An efficient, room temperature, oxygen radical anion (O2?-) mediated, one-pot, and multicomponent synthesis of spirooxindoles

Article abstract of DOI:10.1139/cjc-2017-0432

The present report highlights an efficient use of oxygen radical anion to promote a room temperature multi-component synthesis of spirooxindoles (4a-4l) under mild reaction conditions. The potassium superoxide (KO₂) and tetraethylammonium bromide (TEAB) combination generate the oxygen radical anion in situ to promote this transformation. This method offers a sustainable and direct access to the biologically important spirooxindole derivatives in good to excellent yields.

Full text of DOI:10.1139/cjc-2017-0432

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An Efficient Room Temperature Oxygen Radical Anion (O ) Mediated One–
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Pot Multi–Component Synthesis of Spirooxindoles
*
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Somaiah Gajaganti, Shivam Bajpai, Vandana Srivastava, Sundaram Singh
Department of Chemistry, Indian Institute of Technology–BHU, Varanasi 221 005, Uttar Pradesh,
India.
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Abstract:
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The present report highlights an efficient use of oxygen radical anion to promote a room
temperature multi–component synthesis of spirooxindoles (4a–l) under mild reaction conditions.
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The potassium superoxide (KO ) and tetraethylammonium bromide (TEAB) combination
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generate the oxygen radical anion in situ to promote this transformation. This method offers a
sustainable and direct access to the biologically important spirooxindole derivatives in good to
excellent yields.
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Keywords: Sustainable synthesis, Superoxide ion, Heterocycle synthesis, Room temperature
transformation, Spirooxindoles.
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___________
*Corresponding author: Dr. Sundaram Singh, Associate Professor of Organic Chemistry,
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Department of Chemistry, Indian Institute of Technology–BHU, Varanasi 221 005, Uttar Pradesh,
India; Mobile: +919451658650.
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E–mail: sundaram.apc@iitbhu.ac.in (Dr. Sundaram Singh)
1. Introduction
The nitrogen–containing heterocycles are the prominent entities present in natural
products and drug molecules. In particular, indole heterocycles exhibit a large spectrum of
biological activities such as agonists of migraine associated 5HT1B and 5HT1D serotonin
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receptors , anti–convulsant , anti–depressant , anti–histamine , anti–obesity , anti–diabetic ,
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and anti–allergic .
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Spirocyclic structures are frequently found in numerous natural products, and their
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efficient synthesis is a formidable challenge for synthetic organic chemists . Also, the creation
of spirooxindole derivatives through the involvement of 3–carbon of indole further elevate the
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bioactivity of the indole core
. The high disease control properties of spirooxindole moiety is
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frequently utilized in the formulation of many active pharmaceutical ingredients
; for
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example spirotryprostatin A, an anti–mitotic agent , pteropodine and isopteropodine, modulators
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of rat muscarinic M1 and 5–HT2 receptors , and formosanine, which serves as an active anti–
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cancer agent (Figure 1) .
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Figure 1. Some biologically active spirooxindole–containing molecules.
The spirooxindole compounds are the most wanted synthetic targets because of their
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exclusive structural features and attractive drug like properties . The fusion of the spirooxindole
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ring system with pyranopyrimidine has significant biological relevance because of the analgesic
and anticonvulsant activity and the effects of amphetamine–induced stereotypy of the resultant
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derivatives .
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Azaspiro derivatives are frequently found in nature
, however, the synthesis of the
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subsequent oxa analogs have received less attention . Particularly, the chromene–indole hybrid
molecules that display potential anti–depressant, anti–hypertensive, anti–tubulin, anti–viral and
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anti–oxidative activities
. Recent studies highlighted the potential application of tetrahydro–
4H–chromene derivatives bearing nitrile functionality, i.e., 2–amino–5–oxo–5,6,7,8–tetrahydro–
4H–chromene–3–carbonitriles for the effective treatment of human neurodegenerative disorders
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.
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Because of their attractive biological activities, extensive efforts have been made to
synthesize chromene based spirooxindoles by employing various metals and metal–free
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protocols
. The methods previously reported are helpful to access spirooxindoles in one–pot,
but still they were suffered from various operational and practical issues ranging from the use of
uncommon starting materials, specifically fabricated magnetic catalysts, strong acidic catalysts,
and specialized reaction conditions. So, there is still enough room for the exploration of a highly
efficient method for the synthesis of spirooxindoles.
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The use of molecular oxygen as a promoter is an emerging area . The academic and
industrial research is currently focusing more on the search for new methods which generate
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molecular oxygen in situ and use it more efficiently to promote synthetic transformations . The
problems associated with the use of molecular oxygen as a promoter is its less reactivity, an
essential requirement of low temperatures for activation, the necessity of highly expensive
metals/metal surfaces and expensive techniques are needed to generate the more reactive species
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or to bind an oxygen molecule . Alternatively, reactive oxygen species (ROS) are the better and
promising oxygen containing radicals, which show better reactivity to promote synthetic
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conversions
. The most interesting point to observe in all molecular oxygen promoted
reactions is the intermediacy of ROS.
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Superoxide ion (O2 ) is a reactive oxygen species and have significant biological and
synthetic relevance and the molecule of interest for current scientific investigations. Therefore,
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the research on the reactions promoted by O2 can certainly provide better insights to understand
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the nature and behavior of O . The O is a green oxidant and a reactive replacement of oxygen
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. The in situ generation of O2 from molecular oxygen requires an expensive and costlier
electrochemical or electric arc methods. Alternatively, the simple and cheapest method includes
the decomposition of a stable superoxide salt in the presence of a stable superoxide salt and a
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phase transfer catalyst
.
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In view of all the above facts, we are exploring an insitu generation of O2 and first time
utilizing it for a one–pot multicomponent synthesis of spirooxindoles 4 in excellent yields (80–
88%) through the reaction of isatins 1, dimedone/ barbituric acid and meldrum’s acid 2 and
malononitrile/ethyl cyanoacetate 3, at room temperature (Scheme 1).
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Scheme 1 Superoxide promoted one–pot threeꢀcomponent synthesis of spirooxindoles 4a–l.
4

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2. Experimental (Materials and methods)
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2.1. General Information
The isatins, 1,3–diketones, malononitriles, promoters, additives, and solvents were
purchased from Sigma–Aldrich Chemicals, USA, and E. Merck, Germany and were used as
received. The Thin Layer Chromatography (TLC) was carried out on Merck Kieselgel 60 GF254
plates (thickness 0.25 mm). The solvent system employed was ethyl acetate: n–hexane (2:1) and
the TLC spots were determined by UV or staining the TLC plate to iodine vapors. Infra Red (IR)
spectra were recorded on a PerkinꢀElmer FT–IR spectrometer. The NMR was conducted using a
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JEOL AL300 FT–NMR spectrometer ( H NMR at 300 MHz, C NMR at 75 MHz); chemical
shifts are given in δ ppm, relative to TMS as an internal standard. Melting points were measured
with a Stuart SMP 10 digital melting point apparatus.
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2.2 General experimental procedure for the synthesis of compounds 4a–l
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Potassium superoxide (2 mmol) and tetraethylammonium bromide (1 mmol) were
weighed under N atmosphere using an atmosbag and transferred into a three necked R. B. flask,
2
dry DMF (20 mL) was added to it and the mixture was thoroughly mixed using a magnetic stirrer
for 15 min to facilitate the formation of tetraethylammonium superoxide. To the stirred reaction
mixture, ethylcyanoacetate/malononitrile (3a, b) (1 mmol) was added. After 10 min, the isatin
derivatives (1) (1 mmol) and cyclic 1, 3–diketones (2a–c) (1 mmol) were introduced, and the
stirring was continued for 4 h. After the reaction was over as indicated by TLC, the reaction
mixture was treated with cold brine solution (2 mL) followed by saturated sodium hydrogen
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01
02
03
carbonate solution (2 mL) to decompose the unreacted KO . The mixture was then extracted with
2
dicholoromethane (3 × 15 mL) and the combined organic phase was dried over anhydrous
5

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Na SO , filtered, and evaporated to give the products 4a–l, which was purified by column
2 4
chromatography.
3. Results and discussion
In order to establish an optimized reaction condition for the synthesis of spirooxindoles at
room temperature a model reaction of isatin 1a, dimedone 2a and malononitrile 3a was carried
out in the presence of various unexplored oxidants under nitrogen atmosphere in different
solvents like DMF, THF, CH CN, CH Cl , PEG, DMSO and H O at room temperature (Table
3
2
2
2
1). The solvent study showed that dry DMF provided the best yield. All the reactions were
conducted in an inert atmosphere to avoid a possible helping hand from the oxygen present in the
atmosphere. As it was reported in several investigations that atmospheric air/oxygen serves as a
terminal oxidant for the regeneration of the catalytic species. In the present study, the
investigations were carried out by using 50 mol% iodine as a catalyst in DMF for the synthesis
of spirooxindoles at room temperature, but the iodine delivered the desired product in 27% yield
only (entry 1). Some potential oxidants like tetrabutylammonium iodide (TBAI), sodium
hypochlorite (NaOCl), perchloric acid (HClO ), tert–butylhydroperoxide (TBHP), ceric
4
ammonium nitrate (CAN), potassium periodide (KIO ), diacetoxyiodobenzene (PhI(OAC) ),
3
2
ferrocene, potassium persulfate (K S O ), hydrogen peroxide (H O ), manganese dioxide
2
2
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2
2
(MnO ), copper perchlorate (CuClO ), calcium oxychloride (CaOCl ), and sulphur (S ) were
2
4
2
8
screened but none of them provided a significant yield (entries 2–15). However, when 50 mol%
of potassium superoxide (KO ) was applied, the desired spirooxindole was formed in 57% yield
2
(entry 16). This encouraging result further indicates that the potassium superoxide (K O) can be
2
efficiently used for the optimization of the experimental protocol. A thorough revision of the
literature suggested that the superoxide ion released from the KO must act as a promoter. So, it
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27
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was envisioned that the additives which fasten the decomposition of KO must increase the yield
2
of the reaction (entries 17–19, 32–34). To test this, various phase transfer catalysts as additives
were screened. And it was discovered that 200 mol% of KO2 and 100 mol% of
tetraethylammonium bromide (TEAB) act as the best combination to deliver the spirooxindoles
in 88% yield at room temperature (entry 25).
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Table 1 Evolution of reaction parameters the synthesis of 4a.
O
O
CN
O
Reaction Conditions
O
O
+
+
NH2
N
CN
3a
CN
O
H
O
N
H
1
a
2a
4a
1
1
33
34
a
Entry
Promoter
mol %)
Additive
(mol %)
Atmosphere
Solvent
Temp
( C)
Time Yield (%)
(h)
0
(
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
I2 (50)
TBAI (50)
NaOCl (50)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
27
15
30
26
20
17
24
—
35
37
40
22
28
25
33
57
30
41
52
65
58
55
75
72
88
HClO (50)
4
TBHP (50)
CAN (50)
KIO (50)
3
PhI(OAc) (50)
2
Ferrocene (50)
K S O (50)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
2
2
8
H O (50)
2
2
MnO (50)
2
CuClO (50)
4
CaOCl2
S8 (50)
KO (50)
—
2
KO (50)
TBAF (50)
Et BnNCl (50)
2
KO (50)
2
3
KO (50)
TEAB (50)
TEAB (50)
TEAB (50)
TEAB (50)
TEAB (100)
TEAB (200)
TEAB (100)
2
KO (100)
2
KO (200)
2
KO (300)
2
KO (200)
2
KO (200)
2
KO (200)
2
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2
2
2
2
3
3
3
3
3
6
7
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KO (200)
TEAB (100)
TEAB (100)
TEAB (100)
TEAB (100)
TEAB (100)
O2
air
N2
N2
N2
N2
N2
N2
N2
DMF
DMF
DMSO
rt
rt
rt
rt
rt
rt
rt
rt
60
4
4
4
4
4
4
4
4
4
70
65
15
73
20
45
35
28
15
2
KO (200)
2
KO (200)
2
KO (200)
CH CN
2
3
KO (200)
CH Cl
2
2
2
KO (200)
TEAB (100)
THF
2
KO (200)
Aliquat 336 (100)
18–crown–6 (100)
TEAB (100)
DMF
DMF
DMF
2
KO (200)
2
KO (200)
2
1
1
1
35
36
37
a
Reaction conditions: Isatin (1a) (1 mmol), dimedone (2a) (1 mmol), malononitrile (3a) (1
b
mmol). Isolated yield after column chromatography.
a,b.
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Table 2: Superoxideꢀmediated multicomponent synthesis of spirooxindole derivatives 4
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39
a
1
1
1
40
41
42
Reaction of isatin derivatives (1) (1 mmol), cyclic 1, 3–diketones (2a–c) (1 mmol), and
ethylcyanoacetate/malononitrile (3a, b) (1 mmol) using KO (2 mmol) and TEAB (1 mmol) in dry DMF
at rt for 4 h. Isolated yield after column chromatography.
2
b
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43
44
45
46
47
48
49
50
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The optimized reaction conditions in hand, the generality of the reaction was further
explored. A set of isatin (1a) and 5–chloroisatin (1b) were allowed to undergo a KO /TEAB
2
promoted reaction with dimedone (2a), barbituric acid (2b) and meldrum’s acid (2c); and
malononitrile (3a)/ethyl cyanoacetate (3b) in DMF at room temperature. The unsubstituted isatin
served as a best partner in these reactions, when compared with 5–chloroisatin. Out of the three
cyclic active methylene compounds used dimedone (2a) exhibited the best reactivity. A diverse
set of pure substituted spirooxindoles (4a–4l) have synthesized in good to excellent yields (88–
80). All the products were fully characterized based on their melting points, and spectral data
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(IR, H NMR, and C NMR).
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1
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53
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Based on the reported literature
and isolation of products, a plausible mechanism is
proposed for the superoxide ion induced multicomponent synthesis of spirooxindoles 4a–l has
been described in the Scheme 2.
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Scheme 2. Plausible reaction mechanism.
The reaction was triggered by the abstraction of a proton from active methylene
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compound 3 by the naked superoxide ion which was in–situ generated by the reaction of
potassium superoxide with tetraethylammonium bromide. Now, Knoevenagel condensation takes
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place between isatin 2 and active methylene compound 3; this gives the formation of α, β–
unsaturated adduct. The 1,4–addition of 1,3–dione on α, β–unsaturated adduct followed by an
intramolecular cyclization and subsequent [1,3]–sigmatropic proton shift led to the formation of
product 4.
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3.1 Characterization data for synthesized spirooxindoles (4a–l)
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1
1
1
1
1
1
1
1
1
1
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2–Amino–7,7–dimethyl–2 ,5–dioxo–5,6,7,8–tetrahydrospiro[chromene–4,3 –indoline]–3–
carbonitrile (4a):
–
1
Colorless solid; m.p. = 268 °C; IR (KBr, υ = cm ) 3403, 3252, 3017, 2981, 2978, 2838, 2802,
1
2213, 1708, 1691, 1669, 1610, 1600, 1558, 1453, 1386, 1270, 1184. H NMR (300 MHz,
DMSO–d ): δ = 0.98 (s, 3H, CH ), 1.06 (s, 3H, CH ), 2.10–2.16 (m, 2H, CH ), 2.55–261 (m, 2H,
6
3
3
2
13
CH ), 6.79–7.21 (m, 4H, ArH), 7.22 (s, 2H, NH ), 11.02 (s, 1H, NH) ppm. C NMR (75 MHz,
2
2
DMSO–d ): δ = 26.9, 27.6, 31.1, 36.2, 46.5, 50.1, 61.2, 111.2, 117.5, 120.5, 122.1, 127.3, 134.2,
6
145.4, 157.1, 162.8, 170.0, 191.8 ppm.
’
’
Ethyl–2–amino–7,7–dimethyl–2 ,5–dioxo–5,6,7,8–tetrahydrospiro[chromene–4,3 –
indoline]–3–carboxylate (4b):
–
1
1
1
1
1
1
1
1
75
76
77
78
79
80
81
Colorless solid; m.p. = 258 °C; IR (KBr, υ = cm ): 3451, 3301, 3158, 2999, 2944, 2861 2815,
1
1733, 1711, 1685, 1675, 1621, 1608, 1590, 1551 1485, 1380, 1255, 1196; H NMR (300 MHz,
DMSO–d ): δ = 0.77 (t, J = 6.5 Hz, 3H, Me), 0.99 (s, 3H, CH ), 1.05 (s, 3H, CH ), 2.04– 2.11
6
3
3
(m, 2H, CH ), 2.61–2.65 (m, 2H, CH ), 3.84 (q, 2H, J = 6.9 Hz, CH ), 6.66–7.06 (m, 4H, ArH),
2
2
2
13
7.76 (s, 2H, NH ), 10.54 (s, 1H, NH) ppm; C NMR (75 MHz, DMSO–d ): δ = 14.6, 26.2, 27.1,
2
6
30.9, 35.1., 46.9, 50.4, 59.6, 79.3, 106.8, 118.3, 121.2, 122.6, 126.9, 132.7, 143.4, 159.1, 165.0,
167.8, 174.2, 194.3 ppm.
1
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1
1
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1
1
1
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83
84
85
86
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88
2–Amino–5–chloro–7,7–dimethyl–2',5–dioxo–5,6,7,8–tetrahydrospiro[chromene–4,3'–
–
1
indoline]–3–carbonitrile (4c): Colorless solid; m.p. = 291 °C; IR (KBr, υ = cm ) 3425, 3300,
1
3013, 2911, 2890, 2851, 2210, 1701, 1678, 1659, 1616, 1605, 1569, 1458, 1348, 1257, 1173; H
NMR (300 MHz, DMSO–d ): δ = 0.97 (s, 3H, CH ), 1.02 (s, 3H, CH ), 2.16–2.22 (m, 2H, CH ),
6
3
3
2
1
3
2.47–2.54 (m, 2H, CH ), 6.80 –7.21(m, 3H, ArH), 7.24 (s, 2H, NH ), 11.11 (s, 1H, NH) ppm; C
2
2
NMR (75 MHz, DMSO–d ): δ = 26.8, 32.2, 37.3, 48.1, 50.5, 61.0, 109.3, 116.8, 121.7, 122.9,
6
127.1, 133.2, 142.5, 156.9, 160.1, 168.5, 191.1 ppm.
1
1
1
1
1
1
1
1
89
90
91
92
93
94
95
96
Ethyl–2–amino–5–chloro–7,7–dimethyl–2',5–dioxo–5,6,7,8–tetrahydrospiro[chromene–
–
1
4,3'–indoline]–3–carboxlate (4d): Colorless solid; m.p. = 292 °C; IR (KBr, υ = cm ) 3393,
3203, 3022, 2985, 2941, 2878, 2815, 1729, 1712, 1694, 1672, 1610, 1606, 1569, 1481, 1375,
1
1224, 1170; H NMR (300 MHz, DMSO–d ): δ = 0.80 (t, 3H, J = 6.9 Hz, CH ), 0.97 (s, 3H,
6
3
CH ), 1.01 (s, 3H, CH ), 2.10–2.16 (m, 2H, CH ), 2.51–2.58 (m, 2H, CH ), 3.68 (q, 2H, J = 7.2
3
3
2
2
13
Hz, CH ), 6.67–7.12 (m, 3H, ArH), 7.84 (s, 2H, NH ), 10.51 (s, 1H, NH) ppm; C NMR (75
2
2
MHz, DMSO–d ): δ = 16.5., 27.2 27.5, 32.8, 37.6., 45.4, 48.9, 57.6, 74.1, 108.9, 117.5, 121.1,
6
122.8, 127.2, 135.7, 144.3, 158.1, 164.9, 167.1, 172.1, 190.1 ppm.
1
1
97
98
7'–amino–2,2',4'–trioxo–1',2',3',4'–tetrahydrospiro[indoline–3,5'–pyrano[2,3–
d]pyrimidine]–6'–carbonitrile (4e):
–
1
1
2
2
2
2
99
00
01
02
03
Colorless solid; m.p. = 276 °C; IR (KBr, υ = cm ) 3423, 3298, 3134, 3001, 2213, 1701, 1682,
1
1620, 1609, 1566, 1453, 1372, 1289, 1192; H NMR (300 MHz, DMSO–d ): δ = 6.88–7.26 (m,
6
4H, aromatic protons), 7.56 (s, 2H, NH ), 10.01 (s, 1H, NH), 11.10 (s, 1H, NH), 11.25 (s, 1H,
2
1
3
NH) ppm; C NMR (75 MHz, DMSO–d ): δ = 48.1, 74.5, 87.2, 111.1, 121.1, 123.2, 126.4,
6
133.1, 142.5, 148.7, 151.2, 159.1, 162.2, 167.6, 175.1 ppm.
1
2

Page 13 of 18
2
2
04
05
Ethyl7'–amino–2,2',4'–trioxo–1',2',3',4'–tetrahydrospiro[indoline–3,5'–pyrano[2,3–
d]pyrimidine]–6'–carboxylate (4f):
–
1
2
2
2
2
2
2
06
07
08
09
10
11
Pale yellow solid; m.p. = 190 °C; IR (KBr, υ = cm ) 3405, 3315, 3188, 3014, 1732, 1705, 1680,
1
1621, 1614, 1558, 1491, 1347, 1270, 1188; H NMR (300 MHz, DMSO–d ): δ = 1.05–1.10 (t, J
6
= 6.6, 3H, CH ), 4.25–4.30 (q, J= 7.4, 2H, CH ), 7.00–7.31 (m, 4H, aromatic protons), 7.86 (s,
3
2
1
3
2H, NH ), 10.12 (s, 1H, NH), 10.99 (s, 1H, NH), 11.20 (s, 1H, NH) ppm; C NMR (75 MHz,
2
DMSO–d ) δ = 13.9, 44.9., 60.3, 74.8, 88.1, 109.1, 119.3, 122.6, 127.8, 134.1, 144.1, 150.1,
6
153.2, 159.5, 163.2, 166.3, 177.1 ppm.
2
2
12
13
7'–amino–5–chloro–2,2',4'–trioxo–1',2',3',4'–tetrahydrospiro[indoline–3,5'–pyrano[2,3–
d]pyrimidine]–6'–carbonitrile (4g):
–
1
2
2
2
2
2
14
15
16
17
18
Colorless solid; m.p. = 261 °C; IR (KBr, υ = cm ) 3430, 3263, 3111, 3020, 2234, 1710, 1685,
1
1622, 1612, 1572, 1460, 1352, 1248, 1171; H NMR (300 MHz, DMSO–d ): δ = 6.79–7.17 (m,
6
3H, aromatic protons), 7.95 (s, 2H, NH ), 10.15 (s, 1H, NH), 11.18 (s, 1H, NH), 11.23 (s, 1H,
2
1
3
NH) ppm; C NMR (75 MHz, DMSO–d ): δ = 48.9, 76.1, 89.5, 106.2, 120.9, 123.5, 127.1,
6
134.1, 144.3, 149.6, 152.7, 158.9, 162.2, 169.2, 179.3 ppm.
2
2
19
20
Ethyl 7'–amino–5–chloro–2,2',4'–trioxo–1',2',3',4'–tetrahydrospiro[indoline–3,5'–
pyrano[2,3–d]pyrimidine]–6'–carboxylate (4h):
–
1
2
2
2
2
21
22
23
24
Pale yellow solid; m.p. = 248 °C; IR (KBr, υ = cm ) 3391, 3281, 3112, 2990, 1739, 1705, 1684,
1
1625, 1613, 1605, 1562, 1478, 1380, 1271, 1183; H NMR (300 MHz, DMSO–d ): δ = 1.15–
6
1.21 (t, J= 7.2, 3H, CH ), 4.21–4.26 (q, J= 7.2, 2H, CH ), 6.92–7.23 (m, 3H, aromatic protons),
3
2
1
3
8.00 (s, 2H, NH ), 10.20 (s, 1H, NH), 11.02 (s, 1H, NH), 11.21 (s, 1H, NH) ppm; C NMR (75
2
1
3

Page 14 of 18
2
2
25
26
MHz, DMSO–d ): δ = 14.5, 49.1, 59.5, 76.6, 88.4, 106.2, 120.2, 122.3, 127.9, 134.1, 143.5,
6
148.3, 153.3, 158.2, 162.1, 168.1, 179.1 ppm.
2
2
27
28
7'–amino–2',2'–dimethyl–2,4'–dioxo–4'H–spiro[indoline–3,5'–pyrano[2,3–d][1,3]dioxine]–
6'–carbonitrile (4i):
–
1
2
2
2
2
2
29
30
31
32
33
Pale yellow solid; m.p. = 294 °C; IR (KBr, υ = cm ) 3413, 3251, 3011, 2946, 2933, 2838, 2827,
1
2211, 1706, 1698, 1661, 1615, 1609, 1600, 1568, 1455, 1456, 1378, 1351, 1255, 1200; H NMR
(300 MHz, DMSO–d ): δ = 1.41 (s, 6H, CH ), 7.11–7.75 (m, 4H, aromatic protons), 8.12 (s, 2H,
6
3
13
NH ), 11.14 (s, 1H, NH) ppm; C NMR (75 MHz, DMSO–d ): δ = 24.9, 46.4, 75.6, 88.6, 105.0,
2
6
118.2, 122.6, 129.1, 135.9, 144.3, 145.6, 161.2, 163.4, 169.2 ppm.
2
2
34
35
Ethyl 7'–amino–2',2'–dimethyl–2,4'–dioxo–4'H–spiro[indoline–3,5'–pyrano[2,3–
d][1,3]dioxine]–6'–carboxylate (4j):
–
1
2
2
2
2
2
2
36
37
38
39
40
41
Yellow solid; m.p. = 298 °C; IR (KBr, υ = cm ) 3391, 3259, 3033, 2968, 2941, 2823, 2810,
1
1735, 1710, 1701, 1658, 1620, 1613, 1599, 1571, 1449, 1435, 1389, 1363, 1251, 1185; H NMR
(300 MHz, DMSO–d ): δ = 1.10–1.15 (t, J = 6.9, 3H, CH ), 1.68 (s, 6H, CH ), 4.20– 4.28 (q, J =
6
3
3
6.9, 2H, CH ), 6.88–7.63 (m, 4H, aromatic protons), 8.00 (s, 2H, NH ), 11.29 (s, 1H, NH) ppm;
2
2
1
3
C NMR (75 MHz, DMSO–d ): δ = 13.9, 27.8, 48.5, 58.7, 79.2, 86.5, 110.0, 117.6, 121.2,
6
127.5, 129.2, 134.1, 142.5, 145.2, 158.1, 162.2, 164.2, 168.1, 188.8 ppm.
2
2
42
43
7'–amino–5–chloro–2',2'–dimethyl–2,4'–dioxo–4'H–spiro[indoline–3,5'–pyrano[2,3–
d][1,3]dioxine]–6'–carbonitrile (4k):
–
1
2
2
2
44
45
46
Yellow solid; m.p. = 301 °C; IR (KBr, υ = cm ) 3400, 3261, 3023, 2978, 2959, 2877, 2855,
1
2227, 1711, 1703, 1665, 1618, 1610, 1590, 1570, 1465, 1435, 1372, 1352, 1264, 1192; H NMR
(300 MHz, DMSO–d ): δ = 1.63 (s, 6H, CH ), 6.92–7.54 (m, 3H, aromatic protons), 8.05 (s, 2H,
6
3
1
4

Page 15 of 18
1
3
2
2
47
48
NH ), 10.80 (s, 1H, NH) ppm; C NMR (75 MHz, DMSO–d ): δ = 25.1, 48.2, 72.2, 89.5, 107.3,
2 6
117.9, 123.5, 127.4, 132.1, 141.3, 145.7, 158.1, 162.3, 164.1, 167.8 ppm.
2
2
49
50
Ethyl 7'–amino–5–chloro–2',2'–dimethyl–2,4'–dioxo–4'H–spiro[indoline–3,5'–pyrano[2,3–
d][1,3]dioxine]–6'–carboxylate (4l):
–
1
2
2
2
2
2
2
51
52
53
54
55
56
Yellow solid; m.p. = 315 °C; IR (KBr, υ = cm ) 3400, 3231, 3008, 2970, 2953, 2829, 2823,
1
1732, 1711, 1703, 1667, 1617, 1611, 1601, 1560, 1463, 1446, 1388, 1295, 1189; H NMR (300
MHz, DMSO–d ): δ = 1.02–1.08 (t, J = 7.2, 3H, CH ), 1.56 (s, 6H, CH ), 4.12–4.19 (q, J = 6.9,
6
3
3
13
2H, CH ), 6.96–7.51 (m, 3H, aromatic protons), 8.12 (s, 2H, NH ), 11.13 (s, 1H, NH) ppm; C
2
2
NMR (75 MHz, DMSO–d ) δ = 14.2, 26.1, 46.5, 60.1, 75.2, 89.4, 112.8, 119.2, 122.7, 127.6,
6
128.8, 135.1, 141.9, 144.2, 159.1, 161.6, 164.5, 167.5, 184.1 ppm.
2
57 4. Conclusion
2
2
2
2
2
58
59
60
61
62
In conclusion, this work addresses the successful synthesis of a variety of spirooxindoles
by employing a superoxide ion mediated one–pot multicomponent reaction of isatin derivatives,
ethyl cyanoacetate/malononitrile and cyclic 1,3–diketones under ambient temperature. Further,
the developed protocol explores the new avenues of the superoxide ion reactivity and focuses a
limelight on the unexplored side of the superoxide ion chemistry.
2
63
Acknowledgement
2
2
2
2
2
64
65
66
67
68
The authors are thankful to Dr. Bharat Kumar Allam for his precious support during the
preparation of this manuscript. Mr. Prabhu Das is grateful to the IIT(BHU) for financial support
in the form of Institute Fellowship. Dr. Sundaram Singh acknowledges the fund received
[Sanction Letter No.41ꢀ294/2012(SR)] from the University Grants Commission, Government of
India, New Delhi.
1
5

Page 16 of 18
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69
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