Synthesis of Spiro[indoline-3,4′-pyrano[3,2-c]chromene]diones

Article abstract of DOI:10.1002/jhet.3326

A new series of isatin-based spiro-fused derivatives were prepared, via three-component reaction of N-alkyl-1-(methylthio)-2-nitroethenamine derived from the addition of various amines to nitroketene dithioacetal with isatin derivatives and 4-hydroxycouma

Full text of DOI:10.1002/jhet.3326

Month 2018
Synthesis of Spiro[indoline-3,40-pyrano[3,2-c]chromene]diones
*
Sakineh Ghadiri, Mohammad Bayat,
and Fahimeh Sadat Hosseini
Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran
*E-mail: bayat_mo@yahoo.com; m.bayat@sci.ikiu.ac.ir
Received April 22, 2018
DOI 10.1002/jhet.3326
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A new series of isatin-based spiro-fused derivatives were prepared, via three-component reaction of N-
alkyl-1-(methylthio)-2-nitroethenamine derived from the addition of various amines to nitroketene
dithioacetal with isatin derivatives and 4-hydroxycoumarin in ethanol as a solvent at reflux. The
significant advantages of this protocol include simple operation under mild conditions, easy purification,
good yields, and catalyst-free approach.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
RESULTS AND DISCUSSION
Isatin, is a versatile chemical building block, which is
able to form a large number of heterocyclic molecules
[1]. Isatin and its derivatives possess various activities
such as antidepressant, antiepileptic, antimicrobial,
anticancer, analgesic [2], anxiogenic, anticonvulsant [3],
antimalarial, antitumor, antiviral, anti-HIV, and MDM2
inhibitor [4] (Fig. 1).
Spiro heterocycles represent an important class of
naturally occurring substances with biological activities
[5] and diversified pharmacological and therapeutical
properties [6]. In recent years, isatin-related articles have
been published on synthesis of spiro and multispiro
heterocyclic compounds from isatin [7–14].
Enamines and dienamines derived from Ketene
dithioacetals as powerful synthetic intermediates for the
synthesis of a variety of complex fused heterocycles
have attracted considerable attention in the past decades
[15–21].
To continue our studies on the synthesis of
pharmacologically active heterocyclic compounds using
nitroketene dithioacetal [22–27] and considering the
importance of isatin-based spiro-fused frameworks in
organic synthesis, herein we report an efficient synthesis
of six-membered spiro-fused compounds trough
multicomponent reactions of enamines derived from the
addition of various amines to nitroketene dithioacetal
with isatin derivatives and 4-hydroxycoumarin.
In this article, we have prepared isatin-based spiro-fused
compounds in a one-pot three-component condensation of
N-alkyl-1-(methylthio)-2-nitroethenamine derived from the
addition of various amines 1 to nitroketene dithioacetal 2
with isatin derivatives 3 and 4-hydroxycoumarin 4 in
ethanol at reflux (Scheme 1).
In order to optimize the reaction conditions, several
solvents with the absence and presence of a catalyst were
examined to set up a standard reaction condition, and
experimental results showed that the reaction proceeds
with good yields when ethanol was used as the solvent
(Entry 8, Table 1). We examined the scope of this
reaction by varying the structure of the amines and isatin
derivatives. The reactions were completed after 10–12 h
to afford corresponding isatin-based spiro-fused systems
5a–j, in moderate to good yields (50–84%). The results
are summarized in Table 2.
The structures of the products were deduced from
their elemental analyses, Mass, IR, 1H, and 13C
NMR spectra. The mass spectra of 5a displayed
molecular ion peak at appropriate value (m/z 419).
The IR spectrum of 5a displayed characteristic absorption
bands (3367, 1716, 1656, 1608, 1465, 1343, and
1215 cmꢀ1) due to the NH, two C═O groups, Ar, NO2,
1
and C–N groups. The H NMR spectrum of 5a consisted
of two doublets (δ 1.51 and 1.54 ppm) for the two CH3
groups, a multiplet for the CH group (δ 4.40–4.49 ppm),
© 2018 Wiley Periodicals, Inc.

S. Ghadiri, M. Bayat, and F. S. Hosseini
Vol 000
Figure 1. Pharmacologically active isatin derivatives.
Scheme 1. Synthesis of isatin-based spiro-fused compounds 5.
Table 1
Optimization of reaction conditions for the synthesis of 5f.
Entry
Solvent
Catalyst
T (°C)
Time (h)
Yield (%)
40
1
2
3
4
5
6
7
8
H2O:EtOH (1:1)
CH3CN
DMF
CHCl3
EtOH
EtOH
EtOH
EtOH
-
-
-
-
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
7
7
10
7
10
10
10
10
50
No reaction
No reaction
No reaction
No reaction
60
Piperidine
Et3N
p-TSA
-
84
and two singlets for the NH protons (δ 10.47 and
Table 2
10.50 ppm), together with characteristic signals for the
Products 5a–j.
1
aromatic moiety (δ 6.91–7.79 ppm). The H decoupled
Entry
X
R1
R2
Product
Yield (%)
13CNMR spectrum of 5a showed 22 distinct signals in
agreement with proposed structure. The characteristic
signals of two CH3 carbons and CH carbon were observed
at δ 22.7, 22.8, and 45.7 ppm, respectively. Also, the
signal of Cspiro was showed at δ 49.6 ppm.
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Cl
Cl
Cl
H
H
H
H
H
H
CH (CH3)2
CH2CH3
CH3
CH2Ph
CH3
CH3
CH (CH3)2
CH3
CH2CH3
CH (CH3)2
CH2Ph
4-F-CH2Ph
CH2CH3
CH (CH3)2
5a
5b
5c
5d
5e
5f
5g
5h
5i
74
78
55
70
70
84
50
80
CH2CH3
H
CH3
H
CH3
H
A plausible mechanistic pathway for the formation of 5
is outlined in Scheme 2. Initially, the Knoevenagel
condensation between isatin derivatives
3 and 4-
9
H
H
75
73
hydroxycoumarin 4 affords 7 which undergoes Michael
addition with N-alkyl-1-(methylthio)-2-nitroethenamine 6
(derived from the addition of various amines 1 to
nitroketene dithioacetal 2), to give 8. Thus, the
intermediate 8 undergoes imine–enamine tautomerization
to form 9 followed by O-cyclization to form 5 via the
elimination of MeSH.
10
11
12
13
14
5j
CH3
CH3
CH2CH3
CH2CH3
---
---
---
---
No reaction
No reaction
No reaction
No reaction
aVarious amines (1 mmonl), nitroketene dithioacetal (1 mmol), isatin de-
rivatives (1 mmol), and 4-hydroxycoumarin (1 mmol) were used in EtOH
at reflux.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Spiro Heterocycles
Scheme 2. Plausible mechanism for the formation of product 5.
CONCLUSION
General procedure for the synthesis of product 5.
A
mixture of various amines (1 mmol), nitroketene
dithioacetal (1 mmol, 0.165 g), and 10 mL EtOH in a
50 mL flask was refluxed for 6 h. After completion of the
reaction (monitored by thin-layer chromatography, ethyl
acetate/n-hexane, 6:4), isatin derivatives (1 mmol) and
4-hydroxycoumarin (1 mmol, 0.162 g) were added to the
reaction mixture, and it was stirred under reflux for
10–12 h. Then, the reaction mixture was cooled to room
temperature and filtered to give the crude product. The
solid was washed with ethanol to give pure product 5 in
good to high yields.
The present work reports the one-pot three-component
domino reactions for the expedient synthesis of novel
isatin-based spiro-fused derivatives in good yields. To the
best of our knowledge, there are no reports on the
synthesis of these compounds in the literature yet.
Prominent among the advantages of this reaction are
operational simplicity, absence of catalyst, good yields,
and easy work-up procedures. It provides a powerful
entry into spiro-fused polycyclic structures related to
bioactive heterocycles.
20-(Isopropylamino)-30-nitro-50H-spiro[indoline-3,40-pyrano
[3,2-c]chromene]-2,50-dione (5a). Yellow solid, mp: 294–
296°C, 0.310 g, yield 74%. IR (KBr) (νmax/cmꢀ1): 3367
(NH), 1716 (C═O), 1656 (C═O), 1608 (Ar), 1465 and
1343 (NO2), 1215 (C-N). 1H NMR (300 MHz, CDCl3): δ
EXPERIMENTAL SECTION
General. The various amines, nitro ketene dithioacetal,
isatin, 4-hydroxycumarin, and other chemicals and solvents
were obtained from Merck and Aldrich and were used
without further purification. NMR spectra were recorded
with a Bruker DRX-300 Avance instrument (300 MHz for
1H and 75.4 MHz for 13C) with dimethyl sulfoxide
(DMSO) and deuterated chloroform (CDCl3) as solvent.
Chemical shifts are given in ppm (δ), and coupling constant
(J) are reported in hertz (Hz). Melting points were measured
with an electrotherma1 9100 apparatus. Mass spectra were
recorded with an Agilent 5975C VL MSD with Triple-Axis
Detector operating at an ionization potential of 70 eV. IR
spectra were measured with, Bruker Tensor 27
spectrometer. Elemental analyses for C, H, and N were
performed using a PerkinElmer 2004 series [II] CHN
elemental analyzer (Perkin Elmer Company, Waltham, MA).
3
1.51 (3H, d, JHH = 6.6 Hz, CH3), 1.54 (3H, d,
3JHH = 6.6 Hz, CH3), 4.40–4.49 (1H, m, CH), 6.91–7.79
(8H, m, Ar), 10.47 (1H, s, NH), 10.50 (1H, s, NH). 13C
NMR (75.4 MHz, DMSO): δ 22.7 (CH3), 22.8 (CH3),
45.7 (CH), 49.6 (CSpiro), 104.4, 107.3, 109.1, 112.4,
116.9, 121.6, 123.5, 123.9, 125.7, 129.1, 130.0, 134.3,
145.0, 152.2, 153.4, 155.8, 157.5, 176.0. MS (EI,
70 eV): m/z (%) = 419 (M+, 12), 358 (100), 331 (35),
316 (86), 303 (32), 286 (26), 190 (14), 121 (86), 92 (20),
43 (40). Anal. Calcd for (%) for C22H17N3O6 (419.39):
C, 63.01; H, 4.09; N, 10.02. Found C, 63.5; H, 4.4; N, 9.7.
20-(Ethylamino)-30-nitro-50H-spiro[indoline-3,40-pyrano[3,2-
c]chromene]-2,50-dione (5b). White solid, mp: 303–305°C,
1
0.316 g, yield 78%. H NMR (300 MHz, DMSO): δ 1.35
(3H, t, CH3), 3.79 (2H, q, CH2), 6.72–7.79 (8H, m, Ar),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Ghadiri, M. Bayat, and F. S. Hosseini
Vol 000
10.69 (1H, s, NH), 10.75 (1H, s, NH). 13C NMR (75.4 MHz,
DMSO): δ 15.4 (CH3), 37.7 (CH2), 49.6 (CSpiro), 104.4,
107.3, 109.1, 112.5, 116.9, 121.6, 123.5, 123.8, 125.7,
129.1, 130.1, 134.3, 145.0, 152.2, 153.4, 156.4, 157.5,
176.2. Anal. Calcd for (%) for C21H15N3O6 (405.36): C,
176.1. MS (EI, 70 eV): m/z (%) = 160 (30), 147 (36), 131
(30), 119 (89), 92 (100), 63 (51), 55 (36), 43 (29).
20-(Isopropylamino)-1-methyl-30-nitro-50H-spiro [indoline-
3,40-pyrano[3,2-c]chromene]-2,50-dione (5g).
White solid,
mp: 309–311°C, 0.216 g, yield 50%. IR (KBr) (νmax
/
cmꢀ1): 3426 (NH), 1723 (C═O), 1662 (C═O), 1611
62.22; H, 3.73; N, 10.37. Found C, 62.6; H, 4.0; N, 10.2.
(Ar), 1465 and 1343 (NO2), 1213 (C-N). 1H NMR
1-Ethyl-20-(methylamino)-30-nitro-50H-spiro[indoline-3,40-
3
pyrano[3,2-c]chromene]-2,50-dione (5c).
White solid, mp:
(300 MHz, CDCl3): δ 1.43 (3H, d, JHH = 6.6 Hz,
311–313°C, 0.230 g, yield 55%. IR (KBr) (νmax/cmꢀ1):
3447 (NH), 3229 (NH), 1728 (C═O), 1666 (C═O), 1613
(Ar), 1453 and 1339 (NO2), 1252 (C-N). 1H NMR
CH3), 1.45 (3H, d, JHH = 6.6 Hz, CH3), 3.23 (NCH3),
3
4.48–4.55 (1H, m, CH), 6.85–8.48 (8H, m, Ar), 10.49
(1H, d, NH). 13C NMR (75.4 MHz, DMSO): δ 22.7
(CH3), 22.8 (CH3), 27.1 (NCH3), 45.8 (CH), 49.6
(CSpiro), 104.2, 107.0, 108.1, 112.4, 112.8, 117.0, 122.3,
123.7, 125.8, 129.2, 129.3, 134.4, 146.3, 152.2, 153.4,
155.8, 157.5, 176.0. Anal. Calcd for (%) for
C23H19N3O6 (433.41): C, 63.74; H, 4.42; N, 9.70.
3
(300 MHz, DMSO): δ 1.19 (3H, t, JHH = 6.9 Hz, CH3),
3.19 (3H, s, NHCH3), 3.74 (2H, q, NCH2), 6.83–8.05 (8H,
m, Ar), 10.65 (1H, s, NH). 13C NMR (75.4 MHz, DMSO):
δ 12.2 (CH3), 29.3 (NHCH3), 35.0 (NCH2), 49.2 (CSpiro),
104.3, 107.2, 108.0, 112.4, 116.9, 122.1, 123.7, 125.6,
129.2, 129.6, 134.4, 145.4, 152.2, 153.5, 156.8, 157.5,
174.2. Anal. Calcd for (%) for C22H17N3O6 (419.39): C,
Found C, 63.4; H, 4.7; N, 9.4.
20-(Methylamino)-30-nitro-50H-spiro[5-chloro-indoline-3,40-
pyrano[3,2-c]chromene]-2,50-dione (5h). Yellow solid, mp:
63.01; H, 4.09; N, 10.02. Found C, 63.4; H, 4.3; N, 10.1.
298–300°C, 0.340 g, yield 80%. IR (KBr) (νmax/cmꢀ1):
3354 (NH), 1732 (C═O), 1664 (C═O), 1612 (Ar), 1471
and 1345 (NO2), 1219 (C-N). 1H NMR (300 MHz,
DMSO): δ 3.32 (3H, s, NHCH3), 6.75–8.46 (7H, m, Ar),
10.65 (1H, m, NH), 10.82 (1H, s, NH). 13C NMR
(75.4 MHz, DMSO): δ 29.3 (NHCH3), 49.8 (CSpiro), 103.8,
107.2, 110.3, 112.5, 116.9, 123.7, 124.2, 125.6, 128.8,
20-(Benzylamino)-30-nitro-50H-spiro[indoline-3,40-
pyrano[3,2-c]chromene]-2,50-dione (5d). White solid, mp:
297–299°C, 0.326 g, yield 70%. 1H NMR (300 MHz,
DMSO): δ 5.00 (2H, s, CH2Ph), 6.72–7.80 (13H, m, Ar),
10.72 (H, s, NH), 11.12 (1H, m, NH). 13C NMR
(75.4 MHz, DMSO): δ 45.8 (CH2Ph), 49.6 (CSpiro),
104.6, 107.8, 112.2, 116.9, 121.7, 123.4, 123.8, 125.5,
127.3, 127.4, 128.0, 129.2, 129.3, 130.0, 134.3, 138.0,
145.0, 152.2, 153.2, 156.5, 157.5, 176.1. MS (EI,
70 eV): m/z (%) = 467 (M+, 0.78), 406 (5), 121 (8), 105
(5), 91 (100), 77 (5), 65 (10). Anal. Calcd for (%) for
C26H17N3O6 (467.43): C, 66.81; H, 3.67; N, 8.99. Found
132.2, 134.4, 144.0, 152.3, 153.6, 156.9, 157.7, 176.0.
20-(Ethylamino)-30-nitro-50H-spiro[5-chloro-indoline-3,40-
pyrano[3,2-c]chromene]-2,50-dione (5i).
White solid, mp:
306–308°C, 0.329 g, yield 75%. IR (KBr) (νmax/cmꢀ1):
3352 (NH), 1721 (C═O), 1658 (C═O), 1611 (Ar), 1473
and 1344 (NO2), 1220 (C-N). 1H NMR (300 MHz,
DMSO): δ 1.37 (3H, t, CH3), 3.78 (2H, q, CH2), 6.76–
8.44 (7H, m, Ar), 10.76 (1H, m, NH), 10.83 (1H, s, NH).
13C NMR (75.4 MHz, DMSO): δ 15.4 (CH3), 37.8
(CH2), 49.8 (CSpiro), 103.1, 107.0, 110.3, 112.8, 116.9,
123.9, 123.5, 125.4, 125.9, 128.8, 132.2, 134.3, 144.1,
C, 66.2; H, 3.5; N, 8.7.
1-Methyl-20-(methylamino)-30-nitro-50H-spiro[indoline-3,40-
pyrano[3,2-c]chromene]-2,50-dione (5e). White solid, mp:
284–286°C, 0.283 g, yield 70%. IR (KBr) (νmax/cmꢀ1):
3422 (NH), 1727 (C═O), 1667 (C═O), 1613 (Ar), 1458
and 1342 (NO2), 1222 (C-N). 1H NMR (300 MHz,
DMSO): δ 3.18 (3H, s, NCH3), 3.23 (3H, s, NHCH3),
6.85–8.07 (8H, m, Ar), 10.65 (1H, m, NH). 13C NMR
(75.4 MHz, DMSO): δ 27.1 (NHCH3), 29.3 (NCH3),
49.1 (CSpiro), 104.3, 107.2, 108.0, 112.4, 116.9, 122.3,
123.5, 123.7, 125.6, 129.3, 129.4, 134.4, 146.4, 152.2,
153.5, 156.9, 157.6, 174.8. MS (EI, 70 eV): m/z
(%) = 405 (M+, 25), 359 (13), 344 (100), 315 (19), 303
152.2, 153.7, 156.4, 157.6, 176.0.
20-(Isopropylamino)-30-nitro-50H-spiro[5-chloro-indoline-
3,40-pyrano[3,2-c]chromene]-2,50-dione (5j).
Yellow solid,
mp: 330–333°C, 0.331 g, yield 73%. IR (KBr) (νmax
/
cmꢀ1): 3300 (NH), 1726 (C═O), 1660 (C═O), 1613 (Ar),
1
1473 and 1342 (NO2), 1225 (C-N). H NMR (300 MHz,
CDCl3): δ 1.42 (3H, d, 3JHH = 6.3 Hz, CH3), 1.45 (3H, d,
3JHH = 6.3 Hz, CH3), 4.45–4.65 (1H, m, CH), 6.75–8.46
(7H, m, Ar), 10.50 (1H, d, NH), 10.84 (1H, s, NH). 13C
NMR (75.4 MHz, DMSO): δ 22.6 (CH3), 22.7 (CH3),
45.8 (CH), 49.8 (CSpiro), 103.1, 107.0, 110.4, 112.5,
116.9, 123.6, 123.9, 125.7, 125.9, 128.9, 132.0, 134.4,
144.1, 152.2, 153.7, 155.8, 157.6, 175.9.
(22), 179 (18), 121 (27), 92 (27).
20-(Methylamino)-30-nitro-50H-spiro[indoline-3,40-pyrano
[3,2-c]chromene]-2,50-dione (5f). White solid, mp: 317–
319°C, 0.340 g, yield 84%. IR (KBr) (νmax/cmꢀ1): 3367
(NH), 3211 (NH), 1709 (C═O), 1665 (C═O), 1614 (Ar),
1
1471 and 1345 (NO2), 1222 (C-N). H NMR (300 MHz,
DMSO): δ 3.32 (3H, s, NHCH3), 6.75–8.03 (8H, m, Ar),
10.61 (1H, m, NH), 10.68 (1H, s, NH). 13C NMR
(75.4 MHz, DMSO): δ 29.3 (NHCH3), 49.7 (CSpiro), 104.5,
107.4, 109.1, 112.4, 116.8, 121.6, 123.7, 123.8, 125.6,
129.0, 130.2, 134.3, 145.0, 152.2, 153.3, 156.8, 157.5,
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Synthesis of Spiro Heterocycles
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet