Monoclinic zirconia nanoparticle-catalyzed regioselective synthesis of some novel substituted spirooxindoles through one-pot multicomponent reaction in a ball mill: A step toward green and sustainable chemistry

Article abstract of DOI:10.1080/00397911.2017.1336244

A highly efficient, green as well as atom economical protocol for the synthesis of substituted spirooxindoles from m-ZrO₂ NPs catalyzed multicomponent reaction of isatin derivatives with ethyl cyanoacetate and 1,3-dicarbonyl compounds in a ball mill has been established. Because of the simple and readily available starting materials, easy operation, and high bioactivity of substituted spirooxindoles, this strategy can be broadly applied to medicinal chemistry. The recyclability of the m-ZrO₂ Nps catalyst is another emphasis of proposed methodology.

Full text of DOI:10.1080/00397911.2017.1336244

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Monoclinic zirconia nanoparticle-catalyzed
regioselective synthesis of some novel substituted
spirooxindoles through one-pot multicomponent
reaction in a ball mill: A step toward green and
sustainable chemistry
Shivam Bajpai, Sundaram Singh & Vandana Srivastava
To cite this article: Shivam Bajpai, Sundaram Singh & Vandana Srivastava (2017) Monoclinic
zirconia nanoparticle-catalyzed regioselective synthesis of some novel substituted spirooxindoles
through one-pot multicomponent reaction in a ball mill: A step toward green and sustainable
chemistry, Synthetic Communications, 47:16, 1514-1525, DOI: 10.1080/00397911.2017.1336244
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1336244
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Jun 2017.
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Date: 07 August 2017, At: 01:54

SYNTHETIC COMMUNICATIONS®
017, VOL. 47, NO. 16, 1514–1525
2
https://doi.org/10.1080/00397911.2017.1336244
Monoclinic zirconia nanoparticle-catalyzed regioselective
synthesis of some novel substituted spirooxindoles through
one-pot multicomponent reaction in a ball mill: A step
toward green and sustainable chemistry
Shivam Bajpai, Sundaram Singh, and Vandana Srivastava
Department of Chemistry, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India
ABSTRACT
ARTICLE HISTORY
A highly efficient, green as well as atom economical protocol for the
Received 24 February 2017
synthesis of substituted spirooxindoles from m-ZrO NPs catalyzed
2
KEYWORDS
Ball milling;
isatin derivatives;
m-ZrO nanoparticles;
2
spirooxindoles
multicomponent reaction of isatin derivatives with ethyl cyanoace-
tate and 1,3-dicarbonyl compounds in a ball mill has been
established. Because of the simple and readily available starting
materials, easy operation, and high bioactivity of substituted
spirooxindoles, this strategy can be broadly applied to medicinal
chemistry. The recyclability of the m-ZrO Nps catalyst is another
2
emphasis of proposed methodology.
GRAPHICAL ABSTRACT
Introduction
These days, the focal point of research is the development of nonhazardous alternatives for
the sustainable growth of chemical endeavor that includes solventless organic synthesis,
multicomponent reactions, and use reusable heterogeneous catalysts. Such organic
reactions possess various advantages over traditional reactions in organic solvents. They
not only reduce the consumption of environmentally perilous solvents but also minimize
the formation of other waste material.[1]
Subsequently, in recent years, ball milling has emerged as an efficient mechanical
method for the grinding of metals and inorganic substances into fine particles.[2–6] Besides
CONTACT Sundaram Singh
BHU), Varanasi, Uttar Pradesh 221 005, India.
Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/lsyc.
sundaram.apc@itbhu.ac.in
Department of Chemistry, Indian Institute of Technology
(
1
13
Supplemental data (full experimental detail, characterization data and H and C NMR spectra of all synthesized
compounds) can be accessed on the publisher’s website.
©
2017 Taylor & Francis

SYNTHETIC COMMUNICATIONS®
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the broad applications of ball milling in inorganic synthesis,[5] the potential application and
usefulness of ball milling technology as a one-pot, solvent-free route in organic synthesis
[
5]
have largely been overlooked.
In past few decades, nanostructured materials are used as heterogeneous catalysts
for various organic transformations, particularly because they meet the goals of green
[
7–17]
and sustainable chemistry.
investigated due to their multiple potential applications.
ZrO2 (tetragonal and monoclinic) strongly influences the catalyst activities and
Among them, nanozirconia (ZrO ) have been extensively
2
[
18–23]
The crystal phase of nano
[
24,25]
selectivities.
ZrO2 nanoparticle catalyst as nontoxic, moisture stable, reusable,
inexpensive, and commercially available white powder is of great interest to many
researchers in last few years. In general, several similar applications of nano ZrO , as an
2
effective catalyst in green synthetic organic chemistry, have already been highlighted in
[
26–35]
the literature.
The indole moiety, being a “privileged scaffold,” is an important active feature
and structural unit of variety of natural products.[36] Furthermore, an enhancement in
biological activity was observed in spirooxindole derivatives due to the presence of a
[
37]
sterically constrained spiro structure at the C-3 position.
For example, some cytostatic
alkaloids, like spirotryprostatins and pteropodines, are effective inhibitors of microtubule
activity and modulators of muscarinic serotonin receptor functions.
[
38–49]
A variety of protocols
have been reported for the synthesis of substituted
spirooxindole derivatives. However, these methods show varying degrees of success as well
as limitations such as high temperatures, prolonged reaction times, unsatisfactory yield, use
of toxic solvents and catalysts, tedious steps for the preparation of catalyst, lack of catalyst
reusability, laborious work-up procedures, harsh reaction conditions and lack of generality.
Thus, the development of an alternate milder, clean as well as environmentally friendly
procedure is highly demanding for the synthesis of substituted spirooxindoles, which sur-
passes those limitations.
As a part of our ongoing efforts to develop cost-effective and simpler new methodolo-
gies for the synthesis of hybrid pharmacophores,[50–52] we report herein, a simple,
convenient, and green synthesis of substituted spirooxindoles through monoclinic ZrO2
NP-catalyzed one-pot three-component reaction of substituted isatin with 1,3-dicarbonyl
compounds and ethyl cyanoacetate in a ball mill.
Results and discussion
m-ZrO NPs were synthesized and characterized by FTIR, X-ray diffraction (XRD),
2
scanning electron microscopy (SEM), and transmission electron microscopy (TEM)
analysis. The specific surface area of synthesized m- ZrO NPs was calculated by BET
2
surface area analyzer.
It has been observed that the sample of m-ZrO NPs was highly crystalline as evident
2
from XRD pattern in which broad peaks with high intensity extended over the 2θ scale.
The peaks observed at 2θ ¼ 24.3 (011), 28.3 À (111), 31.5 (111), 35.1 (200), 38.6 (021),
4
0.5 À (211), 45.2 À (202), 50.4 (122), 53.9 (300), 55.3 (013), 57.7 À (222), and 60.0 (302)
are corresponding to monoclinic zirconia (JCPDS card no. 37-1484). No characteristic
peak of cubic or tetragonal phase and any other impurities are found in the XRD pattern.
This observation suggests that the high purity of monoclinic phase ZrO was obtained.
2

1
516
S. BAJPAI ET AL.
The broadening of peaks indicates the smaller particle size of m-ZrO NPs (Fig. 1). The
2
average particle size has been estimated using Debye–Scherrer formula.
D ¼ 0:94k=bcosh
where λ is wave length of X-ray (0.1540 nm), β is full width at half maximum, θ is
diffraction angle, and D is particle diameter size. On the basis of this investigation, the
average particle size was found 10 nm.
Further, the bonding nature and purity of nanoparticles are studied by the FTIR.
Figure S1 (Supplementary Material) shows the FTIR spectra of m-ZrO NPs. It revealed
2
À 1
the presence of major bands at 774 and 481 cm which are attributed to the strong
stretching vibrations of the Zr–O group. These bands are the characteristic monoclinic
[
53]
phase of ZrO2.
The FTIR studies are in agreement with the XRD patterns of the
ZrO that both confirm the presence of a monoclinic ZrO phase.
2
2
Morphological investigations of 750 °C calcinated m-ZrO NP sample were performed
2
using SEM and TEM analysis that are shown in Figs. 2 and 3, respectively. The morphological
characterization highlighted the importance of nanocrystalline ZrO preparation in main-
2
taining the nanostructured phase. It is clear from Fig. 2 that m-ZrO particles are spherical
2
in nature and size of the particles is in the nanometer regime, but size could not be finely
resolved from SEM. For this purpose, TEM of sample has been shown in Fig. 3.
Transmission electron microscopy analysis was performed to confirm actual particle
size of ZrO NPs. TEM observations clearly revealed spherical nanoparticles with size
2
ranging between 05 and 09 nm which is also in the agreement with XRD studies
m-ZrO NPs (Fig. 3 and Fig. S2, Supplementary Material).
2
Surface area analysis of m-ZrO NPs was performed by nitrogen absorption using BET
2
surface area analyzer, and the surface area of synthesized m-ZrO NPs was found to be 69.
2
2
À 1
2
2 m g (Fig. S3, Supplementary Material).
Figure 1. XRD spectra of m-ZrO NPs. Note: XRD, X-ray diffraction.
2

SYNTHETIC COMMUNICATIONS®
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Figure 2. SEM image of m-ZrO NPs. Note: SEM, scanning electron microscopy.
2
m-ZrO2 NP-catalyzed multicomponent reaction of isatin derivatives 1a–h with
,3-dicarbonyl compounds 2a–c and ethyl cyanoacetate 3 afforded substituted spirooxin-
1
doles 4a–r in excellent yields in the ball mill (Scheme 1 and Table 1). The atom economy
of all products 4a–r was calculated and summarized in Table 1.
The chemical structure of the respective synthesized spirooxindole derivative was
established by their spectral data.
Mechanistically, the reaction was proposed to proceed through the activation of isatin
derivatives 1a–h by m-ZrO NPs A to generate α,β-unsaturated adduct 4. Subsequent
2
1
,4-addition of 1,3-dione 2a-c on α,β-unsaturated adduct 4 followed by an intramolecular
Figure 3. TEM image of m-ZrO NPs. Note: TEM, Transmission electron microscopy.
2

1
518
S. BAJPAI ET AL.
Scheme 1. Synthesis of substituted spirooxindoles 4a–r.
cyclization of the adduct through [1,3]-sigmatropic proton shift of the iminopyrans led to
the formation of a stable spirooxindole ring system 9. In the presence of both nitrile and
ester groups, the nucleophilic addition of enolic oxygen occurs predominantly to nitrile
rather than to the ester group affording the desired product. This predominance can be
explained by the higher electrophilicity and lower steric hindrance of the nitrile group
toward nucleophilic addition compared to ester functionality. Thus the formation of
[
54]
spirooxindole ring system is highly regioselective (Scheme 2).
To find optimum reaction conditions, several parameters were investigated. Expectedly,
efficiency of the m-ZrO NPs was affected by their amount (mol%). Therefore, a set of
2
experiments using different amounts of m-ZrO NPs were taken into account for the
2
multicomponent reaction of 5-chloroisatin with ethyl cyanoacetate and barbituric acid
(
Table 2). It was found that product yield is increased with enhancing catalyst concen-
tration and the best yield of 97% was obtained with 20 mol% of m-ZrO NPs (Entry 7,
2
Table 2). However, further addition of catalyst concentration (>20 mol%) did not improve
the reaction rate and product yield (Entries 8 and 9, Table 2).
The effect of type of ZrO (bulk, mixed phase nano, monoclinic nano) was investigated
2
in the multicomponent reaction of 5-chloroisatin with ethyl cyanoacetate and barbituric
a
Table 1. Synthesis of spirooxindoles (4a–r).
0
b
c
Entry
R
R
–X–Y–Z–
Yield (%)
Atom economy
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Cl
H
Cl
H
Cl
H
Cl
H
H
Cl
H
Cl
H
H
Cl
H
H
Cl
H
–NH–CO–NH–
–NH–CO–NH–
–NH–CO–NH–
–NH–CO–NH–
–NH–CO–NH–
–NH–CO–NH–
–NH–CO–NH–
–NH–CO–NH–
97
96
97
91
93
94
95
90
96
96
95
92
89
90
88
82
86
88
93.9
95.7
96.2
96.3
96.6
96.3
96.6
95.9
95.9
96.3
96.4
96.7
95.9
95.9
96.3
96.5
96.4
96.7
Et
Et
COOEt
COOEt
CH
CH
2
2
CH
CH
2
Ph
Ph
2
3 7
C H
Et
Et
COOEt
COOEt
C H
3 7
Et
Et
–CH
–CH
–CH
–CH
–CH
2
2
2
2
2
–C(CH
–C(CH
–C(CH
–C(CH
–C(CH
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
2
–CH
2
–CH
2
–CH
2
–CH
2
–CH
2
–O–
2
–O–
2
–O–
2
–O–
2
–O–
2
–
2
–
2
–
2
–
2
–
CH
CH
2
2
–O–C(CH
–O–C(CH
–O–C(CH
–O–C(CH
–O–C(CH
2
CH COOEt
CH
CH
2
Ph
Ph
2
a
Reaction condition: isatin derivatives 1a–h, 1,3-dicarbonyl compounds 2a–c, ethyl cyanoacetate 3(1.0:1.0:1.0), m-ZrO
0 mol%, and 1 mL water were subjected to ball mill for 25–35 min to produce solid products 4a–r.
2
NPs,
2
b
c
Isolated yield.
Atom economy ¼ (molecular weight of desired product/sum of molecular weight of all reactants) � 100%.

SYNTHETIC COMMUNICATIONS®
1519
Scheme 2. Proposed mechanism for the formation of substituted spirooxindoles 4a–r.
acid under the optimized reaction conditions (Table 3). Four concentrations 5, 10, 15, and
2
0 mol% of ZrO were used to study this important parameter. These data proved that
2
particle size, surface area as well as a particular phase of ZrO NPs are the important factor
2
for its catalytic efficacy (Figs. S2 and S3, Supplementary Material).
A comparison of the efficiency of catalytic activity of the m-ZrO NPs with several other
2
catalysts is presented in Table 4. Multicomponent reaction of 5-chloroisatin with ethyl
a
Table 2. Effect of catalyst amount (mol%) on yield of the product 4a.
Entry
m-ZrO
2
(mol%)
Time (min)
Yield (%)
1
2
3
4
5
6
7
0
150
120
90
60
55
40
30
33
56
68
77
85
90
97
5
10
12
15
17
20
22
25
8
9
30
30
97
96
Bold values represents the optimized values and these are the best results obtained during
the respective optimization.
a
Reaction condition: 5-chloroisatin, barbituric acid, ethyl cyanoacetate, m-ZrO
2
NPs, and
water 1 mL were subjected to ball mill to produce solid product 4a.

1
520
S. BAJPAI ET AL.
a
Table 3. Effect of type of ZrO on the yield of the product 4a.
2
Type of ZrO
2
mol%
Yield (%)
b
ZrO
2
(Bulk)
5
10
15
40
55
59
68
50
60
73
83
56
68
85
97
2
Surface area: 6.95 m /g
Average particle size: 2 µm
2
0
c
2
ZrO (mixed phase nano)
2
5
Surface area: 44.70 m /g
10
15
Average particle size: 20 nm
2
0
2
ZrO (single-phase monoclinic)
2
5
Surface area: 69.22 m /g
10
15
Average particle size:>10 nm
20
a
Reaction condition: 5-chloroisatin, barbituric acid, ethyl cyanoacetate, and water 1 mL were
b,c
subjected to ball mill to produce solid product 4a. [52]
Data were already published in our previous work.
cyanoacetate and barbituric acid was taken into account and the comparison was in terms
of mol% of catalyst, reaction time, and percentage yield. The result showed that m-ZrO2
NPs were the best catalyst in terms of mol%, reaction time, and percentage yield. Although
some of the catalysts led to good yield, some of them are environmentally hazardous and
require longer reaction time and higher mol% of catalyst (Table 4).
The reusability of m-ZrO NPs was examined under optimized reaction conditions
2
(
Table 5). The catalyst was separated by centrifuging, washed, dried, and reused for a fresh
reaction mixture up to run no. 10. The results showed that there is no appreciable decrease
in product yield in subsequent reuse, which proves the reusability and recyclability of
m-ZrO NPs (Table 5).
2
Besides chemical variables, technical parameters like rotation frequency of ball mill and
the number of milling balls also significantly influence the outcome of reactions performed
in ball mills. Recent publications indicate that for organic synthesis, consideration of these
[
55]
parameters is also important.
Therefore, the influence of the rotation frequency on the
yield of the product 4a was investigated (Table 6).
a
Table 4. Effect of different catalysts on the yield of the product 4a.
Entry
Type of catalyst
mol%
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
Bentonite clay
K-10 clay
PTSA
20
20
30
30
40
20
20
30
30
25
25
40
40
25
20
200
200
200
165
150
120
50
160
120
150
180
220
150
180
30
70
68
51
60
64
72
82
65
50
70
76
72
69
70
97
4
NH Cl
EDTA
Yb(OTf)
TiO
2
(Nano)
TiCl
MgClO
3
4
1
1
1
1
1
1
DABCO
TEBA
NaHCO
CO
TBAB
m-ZrO NPs
3
K
2
3
2
Bold values represents the optimized values and these are the best results obtained during the
respective optimization.
a
Reaction condition: 5-chloroisatin, barbituric acid, ethyl cyanoacetate, and water 1 mL were
subjected to ball mill to produce solid product 4a.

SYNTHETIC COMMUNICATIONS®
1521
a
Table 5. Reusability and recyclability of ZrO NPs catalyst.
2
Entry
Number of cycle
Yield (%)
1
2
3
4
5
6
7
8
9
—
1
97
b
97
b
2
96
b
3
94
b
4
94
b
5
92
b,c
6
95
b
7
93
b
8
93
b
1
1
0
1
9
90
b,c
10
95
a
Reaction condition: 5-chloroisatin, barbituric acid, ethyl cyanoacetate,
2
2
0 mol%, m-ZrO NPs, and water 1 mL were subjected to ball mill to
produce solid product 4a.
The catalyst was washed and dried at 80–90 °C for 12 h.
b
c
2
m-ZrO NPs were calcinated at 750 °C for 4 h.
a
Table 6. Effect of rotation frequency of ball mill on yield of the product 4a.
Entry
Rotation frequency (rpm)
Yield (%)
1
2
3
4
5
6
7
8
100
200
300
400
500
600
700
800
Trace
55
70
75
85
88
93
97
Bold values represents the optimized values and these are the best results obtained during
the respective optimization.
a
2
Reaction condition: 5-chloroisatin, barbituric acid, ethyl cyanoacetate, 20 mol% m-ZrO NPs,
and water 1 mL were stirred in ball mill to produce solid product.
Another critical parameter in ball-milling experiments is the number of milling balls. So
far, the experiments were performed with 16 milling balls made of Al O with a diameter d of
2
3
10 mm. Table 7 summarizes the results from experiments with number of milling balls vary-
ing from 2 to 18. It has to be stated expressly that a minimum of 10 milling balls are necessary
to guarantee a quantitative yield of product 4a, However, the best yield of the product 4a was
obtained using 16 milling balls under the optimized experimental conditions.
a
Table 7. Effect of number of milling balls on the yield of the product 4a.
Entry
Number of milling balls
Yield (%)
1
2
3
4
5
6
7
8
2
4
0
trace
20
6
8
35
10
12
14
16
18
60
80
88
97
9
97
Bold values represents the optimized values and these are the best results obtained during
the respective optimization.
a
2
Reaction condition: 5-chloroisatin, barbituric acid, ethyl cyanoacetate, 20 mol % m-ZrO NPs,
and water 1 mL were stirred in ball mill to produce solid product.

1
522
S. BAJPAI ET AL.
Table 8. E-factor data of various methodologies used for the synthesis of spirooxindoles under similar
chemistry.
Entry
a,b,c
d,e
Reaction conditions
L-Proline/EtOH
NH Cl/H O, 80 °C
O, TEBA/60 °C
E-factor
Reference
1
2
3
4
5
6
7
8
9
0.14
0.14
0.17
0.16
0.12
0.13
0.16
0.13
0.09
0.07
[38–45]
[38]
[39]
4
2
H
2
[40]
SBA-Pr-NH
LTTM/RT
2
/H
2
O, reflux
[41]
[42]
ROH, NaBr/electrolysis
Mg(ClO /EtOH:H O (1:1), 50 °C
C-SO H/EtOH, reflux
ZnS NPs, H O/sonication
m-ZrO NPs/H O, ball milling
[43]
4
)
2
2
[44]
3
[45]
2
[46]
10
2
2
This work
a
b
c
For entries 1–8, isatin, malononitrile, and dimedone were subjected for reaction.
For entry 9, isatin, ethyl cyanoacetate, and dimedone were subjected for reaction.
[46]
For entry 10, 5-chloroisatin, ethyl cyanoacetate, and barbituric acid were subjected for reaction.
d
E-factor ¼ amount of waste/amount of product.
e
Amount of solvent and catalyst was excluded in the calculation of E-factor.
To compare the efficiency of the proposed methodology with other reported methodol-
ogies, E factor was calculated for compound 4a and compared with the E factor of first/
optimized compound of reported procedures (Table 8). Data obtained are presented in
the Table 8 which clearly indicates that the proposed method is highly efficient than other
procedures reported in the literature for the synthesis of spirooxindoles under similar
chemistry (lesser the E- factor, more efficient the synthesis procedure, Table 8).
Conclusion
All the compounds synthesized using this methodology are novel (reported first time). How-
ever, similar chemistry has been reported in the literature.[38–49] Proposed methodology is
highly efficient and has several advantages over the reported methodologies that are listed
as. It explores relatively newer approach for organic synthesis (ball milling), it explores
use of monoclinic zirconia nanoparticles as a catalyst which is relatively less explored for
multicomponent reactions. The catalyst is inexpensive and easily synthesized in laboratory,
no need of excess amount of solvent for perform the synthesis of spirooxindoles, all the reac-
tions are performed at room temperature in less time (no need of high temperature), the
yield of the products was obtained up to 97% with atom economy up to 96.7%, the product
can be isolated very easily without the use of column chromatography and the recyclability of
the catalyst. The simplicity of the presented protocol makes it an interesting alternative to
other approaches. The catalyst is expected to contribute to the development of environmen-
tally benign methods and forms a part of the nanomaterial chemistry.
Experimental
General
All chemicals were procured from Aldrich, USA, and E. Merck, Germany and used without
further purification. Isatin derivatives were synthesized in the laboratory. TLC was performed
on SiO gel (HF254, 200 mesh). The solvent system used was ethyl acetate: n-hexane and the
2
spots were identified by placing the plate in iodine chamber. IR spectra were recorded on a

SYNTHETIC COMMUNICATIONS®
1523
PerkinElmer FTIR version10.03.05 spectrometer. NMR spectra were run on JEOL AL 300
1
13
and 75.45 MHz FTNMR spectrometer for H NMR and C NMR, respectively; chemical
shifts are given in δ ppm, relative to TMS as internal standard. Elemental microanalysis
was performed on Exeter Analytical Inc Model CE-440 CHN Analyzer. Melting points were
measured in open capillaries and are uncorrected. XRD spectra were recorded on a Scifert
XRD system. TEM image was taken from TECNAI G2, FEI. SEM image was recorded from
scanning electron microscope, QUANTA 200 F. BET surface area analysis was performed by
Smart Sorb-93 manufactured by Smart Instruments Pvt. Ltd. All experiments were
performed in a ball mill manufactured Shivam Instruments Pvt. Ltd., India.
Typical procedure for the synthesis of m-ZrO NPs
2
[
56]
A solution of ZrOCl · 8H O (0.003 mol) in distilled
water was prepared. After that,
2
2
citric acid (0.126 mol) and ethylene glycol (0.126 mol) were subsequently added to this
solution. The resulting mixture was stirred at 80 °C for 30 min to give rise to a clear
solution. Now, the solution was refluxed at 95 °C for 12 h which turned it white, this is
due to the formation of a metal–citrate homogeneous complex. After cooling down, to
bring about the required chemical reactions for the development of polymerization and
evaporation of the solvent, the sol was further slowly heated at 80 °C for 5 h in an open
bath. During continuous heating at this temperature, the polymerization between citric
acid, ethylene glycol and the complexes is developed, and ultimately the sol became more
viscous as a wet gel. In the final step of the sol–gel process, the wet gel was fully dried by
direct heating on the hot plate at 120 °C for 3 h. The resultant production was a light brown
powder. Then it was calcined in a furnace at 750 °C for 4 h at a rate of 4 °C min to the
formation of white monoclinic nano zirconia powder.
Procedure for the synthesis of substituted spirooxindole 4a
A milling beaker (100 mL) was equipped with 16 milling balls (Al O , d: 10 mm).
2
3
Afterward, 5-chloroisatin 1a (0.01 mol), barbituric acid 2a (0.01 mol), ethyl cyanoacetate
3
(0.01 mol), water 1 mL, and 20 mol% of m-ZrO NPs were placed to the milling beaker
The parameters, rotations per minute, and milling time were set up and the milling process
was started. The progress of the reaction was monitored by thin-layered chromatography
2
(n-hexane: ethyl acetate). After the milling process (30 min), the beaker was opened and
the milling balls were removed. Subsequently, 50 mL of acetone was added to dissolve
the product; the catalyst was separated by centrifuging followed by decantation and then
washed with several times by acetone (4 � 10 mL), dried at 80–90 °C for 12 h, calcinated
at 750 °C for 4 h, and reused again. The liquid portion was evaporated and dried to get
crude product. The crude products were recrystallized from ethanol.
Characterization data of synthesized substituted spirooxindole 4a
0
0
0
0
0
0
0
0
Ethyl
[
7 -amino-5-chloro-2,2 ,4 -trioxo-1 ,2 ,3 ,4 -tetrahydrospiro[indoline-3,5 -pyrano
0
2,3-d]pyrimidine]-6 -carboxylate (4a)
Light yellowish white solid, mp 246–248 °C, IR (KBr) υ: 3395, 3305, 3112, 2955, 1729, 1698,
À 1
1
1
688, 1632, 1623, 1611, 1570, 1458, 1368, 1284 cm . H NMR (300 MHz, DMSO-d ) δ:
6

1
524
S. BAJPAI ET AL.
1
.19–1.23 (t, J ¼ 6.0 Hz, 3H, CH ), 4.10–4.17 (q, J ¼ 7.2 Hz, 2H, CH ), 6.86–7.16 (m, 3H,
3
2
aromatic protons), 7.34 (s, 2H, NH ), 10.45 (s, 1H, NH), 11.09 (s, 1H, NH), 11.59
2
(
1
s, 1H, NH) ppm. 13C NMR (75.45 MHz, DMSO-d ) δ: 13.0, 46.2., 59.1, 76.2, 89.2,
6
08.1, 120.6, 122.7, 127.3, 135.3, 144.0, 149.1, 152.1, 158.6, 161.2, 167.4, 179.3 ppm. Anal.
calcd. for C H ClN O : C, 50.45; H, 3.24; N, 13.84. Found: C, 50.38; H, 3.34; N, 13.80%.
1
7
13
4 6
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