An Efficient and Easy Method for the One-pot Synthesis of Spirooxindoles in the Presence of Na2CO3

Article abstract of DOI:10.1002/jhet.3580

An efficient and easy procedure for the one-pot synthesis of spirooxindoles in the presence of Na₂CO₃ in water?:?methanol (1:1) is described. The salient features of this method are simple methodology, shorter reaction time, easy pro

Full text of DOI:10.1002/jhet.3580

Month 2019 An Efficient and Easy Method for the One-pot Synthesis of Spirooxindoles
in the Presence of Na2CO3
*
Khadhar Navaz Umar Basha and Shanthi Gnanamani
Sona Advanced Organic Materials Laboratory, Department of Chemistry, Sona College of Technology, Junction Main
Road, Salem, Tamil Nadu 636005, India
*E-mail: shanthiglo19@gmail.com
Received January 9, 2019
DOI 10.1002/jhet.3580
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and easy procedure for the one-pot synthesis of spirooxindoles in the presence of Na2CO3 in
water : methanol (1:1) is described. The salient features of this method are simple methodology, shorter re-
action time, easy product isolation, and no chromatographic purification.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
reaction conditions, toxicity, corrosiveness, cost,
preparation of catalyst, and so forth. Thus, there is still
ample room for design of a convenient, low cost, and
clean method to assemble these compounds using mild
catalyst.
Spirooxindoles have become privileged skeletal
framework with significant and promising
pharmacological properties in various therapeutic areas
[1]. They possess biological activities like anti-human
immunodeficiency virus [2], antifungal [3], anticancer
[4], antitubercular [5], antimalarial [6], progesterone
receptor modulator [7], and MDM2 inhibitor [8]. A
number of spirooxindole-based motifs are present in
many natural products and biologically active molecules
(Fig. 1) [9]. For example, spirotryprostatins A and B
inhibits the G21M progression of cell division in
mammalian tsFT210 cells [10]. MI-219 is a novel orally
active MDM2 inhibitor that activates the p53 pathway
and is selectively toxic to tumor cells [11]. NITD609 is
used for the treatment of malaria [12]. The therapeutic
activity of spirooxindoles is extraordinary and has been a
key driving force in the development of new, easy, and
convenient method for their synthesis.
In continuation of our ongoing research on the synthesis
of spirooxindoles [19,24], we herein describe an
improved, new, and convenient method for synthesis of
spirooxindoles in H2O/MeOH system using Na2CO3 as
catalyst at room temperature within a shorter period of
time. We believe that our method will serve as an easy and
clean method for the synthesis of spirooxindoles under
column chromatography-free condition. High yield,
shorter reaction time under room temperature condition
and water : methanol (1:1) medium, use of cheap and
nontoxic catalyst, easy product isolation, and no column
chromatographic purification make this procedure a
sustainable one.
Multicomponent reactions in aqueous media will serve
as an attractive tool for rapid construction of heterocycles
in terms of cost, safety, and environmental concern [13].
There are many methods available for the preparation of
spirooxindoles. Among which, three-component reactions
of isatin, malononitrile, and 1,3-dicarbonyl compound
offer a convenient method for the synthesis of these
elegant targets in the presence of NEt3 [14], sodium
stearate [15], tris(2-hydroxyethyl)amine [16], NH4Cl [17],
RESULTS AND DISCUSSION
Initially, we investigated the reaction of isatin,
malononitrile, and ethyl acetoacetate with various
carbonate catalysts such as Na2CO3, K2CO3, Li2CO3, and
Cs2CO3. Among the four catalysts employed, Na2CO3
catalyst was found to be the best one in terms of yield and
reaction time (Table 1). The product formation was
observed within an hour and went to completion within
few hours when the reaction was carried out with Na2CO3.
In order to optimize the best condition, the reaction was
conducted with 1 equiv of Na2CO3 catalyst at room
temperature using various solvents (Table 2). Excellent
results were obtained when the reaction was carried out in
water : methanol (1:1). Similarly, the mole ratio of
ethylenediamine
diacetate
[18],
InCl3
[19],
tetrabutylammonium bromide [20], β-cyclodextrin [21],
L-proline [22], and lipase [9h]. This reaction can also be
performed by electrocatalytic method [23]. However, to
the best of my knowledge, most of these methods suffer
from tedious synthetic routes, long reaction times, drastic
© 2019 Wiley Periodicals, Inc.

K. N. Umar Basha and S. Gnanamani
Vol 000
Figure 1. Examples of biologically active spirooxindole core structures.
Table 1
Screening of various carbonate catalystsa.
Table 3
Optimization of the reaction conditions.
Entry
Solvent
Time (h)
Yield (%)a
Entry
Catalyst (equiv)
Time (h)
Yield (%)a
1
2
3
4
Na2CO3
K2CO3
Li2CO3
Cs2CO3
6
11
10
12
55
40
38
35
1
2
3
4
5
1
4
4
4
4
4
90
90
90
70
60
0.5
0.4
0.2
0.1
aReaction carried out in methanol.
Reactions were carried out in 1-mmol scale.
aIsolated yields.
Table 2
Screening of various solvents.
with ethanol, and dried to afford the product in pure form.
The desired product was obtained in highly pure form just
by filtration and does not require any column
chromatographic purification. Another advantage of this
method is that the progress of the reaction was easily
followed from color changes.
Entry
Solvent
Time (h)
Yield (%)a
1
2
3
4
5
Ethanol
Methanol
6
6
50
55
50
90
80
Water
Water : Methanol (1:1)
Water : Ethanol (1:1)
12
4
4
With this established optimum condition, we intended to
explore the generality of the developed protocol with
several substituted isatins as well as ethyl cyanoacetate,
and results are summarized in Scheme 2 and Table 4. We
were delighted to find that array of isatin derivatives with
diverse functional groups were well tolerated and
afforded desired products in quantitative yield with very
good purity under optimized condition without column
chromatographic purification.
The structures of compounds 5a–j were confirmed by
IR, 1H-NMR, and 13C-NMR spectroscopy, mass
spectrometry, and elemental analysis. The IR spectrum of
5a showed absorptions at 3479, 2189, 1678, and
1595 cmꢀ1, indicating the presence of –NH2, cyano,
aIsolated yields.
Na2CO3 was studied, and the results are listed in Table 3.
The amount of Na2CO3 was found to be an important
parameter for enhancement of yield of the reaction,
with 40 mol % of Na2CO3 being optimum (Scheme 1).
In the beginning of the reaction, we observed reddish
precipitate when malononitrile was added to isatin. After
sequential addition of ethyl acetoacetate to the reaction
mixture, the color of the reaction mixture changed from
reddish to orange to pale yellow. Finally, after 4 h, we
found the formation of a creamy white precipitate
(Fig. 2). The obtained precipitate was filtered, washed
Journal of Heterocyclic Chemistry
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One-pot Synthesis of Spirooxindoles
Scheme 1. One-pot three-component synthesis of spirooxindole 5a.
Figure 2. (A) Reaction mixture of isatin 1 (0.147 g, 1 mmol) and malononitrile 2 (0.066 g, 1 mmol) in 8-mL water : methanol (1:1) at room temperature.
(B) Catalytic amount of Na2CO3 (0.042 g, 40 mol %) and ethyl acetoacetate 3 (0.130 g, 1 mmol) was added to the formed in situ isatylidenemalononitrile
and stirring after 2 h, (C) stirring after 3.5 h, and (D) at the end of the reaction. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 2. One-pot three-component synthesis of spirooxindoles 5a–j.
Table 4
One-pot three-component synthesis of spirooxindoles.
Entry
1
Product
Time (h)
4
Yield (%)a
90
(Continues)
Journal of Heterocyclic Chemistry
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K. N. Umar Basha and S. Gnanamani
Vol 000
Table 4
(Continued)
Entry
2
Product
Time (h)
Yield (%)a
3
2
2
82
86
92
3
4
5
6
7
8
2
87
85
92
94
3
2.5
1
(Continues)
Journal of Heterocyclic Chemistry
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One-pot Synthesis of Spirooxindoles
Table 4
(Continued)
Entry
9
Product
Time (h)
7
Yield (%)a
78
10
5
82
aIsolated pure product.
carbonyl, and double-bond functionalities, respectively. In
the H-NMR spectrum, aromatic signals were seen at δ
malononitrile
2
to afford isatylidenemalononitrile
1
derivative 4. This step can be regarded as a fast
Knoevenagel reaction. The second step involves Michael
addition of ethyl acetoacetate 3 on the electrophilic C═C
double bond followed by intramolecular nucleophilic
attack of the enolic─OH group on the cyano group
(Scheme 4) [25].
The efficiency of Na2CO3 has been compared with some
of bases and catalysts reported previously in the literature
for the synthesis of spirooxindoles (Table 5). From
Table 5, it can be inferred that heating is not required and
the reaction catalyzed by Na2CO3 proceeds smoothly at
room temperature itself with higher yield of products.
6.79–7.16, methyl at δ 2.32, and ethyl group of ester at δ
0.80 and 3.72, and –NH2 and –NH groups were observed
as a broad singlet at δ 7.14 and 10.39, respectively. The
carbonyl resonated at δ 179.0 in the 13C-NMR spectrum.
To further explore the potential of this protocol for
heterocyclic synthesis, we investigated one-pot reaction
of isatin and malononitrile with 1,3-dimethylbarbituric
acid and obtained spirooxindoles7a–c in good yields
(Scheme 3). The reaction proceeded smoothly at room
temperature and yielded the products within 4–5 h.
We propose the possible mechanism to account for the
formation of 5. The process represents a typical cascade
reaction in which the isatin 1 first condenses with
Moreover, Na2CO3 is
available, easy to handle, and a mild base.
a cheap, nontoxic, readily
Scheme 3. One-pot three-component synthesis of spirooxindoles 7a–c.
Journal of Heterocyclic Chemistry
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K. N. Umar Basha and S. Gnanamani
Vol 000
Scheme 4. Plausible mechanism for the formation of spirooxindoles 5a–j.
Table 5
Comparison of the efficiency of Na2CO3 with other catalysts for the synthesis of 5a.
Entry
Catalyst
Solvent
T (°C)
Time
Yield (%)
Ref
1
2
3
4
5
6
7
8
9
Et3N
Sodium stearate
Tris(2-hydroxyethyl)amine
Ammonium chloride
EDDA
EtOH
H2O
EtOH
H2O
H2O
H2O
H2O
Reflux
60°C
Reflux
80°C
60°C
Reflux
60°C
80°C
RT
30 min
3 h
1–2 h
10 min
1 h
1 h
5 h
1 h
4 h
80
93
90
92
85
90
90
92
90
[14]
[15]
[16]
[17]
[18]
[20]
[21]
[22]
This work
TBAB
β-Cyclodextrin
L-Proline
H2O
Na2CO3
H2O : Methanol (1:1)
RT, room temperature.
CONCLUSIONS
EXPERIMENTAL
Isatin, 5-chloroisatin, 5-bromoisatin,
In conclusion, we have developed a new, easy, and clean
method for the synthesis of spirooxindoles catalyzed by
Na2CO3 in water : methanol (1:1) at room temperature.
The use of Na2CO3 as mild and easily available base
catalyst and water : methanol (1:1) as the reaction
medium makes this protocol a cheap and environmentally
friendly approach. Further merits of this method are its
shorter reaction times, high yields, wide substrate scope,
easy product isolation, and no chromatographic
purification. The protocol was also extended by replacing
ethyl acetoacetate with 1,3-dimethylbarbituric acid.
General.
malononitrile, ethyl cyanoacetate, ethyl acetoacetate,
ethyl benzoacetate, and 1,3-dimethylbarbituric acid were
purchased from Sigma-Aldrich. Na2CO3 was purchased
from S.D. Fine-Chem. Limited, Chennai, India. Melting
points were determined in capillary tubes and are
uncorrected. IR measurements were performed as KBr
pellets for solid using Fourier transform infrared (FTIR)
(Thermo Electron Scientific Instruments, Madison, WI,
USA) and Shimadzu Prestige 20 IR spectrometer (Shimadzu
1
Corp., Kyoto, Japan). The H-NMR and 13C-NMR spectra
Journal of Heterocyclic Chemistry
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Month 2019
One-pot Synthesis of Spirooxindoles
were recorded in DMSO-d6 with Bruker 400- and 100-
MHz high-resolution NMR spectrometer (Bruker Corp.,
Billerica, MA). DMSO-d6 was used as the solvent for the
NMR spectral measurements, and spectra were recorded
in ppm with TMS as internal standard. Multiplicities are
abbreviated as follows: singlet (s), doublet (d), triplet (t),
multiplet (m), and broad (br). The mass spectra were ana-
lyzed by using an electrospray ionization method with
Thermo Finnigan mass spectrometer (Thermo Fisher Sci-
entific, Waltham, MA). Elemental analyses were recorded
using a Thermo Finnigan FLASH EA 1112 CHN analyzer
(Thermo Fisher Scientific). Analytical Thin layer chroma-
tography was performed on precoated plastic sheets of sil-
ica gel G/UV-254 of 0.2-mm thickness (Macherey–Nagel).
DMSO-d6): δ 0.84 (s, 3H), 2.34 (s, 3H), 3.82 (s, 2H),
6.77 (s, 1H), 7.23 (s, 4H), 10.55 (s, 1H, NH); 13C-NMR
(100 MHz, DMSO-d6): δ 13.5, 19.2, 49.7, 56.4, 60.9,
104.2, 111.8, 113.9, 117.8, 126.7, 131.3, 137.7, 141.9,
159.4, 160.0, 164.8, 178.7; Anal. Calcd. for
C17H14BrN3O4 (404): C, 50.51; H, 3.49; N, 10.40%.
Found: C, 50.47; H, 3.46; N, 10.36%.
Ethyl
1-allyl-20-amino-30-cyano-60-methyl-2-oxospiro-
[indoline-3,40-pyran]-50-carboxylate (5d). Tan white solid;
1
mp 145–147°C; H-NMR (400 MHz, DMSO-d6): δ 0.71
(t, 3H, J = 7.2 Hz), 2.33 (s, 3H), 3.71 (m, 2H), 5.17 (m,
1H), 5.20 (m, 1H), 5.20 (m, 1H), 5.37 (m, 1H), 5.42 (m,
2H), 6.91 (m, 2H), 7.00 (m, 1H), 7.15 (m, 1H), 7.27 (m,
1H); Anal. Calcd. for C20H19N3O4 (365): C, 65.74; H,
5.24; N, 11.50%. Found: C, 65.70; H, 5.21; N, 11.46%.
Diethyl 20-amino-60-methyl-2-oxospiro-[indoline-3,40-pyran]-
30,50-dicarboxylate (5e). Tan white solid; mp 165–167°C
General procedure for the synthesis of spirooxindoles 5a–j
and 7a–c. Representative procedure for spirooxindole 5a.
To a stirred mixture of isatin (0.147 g, 1 mmol) and
(reported 169–170°C) [26]; FTIR (cmꢀ1): 3359, 3250,
2980, 2780, 2700, 1725, 1701, 1630, 1582, 1475, 1380,
1350, 1297, 1150, 1132, 1064; 1H-NMR (400 MHz,
DMSO-d6): δ 0.73 (t, 3H, J = 7.2 Hz), 0.86 (t, 3H,
J = 6.8 Hz), 2.16 (s, 3H), 3.69 (m, 4H), 6.67 (d, 1H,
J = 7.6 Hz), 6.79 (t, 1H, J = 7.2 Hz), 6.91 (d, 1H,
J = 7.2 Hz), 7.07 (t, 1H, J = 6.4 Hz), 7.75 (br s, 2H, NH2),
10.17 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): δ
13.6, 18.8, 49.4, 59.2, 60.6, 75.7, 108.5, 108.8, 121.3,
123.5, 128.0, 136.4, 144.1, 154.1, 160.0, 165.5, 168.0,
180.2; Anal. Calcd. for C19H20N2O6 (372): C, 61.28; H,
malononitrile (0.066 g,
1
mmol) in
8
mL
water : methanol (1:1), a catalytic amount of Na2CO3
(0.042 g, 40 mol %) and ethyl acetoacetate (0.130 g,
1 mmol) was added (Table 4, entry 1). The reaction
mixture was stirred at room temperature for about 4 h.
After complete conversion as indicated from the color
change and also from thin-layer chromatography, the
precipitated solid was filtered and washed with ethanol to
furnish analytically pure product.
Ethyl 20-amino-30-cyano-60-methyl-2-oxospiro[indoline-3,40-
pyran]-50-carboxylate (5a).
Tan white solid; mp 257–
259°C (reported 260–262°C) [26]; FTIR (cmꢀ1): 3479,
5.41; N, 7.52%. Found: C, 61.24; H, 5.37; N, 7.48%.
Diethyl 20-amino-5-chloro-60-methyl-2-oxospiro-[indoline-
3155, 2978, 2189, 1678, 1595, 1467, 1381, 1286, 1211,
3,40-pyran]-30,50-dicarboxylate (5f).
Tan white solid; mp
1
1070, 754, 678; H-NMR (400 MHz, DMSO-d6): δ 0.80
217–219°C (reported 213–219°C) [25]; FTIR (cmꢀ1):
3379, 3270, 3198, 1720, 1693, 1630, 1580, 1527, 1447,
1381, 1349, 1214, 1060; 1H-NMR (400 MHz,
DMSO-d6): δ 0.78 (t, 3H, J = 7.2 Hz), 0.90 (t, 3H,
J = 7.2 Hz), 2.19 (s, 3H), 3.68 (m, 4H), 6.68 (m, 1H),
6.98 (m, 1H), 7.13 (m, 1H), 7.81 (br s, 2H, NH2), 10.23
(s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): δ 13.6,
13.7, 19.0, 49.7, 59.3, 60.8, 75.1, 107.6, 110.2, 123.6,
125.2, 127.9, 138.6, 143.1, 155.1, 160.0, 165.4, 167.7,
180.0; Anal. Calcd. for C19H19ClN2O6 (406): C, 56.09;
(t, 3H, J = 1.6 Hz), 2.32 (s, 3H), 3.72 (m, 2H), 6.79 (d,
1H, J = 7.6 Hz), 6.9 (t, 1H, J = 7.2 Hz), 7.05 (d, 1H,
J = 7.2 Hz), 7.14 (br s, 2H, NH2), 7.16 (m, 1H), 10.39 (s,
1H, NH); 13C-NMR (100 MHz, DMSO-d6): δ 13.4, 19.0,
49.4, 57.0, 60.7, 105.1, 109.8, 117.9, 122.3, 123.9,
129.0, 135.0, 142.6, 158.9, 159.4, 164.9, 179.0; Anal.
Calcd. for C17H15N3O4 (325): C, 62.76; H, 4.65; N,
12.92%. Found: C, 62.70; H, 4.62; N, 12.90%.
Ethyl
20-amino-5-chloro-30-cyano-60-methyl-2-oxospiro
[indoline-3,40-pyran]-50-carboxylate (5b). Tan white solid;
mp 258–260°C (reported 263–265°C) [26]; FTIR (cmꢀ1):
3360, 3230, 3149, 2790, 2201, 1715, 1680, 1630, 1590,
1450, 1375, 1340, 1280, 1220, 1075; 1H-NMR
(400 MHz, DMSO-d6): δ 0.83 (t, 3H, J = 7.2 Hz), 2.34 (s,
3H), 3.77 (m, 2H), 6.81 (d, 1H, J = 8.4 Hz), 7.19 (m, 4H),
10.54 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): δ
13.5, 19.2, 49.8, 56.4, 60.9, 104.2, 111.2, 117.8, 124.1,
126.2, 128.9, 137.3, 141.5, 159.3, 159.9, 164.8, 178.8;
Anal. Calcd. for C17H14ClN3O4 (359): C, 56.75; H, 3.92;
N, 11.68%. Found: C, 56.70; H, 3.90; N, 11.65%.
H, 4.71; N, 6.89%. Found: C, 56.05; H, 4.67; N, 6.85%.
Diethyl 20-amino-5-bromo-60-methyl-2-oxospiro-[indoline-
3,40-pyran]-30,50-dicarboxylate (5g).
Tan white solid; mp
1
280–282°C; H-NMR (400 MHz, DMSO-d6): δ 0.79 (m,
6H), 2.19 (s, 3H), 3.73 (m, 4H), 6.66 (s, 1H), 7.09 (m,
2H), 7.76 (br s, 2H, NH2), 10.34 (s, 1H, NH); 13C-NMR
(100 MHz, DMSO-d6): δ 13.7, 19.0, 49.6, 59.3, 60.8,
75.1, 107.6, 110.8, 112.8, 126.3, 130.8, 139.0, 143.6,
155.1, 160.0, 165.4, 167.7, 179.9; Anal. Calcd. for
C19H19BrN2O6 (451): C, 50.57; H, 4.24; N, 6.21%.
Ethyl
20-amino-5-bromo-30-cyano-60-methyl-2-oxospiro-
Found: C, 50.53; H, 4.21; N, 6.18%.
[indoline-3,40-pyran]-50-carboxylate (5c). Tan white solid;
mp 262–264°C; FTIR (cmꢀ1): 3392, 3300, 3204, 3182,
2204, 1704, 1662, 1608, 1585; 1H-NMR (400 MHz,
Diethyl 1-allyl-20-amino-60-methyl-2-oxospiro[indoline-3,40-
pyran]-30,50-dicarboxylate (5h). Tan pink solid; mp 158–
1
160°C; H-NMR (400 MHz, DMSO-d6): δ 0.60 (t, 3H,
Journal of Heterocyclic Chemistry
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K. N. Umar Basha and S. Gnanamani
Vol 000
1
J = 7.2 Hz), 0.78 (t, 3H, J = 7.2 Hz), 2.17 (s, 3H), 3.59 (m,
4H), 4.23 (m, 1H), 4.32 (m, 1H), 5.22 (d, 1H, J = 1.2 Hz),
5.47 (d, 1H, J = 1.6 Hz), 5.82 (m, 1H), 6.84 (d, 1H,
J = 7.6 Hz), 6.90 (t, 1H, J = 7.2 Hz), 6.99 (d, 1H,
J = 6.4 Hz), 7.15 (t, 1H, J = 6.8 Hz), 7.82 (br s, 2H,
NH2); 13C-NMR (100 MHz, DMSO-d6): δ 13.8, 18.9,
43.1, 48.8, 58.9, 60.6, 75.4, 108.2, 118.4, 122.1, 123.3,
128.1, 132.9, 135.6, 144.4, 154.2, 160.2, 165.4, 167.7,
178.1; Anal. Calcd. for C22H24N2O6 (412): C, 64.07; H,
1640, 1265; H-NMR (400 MHz, DMSO-d6): δ 3.01(s,
3H), 3.35 (s, 3H), 6.80 (d, 1H, J = 8.4 Hz), 7.34 (s, 2H),
7.59 (br s, 2H, NH2), 10.71 (s, 1H, NH); 13C-NMR
(100 MHz, DMSO-d6): δ 28.1, 29.8, 48.1, 57.4, 86.9,
111.9, 114.2, 117.1, 127.1, 131.8, 136.4, 141.7, 150.2,
152.8, 158.8, 160.1, 178.1; Anal. Calcd. for
C17H12BrN5O4 (430): C, 47.46; H, 2.81; N, 16.28%.
Found: C, 47.42; H, 2.79; N, 16.24%.
5.87; N, 6.79%. Found: C, 64.03; H, 5.81; N, 6.75%.
Ethyl 20-amino-30-cyano-2-oxo-60-phenylspiro-[indoline-3,40-
Acknowledgment. The authors thank the Sona College of
Technology, Salem, for the research facilities.
pyran]-50-carboxylate (5i).
Tan white solid; mp: 200–
202°C; 1H-NMR (400 MHz, DMSO-d6): δ 0.6 (t, 3H,
J = 7.2 Hz), 3.62 (q, 2H, J = 3.6 Hz), 6.82 (d, 1H,
J = 7.6 Hz), 6.96 (m, 1H), 7.18 (m, 2H), 7.28 (br s, 2H,
NH2), 7.42 (m, 5H), 10.50 (s, 1H, NH); 13C-NMR
(100 MHz, DMSO-d6): δ 13.3, 50.2, 56.6, 60.8, 107.1,
110.0, 118.0, 122.5, 124.5, 128.6, 128.7, 128.8, 129.4,
130.8, 133.0, 133.6, 142.7, 155.8, 160.4, 165.0, 178.5;
Anal. Calcd. for C22H17N3O4 (387): C, 68.21; H, 4.42;
N, 10.85%. Found: C, 68.19; H, 4.40; N, 10.80%.
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Y.; Biot, C.; Kumar, V. Organometallics 2013, 32, 5713; (b) Mondal,
P.; Jana, S.; Balaji, A.; Ramakrishna, R.; Kanthal, L. J Young Pharm
2013, 4, 38.
[6] Raj, R.; Singh, P.; Singh, P.; Gut, J.; Rosenthal, P. J.; Kumar,
V. Eur J Med Chem 2013, 62, 590.
Ethyl
20-amino-5-chloro-30-cyano-2-oxo-60-phenylspiro-
[indoline-3,40-pyran]-50-carboxylate (5j).
Tan white solid;
1
mp 180–182°C; H-NMR (400 MHz, DMSO-d6): δ 0.59
(t, 3H, J = 7.2 Hz), 3.64 (m, 2H), 6.84 (d, 1H, J = 8 Hz),
7.23 (m, 1H), 7.33 (m, 3H), 7.44 (m, 5H), 10.65 (s, 1H,
NH); Anal. Calcd. for C22H16ClN3O4 (421): C, 62.64; H,
3.82; N, 9.96%. Found: C, 62.60; H, 3.80; N, 9.93%.
70-Amino-10,30-dimethyl-2,20,40-trioxo-10,20,30,40-
tetrahydrospiro[indoline-3,50-pyrano[2,3-d]pyrimidine]-60-
carbonitrile (7a). Tan white solid; mp 230–231°C (reported
231–233°C) [27]; FTIR (cmꢀ1): 3315, 1637, 1267; 1H-NMR
(400 MHz, DMSO-d6): δ 3.09 (s, 3H), 3.16 (s, 3H), 6.83 (d,
1H, J = 7.6 Hz), 6.92 (t, 1H, J = .6 Hz), 7.08 (d, 1H,
J = 7.6 Hz), 7.17 (m, 1H), 7.50 (br s, 2H, NH2), 10.48 (s,
1H, NH); 13C-NMR (100 MHz, DMSO-d6): δ 28.1, 29.8,
47.9, 58.1, 87.5, 110.0, 117.2, 122.6, 124.2, 129.1, 133.9,
142.3, 150.2, 152.6, 158.7, 160.0, 178.5; Anal. Calcd. for
C17H13N5O4 (351): C, 58.12; H, 3.73; N, 19.93%. Found:
[7] Fensome, A.; Adams, W. R.; Adams, A. L.; Berrodin, T. J.;
Cohen, J.; Huselton, C.; Illenberger, A.; Kern, J. C.; Hudak, V. A.;
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Slayden, O. D.; Yudt, M.; Zhang, Z. M.; Zhang, P. W.; Zhu, Y.;
Winneker, R. C.; Wrobel, J. E. J Med Chem 2008, 51, 1861.
[8] Yu, S.; Qin, D.; Shangary, S.; Chen, J.; Wang, G.; Ding, K.;
McEachern, D.; Qiu, S.; Nikolovska-Coleska, Z.; Miller, G.; Kang, S.;
Yang, D.; Wang, S. J Med Chem 2009, 52, 7970.
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Kitajima, M.; Aimi, N.; Watanabe, H. Eur J Pharmacol 2002, 444, 39; (b)
Ma, J.; Hecht, S. M. Chem Commun 2004, 1190; (c) Usui, T.; Kondoh,
M.; Cui, C.–B.; Majumi, T.; Osada, H. Biochem J 1998, 333, 543; (d)
Khafagy, M. M.; El-Wahas, A. H. F. A.; Eid, F. A.; El-Agrody, A. M.
Farmaco 2002, 57, 715; (e) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C.
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Int Ed 2007, 46, 8748; (h) Chai, S. J.; Lai, Y. F.; Xu, J. C.; Zheng, H.;
Zhu, Q.; Zhang, P. F. Adv Synth Catal 2011, 353, 371; (i) Galliford, C.
V.; Martenson, J. A.; Stern, C.; Scheidt, K. A. Chem Commun 2007 631.
[10] Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.;
Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish,
D. A.; Deschamps, J.; Wang, S. J Am Chem Soc 2005, 127, 10130.
[11] Shangary, S.; Qin, D.; McEachern, D.; Liu, M.; Miller, R. S.;
Qiu, S.; Nikolovska-Coleska, Z.; Ding, K.; Wang, G.; Chen, J.; Bernard,
D.; Zhang, J.; Lu, Y.; Gu, Q.; Shah, R. B.; Pienta, K. J.; Ling, X.; Kang,
S.; Guo, M.; Sun, Y.; Yang, D.; Wang, S. Proc Natl Acad Sci U S A 2008,
105, 3933.
C, 58.08; H, 3.67; N, 19.87%.
70-Amino-5-chloro-10,30-dimethyl-2,20,40-trioxo-10,20,30,40-
tetrahydrospiro[indoline-3,50-pyrano[2,3-d]pyrimidine]-60-
carbonitrile (7b).
White solid; mp 220–222°C; FTIR
(cmꢀ1): 3356, 2921, 1651, 1264; 1H-NMR (400 MHz,
DMSO-d6): δ 3.04 (s, 3H), 3.36 (s, 3H), 6.81 (d, 1H,
J = 8.0 Hz), 7.21 (d, 1H, J = 8.0 Hz), 7.23 (s, 1H), 7.65
(br s, 2H, NH2), 10.64 (s, 1H, NH). 13C-NMR
(100 MHz, DMSO-d6): δ 28.1, 29.8, 48.1, 57.5, 86.9,
111.1, 117.2, 124.5, 126.2, 128.8, 136.2, 141.5, 150.1,
152.7, 158.6, 160.0, 177.8; Anal. Calcd. for
C17H12ClN5O4 (385): C, 52.93; H, 3.14; N, 18.15%.
Found: C, 52.89; H, 3.11; N, 18.11%.
[12] (a) Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C.
S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.;
Cohen, S. B.; Spencer, K. R.; Gonzalez-Paez, G. E.; Lakshminarayana,
S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H.–P.;
Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.; Fidock, D.
A.; Winzeler, E. A.; Diagana, T. T. Science 2010, 329, 1175; (b) Yeung,
B. K. S.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.; Ang, S. H.;
70-Amino-5-bromo-10,30-dimethyl-2,20,40-trioxo-10,20,30,40-
tetrahydrospiro[indoline-3,50-pyrano[2,3-d]pyrimidine]-60-
carbonitrile (7c).
Tan white solid; mp 292–294°C
(reported 295–297°C) [27]; FTIR (cmꢀ1): 3320, 2933,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
One-pot Synthesis of Spirooxindoles
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SUPPORTING INFORMATION
[20] Mobinikhaledi, A.; Foroughifar, N.; Fard, M. A. B. Synth
Commun 2011, 41, 441.
[21] Sridhar, R.; Srinivas, B.; Madhav, B.; Reddy, V. P.; Nageswar,
Y. V. D.; Rao, K. R. Can J Chem 2009, 87, 1704.
[22] Li, Y. L.; Chen, H.; Shi, C. L.; Shi, D. Q.; Ji, S. J Comb Chem
2010, 12, 231.
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet