Convenient synthesis of spirooxindoles using SnO2 nanoparticles as effective reusable catalyst at room temperature and study of their in vitro antimicrobial activity

Article abstract of DOI:10.1007/s13738-019-01598-2

New highly efficient method for safe, green and facile synthesis of spirooxindole derivatives have been presented. SnO₂ nanoparticles (SnO₂ NPs) as effective catalyst were synthesized through chemical precipitation method and charact

Full text of DOI:10.1007/s13738-019-01598-2

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01598-2
ORIGINAL PAPER
Convenient synthesis of spirooxindoles using SnO2 nanoparticles
as effective reusable catalyst at room temperature and study of their
in vitro antimicrobial activity
Leila Moradi1 · Zeynab Ataei1 · Zohreh Zahraei2
Received: 20 May 2018 / Accepted: 11 January 2019
© Iranian Chemical Society 2019
Abstract
New highly efficient method for safe, green and facile synthesis of spirooxindole derivatives have been presented. SnO2
nanoparticles (SnO2 NPs) as effective catalyst were synthesized through chemical precipitation method and characterized
in details using FTIR, XRD, SEM and EDS methods. Obtained nano tin oxide particles were used as heterogeneous catalyst
for the one-pot synthesis of spirooxindoles at room temperature. High–excellent yields of products, short reaction times,
room temperature conditions and reusability of catalyst are the main advantages of this method. Evaluation of antimicro-
bial activity of some synthesized compounds were performed against eight bacteria. Agar diffusion method was used for
determining preliminary antibacterial activities and to assess the bacterio-static activity of compounds with inhibition zone,
micro-well dilution assay method was used. Obtained results showed that (5j) was active against all tested microorganisms
and was the most effective compound.
Keywords Multicomponent reactions · Spirooxindoles · SnO2 nanoparticles · Reusable catalyst · Antibacterial activity
Introduction
one pot conditions, where basically all or most of the atoms
contribute to the newly formed product.
During the past decade, intensive attentions have been
focused on the application of nano metal oxides as cata-
lyst [1–6]. This is Due to reusability and high surface area
of nano particles, which enhanced the collision between
reactants and catalyst surfaces. In recent years, SnO2 nano
particles with unique properties, have been widely used in
different fields such as anode for Lithium batteries [7], solar
cells [8], gas sensors [9, 10] and catalyst in organic synthesis
[3–6, 11–13].
Because of spirooxindoles have interesting and unique
structures with therapeutic and biological activities [15–18].
Study on the facile and applicable methods for preparation
of this class of chemicals have been considered as an attrac-
tive field in organic synthesis. Recently, new pathways
and various catalysts have been used for the synthesis of
spirooxindoles such as cesium fluoride [19], [bmim]OH
[20], p-TSA [21], (SB-DBU)Cl [22], Mg(ClO4)2 [23], meg-
lumine [24], piperidine [14], carbon-SO3H [25], bmim(OH)/
chitosan/EtOH [26], chitosan/ionic liquid [27], TBA ace-
tate [28], piperidine (under ultrasonic irradiation) [29],
(H3N+CH2CH2OH) (HCOO−) [30], NaBr [31], [BMIm]
BF4 [32], [Ch-OSO3H]3W12PO40 [33], gluconic acid [34]
and nickel chloride [35].
Multicomponent reactions (MCRs) are one of the best
options for the synthesis of organic compounds especially
polyheterocycles [14]. MCRs provided a powerful synthetic
route in which various starting materials reacted together in
Some of these methods are very sufficient and some of
them performed through long reaction times and reflux
conditions. Furthermore, there are few reports about the
synthesis of spirooxindoles in the presence of metal oxide
nanoparticles. Recently, methylene dipyridine stabilized on
Fe3O4 nanoparticles [36], manganese ferrite nanoparticles
[37] and zirconium(IV) oxide [38] have been used as catalyst
for the preparation of spirooxindole derivatives. Considering
* Leila Moradi
l_moradi@kashanu.ac.ir
1
Department of Organic Chemistry, Faculty of Chemistry,
University of Kashan, P.O. Box 8731753153, Kashan,
Islamic Republic of Iran
2
Department of Cell and Molecular Biology, Faculty
of Chemistry, University of Kashan, P.O. Box 8731753153,
Kashan, Islamic Republic of Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
the good efficiency of this type of catalysts, further studies
on new metal oxide nanoparticles can develop new routes
to the efficient synthesis of spirooxindoles. In continuation
of our studies on environmentally benign multi-component
synthesis of heterocyclic compounds in the presence of new
catalysts [39–41], herein, we prepared, characterized and
used SnO2 nanoparticles as effective and reusable catalyst
for green synthesis of spirooxindoles at room temperature.
Three component reaction occurred between isatin, malon-
onitrile (or ethyl cyanoacetate) and β-diketone (dimedone,
cyclohexanedione and barbituric acid derivatives) in the
presence of SnO2 nanoparticles at room temperature and
short reaction times (Scheme 1).
Typical procedure for the synthesis
of spirooxindoles
A mixture of isatin (1 mmol), malononitrile (1 mmol) and
dimedone (1 mmol) was stirred at room temperature in
the presence of SnO2 nanoparticles and 2 mL of EtOH.
The reaction progress was monitored by TLC (n-hexane/
ethyl acetate, 2:1 ratio). After that, the resulted mixture
(containing the solid product and nano catalyst) was dis-
solved in acetone and filtered for separation of the catalyst.
Finally, the product 5a was obtained after evaporation of
acetone and for further purification recrystallized from
EtOH.
Spectral data
Experimental
2‑Amino‑7,7‑dimethyl‑2′,5‑dioxo‑5,6,7,8‑tetrahydrospiro
[chromene‑4,3′‑indoline]‑3′‑carbonitrile (5a) M.p.: 266–
268 °C; FTIR (KBr): Vmax =3339, 3312, 2879, 2191, 1723,
1683, 1219 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ=1.30
(s, 6H, 2CH3), 1.92 (s, 2H, CH2), 2.51 (s. 2H, CH2), 6.79
(d, 1H, J = 8 Hz ArH), 6.89 (m, 2H, ArH), 6.99 (d, 1H,
J=8 Hz ArH), 7.25 (s, 2H, NH2), 10.41 (s, 1H, NH) ppm;
13C NMR (DMSO-d6, 100 MHz): δ=27.4, 28.1, 31.4, 47.2,
49.7, 57.8, 108.8, 111.2, 116.9, 121.1, 123.4, 128.5, 134.8,
142.3, 158.1, 163.5, 177.1, 194.4 ppm.
Materials and methods
The products have separated and identified by physical
and spectral data. The FTIR spectra have been recorded
on FTIR Magna 550 apparatus using KBr plates. 1H NMR
and 13CNMR spectra were recorded with a Bruker Avance
DPX-400 spectrometer at 400 and 100 MHz, respectively.
Powder X-ray diffraction (XRD) was carried out on a Philips
diffractometer of X’pert Company with monochromatized
Cu Kα radiation (λ=1.5406 Å). Microscopic morphology
of products was visualized by electron scanning microscopy
(SEM) (LEO 1455VP).
2‑Amino‑2′,5‑dioxo‑5,6,7,8‑tetrahydrospiro[chromene‑4,
3′‑indoline]‑3‑carbonitrile (5b) M.p.: 250–252 °C; FTIR
(KBr): Vmax = 3289, 3158, 2958, 2193, 1726, 1653, 1220,
1050 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ=1.90 (2H,
q, J=6.4 Hz CH2), 2.28 (2H, t, J=8 Hz, CH2), 2.65 (2H, t,
J = 8 Hz, CH2), 6.8–7.3 (4H, m, ArH), 7.24 (2H, s, NH2),
10.41 (1H, s, NH) ppm.
Preparation of SnO2 nanoparticles
SnO2 nanoparticles were prepared using chemical precip-
itation method by dissolving 2 g (0.1 mol) of SnCl2 and
2H2O in 100 mL distilled water. After dissolving of tin salt,
ammonia solution (25 vol%) was added dropwise to the
solution through continuous stirring. The obtained gel type
precipitate was filtered and dried at 80 °C for 24 h. After
that, resulting powder was calcined at 550 °C for 2 h [42].
2‑Amino‑5′‑bromo‑7,7‑dimethyl‑2′,5‑dioxo‑5,6,7,8 tetrahy
drospiro[chromene‑4,3′‑indoline]‑3‑carbonitrile (5c) M.p.:
300–302 °C; FTIR (KBr): Vmax = 3371, 3179, 2958,
2193, 1718, 1678, 1219, 1011 cm−1; 1H NMR (DMSO-
d6, 400 MHz): δ = 1.10 (s, 6H, 2CH3), 2.13 (s, 2H, CH2),
2.52 (s, 2H, CH2), 6.77 (s, 1H, ArH), 7.23–7.34 (m, 4H,
ArH),7.36 (s, 2H, NH2), 10.58 (s, 1H, NH) ppm; 13C NMR
(DMSO-d6, 100 MHz): δ=27.3, 28.1, 31.9, 39.8, 46.9, 50.1,
55.7, 110.3, 111.4, 113.2, 116.4, 126.6, 130.1, 135.8, 140.6,
157.9, 162.2, 178.1, 194.9 ppm.
R
3 R3
O
NH2
R1
N
SnO2 NPs
EtOH, r.t.
O
X
+
NC
X
+
O
O
R2
O
O
R2
O
N
Or
Y
R1
R1= H, CH3
R2= H, Br
R3= H, CH3
R4= H, CH3
2‑Amino‑5′‑bromo‑2′,5‑dioxo‑5,6,7,8‑tetrahydrospiro[chro
mene‑4,3′‑indoline]‑3‑carbonitrile (5d) M.p.: 279–281 °C;
FTIR (KBr): Vmax = 3372, 3176, 2956, 1718, 1647, 1219,
1011 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ=1.25–1.31
(2H, m, CH2), 1.91 (2H, t, J = 6.8 Hz, CH2), 2.26 (2H, t,
R4
O
R4
O
X= CN , CO2Et
Y= O, S
N
N
Scheme 1 Synthesis of spirooxindole derivatives catalyzed by SnO2
nanoparticles
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Journal of the Iranian Chemical Society
J=6.4 Hz CH2), 6.78 (1H, s, ArH), 7.26–7.34 (2H, m, ArH),
CH3), 1.16 (3H, s, CH3), 2.10 (2H, s, CH2), 2.21 (2H, s,
CH2), 3.52 (2H, q, J = 6.1 Hz, CH2), 6.64 (1H, m, ArH),
6.71–7.04 (3H, m, ArH), 7.80 (2H, s, NH2), 10.25 (1H, s,
NH) ppm.
7.35 (2H, s, NH2), 10.57 (1H, s, NH) ppm.
2‑Amino‑1′,2′,5,6,7,8‑hexahydro‑7,7‑dimethyl‑2′,5‑dio
xo‑1′‑(phenylmethyl)spiro[4H‑1‑benzopyran‑4,3′‑[3H]
indole]‑3‑carbonitrile (5e) M.p.: 268–270 °C; FTIR (KBr):
Vmax =3346, 2962, 2197, 1716, 1661, 1218 cm−1; 1H NMR
(DMSO-d6, 400 MHz): δ = 1.01 (6H, s, 2CH3), 2.10 (2H,
s, CH2), 2.42 (2H, s, CH2), 4.91 (2H, s, CH2), 6.46 (1H, d,
J=7 Hz, ArH), 6.98–7.39 (m, 8H, ArH), 7.43 (2H, s, NH2)
ppm.
7′‑Amino‑2,2′,4′‑trioxo‑1′,2′,3′,4′‑tetrahydrospiro[indoline
‑3,5′‑pyrano[2,3‑d]pyrimidine]‑6′‑carbonitrile (6a) M.p.:
297–299 °C; FTIR (KBr): Vmax =3320, 3305, 2197, 1716,
1662, 1218 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ=6.75
(1H, d, J=8.4 Hz, ArH), 6.83 (1H, t, J=7.2 Hz, ArH), 7.10
(1H, t, J=6.8 Hz, ArH), 7.43 (1H, d, J=11.2 Hz, ArH), 7.22
(2H, s, NH2), 10.15 (2H, s, 2 NH), 11.08 (1H, s, NH) ppm.
2‑Amino‑1′‑benzyl‑2′,5‑dioxo‑1′,2′,5,6,7,8‑hexahydrospiro[c
hromene‑4,3′‑indole]‑3‑carbonitrile (5f) M.p.: 282–284 °C;
FTIR (KBr): Vmax = 3371, 2958, 2193, 1718, 1678, 1219,
1011 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ=1.71 (2H,
m, CH2), 1.95 (2H, t, J=7.2 Hz, CH2), 2.24 (2H, t, J=8 Hz
CH2), 4.89 (2H, s, CH2), 6.68 (1H, t, J=7.2 Hz, ArH), 6.95–
7.46 (8H, m, ArH), 7.52 (2H, s, NH2) ppm.
7′‑Amino‑5‑bromo‑1,1′,2,2′,3′,4′‑hexahydro‑2,2′,4′‑trioxo
spiro[indole‑3,5′‑pyrano[2,3‑d]pyrimidine]‑6′‑carbonitrile
(6b) M.p.: 221–223 °C; FTIR (KBr): Vmax = 3320, 3305,
2197, 1716, 1662, 1218; 1H NMR (DMSO-d6, 400 MHz):
σ= 66.75–7.43 (3H, m, ArH), 7.22 (2H, s, NH2), 10.15 (1H,
s, NH), 11.08 (1H, s, NH), 11.25 (1H, s, NH) ppm.
2‑Amino‑5‑oxo‑7,7‑dimethyl‑spiro[(4H)‑5,6,7,8‑tetrahydro‑
chromene‑4,3′‑(3′H)‑1′‑methylindol]‑(1′H)‑2′‑one‑3‑carbo
nitrile (5g) M.p.: 255–257 °C; FTIR (KBr): Vmax = 3372,
2958, 2192, 1706, 1667, 1221 cm−1; 1H NMR (DMSO-d6,
400 MHz): δ = 1.01 (3H, s, CH3), 1.05 (3H, s, CH3), 2.08
(2H, s, CH2), 2.51 (2H, s, CH2), 3.15 (3H, s, CH3), 6.98–
7.29 (4H, m, ArH), 7.30 (2H, s, NH2) ppm.
7′‑Amino‑5‑bromo‑1′,3′‑dimethyl‑2,2′,4′‑trioxo‑1′,
2′,3′,4′‑tetrahydrospiro[indoline‑3,5′‑pyrano[2,3‑d]
pyrimidine]‑6′‑carbonitrile (6c) M.p.: 295–297 °C; FTIR
(KBr): Vmax =3376, 2197, 1731, 1684, 1662, 1194 cm−1; 1
H
NMR (DMSO-d6, 400 MHz): δ=3.10 (6H, s, 2CH3), 6.76–
7.71(3H, m, ArH), 7.49 (2H, s, NH2), 10.73 (1H, s, NH)
ppm. 13C NMR (DMSO-d6, 100 MHz): δ=28.2, 29.7, 48.1,
56.9, 86.1, 113.5, 117.2, 118.0, 126.4, 130.6, 136.3, 140.6,
151.1, 152.6, 157.9, 156.9, 178.1 ppm.
2‑Amino‑1′‑methyl‑2′,5‑dioxo‑1′,2′,5,6,7,8‑hexahydrospir
o[chromene‑4,3′‑indoline]‑3‑carbonitrile (5h) M.p.: 245–
247 °C; FTIR (KBr): Vmax =3372, 2958, 2192, 1706, 1667,
1221 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ = 1.9–1.93
(2H, m, CH2), 2.25 (2H, t, J = 6.8 Hz, CH2), 2.60 (2H, t,
J=6.8 Hz, CH2), 3.2 (3H, s, CH3), 6.91–7.23 (4H, m, ArH),
7.29 (2H, s, NH2) ppm; 13C NMR (DMSO-d6, 100 MHz):
δ=19.7, 26.5, 27.1, 36.5, 46.2, 58.1, 109.2, 112.1, 117.4,
122.6, 123.0, 128.5, 133.2, 143.6, 158.4, 166.1, 175.6,
195.2 ppm.
7′‑Amino‑1,1′,2,2′,3′,4′‑hexahydro‑1′,3′‑dimethyl‑2,2′,4′‑trio
xospiro[indole‑3,5′‑pyrano[2,3‑d]pyrimidine]‑6′‑carbonitrile
(6d) M.p.: 231–233 °C; FTIR (KBr): Vmax = 3428, 3317,
2924, 2000, 1693, 1652, 1130 cm−1; 1H NMR (DMSO-d6,
400 MHz): δ=3.01 (6H, s, 2CH3), 6.71–7.51 (4H, m, ArH),
7.69 (2H, s, NH2), 12.52 (1H, s, NH) ppm.
7′‑Amino‑2,4′‑dioxo‑2′‑thioxo‑1′,2′,3′,4′‑tetrahydrospiro
[indoline‑3,5′‑pyrano[2,3‑d]pyrimidine]‑6′‑carbonitrile
(6e) M.p.: 242–244 °C; FTIR (KBr): Vmax = 3427, 2202,
1694, 1187 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ=6.77–
7.52 (m, 4H, ArH), 7.18 (s, 2H, NH2), 10.39 (s, 1H, NH),
11.35 (s, 1H, NH), 12.40 (s, 1H, NH) ppm; 13C NMR
(DMSO-d6, 100 MHz): δ=45.1, 57.5, 85.2, 112.4, 119.6,
123.7, 124.3, 129.1, 133.7, 142.6, 163.9, 166.1, 167.9,
176.6, 183.2 ppm.
Ethyl‑2‑amino‑7,7‑dimethyl‑2′,5‑dioxo‑5,6,7,8‑tetrahydr
ospiro[chromene‑4,3′‑indoline]‑3‑carboxylate (5i) M.p.:
258–260 °C; FTIR (KBr): Vmax =3371, 3245, 2956, 1718,
1670, 1219, 1011 cm−1. 1H NMR (DMSO-d6,400 MHz):
δ=0.90 (3H, t, J=4.8 Hz CH3), 1.15 (6H, s, 6CH3), 2.10
(2H, s, CH2), 2.35 (2H, s, CH2), 3.70 (2H, q, J = 6.3 Hz,
CH2), 6.64–7.12 (4H, m, ArH),7.80 (2H, s, NH2), 10.25 (1H,
s, NH) ppm.
Evaluation of in vitro antimicrobial activity
Ethyl‑2‑amino‑5′‑bromo‑7,7‑dimethyl‑2′,5‑dioxo‑5,6,7
,8‑tetrahydrospiro [chromene‑4,3′‑indoline]‑3‑carboxy
late (5j) M.p.: 257–259 °C; FTIR (KBr): Vmax = 3272,
2927, 1722, 1690, 1229, 1049 cm−1; 1H NMR (DMSO-d6,
400 MHz): δ = 0.92(t, J = 8.3 Hz, 3H, CH3), 1.04 (3H, s,
Some synthesized spirooxindole derivatives (5a, 5c, 5e, 5i,
5j) were screened for their antibacterial activity against 8
bacterial strains. The microorganisms used in this research
were provided by Iranian Research Organization for Science
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Journal of the Iranian Chemical Society
and Technology (IROST). The test microorganisms were
used as follows: Escherichia coli (ATCC 10536), Kleb-
siella pneumonia (ATCC 10031), Shigella dysenteriae
(PTCC 1188), Proteus vulgaris (PTCC 1182) and Salmo-
nella paratyphi-A serotype (ATCC 5702) as examples of
Gram-negative bacteria, Bacillus subtilis (ATCC 6633),
Staphylococcus aureus (ATCC 29737) and Staphylococcus
epidermidis (ATCC 12228) as examples of Gram-positive
bacteria. Agar diffusion method was used for determining
preliminary antibacterial activities and to assess the bacte-
rio-static activity of the active compounds with inhibition
zone, micro-well dilution assay method was used [43]. Tetra-
cycline was used as positive control for bacteria and DMSO
as a negative control.
Fig. 2 SEM images of synthesized SnO2 NPs
Compound 5j was active against all test microorganisms
and it was the most effective compound as compared with
others. This compound was most effective against p. vulgaris
with MIC value of 250 µg/mL.
in Fig. 3. Strong peaks of Stannous and Oxygen was
observed in this spectrum and confirmed the composition
and purity of synthesized nanometal oxide.
In continue, optimum conditions of reaction includ-
ing the amount of catalyst and solvent were examined.
In this way, a model reaction contained isatin (1 mmol),
malononitrile (1 mmol) and dimedone (1 mmol) was used
in the presence of various amounts of SnO2 NPS and dif-
ferent solvents. As can be seen in Table 1, when 0.01 g
of catalyst was used (in EtOH), the yield of the product
was 55% after 15 min (entry 3) and when 0.02 g of cata-
lyst was applied, the yield of product become 85% after
12 min (entry 6). In continue, the effect of 0.03 g of SnO2
nanoparticles on the yield and time of reaction was inves-
tigated. As shown in entry 9, the yield of product increased
to 96% and the time of reaction decreased to 9 min. Fur-
thermore, 0.04 g of SnO2 nanoparticles did not improve
the yield of product (entry 14). From the results in Table 1,
it was clear that every amount of catalyst have the most
activity when EtOH was used as solvent (entry 3, 6, 9, 14).
From optimization study, it concluded that 0.03 g of SnO2
NPs was the best amount for obtaining the highest yield
in EtOH as solvent.
Results and discussion
In the first step of this study, SnO2 nanoparticles were pre-
pared by co-precipitation method [42] and the structure
of SnO2 nanoparticles was evaluated by X-ray diffraction
method at room temperature. The peak position of SnO2
nanoparticles relevant to standard pattern, demonstrated that
they have been prepared at nanoscale with excellent purity
(Fig. 1).
The morphology and size distribution of SnO2 nanoparti-
cles were estimated by SEM images. As shown in Fig. 2, the
size range of nanoparticles was 20–32 nm with a good distri-
bution. In addition, the size of nano particles calculated by
Debye Scherrer equation (from XRD pattern) shows that the
particle size was about 22 nm. Results from SEM and XRD,
confirmed the preparation of SnO2 particles in nano scale.
X-ray diffraction spectroscopy (EDX) as an analytical
method for chemical composition evaluation of SnO2 NPs
was applied. EDX pattern of SnO2 NPs has been displayed
After determining the optimum conditions of reac-
tion, for development of the catalyst performance, some
spirooxindole derivatives were prepared using isatin
derivatives, various diketones and malononitrile or ethyl
cyanoacetate in the presence of SnO2 NPs. According to
results depicted in Table 2, it is clearly observed that in
most cases, spirooxindole derivatives were obtained at
short times and high–excellent yields. On the other hand,
when ethyl cyanoacetate or barbituric acid derivatives
were employed, the time of reaction was longer (5i, 5j and
6a–6f). This is due to lower reactivity of ethyl cyanoac-
etate and barbituric acid derivatives versus malononitrile
or dimedone derivatives [35, 44].
Fig. 1 XRD pattern of synthesized SnO2 NPs
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Journal of the Iranian Chemical Society
Fig. 3 EDX spectrum of SnO2
nanoparticles
Table 1 Optimization of reaction conditions
H
O
NH2
N
SnO2 NPs
EtOH,r.t.
+
+
O
NC
CN
CN
O
O
O
O
O
N
H
Entry
Catalyst (g)
Solvent
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
0.01
0.01
0.01
0.01
0.01
0.02
0.02
0.02
0.03
0.03
0.03
0.03
0.03
0.04
0.04
CH3OH
H2O
C2H5OH
CH3CN
CH3Cl
C2H5OH
H2O
CH3CN
C2H5OH
H2O
CH3OH
CH3CN
CH3Cl
C2H5OH
H2O
20
30
15
120
110
12
20
120
9
10
8
80
120
10
10
35
48
55
46
35
85
42
54
96
85
88
64
40
90
80
9
10
11
12
13
14
15
aIsolated yield
catalyst was reused up to five times without substantial
loss of activity. The obtained yield of product from first
to final run was 98–88% (Fig. 4).
Reusability of catalyst
The reusability of the catalyst was examined as a measure
of the efficiency of the catalyst. After the separation of
product (obtained from the model reaction), the catalyst
was separated and reused in the next run of the same reac-
tion and the isolated yield of product was determined. The
A reasonable mechanism for the synthesis of mentioned
products have been displayed in Scheme 2. In the first step,
isatin is activated by SnO2 nanoparticles and condensed with
malononitrile (or ethyl cyanoacetate) via Knoevenagel con-
densation reaction to afford intermediate (I) After that, the
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Journal of the Iranian Chemical Society
Table 2 Synthesis of spirooxindole derivatives using SnO2 NPs at room temperature
Y
R3
R3
R4
N
R4
O
R4
O
R3
R3
N
N
O
NH2
O
NH2
O
R1
N
O
O
N
4
X
O
3
X
O
O
R4
NC
X
+
O
O
SnO2 NPs
EtOH, r.t.
SnO2 NPs
EtOH, r.t.
R2
R2
R2
N
N
O
R1
R1
1
2
5 (a-j)
6 (a-e)
1a: R1=H, R2=H
1b R1= H, R2= Br
4a: R3=CH3
4b: R3=H
2a: X=CN
2b: X=CO2Et
3a: R4=H, Y=O
3b: R4= CH3, Y=O
3c: R4=H, Y=S
1c: R1= CH3, R2=H
1d: R1= CH2Ph, R2=H
Time
(min)
Yield
(%)a
Product Isatin
Diketon
Malonate
Product
m.p (°C)
O
NH 2
266-268
CN
O
5a
5b
5c
5d
1a
1a
1b
1b
4a
2a
2a
2a
2a
8
96
91
92
81
O
(268-270)[45]
NH
O
NH
2
250-252
CN
4b
4a
4b
10
20
20
O
O
(251-252) [45]
NH
O
NH2
300-302
CN
O
O
(304-305) [46]
N
Br
H
O
NH 2
279-281
CN
O
O
(278-280) [25]
NH
Br
O
NH2
CN
O
268-270
5e
5f
1d
1d
1c
4a
4b
4a
2a
2a
2a
20
10
8
95
95
94
O
N
(269-271) [47]
Ph
O
NH 2
282-284
CN
O
O
(283-285) [48]
N
Ph
O
NH2
CN
O
255-257
5g
O
N
(254-256) [47]
CH3
O
NH
2
245-247
CN
O
5h
5i
1c
1a
4b
4a
2a
8
92
O
(245-246) [46]
N
CH
3
O
NH
2
CO Et
2
O
258-260
2b
O
20
82
N
(257-258) [45]
H
O
NH
2
CO Et
2
O
257-259
5j
1b
4a
2b
25
80
O
NH
Br
(260-262) [46]
1 3

Journal of the Iranian Chemical Society
Table 2 (continued)
Time
(min)
Yield
(%)a
Product Isatin
Diketon
Malonate
Product
m.p (°C)
H
O
N
O
NH2
297-299
HN
O
CN
O
6a
6b
1a
1b
3a
2a
90
96
88
(296-298) [49]
NH
H
N
O
O
NH2
221-223
HN
O
CN
O
3a
2a
110
(220-222) [50]
NH
Br
Me
N
O
O
O
O
NH
2
295-297
MeN
O
CN
O
6c
6d
1b
1a
3b
3b
2a
2a
120
100
89
91
>300 [51]
NH
NH
Br
Me
N
O
NH
2
231-233
MeN
CN
O
O
(229-231) [49]
H
N
S
NH2
HN
O
CN
O
242-244
6e
1a
3c
2a
110
93
(240-241) [49]
NH
a Isolated yiela
enol form of 1,3 dicarbonyl derivative attacks to intermedi-
ate I through Michael addition reaction to produce interme-
diate (II). Finally, cyclization and tautomerization of II lead
to desired spirooxindole product.
Antibacterial activity
In this study, some synthesized compounds (5a, 5c, 5e,
5i, 5j) were screened in vitro for their antibacterial activi-
ties by agar diffusion method and micro-well dilution
assay. The results of antibacterial activity of compounds
are summarized in Table 3. As can be seen in this table,
compounds 5a and 5e were only effective against Gram-
positive bacteria, S. epidermidis, while compound 5i was
active against S. epidermidis and S. aureus. Also, com-
pound 5c showed activity against S. epidermidis and E.
coli. Compound 5j was active against all test microorgan-
isms and it was the most effective compound as compared
with others. This compound was most effective against
p. vulgaris with MIC value of 250 µg/mL. Compound 5d
had no antibacterial activity (the results were not shown).
Finally, the efficiency of presented protocol in the
synthesis of 4a and 6a, has been compared to some of
the reported methods. As can be seen in Table 4, this
method is superior in terms of reaction time, yields and
temperature.
Fig. 4 Recycling behaviour of SnO2 nanoparticles catalyst
NC
NC
H
H
-H
H
OH
H
N
NC
X
O
H
X
NC
O
-H2O
NH
NH
O
NC
X
HO
O
O
O
X
I
H
H
N
H
N
N
O
X
O
H
H
tautomerization
H
O
O
O
X
NH2
C
NH
O
O
O
N
II
: SnO2 nanoparticles
Scheme 2 Reaction mechanism of spirooxindoles synthesis using
SnO2 NPs as catalyst
1 3

Journal of the Iranian Chemical Society
Table 3 In vitro antimicrobial
activity of the synthesized
compounds (5a, 5c, 5e, 5i, 5j)
Microorganism 5a
5c
5e
5i
5j
Tetracycline
AD MIC AD MIC AD MIC AD MIC AD MIC AD MIC
S. aureus
S. epidermidis
E. coli
K. pneumonia
S. dysenteriae
p. vulgaris
–
10
–
–
–
–
–
–
–
–
–
–
9
2000 10
2000 10
500 24
2500 39
2000 21
1000 22
500 25
250 20
500 20
250
250
500
250
250
125
250
2000 10
–
––
–
–
2000 12
2000
–
–
–
–
2000 11
13
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
11
8
10
14
8
S. paratyphi-A
–
AD agar diffusion method, inhibition zones in diameter (mm), MIC minimal inhibitory concentrations as
µg/mL, – no antimicrobial activity
Table 4 Study on SnO2 NPs
efficiency in compare with
other reported catalysts for the
synthesis of 5a and 6a
Entry
Catalyst
Time
T (°C)
Yield (%)
References
1
2
4
6
7
8
9
10
11
12
13
14
15
16
17
MgO nanoparticles
2 h
2 h
3 h
35 min
4 h
4 h
7 h
8 min
90 min
1 h
90 min
3 h
80
60
80
80
80
20
20
r.t.
80
60
80
60
80
75
r.t.
95
94
81
85
86
89
91
98
92
93
91
88
88
77
96
[52]
[48]
[25]
[53]
[54]
[55]
[56]
This work
[57]
[58]
[59]
[48]
[60]
[61]
This work
N-Benzyl-triethylammonium chloride
Carbon sheets with sulfonic acid
Functionalized mesoporous SBA-15
Cu(OAc)2,H2O
PEG-600
Modified β-cyclodextrin
SnO2 nanoparticles
Silica@organocatalysta
l-Prolinate supported on amberlitea
Glycerola
N-Benzyl-triethylammonium chloridea
Magnesiaa
90 min
4 h
90 min
1,4-Diaza-bicyclo[2,2,2]octanea
SnO2 nanoparticlesa
aCatalyst for the synthesis of 6a
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Conclusion
In summary, SnO2 NPs were synthesized in a clean and
soft route and showed some advantages in the preparation
of spirooxindole derivatives such as short reaction times,
easy work-up with high–excellent yields and low cost, as
well as nontoxic catalyst. In addition, the antibacterial
activity of some synthesized compounds is considerable.
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