CsF promoted rapid synthesis of spirooxindole-pyran annulated heterocycles at room temperature in ethanol

Article abstract of DOI:10.1002/jhet.3846

A newer, versatile, and straightforward synthetic strategy for the construction of functionalized spirooxindole-pyran annulated heterocycles is described. The procedure is based on CsF-promoted rapid tandem Knoevenagel-Michael-Cyclocondensation reaction o

Full text of DOI:10.1002/jhet.3846

Received: 25 June 2019
DOI: 10.1002/jhet.3846
Revised: 9 November 2019
Accepted: 15 November 2019
A R T I C L E
CsF promoted rapid synthesis of spirooxindole-pyran
annulated heterocycles at room temperature in ethanol
Yogesh B. Wagh1
| Swapnil A. Padvi2 | Pramod P. Mahulikar1 | Dipak S. Dalal1
1School of Chemical Sciences, Kavayitri
Bahinabai Chaudhari North Maharashtra
University, Jalgaon, India
2Department of Chemistry, JET's Z. B.
Patil College, Dhule, India
Abstract
A newer, versatile, and straightforward synthetic strategy for the construction
of functionalized spirooxindole-pyran annulated heterocycles is described. The
procedure is based on CsF-promoted rapid tandem Knoevenagel-Michael-
Cyclocondensation reaction of isatin, malononitrile, and 4-hydroxycoumarin/
barbituric acids/pyrazolone at room temperature in ethanol. This methodology
has various advantages like easy operational, excellent yields within short reac-
tion time (3-25 min), and simple isolation of products. The CsF has a dual role
as a base and carbonyl activator.
Correspondence
Dipak S. Dalal, School of Chemical
Sciences, Kavayitri Bahinabai Chaudhari
North Maharashtra University, Jalgaon,
Maharashtra 425001, India.
Email: dsdalal2007@gmail.com
Funding information
Council of Scientific & Industrial Research
(CSIR), New Delhi, India, Grant/Award
Number: 09/728(0036)/2019
1 | INTRODUCTION
expensive reagents. Consequently, there is scope for further
work toward the development of the clean, efficient, and
Efficient synthesis of structurally diverse small molecules
affords a validated source of chemical investigations for
biomedical research and to address the demand of bioactive
small molecules for chemical biology.[1,2] Knoevenagel-
Michael-Cyclocondensation reaction between a carbonyl
group and a methylene-activated group is known as an
excellent tool in organic chemistry to form new C−C
bonds.[3] The spirocyclic compounds are important for their
unique three-dimensional skeletal units that are extensively
distributed in several natural products and biologically
active compounds.[4]
The spirooxindole system is used as the core structure of
many useful alkaloids and pharmacological agents.[5] These
compounds are acknowledged for display of various biologi-
cal activities like anti-HIV,[6] antitumor,[7] antitubercular,[8]
antimalarial,[9] and central nervous system (CNS) activities
and effects.[10] Therefore, different catalysts have been used
to synthesize these spirooxindole scaffolds such as alum,[11]
L-proline,[12] Caspian Isinglass,[13] borax,[14] and gold (III)
chloride.[15] Although such protocols reported by others
find certain merits of their own. But they suffer from several
demerits like prolonged reaction times, poor yields, and
high yielding route in short reaction time.
The use of fluoride ion (F−) as a base or catalyst in
organic syntheses has gained significant popularity
for display a high tolerance for functional groups.[16]
We have linked several other investigators in reporting
on CsF-catalyzed conversions of various carbonyl
compounds with a variety of functional groups like
benzamides,[17] disulfides,[18] ethers,[19] amines,[20] and
fluoromethanimine.[21] CsF as well famous for the
desilylative elimination,[22] palladium, coupling,[23]
Julia-Kocienski olefination,[24] Aza-Michael,
and
[25]
Claisen rearrangement.[26] Based on these reports, we
anticipated that the CsF shows unique activation of typi-
cal carbonyl compounds, but its use as carbonyl activa-
tor and base catalyst specifically in multicomponent
reactions is still missing.
In the past few years, we investigated the mul-
ticomponent reactions by employing easily generated
nitrogen based as the main substrates and have success-
fully developed a few highly efficient protocols for the syn-
thesis of some biologically important nitrogen-containing
heterocyclic compounds.[27] Thus, as a part of our research
J Heterocyclic Chem. 2019;1–10.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
WAGH ET AL.
program to develop efficient and greener methodologies,
herein, a rapid and practical method for the functionalized
spirooxindole-pyran annulated heterocycles by the reac-
tion of isatins, malononitrile with C−H activated com-
pounds 4-hydroxycoumarin/1,3-dimethylbarbituric acid/
thiobarbituric acids/pyrazolones in the presence of CsF at
room temperature in ethanol is described (Scheme 1).
a model reaction. We have performed the model reaction
in different solvents and observed that ethanol is the best
solvent. Similarly, model reactions were performed by
using various amounts of catalyst CsF (Table 1).
The best result was obtained for 10 mol% of CsF,
affording 96% of 4a within 5 min (Table 1, entry 4). A fur-
ther increase in the amount of CsF up to 15 and 20 mol%
has no significant effect on the yield and reaction time
(Table 1, entries 5 and 6). The role of CsF as the promoter
has been confirmed when a similar reaction was carried
out in the absence of catalyst, giving only 20% yield with a
longer reaction time 3 h (Table 1, entry 2). The reaction
between 4-hydroxycoumarin and 2-(2-oxoindolin-3-ylidene)
malononitrile requires catalyst, since without catalyst the
reaction does not lead to the complete formation of the
desired product (Table 1, entries 1 and 2). In order to check
2 | RESULTS AND DISCUSSION
In order to optimize the reaction condition and the
performance of CsF as a promoter for 20-amino-2,50-
dioxo-50H-spiro[indoline-3,40-pyrano[3,2-c]chromene]-30-
carbonitrile 4a, the reaction between simple isatin,
malononitrile, and 4-hydroxy coumarin were selected as
SCHE ME 1 Synthesis of
spirooxindole-pyran annulated
heterocycles using CsF
TABLE 1 Optimization of reaction conditions in the synthesis of 4a
Entry
Catalyst
Solvent/condition
No solvent, rt
EtOH, rt
Time (h/min)
Yields (%)a
1
No catalyst
3 h
3 h
10
5
Trace
20
2
No catalyst
3
CsF (5 mol%)
CsF (10 mol%)
CsF (15 mol%)
CsF (20 mol%)
NaF (10 mol%)
KF (10 mol%)
Cs2CO3 (10 mol%)
EtOH, rt
89
4
EtOH, rt
96
5
EtOH, rt
5
92
6
EtOH, rt
5
90
7
EtOH, rt
30
30
30
51
9
EtOH, rt
49
10
EtOH, rt
46
aIsolated yield, bold values show the best reaction conditions in terms of reaction time and yield.

WAGH ET AL.
3
the effective participation of CsF in the model reaction, we
carried out the reaction with various metal salts including
NaF, KF, and Cs2CO3 (Table 1, entries 7-10). In all cases,
the reaction proceeded to completion and the results were
insignificant. This clearly indicates that the catalytic role of
CsF on the effective synthesis of 4a to excellent yield and
speed up the reaction. Encouraged by the above results, we
expanded the scope of the present method to a one-pot
synthesis of various spirooxindoles by reacting isatins, C
−H-activated compounds and malononitrile. To our sur-
prise, various isatins get reacted with C−H-activated acids
like 4-hydroxycoumarin 3a, 1,3-dimethylbarbituric acid 3b,
thiobarbituric acids 3c, 1-phenyl-3-methyl-5-pyrazolone 3d,
3-methyl-2-pyrazolin-5-one 3e smoothly under the present
conditions affording good to the excellent yield of the prod-
ucts in a very short time (Table 2).
TABLE 2 Synthesis of spirooxindole-pyran derivatives [4a-aa]a
4a, 5 min (96%)
4b, 5 min (92%)
4c, 5 min (93%)
4d, 5 min (94%)
4e, 10 min (91%)
4f, 5 min (95%)
4g, 15 min (92%)
4h, 15 min (95%)
4i, 25 min (96%)
4j, 15 min (95%)
4k, 15 min (93%)
4l 10 min (92%)
4m, 10 min (94%)
4n, 10 min (93%)
4o, 10 min (94%)
4p, 5 min (98%)
(Continues)

4
WAGH ET AL.
TABLE 2 (Continued)
4q, 5 min (93%)
4r, 10 min (98%)
4s, 5 min (99%)
4t, 5 min (98%)
4u, 10 min (95%)
4v, 3 min (98%)
4w, 4 min (99%)
4x, 5 min (98%)
4y, 5 min (95%)
4z, 3 min (98%)
4aa, 7 min (99%)
aExperimental conditions: Isatin (2.0 mmol), malononitrile (2.2 mmol), carbonyl compounds possessing a reactive C−H-activated compounds like
4-hydroxycoumarin/barbituric acids/pyrazolones (2.0 mmol), CsF (10 mol%), and 8 mL of ethanol at room temperature.
Under the optimum conditions, various substituted
isatins as well as N-alkylated isatins were reacted success-
fully with 4-hydroxycoumarin (Table 2, 4a–4k), barbituric
acids (Table 2, 4r–4o), and pyrazolones (Table 2, 4p–4aa).
All reactions furnished the corresponded products in high
yields in short reaction time (3-25 min). The reaction of
simple isatins with 4-hydroxycoumarin completed within
5 min (Table 2, 4a–4d) as compared to alkylated isatins
need more reaction times (15-25 min) for the completion
(Table 2, 4g–4k). The 5-Nitro (Table 2, 4d), 5-Methyl
(Table 2, 4e), 7-Fluoro (Table 2, 4f) substitution on isatin
ring also tolerate given reaction conditions to give excel-
lent yield. While all barbituric acids are reacted with
isatin within 10 min and yield up to 92%-94% (Table 2,
4r–4o). In the case of pyrazolones, all reactions take
place very smoothly and completed within 3-10 min
(Table 2, 4p-4aa). In comparison to all given products, 4z
completed with the lowest time (3 min) and 4f needed
the highest reaction time (25 min) and products 4s, 4w,
and 4aa were obtained in high yield up to 99%. The struc-
tures of the synthesized compounds were elucidated
through IR, 1H NMR, 13C NMR, and HRMS analysis. The
structure of product 4h was also confirmed by taking sin-
gle crystal XRD (Figure 1).
After the successful synthesis of spiro-4H-pyran deriv-
atives 4a–4aa, the scope of this methodology was further
extended toward bis-spiro-4H isatin derivatives. The bio-
logical activities were usually enhanced when different
substitutions are present on the two heterocyclic moieties
in the bis-compound.[28] However, the extreme steric
conjugation in bis-heterocycles makes the construction of
all-carbon quaternary centers a formidable challenge for

WAGH ET AL.
5
synthetic organic chemists.[29] In the literature, an inter-
esting report available on a biologically active bis-
heterocycles possessing two spirocyclic rings, each con-
structed by using heterocyclic moiety.[30] Therefore, we
synthesized bis-spirooxindoles from the reaction between
bis-isatins, malononitrile and C−H activated compounds
were also achieved by this protocol (Table 3). As
expected, all the reaction showed good functional com-
patibility. The given bis-spirooxindole systems are skill-
fully and proficiently synthesized from simple, readily
available starting materials.
All bis-spirooxindole-pyran were formed within short
reaction time (10 min) and in excellent yield (92%-96%).
The FT-IR spectrum of bis-spirooxindole-pyran structure
shows NH band in between 3410 and 3315 cm−1. All the
products were isolated pure just by pouring in ice water
mixture followed by recrystallization from ethanol; no
FIGURE 1 ORTEP diagram for compound 4h (CCDC
1551670)
TABLE 3 Synthesis of bis-spirooxindole derivatives [5a-f]a
5a, 10 min (92%)
5b, 10 min (95%)
5c, 10 min (94%)
5d, 10 min (94%)
5e, 10 min (96%)
5f, 10 min (96%)
aExperimental conditions: Isatin (1.0 mmol), malononitrile (2.2 mmol), 4-hydroxycoumarin/pyrazolone (2.0 mmol), 10 mol% CsF, and 8 mL of ethanol at room
temperature.

6
WAGH ET AL.
tedious chromatographic purification was needed.
The synthesized products were again characterized based
on analytical data and detailed spectral studies. All
the known compounds had physical and spectroscopic
data identical to the literature values. Herein, we propose
a mechanism in Scheme 2, for the formation of
functionalized spirooxindole-pyran annulated heterocycles
under the reaction conditions where CsF acts as a car-
bonyl activator as well as base.[31] It is proposed that the
intermediate (X) is formed in situ by the Knoevenagel con-
densation of isatin with malononitrile which is attacked
by the enolate (Y) of C−H activated compound through
Michael addition giving the adduct (Z). The adduct
(Z) undergoes cyclization to afford the desired product.
Finally, to manifest the efficiency and capability of
the present protocol in the synthesis of different
spirooxindole-pyran derivatives, it has been compared
with some of the previously reported and published pro-
cedures. Results are summarized in Table 4. Comparison
clearly illustrates that the present method is indeed supe-
rior to several of the others in terms of high product
yield, short reaction time, no additional energy required
(ie, heating and ultrasonication), and easy isolation of
final products by simple work-up. The above results
clearly indicate the present catalytic procedure is extend-
able to a wide variety of substrates to construct a
diversity-oriented library of 4H-pyrans.
3 | CONCLUSION
In conclusion, we have developed an efficient, rapid, one-
pot, CsF promoted multicomponent method for the
synthesis of functionalized spirooxindole-pyran and bis-
spirooxindole-pyran derivatives. Using this protocol,
33 compounds were synthesized by reacting isatins
and bis-isatins, malononitrile with 4-hydroxycoumarin,
1,3-dimethylbarbituric acid, thiobarbituric acids, 1-phenyl-
3-methyl-5-pyrazolone, and 3-methyl-2-pyrazolin-5-one.
All reactions were completed within 25 min with excellent
yields (92%-99%). The final products were isolated by
simple filtration which makes it a valuable alternative
to the previously reported methods for constructing librar-
ies of spirooxindole-pyran annulated heterocycles. The
SCHE ME 2 Plausible
mechanism for the synthesis of
spirooxindole-pyran derivatives
TABLE 4 Comparison between CsF-catalyzed protocols with earlier reported protocols for the synthesis of 4a
Temp. (ꢀC)/
Entry
Catalyst (mol%/mg)
Alum (0.35 mol%)
L-proline (10 mol%)
Caspian Isinglass (5 mg)
DABCO (6 mol%)
TEBA (20 mol%)
Solvent
H2O
power
Time (min)
Yield (%)
Ref.
1
2
3
4
5
6
7
80
30
15
20
24
180
60
5
80
94
90
98
88
88
96
[11]
H2O
80
[12]
H2O
60
[13]
EtOH
H2O
Reflux
60
[32]
[33]
TBAB (10 mol%)
H2O
100
r.t.
[34]
CsF (10 mol%)
EtOH
This work
Note: Some reported results for the synthesis of compound 4a.

WAGH ET AL.
7
interesting activities of the CsF described here will be help-
ful for further combinatorial synthesis and new protocol
designing.
and a catalytic amount of CsF (10 mol%) in ethanol at
room temperature. The progress of the reaction was moni-
tored by TLC in mixture of n-hexane and ethyl acetate
(7:3) solvent system. During the reaction, solid observed in
flask within 10 min and after complete conversion, the
reaction mass was transferred to an ice-water mixture
under vigorous stirring. Then the solid was collected by fil-
tration, washed with cold aq. ethanol, and dried. The
authenticity of products was established by comparing
their melting points with those reported in the literature
and by the spectral data of FT-IR, NMR, and mass analysis.
4 | EXPERIMENTAL
4.1 | General
All solvents and chemicals used in this work were
obtained commercially and used as received. Melting
points were measured in open capillary tubes and are
uncorrected. FT-IR spectra were obtained on Shimadzu
IR-Affinity spectrometer (KBr pellets). The NMR were
recorded on an NMR spectrometer, model Advance-II
(Bruker). The instrument is equipped with a cryomagnet
20-amino-1-ethyl-2,50-dioxo-50H-spiro[indoline-3,40-
pyrano[3,2-c]chromene]-30-carbonitrile (4g)
White Solid, Yield: 94%; M. P. 292 to 294ꢀC; IR (KBr):
ν
max 3302, 3184, 2196, 1710, 1676, 1606, 1473, 1361, 1222,
1
of field strength 9.4 T. Its H frequency is 400/500 MHz,
1093, 966, 761, 561, 499 cm−1 1H NMR (400 MHz,
;
and 13C frequency is 100/125 MHz, using TMS as an
internal standard and DMSO-d6 as a solvent. Chemical
shifts are given in parts per million (δ) and the coupling
constants are given in Hertz. Silica gel-G plates (Merck)
were used for thin-layer chromatography (TLC) analysis.
CsF was obtained from Sigma Aldrich-Indian company
and was used without further purification.
DMSO-d6): δ 1.22 (t, J = 7.0 Hz, 3H), 3.79 (q, J = 7.0 Hz,
2H), 7.01 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 7.24
(d, J = 7.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.44 (d,
J = 8.3 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.68 (s, 2H), 7.74
(t, J = 7.3 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): δ 12.0, 34.5, 47.0, 56.7, 101.2,
108.4, 112.4, 116.5, 116.6, 122.4, 122.7, 123.8, 124.8, 128.9,
132.4, 133.5, 142.5, 152.0, 155.1, 158.1, 158.4, 175.0;
HRMS (ESI): m/z calcd for C22H15N3O4 [M + Na]+,
408.0960 found, 408.0933.
4.1.1 | General procedure for the
preparation of spirooxindole-pyran
derivatives (4a–4aa)
20-amino-5-chloro-1-ethyl-2,50-dioxo-50H-spiro
[indoline-3,40-pyrano[3,2-c]chromene]-30-
carbonitrile (4h)
To a magnetically stirred solution of aromatic aldehydes
or isatins (2 mmol), malononitrile (2.2 mmol), C−H-
activated acidic compounds (2 mmol), and a catalytic
amount of CsF (10 mol%) in ethanol at room tempera-
ture. The progress of the reaction was monitored by TLC
in mixture of n-hexane and ethyl acetate (7:3) solvent sys-
tem. During the reaction, solid observed in flask within
3 to 25 min and after complete conversion, the reaction
mass was transferred to an ice-water mixture under vig-
orous stirring. Then the solid was collected by filtration,
washed with cold aq. ethanol, and dried. The authenticity
of products was established by comparing their melting
points with those reported in the literature and by the
spectral data of FT-IR, NMR, and mass analysis.
White Solid, Yield: 95%; M. P. 282 to 284ꢀC; IR (KBr):
ν
max 3568, 3441, 3329, 3155, 2204, 1712, 1687, 1606, 1475,
1438, 1357, 1236, 1168, 1089, 968, 819, 759, 601,
1
565 cm−1; H NMR (500 MHz, DMSO-d6): δ 1.20 (s, 3H),
3.75 to 3.84 (m, 2H), 7.16 (d, J = 10 Hz 1H), 7.38 (d,
J = 10 Hz 1H), 7.48 to 7.56 (m, 3H), 7.76 to 7.79 (m, 3H),
7.96 (d, J = 10 Hz, 1H); 13C NMR (125 MHz, DMSO-d6):
δ 12.5, 35.2, 47.7, 56.6, 96.5, 109.6, 118.2, 120.6, 123.6,
125.2, 127.0, 129.9, 131.9, 137.7, 142.8, 144.4, 145.5, 161.5,
176.4; HRMS (ESI): m/z calcd for C22H14ClN3O4 [M
+ Na]+, 442.0571 found, 442.1509.
20-amino-1-benzyl-2,50-dioxo-50H-spiro[indoline-
3,40-pyrano[3,2-c]chromene]-30-carbonitrile (4i)
White Solid, Yield: 96%; M. P. 280 to 282ꢀC; IR (KBr):
4.1.2 | General procedure for the
preparation of bis-spirooxindole derivatives
(5a-f)
ν
max 3568, 3348, 3186, 3074, 2929, 2204, 1681, 1610, 1475,
1359, 1178, 1097, 958, 754, 694, 555 cm−1 1H NMR
;
(400 MHz, DMSO-d6): δ 2.06 (dd, J = 16.1, 11.4 Hz, 2H,
−CH2), 6.75 (d, J = 7.7 Hz, 1H), 7.00 (t, J = 7.48 Hz, 1H),
7.17 to 7.22 (m, 2H), 7.26 (d, J = 7.16 Hz, 1H), 7.30 to
7.33 (m, 2H ), 7.40 (d, J = 8.3 Hz, 1H), 7.45 to 7.49
(m, 3H), 7.65 (s, 2H, NH2), 7.71(t, J = 7.4 Hz, 1H), 8.00
To a magnetically stirred solution of bis-isatins (1 mmol),
malononitrile (2.2 mmol), 4-hydroxycoumarin/1-phenyl-
3-methyl-5-pyrazolone/3-methyl-2-pyrazolin-5-one (2 mmol),

8
WAGH ET AL.
(d, J = 7.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ
43.7, 47.4, 56.8, 101.2, 109.1, 112.5, 116.4, 117.0, 122.8,
122.9, 123.7, 124.7, 127.0, 127.1, 128.3, 128.8, 132.2, 133.4,
135.7, 142.7, 152.1, 155.3, 158.36, 158.7, 175.9; HRMS
(ESI): m/z calcd for C27H17N3O4 [M + Na]+, 470.1117
found, 442.1509.
175.6; HRMS (ESI): m/z calcd for C23H18ClN5O2 [M
+ Na]+, 431.1149 found, 432.1160.
20-amino-1-(4-(20-amino-30-cyano-2,50-dioxo-50H-
spiro[indoline-3,40-pyrano[3,2-c]chromen]-1-yl)
butyl)-2,50-dioxo-50H-spiro[indoline-3,40-pyrano
[3,2-c]chromene]-30-carbonitrile (5a)
20-amino-1-benzyl-5-chloro-2,50-dioxo-50H-spiro
[indoline-3,40-pyrano[3,2-c]chromene]-30-
carbonitrile (4j)
Brown Solid, Yield: 92%; M. P. >310ꢀC; IR (KBr): νmax
3410, 3315, 3047, 2872, 2193, 1647, 1610, 1598, 1510, 1487,
1
1427, 1155, 1070, 871, 796, 559 cm−1; H NMR (500 MHz,
White Solid, Yield: 95%; M. P. 296 to 298ꢀC; IR (KBr):
DMSO-d6): δ 1.79 (s, 2H), 3.72 to 3.82 (m, 2H), 6.99 to 7.02
(m, 1H), 7.12 to 7.14 (m, 1H), 7.26 to 7.30 (m, 2H), 7.50 to
7.51 (m, 1H), 7.54 to 7.57 (m, 1H), 7.73 (s, 2H), 7.76 to 7.81
(m, 1H), 7.96 to 7.98 (m, 1H); 13C NMR (125 MHz, DMSO-
d6): δ 24.22, 24.26, 47.1, 56.7, 101.2, 108.7, 112.3, 116.6,
116.7, 122.6, 123.8, 124.9, 129.0, 132.2, 133.6, 142.9, 151.9,
155.1, 158.1, 158.4, 175.5; HRMS (ESI): m/z calcd for
C44H28N6O8 [M + Na]+, 791.1866 found, 791.3235.
ν
max 3481, 3450, 3332, 2960, 2196, 1685, 1593, 1346, 1253,
1112, 1039, 829, 621 cm−1; H NMR (400 MHz, DMSO-
d6): δ 4.99 (dd, J = 16.2, 5.4 Hz, 2H), 6.77 (d, J = 8.36 Hz,
1H), 7.21 to 7.34 (m, 4H), 7.40 to 7.52 (m, 5H), 7.73 (d,
J = 7.32 Hz, 1H), 7.77 (s, 2H), 8.00 (d, J = 7.28 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): δ 43.6, 47.4, 56.0, 100.5,
100.3, 112.5, 116.4, 116.8, 122.8, 124.2, 124.7, 126.9, 127.1,
127.2, 128.3, 128.6, 133.4, 134.0, 135.2, 141.5, 152.1, 155.5,
158.4, 158.7, 175.5; HRMS (ESI): m/z calcd for
C27H16ClN3O4 [M + Na]+, 504.0727 found, 504.1324.
1
20-amino-1-(4-(20-amino-5-chloro-30-cyano-2,50-
dioxo-50H-spiro[indoline-3,40-pyrano[3,2-c]
chromen]-1-yl)butyl)-5-chloro-2,50-dioxo-50H-spiro
[indoline-3,40-pyrano[3,2-c]chromene]-30-
carbonitrile (5b)
1-allyl-20-amino-2,50-dioxo-50H-spiro[indoline-3,40-
pyrano[3,2-c]chromene]-30-carbonitrile (4k)
White Solid, Yield: 93%; M. P. 296 to 298ꢀC; IR (KBr):
Brown Solid, Yield: 95%; M. P. 232 to 234ꢀC; IR (KBr):
ν
max 3454, 3271, 3153, 2198, 1703, 1602, 1479, 1361, 1192,
νmax 3473, 3290, 3221, 3197, 3045, 2889, 2195, 1654, 1597,
1062, 948, 688, 497 cm−1; 1H NMR (400 MHz, DMSO-d6):
δ 4.30 to 4.35 (m, 1H), 4.41 to 4.46 (m, 1H), 5.19 (d,
J = 10.52 Hz, 1H), 5.44 (d, J = 17.2 Hz, 1H), 5.82 to 5.91
(m, 1H), 6.94 (d, J = 7.8 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H ),
7.24 to 7.30 (m, 2H), 7.44 (d, J = 8.28 Hz, 1H), 7.51 (t,
J = 7.6 Hz, 1H), 7.70 (s, 2H), 7.72 to 7.76 (m, 1H), 7.96 to
7.98 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 42.1,
47.2, 56.6, 101.1, 109.0, 112.4, 116.5, 116.7, 116.8, 122.6,
122.7, 123.7, 124.8, 128.8, 131.3, 132.1, 133.5, 142.7, 152.0,
155.1, 158.2, 158.5, 175.3; HRMS (ESI): m/z calcd for
C23H15N3O4 [M + Na]+, 420.0960 found, 420.1235.
1581, 1516, 1490, 1400, 1350, 1327, 1199, 1076, 1049,
1
987, 758 cm−1; H NMR (400 MHz, DMSO-d6): δ 1.80 (s,
2H), 3.80 (s, 2H), 7.13 to 7.60 (m, 5H), 7.76 (s, 3H), 7.97
to 7.99 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 18.4,
24.0, 47.3, 56.1, 100.6, 110.1, 112.5, 116.5, 116.7, 122.8,
124.2, 124.7, 126.8, 128.7, 133.5, 134.1, 141.8, 152.1, 155.4,
158.3, 158.6, 175.4; HRMS (ESI): m/z calcd for
C44H26Cl2N6O8 [M + Na]+, 859.1087; found, 859.2521.
60-amino-1-(4-(60-amino-5-chloro-50-cyano-30-
methyl-2-oxo-10H-spiro[indoline-3,40-pyrano[2,3-c]
pyrazol]-1-yl)butyl)-5-chloro-30-methyl-2-oxo-10H-
spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-
carbonitrile (5d)
60-amino-5-chloro-1-ethyl-30-methyl-2-oxo-10-
phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]
pyrazole]-50-carbonitrile (4w)
Brown Solid, Yield: 94%; M. P. 258 to 260ꢀC; IR (KBr):
White Solid, Yield: 99%; M. P. 210 to 212ꢀC; IR (KBr):
νmax 3311, 3228, 3180, 3126, 2845, 2196, 1732, 1645, 1593,
1
ν
max 3392, 3329, 3196, 2960, 2193, 1681, 1365, 1251, 1211,
1481, 1398, 1346, 1161, 1085 cm−1; H NMR (400 MHz,
DMSO-d6): δ 1.48 to 1.51 (m, 3H), 1.72 (s, 2H), 3.8 (s,
2H), 7.16 to 7.21 (m, 3H), 7.33 (s, 2H), 12.34 (s, 1H); 13C
NMR (100 MHz, DMSO-d6): δ 9.1, 24.4, 47.1, 54.4, 94.4,
110.5, 118.5, 124.5, 127.3, 127.39, 128.9, 134.03, 134.05,
134.7, 134.8, 141.0, 141.1, 155.2, 162.6, 176.1; HRMS
(ESI): m/z calcd for C34H26Cl2N10O4 [M + Na]+,
731.1413 found, 731.2646.
1159, 1091, 1035, 559 cm−1; H NMR (500 MHz, DMSO-
d6): δ 1.23 (t, J = 7.1 Hz, 3H), 1.56 (s, 3H), 3.81 to 3.84
(m, 2H), 7.24 to 7.25 (m, 2H), 7.35 to 7.38 (m, 2H), 7.43 to
7.46 (m, 1H), 7.51 to 7.55 (m, 2H), 7.67 (s, 2H, −NH2),
7.80 to 7.82 (m, 2H); 13C NMR (125 MHz, DMSO-d6): δ
12.3, 12.9, 35.3, 47.9, 55.9, 95.9, 110.9, 118.1, 120.7, 125.6,
127.1, 127.8, 129.8, 134.2, 137.7, 141.2, 144.2, 145.6, 161.5,
1

WAGH ET AL.
9
60-amino-1-(4-(60-amino-50-cyano-30-methyl-2-oxo-
10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]
pyrazol]-1-yl)butyl)-30-methyl-2-oxo-10-phenyl-10H-
spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-
carbonitrile (5e)
REFERENCES AND NOTES
[1] G. S. Singh, Z. Y. Desta, Chem Rev 2012, 112, 6104.
[2] (a) M. Xia, R. Z. Ma, J Heterocyclic Chem 2014, 51, 539.
(b) H. Salamon, M. Klika Skopic, K. Jung, O. Bugain,
A. Brunschweiger, ACS Chem Biol 2016, 11, 296.
[3] R. A. Kudirka, R. M. Barfield, J. M. McFarland, P. M. Drake,
A. Carlson, S. Banas, W. Zmolek, A. W. Garofalo, D. Rabuka,
ACS Med Chem Lett 2016, 7, 994.
[4] (a) U. P. Patil, R. C. Patil, S. S. Patil, J Heterocyclic Chem 2019, 56,
1898. https://doi.org/10.1002/jhet.3564. (b) R. Ghahremanzadeh,
T. Amanpour, A. Bazgir, J Heterocyclic Chem 2010, 47, 46.
[5] A. Dandia, A. K. Laxkar, R. Singh, Tetrahedron Lett 2012, 53,
3012.
[6] N. S. Gupta, Bioorg Med Chem Lett 2004, 14, 3913.
[7] K. Ding, Y. Lu, Z. Nikolovska-Coleska, G. Wang, S. Qiu,
S. Shangary, W. Gao, D. Qin, J. Stuckey, K. Krajewski,
P. P. Roller, J Med Chem 2006, 49, 3432.
Pale Yellow Solid, Yield: 96%; M. P. 188 to 190ꢀC; IR
(KBr): νmax 3633, 3441, 3311, 3172, 3066, 2196, 1707,
1649, 1599, 1510, 1381, 1139, 1080, 925, 752, 551 cm−1
;
1H NMR (500 MHz, DMSO-d6): δ 1.47 (s, 3H), 1.82
(s, 2H), 3.87 (s, 2H), 7.12 (s, 1H), 7.25 (s, 2H), 7.36
(s, 2H), 7.53 (s, 2H), 7.67 (s, 2H), 7.83 (s, 2H); 13C NMR
(125 MHz, DMSO-d6): δ 12.3, 25.1, 47.9, 56.6, 96.5, 109.6,
118.2, 120.6, 123.6, 125.2, 127.0, 129.9, 131.9, 137.7, 142.8,
144.4, 145.5, 161.5, 176.4; HRMS (ESI): m/z calcd for
C34H26Cl2N10O4 [M + Na]+, 815.2819 found, 815.4206.
[8] P. Prasanna, K. Balamurugan, S. Perumal, P. Yogeeswari,
D. Sriram, Eur J Med Chem 2010, 45, 5653.
[9] B. K. Yeung, B. Zou, M. Rottmann, S. B. Lakshminarayana,
S. H. Ang, S. Y. Leong, J. Tan, J. Wong, S. Keller-Maerki,
C. Fischli, A. Goh, J Med Chem 2010, 53, 5155.
[10] J. Skommer, D. Wlodkowic, M. Matto, M. Eray, J. Pelkonen,
Leukemia Res 2006, 30, 322.
[11] H. A. Oskooie, M. M. Heravi, N. Karimi, H. Hamidi, Synth
Commun 2011, 41, 3344.
[12] Y. Li, H. Chen, C. Shi, D. Shi, S. Ji, J Comb Chem 2010, 12, 231.
[13] S. Javanshir, N. S. Pourshiri, Z. Dolatkhah, M. Farhadnia,
Monatsh Chem 2017, 148, 703.
[14] A. Molla, S. Ranjan, M. S. Rao, A. H. Dar, M. Shyam,
V. Jayaprakash, S. Hussain, ChemistrySelect 2018, 3, 8669.
[15] M. Kidwai, A. Jahan, N. K. Mishra, Appl Catal A: Gen 2012,
425, 35.
[16] K. M. Khan, I. Khan, S. Perveen, M. I. Malik, J Fluorine Chem
2014, 158, 1.
[17] G. Parhizkar, A. R. Khosropour, I. Mohammadpoor-Baltork,
E. Parhizkar, H. Amiri Rudbari, ACS Comb Sci 2018, 20, 358.
[18] S. T. A. Shah, K. M. Khan, M. Fecker, W. Voelter, Tetrahedron
Lett 2003, 44, 6789.
[19] S. T. A. Shah, K. M. Khan, A. M. Heinrich, M. I. Choudhary,
W. Voelter, Tetrahedron Lett 2002, 43, 8603.
[20] D. D. DesMarteau, B. A. O'Brien, Q. C. Mir, Y. Y. Zheng,
J Fluorine Chem 1983, 23, 426.
[21] Q. C. Mir, D. D. Desmarteau, J Fluorine Chem 1990, 48, 367.
[22] L. Zhang, Y. Geng, Z. Jin, J Org Chem 2016, 81, 3542.
[23] W. P. Gallagher, R. E. Maleczka, J Org Chem 2003, 68, 6775.
[24] D. O. Ayeni, S. K. Mandal, B. Zajc, Tetrahedron Lett 2013, 54, 6008.
[25] K. M. Khan, M. T. Muhammad, I. Khan, S. Perveen,
W. Voelter, Monatsh Chem 2015, 146, 1587.
60-amino-1-(4-(60-amino-5-chloro-50-cyano-30-
methyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-
pyrano[2,3-c]pyrazol]-1-yl)butyl)-5-chloro-30-
methyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-
pyrano[2,3-c]pyrazole]-50-carbonitrile (5f)
Pale Yellow Solid, Yield: 96; M. P. 238 to 240ꢀC; IR (KBr):
ν
max 3641, 3448, 3315, 3174, 2939, 2196, 1712, 1649, 1599,
1504, 1388, 1153, 1072, 815, 750, 559 cm−1 1H NMR
;
(400 MHz, DMSO-d6): δ 1.50 to 1.51 (m, 3H), 1.76 (s, 2H),
3.85 (s, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.35 to 7.45 (m, 3H),
7.53 (t, J = 7.6 Hz, 2H), 7.72 (s, 2H, −NH2), 7.81 (d,
J = 7.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ 11.8,
24.3, 47.4, 55.2, 95.2, 95.3, 110.7, 117.7, 120.2, 124.9,
126.5, 127.3, 129.2, 129.3, 133.5, 137.1, 141.0, 143.6, 145.0,
161.0, 175.5; HRMS (ESI): m/z calcd for C46H34Cl2N10O4
[M + Na]+, 883.2039 found, 883.3267.
ACKNOWLEDGMENTS
The author Y.B.W. is grateful to Council of Scientific &
Industrial Research (CSIR), New Delhi India for the post-
doctoral research fellowship under CSIR-RA [Award
No. 09/728(0036)/2019 (EMR-I)]. We are thankful to the
University Grants Commission (UGC) New Delhi, India
for Financial assistance under the Special Assistance Pro-
gramme (SAP) and Department of Science and Technol-
ogy (DST), Government of India for infrastructural
facilities under the FIST program to KBC NMU. We are
also thankful to the SAIF-Punjab University, Chandigarh
for characterization support to this work and SAIF IIT
Madras for single crystal analysis.
[26] M. G. Menkir, V. Srinivasadesikan, S. L. Lee, Struct Chem
2016, 27, 1383.
[27] (a) Y. B. Wagh, A. S. Kuwar, D. R. Patil, Y. A. Tayade,
A. D. Jangale, S. S. Terdale, D. R. Trivedi, J. Gallucci,
D. S. Dalal, Ind Eng Chem Res 2015, 54, 9675. (b) K. S. Dalal,
Y. B. Wagh, Y. A. Tayade, D. S. Dalal, B. L. Chaudhari, Catal
Lett 2018, 148, 3335. (c) Y. B. Wagh, Y. A. Tayade, S. A. Padvi,
B. S. Patil, N. B. Patil, D. S. Dalal, Chin Chem Lett 2015, 26,
1273.
ORCID
Yogesh B. Wagh https://orcid.org/0000-0002-3364-7519

10
WAGH ET AL.
[28] A. Hasaninejad, M. Beyrati, RSC Adv 2018, 8, 1934.
[29] A. Raasch, O. Scharfenstein, C. Trankle, U. Holzgrabe,
K. Mohr, J Med Chem 2002, 45, 3809.
[30] (a) R. Sakhuja, S. S. Panda, L. Khanna, S. Khurana, S. C. Jain,
Bioorg Med Chem Lett 2011, 21, 5465. (b) S. A. Padvi,
Y. A. Tayade, Y. B. Wagh, D. S. Dalal, Chin Chem Lett 2016,
27, 714.
[31] F. Bartoccini, M. Casoli, M. Mari, G. Piersanti, J Org Chem
2014, 79, 3255.
[32] A. Hasaninejad, F. Mandegani, M. Beyrati, A. Maryamabadi,
G. Mohebbi, ChemistrySelect 2017, 2, 6784.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Wagh YB, Padvi SA,
Mahulikar PP, Dalal DS. CsF promoted rapid
synthesis of spirooxindole-pyran annulated
heterocycles at room temperature in ethanol.
J Heterocyclic Chem. 2019;1–10. https://doi.org/10.
1002/jhet.3846
[33] S. L. Zhu, S. J. Ji, Y. Zhang, Tetrahedron 2007, 63, 9365.
[34] A. Mobinikhaledi, N. Foroughifar, M. A. B. Fard, Synth
Commun 2011, 41, 441.