Synthesis of spiro[pyrazoloquinoline-oxindoles] and spiro[chromenopyrazolo-oxindoles] promoted by guanidine-functionalized magnetic Fe3O4 nanoparticles

Article abstract of DOI:10.1007/s13738-018-1361-8

Magnetic nanoparticles (MNPs) Fe₃O₄-immobilized guanidine (Fe₃O₄ MNPs-guanidine) have been used as an efficient catalyst for the preparation of spiro[pyrazoloquinoline-oxindoles] and spiro[chromenopyrazolo-oxindoles] by four-component reactions of phenylhydrazine or hydrazine hydrate, isatins, ketoesters and naphthylamine or 2-naphthol under reflux condition in ethanol. This method provides several advantages including mild reaction conditions, the applicability to a wide range of substrates, the reusability of the catalyst and low catalyst loading.

Full text of DOI:10.1007/s13738-018-1361-8

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1361-8
ORIGINAL PAPER
Synthesis of spiro[pyrazoloquinoline‑oxindoles]
and spiro[chromenopyrazolo‑oxindoles] promoted
by guanidine‑functionalized magnetic Fe3O4 nanoparticles
Fatemeh Alemi Tameh1 · Javad Safaei‑Ghomi1
Received: 26 May 2017 / Accepted: 9 April 2018
© Iranian Chemical Society 2018
Abstract
Magnetic nanoparticles (MNPs) Fe3O4-immobilized guanidine (Fe3O4 MNPs-guanidine) have been used as an efcient cata-
lyst for the preparation of spiro[pyrazoloquinoline-oxindoles] and spiro[chromenopyrazolo-oxindoles] by four-component
reactions of phenylhydrazine or hydrazine hydrate, isatins, ketoesters and naphthylamine or 2-naphthol under refux condition
in ethanol. This method provides several advantages including mild reaction conditions, the applicability to a wide range of
substrates, the reusability of the catalyst and low catalyst loading.
Keywords Fe3O4 nanoparticles · Heterogeneous catalyst · Spirooxindoles · One pot reaction
Introduction
and organocatalysts [16, 17]. The expansion of surface mod-
ifcation of magnetic nanoparticles as signifcant candidates
in the search for supporting catalysts is presently a subject
of increasing interest [18, 19].
Spirooxindoles have emerged as a group of important hete-
rocycles due to their presence in a broad spectrum of natural
and synthetic organic compounds [1–3], with diverse bio-
logical properties such as antimicrobial [4–6], antitumor [7,
8], antidiabetic [9] and can also serve as synthetic intermedi-
ates for diverse kinds of pharmaceuticals or drug precursors
[10]. These activities make spirooxindoles attractive targets
in organic synthesis. Recently, multicomponent reactions
performed with a heterogeneous catalyst under moderate
conditions have attracted much attention [11–13]. Magnetic
materials have emerged as a particularly useful group of
heterogeneous catalysts due to their diverse applications in
synthesis and catalysis [14, 15]. The surface of MNPs can
be functionalized simply through suitable surface modif-
cations to provide the attachment of a variety of favorable
functionalities. Recently, MNPs have been successfully used
to immobilize enzymes, polymers, transition metal catalysts
Herein, we report the use of magnetic nanoparticles
Fe3O4-immobilized guanidine as an efcient catalyst for
the preparation of spirooxindoles (Scheme 1). The synthe-
sis of spirooxindoles has been reported in the presence of
diverse catalysts such as p-TSA [20, 21], piperidine [22],
alum (KAl(SO4)2·12H2O) [23], amino-functionalized SBA-
15 (SBA-Pr-NH2) [24], nanocrystalline MgO [25] and l-Pro-
line [26]. However, some of the reported methods tolerate
disadvantages including long reaction times and harsh reac-
tion conditions. Therefore, to avoid these limitations, the
exploration of an efcient, easily available catalyst with high
catalytic activity and short reaction time for the preparation
of spirooxindoles is still favored.
Experimental
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-018-1361-8) contains
supplementary material, which is available to authorized users.
Chemicals and apparatus
Reagent grade chemicals were purchased from Sigma-
Aldrich or Merck and were used without further purifcation.
All melting points are uncorrected and were determined in a
capillary tube on Boetius melting point microscope. NMR
spectra were obtained on a Bruker 400 MHz spectrometer
* Javad Safaei-Ghomi
safaei@kashanu.ac.ir
1
Department of Chemistry, Science and Research Branch,
Islamic Azad University, Tehran, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
R'
N
N
R
OH
"R
O
O
R
Fe3O4 MNPs-guanidine
EtOH
+
NH2
NH-R'
O
+
O
O
4a
N
+
O
N
H
H
or
"R
OEt
5a-d
NH2
R' H, Ar
or
R
R'
N
3a or 3b
N
"R
2a or 2b
1 a-h
NH
4b
HN
O
6 a-d
Scheme 1 Synthesis of spirooxindoles using MNPs-guanidine
(1H NMR at 400 Hz, 13C NMR at 100 Hz) in DMSO-d6
using TMS as an internal standard. Chemical shifts (δ) are
given in ppm, and coupling constants (J) are given in Hz.
FT-IR spectra were obtained by WQF-510, spectrometer 550
Nicolet in KBr in the range of 400–4000 cm−1. The energy-
dispersive X-ray spectroscopy (EDS) measurement was car-
ried out with the SAMX analyzer. X-ray photoelectron spec-
troscopy (XPS) spectra were measured on an ESCA-3000
electron spectrometer. DLS was performed using a Malvern
apparatus. Magnetic properties were measured by a vibrat-
ing sample magnetometer (Meghnatis Daghigh Kavir Co.;
Kashan Kavir; Iran) at room temperature in an applied mag-
netic feld sweeping between 10,000 Oe). Powder XRD
was performed on a Philips difractometers X’pert with
monochromatized Cu Kα radiation (λ = 1.54056 Å). The
SEM images were prepared by MIRA3-TESCAN. A TGAQ5
thermogravimetric analyzer was used to study the thermal
characteristics of the nanoparticles under heating at a rate
of 10 °C min−1 and an inert N2 atmosphere at 20 mL min−1.
Spectral data of new products
5′‑Chloro‑10‑methyl‑8H‑spiro[benzo‑[5, 6]‑chromeno‑[2,
3‑c]‑pyrazole‑11, 3′‑indolin]‑2′‑one (5a)
Yellow solid; yield: 87%; M. p. 196–198 °C,—IR (KBr):
ν = 3321, 3201, 3071, 1689, 1618, 1433 cm−1. H NMR
1
(400 MHz, DMSO-d6): δ (ppm) = 1.86 (s, 3H, CH3),
6.90–6.95 (m, 2H, ArH), 7.10–7.15 (m, 6 H, ArH), 7.70
(s, 1H, ArH), 10.24 (s, 1H, NH–CO), 11.25 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6): δ (ppm) = 10.13 (CH3),
48.80 (C), 108.70 (C), 111.09 (C), 117.51 (CH), 120.28
(2CH), 123.20 (CH) 124.51 (C), 125.90 (2CH), 125.99
(2C), 128.35 (C), 130.74 (CH), 133.93 (C–Cl), 133.98
(C), 136.70 (CH), 137.92 (C), 142.56 (CH–C–Cl), 156.70
(CH–C–O), 163.74 (C=O). Analysis for C22H14ClN3O2:
calcd. C 68.13, H 3.64, N 10.83; Found C 68.08; H 3.57,
N, 10.73.
General procedure for the preparation
of spirooxindoles
10‑Methyl‑8H‑spiro[benzo‑[5, 6]‑chromeno‑[2,
3‑c]‑pyrazole‑11, 3′‑indolin]‑2′‑one (5b)
A mixture of isatin derivatives (1 mmol), phenylhydrazine
or hydrazine hydrate (1 mmol), alkyl acetoacetate (1 mmol)
and naphthalene amine or 2-naphthol (1 mmol) and MNPs-
guanidine (20 mg) were heated in EtOH (10 mL) under
refux conditions. The completion of the mixture was moni-
tored by TLC, and the catalyst was separated from reaction
before work up by an external magnet feld. Then, the mix-
ture was poured into cold water, and the precipitate obtained
was fltered and recrystallized twice by (EtOAc/n-hexane
Yellow solid; yield: 85%; M. p. 185–187 °C,—IR (KBr):
1
ν = 3332, 3202, 3071, 1680, 1616, 1435 cm−1. H NMR
(400 MHz, DMSO-d6): δ (ppm) = 1.92 (s, 3H, CH3),
6.45 (m, 2H, ArH), 6.75 (m, 2H, ArH), 6.86 (m, 2H,
ArH), 6.96–7.21 (m, 4H, ArH), 10.18 (s, 1H, NH-CO),
11.20 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ
(ppm) = 10.10 (CH3), 49.07 (C), 106.72 (C), 111.07 (C),
112.09 (CH), 117.34 (2CH), 120.13 (CH), 123.20 (2CH),
124.37 (CH), 125.99 (CH), 126.90 (CH), 128.63 (C),
128.82 (CH), 130.66 (C), 133.92 (C), 135.90 (C), 137.00
1
3:1). Afterward, the products were characterized by H
NMR, FT-IR and 13C NMR spectroscopy.
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Journal of the Iranian Chemical Society
(C), 141.33 (C), 156.60 (CH–C–O), 165.07 (C=O). Anal-
ysis for C22H15N3O2: calcd. C 74.78, H 4.28, N 11.89;
Found C 74.69, H 4.21, N 11.76.
(CH–C–O), 163.95 (C=O). Analysis for C22H14N4O4: calcd.
C 66.33, H 3.54, N 14.06; Found C 66.25, H 3.44, N 14.12.
5′‑Methyl‑10‑methyl‑8H‑spiro[benzo‑[5, 6]‑chromeno‑[2,
3‑c]‑pyrazole‑11, 3′‑indolin]‑2′‑one (5c)
Results and discussion
Initially, we explored and optimized different reaction
parameters for the synthesis of spirooxindoles by the con-
densation reaction of hydrazine hydrate, 5-chloro-isatin,
ethyl acetoacetate and 2-naphthol as a model reaction. The
model reaction was carried out in the presence of various
catalysts including CAN NPs, NaHSO4 NPs, Et3N, Fe3O4
NPs and MNPs-guanidine. Several reactions were scruti-
nized using various solvents such as EtOH, CH3CN, water
or DMF. The best results were obtained in ethanol, and we
found that the reaction gave satisfying results in the presence
of MNPs-guanidine which gave excellent yields of prod-
ucts (Table 1). The catalyst showed best activity in ethanol
compared to other organic solvents such as DMF, CH3CN
and H2O.
Yellow solid; yield: 82%; M. p. 171–173 °C,—IR (KBr):
1
ν = 3330, 3209, 3075, 1682, 1613, 1433 cm−1. H NMR
(400 MHz, DMSO-d6): δ (ppm)=1.90 (s, 3H, CH3), 2.30 (s,
3H, CH3), 6.50–6.80 (m, 4H, ArH), 6.82–6.87 (m, 2H, ArH),
7.16–7.35 (m, 3H, ArH), 10.18 (s, 1H, NH–CO), 11.20 (s,
1H, NH). 13C NMR (100 MHz, DMSO-d6): δ (ppm)=10.19
(CH3), 23.45 (CH3), 49.10 (C), 107.75 (C), 112.04 (C),
112.18 (CH), 117.44 (2CH), 120.22 (CH), 123.25 (2 CH),
124.41 (C), 125.90 (C), 126.84 (CH), 128.74 (CH), 128.84
(C), 130.72 (CH), 133.94 (C), 135.96 (C), 137.21 (C),
141.43 (C), 156.64 (CH–C–O), 165.12 (C=O). Analysis
for C23H17N3O2: calcd. C 75.19, H 4.66, N 11.44; Found C
75.25, H 4.59, N 11.40.
To investigate the scope and limitation of this catalytic
process, phenylhydrazine or hydrazine hydrate, isatins,
ketoesters and naphthylamine or 2-naphthol were chosen as
substrates. The above results obviously show the present cat-
alytic procedure is extendable to a wide variety of substrates
to construct a diversity-oriented library of spirooxindoles.
Investigations of the reaction scope revealed that various
isatins (bearing electron-withdrawing and electron-donating
groups) can be utilized in this protocol (Table 2).
5′‑Nitro‑10‑methyl‑8H‑spiro[benzo‑[5, 6]‑chromeno‑[2,
3‑c]‑pyrazole‑11, 3′‑indolin]‑2′‑one (5d)
Yellow solid; yield: 87%; M. p. 190–192 °C,—IR (KBr):
1
ν = 3335, 3223, 3087, 1692, 1627, 1437, cm−1. H NMR
(400 MHz, DMSO-d6): δ (ppm) = 1.88 (s, 3H, CH3),
6.92–6.98 (m, 2H, ArH), 7.14–7.18 (m, 6H, ArH), 7.92
(s, 1H, ArH), 10.24 (s, 1H, NH–CO), 11.25 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6): δ (ppm)= 10.18 (CH3),
48.78 (C), 107.78 (C), 111.29 (C), 117.63 (2CH), 120.38
(CH), 124.22 (2CH), 124.55 (CH), 125.93 (C), 126.80
(CH), 128.10 (CH), 128.25 (CH), 130.87 (C), 133.76 (C),
134.57 (C), 137.88 (C), 139.62 (C), 143.42 (C–NO2), 156.62
The reusability is one of the signifcant properties of this
catalyst. The reusability of MNPs-guanidine was studied
for the reaction of hydrazine hydrate, 5-chloro-isatin, ethyl
acetoacetate and 2-naphthol, and it was found that product
yields decreased to a small extent on each reuse (run 1, 87%;
Table 1 Optimization of
reaction conditions using
diferent catalysts
Entry
Solvent (refux)
Catalyst
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
DMF
CH3CN
EtOH
EtOH
EtOH
–
200
120
120
120
120
120
25
25
25
25
25
Trace
17
32
38
22
51
58
62
80
CAN (5 mol%)
NaHSO4 (10 mol)
Et3N (10 mol%)
Fe3O4 NP (50 mg)
TsOH (20 mol%)
MNPs-guanidine (20 mg)
MNPs-guanidine (20 mg)
MNPs-guanidine (20 mg)
MNPs-guanidine (10 mg)
MNPs-guanidine (20 mg)
MNPs-guanidine (30 mg)
9
10
11
12
84
87
87
25
Hydrazine hydrate (1 mmol), 5-chloro-isatin (1 mmol), ethyl acetoacetate (1 mmol) and 2-naphthol
(1 mmol)
aIsolated yield
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Journal of the Iranian Chemical Society
Table 2 Synthesis of
spirooxindoles by MNPs-
guanidine
Entry Isatins R R′ Rʺ 4a or 4b Product Time (min) Yield (%)a M.p. (°C) found M.p. (°C)
literature
[Refs.]
1
2
3
4
5
6
7
8
Cl
H
Me
NO2
H
Cl
H
Cl
H
H
H
H
Me
Me
Me
Me
4a
4a
4a
4a
4b
4b
5a
5b
5c
5d
6a
6b
6c
6d
25
25
30
23
35
30
35
33
87
85
82
87
81
84
79
82
196–198
185–187
171–173
190–192
255–258
262–264
300–302
295–297
–
–
–
–
Ar Me
Ar Me
Ar n-Pr 4b
Ar n-Pr 4b
255–258 [20]
264–267 [20]
304–307 [20]
298–301 [20]
aIsolated yield
run 2, 87%; run 3, 86%; run 4, 86%; run 5, 85%; run 6,
85%;). After completion of the reaction, the nanocatalyst
was easily separated using an external magnet. The recov-
ered magnetite nanoparticles were washed several times with
acetone and then dried at room temperature.
hydrazine on the alkyl acetoacetate to form the intermedi-
ate (I) and then, the reaction of isatin with intermediate (I)
to give intermediate II. In the next step, the reaction can
be followed by attack of the naphthylamine or 2-naphthol
that leads to the formation of III and IV. The fnal product
is formed by the intramolecular cyclization reaction. This
mechanism has been supported by literature [20].
A reasonable mechanism for the synthesis of spiroox-
indoles using MNPs-guanidine is shown in Scheme 2.
The mechanism involves the initial nucleophilic attack of
N
NR'
R'
N
O
O
N
O
+ H2N NHR'
EtO
O
R
R
N
O
O
N
R
I
R
O
II
R'
N
NR'
N
N
H
N
O
H
NH2
O
O
+
NH2
R
R
R
O
+
O
N
R
O
H2N
N
H
N
II
R'
N
IV
III
R'
R'
OH
NH
N
N
N
N
R
=
NH
R
HN
HN
O
O
6
V
Fe3O4 MNPs-Guanidine
Scheme 2 Proposed reaction pathway for the synthesis of spirooxindoles using Fe3O4 MNPs-guanidine as catalyst
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Journal of the Iranian Chemical Society
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In conclusion, we have developed a straightforward and
efcient method for the synthesis of spirooxindoles using
magnetic nanoparticles Fe3O4-immobilized guanidine
(MNPs-guanidine). The method ofers several advantages
including cleaner reaction profles, easy availability, high
yields, shorter reaction times, reusability of the catalyst and
low catalyst loading.
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Acknowledgements The authors gratefully acknowledge the fnancial
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