Synthesis of Spirooxindoles through Cyclocondensation of Isatin and Cyclic 1,3-Diones

Article abstract of DOI:10.1002/jhet.3217

A simple, clean, and efficient method for the synthesis of spirooxindole derivatives via condensation of isatin with enolizable cyclic β-diketones has been developed. The use of water as a solvent allows avoiding the use of toxic organic solvents, which makes this reaction safe and environmentally friendly. The mechanism of the condensation reaction has been investigated using first-principles-based density functional theory calculations.

Full text of DOI:10.1002/jhet.3217

Month 2018
Synthesis of Spirooxindoles through Cyclocondensation of Isatin and
Cyclic 1,3-Diones
Rahul Joshi,a*
Anita Kumawat, Saurabh Singh, Tapta Kanchan Roy, and Ram T. Pardasanic*
a
b
c,d
a
Department of Chemistry, University of Rajasthan, Jaipur 302004, India
b
M.L.V. Government P.G. College, Bhilwara, Rajasthan, India
c
Department of Chemistry, Central University of Rajasthan, Bandar Sindri, Kishangarh, Ajmer, Rajasthan, India
d
Department of Chemistry and Chemical Sciences, Central University of Jammu, Jammu 180011, India
*
E-mail: rtpardasani@curaj.ac.in; rjsfs2018@gmail.com
Received December 30, 2017
DOI 10.1002/jhet.3217
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A simple, clean, and efficient method for the synthesis of spirooxindole derivatives via condensation of
isatin with enolizable cyclic β-diketones has been developed. The use of water as a solvent allows avoiding
the use of toxic organic solvents, which makes this reaction safe and environmentally friendly. The mecha-
nism of the condensation reaction has been investigated using first-principles-based density functional theory
calculations.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
and anti-proliferative [15] activities. The xanthene
derivatives are also being utilized as antagonists for
paralyzing action of zoxazolamine [16] and in
photodynamic therapy [17] and photostable dyes and
polymerizable light-emitting dyes [18], in addition to
their uses as fluorescent dyes and pH-sensitive fluorescent
materials for visualization of biomolecules [19], along
with their use in laser technologies [20]. Many xanthene
derivatives are also potent nonpeptidic inhibitors of
recombinant human calpain I [21] and novel CCRl
receptor antagonists [22] (Fig. 2).
Indole moiety is part of various natural products and
medicinal agents. In literature, it has been reported that
sharing of the indole-3 carbon atom during formation of
spiroindoline derivatives greatly enhances its biological
activity [23–25]. Mitomycins are natural antibiotics and
anticancer compounds acting as DNA cross-linking
agents, having an indole moiety [26].
The synthesis of spiroheterocycles presents an
interesting synthetic challenge to an organic chemist
because of their structural rigidity and complexity [1,2].
Spirooxindoles constitute the core structure of many
synthetic drugs [3], exhibit remarkable biological
properties, and are frequently observed in natural
alkaloids [4,5], such as spirotryprostatin B, marefortine,
pteropodine, and isopetropodine (Fig. 1). The spiro center
provides structural rigidity and complexity to the
molecules, thereby increasing its affinity towards proteins
by reducing the loss of conformational entropy [6].
Considerable efforts have been directed towards the
construction of spirooxindole derivatives in which the
classical cyclocondensation method has been used [7].
Consequently, a number of spiro compounds have been
obtained with diverse biological activities. These
activities mainly include antibacterial, antiviral, anti-
inflammatory, and antimicrobial [8]. They are also useful
in photodynamic therapy [9].
Xanthene derivatives are also part of many dyes and
fluorescent materials for visualization of biomolecules
and in laser technologies [10]. Synthetic xanthene
derivatives were evaluated as trypanothione reductase
inhibitors and chloroquine-potentiating agents [11].
Xanthene derivatives are present as structural building
blocks in various natural products exhibiting analgesic,
antibacterial [12], antiviral [13], anti-inflammatory [14],
Scanty information is available in the literature
concerning the chemistry of such heterocyclic systems
containing spirooxindole system and their mass
fragmentation studies [27], and no attention seems to have
been given to their computational studies. We now wish to
report the synthesis and computational studies of new
spirooxindole derivatives, that is, 2,3,5,6-tetrahydro-1H-
0
0
0
spiro[dicyclopenta[b,e]pyran-8,3 -indoline]1,2 ,7-trione and
0
0
10H,12H-spiro[diindeno[1,2-b:2 ,1 -e)pyran-11,3 -indoline]-
0
2 ,10,12-trione. Spirooxindole derivatives were also
derived in the presence of SBA-15-Pr–SO H as an
3
©
2018 Wiley Periodicals, Inc.

R. Joshi, A. Kumawat, S. Singh, T. K. Roy, and R. T. Pardasani
Vol 000
Figure 1. Naturally occurring and biologically active spiroheterocyclic compounds.
Figure 2. Some biologically important xanthene derivatives.
Scheme 1. Synthesis of spirooxindole derivatives. [Color figure can be
viewed at wileyonlinelibrary.com]
efficient heterogeneous nanosolid acid catalyst [28].
An environmentally benign, readily available, and cost-
effective β-cyclodextrin serves as a good alternative to the
expensive catalysts containing metals for the synthesis of
spirooxindole derivatives [29]. The fluoroboric acid
(
HBF ) adsorbed on mesoporous silica nanoparticles was
4
probed through a library synthesis of tetraketones or their
tautomeric enol forms. These tetraketones are further
transformed into xanthenes [30].
As part of our program aimed at developing new
selective and environmentally friendly methodologies for
the preparation of heterocyclic compounds [31], a
number of spirooxindole derivatives have been
nitrate in water with constant stirring at 100°C. The
structure of the new products was unambiguously
1
confirmed by spectral techniques such as IR, H-NMR,
13
C-NMR, and mass spectroscopies, and the physical
synthesized through
employing water as the reaction medium.
a
cyclocondensation reaction
data of the synthesized compounds are presented in
Table 1.
The >C¼O group of isatin in the range of 1720–
ꢀ
1
13
1
750 cm disappeared in IR as well as in C-NMR
RESULTS AND DISCUSSION
in the range of 185–190 ppm, and simultaneously, the
1
3
appearance of spiro carbon in C-NMR in the range
of 40–60 ppm was decisively indicative of product
formation (11a–h). Additional evidence was gathered
from the mass spectrum of spirooxindole derivatives.
The molecular ion peak and the base peak for 11a
appear at m/z 308 (M + 1) and 276 (100%),
respectively. The mass spectrum of spirooxindole
product 11b gave molecular ion peak at m/z 404
(M + 1) and an additional peak at m/z 319 (M–CO),
and for compound 11c, molecular ion peak and other
peaks were obtained at 336 (M + 1) and 307 (M–CO)
and 214 (M–CO–C H O), respectively; 11d exhibited
The construction of spirooxindole derivatives has
been explored by the Knoevenagel condensation of isatin
with active methylene group of cyclic β-diketones, which
was dehydrated easily to yield the α,β-unsaturated
carbonyl compound. The cyclization reaction of
appropriate α,β-unsaturated compound with a second
molecule of cyclic β-diketone in aqueous medium
resulted in the exclusive formation of the spirooxindole
products (11a–h) in 43–84% yields (Scheme 1). The
plausible mechanism of cyclocondensation reaction of
isatin derivatives with cyclic β-diketones was shown in
Scheme 2. The cyclocondensation reaction of isatin with
cyclic β-diketones was carried out with ceric ammonium
6
6
molecular ion peak and other peaks at 392 (M + 1)
and 363 (M–CO) and 307 (M–3CO), respectively.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Spirooxindoles through Cyclocondensation of Isatin and Cyclic 1,3-
Diones
Scheme 2. Plausible mechanism of cyclocondensation reaction. [Color figure can be viewed at wileyonlinelibrary.com]
Table 1
Physical data of spirooxindole derivatives (11a–h).
EXPERIMENTAL
General procedure. All chemicals were purchased from
Compound
no.
Molecular
formula
Time
(h)
mp
(°C)
Yield
(%)
Entry
Aldrich Chemical Company (St. Louis, MO) and used
1
13
without further purification. The H-NMR and C-NMR
were obtained from Bruker’s 500 spectrometer (at 500 and
125 MHz, respectively) (Bruker, Rheinstetten, Germany),
and chemical shifts are reported in ppm scale with respect
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
11f
C
18
C
26
C
20
C
24
H13NO
H13NO
H17NO
H25NO
4
4
4
4
9
7
11
4
3
3
>300
235
>300
>300
240
220
110
274
43
78
54
52
58
84
45
58
C
18
C
26
C
20
C
24
H
12
12
16
24
N
2
N
2
N
2
N
2
O
6
6
6
6
1
13
to CDCl 7.269 ppm for H-NMR and 77.00 ppm for C-
3
H
H
H
O
O
O
NMR as internal standard. Fourier transform infrared
spectra were employed on Shimadzu FTIR 8300
spectrophotometer (Kyoto, Japan) for the characterization of
the obtained product. Mass spectral studies were performed
on XEVO G-2S QTOF. Melting points were determined in
open capillary tubes with a Barnstead Electrothermal 9100
BZ circulating oil melting point apparatus and are
uncorrected. Analytical thin-layer chromatography was
performed using 2.5- to 5-cm plates coated with 0.25 mm
thickness of silica gel 60F-254 Merck (Kenilworth, NJ),
and visualization was accomplished with ultraviolet light,
11g
11h
4
4
A careful literature survey and mechanistic rationale
suggest a plausible pathway for the synthesis of
spiroheterocycle 11b as depicted in Scheme 3.
Knoevenagel condensation of 1 and 4 would generate
isatilidine 8, which can react with a second molecule of 4
through Michael addition, generating an intermediate 10
followed by water condensation to generate 11b
(Knoevenagel–Michael addition).
iodine, and/or KMnO staining.
4
Scheme 3. A plausible mechanism for synthesis of spirooxindole 11b. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Joshi, A. Kumawat, S. Singh, T. K. Roy, and R. T. Pardasani
Vol 000
1
3
Experimental procedure for the synthesis of spirooxindole
derivatives. General procedure for ceric ammonium
NH); C-NMR (125 MHz, CDCl ) (δ ppm): 14.22,
3
2
1.09, 25.40, 29.62, 34.00, 60.43, 110.13, 118.13, 122.79,
nitrate-catalyzed synthesis of spirooxindole derivatives.
A
1
23.57, 129.28, 179.35, 199.74 (>C¼O); MS (m/z):
mixture of isatin 1 (1 mmol), β-dicarbonyl compound
2 mmol), and ceric ammonium nitrate (10 mol%) was
added to a 50-mL round bottom flask containing water
2 mL) and was stirred at 100°C for an appropriate
period of time (4–12 h). After completion of the reaction
as indicated by thin-layer chromatography, the reaction
mixture was filtered and washed with water to separate
the catalyst and then was subjected to column
chromatography (with ethyl acetate + petroleum ether) to
remove organic impurities. The obtained solution of the
desired compound was evaporated, and the residue was
+
HRMS (ESI) calcd for C H NO ([M + 1] ): 308.3123;
18
13
4
(
found: 308.2100. Anal calcd for C H NO : C, 70.35; H,
.26; N, 4.56; found: C, 70.30; H, 4.21; N, 4.52.
0H,12H-Spiro[diindeno[1,2-b:2 ,1 -e)pyran-11,3 -indoline]-
2 ,10,12-trione (11b). C H NO : mp 235°C, IR (KBr,
18
13
4
4
(
0
0
0
1
0
26
13
4
ꢀ
1
1
cm ): 3300 (NH), 1735, 1650 (>C¼O); H-NMR
(500 MHz, CDCl ) (δ ppm): 6.77–6.89 (m, Ar–2H), 7.03
3
(d, Ar–2H), 7.15–7.19 (m, Ar–4H), 7.99–8.03 (m, Ar–
4H), 8.33 (NH); C-NMR (125 MHz, CDCl ) (δ ppm):
52.38, 60.43, 110.33, 122.82, 123.21, 123.31, 123.35,
123.76, 128.03, 129.32, 135.65, 135.91, 137.30, 141.50,
142.38, 171.22, 175.94; MS (m/z): HRMS (ESI) calcd for
13
3
recrystallized from ethanol to obtain the pure product.
+
Characterization of synthesized compounds (11a–h).2,3,5,6-
C H NO ([M + 1] ): 404.0918; found: 404.2084. Anal
26
13
4
0
Tetrahydro-1H-spiro[dicyclopenta[b,e]pyran-8,3 -
calcd for C H NO : C, 77.41; H, 3.25; N, 3.44; found:
26
13
4
0
indoline]1,2 ,7-trione (11a).
C H NO : mp ≥300°C,
1
8
13
4
C, 77.42; H, 4.18; N, 4.50.
ꢀ
1
1
0 0 0 0 0
3 ,4 ,6 ,7 -Tetrahydrospiro[indoline-3,9 -xanthene]-
IR (KBr, cm ): 3200 (NH), 1740 (>C¼O); H-NMR
0
0
0
0
1
(
2
500 MHz, CDCl ) (δ ppm): 2.56 (t, 2CH ), 2.89 (t,
1 ,2,8 (2 H,5 H)-trione (11c).
C H17NO : mp ≥300°C, IR
20 4
1
3
2
ꢀ
CH ), 6.90 (dd, 2H), 6.95 (dt, 1H), 7.22 (t, 1H), 7.78 (s,
(KBr, cm ): 3350 (NH), 1740, 1650 (>C¼O); H-NMR
2
Figure 3. Energy profile diagram for synthesis of 11b. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Spirooxindoles through Cyclocondensation of Isatin and Cyclic 1,3-
Diones
(
2
500 MHz, CDCl ) (δ ppm): 1.93–1.99 (m, 4H, 2CH ),
(>C¼O); MS (m/z): HRMS (ESI) calcd for C H N O
20 16 2 6
+
3
2
.03–2.10 (m, 4H, 2CH ), 2.64 (t, 4H, 2CH ), 6.85–7.25
([M + 1] ): 381.1081; found: 381.2126. Anal calcd for
2
2
1
3
(
(
m, Ar–H), 7.60 (s, NH); C-NMR (125 MHz, CDCl3)
δ ppm): 20.01, 27.58, 41.1, 45.89 (spiro-C), 109.20,
C H N O : C, 63.16; H, 4.24; N, 7.37; found: C,
20
16 2 6
63.19; H, 4.25; N, 7.39.
114.82, 121.91, 122.69, 128.47, 133.80, 142.34, 164.9,
1
79.08 (>C¼O), 195.39 (>C¼O); MS (m/z): HRMS
+
(ESI) calcd for C H NO ([M + 1] ): 336.1231; found:
20 17 4
3
36.2078. Anal calcd for C H NO : C, 71.63; H, 5.11;
20 17 4
N, 4.18; found: C, 71.60; H, 5.09; N, 4.16.
0
0 0 0 0 0 0 0
,3 ,6 ,6 -Tetramethyl-3 ,4 ,6 ,7 -tetrahydrospiro[indoline-
3
0
0
0
0
0
3
,9 -xanthene]-1 ,2,8 (2 H,5 H)-trione (11d).
C H NO :
24 25 4
ꢀ
1
mp ≥300°C, IR (KBr, cm ): 3200 (NH), 1650 (>C¼O);
1
H-NMR (500 MHz, CDCl ) (δ ppm): 1.03 (s, 6H,
3
2
2
7
CH ), 1.11 (s, 6H, 2CH ), 2.14 (s, 4H, CH ), 2.53 (s,
3 3 2
H, CH ), 2.54 (s, 2H, CH ), 6.85–6.88 (m, Ar–3H),
2
2
1
3
.14 (t, Ar–1H), 8.06 (s, NH); C-NMR (125 MHz,
CDCl ) (δ ppm): 27.17, 28.98, 31.98, 41.27, 50.95
3
(
spiro-C), 109.58, 113.55, 122.00, 122.29, 128.51,
33.65, 142.33, 163.62, 178.92 (>C¼O), 195.38
>C¼O); MS (m/z): HRMS (ESI) calcd for C H NO
Figure 4. Optimized molecular structure of TS-1. [Color figure can be
viewed at wileyonlinelibrary.com]
1
(
(
2
4
25
4
+
[M + 1] ): 392.1857; found: 392.2856. Anal calcd for
C H NO : C, 73.64; H, 6.44; N, 3.58; found: C, 73.60;
2
4
25
4
H, 6.49; N, 4.60.
0
5
-Nitro-2,3,5,6-tetrahydro-1H-spiro[dicyclopenta[b,e]pyran-
0
0
8
,3 -indoline]-1,2 ,7-trione (11e). C H N O : mp 240°C;
IR (KBr, cm ): 3350, 1745, 1650; H-NMR (500 MHz,
1
8 12 2 6
1
ꢀ
1
CDCl ) (δ ppm): 2.49 (t, 4H, 2CH ), 3.79 (t, 4H, 2CH ),
3
2
2
1
3
6
.66–7.80 (m, Ar–H), 10.81 (s, NH);
C-NMR
(
125 MHz, CDCl ) (δ ppm): 29.18, 35.50, 46.13 (spiro-
3
C), 105.29, 112.80, 114.82, 121.67, 125.12, 144.21,
1
48.31, 160.1, 175.26 (>C¼O), 195.07 (>C¼O); MS
+
(
m/z): HRMS (ESI) calcd for C H N O ([M + 1] ):
18 12 2 6
Figure 5. Optimized molecular structure of TS-2. [Color figure can be
viewed at wileyonlinelibrary.com]
3
53.0768; found: 353.1028. Anal calcd for C H N O :
18 12 2 6
C, 61.37; H, 3.43; N, 7.95; found: C, 61.39; H, 3.45; N,
7
.97.
0
0
0
0
5
-Nitro-10H,12H-spiro[diindeno[1,2-b:2 ,1 -e)pyran-11,3 -
0
indoline]-2 ,10,12-trione (11f).
IR (KBr, cm ): 3400, 1745, 1660; H-NMR (500 MHz,
C H N O : mp 220°C;
26 12 2 6
1
ꢀ
1
CDCl ) (δ ppm): 6.98–8.15 (m, Ar–H), 10.65 (s, NH);
3
1
3
C-NMR (125 MHz, CDCl ) (δ ppm): 45.91 (spiro-C),
3
1
1
26.7, 128.3, 128.7, 129.45, 134.2, 134.4, 136.1, 144.5,
48.2, 160.0, 168.2 (>C¼O), 187.0 (>C¼O); MS (m/z):
+
HRMS (ESI) calcd for C H N O ([M + 1] ):
2
6 12 2 6
4
48.0695; found: 448.1995. Anal calcd for C H N O :
26 12 2 6
C, 69.65; H, 2.70; N, 6.25; found: C, 69.67; H, 2.72; N,
.23.
6
0 0 0 0 0
-Nitro-3 ,4 ,6 ,7 -tetrahydrospiro[indoline-3,9 -
5
0
0
0
0
xanthene]1 ,2,8 (2 H,5 H)-trione (11g).
C H N O : mp
20 16 2 6
1
ꢀ
1
110°C; IR (KBr, cm ): 3460, 1722, 1665; H-NMR
(
500 MHz, DMSO-d ) (δ ppm): 1.03 (t, 4H, 2CH ),
6
2
1
1
.27–1.32 (t, 4H, 2CH ), 1.38 (t, 4H, 2CH ), 5.89 (t, Ar–
2 2
H), 5.99 (d, Ar–1H), 6.19 (t, Ar–1H), 9.44 (s, NH); C-
13
NMR (125 MHz, DMSO-d ) (δ ppm): 20.20, 27.37,
6
37.46, 45.81 (spiro-C), 108.71, 121.09, 123.12, 128.1,
Figure 6. Optimized molecular structure of TS-3. [Color figure can be
134.75, 144.26, 148.31, 165.57, 178.85 (>C¼O), 195.62
viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Joshi, A. Kumawat, S. Singh, T. K. Roy, and R. T. Pardasani
Vol 000
0
0
0
0
0
0
0
0
0
0
5
-Nitro-3 ,3 ,6 ,6 -tetramethyl-5-nitro-3 ,4 ,6 ,7 -
COMPUTATIONAL DETAILS
0
0
0
ꢀ
tetrahydrospiro[indoline-3,9 -xanthene]-1 ,2,8 (2 H,5 H)-trione
1
(
1
(
2
11h). C H N O : mp 274°C; IR (KBr, cm ): 3360,
24 24 2 6
1
To validate the proposed reaction mechanism, we
carried out first-principles-based theoretical calculations
using the density functional theory-based triple hybrid
B3LYP functional [32]. The initial conformational search
for each reactants, intermediates, and products was
performed at B3LYP/6-31G* level of theory. Considering
the lowest energy structures for each case, further full
geometry optimization and subsequent harmonic
frequency calculations were performed using B3LYP
with 6-31G** basis [33], to determine the extrema for all
the reactants, intermediates, and products. The
corresponding transition states were explored by looking
at the reaction and product intermediates. Each minima
were confirmed by no imaginary frequency, and
transition states at each step were confirmed by a single
imaginary frequency characterized by the corresponding
desired reaction coordinates. The vibrational zero-point
energy was considered for all the molecules in evaluating
the final energy profiles of the suggested reaction
mechanisms as (Fig. 3) shown in Scheme 3. All the
calculations were carried out with Gaussian 09 program
suit [34].
720, 1665; H-NMR (500 MHz, CDCl ) (δ ppm): 1.09
3
s, 6H, 2CH ), 1.17 (s, 6H, 2CH ), 2.21 (4H, s, CH ),
.32 (4H, s, CH ), 6.96–8.33 (4H, m, Ar–H), 8.53 (s,
NH); C-NMR (125 MHz, CDCl ) (δ ppm): 27.10,
3 3 2
2
13
3
2
1
1
(
9.01, 33.07, 43.25, 46.49, 54.60 (spiro-C), 109.81,
10.94, 116.62, 125.78, 133.73, 143.46, 149.05, 170.39,
81.79 (>C¼O), 195.82 (>C¼O); MS (m/z): HRMS
+
ESI) calcd for C H N O ([M + 1] ): 436.1634; found:
24 24 2 6
4
36.2011. Anal calcd for C H N O : C, 66.05; H, 5.54;
N, 6.42; found: C, 66.07; H, 5.56; N, 6.43.
24 24 2 6
We started with the reaction of 1 with the enol form of
4. In the first step, enolic carbon attacked the carbonyl
carbon with a concerted proton transfer from enolic
oxygen to carbonyl oxygen forming a six-membered
transition state. The optimized structure of this first
transition state was shown in Figure 4. The
corresponding reaction barriers are found to be only
5
.62 kcal/mol, which shows the high feasibility of this
step. This reaction is exothermic by 10.89 kcal/mol,
which shows that this step is kinetically as well as
thermodynamically favorable. This is followed by water
elimination, which formed an α,β-unsaturated compound
Figure 7. Optimized molecular structure of product 11b. [Color figure
can be viewed at wileyonlinelibrary.com]
Figure 8. Optimized geometries of spirooxindole derivatives. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Spirooxindoles through Cyclocondensation of Isatin and Cyclic 1,3-
Diones
Figure 9. Reactants and products. [Color figure can be viewed at wileyonlinelibrary.com]
8
. In the next step, another cyclic 1,3-dione (4) attacked to
of spirooxindole derivatives has been reported. A
significant observation of the reported method is the
employment of greener approach using water as a
solvent and environmentally benign protocol. This
cyclocondensation process involves formation of two C–
C bonds and two C–O bonds during synthesis of the
spirooxindoles. This protocol would have significant
relevance in the area of pharmaceutical and medicinal
chemistry.
carbon of α,β-unsaturated compound with a proton
transfer to oxygen via six-membered transition state. The
optimized structure of this second transition state was
shown in Figure 5. We found the barrier of this step is
very low (0.33 kcal/mol), which indicates that this step
is instantaneous and the reaction is once again
exothermic by ~21 kcal/mol with a formation of the
product 9. The next step is the keto–enol tautomerization
to form 9 (keto form) to 10 (enol form). It was happened
through transition state 3 and the optimized structure of
third transition state shown in Figure 6. The reaction
barrier for the tautomerization is found to be 26.32 kcal/
mol, which was followed by water elimination to form
the product 11b. Optimized structure of the product 11b
was shown in Figure 7. Overall, it is found that the
proposed mechanism is highly favorable for the
formation of 11b starting from 1 and 4. Optimized
geometries of all spirooxindole derivatives from 11a to
Significance of the work.
Ceric ammonium nitrate
(CAN) can be easily soluble in water and easily removed
from crude product by washing from water and easily
recrystallized from ethanol. CAN provides good
oxidizing ability to synthesize spirooxindoles rather than
other catalyst.
In terms of CAN, redox process Ce(IV) is converted
to Ce(III), one negative electron change signaled by the
fading of the solution color from orange to pale
yellow; thus, it also works as indicator to complete the
reaction.
11h were shown in Figure 8. All the optimized
geometries were carried out with Gaussian 09 program
suit. Structure of all types of reactants and synthesized
spirooxindole derivatives from 11a to 11h was shown in
Figure 9.
Products 11a, 11b, 11e, and 11f have been constructed
with appropriate yield. These compounds have not been
reported in any journal. We are delivering here a new
methodology or experimental criteria for the synthesis of
these compounds.
Furthermore, the computational criterion is one of the
most important terms in providing the better reaction
pathway (mechanism) to understanding the transition
state (TS) and stability of the product by optimizing the
energy profile diagram.
CONCLUSIONS
An expedient, delicate, and efficient cyclocondensation
methodology giving higher yields for the facile synthesis
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Joshi, A. Kumawat, S. Singh, T. K. Roy, and R. T. Pardasani
Vol 000
Acknowledgments. The authors are thankful to the Central
University of Rajasthan for carrying out spectral analysis of
representative samples. One of us (A. K.) is thankful to the
CSIR New Delhi for award of Junior Research Fellowship.
T. K. R. thanks the DST-FIST grant [SR/FST/CSI-257/2014(c)],
Central University of Rajasthan, CMSD, University of
Hyderabad for computational support, and Central University of
Jammu for infrastructural support.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet