γ-Valerolactone as a Promising Bio-Compatible Media for One-Pot Synthesis of Spiro[indoline-3,4'-pyrano[3,2-c]chromene Derivatives

Article abstract of DOI:10.1002/jhet.3351

A general, highly efficient, and green protocol for the synthesis of biologically important spiro[indoline-3,4′-pyrano[3,2-c]chromene derivatives is developed by one-pot, three-component approach involving substituted isatin, active methylene group, and 4

Full text of DOI:10.1002/jhet.3351

Month 2018
γ-Valerolactone as a Promising Bio-Compatible Media for One-Pot
Synthesis of Spiro[indoline-3,4’-pyrano[3,2-c]chromene Derivatives
Furqan Diwan and Mazahar Farooqui*
Department of Chemistry, Dr. RafiqZakaria College for Women, Aurangabad 431001, India
*
E-mail: mazahar_64@rediffmail.com
Received May 27, 2018
DOI 10.1002/jhet.3351
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A general, highly efficient, and green protocol for the synthesis of biologically important spiro[indoline-
0
3
,4 -pyrano[3,2-c]chromene derivatives is developed by one-pot, three-component approach involving
substituted isatin, active methylene group, and 4-hydroxy coumarin. This report describes the use of γ-
valerolactone as a green reaction media for a variety of substrates. The advantageous features of this meth-
odology are the environmentally benign character, operational simplicity, high yield processing (91–96%),
easy handling, and the reaction medium can be recycled and reused several times without significant loss
of its efficiency.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
community is continuously searching for new sustainable
media in order to widen their use in chemical
transformation. In this regard, γ-valerolactone is naturally
occurring chemical found in fruits and frequently used
food additive, demonstrates the most important attributes
of an ideal sustainable solvent such as high boiling point,
high polarity, low melting point, nontoxic, and good
stability towards acids and bases [14]. Therefore, the use
of γ-valerolactone as a green reaction media in organic
reaction may constitute alternative solvents for the
development of sustainable chemistry.
Multicomponent reactions (MCRs) have drawn great
efforts in recent years owing to exceptional synthetic
efficiency, high selectivity, intrinsic atom economy,
operational simplicity, and ability to generate expedient
construction of molecules from three or more components
in one-pot operation with minimum waste production.
One-pot MCRs often shorten reaction periods, giving
higher overall chemical yields than multi-step syntheses,
and therefore can reduce the use of energy and manpower
[15]. These reactions constitute straightforward approach
for creation of large libraries of structurally related, drug-
like molecules, thereby enabling lead identification and
lead optimization in drug discovery. Because of these
advantages, the design of new MCRs with
environmentally benign method is a continuing challenge
at the forefront area of green chemistry [16].
Solvents have a significant impact on the environment
because a large quantity of these are generally used in
pharmaceutical productions. They typically account for
between 80% and 90% of the mass utilization of a batch
operation [1]. Consequently, replacing conventional
solvents, which are usually volatile organic compounds,
with more environmentally benign media is one of the
central tenets of the green chemistry and a subject of
significant academic and commercial interest [2]. In this
regard, a variety of unconventional solvents, such as
water [3], ionic liquids [4], fluorous media [5],
supercritical fluids [6], and polyethylene glycol [7], have
been extensively studied and fascinating results have
been reported. However, the use of these solvents are still
subject to strict limitations, such as the low solubility of
starting material and instability of reactive reagents or
substrates in water, high prices and lack of data about the
toxicity and bio-compatibility for ionic liquids, and the
necessity of sophisticated equipment for supercritical
fluids. Therefore, the search of new reaction media is still
desirable.
In recent years, the use of bio-based solvents as
alternative to conventional organic solvents has received
considerable interest among the scientific community
8,9]. Many naturally available products, such as glycerol
10], ethyl lactate [11], gluconic acid aqueous solution
12], and carbohydrates-based low melting mixtures [13],
have been recognized as safer, sustainable, and
biodegradable solvents in catalysis for organic
transformation. However, the number of bio-based
solvents is still limited at this stage and scientific
[
[
[
The spirooxindole unit is a privileged heterocyclic motif
that forms the core of a large family of alkaloid and
natural products with strong bioactivity profiles and
interesting structural properties [17–19]. Significant recent
advances in the synthesis of this fused heterocyclic system
have led to an intense interest in the development of
©
2018 Wiley Periodicals, Inc.

F. Diwan and M. Farooqui
Vol 000
related compounds as potential medicinal agents or
biological probes. For example, Alstonisine, a natural
alkaloid, was firstly isolated from Alstoniamuelleriana
Table 1
Reaction of isatin, malononitrile, and 4-hydroxycoumarin in different
a
solvents .
[
20] and has been identified for its biomimetic
Yield
(%)
b
transformations [21]. Further, Strychnofoline has been
found to inhibit mitosis in a number of cell lines including
mouse melanoma B16, Ehrlich, and Hepatom HW165
Entry
Solvent
Temp (°C)
Time (h)
1
2
3
4
5
6
7
8
Neat
100
82
66
100
64
100
100
100
10
10
10
10
10
10
10
10
Trace
Trace
Trace
Trace
Trace
Trace
28
Acetonitrile
Tetrahydrofuran
Dimethyl sulfoxide
Methanol
Water
Acetic acid
[22]. Chitosenine is another structurally interesting natural
product, which exhibits short-lived inhibitory activity of
ganglionic transmission in vivo in rats and rabbits [23].
The unique structural array and the highly pronounced
pharmacological activities displayed by the class of
spirooxindole compounds have made them attractive
synthetic targets.
As a part of our ongoing program in the development of
environmentally benign and sustainable process [24–26],
herein, we wish to report a straightforward one-pot three-
component reaction of substituted isatin, active methylene
group, and 4-hydroxycoumarin in γ-valerolactone for the
synthesis of spirooxindoles with fused pyrano[3,2-c]
chromene derivatives. To the best of our knowledge,
there is no report available in the literature for the
synthesis of spirooxindoles with fused pyrano[3,2-c]
chromene derivatives using γ-valerolactone as green and
reusable bio-based solvent (Scheme 1).
Citric acid-DMU
40:60)
54
(
9
L-(+)-Tartaric
acid-DMU(30:70)
D-(ꢀ)-Fructose-
DMU(70:30)
γ-valerolactone
γ-valerolactone
γ-valerolactone
γ-valerolactone
100
100
10
10
58
45
10
1
1
1
1
2
3
30
50
80
4
1
0.5
0.5
47
70
95
88
14
100
a
Reaction condition: isatin (1 mmol), malononitrile (1 mmol),
4-hydroxycoumarin (1 mmol), and solvent (5 mL).
Isolated yield.
b
D-(ꢀ)-Fructose-DMU, slightly improved yields were
obtained (Entry 8–10). To our great delight, the yield of
4
a was enhanced to 95% when γ-valerolactone was used
as the solvent (Entry 12).
RESULTS AND DISCUSSION
Encouraged by these results, we have extended this
reaction to substituted isatin bearing electron-donating
and electron-withdrawing groups underwent the reaction
under similar conditions to furnish the respective
spirooxindole derivatives in excellent yields (Scheme 2,
Table 2) without the formation of any side products.
Furthermore, the nitrogen protected isatin substrates also
gave the excellent yield under optimized conditions.
The plausible mechanism for the formation of spiro
derivatives 4 is described in Scheme 3. The process
represents a typical cascade reaction in which the isatin 1
To establish suitable experimental conditions for the
0
synthesis of spiro[indoline-3,4 -pyrano[3,2-c]chromene
system, we tried the model reaction of isatin (1a),
malononitrile (2a), and 4-hydroxycoumarin (3) in
different solvent system. The results are shown in
Table 1. Only a trace amount of products were detected
in acetonitrile, tetrahydrofuran, dimethyl sulfoxide,
methanol, water, and neat conditions (Table 1, Entry
1
–6). It has previously been reported in the literature
that this three-component reaction was usually carried
out in the presence of acid catalysts, which prompted us
to investigate acidic solvent to improve the reaction.
Acetic acid was examined and displayed less efficiency
for this transformation (Entry 7). When the reaction
proceeded in low melting mixtures, such as citric acid-
dimethylurea (DMU), L-(+)-tartaric acid-DMU, and
condenses
with
malononotrile
2
to
afford
0
isatylidenemalononitrile derivative 2 . This step is
regarded as fast Knoevenagel condensation. The second
step involves the 4 C-alkylation of 4-hydroxycoumarin
by the reaction with electrophilic C═C double bond of 2
and the nucleophilic addition of the ─OH group on the
cyano moiety to form the desired product 4.
0
Scheme 1. Model reaction of isatin, malononitrile, and 4-hydroxycoumarin. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
γ-Valerolactone as a Promising Bio-Compatible Media for Spiro Chromene
Derivatives
0
Scheme 2. Synthesis of spiro[indoline-3,4 -pyrano[3,2-c]chromene] derivatives 4a–q in γ-valerolactone. [Color figure can be viewed at
wileyonlinelibrary.com]
Table 2
0
Synthetic results of spiro[indoline-3,4 -pyrano[3,2-c]chromene] derivatives 4a–q.
1
a
Entry
R
R
X
Compound
Time (min)
Yield (%)
MP (°C)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
H
H
H
H
H
H
H
CH
Allyl
CN
CN
CN
CN
CN
CN
CN
CN
CN
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
30
45
20
25
15
50
30
25
25
40
45
40
45
40
30
35
25
95
94
92
91
94
93
96
95
95
94
92
92
91
92
95
96
92
>300
>300
>300
>300
>300
5-CH
5-Cl
5-Br
5-NO
5,7-diCH
H
H
H
H
5-CH
5-Cl
5-Br
5-NO
H
H
3
2
3
>300
3
225–227
243–245
176–178
258–260
242–244
280–282
232–234
258–260
253–255
230–232
176–178
CH
2
Ph
0
1
2
3
4
5
6
7
H
H
H
H
H
3
2
CH
3
Allyl
CH Ph
H
2
a
Isolated yield.
EXPERIMENTAL
filtered, washed with water, and found to be pure by thin-
layer chromatography, with no need of further
purification. For analytical and spectral studies, the
products were crystallized from ethanol and acetone (1:1)
to give analytically pure spirooxindole derivatives (4a–q).
The melting points of all compounds were determined
on a Toshniwal apparatus and are uncorrected. IR spectra
were recorded on Shimadzu FTIR-8400S
spectrophotometer using KBr pellets. H and C NMR
spectra were recorded in DMSO-d6 using
a
1
13
0
0
Spectral data of compounds 4 (a–q). (4a) 2 -Amino-2,5 -
0
0
0
dioxo-5 H-spiro[indoline-3,4 -pyrano[3,2-c]chromene]-3 -
tetramethylsilane as an internal standard on a Bruker
spectrophotometer at 400 and 100 MHz, respectively.
Mass spectra of representative compounds were recorded
on JEOL SX-102 spectrometer at 70 eV. Elemental
microanalyses were carried out on a Carlo Erba1108
CHN analyzer.
General procedure for the synthesis of spiro[indoline-3,4 -
pyrano[3,2-c]chromene] derivatives (4a–q). An equimolar
mixture of substituted isatin (4a–i, 1 mmol), active
carbonitrile. White solid; (Yield: 95%); mp >300°C;
ꢀ
1
IR (KBr) (νmax, cm ): 3392, 3276, 3048, 2206, 1730,
1
1675, 1604, 1484, 1360, 1219, 1130, 992, 736;
NMR (400 MHz, DMSO-d , ppm): δ 6.87–7.95 (m,
0H, ArH and NH ), 10.67 (s,1H, NH); C{1H}
H
6
1
3
1
2
NMR (100 MHz, DMSO-d , ppm): δ 48.1, 57.5,
6
0
101.9, 109.9, 112.9, 117.1, 117.4, 122.5, 123.1,
124.5, 125.4, 129.3, 133.5, 134.1, 142.6, 152.5,
155.5, 158.7, 158.9, 177.6; MS (ESI) m/z: 358
+
methylene compound (2a–b,
1
mmol), and 4-
[M + H] . Anal. Calcd for C H N O : C, 67.23; H,
2
0
11
3
4
hydroxycoumarin (3, 1 mmol) in γ-valerolactone (5 mL)
was stirred magnetically at 80°C for the appropriate time
3.10; N, 11.76. Found: C, 67.19; H, 3.04; N, 11.73.
0
0
0
0
(4b) 2 -Amino-5-methyl-2,5 -dioxo-5 H-spiro[indoline-3,4 -
0
(Table 2). After completion of the reaction as indicated
pyrano[3, 2-c]chromene]-3 -carbonitrile.
White solid;
ꢀ
1
by thin-layer chromatography, cold water (10 ml) was
added and stirred for 5 min. The solid precipitate was
(Yield: 94%); mp >300°C; IR (KBr) (νmax, cm ): 3408,
3360, 2209, 1720, 1660, 1605, 1490, 1355, 1230, 1090,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

F. Diwan and M. Farooqui
Vol 000
0
Scheme 3. Plausible mechanism of spiro[indoline-3,4 -pyrano[3,2-c]chromene derivatives 4a–q. [Color figure can be viewed at wileyonlinelibrary.com]
1
+
9
80, 775; H NMR (400 MHz, DMSO-d , ppm): δ 2.19 (s,
m/z: 435 [M + H] . Anal. Calcd for C H BrN O : C,
20 10 3 4
6
3
H, CH ), 6.74–7.96 (m, 9H, ArH and NH ), 10.58 (s,1H,
55.07; H, 2.31; N, 9.63. Found: C, 55.12; H, 2.37; N, 9.69.
3
2
13
0
0
0
0
NH); C{1H} NMR (100 MHz, DMSO-d , ppm): δ 20.6,
(4e)
2 -Amino-5-nitro-2,5 -dioxo-5 H-spiro[indoline-3,4 -
6
0
4
1
1
7.9, 57.2, 101.5, 109.1, 112.5, 116.7, 116.9, 122.4, 124.3,
25.3, 129.2, 131.2, 133.0, 133.7, 139.3, 151.8, 155.3,
58.0, 158.3, 177.2; MS (ESI) m/z: 372 [M + H] . Anal.
pyrano[3,2-c]chromene]-3 -carbonitrile.
(Yield: 94%); mp >300°C; IR (KBr) (νmax, cm ): 3410,
White
solid;
ꢀ
1
+
3320, 2210, 1740, 1670, 1605, 1550, 1475, 1340, 1210,
1
Calcd for C H N O : C, 67.92; H, 3.53; N, 11.32.
1160, 980, 770; H NMR (400 MHz, DMSO-d
, ppm): δ
6
21 13 3 4
Found C, 67.87; H, 3.58; N, 11.38.
7.08–8.38 (m, 9H, ArH and NH
C{1H} NMR (100 MHz, DMSO-d , ppm): δ 47.8,
2
), 11.47 (s, 1H, NH);
0
0
0
0
13
(
4c) 2 -Amino-5-chloro-2,5 -dioxo-5 H-spiro[indoline-3,4 -
6
0
pyrano[3, 2-c]chromene]-3 -carbonitrile.
White solid;
5
5.8, 100.3, 109.8, 112.4, 116.8, 120.6, 122.7, 125.1,
ꢀ
1
(Yield: 92%); mp >300°C; IR (KBr) (νmax, cm ): 3320,
126.7, 133.6, 134.0, 142.8, 148.4, 152.4, 156.2, 159.3,
+
3
9
6
201, 2206, 1740, 1670, 1610, 1475, 1355, 1230, 1095,
70, 820, 770; H NMR (400 MHz, DMSO-d , ppm): δ
1
77.9; MS (ESI): m/z: 403 [M + H] . Anal. Calcd for
1
6
C H N O : C, 59.71; H, 2.51; N, 13.93. Found: C,
20 10 4 6
.86–7.96 (m, 9H, ArH and NH ), 10.84 (s, 1H, NH);
2
59.77; H, 2.56; N, 13.98.
1
3
0
0
0
C{1H} NMR (100 MHz, DMSO-d , ppm): δ 47.8,
6
(4f)
2 -Amino-5,7-dimethyl-2,5 -dioxo-5 H-spiro[indoline-
0
0
5
1
1
6.3, 100.7, 110.9, 112.6, 116.6, 116.9, 122.6, 124.4,
24.9, 125.9, 128.8, 133.6, 135.0, 141.0, 152.0, 155.3,
58.5, 176.9; MS (ESI) m/z: 392 [M + H] . Anal. Calcd
3,4 -pyrano[3,2-c]chromene]-3 -carbonitrile.
White solid;
ꢀ
1
(Yield: 93%); mp >300°C; IR (KBr) (νmax, cm ): 3410,
+
3310, 2210, 1720, 1670, 1610,1490, 1345, 1210, 1120,
1
for C H ClN O : C, 61.32; H, 2.57; N, 10.73. Found:
980, 760; H NMR (400 MHz, DMSO-d , ppm): δ 2.16
20
10
3
4
6
C, 61.38; H, 2.62; N, 10.79.
(s, 3H, CH ), 2.21 (s, 3H, CH ), 6.84–7.97 (m, 8H, ArH
3
3
13
0
0
0
0
(
4d) 2 -Amino-5-bromo-2,5 -dioxo-5 H-spiro[indoline-3,4 -
and NH ), 10.62 (s, 1H, NH); C{1H} NMR (100 MHz,
2
0
pyrano[3, 2-c]chromene]-3 -carbonitrile.
White solid;
DMSO-d , ppm): δ 16.7, 20.8, 48.3, 57.9, 102.0, 112.8,
6
ꢀ
1
(Yield: 91%); mp >300°C; IR (KBr) (νmax, cm ): 3338,
117.0, 117.5, 118.8, 122.3, 123.1, 125.1, 130.9, 131.2,
3
9
8
212, 2210, 1740, 1670, 1610, 180, 1360, 1228, 1090,
84, 760; H NMR (400 MHz, DMSO-d , ppm): δ 7.48–
1
33.2, 134.2, 139.0, 152.4, 144.2, 158.5, 158.7, 177.8;
1
+
6
MS (ESI): m/z: 385 [M + H] . Anal. Calcd for
13
.65 (m, 9H, ArH and NH ), 11.50 (s, 1H, NH); C{1H}
2
C H N O : C, 68.57; H, 3.92; N, 10.90. Found C,
22 15 3 4
NMR (100 MHz, DMSO-d , ppm): δ 47.7, 56.2, 100.8,
6
68.63; H, 3.97; N, 10.96.
0
0
0
0
111.3, 112.5, 113.7, 116.6, 122.7, 125.1, 127.1, 131.7,
(
4g) 2 -Amino-1-methyl-2,5 -dioxo-5 H-spiro[indoline-3,4 -
0
133.7, 135.4, 141.4, 151.9, 155.5, 158.5, 176.9; MS (ESI):
pyrano[3, 2-c]chromene]-3 -carbonitrile.
White solid;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
γ-Valerolactone as a Promising Bio-Compatible Media for Spiro Chromene
Derivatives
ꢀ
1
(
Yield: 96%); mp 225–227°C; IR (KBr) (νmax, cm ):
DMSO-d , ppm): δ 1.06 (t, 3H, J = 5.5 Hz, CH ), 2.51
6 3
3
410, 3305, 2205, 1730, 1665, 1608, 1490, 1355, 1170,
(s, 3H, CH ), 3.81 (q, 2H, CH ), 6.72–8.47 (m, 9H, ArH
3 2
1
13
1110, 1080, 970, 770; H NMR (400 MHz, DMSO-d ,
and NH ), 10.74 (s, 1H, NH); C{1H} NMR (100 MHz,
6
2
ppm): δ 3.21 (s, 3H, N─CH ), 7.01–7.96 (m, 10H, ArH
DMSO-d , ppm): δ 13.3, 20.4, 47.8, 57.5,75.2, 101.5,
109.2, 112.5, 116.7, 118.9, 120.4, 123.3, 127.3, 130.2,
3
6
13
and NH2); C{1H} NMR (100 MHz, DMSO-d , ppm): δ
6
2
1
1
7.1, 47.6, 58.0, 101.3, 108.4, 113.2, 117.5, 122.8,
131.2, 133.1, 135.7, 140.3, 150.8, 155.5, 157.0, 158.3,
178.2; MS (ESI): m/z: 419 [M + H] . Anal. Calcd for
+
24.1, 125.8, 129.4, 132.2, 134.7, 144.3, 152.4, 155.5,
+
59.5, 176.3; MS (ESI): m/z: 372 [M + H] . Anal. Calcd
C H N O : C, 66.02; H, 4.34; N, 6.70. Found C,
23 18 2 6
for C H N O : C, 67.92; H, 3.53; N, 11.32. Found C,
66.09; H, 4.41; N, 6.77.
21 13 3 4
0
0
0
6
7.97; H, 3.59; N, 11.38.
(4l) Ethyl 2 -amino-5-chloro-2,5 -dioxo-5 H-spiro[indoline-
0
0
0
0
0
0
(
4h)
1-Allyl-2 -amino-2,5 -dioxo-5 H-spiro[indoline-3,4 -
3,4 -pyrano[3,2-c]chromene]-3 -carboxylate.
White solid;
0
ꢀ1
pyrano[3,2-c]chromene]-3 -carbonitrile.
White
solid;
(Yield: 92%); mp 280–282°C; IR (KBr) (νmax, cm ):
3477, 3385, 3277, 3144, 3082, 1720, 1687, 1650, 1614,
1489, 1354, 1276, 1107, 1022, 758; H NMR (400 MHz,
ꢀ
1
(Yield: 95%); mp 243–245°C; IR (KBr) (νmax, cm ):
1
3
400, 3280, 3150, 2210, 1740, 1680, 1610, 1495, 1460,
1
1370, 1210, 1120, 1080, 980, 760; H NMR (400 MHz,
DMSO-d , ppm): δ 0.87 (t, 3H, J = 5.0 Hz, CH ), 3.75–
6
3
DMSO-d , ppm): δ 4.24–4.47 (m, 2H, CH ), 5.13–5.21
3.84 (m, 2H, CH ), 6.74–8.19 (m, 9H, ArH and NH ),
6
2
2
2
13
(
d, J = 15.2 Hz, 1H, CH ), 5.38–5.45 (d, J = 14 Hz, 1H,
10.58 (s, 1H, NH);
C{1H} NMR (100 MHz,
2
CH ), 5.78–5.84 (m, 1H, CH), 6.94–7.99 (m, 10H, ArH
DMSO-d , ppm): δ 13.4, 47.8, 59.6, 75.4, 103.4, 109.8,
113.1, 116.6, 123.7, 126.0, 128.2, 133.8, 136.9, 138.3,
2
6
13
and NH2); C{1H} NMR (100 MHz, DMSO-d , ppm): δ
6
4
1
1
2.5, 47.6, 57.3, 101.5, 109.7, 112.0, 117.0, 117.3,
23.1, 124.4, 125.0, 129.4, 132.1, 133.1, 134.5, 143.7,
143.9, 152.9, 158.3, 159.5, 164.5, 167.3, 179.1; MS
+
(ESI): m/z: 439 [M
+
H] . Anal. Calcd for
52.5, 156.1, 158.6, 159.3, 176.0; MS (ESI) m/z: 398
C H ClN O : C, 60.22; H, 3.45; Cl, 8.08; N, 6.38.
22 15 2 6
+
[M + H] . Anal. Calcd for C H N O : C, 69.52; H,
Found: C, 60.28; H, 3.51; Cl, 8.13; N, 6.42.
2
3 15 3 4
0
0
0
(
4m) Ethyl 2 -amino-5-bromo-2,5 -dioxo-5 H-spiro[indoline-
3.80; N, 10.57. Found: C, 69.57; H, 3.87; N, 10.63.
0
0
0
0
0
0
3
,4 -pyrano[3,2-c]chromene]-3 -carboxylate.
(Yield: 91%); mp 232–234°C; IR (KBr) (νmax, cm ):
White solid;
(
4i)
2 -Amino-1-benzyl-2,5 -dioxo-5 H-spiro[indoline-3,4 -
0
ꢀ1
pyrano[3, 2-c]chromene]-3 -carbonitrile.
White solid;
ꢀ
1
(Yield: 95%); mp 176–178°C; IR (KBr) (νmax, cm ):
3477, 3385, 3277, 3144, 3082, 1720, 1687, 1650, 1614,
1
3
1
410, 3310, 3155, 2970, 2210, 1720, 1680, 1605, 1490,
360, 1210, 1110, 1040, 970; H NMR (400 MHz,
1489, 1354, 1276, 1107, 1022, 758; H NMR (400 MHz,
1
DMSO-d , ppm): δ 0.86 (t, 3H, J = 5.0 Hz, CH ), 3.78–
6
3
DMSO-d , ppm): δ 4.96–4.99 (m, 2H, CH ), 6.78–8.01
3.82 (m, 2H, CH ), 6.70–8.20 (M, 9H, ArH and NH ),
6
2
2
2
1
3
13
(m, 15H, ArH and NH2); C{1H} NMR (100 MHz,
10.58 (s, 1H, NH); C{1H} NMR (100 MHz, DMSO-d6,
ppm): δ 13.1, 30.2, 47.2, 59.3, 75.0, 103.0, 110.2, 112.4,
116.2, 122.9, 124.6, 126.2, 130.3, 133.3, 137.1, 143.5,
151.9, 154.1, 157.8, 158.6, 167.0, 178.4; MS (ESI): m/z:
DMSO-d , ppm): δ 43.4, 47.3, 56.7, 101.1, 109.1, 112.4,
6
1
1
1
16.7, 117.0, 122.7, 122.9, 124.0, 125.0, 127.1, 127.2,
28.3, 128.9, 132.2, 133.7, 135.8, 142.7, 152.0, 155.3,
58.3, 158.6, 175.9; MS (ESI) m/z: 448 [M + H] . Anal.
+
+
484 [M + H] . Anal. Calcd for C H BrN O : C, 54.68;
22
15
2 6
Calcd for C H N O : C, 72.48; H, 3.83; N, 9.39.
H, 3.13; N, 5.80. Found: C, 54.73; H, 3.18; N, 5.88.
27 17 3 4
0 0 0
(4n) Ethyl 2 -amino-5-nitro-2,5 -dioxo-5 H-spiro[indoline-
Found: C, 72.53; H, 3.88; N, 9.43.
0
0
0
0
0
0
3
,4 -pyrano[3,2-c]chromene]-3 -carboxylate.
White solid;
(
4j)
Ethyl
2 -amino-2,5 -dioxo-5 H-spiro[indoline-3,4 -
0
ꢀ1
pyrano[3,2-c]chromene]-3 -carboxylate.
White
solid;
(Yield: 92%); mp 258–260°C; IR (KBr) (νmax, cm ):
ꢀ
1
(Yield: 94%); mp 258–260°C; IR (KBr) (νmax, cm ):
3477, 3385, 3277, 3144, 3082, 1720, 1687, 1650, 1614,
1
3
477, 3385, 3277, 3144, 3082, 1720, 1687, 1650, 1614,
1489, 1354, 1276, 1107, 1022, 758; H NMR (400 MHz,
1
1489, 1354, 1276, 1107, 1022, 758; H NMR (400 MHz,
DMSO-d , ppm): δ 0.89 (t, 3H, J = 5.4 Hz, CH ), 3.79–
6
3
DMSO-d , ppm): δ 0.83 (t, 3H, J = 9.4 Hz, CH ), 3.79
3.87 (m, 2H, CH ), 6.80–8.19 (M, 9H, ArH and NH ),
6
3
2
2
13
(
(
q, 2H, CH ), 6.74–8.11 (m, 10H, ArH and NH ), 10.43
s, 1H, NH); C{1H} NMR (100 MHz, DMSO-d6,
11.18 (s, 1H, NH); C{1H} NMR (100 MHz, DMSO-d6,
ppm): δ 13.0, 47.5, 59.1, 74.4, 102.4, 108.4, 112.6, 116.3,
119.3, 122.9, 124.7, 125.6, 133.6, 135.7, 151.9, 150.6,
151.9, 154.5, 158.1, 158.7, 167.6, 179.6; MS (ESI): m/z:
2
2
13
ppm): δ 13.3, 47.8, 59.5, 75.7, 97.6, 108.5, 113.1, 116.8,
1
21.6, 123.1, 125.3, 128.4, 134.0, 135.0, 144.5, 152.5,
+
+
154.4, 158.8, 179.7; MS (ESI): m/z: 405 [M + H] . Anal.
450 [M + H] . Anal. Calcd for C H N O : C, 58.80; H,
2
2 15 3 8
Calcd for C H N O : C, 65.34; H, 3.99; N, 6.93.
3.36; N, 9.35. Found: C, 58.87; H, 3.43; N, 9.41.
22 16 2 6
0
0
0
Found: C, 65.43; H, 4.08; N, 6.85.
(4o) Ethyl 2 -amino-1-methyl-2,5 -dioxo-5 H-spiro[indoline-
0
0
0
0
0
(
4k) Ethyl 2 -amino-5-methyl-2,5 -dioxo-5 H-spiro[indoline-
3,4 -pyrano[3,2-c]chromene]-3 -carboxylate.
White solid;
0
0
ꢀ1
3
,4 -pyrano[3,2-c]chromene]-3 -carboxylate.
White solid;
(Yield: 95%); mp 253–255°C; IR (KBr) (νmax, cm ):
ꢀ
1
(Yield: 92%); mp 242–244°C; IR (KBr) (νmax, cm ):
3477, 3385, 3277, 3144, 3082, 1720, 1687, 1650, 1614,
1
3
477, 3385, 3277, 3144, 3082, 1720, 1687, 1650, 1614,
1489, 1354, 1276, 1107, 1022, 758; H NMR (400 MHz,
1
1489, 1354, 1276, 1107, 1022, 758; H NMR (400 MHz,
DMSO-d , ppm): δ 0.89 (t, 3H, J = 5.4 Hz, CH ), 3.25 (s,
6
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

F. Diwan and M. Farooqui
Vol 000
3
H, N─CH ), 3.79–3.87 (m, 2H, CH ), 6.87–8.09 (m, 10H,
REFERENCES AND NOTES
1] Constable, D. J. C.; Gonzalez, C. J.; Henderson, R. K. Org
3
2
1
3
ArH and NH2); C{1H} NMR (100 MHz, DMSO-d6,
ppm): δ 13.0, 18.6, 47.8, 59.7, 74.3, 102.4, 107.9, 112.8,
[
Proc Res Dev 2007, 11, 133.
1
1
4
4
16.8, 120.3, 122.8, 123.7, 126.6, 132.6, 136.7, 142.9,
[2] Clarke, C. J.; Tu, W. C.; Levers, O.; Brohl, A.; Hallett, J. P.
Chem Rev 2018, 118, 747.
50.8, 151.9, 155.6, 158.3, 166.6, 178.6; MS (ESI): m/z:
+
[3] Butler, R. N.; Coyne, A. G. Chem Rev 2010, 110, 6302.
19 [M + H] . Anal. Calcd for C H N O : C, 66.02; H,
2
3 18 2 6
[
[
4] Chaturvedi, D. Curr Org Synth 2011, 8, 438.
5] Shanab, K.; Neudorfer, C.; Schirmer, E.; Spreitzer, H. Curr
.34; N, 6.70. Found: C, 66.09; H, 4.41; N, 6.77.
0
0
0
(
4p)
Ethyl1-allyl-2 -amino-2,5 -dioxo-5 H-spiro[indoline-
Org Chem 2013, 17, 1179.
[6] Oakes, R. C.; Clifford, A. A.; Rayner, C. M. J Chem Soc
Perkin Trans 1 2001 917.
0
0
3
,4 -pyrano[3,2-c]chromene]-3 -carboxylate.
White solid;
ꢀ
1
(Yield: 96%); mp 230–232°C.; IR (KBr) (νmax, cm ):
[
[
7] Vafaeezadeh, M.; Hashemi, M. M. J Mol Liq 2015, 207, 73.
8] Gu, Y.; Jerome, F. Chem Soc Rev 2013, 42, 9550.
3
1
456, 3268, 3153, 2196, 1708, 1674, 1608, 1489,1361,
1
203, 1070, 961, 755; H NMR (400 MHz, DMSO-d ,
[9] Santoro, S.; Ferlin, F.; Luciani, L.; Ackermann, L.; Vaccaro, L.
Green Chem 2017, 19, 1601.
6
ppm): δ 0.86 (t, 3H, J = 5.2 Hz, CH ), 3.76–3.89 (m, 2H,
CH ), 4.33–4.46 (m, 2H, CH ), 5.16–5.23 (d, J = 15.2 Hz,
1
3
[10] Alvarez, A. E. D.; Francos, J.; Crochet, P.; Cadierno, V. Curr
2
2
Green Chem 2014, 1, 51.
[11] Sanjay, P.; Koyel, P.; Das, A. R. Curr Green Chem 2016, 3,
111.
H, CH ), 5.57–5.64 (d, J = 14 Hz, 1H, CH ), 5.90–5.98
2
2
(
m, 1H, CH), 6.88–8.49 (m, 10H, ArH and NH );
2
1
3
[12] Yang, J.; Zhou, B.; Li, M.; Gu, Y. Tetrahedron 2013, 69,
C{1H} NMR (100 MHz, DMSO-d , ppm): δ 13.7, 19.4,
6
1057.
4
1
1
4
4
2.8, 47.6, 57.3, 74.8, 101.5, 109.7, 112.0, 117.0, 117.3,
23.1, 124.4, 125.0, 129.4, 132.1, 133.1, 134.5, 143.7,
52.3, 156.7, 158.6, 159.3, 159.6, 176.4; MS (ESI) m/z:
[13] Ilgen, F.; Konig, B. Green Chem 2009, 11, 848.
[14] Strappaveccia, G.; Luciani, L.; Bartollini, E.; Marrocchi, A.;
Pizzo, F.; Vaccaro, L. Green Chem 2015, 1071s, 17.
+
[15] Haji, M. Beilstein J Org Chem 2016, 12, 1269.
45 [M + H] . Anal. Calcd for C H N O : C, 67.56; H,
2
5 20 2 6
[16] Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem Rev
.54; N, 6.30. Found: C, 67.62; H, 4.59; N, 6.37.
2014, 114, 8323.
0
0
0
(
4q) Ethyl 2 -amino-1-benzyl-2,5 -dioxo-5 H-spiro[indoline-
[17] Trost, B. M.; Brennan, M. K. Synthesis 2009, 18, 3003.
[18] Galliford, C. V.; Scheidt, K. A. Angew Chem Int Ed 2007, 46,
8748.
0
0
3
,4 -pyrano[3,2-c]chromene]-3 -carboxylate.
White solid;
ꢀ
1
(Yield: 92%); mp 176–178°C; IR (KBr) (νmax, cm ):
[19] Marti, C.; Carreira, E. M. Eur J Org Chem 2003, 63, 2209.
3
9
3
316, 3182, 2194, 1718, 1672, 1607, 1458, 1362, 1112,
[20] Wong, W. H.; Lim, P. B.; Chuah, C. H. Phytochemistry 1996,
1
62, 760; H NMR (400 MHz, DMSO-d , ppm): δ 0.56 (t,
41, 313.
6
[21] Garnick, R. L.; Lequesne, P. W. J Am Chem Soc 1978, 100,
H, J = 5.2 Hz, CH ), 3.79–3.84 (m, 2H, CH ), 4.96–4.99
3
2
4213.
(
m, 2H, CH ), 6.79–8.22 (m, 15H, ArH and NH );
2
2
[22] Bassleer, R.; Depauw-Gillet, M. C.; Massart, B.; Marnette, J.
1
3
C{1H} NMR (100 MHz, DMSO-d , ppm): δ 14.1, 44.8,
M.; Wiliquet, P.; Caprasse, M.; Angenot, L. Planta Med 1982, 45, 123.
[23] Sakai, S.; Aimi, N.; Yamaguchi, K.; Yamanaka, E.; Haginiwa,
J. J Chem Soc Perkin Trans 1 1982 1257.
6
4
1
1
7.4, 59.2, 76.0, 103.8, 108.3, 112.9, 116.8, 122.3, 123.4,
23.5, 125.3, 127.6, 128.4, 128.6, 134.7, 134.4, 137.2,
[24] Jadhav, S. A.; Sarkate, A. P.; Farooqui, M.; Shinde, D. B.
45.9, 152.3, 154.5, 158.3, 159.1, 167.2, 178.8; MS (ESI)
Synth Commun 2017, 47, 1676.
[25] Wagare, D. S.; Netankar, P. D.; Shaikh, M.; Farooqui, M.;
Durrani, A. Environ Chem Lett 2017, 15, 475.
+
m/z: 495 [M + H] . Anal. Calcd for C H N O : C,
7
2
9 22 2 6
0.44; H, 4.48; N, 5.67. Found: C, 70.51; H, 4.52; N, 5.74.
[26] Wagare, D. S.; Shaikh, M.; Farooqui, M.; Durrani, A. Environ
Chem Biol Interface 2016, 6, 405.
CONFLICT OF INTEREST
The authors confirm that there are no known conflicts of
interest associated with this publication.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet