).
Ethyl‑6′‑Amino‑3′‑methyl‑2‑oxo‑1′H‑spiro[indoline‑3,4′‑pyrano[2,3‑c]
pyrazole]‑5′‑carboxylate (5g) IR (KBr, cm−1): 3385, 3281, 3188, 2578, 1715,
1 3

Novel organometallic nanomagnetic catalyst for multicomponent…
1
1666. H NMR (300 MHz, DMSO-d6, ppm): 0.70–0.73 (t, 3H, CH3), 1.58 (s, 3H,
CH3), 3.65–3.75 (m, 2H, CH2), 6.81–7.15 (m, 4H, Ar), 8.02 (s, 2H, NH2), 10.37 (s,
1H, NH), 12.15 (s, 1H, NH).
Ethyl‑6′‑Amino‑3′‑methyl‑2‑oxo‑1′H‑spiro[5‑chloroindoline‑3,4′‑pyrano[2,3‑c]
pyrazole]‑5′‑carboxylate (5h) IR (KBr, cm−1): 3390, 3346, 3136, 2967, 2179,
1
1713, 1642, 1580, 1497, 1414, 1298, 1157, 1055, 823, 697. H NMR (300 MHz,
DMSO-d6, ppm): 1.06 (s, 3H, CH3), 6.92 (d, J = 8.4 Hz, 1H, Ar), 7.12 (s, 1H, Ar),
7.27 (s, 2H, NH2), 7.29–7.31 (m, 1H, Ar), 10.73 (s, 1H), 12.32 (s, 1H,).
Ethyl‑6′‑Amino‑1,3′‑methyl‑2‑oxo‑1′H‑spiro[indoline‑3,4′‑pyrano[2,3‑c]
pyrazole]‑5′‑carboxylate (5j) IR (KBr, cm−1): 3514, 3368, 3252, 2980, 2904,
1
2361, 1695, 1609, 1543, 1492, 1477, 1399, 1372, 1354. H NMR (300 MHz,
DMSO-d6, ppm): 0.61 (3H, t, J 6.7 Hz), 1.52 (s, 3H), 3.12 (s, 3H), 3.75 (2H, q, J
6.8 Hz), 6.8–7.10 (m, 3H), 7.22 (1H, t, J 7.6 Hz), 8.10 (s, 2H, NH2), 12.27 (s, 1H,
NH).
Ethyl‑6′‑amino‑3′‑methyl‑2‑oxo‑1′H‑spiro[5‑bromoindoline‑3,4′pyrano[2,3‑c]
1
pyrazole]‑5′‑carboxylate (5k) IR (KBr, cm−1): 3349, 1718, 1649, 1573. H NMR
(300 MHz, DMSO-d6, ppm): 0.95 (3H, t, J = 6.9 Hz), 1.55 (s, 3H, CH3), 3.91 (2H,
q, J = 6.9 Hz), 6.75-6.83 (2H, m), 7.31 (1H, d, J = 7.8 Hz), 7.52 (2H, s, NH2), 10.68
(1H, s, NH), 10.93 (1H, s, NH).
4,3′‑Spiro[(6‑amino‑5‑carbethoxy‑3‑methyl‑2H,4H‑pyrano[2,3‑c]pyrazolo)‑N′‑benz
yl‑2′‑oxindole] (5l) IR (KBr, cm−1): 3276, 2978, 1676, 1612, 1546, 1485, 1466,
1397. 1H NMR (300 MHz, DMSO-d6, ppm): 0.55 (3H, t, J = 6.7 Hz), 1.00 (s, 3H),
3.28 (2H, q, J = 7.1 Hz), 4.50 (s, 2H), 6.9–7.2 (m, 3H), 7.22–7.48 (m, 6H), 7.85 (s,
2H, NH2), 11.85 (s, 1H, NH).
6′‑Amino‑3′‑methyl‑2‑oxo‑1′‑phenyl‑1′H‑spiro[indoline‑3,4′‑pyrano[2,3‑c]
pyrazole]‑5′‑carbonitrile (5m) IR (KBr, cm−1): 3412, 3280, 3174, 2200, 1692,
1
1650, 1526, 1132. H NMR (300 MHz, DMSO-d6, ppm): 1.55 (s, 3H, CH3), 6.94
(d, J = 7.4 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H),7.18 (d, J = 7.2 Hz, 1H), 7.28 (t,
J = 7.5 Hz,1H), 7.36 (t, J = 7.6 Hz,1H), 7.52 (t, J = 7.8 Hz, 2H), 7.58 (br s, 2H,
NH2), 7.79 (d, J = 7.9 Hz, 2H), 10.76 (s,1H, NH).
6′‑Amino‑3′‑methyl‑2‑oxo‑1′‑phenyl‑1′H‑spiro[5‑chloroindoline‑3,4′‑pyrano[2,3‑c]
pyrazole]‑5′‑carbonitrile (5n) IR (KBr, cm−1): 3440, 3264, 3172, 2196, 1698,
1652, 1576, 1174. 1H NMR (300 MHz, DMSO-d6, ppm): 1.58 (s, 3H, CH3), 6.96 (d,
J = 8.4 Hz, 1H), 7.34–7.42 (3H, m), 7.52 (t, J = 8.2 Hz, 2H), 7.63 (br s, 2H, NH2),
7.78 (d, J = 8 Hz, 2H), 10.89 (s, 1H, NH).
6′‑Amino‑3′‑methyl‑2‑oxo‑1′‑phenyl‑1′H‑spiro[5‑nitroindoline‑3,4′‑pyrano[2,3‑c]
pyrazole]‑5′‑carbonitrile (5p) IR (KBr, cm−1): 3446, 3269, 3176, 2208, 1710,
1
1650, 1576, 1178. H NMR (300 MHz, DMSO-d6, ppm): 1.59 (s, 3H, CH3), 7.12
1 3

S. F. Hojati et al.
(d, J = 8.4 Hz, 1H), 7.38–7.55 (m, 3H), 7.68 (br s, 2H, NH2), 7.78 (m, 2H), 7.98 (d,
J = 6.8 Hz, 2H), 11.44 (s, 1H, NH).
6′‑Amino‑1,3′‑dimethyl‑2‑oxo‑1′‑phenyl‑1′H‑spiro[indoline‑3,4′‑pyrano(3,2‑c)
pyrazol]‑5‑carbonitrile (5q) IR (KBr, cm−1): 3450, 2198, 1686, 1603, 1572, 1179.
1H NMR (300 MHz, DMSO-d6, ppm): 1.43 (s, 3H, CH3), 3.22 (s, 3H, CH3), 7.07 (t,
1H, J = 7.4 Hz), 7.12 (d, 1H, J = 8.0 Hz), 7.21 (d, J = 6.9 Hz,1H), 7.31 (m, 2H),
7.47 (t, J = 8.6 Hz, 2H), 7.62 (s, 2H, NH2), 7.75 (d, J = 8.0 Hz, 2H).
6′‑Amino‑3′‑methyl‑2‑oxo‑1′‑phenyl‑1′H‑spiro[5‑bromoindoline‑3,4′‑pyrano[2,3‑c]
pyrazole]‑5′‑carbonitrile (5r) IR (KBr, cm−1): 3436, 3269, 3168, 2198, 1706,
1650, 1576, 1168. 1H NMR (300 MHz, DMSO-d6, ppm): d 1.58 (s, 3H, CH3), 6.91
(d, J = 7.6 Hz, 1H), 7.42–7.54 (4H, m), 7.28 (t, J = 7.9 Hz, 1H), 7.64 (s, 2H, NH2),
7.79 (d, J = 7.8 Hz, 2H), 10.90 (s, 1H, NH).
6′‑amino‑3′‑methyl‑2‑oxo‑1′‑phenyl‑1′H‑spiro[1‑benzylindoline‑3,4′‑pyrano[2
,3‑c]pyrazole]‑5′‑carbonitrile (5t) IR (KBr, cm−1): 3406, 1705, 1656, 1608,
1
1542, 1162. H NMR (300 MHz, DMSO-d6, ppm): 1.42 (s, 3H, CH3), 4.89 (d, 1H,
J = 15.6 Hz, benzylic proton), 5.09 (d, 1H, J = 15.6 Hz, benzylic proton), 6.97–7.42
(m, ArH, 14H), 8.13 (brs, 2H, NH2).
Fig. 1 FT-IR spectra of a Fe3O4NPs, b polyaniline, and c PANI/Fe3O4/CNT
1 3

Novel organometallic nanomagnetic catalyst for multicomponent…
Results and discussion
Characterization of nanocomposite
In continuation of our previous work on improvement of biologically active hetero-
cycle synthesis by description of green and reusable catalytic systems [9, 20–24], we
report herein a simple, facile, and environmentally benign procedure for synthesis of
spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives. In the frst step, PANI/Fe3O4/
CNT was prepared and the structure of this novel nanomagnetic catalyst identifed
by FT-IR spectroscopy, TEM, and XRD analysis.
The FT-IR spectra of Fe3O4 (a), polyaniline (b), and PANI/Fe3O4/CNT (c) are
presented in Fig. 1. The peaks at 587 and 3340 cm−1 in Fig. 1a correspond to Fe–O
bond absorption [19]. In the FT-IR spectrum of polyaniline (Fig. 1b), the peaks
appearing at 1565, 1487, 1240, and 1150 cm−1 correspond to quinoid and benzoin
ring, C–N stretching vibrations, and C=C stretching band, respectively. The FT-IR
spectrum of PANI/Fe3O4/CNT (Fig. 1c) shows typical characteristic peaks of Fe3O4
and polyaniline, confrming successful preparation of PANI/Fe3O4/CNT.
TEM of PANI/Fe3O4/CNT clearly revealed the size and crystalline morphol-
ogy of the catalyst as well as the distribution of the Fe3O4 nanoparticles in carbon
nanotubes covered by polyaniline (Fig. 2). As described in “Experimental” section,
Fe3O4 nanoparticles were deposited onto carbon nanotubes (CNTs) and polyaniline
(PANI) was coated onto the Fe3O4/CNT nanocomposite. TEM confrmed entrap-
ment of Fe3O4/CNT in a PANI layer, with average crystalline size of Fe3O4 nanopar-
ticles estimated as 30 nm.
The XRD pattern of PANI/Fe3O4/CNT is shown in Fig. 3. The characteristic
peaks at 2θ = 30.1°, 36.1°, 43.5°, 44.7°, 57.3°, and 72.6° confrm the crystalline
Fig. 2 TEM micrograph of
PANI/Fe3O4/CNT
1 3

S. F. Hojati et al.
Fig. 3 XRD pattern of PANI/Fe3O4/CNT
nature of the Fe3O4 NPs. The difraction peak for CNTs was observed at 2θ = 25.9°,
while the peaks at 18.8° and 25.1° indicate PANI in crystalline form [19].
Catalytic activity studies
Synthesis of spiroindoline derivatives
After synthesis and characterization of PANI/Fe3O4/CNT, the reaction conditions
were optimized using the reaction of isatin, malononitrile, hydrazine hydrate, and
ethyl acetoacetate. To this aim, several experiments were performed using difer-
ent amounts of catalyst in various solvents and at various temperatures (Table 1,
entries 1–11). The best result was obtained when using 1.2 mg catalyst in H2O at
r.t. (Table 1, entry 2). Furthermore, the model reaction was performed in absence
of catalyst, yielding no product after 10 min (Table 1, entry 12). As described in
the previous section, polyaniline covered the Fe3O4/CNT nanocomposite as a thin
layer. To show the efect of the polymer on the catalytic activity of PANI/Fe3O4/
CNT, the model reaction was also carried out in presence of 1.2 mg uncoated Fe3O4/
CNT under the optimized reaction condition, leading to 75% yield after 8 min.
A mixture of ethyl acetoacetate (3; 1 mmol), hydrazine hydrate or phenylhydra-
zine (4; 1.3 mmol), and PANI/Fe3O4/CNT (10 mg) in H2O (4 mL) was prepared
and stirred at room temperature. After 10 min, isatin (1; 1 mmol) and malononitrile
or ethyl cyanoacetate (2; 1 mmol) were added to the reaction mixture and stirred
at room temperature. Reaction was continued for the required time according to
Table 2. Reaction completion was detected by thin-layer chromatography (TLC)
(2:1 n-hexane/ethyl acetate). Then, catalyst was separated using an external magnet
1 3

Novel organometallic nanomagnetic catalyst for multicomponent…
Table 1 Optimization of reaction condition for synthesis of 5aa
O
H
N
O
O
N
NC
NC
NH2
CN
N
H
PANI/Fe3O4/CNT
Me
+
O
O
O
H2N NH2
N
H
Me
OEt
Entrya
Amount of cata- Conditions
lyst (mg)
Solvent
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
0.6
1.2
2.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
–
rt
rt
rt
rt
rt
rt
rt
rt
H2O
H2O
H2O
EtOH
Ethyl acetate
n-Hexane
H2O:EtOH (1:1)
CHCl3
H2O
10
8
75
95
80
65
60
70
75
30
95
95
95
–
10
20
70
30
40
90
10
10
10
10
9
50 °C
80 °C
100 °C
rt
10
11
12
H2O
H2O
H2O
aEthyl acetoacetate (1 mmol), hydrazine hydrate (1.3 mmol), malononitrile (1 mmol), isatin (1 mmol)
bIsolated yields
(Fig. 4) and dried at 100 °C for 1 h, after which it could be reused. The reaction mix-
ture was fltered, and the precipitate washed with cold water and ethanol to aford
pure product. Products were confrmed by comparison of their physical and spectra
data with those reported in literature (5a–t).
To investigate the generality of this method, various isatins were reacted with
hydrazine hydrate or phenylhydrazine, malononitrile or ethyl cyanoacetate, and ethyl
acetoacetate in presence of PANI/Fe3O4/CNT under optimized reaction condition.
The corresponding spiro[indoline-3,4′-pyrano[2,3-c]pyrazoles] were generated in
good to excellent yield in short reaction time (Table 2).
Furthermore, acenaphthylene-1,2-dione was used in the current method instead
of isatin and reacted with hydrazine hydrate, malononitrile, and ethyl acetoacetate
under the optimized conditions. As expected, the reaction proceeded well to aford
corresponding spiro[acenaphthylene-1,4′-pyrano[2,3-c]pyrazole] in 95% yield after
5 min (Scheme 2). So, the present method can be used successfully for preparation
of diferent pyran-structured compounds.
1 3

S. F. Hojati et al.
Table 2 Synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives in H2O catalyzed by nano-
magnetic PANI/Fe3O4/CNT
Entry R1 R2
R3
X
Product Time (min) Yield (%)a M.p. (°C) M.p. (°C) [Refer-
ences]
1
2
3
4
5
6
7
8
H
H
H
Me
H
Bn
H
H
Me
H
Bn
H
H
H
Me
H
Bn
H
H
H
H
H
H
H
H
H
H
H
H
CN
CN
CN
CN
CN
CN
CO2Et 5g
CO2Et 5h
CO2Et 5j
CO2Et 5k
CO2Et 5l
5a
5b
5c
5d
5e
5f
8
30
15
10
25
30
10
25
25
30
45
20
25
30
25
45
45
95
90
80
90
80
90
80
90
80
80
75
90
85
80
80
87
80
279–280
296–298
268–270
270
282–283
266–268
285–287
296–297
193–195
>250
126–128
236–238
231–232
226–228
200
278–280 [9]
296–298 [9]
270–272 [9]
268–270 [9]
283–285 [9]
266–268 [9]
285–287 [9]
295–297 [20–24]
193–195 [25]
>250 [26]
125–128 [25]
237–238 [27]
230–231 [27]
226–228 [27]
200 [11]
Cl
NO2
H
Br
H
H
Cl
H
9
10
11
12
13
14
15
16
17
Br
H
H
Ph CN
Ph CN
5m
5n
5p
5q
5r
Cl
NO2 Ph CN
H
Br
H
Ph CN
Ph CN
Ph CN
241–242
232–234
241–243 [27]
232–234 [28]
5t
aIsolated yields
Fig. 4 Separation of catalyst
A reasonable mechanism for this synthesis is proposed in Scheme 3. Further-
more, the reusability of PANI/Fe3O4/CNT was investigated in the model reaction
under optimized condition. After reaction completion, catalyst was removed from
the reaction mixture using an external magnet, washed with hot ethanol, and reused
in an alternative reaction without further activation. It was demonstrated that the
catalytic activity of nanomagnetic PANI/Fe3O4/CNT was not signifcantly reduced
after 10 continuous runs (Fig. 5).
Finally, the superiority of the current method for preparation of spiro[indoline-
3,4′-pyrano[2,3-c]pyrazole] over previously reported catalytic systems was con-
frmed by comparison with others in literature (Table 3). As shown in Table 3, most
previously reported procedures were carried out in organic solvents, whereas the
current method was performed in aqueous medium.
1 3

Novel organometallic nanomagnetic catalyst for multicomponent…
H
N
O
H2N
NC
N
O
O
OEt
Me
CN
CN
H2N
NH2
O
O
PANI/Fe3O4/CNT
H2O, rt
O
+
+
+
Scheme 2 Synthesis of 6′-amino-2-oxospiro[acenaphthylene-1,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile
using PANI/Fe3O4/CNT magnetic nanocatalyst
NH
O
O
2CN
PANI/Fe3O4
/CNT
OH
O
O
O
NH
PANI/Fe3O4/CNT
NH2NH2
N
HN
OEt
OEt
H
N
N
O
OEt
NH
CN
T
N
C
/
O
N
4
O
O
NH2
3
e
F
N
H
/
I
AN
P
H
N
N
H2N
OH
O
N
N
O
N
O
CN
N
H
Et
EtOH
CN
CN
N
T
Fe3O4
PANI
N
/C
O4
e3
/F
I
N
A
H
N
P
O
O
N
H
PANI/Fe3O4/CNT
O
O
H
N
NH
O
H
N
H
O
H2O
HN
O
OH
O
N
N
H
H
N
PANI/Fe3O4/CNT
H
Scheme 3 Plausible mechanism for synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives
1 3

S. F. Hojati et al.
Fig. 5 Reusability of nanomagnetic PANI/Fe3O4/CNT for synthesis of 5a
Conclusions
A novel, green, reusable nanocatalyst was prepared and characterized by FT-IR
spectroscopy, transmission electron microscopy (TEM), and X-ray difraction
(XRD) analysis. Catalytic application of PANI/Fe3O4/CNT was studied in four-
component synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives from
isatin, hydrazine hydrate or phenylhydrazine, ethyl acetoacetate, and malononitrile
or ethyl cyanoacetate in aqueous medium at room temperature. Use of water as safe
and environmentally benign solvent is a considerable beneft of this approach. Short
reaction time, high product yield, easy workup procedure due to the insolubility of
Table 3 Comparison of methods for synthesis of spiro[indoline-3,4′-pyrano [2,3-c]pyrazole]
Entry
Conditions
Time (min)
Yield (%)
5a
PANI/Fe3O4/CNT/H2O/rt (present work)
Nano PFu@Fe3O4/EtOH/refux/rt [9]
Piperidine/EtOH/ultrasound/rt [8]
4-DMAP/EtOH/stirring/60 °C [3]
NaHCO3/grinding/rt [12]
PANI/Fe3O4/CNT/H2O/rt (present work)
Nano PFu@Fe3O4/EtOH/refux/rt [9]
Piperidine/EtOH/ultrasound/rt [8]
PANI/Fe3O4/CNT/H2O/rt (present work)
NaHCO3/grinding/rt
8
10
60
60
7
9
9
60
30
7
95
95
92
80
92
92
92
81
90
86
60
5d
5b
Piperidine/EtOH/ultrasound/rt [8]
89
1 3

Novel organometallic nanomagnetic catalyst for multicomponent…
the products in water, easy catalyst separation from the reaction mixture, and reus-
ability of nanomagnetic PANI/Fe3O4/CNT are other advantages of this protocol that
make it a good choice for industrial applications.
Acknowledgements Authors wish to dedicate the present work to Hakim Sabzevari for his research in
chemistry and constant inspiration of his students.
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