Ultrasound-assisted synthesis of 3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-ones by novel core-shell bio-based nanocatalyst anchoring sulfonated L-histidine on magnetized silica (SO3H-L-Hi

Article abstract of DOI:10.1002/jccs.201900365

An efficient synthesis of 3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-ones is reported via a one-pot three-component reaction of 3-phenacylidenoxindoles, tryptamine, and dimedone under ultrasound irra

Full text of DOI:10.1002/jccs.201900365

Received: 29 September 2019
DOI: 10.1002/jccs.201900365
Revised: 20 January 2020
Accepted: 20 January 2020
A R T I C L E
Ultrasound-assisted synthesis of 3-(1-(2-(1H-indol-3-yl)
ethyl)-2-aryl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-
3-yl)indolin-2-ones by novel core-shell bio-based
nanocatalyst anchoring sulfonated L-histidine on
magnetized silica (SO3H-L-His@SiO2-nano Fe3O4)
Kobra Nikoofar
| Seyedeh S. Peyrovebaghi
Department of Chemistry, Faculty of
Physics and Chemistry, Alzahra
University, Tehran, Iran
Abstract
An efficient synthesis of 3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-
4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-ones is reported via a one-pot
three-component reaction of 3-phenacylidenoxindoles, tryptamine, and
dimedone under ultrasound irradiation using a newly prepared core-shell
nanostructure. The utilized nanocatalyst is obtained by anchoring sulfonated
L-histidine amino acid shell, as the bio part, on silica-nanomagnetite core
(SO3H-L-His@SiO2-nano Fe3O4) and characterized by Fourier transform infra-
red spectroscopy, nuclear magnetic resonance spectroscopy (1H NMR), field
emission scanning electron microscopy, energy-dispersive X-ray spectroscopy,
thermogravimetric/differential thermal analysis, vibrating sample magnetome-
ter measurements, transmission electron microscopy, and back-titration. The
protocol contains several advantages, such as relatively short reaction times,
simple work-up procedure by separation of the catalyst with an external mag-
net, the use of economical and environmentally friendly ultrasonic waves, and
reusability and recoverability of the core-shell nano-promoter for three runs
without significant activity loss.
Correspondence
Kobra Nikoofar, Department of
Chemistry, Faculty of Physics and
Chemistry, Alzahra University, Tehran,
Iran.
Email: k.nikoofar@alzahra.ac.ir,
kobranikoofar@yahoo.com
Funding information
Alzahra University
K E Y W O R D S
3-phenacylidenox, indole, core-shell nanostructure, indole, nanomagnetite, tetrahydro-1H-
indolyl-indolin-2-ones, tryptamine, ultrasound irradiation
1 | INTRODUCTION
(Figure 1b) as a growth hormone secretagogue receptor
agonist[3] are two examples of potent drugs containing
Indoline-2-one (2-oxindole), a bicyclic compound made
up of a fused benzene to 2-pyrrolidone, is a versatile het-
erocycle which is also a building block in various
kinds of organics and pharmaceuticals.[1] Semaxanib
(Figure 1a) as tyrosine kinase inhibitor[2] and SM-130686
the indoline-2-one scaffold.
The indoline-2-one motif is associated in some com-
pounds with various properties such as anti-angiogenic
and antitumor,[4,5] antibacterial and antifungal,[6]
antiplasmodial,[7] and anti-human immunodeficiency
© 2020 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2020;1–11.
http://www.jccs.wiley-vch.de
1

2
NIKOOFAR AND PEYROVEBAGHI
virus.[8] Because of the critical importance of
2-indlolinone motif in organic heterocycles with proven
and/or potent therapeutic properties, methods for their
synthesis have been of great interest since the last
decade.[9–13]
three-component reaction of 3-phenacylideneoxindoles (1),
tryptamine (2), and dimedone (3) in acetonitrile in the
presence of a novel nano core-shell prepared from
functionalized L-histidine and magnetized silica (SO3H-L-
His@SiO2-nano Fe3O4) though ultrasound irradiation of
power 60 W/cm2 (Scheme 1). It is noteworthy that Jiang
and Yan in 2016 obtained some derivatives of this class of
N-containing multi-cycles in the presence of p-TsOH within
6 h in 72–87% yield.[35]
Sonochemistry, which is the study of the effects of
ultrasound on chemical reactions, has been recognized as
an efficient strategy for a vast range of organic transfor-
mations as a green and economical technique. Because of
its specific characteristics, it could assist in high-energy
chemical reactions in shorter periods in comparison to
traditional methods. Actually, when the reaction mixture
is exposed to sonic waves, they generate high microscopic
pressure, due to cavity and hot-spot effects, which
increases the energy in seconds and leads to the accelera-
tion of the reaction.[14–16] Nowadays it is also an opera-
tional technique to obtain nano-sized materials.[17,18]
Magnetic nanoparticles have attracted special attention
in various fields of study such as the environment,[19] bio-
medicine and drug delivery,[20,21] treatment monitoring,[22]
magnetic resonance imaging,[23] and waste removal form
water.[24] Besides, it is very important for chemists as a cata-
lyst in various kinds of transformations, especially mul-
ticomponent reactions (MCRs).[25–29]
2 | RESULTS AND DISCUSSION
In this study, a novel functionalized core-shell multilayered
nanostructure was prepared by anchoring sulfonated histi-
dine on magnetized silica (SO3H-L-His@SiO2-nano Fe3O4).
The four-step schematic procedure is illustrated in
Scheme 2.
The Fourier transform infrared (FT-IR) spectra of
final nanostructures, in addition to those at each step, are
shown in Figure 2. As seen from Figure 2a, the stretching
vibrations of the Fe–O bond at 1646 and 1455 cm−1 and
the bending vibration of this bond at 575 cm−1 are the
fingerprints of commercial Fe3O4. The spectrum of L-
In continuation of our research interest in green
and economical routes for the synthesis of heterocycles by
novel nanostructures,[30–34] here we report the preparation
histidine (Figure 2b) shows
a
broad peak at
2708–3124 cm−1, which is due to the stretching vibration
+
of the NH3 group and bending vibrations of the N–H
of
3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-
bond at 1591 and 804 cm−1. The asymmetric and sym-
metric stretching of the COO− group at 1635 and
1340 cm−1, in addition to the peaks at 1461, 1416, and
1249 cm−1 corresponding to the C═C, C═N, and C─N
bonds, respectively, confirmed the histidine structure.
The SiO2-nano Fe3O4 spectra in Figure 1c contain the
magnetic nanoparticles peaks in addition to the bands
corresponding to the stretching vibration of the OH
group in silanol at 3419 cm−1, the stretching of the Si–O–
H bond at 1121 cm−1, and the stretching of the Si–O–Si
bond at 1214 cm−1. Anchoring of L-histidine to this core
led to the appearance of the amino acid peaks
(Figure 1d). The FT-IR spectra of the SO3H-L-His@SiO2-
nano Fe3O4 (Figure 2e) show peaks at 1260, 1085, and
4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-ones via the
(a)
(b)
Me
HO
F3C
Me
HN
Cl
O
NC
N
O
O
N
H
HCl
N
FIGURE 1 (a) Semaxanib and (b) SM-130686
SCHEME 1 Preparation of
3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-
6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-
1H-indol-3-yl)indolin-2-ones

NIKOOFAR AND PEYROVEBAGHI
3
SCHEME 2 Synthetic procedure of
SO3H-L-His@SiO2-nano Fe3O4
His@SiO2-nano Fe3O4 is 50–70 nm and the average
diameter for the final core-shell nanostructure is between
70 and 90 nm. The increased particle size confirmed the
layer structure of the core due to the functionalization
process.
Figure 4 presents the energy-dispersive X-ray spec-
troscopy (EDAX) patterns of (a) L-His@SiO2-nano Fe3O4
and (b) SO3H-L-His@SiO2-nano Fe3O4. The measure-
ment confirmed the presence of elements such as C
(23.47%), N (9.34%), Si (1.46%), O (41.05%), and Fe
(29.97%) in L-His@SiO2-nano Fe3O4, proving its success-
ful preparation. The presence of sulfur (0.16%) in the
final nano core-shell confirmed its functionalization. No
other impurities related to the solvents and materials
used in the catalyst manufacturing process were
observed.
FIGURE 2 FT-IR spectra of (a) nano Fe3O4, (b) L-Histidine,
(c) SiO2-nano Fe3O4, (d) L-His@SiO2-nano Fe3O4, and (e) SO3H-L-
His@SiO2-nano Fe3O4
In the transmission electron microscopy (TEM)
images of SO3H-L-His@SiO2-nano Fe3O4 (Figure 5), the
dark parts are related to the internal nucleus of the
nanostructures while the lighter parts explain the outer
parts (shell) of the core. The particle size correlates with
that in the FESEM images.
The magnetic properties of the compound were inves-
tigated by vibrating sample magnetometer (VSM) analy-
sis at room temperature (Figure 6). Based on the curves
1–3, the saturation magnetization values of 63, 56, and
42 emu g−1 are due to commercial nano-magnetite, L-
His@SiO2-nano Fe3O4, and functionalized SO3H-L-
His@SiO2-nano Fe3O4, respectively. The decreasing value
from curve 1 to curve 3 can be attributed to the layers on
873 cm−1 corresponding to the asymmetric and symmet-
ric stretching vibrations of S═O and stretching vibrations
of the S–O bond, respectively. It must be mentioned that
the band at 3423 cm−1, due to the hydroxyl moiety of
SO3H, is partially covered by the stretching band of NH.
The field emission scanning electron microscopy
(FESEM) images of L-His@SiO2-nano Fe3O4 (top) and
SO3H-L-His@SiO2-nano Fe3O4 (bottom) are shown in
Figure 3. The average size of the nanoparticles in L-

4
NIKOOFAR AND PEYROVEBAGHI
FIGURE 3 FESEM images of L-
His@SiO2-nano Fe3O4 (top) and SO3H-
L-His@SiO2-nano Fe3O4 (bottom)
the nano Fe3O4 internal core. The significant super-
paramagnetism of the synthesized nanomaterials is suffi-
ciently strong to offer a simple and efficient method to
separate the catalyst from the reaction media by an exter-
nal magnet.
The total acidity of the core-shell nanostructure (SO3H-
L-His@SiO2-nano Fe3O4) was investigated by back-titration.
First, 0.1 g of the nanocatalyst and 25 mL of NaOH (0.1 M)
were mixed together and stirred for 24 h on a magnetite
stirrer. After that, five drops of phenolphthalein, as an acid–
base indicator, was added to the mixture and titrated by an
HCl solution (0.1 N) up to the equivalent point. After calcu-
lation, the the total acidic sites on SO3H-L-His@SiO2-nano
Fe3O4 were 0.045 equiv/g of the catalyst and the pH value
of 1 g was obtained as 0.74.
In the next step, the efficacy of SO3H-L-His@SiO2-
nano Fe3O4 was examined for the synthesis of
3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-
4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-ones. In order to
optimize the reaction condition, the reaction between
3-phenacylideneoxindole 1a, triptamine 2, and dimedone 3,
in 0.5:1:1 molar ratio was considered as a model reaction
(Table 1).
Thermogravimetric/differential
thermogravimetry
(TG/DTG) analyses results of L-His@SiO2-nano Fe3O4 and
the final nanocatalyst SO3H-L-His@SiO2-nano Fe3O4 are
shown in Fig. 7a and b, respectively. As can be seen from
the figure, the endothermic degradation of L-His@SiO2-
nano Fe3O4 (Figure 7a) occurs in two stages. The first one
occurring at 260–290ꢀC (about 10% weight loss) is due to
the degradation of the organic layer, whereas the second
weight loss of about 70% at 630–700 ꢀC is due to the total
decay of the structure. In the case of SO3H-L-His@SiO2-
nano Fe3O4 (Figure 7b), desulfonation occurs at 190–210 ꢀC
(about 5% weight loss) and total degradation occurs at
310–550 ꢀC. These observations are in agreement with the
fact that the systems are binary organic–inorganic frame-
works and that the organic parts are less heat-resistant and
are destroyed earlier.
In order to determine the influence of the sonication
power on the reaction progress, the model reaction was
performed in the presence of 40, 60, and 75 W/cm2 waves

NIKOOFAR AND PEYROVEBAGHI
5
of the apparatus (entries 1–3). The best results were
obtained in 60 W/cm2, and increasing the power up to
75 W/cm2 did not change the situation notably. The
effect of solvents was also examined (entries 4–7). The
results confirmed that CH3CN was the best choice. The
catalyst amount was investigated as another parameter.
Utilization of 0.02 g of SO3H-L-His@SiO2-nano Fe3O4
under the same reaction conditions revealed that 0.028
was better (compare entries 8 and 2). In order to clarify
the critical role of sonic waves in promoting the reac-
tion, the model reaction was carried out in the absence
of ultrasound at room temperature and also in
refluxing CH3CN. The results were not satisfactory.
This established that the presence of ultrasonic waves
was necessary for the reaction to progress (entries
9 and 10). All the reactions were performed in a one-
step, one-pot manner.
After optimizing the reaction condition, the reactions
between different 3-phenacylideneoxindoles 1a–h, trip-
tamine 2, and dimedone 3 were examined in acetonitrile
in the presence of 0.028 g of the nanocatalyst under ultra-
sonic irradiation with power 60 W/cm2 to obtain the
desired products 4a–h. As can be seen (Table 2), the
adducts were obtained within 15–40 min in 71–81% yield.
In order to clarify the effect of ultrasonic waves in pro-
moting the reaction, the preparation of 4a was also car-
ried out in the presence of SO3H-L-His@SiO2-nano Fe3O4
(0.028 g) in CH3CN
a
room temperature. The
corresponding product was obtained in less than 20%
yield within 120 min. This model reaction was carried
out in refluxing acetonitrile, but the time was more than
when using sonic waves (120 min). This proved the key
role of sonication in the synthesis of 6a, which is due to
hot spot theory.
Although the real route for this MCR is not obvious,
a proposed mechanism for the synthesis of 3-(1-(2-(1H-
indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-4,5,6,7-tetra-
hydro-1H-indol-3-yl)indolin-2-ones is illustrated in
80
60
40
20
0
-20
1
-40
2
-60
3
-80
-10000-8000 -6000 -4000 -2000
0
2000 4000 6000 8000 10000
Applied Field (Oe)
FIGURE 4 EDAX spectrum of the (a) L-His@SiO2-nano
Fe3O4 and (b) SO3H-L-His@SiO2-nano Fe3O4
FIGURE 6 VSM curve of (1) commercial nano Fe3O4, (2) L-
His@SiO2-nano Fe3O4, and (3) SO3H-L-His@SiO2-nano Fe3O4
FIGURE 5 TEM images of SO3H-
L-His@SiO2-nano Fe3O4

6
NIKOOFAR AND PEYROVEBAGHI
Scheme 3. First, the attack of tryptamine 2 to the acti-
vated carbonyl group of dimedone 3, followed
by
dehydration,
formed
the
β-enaminone
A intermediate. Then, nucleophilic attack of A on
3-phenacylideneoxindole 1 gave the intermediate B.
Intramolecular cyclization followed by water release
gave the desired products 4.
Recyclability and reusability of catalyst is an impor-
tant feature in any synthetic methodology. In order to
examine this property, preparation of 4a under ultra-
sound irradiation was done in the presence SO3H-L-
His@nano Fe3O4-SiO2 in CH3CN. After completion, the
catalyst was separated with an external magnet, washed
with methanol (3 × 5 mL), and air-dried. The recovered
nanocatalyst was used in two more runs of 4a synthesis
successfully (Table 3).
3 | EXPERIMENTAL
3.1 | Materials and apparatus
All materials and solvents were purchased form Aldrich,
Merck, or Alfa-Aesar and used without further purifica-
tion. Commercial nano-magnetite (average particle size
of 40–60 nm, purity of 98%) was obtained from Nanosav
Co. The FT-IR spectra were recorded from KBr disks by a
Bruker FT-IR infrared spectrometer (Transor 27). Melting
points were determined by an Electrothermal 9200
1
instrument and are uncorrected. H NMR spectra were
FIGURE 7 TGA/DTG curve of (a) L-His@SiO2-nano Fe3O4
and (b) SO3H-L-His@SiO2-nano Fe3O4
recorded with a Bruker drx (300 MHz) machine in
DMSO-d6 solvent. A field-emission scanning electron
microscope (FESEM, VEGA\\TESCAN-LMU) was used
for measuring the size and morphology of the
nanostructures. Mass spectra were obtained by a Gc-Mass
5973 network mass-selective detector on a Gc 6690
Agilent device. EDAX was carried out by a VEGA3 TES-
CAN machine. TEM images were recorded with a Philips
(model MC30) instrument at an accelerating voltage of
300 kV. Magnetization measurements were carried out
on a MKTFD VSM. A centrifuge (UNIVERSAL 320) oper-
ating at 5000–10,000 rpm was used for the preparation of
the nanocatalyst. TGA was recorded by a TGA1
METTLER TOLEDO instrument. Homogenization of the
nanostructure was performed in a Wise clean bath with a
power of 90 W. The ultrasonic device was an HD 3100
ultrasonic homogenizer (Bandelin Co., Germany). A
standard horn SH 70 G emitting 20 kHz 500 Hz ultra-
sound at intensity levels tunable up to a maximum sonic
power density of 100 W/cm was used. Sonication was car-
ried out at 100% (maximum amplitude 245 μm). An
MS73 probe of 3 mm diameter was immersed directly
into the reaction mixture.
3.2 | Catalyst preparation
3.2.1 | Preparation of L-His@ SiO2-nano
Fe3O4
A mixture of nano Fe3O4 (1 g), distilled water (20 mL),
absolute ethanol (60 mL), and ammonia (25%, 2 ml) was
stirred at room temperature for 10 min and placed in the
ultrasound bath for 30 min. Then a mixture of tetraethyl
orthosilicate (0.5 mL) in absolute ethanol (1 mL) was added
to it dropwise and stirred for 20 h at room temperature.
Subsequently, an external magnet was used to collect the
solid form the mixture, which was washed further with
absolute ethanol (3 × 5 ml). The obtained solid was dried in
oven at 70 ꢀC for 5 h. After that, a suspension of L-histidine
(0.5 g) in diethyl ether (10 mL) was added to the dried solid
and stirred for 2 h. Then chloroform (10 mL) was added to
the mixture and filtered. The filtrate was washed with chlo-
roform (2 × 10 mL). The obtained solid was air-dried for
1 h and dried at 50 ꢀC for 2 h. The black powder obtained
was L-His@SiO2-nano Fe3O4 (Scheme 2).

NIKOOFAR AND PEYROVEBAGHI
7
TABLE 1 Optimization the reaction conditions in the ultrasound-assisted synthesis of 3-(1-(2-(1H-indol-3-yl)ethyl)-6,6-dimethyl-4-oxo-
2-phenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-one 4aa
Conditions
Entry
Solvent (5 mL)/SO3H-L-His@SiO2-nano Fe3O4 (g)
Ultrasound power (W/cm2)
Time (min)
Yieldb (%)
1
CH3CN/0.028
CH3CN/0.028
CH3CN/0.028
EtOAc/0.028
EtOH/0.028
H2O/0.028
40
60
75
60
60
60
60
60
—
—
45
30
70
77
75
70
70
20
33
55
—
72
2
3
30
4
60
5
60
6
60
7
DMSO/0.028
CH3CN/0.02
CH3CN/0.028
CH3CN/0.028
60
8
30
9c
10d
120
140
aPhenacylideneoxindole (0.5 mmol), triptamine (1 mmol),dimedone (1 mmol).
bIsolated yield.
cIn the absence of sonic waves at room temperature.
dIn the absence of sonic waves under reflux conditions.
3.2.2 | Preparation of SO3H-L-his@SiO2-
nano Fe3O4
of isatins (20 mmol) and acetophenone derivatives
(20 mmol) in the presence of dimethylamine (20 mmol)
was stirred for 5 min. Then acetic acid (20 mL) and HCl
(37%, 20 mL) were added and refluxed at 78 ꢀC for
30 min. The progress of the reaction was monitored by
TLC (eluent, n-hexane/EtOAc, 1:1). The reaction mixture
was extracted with equal amounts of water and EtOAc.
Evaporating the solvent and crystallization from absolute
ethanol gave the corresponding 3-phenacylidene-
oxindoles 1a–h as colored powders (orange, red, brown)
in 71–97% yield.
A mixture of the obtained L-His@SiO2-nano Fe3O4
from the previous section (1 g) in n-hexane (10 ml) was
sonicated in a bath for 30 min. Then the suspension
was poured into a two-necked flask in an ice-bath, and
a mixture of chlorosulfonic acid (0.5 g) in n-hexane
(10 mL) in a drop-funnel was added dropwise to the
flask while mixing. The stirring was continued for
30 min in order to remove the HCl gas form the flask.
Subsequently, methanol (10 mL) added to the mixture
and stirred at room temperature for 45 min. Filtrating
the mixture followed by washing the solid with n-
hexane (10 mL) and distilled water (20 mL) gave a
black solid, which was dried at 60 ꢀC in an oven for
3.4 | General procedure for the synthesis
of 3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-
6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-
indol-3-yl)indolin-2-ones 4a–h
4
h, resulting in SO3H-L-His@SiO2-nano Fe3O4
(Scheme 2).
A mixture 3-phenacylideneoxindoles 1a–h (0.5 mmol),
tryptamine 2 (1 mmol), and dimedone 3 (1 mmol) in the
presence of SO3H-L-His@SiO2-nano Fe3O4 (0.028 g) in
CH3CN (20 mL) was irradiated with ultrasonic waves
(60 W/cm2( for an appropriate time as monitored by TLC
(eluent, n-hexane/EtOAc, 1:1). After completion of the
reaction, the reaction mixture was dissolved in methanol
3.3 | General procedure for the synthesis
of 3-phenacylideneoxindoles 1a–h
The substrates, 3-phenacylideneoxindoles, were synthe-
sized according to the previously procedure.[36] A mixture

8
NIKOOFAR AND PEYROVEBAGHI
TABLE 2 Ultrasound-assisted synthesis of 3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)
indolin-2-ones 4a–h by SO3H-L-His@SiO2-nano Fe3O4 in CH3CN at room temperaturea
4a
4c
4b
25 min, 77%b
101–104ꢀC
15 min, 80%
67–70ꢀC
25 min, 81%
66–68ꢀC
4d
4e
4f
20 min, 76%
73–76ꢀC
40 min, 71%
80–83ꢀC
20 min, 73%
85–87ꢀC
4g
4h
35 min, 74%
67–70ꢀC
20 min, 71%
68–71ꢀC
a3-Phenacylideneoxindoles 1a–h (0.5 mmol), triptamine 2 (1 mmol), dimedone 3 (1 mmol), and SO3H-L-His@SiO2-nano Fe3O4 (0.028 g).
bIsolated yields.
(20 mL) and the catalyst separated by an external magnet
(0.7 T). The pure products 4a–h were obtained from the
crude mixture through plate chromatography in 71–81%
yield (Table 2).
1271, 1151, 1367, 812, 742, 610. 1H NMR (300 MHz, DMSO-
d6): δ (ppm) 0.95 (s, 6H, 2Me), 1.96–2.17 (m, 4H, 2CH2),
2.91 (m, 2H, CH2), 3.09–3.26 (m, 2H, CH2), 4.88 (s, 1H,
CH), 6.82–7.17 (m, 7H, Ar), 7.32–7.34 (m, 3H, Ar),
7.48–7.50 (m, 4H, Ar), 10.26 (s, 1H, NH), 10.87 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): δ (ppm) 23.68, 28.21, 32.20,
42.11, 43.01, 50.33, 93.25, 111.43, 118.28, 120.91, 122.81,
127.13, 136.20, 162.72, 193.85. MS (ESI) m/z 513 [M+],
485 [M+] – 2CH3, 461 [M+]─C(CH3)2, ─CO, 429 [M+]─C
(CH3)4, ─CO, 403 [M+]─C(CH3)4, ─CO, ─CH2CH2,
280 [M+]─CH2CH2, ─2Me, ─indolyl, 254 [M+]─CH2,
─CMe2, ─indolyl, 212 [M+]─CH2CMe2CH2, ─indolyl,
─CO, 130 (oxindolyl), 67 (pyrolyl).
3.4.1 | 3-(1-(2-(1H-indol-3-yl)ethyl)-
6,6-dimethyl-4-oxo-2-phenyl-
4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-
2-one (4a)
Dark yellow powder; m.p.: 101–104ꢀC. FT-IR (KBr) ν
(cm−1): 3248, 3057, 2955, 2927, 2869, 1706, 1538, 1461,

NIKOOFAR AND PEYROVEBAGHI
9
3.4.2 | 3-(1-(2-(1H-indol-3-yl)ethyl)-
2-(3,4-dimethoxyphenyl)-6,6-dimethyl-
4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)
indolin-2-one (4b)
NH), 10.93 (s, 1H, NH). 13C NMR (300 MHz, DMSO-d6): δ
(ppm) 23.71, 28.02, 32.23, 42.15, 43.06, 50.33, 93.25, 111.47,
118.14, 118.32, 120.95, 122.90, 127.15, 136.25, 162.81, 193.96.
Lemon powder; mp: 66–68ꢀC. FT-IR (KBr) ν (cm−1):
3.4.5 | 3-(1-(2-(1H-indol-3-yl)ethyl)-
2-(2-hydroxyphenyl)-6,6-dimethyl-4-oxo-
4,5,6,7-tetrahydro-1H-indol-3-yl)-
5-chloroindolin-2-one (4e)
3,385, 3,256, 3,058, 2,954, 2,926, 1,513, 1,460, 1,382, 1,269,
1
1,150, 1,100, 811, 742. H NMR (300 MHz, DMSO-d6): δ
(ppm) 0.96 (s, 6H, 2Me), 1.96 (s, 3H, OMe), 2.17 (s, 3H,
OMe), 2.49 (s, 1H, CH2), 2.52 (s, 1H, CH2), 2.89–2.95 (m,
1H, CH2), 3.26–3.35 (m, 3H, CH2), 4.89 (s, 1H, CH),
6.44–6.99 (m, 2H, Ar), 7.03–7.06 (m, 4H, Ar), 7.08 (s, 1H,
Ar), 7.18 (s, 1H, Ar), 7.32–7.35 (m, 2H, Ar), 7.48–7.51 (m,
2H, Ar), 10.52 (s, 1H, NH), 10.87 (s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6): δ (ppm) 23.65, 27.98, 32.19, 42.10,
42.97, 50.32, 93.22, 111.39, 111.44, 118.07, 118.27, 120.91,
122.85, 127.11, 136.19, 162.57, 193.75. MS (ESI) m/z
573 [M+], 503 [M+ – 2CH2 – CMe2], 429 [M+ – 2CH2 –
CMe2 – MeO – CO – NH], 405 [M+ – C6H4(OMe)2
– 2Me], 323 [M+ – C6H4(OMe)2 – indolyl], 298 [M+–
indolyl – oxindolyl – 2CH2], 282 [M+ – C6H4(OMe)2 –
indolyl –2CH2], 267 [M+– C6H4(OMe)2 – indolyl – 2CH2
–Me], 223 [M+ – C6H4(OMe)2 – indolyl – 2CH2 – 2Me –
CO], 138 (C6H4(OMe3)2), 130 (oxindolyl), 117 (indolyl).
Light brownish orange powder; m.p.: 80–83 ꢀC. IR (KBr) ν
(cm−1): 3649, 3419, 2925, 2854, 1715, 1634, 1592, 1456,
1523, 1199, 1155, 1283, 596, 744. 1H NMR (300 MHz,
DMSO-d6): δ (ppm) 0.95 (s, 6H, 2CH3), 1.84 (m, 2H, CH2),
1.95 (m, 2H, CH2), 2.17 (m, 2H, CH2), 2.91–2.93 (m, 2H,
CH2), 4.87 (s, 1H, CH), 6.77–6.79 (m, 1H, Ar), 6.82–6.88 (m,
1H, Ar), 6.91–6.99 (m, 2H, Ar), 7.02–7.05 (m, 3H, Ar),
7.17–7.32 (m, 3H, Ar), 7.48–7.50 (m, 2H, Ar), 7.65 (brs, 1H,
OH), 10.48 (brs, 1H, NH), 10.91 (brs, 1H, NH). MS (ESI) m/
z 503 [M+ – 2CH2 – Cl], 451 [M+ – Cl – C6H5], 435 [M+
– C6H4OH – Cl], 420 [M+ – C6H4OH – Cl – Me], 365 [M+ –
C6H4OH – Cl – Me – CH2CMe2CH2], 365 [M+ C6–H4OH –
Cl – Me – CH2CMe2CH2 – CO], 168 (5-cloxindolyl),
130 (oxindolyl), 117 (indolyl).
3.4.3 | 3-(1-(2-(1H-indol-3-yl)ethyl)-
2-(4-hydroxyphenyl)-6,6-dimethyl-4-oxo-
4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-
2-one (4c)
3.4.6 | 3-(1-(2-(1H-indol-3-yl)ethyl)-
2-(2-bromophenyl)-6,6-dimethyl-4-oxo-
4,5,6,7-tetrahydro-1H-indol-3-yl)-
5-chloroindolin-2-one (4f)
Brownish red powder; m.p.: 67–70 ꢀC. FT-IR (KBr) ν
(cm−1): 3675, 3394, 3061, 2924, 2855, 1680, 1605, 1510,
1461, 1377, 1228, 1184, 742. 1H NMR (300 MHz, DMSO-d6):
δ (ppm) 0.92 (s, 6H, 2Me), 2.49–2.52 (m, 2H, CH2),
2.97–3.02 (m, 2H, CH2), 3.03–3.07 (m, 2H, CH2), 3.34–3.49
(m, 2H, CH2), 3.50 (s, 1H, CH), 6.82–7.11 (m, 6H, Ar, OH),
7.23–7.31 (m, 1H, Ar), 7.50–7.52 (m, 2H, Ar), 7.52–7.85 (m,
1H, Ar), 7.83–8.13 (m, 2H, Ar), 8.50–8.53 (m, 1H, Ar), 10.84
(s, 1H, NH), 12.14 (s, 1H, NH).
Dark brownish orange powder; m.p.: 85–87ꢀC. IR (KBr) ν
(cm−1): 3422, 2925, 2855, 1647, 1560, 1457, 1384, 1269,
1
1115, 695, 743. H NMR (300 MHz, DMSO-d6): δ (ppm)
0.95 (s, 6H, 2CH3), 1.21 (m, 1H, CH), 1.79–1.95 (m, 2H,
CH2), 2.17 (m, 2H, CH2), 2.48–2.52 (m, 1H, CH), 2.91–2.93
(m, 2H, CH2), 4.87 (s, 1H, CH), 6.94–6.99 (m, 2H, Ar),
7.02–7.07 (m, 3H, Ar), 7.13–7.17 (m, 3H, Ar), 7.33 (d,
J = 7.82 Hz, 2H, Ar), 7.49 (d, J = 7.48 Hz, 2H, Ar), 10.25
(s, 1H, NH), 10.91 (s, 1H, NH). MS (ESI) m/z 553 [M+
–
C(Me)4], 491 [M+ – C(Me)4 – CO – Cl], 413 [M+ – C(Me)4 –
CO – Cl – Br], 387 [M+ – C(Me)2CH2CH2 – CO – (CH2)2
– indolyl], 323 [M+ – C(Me)2 – (CH2)2 – indolyl –Br –Cl],
182 (3-Me-5-cloxindolyl), 130 (oxindolyl).
3.4.4 | 3-(1-(2-(1H-indol-3-yl)ethyl)-
6,6-dimethyl-2-(4-nitrophenyl)-4-oxo-
4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-
2-one (4d)
3.4.7 | 3-(1-(2-(1H-indol-3-yl)ethyl)-
2-(4-methoxyphenyl)-6,6-dimethyl-4-oxo-
4,5,6,7-Tetrahydro-1H-indol-3-yl)-
5-chloroindolin-2-one (4g)
Brownish orange powder; m.p.: 73–76ꢀC. IR (KBr) ν (cm−1):
3383, 3249, 3057, 2954, 2926, 2867, 1531, 1457, 1383, 1270,
1
1366, 1189, 1151, 741. H NMR (300 MHz, DMSO-d6): δ
(ppm) 0.96 (s, 6H, 2CH3), 1.99–2.19 (m, 4H, 2CH2), 2.94–3.11
(m, 2H, CH2), 2.95–3.28 (m, 2H, CH2), 4.94 (s, 1H, CH),
6.98–7.18 (m, 8H, Ar), 7.35–7.50 (m, 5H, Ar), 10.28 (s, 1H,
Yellow crystal; m.p.: 67–70ꢀC. IR (KBr) ν (cm−1); 3384,
3249, 3057, 2954, 2925, 2867, 1536, 1458, 1366, 1150, 1270,

10
NIKOOFAR AND PEYROVEBAGHI
SCHEME 3 Proposed mechanism
for the sonosynthesis of 4
1
1270, 1150, 1100, 741, 611. H NMR (300 MHz, DMSO-
TABLE 3 Recyclability of SO3H-L-His@nano Fe3O4-SiO2 in
sono-synthesis of 4a
d6): δ (ppm) 0.96 (m, 6H, 2CH3), 1.97 (m, 2H, CH2), 2.17
(m, 2H, CH2), 2.48–2.52 (m, 2H, CH2), 2.90–2.94 (m, 2H,
CH2), 3.24–3.28 (m, 2H, CH2), 4.90 (s, 1H, CH), 6.95–6.99
(m, 2H, Ar), 7.03–7.10 (m, 6H, Ar), 7.18 (m, 2H, Ar), 7.34
(d, J = 7.95 Hz, 2H, Ar), 7.50 (d, J = 7.70 Hz, 2H, Ar),
10.89 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): δ
(ppm) 23.66, 28, 32.21, 42.10, 42.99, 50.23, 93.23, 111.42,
111.45, 118.09, 118.27, 120.92, 122.87, 127.12, 136.20,
162.62, 193.79. MS (ESI) m/z 504 [M+ – CO –
No. of cycle
Time (min)
Yield (%)
1
2
3
25
25
25
77
75
73
1
741, 873. H NMR (300 MHz, DMSO-d6): δ (ppm) 0.96 (m,
6H, 2CH3), 1.98 (m, 2H, CH2), 2.18 (m, 2H, CH2), 2.93 (m,
2H, CH2), 3.27 (m, 5H, CH2, OMe), 4.91 (s, 1H, CH), 6.98
(d, J = 6.35 Hz, 2H, Ar), 7.06–7.09 (m, 5H, Ar), 7.18 (m, 1H,
Ar), 10.35 (s, 1H, NH), 10.90 (s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6): δ(ppm) 23.67, 27.48, 32.19, 42.11,
42.98, 50.33, 93.23, 111.44, 118.07, 118.27, 120.41, 122.86,
127.12, 136.21, 162.65, 193.80. MS (ESI) m/z 505 [M+ – CO
– C(Me)2CH2CH2], 432 [M+ – indolyl – CH2CH2], 402 [M+
– indolyl – CH2CH2 – 2Me], 384 [M+– indolyl –CH2CH2 –
3Me – Cl], 327 [M+– indolyl – CH2CH2 – Cl –
C(Me)2CH2CH2], 282 [M+ – 5-cloxindolyl – indolyl – Me],
267 [M+ – 5-cloxindolyl – indolyl – Me – CH2CH2],
182 (3-Me-5-cloxindolyl), 130 (oxindolyl).
C(Me)2CH2CH2], 479 [M+ – benzyl – 2Me], 401 [M+
benzyl – CH2CH2 – CMe2], 282 [M+ –CMe2CH2CH2
–
– indolyl – phenyl – CO – CH2CH2], 267 [M+
–
benzyloxindolyl – indolyl], 252 [M+ – benzyloxindolyl –
indolyl – Me], 225 (N-benzyloxindolyl), 130 (oxindolyl).
4 | CONCLUSIONS
In summary, a novel and simple procedure for the
sonosynthesis of 3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,-
6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-
ones through a three-component reaction of tryptamine,
dimedone, and 3-phenacylideneoxindoles by a novel core-
shell nanocatalyst anchoring sulfonated L-histidine on mag-
netized silica (SO3H-L-His@SiO2-nano Fe3O4) is reported
for the first time. This procedure has several advantages,
such as utilizing a bio-based nanocatalyt in the synthesis of
some valuable heterocycles, performing the reaction in the
presence of ultrasound irradiation as a powerful and green
technique, separating the SO3H-L-His@SiO2-nano Fe3O4
with an external magnet, recoverability of the catalyst as a
3.4.8 | 3-(1-(2-(1H-indol-3-yl)ethyl)-
6,6-dimethyl-4-oxo-2-phenyl-
4,5,6,7-tetrahydro-1H-indol-3-yl)-
1-benzylindolin-2-one (4h)
Mustardy powder; m.p.: 68–71 ꢀC. IR (KBr) ν (cm−1);
3384, 3250, 3057, 2954, 2925, 2859, 1537, 1459, 1381,

NIKOOFAR AND PEYROVEBAGHI
11
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green aspect of the method, to obtain the desired products
as novel substances.
[21] O. A. Inozemtseva, S. V. German, N. A. Navolokin,
A. B. Bucharskaya, G. N. Maslyakova, D. A. Gorin,
Nanotechnol. Biosensors Adv. Nanomater. 2018, 2018, 175.
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O. A. Inozemtseva, A. A. Anis'kov, E. K. Volkova,
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G. S. Terentyuk, E. L. Vodovozova, D. A. Gorin, Colloids Surf.
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ACKNOWLEDGMENTS
This work was supported by Alzahra University.
ORCID
Kobra Nikoofar https://orcid.org/0000-0002-3950-8229
[24] M. F. Zawrah, E. S. E. El Shereefy, A. Y. Khudir, Silicon 2019,
11, 85.
[25] M. B. Gawande, P. S. Branco, R. S. Varma, Chem. Soc. Rev.
2013, 42, 3371.
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How to cite this article: Nikoofar K,
Peyrovebaghi SS. Ultrasound-assisted synthesis of 3-
(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-
4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-ones by
novel core-shell bio-based nanocatalyst anchoring
sulfonated L-histidine on magnetized silica (SO3H-L-
His@SiO2-nano Fe3O4). J Chin Chem Soc. 2020;1–11.
https://doi.org/10.1002/jccs.201900365
[19] C. Su, J. Hazard. Mater. 2017, 322, 48.