Iodine-Catalyzed One-Pot Four-Component Synthesis of Spiro[indoline-3,4′-pyrano-pyrazole] Derivatives

Article abstract of DOI:10.1002/jhet.3342

An efficient, facile, and useful synthetic method was developed for the production of spiro[indoline-3,4′-pyrano-pyrazole] carbonitrile derivatives through a one-pot, four-component reaction involving hydrazine hydrate, diketene, substituted isatins, and malononitrile or ethyl cyanoacetate in the presence of iodine as the efficient catalyst in ethanol at room temperature. Significantly, this remarkable method provides novel spiropyranopyrazole derivatives in good to high yields. The significant aspects of this protocol are facile work-up approach and a greener process because the use of toxic and hazardous solvents are avoided.

Full text of DOI:10.1002/jhet.3342

Month 2018
Iodine-Catalyzed One-Pot Four-Component Synthesis of Spiro[indoline-
3,40-pyrano-pyrazole] Derivatives
*
*
Vahideh Zadsirjan, Pegah Saedi, and Majid M. Heravi
Atieh Rezvanian,
Physics and Chemistry Faculty, Alzahra University, Tehran, Iran
*E-mail: rezvaniana@alzahra.ac.ir; mmh1331@yahoo.com; mmheravi@alzahra.ac.ir
Received May 23, 2018
DOI 10.1002/jhet.3342
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
An efficient, facile, and useful synthetic method was developed for the production of spiro[indoline-3,40-
pyrano-pyrazole] carbonitrile derivatives through a one-pot, four-component reaction involving hydrazine
hydrate, diketene, substituted isatins, and malononitrile or ethyl cyanoacetate in the presence of iodine as
the efficient catalyst in ethanol at room temperature. Significantly, this remarkable method provides novel
spiropyranopyrazole derivatives in good to high yields. The significant aspects of this protocol are facile
work-up approach and a greener process because the use of toxic and hazardous solvents are avoided.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
are identified by the functionalities produced in the
previous stage. Multicomponent and domino reactions are
important and effective methodologies in the synthesis of
molecular libraries with multifunctional scaffolds,
heterocyclic motifs, high molecular complexity, and
diversity. Remarkably, MCRs provide an especially
attractive synthetic method because they offer fast and
facile admittance to large libraries of organic compounds
having various substitution patterns [18–20].
We are interested in heterocyclic chemistry, herein, we
want to provide a single structural motif by combining
spirooxindole, pyran, and pyrazole motifs for interest in
designing novel polycyclic heterocycle derivatives by
combining various structurally various scaffolds via
MCR. Recent improvement of efficient methods for the
formation of spirocyclic derivatives is an exciting and
challenging task in organic synthesis.
Spirooxindoles are heterocyclic compounds that
are commonly present as scaffolds in different
pharmaceuticals and naturally occurring products [1–5]
such as cyclopiamine B [6], spirotryprostatin B [7],
elacomine [8], and strychnofoline [9]. The main structural
characteristic of these molecules is the spiro ring fused at
the C3 position of the oxindole core having different
heterocyclic scaffolds [10]. The synthesis of heterocyclic
spirooxindole molecules has attracted significant attention
of organic chemists as well as medicinal chemists because
of their improved range of biological properties [11].
Isatin-based spiro molecules or spirooxindole derivatives
are significant unit structures that are present in diverse
naturally occurring alkaloids as well as synthetic
pharmaceuticals [12] including spirotryprostatin (A and
B), NTD609, pteropodine, and strychnofoline [13] (Fig. 1).
Dihydropyrano[2,3-c]pyrazoles, an important class of
nitrogen heterocyclic molecules, demonstrate various
biological activities [14] including anticancer [15], anti-
inflammatory [16], antimicrobial [17], and molluscicidal
activities [14e].
Thus, several synthetic methods for the formation of
spirooxindole-fused
heterocycle
derivatives
were
reported and their chemistry was widely reviewed [21].
Remarkably, various approaches have been already
reported for the synthesis of spiro[pyrano[2,3-c]pyrazoles]
[22], dihydropyrano[2,3-c]pyrazoles [23], functionalized
trifluoromethylatedspirocy-clic[indole-3,40-pyrano[2,3-c]
pyrazole] derivatives [24], spiro[indoline-3,40-pyrano[2,3-
c]pyrazole] derivatives [25], 6-amino-4-alkyl/aryl-3-
methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles
A multicomponent reaction (MCR) is a method in
which three or more readily available components are
joined together in a single reaction vessel to provide a
target product exhibiting aspects of all inputs and hence
gives greater possibilities for molecular diversity per
stage with the least of synthetic effort and time. A MCR
is a domino protocol, a sequence of elementary steps
based on a program in which subsequent transformations
[26],
spiro[indole-3,4]pyrano[2,3-c]pyrazole-5-
carbonitriles [27], and pyrano[2,3-c]pyrazole derivatives
[28]. Also, Choudhury and coworkers reported an
efficient method for the synthesis of spiro[indoline-3,40-
© 2018 Wiley Periodicals, Inc.

A. Rezvanian, V. Zadsirjan, P. Saedi, and M. M. Heravi
Vol 000
Figure 1. Three biologically active important products having spirooxindole scaffold.
pyrano[2,3-c]pyrazole]-30-carboxylates using triethylamine
and ethanol [29]. Trifluoromethylated spiropyranopyrazoles
were also synthesized from the treatment of isatin,
malononitrile, hydrazine hydrate, and ethyl 4,4,4-
thiophenes, benzopyrans, benzoselenophenes, α-pyrones,
selenophenes, isocoumarins, chromones, isoxazoles, β-
lactams,
pyrroles,
2,3-dihydropyrroles,
furanones,
furopyridines, and isochromenes, were synthesized by
iodine-catalyzed domino or one-pot MCRs. Noticeably,
iodine has obtained significant attention as it is non-toxic,
inexpensive, easily accessible, easy to handle, and therefore
has become a favored alternative for expensive and toxic
acid catalysts [39], and a review on the MCRs use of
molecular iodine has been reported in 2013 [40]. Very
recently, we published three MCRs on the applications of
iodine as a catalyst in the synthesis of heterocyclic
compounds [41]. On the other hand, we also published two
five-component reactions on the applications of diketene
(DK) as a privileged synthon in the synthesis of
heterocyclic molecules [42].
Diketene (4-methyleneoxetan-2-one), a reactive and
useful compound, was used for the introduction of
functionalized C2, C3, and C4 units into organic
compounds, although it is best known as are agent for the
formation of acetoacetic acids. Remarkably, diketene
seems to be an ideal compound for chemical research,
because it is cheap, easily accessible, reactive, and
extremely functionalized [43]. Due to the importance and
unique reactivities of kentens and diketene, very recently,
we have covered the applications of ketenes and diketene
as the privileged synthons in the synthesis of heterocyclic
compounds [44].
trifluoroacetoacetate
[30].
Synthesis
of
new
spiropyranopyrazole derivatives was achieved from the
reaction of isatin, malononitrile, hydrazine hydrate, and
dialkylacetylenedicarboxylate derivatives in ethanol/
water [31].
In 2015, Ablajan and coworkers reported a significant
and quick approach for the one-pot production of
spiro[indoline-3,40-pyrano[2,3-c]pyrazole] derivatives under
ultrasonic irradiation [32]. The reaction of substituted
phenylhydrazine and dialkylacetylenedicarboxylate with
various isatins and malononitrile has been accomplished
using L-proline in ethanol/water [32]. Besides,
spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-30-carboxylate
and trifluoromethylatedspiro[indole-3,40-pyrano[2,3-c]
pyrazole] derivatives have been synthesized through
an efficient one-pot and four-component reaction
using polyethylene glycol (PEG-400) by Nageswar and
coworkers [33]. Furthermore, the formation of
spiro[indoline-3,40-pyrano[2,3-c]pyrazoles] was achieved
through a one-pot condensation reaction of isatin,
activated methylene reagents, and 3-methyl-l-phenyl-5-
pyrazolone using silica-bonded ionic liquids under reflux
in aqueous medium [34].
These methods have their own merits and drawbacks.
Some of them the usage of expensive reagents are
needed, some other only can be performed under harsh
reaction conditions and the products isolation are
cumbersome giving and poor yields in relatively long
reaction time.
We are interested in heterocyclic chemistry [35]
especially those that are synthesized via MCR [36],
especially those that are conducted under green conditions
[37,38]. We try to describe an efficient, eco-friendly,
simple approach for the formation of spiro[indoline-3,40-
pyrano-pyrazole] derivatives through four-component and
one-pot reaction using iodine in EtOH.
Herein, we try to perform the reaction hydrazine hydrate,
diketene, functionalized isatins, and malononitrile or ethyl
Table 1
Exploring optimum reaction conditions for the four-component and one-
pot reaction.
Catalyst
(mol%)
Temp
(°C)
Time
(min)
Yielda
%
Entry
Solvent
1
3
4
5
6
7
8
9
—
EtOH
EtOH
CH2Cl2
MeCN
Toluene r.t.
DMF
EtOH
EtOH
r.t.
r.t.
r.t.
r.t.
180
45
62
92
60
65
50
55
78
90
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (5)
120
180
180
180
60
Molecular iodine is a mild Lewis acid utilized in number of
functional group conversions in organic synthesis either as a
catalyst or in stoichiometric amount. Various heterocycles,
r.t.
r.t.
r.t.
I2 (20)
45
including
furans,
benzofurans,
benzothiophenes,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
One-Pot Four-Component Synthesis of Spiro[indoline-3,40-pyrano-pyrazole]
Derivatives
Table 2
One-pot synthesis of spiro[indoline-3,40-pyrano-pyrazole] derivatives. [Color table can be viewed at wileyonlinelibrary.com]
Entry
1
Products 2, 3
Isatin 1
R
Product
Yield (%)
92
2a
CN
2
3
4
2b
2c
2d
CN
CN
CN
88
86
90
5
2e
CN
85
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Rezvanian, V. Zadsirjan, P. Saedi, and M. M. Heravi
Vol 000
Table 2
(Continued)
Entry
6
Products 2, 3
Isatin 1
R
Product
Yield (%)
3a
CO2Et
80
82
79
7
3b
CO2Et
8
3c
CO2Et
cyanoacetate to evaluate the construction of spiro[indoline-
3,40-pyrano-pyrazole] derivatives using a catalytic amount
of molecular iodine in ethanol.
four-component reaction of diketene (1 mmol) and
hydrazine hydrate (1 mmol), isatin 1a (1 mmol), and
malononitrile (1 mmol) was performed as a model
reaction in different solvents to obtain suitable reaction
medium to give the target compound 2a. The results are
summarized in Table 1 that the best results have been
provided in ethanol. Furthermore, the effects of diverse
quantities of iodine as catalysts were next evaluated, and
the results are summarized in Table 1. The best results
were obtained in EtOH at ambient temperature in the
presence of 10 mol% iodine.
RESULTS AND DISCUSSION
At first, the treatment of diketene and hydrazine hydrate
using various conditions was examined, which afforded
the anticipated pyrazole intermediate. The maximum yield
of pyrazolone 3 has been provided when the reaction has
been performed under solvent free condition at room
temperature for 15 min. In the next stage, one-pot
The scope and efficiency of this method was next
investigated under optimal reaction conditions. For this
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
One-Pot Four-Component Synthesis of Spiro[indoline-3,40-pyrano-pyrazole]
Derivatives
purpose, diketene, hydrazine hydrate, and various isatins
1 (4-NO2, 4-Cl, 5-Br, 1-Me) and malononitrile were
reacted together in EtOH at room temperature to
provide the desired product 2a–e. The results are
summarized in Table 2. The new products were
identified using 1H NMR and 13C NMR spectra. Full
spectra and spectral data of all target compounds can be
found in Data S1.
As can be realized in the identified structure of the
product 3, two stereogenic centers are present leading to
the formation of two diastereoisomers. The IR spectrum
of compound 3a showed absorption bands at 3667 and
3337 cmꢀ1 due to the three NH stretching frequency.
Also, absorption bands at 1744, 1715, and 1615 cmꢀ1 are
due to the CO2Et, C═O and C═N groups stretching
1
frequencies. The H NMR spectrum of 3a showed four
Next, in order to expand the scope of this reaction,
ethyl cyanoacetate was used instead of malononitrile.
Relied on optimized reaction condition, one-pot and
four-component reaction of diketene, hydrazine hydrate,
isatin 1, and ethyl cyanoacetatein ethanol at room
temperature was performed and afforded unexpected
singlet (δ = 1.40, 10.75, and 10.99 ppm) for the methyl
and 2NH groups. Three aromatic hydrogens gave rise to
characteristic signals in the aromatic region of the
1
spectrum. Observation of 17 distinct signals in the H-
decoupled 13C NMR spectrum of 3a is in agreement with
the proposed structure. The most important region of the
spectrum is related to resonances due to C─C═O,
C═C─O, HN─C─O, and C═NH that appear at
δ = 49.99, 97.15, 141.15, and 160.4 ppm.
1
product 3a. H NMR spectra showed two diastereomers
of 2a. Based on this method, various isatins (5-H, 5-Br,
5-Cl) were explored and gave the corresponding
products 2a–e in good to excellent yields. The structures
all of the products 2a–h were deduced from their IR,
mass, 1H NMR, and 13C NMR spectra (Data S1). In
this series, the IR spectrum of compound 2a showed
absorption bands at 3387, 3338, and 3137 cmꢀ1 due to
the NH2 and NH stretching frequencies. Also,
absorption bands at 2182, 1711, and 1641 cmꢀ1 are due
to the CN, C═O, and NC═C groups stretching
A probable mechanism for the one-pot four-components
synthesis of various spiro[indoline-3,40-pyrano-pyrazole]
derivatives using iodine is illustrated in Scheme 1.
Initially, condensation reaction occurs between hydrazine
hydrate and diketene, providing the pyrazole (A) that
treats with the intermediate (B). Remarkably, for the
synthesis of the intermediate (B), it is assumed that
isatin first gets activated in the presence of iodine;
next, the Knoevenagel condensation reaction of isatin 1
and malononitrile or ethyl cyanoacetate provided the
intermediate (B). This vital stage contains Michael
addition reaction of (A) onto intermediate (B), followed
by enolization and intramolecular cyclization reaction
providing the target product 3 in the presence of iodine.
Noticeably, in this stage, oxygen attacks to nitrile group
that was activated with iodine. Once malononitrile used
the tautomerization of imino group to amino group to
provide the expected product 2.
1
frequencies. The H NMR spectrum of 2a showed four
singlet (δ = 1.52, 7.2, 10.57, and 12.26 ppm) for the
methyl, NH2, and 2NH groups. Four aromatic hydrogens
gave rise to characteristic signals in the aromatic region
of the spectrum. Observation of 15 distinct signals in
the 1H-decoupled 13C NMR spectrum of 2a is in
agreement with the proposed structure. The most
important region of the spectrum is related to resonances
due to CC═O, CCN, and C═C─O that appear at
δ = 47.31, 55.22, and 95.42 ppm.
Scheme 1. Proposed mechanism for one-pot domino synthesis of products 2a–e and 3a–c.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Rezvanian, V. Zadsirjan, P. Saedi, and M. M. Heravi
Vol 000
CONCLUSION
60-Amino-30-methyl-5-nitro-2-oxo-10H-spiro[indoline-3,40-
pyrano[2,3-c]pyrazole]-50-carbonitrile (2b). White powder,
mp = 253–255°C, 0.29 g, yield: 88%. IR (KBr) (νmax
,
In conclusion, we have developed a simple and extremely
efficient method for the synthesis of spiro[indoline-3,40-
pyrano-pyrazole]-carbonitriles using iodine as a cheap
catalyst at room temperature in ethanol. This new strategy
affords five novel bonds in one sequence. The outstanding
aspects of this approach are efficiency, eco-friendly benign
method, and excellent yield and simple work-up.
cmꢀ1): 3451 (2NH), 3322 and 3291 (NH2), 2193 (CN),
1731 (C═O), 1643 (C═N), 1613 (NC═C) cmꢀ1. Anal.
Calcd for C15H10N6O4: C, 52.94; H, 3.55; N, 24.7.
Found C, 52.91; H, 3.57; N, 24.73. 1H NMR: δH
(400 MHz, DMSO-d6): 1.6 (s, 3H, CH3), 7.16 (d,
3JHH = 8.8 Hz, 1H, CH of Ar), 7.44 (s, 2H, NH2), 7.94
3
(d, JHH = 2.4 Hz, 1H, CH of Ar), 8.24–8.27 (m, 1H, CH
of Ar), 11.38 (s, 1H, NH), 12.43 (s, 1H, NH). 13C NMR:
δC (100 MHz, DMSO-d6): 9.59 (CH3), 47.95 (C─C═O),
54.32 (CCN), 94.49 (C═C─O), 110.66 (CH of Ar),
118.96 (CN), 120.68 (CH of Ar), 126.77 (CH of Ar),
134.23 (Cipso─Ar), 135.47 (C─CH3), 143.5 (Cipso─Ar),
148.29 (Cipso─Ar), 155.7 (HNCO), 163.18 (C─NH2),
EXPERIMENTAL
The diketene, hydrazine hydrate, various isatins,
malononitrile, and ethyl cyanoacetate obtained from
Merck (Germany) and Fluka (Switzerland) and were used
without further purification. Elemental analyses for C, H,
and N have been accomplished using a Heraeus CHN–
O–Rapid analyzer. Mass spectra have been recorded on a
FINNIGAN-MATT 8430 mass spectrometer operating at an
ionization potential of 70 eV. 1H NMR (300 MHz and 400)
and 13C NMR (100 and 75 MHz) spectra have been provided
using Bruker DRX-400 AVANCE and Bruker DRX-300
AVANCE spectrometers. IR spectra have been recorded as
KBr pellets on a NICOLET FT-IR 100 spectrometer. Melting
points were measured on an Electrothermal 9100 apparatus.
178.96 (C═O).
60-Amino-5-bromo-30-methyl-2-oxo-10H-spiro[indoline-3,40-
pyrano[2,3-c]pyrazole]-50-carbonitrile (2c). White powder,
mp = 281–283°C, 0.32 g, yield: 86%. IR (KBr) (νmax
,
cmꢀ1): 3390 and 3347 (NH2), 3136 (2NH), 2182 (CN),
1712 (C═O), 1643 (C═N), 1609 (NC═C) cmꢀ1. Anal.
Calcd for C15H10N5O2Br: C, 48.02; H, 3.49; N, 18.67.
Found C, 48.05; H, 3.52, N, 18.63. 1H NMR: δH
(400 MHz, DMSO-d6): 1.6 (s, 3H, CH3), 6.9 (d,
3JHH = 8 Hz, 1H, CH of Ar), 7.26 (s, 1H, CH of Ar),
3
7.33 (s, 2H, NH2), 7.44 (d, JHH = 7.2 Hz, 1H, CH of
Typical synthesis procedure.
Hydrazine hydrate
Ar), 10.79 (s, 1H, NH), 12.37 (s, 1H, NH). 13C NMR: δC
(100 MHz, DMSO-d6): 9.56 (CH3), 48.04 (C─C═O),
55.02 (CCN), 95.21 (C═C─O), 112.25 (CH of Ar),
114.74 (Cipso─Ar), 119.17 (CN), 127.83 (CH of Ar),
132.27 (CH of Ar), 135.31 (Cipso─Ar), 135.61 (C─CH3),
141.26 (Cipso─Ar), 155.67 (HNCO), 163.03 (C─NH2),
(1 mmol) and diketene (1 mmol) were mixed and
maintained at room temperature for 15 min under solvent
free. Next, substituted isatin (1 mmol), malononitrile or
ethyl cyanoacetate (1 mmol), and I2 (10 mol%) were
reacted for the appropriate time. The progress of the
reaction
was
monitored
using
Thin-layer
178.13 (C═O).
chromatography (TLC). After the completion of the
reaction (30 min), the mixture was filtered off, washed with
aqueous sodium thiosulfate solution, and purified through
recrystallization from ethanol to give the corresponding
60-Amino-1,30-dimethyl-2-oxo-10H-spiro[indoline-3,40-
pyrano[2,3-c]pyrazole]-50-carbonitrile (2d). White powder,
mp = 270–272°C, 0.27 g, yield: 90%. IR (KBr) (νmax
,
cmꢀ1): 3379 and 3330 (NH2), 3130 (NH), 2189 (CN),
1703 (C═O), 1642 (C═N), 1602 (NC═C) cmꢀ1. Anal.
Calcd for C16H13N5O2: C, 62.13; H, 4.89; N, 22.64.
Found C, 62.14; H, 4.87, N, 22.66. 1H NMR: δH
(400 MHz, DMSO-d6): 1.47 (s, 3H, CH3), 3.22 (s, 3H,
CH3), 7.07–7.14 (m, 2H, 2CH of Ar), 7.3 (s, 2H,
NH2), 7.35–7.39 (m, 2H, 2CH of Ar), 12.32 (s, 1H,
NH). 13C NMR: δC (100 MHz, DMSO-d6): 9.45 (CH3),
26.81 (CH3),47.49 (C─C═O), 55.33 (CCN), 95.77
(C═C─O), 109.18 (CH of Ar), 119.18 (CN), 123.73
(CH of Ar), 124.66 (CH of Ar), 129.59 (CH of Ar),
132.40 (Cipso─Ar), 135.32 (Cipso─Ar), 143.44
(C─CH3), 155.76 (HNCO), 163.15 (C─NH2), 176.83
(C═O).
products 2 and 3 in high purity.
60-Amino-30-methyl-2-oxo-10H-spiro[indoline-3,40-
pyrano[2,3-c]pyrazole]-50-carbonitrile (2a). White powder,
mp = 284–286°C, 0.27 g, yield: 92%. IR (KBr) (νmax
,
cmꢀ1): 3387 and 3338 (NH2), 3137 (NH), 2182 (CN),
1711 (C═O), 1641 (C═N), 1610 (NC═C) cmꢀ1. Anal.
Calcd for C15H11N5O2: C, 61.01; H, 4.44; N, 23.72.
Found C, 61.06; H, 4.41, N, 23.69. 1H NMR: δH
(300 MHz, DMSO-d6): 1.52 (s, 3H, CH3), 6.88–6.91 (m,
2H, 2CH of Ar), 6.97–7.01 (m, 2H, 2CH of Ar), 7.2 (s, 2
H, NH2), 10.57 (s, 1H, NH), 12.26 (s, 1H, NH). 13C
NMR: δC (75 MHz, DMSO-d6): 8.98 (CH3), 47.31
(C─C═O), 55.22 (CCN), 95.42 (C═C─O), 109.69 (CH
of Ar), 118.76 (CN), 122.53 (CH of Ar), 124.54 (CH of
Ar), 128.92 (CH of Ar), 132.7 (Cipso─Ar), 134.75
(C─CH3), 141.52 (Cipso─Ar), 155.29 (HNCO), 162.50
(C─NH2), 178.05 (C═O).
60-Amino-5-chloro-30-methyl-2-oxo-10H-spiro[indoline-3,40-
pyrano[2,3-c]pyrazole]-50-carbonitrile (2e). White powder,
mp = 295–294°C, 0.28 g, yield: 85%. IR (KBr) (νmax
,
cmꢀ1): 3386 and 3347 (NH2), 3137 (2NH), 2182 (CN),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
One-Pot Four-Component Synthesis of Spiro[indoline-3,40-pyrano-pyrazole]
Derivatives
1713 (C═O), 1644 (C═N), 1612 (NC═C) cmꢀ1. Anal.
Calcd for C15H10N5O2Cl: C, 54.64; H, 3.67; N, 21.24.
Found C, 54.66; H, 3.63, N, 21.27. 1H NMR: δH
(400 MHz, DMSO-d6): 1.6 (s, 3H, CH3), 6.95 (d,
3.13 (s, 3H, CH3─N), 3.84–3.89 (m, 2H, CH2), 5.53 (s,
1H, NH═C─O), 7.07–7.14 (m, 2H, 2CH of Ar),
7.4–7.47 (m, 2H, 2CH of Ar), 11.4 (s, 1H, NH). δC
(100 MHz, DMSO-d6): 10.92 (CH3), 13.83 (CH3─CH2),
26.77 (CH3─N), 43.11 (CH), 50.07 (C─C═O), 62.51
(CH2), 95.77 (C═C─O), 109.34 (CH of Ar), 117.01
(Cipso─Ar), 122.83 (CH of Ar), 124.46 (CH of Ar),
128.23 (Cipso─Ar), 130.21 (CH of Ar), 137.17 (C─CH3),
144.83 (HN─C─O), 160.43 (C═NH), 164.08 (C═O),
174.87 (C═O). Minor isomer (34%): δH (400 MHz,
3JHH
=
5.4 Hz, 1H, CH of Ar), 7.15 (d,
4JHH = 1.6 Hz, 1H, CH of Ar), 7.3 (d, JHH = 2 Hz,
1H, CH of Ar), 7.33(s, 2H, NH2), 10.78 (s, 1H, NH),
12.36 (s, 1H, NH). 13C NMR: δC (100 MHz,
DMSO-d6): 9.53 (CH3),48.09 (C─C═O), 55.01 (CCN),
95.21 (C═C─O), 111.72 (CH of Ar), 119.17 (CN),
125.14 (CH of Ar), 127.08 (Cipso─Ar), 129.42
(Cipso─Ar), 135.24 (Cipso─Ar), 135.32 (CH of Ar),
140.85 (C─CH3), 155.68 (HNCO), 163.03 (C─NH2),
3
3
DMSO-d6): 0.93 (t, JHH = 7.2 Hz, 3H, CH3─CH2), 1.22
(s, 3H, CH3), 1.78 (s, 1H, CH─C═O), 3.22 (s, 3H,
CH3─N), 3.92–3.97 (m, 2H, CH2), 5.57 (s, 1H,
NH═C─O), 7–7.07 (m, 2H, 2CH of Ar), 7.28–7.31 (m,
2H, 2CH of Ar), 10.35 (s, 1H, NH). δC (100 MHz,
DMSO-d6): 10.99 (CH3), 13.83 (CH3─CH2), 26.68
(CH3─N), 43.11 (CH), 49.34 (C─C═O), 62.7 (CH2),
97.35 (C═C─O), 109.25 (CH of Ar), 115.46 (Cipso─Ar),
123.08 (CH of Ar), 123.64 (CH of Ar), 131.09
(Cipso─Ar), 129.14 (CH of Ar), 136.12 (C─CH3), 143.15
(HN─C─O), 160.43 (C═NH), 164.08 (C═O), 174.47
178.28 (C═O).
Ethyl 5-bromo-60-imino-30-methyl-2-oxo-50,60-dihydro-10H-
spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carboxylate
(3a).
White powder, mp = 225–227°C, 0.33 g, yield:
80%. IR (KBr) (νmax, cmꢀ1): 3667 and 3337 (3NH),
1744 (CO2Et), 1715 (C═O), 1615 (C═N) cmꢀ1. Anal.
Calcd for C17H15N4O4Br: C, 48.59; H, 3.84; N, 13.33.
Found C, 48.56; H, 3.83, N, 13.17. Major isomer (%):
3
δH (400 MHz, DMSO-d6): 1.07 (t, JHH = 7.2 Hz, 3H,
(C═O).
CH3─CH2), 1.40 (s, 3H, CH3), 1.92 (s, 1H, CH─C═O),
3.92–3.97 (m, 2H, CH2), 5.49 (s, 1H, NH═C─O), 6.88
Ethyl 5-chloro-60-imino-30-methyl-2-oxo-50,60-dihydro-10H-
spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carboxylate
3
(d, JHH = 8 Hz, 1H, CH of Ar), 7.48 (s, 1H, CH of
(3c).
White powder, mp = 242–244°C, 0.29 g, yield:
3
79%. IR (KBr) (νmax, cmꢀ1): 3390 and 3321 (3NH),
1747 (CO2Et), 1722 (C═O), 1618 (C═N) cmꢀ1. Anal.
Calcd for C17H15N4O4Cl: C, 54.48; H, 4.03; N, 14.95.
Found C, 54.46; H, 4.04, N, 14.9. Major isomer (55%):
δH (400 MHz, DMSO-d6): 0.91–0.94 (m, 3H,
CH3─CH2), 1.41 (s, 3H, CH3), 1.92 (s, 1H,
CH─C═O), 3.94–3.97 (m, 2H, CH2), 5.5 (s, 1H,
Ar), 7.51 (d, JHH = 8 Hz, 1H, CH of Ar), 10.75 (s, 1H,
NH), 10.99 (s, 1H, NH). δC (100 MHz, DMSO-d6):
11.13 (CH3), 13.75 (CH3─CH2), 42.74 (CH), 50.71
(C─C═O), 62.71 (CH2), 95.49 (C═C─O), 112.41
(Cipso─Ar), 113.61 (CH of Ar), 116.87 (Cipso─Ar),
127.37 (CH of Ar), 131.62 (CH of Ar), 132.97
(Cipso─Ar), 137.22 (C─CH3), 142.77 (HN─C─O),
160.31 (C═NH), 163.95 (C═O), 175.95 (C═O). Minor
isomer (47%): δH (400 MHz, DMSO-d6): 1.02 (t,
3JHH = 7.2 Hz, 3H, CH3─CH2), 1.40 (s, 3H, CH3), 1.92
(s, 1H, CH─C═O), 3.99–4.04 (m, 2H, CH2), 5.59 (s,
3
NH═C─O), 6.92 (d, JHH = 8 Hz, 1H, CH of Ar), 7.36
3
(s, 1H, CH of Ar), 7.39 (d, JHH = 8.4 Hz, 1H, CH of
Ar), 10.74 (s, 1H, NH), 10.99 (s, 1H, NH). δC
(100 MHz, DMSO-d6): 11.15 (CH3), 13.77 (CH3─CH2),
42.78 (CH), 50.76 (C─C═O), 62.69 (CH2), 95.43
(C═C─O), 111.89 (CH of Ar), 116.91 (Cipso─Ar),
124.61 (CH of Ar), 126.03 (CH of Ar), 128.742
(Cipso─Ar), 129.96 (CH of Ar), 137.12 (C─CH3),
142.39 (HN─C─O), 160.28 (C═NH), 163.98 (C═O),
176.1 (C═O). Minor isomer (45%): δH (400 MHz,
DMSO-d6): 1–1.04 (m, 3H, CH3─CH2), 1.41 (s, 3H,
CH3), 1.92 (s, 1H, CH─C═O), 3.99–4.02 (m, 2H,
3
1H, NH═C─O), 6.82 (d, JHH = 8.4 Hz, 1H, CH of
3
Ar), 7.37 (d, JHH = 7.2 Hz, 1H, CH of Ar), 7.58 (s,
1H, CH of Ar), 10.56 (s, 1H, NH), 11.46 (s, 1H, NH).
δC (100 MHz, DMSO-d6): 11.03 (CH3), 13.84
(CH3─CH2), 41.52 (CH), 49.99 (C─C═O), 62.78
(CH2), 97.15 (C═C─O), 112.2 (Cipso─Ar), 113.87 (CH
of Ar), 115.45 (Cipso─Ar), 126.87 (CH of Ar), 131.53
(CH of Ar), 134.48 (Cipso─Ar), 136.38 (C─CH3),
141.15 (HN─C─O), 160.4 (C═NH), 163.95 (C═O),
175.98 (C═O).
3
CH2), 5.59 (s, 1H, NH═C─O), 6.86 (d, JHH = 8 Hz,
3
1H, CH of Ar), 7.25 (d, JHH = 7.6 Hz, 1H, CH of Ar),
Ethyl
spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carboxylate
(3b).
60-imino-1,30-dimethyl-2-oxo-50,60-dihydro-10H-
7.46 (s, 1H, CH of Ar), 10.50 (s, 1H, NH), 11.40 (s,
1H, NH). δC (100 MHz, DMSO-d6): 11.04 (CH3), 13.87
(CH3─CH2), 41.52 (CH), 50.02 (C─C═O), 62.76
(CH2), 97.14 (C═C─O), 111.66 (CH of Ar), 115.50
(Cipso─Ar), 124.13 (CH of Ar), 126.12 (CH of Ar),
131.15 (CH of Ar), 134.22 (Cipso─Ar), 136.21
(C─CH3), 140.77 (HN─C─O), 160.6 (C═NH), 163.98
(C═O), 176.1 (C═O).
White powder, mp = 233–235°C, 0.29 g, yield:
82%. IR (KBr) (νmax, cmꢀ1): 3444 and 3301 (2NH),
1749 (CO2Et), 1696 (C═O), 1645 (C═CN) cmꢀ1. Anal.
Calcd for C18H18N4O4: C, 61.01; H, 5.12; N, 15.81.
Found C, 61.03; H, 5.09, N, 15.82. Major isomer (66%):
3
δH (400 MHz, DMSO-d6): 1.07 (t, JHH = 6.8 Hz, 3H,
CH3─CH2), 1.22 (s, 3H, CH3), 1.78 (s, 1H, CH─C═O),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Rezvanian, V. Zadsirjan, P. Saedi, and M. M. Heravi
Vol 000
Acknowledgments. Financial support of this research from
Alzahra University, Iran is gratefully acknowledged. M. M. H.
is also thankful to Iran National Science Foundation (INSF) for
the allocated grant by the awarded individual research chair.
M. W. Angew Chem Int Ed 2015, 54, 7621; (d) Brauer, M. C. N.;
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DOI 10.1002/jhet

Month 2018
One-Pot Four-Component Synthesis of Spiro[indoline-3,40-pyrano-pyrazole]
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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