Catalyst-free four-component domino synthetic approach toward versatile multicyclic spirooxindole pyran scaffolds

Article abstract of DOI:10.1039/c9ra03214b

A new versatile strategy involving a sequential four-component reaction of the nitroketene dithioacetals, alkylamine/benzylamine, isatin and various enolizable active methylene structures (pyrazolone, barbituric acid, 1,3-indandione and 2-hydroxy-1,4-naph

Full text of DOI:10.1039/c9ra03214b

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Catalyst-free four-component domino synthetic
approach toward versatile multicyclic
spirooxindole pyran scaffolds†
Cite this: RSC Adv., 2019, 9, 16525
*
Aref Mohammadi, Mohammad Bayat
and Shima Nasri
A new versatile strategy involving a sequential four-component reaction of the nitroketene dithioacetals,
alkylamine/benzylamine, isatin and various enolizable active methylene structures (pyrazolone, barbituric
acid, 1,3-indandione and 2-hydroxy-1,4-naphthoquinone) as precursors under mild and catalyst-free
conditions results in the synthesis of new functionalized spirooxindole pyrans named spiro[indoline-3,40-
pyrano[2,3-c]pyrazol],
spiro[indoline-3,50-pyrano[2,3-d]pyrimidine],
spiro[indeno[1,2-b]pyran-4,30-
indoline] and spiro[benzo[g]chromene-4,30-indoline] in moderate to good yields. The use of various
active methylene compounds affords a range of skeletally distinct spirooxindole-based heterocycles with
potential biological properties. The present strategy has many advantages, such as convenient one-pot
operation, simple workup procedures and straightforward isolation without using tedious purification
steps such as column chromatography, progress under catalyst-free condition and high molecular diversity.
Received 29th April 2019
Accepted 12th May 2019
DOI: 10.1039/c9ra03214b
rsc.li/rsc-advances
development of versatile reactions to synthesize these struc-
tures, new, simple and highly efficient methods are still
Introduction
required.
In organic synthesis, development of synthetically useful and
A signicant challenge to explore biological targets is the design
of an economical and highly efficient chemical reaction to
supply structurally diverse compounds with excellent biological
properties.1 Therefore, to satisfy the need for small molecules
containing bioactive heterocycles as biological targets, access to
a wide variety of compounds with potential biological activities
is highly desirable.2,3 The 4H-pyran derivatives are dened as
useful biological and pharmacological targets with biological
properties such as antiviral,4 antibacterial,5 antitumor,6 and
diuretic activities.7 In addition, isatin and its derivatives have
attractive biological properties and are widely used in the
synthesis of spirooxindole-based organic compounds.8 Spi-
rooxindole system is one of the most phenomenal spirocycles
and the central structural framework found in a diversity of
natural products and bioactive molecules.9 The existence of
a chiral spiro center around a biologically active scaffold leads
to structural rigidity and complexity, which is an ongoing
challenge for synthetic organic chemists.10 Hence, heterocyclic
spirooxindole pyrans are attractive synthetic targets for
synthetic chemists due to their biological activities such as
antiviral, antibacterial, antifungal, anti-HIV, and anti-cancer
activities.11 Various groups have developed synthetic
approaches to access this scaffold.3,11 In spite of the
unique organic reaction methods in eco-friendly media that
generate complex molecular libraries with a minimum number
of synthetic steps is a major challenge that can be resolved by
multicomponent reactions (MCRs) as the most efficient strategy
in modern organic synthesis.12 The inherent advantages of
MCRs including operational simplicity, step efficiency, lower
energy consumption and costs, and high atom economy
without waste production have resulted in designing novel
MCRs using eco-friendly solvents as one of the goals of
sustainable chemistry and synthetic chemistry.13
There are many reports on multicomponent entries in the
synthesis of spirooxindole-4H-pyrans from readily available
starting materials including isatin, malononitrile, and 1,3-
dicarbonyl compounds. This class of reaction has been carried
out under different conditions as follows: in the presence of p-
toluenesulfonic acid (p-TSA) in aqueous media,14 [BMIm]BF4 as
an ionic liquid catalyst at ambient temperature,15 piperidine
under ultrasound irradiation,16 proline-derived thiourea cata-
lyst,3 CuFe2O4 (10 mol%) as an inexpensive, magnetically
recoverable, and reusable catalyst in reuxing water,17 SBA-Pr-
NH2 as an efficient heterogeneous nanoporous solid basic
catalyst in an aqueous medium,18 a-amylase extracted from hog
pancreas,19 silica-bonded N-propyltriethylenetetramine as
heterogeneous solid base catalyst,20 triethylamine in
Department of Chemistry, Faculty of Science, Imam Khomeini International University,
Qazvin, Iran. E-mail: m.bayat@sci.ikiu.ac.ir; bayat_mo@yahoo.com; Tel: +98 28
33780040
a
ethanol,21 silica-bonded ionic liquids as a recyclable catalyst,22
1 mol% of (DHQD)2PYR,23 ytterbium triate as a catalyst at
room temperature,24 under visible-light irradiation in water-
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra03214b
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Scheme 1 Synthesis of spiro(indoline-3,40-pyrano[2,3-c]pyrazol)-2-one derivatives catalyzed by indium trichloride.
ethyl lactate at room temperature,25 in the presence of a catalytic carbonyl compounds or ketene aminal derivatives in the pres-
amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) in ethanol or ence of potassium carbonate (K2CO3) in polyethylene glycol 400
H2O/EtOH mixture under reux conditions,26 in dimethylsulf- (PEG-400) at room temperature (Scheme 2).31
oxide (DMSO) as a highly polar aprotic solvent,11 by dabco-based
ionic liquids,27 using guanidine-functionalized magnetic Fe3O4 catalyst-free approaches by using environmentally friendly
nanoparticles (MNPs) as an efficient heterogeneous catalyst.28
solvents as a green and safe method for the formation of
With this article background and owing to our interest in
Although various catalysts have been applied for the molecular architectures with a wide range of potential biolog-
synthesis of these compounds, the role of catalysts is the same ical activities,32–35 herein, we designed and introduced an
in these reactions and it was to catalyze the Knoevenagel improved, catalyst-free, and easy method to access the spi-
condensation, Michael addition, and cyclization reactions. rooxindoles and 4H-pyrans, for which the results are shown in
Each of the procedures has its own benets with at least one the Results and discussion section.
drawback, such as low yield, long reaction time, harsh reaction
conditions, and use of toxic and expensive catalysts or solvents;
hence, there is still a requirement for simple, efficient and
Results and discussion
economical methods.
Due to the pharmacological activities of spirooxindole motifs
In recent years, ketene aminals (KAs) have been used as
and the bioactivity of pharmacophores such as naph-
powerful and versatile enamine analogues with unique struc-
thoquinone, indandion, pyrazolone, and pyrimidine deriva-
tural properties in the synthesis of various types of fused ve-
tives, we synthesized products 5 which comprise both of
and six-membered heterocycles and drug-like compounds.29 In
spirooxindole and one of these pharmacophores. The hybrid
molecules may inherit biological properties of both spiroox-
this way, specic strategies have been developed for the
synthesis of substituted spirooxindole-4H-pyrans based on
indole and pharmacophore structures. Synthesis of 5 could be
utilizing KAs as starting materials as follows. In 2014, Poomathi
easily achieved by tandem Knoevenagel condensation/Michael
et al. reported a versatile high-yielding indium trichloride-
addition/imine–enamine tautomerism/O-cyclization of the
reaction of amines 1, 1,1-bis(methylthio)-2-nitroethene 2, isatin
3 and enolizable active methylene structures 4a–f (pyrazolone,
mediated one-pot regioselective reaction for the synthesis of
spiroxindoles via domino one-pot, three-component reaction of
isatins,
pyrazoles,
and
(E-)-N-methyl-1-(methylthio)-2-
barbituric
acid,
1,3-indandione
and
2-hydroxy-1,4-
nitroethenamine (Scheme 1).30
naphthoquinone) (Scheme 3).
In 2017, Safari et al. reported the synthesis of novel
symmetrical bis-spirooxindole derivatives from the reaction of
isatins, dihalides, malono derivatives and C–H activated
In this paper, KAs were derived from the addition of various
alkylamine/benzylamine 1 to 1,1-bis(methylthio)-2-nitroethene
2, wherein the electron density of the a-carbon (C1) increased
Scheme 2 The one-pot, multi-component synthesis of bis-spirooxindoles in PEG-400/K2CO3 at room temperature.
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Scheme 3 Synthetic approaches for the formation of spiro[indoline-3,40-pyrano[2,3-c]pyrazol], spiro[indoline-3,50-pyrano[2,3-d]pyrimidine],
spiro[indeno[1,2-b]pyran-4,30-indoline] and spiro[benzo[g]chromene-4,30-indoline] (5a–q).
due to the conjugation effect of both the electron-donating
The acceptable reaction mechanism is designated in Scheme
nitrogen and sulfur atoms.29 Isatin, as an important distin- 4. In the case of the synthesis of 5, it is possible that initially, the
guished building block, is a type of unsymmetrical cyclic ketone formation of ketene aminal (KA) 6 occured through the addition
with excellent reactivity that has been used in the synthesis of of amine 1 to 1,1-bis (methylthio)-2-nitroethene 2. Then,
different types of spirooxaindole skeletons.36 In this study, Michael acceptor 7 formed through Knoevenagel condensation
a variety of multicyclic spirooxindole pyran scaffolds (5a–q) between isatin 3 and enolizable active methylene structures 4,
were synthesized; these derivatives provide a class of structur- which was followed by the loss of water molecules. Then the KA
ally diverse compounds that demonstrate promise for future 6 as an enamine added to the Knoevenagel adduct 7 in
bioassays and medical therapy applications.
a Michael addition type reaction to give open chain interme-
diate 8, which aer successive imine–enamine tautomerization
Scheme 4 A plausible mechanism for the formation of 5 in catalyst-free conditions.
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Table 1 Substrate scope study of multicyclic spirooxindole pyran scaffolds with a series of amines, isatin derivatives, and active methylene
structures
Entry
Active methylene structures
R1
R2
Product
Timea (h)
Yield (%)
1
CH3
H
8
85
2
CH3
Cl
8
80
3
CH3
Br
9
78
4
5
6
CH3
CH3
CH3
H
10
12
10
86
75
80
Br
Cl
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Table 1 (Contd.)
Entry
Active methylene structures
R1
R2
Br
Product
Timea (h)
Yield (%)
7
CH3
10
62
8
CH2Ph
Cl
12
58
9
CH3
Cl
Cl
Cl
Br
10
10
10
12
65
75
76
71
10
11
12
CH2CH2CH3
CH(CH3)2
CH2CH2CH3
13
CH(CH3)2
Br
12
72
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Table 1 (Contd.)
Entry
14
Active methylene structures
R1
R2
Cl
Product
Timea (h)
Yield (%)
CH3
12
65
15
16
CH2Ph
H
12
65
62
CH2CH2CH3
Cl
8
17
CH2CH2CH3
Br
8
60
a
The reaction time of the second step.
underwent O-cyclization via an attack of the enol form of C–H- doublet for 3H of CH3 group attached to NH (d 3.17 ppm, 3JHH
activated compound on KA, leading to product 5 (Scheme 4). 4.8 Hz), aromatic region of the spectrum for the aromatic
¼
We surveyed the scope of these reactions by varying the moieties (d 6.87–7.73 ppm), one multiplet for NH attached to
derivatives of amine 1, isatin 3, and the active methylene CH3 (d 10.71–10.73 ppm) and one singlet for NH group of isatin
compounds 4 to produce product 5 (Table 1). The reaction (d 10.74 ppm). The 1H-decoupled 13C NMR spectrum of 5a
proceeds cleanly and completely in the presence of different exhibited 21 distinguished resonances. One peak appeared at
reagents to afford a series of spiro products 5a–q in 58–86% d 176.6 ppm, which was attributed to one amide carbonyl group
yields. It is noteworthy that the expected product 5 was obtained and the specic peaks of Cspiro, NHCH3 and CH3, were assigned
in good yield when pyrazolone was used, but using other C–H at d 50.0, 29.4 and 12.2 ppm, which conrmed the selective
activated compounds, the expected product 5 was acquired in synthesis of 5a.
moderate yields. The substituents on the aromatic ring of the
isatin like chlorine or bromine affected the reaction and gave
desired products in a long time with fewer yields. The products
Conclusions
5d–5q are novel compounds (Table 1) that have not been re-
ported in the previous literature.
In General, we developed an environment friendly process for
the synthesis of a library of spiro[indoline-3,40-pyrano[2,3-c]
pyrazol], spiro[indoline-3,50-pyrano[2,3-d]pyrimidine], spiro
[indeno[1,2-b]pyran-4,30-indoline] and spiro[benzo[g]chromene-
4,30-indoline] compounds in moderate to good yields (58–86%).
This reaction proceeded via sequential four-component reac-
tion between alkylamine/benzylamine, 1,1-bis(methylthio)-2-
nitro ethylene, isatin and various active methylene
The structures of synthesized derivatives were concluded by
elemental and spectral analysis such as FT-IR, 1H, 13C NMR and
mass spectroscopy. The mass spectrum of compound 5a
exhibited a molecular ion peak at m/z 403, which was in
accordance with the offered structure. The 1H NMR spectrum of
5a displayed one singlet for CH3 group (d 1.58 ppm), one
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5-Chloro-30-methyl-60-(methylamino)-50-nitro-10-phenyl-10H-
spiro[indoline-3,40-pyrano[2,3-c]pyrazol]-2-one (5b). White
compounds in EtOH or H2O medium. Prominent advantages of
this method are the diversity of molecular structure, an easy
workup, the absence of a catalyst and operational simplicity.
powder, mp: 285–287 ꢀC, yield 0.349 g (80%); IR (KBr) (nmax
/
cmꢁ1): 3372, 3025 (NH), 1686 (C]O), 1498 and 1363 (NO2), 1213
(C–N), 1102 (C–O) 776 (Ar), 585 (C–Cl). 1H NMR (300 MHz,
Experimental section
General
3
DMSO): d 1.65 (3H, s, CH3), 3.16 (3H, d, JHH ¼ 4.8 Hz, NCH3),
6.90 (1H, d, 3JHH ¼ 8.1 Hz, ArH), 7.24 (1H, d, 3JHH ¼ 8.4 Hz, ArH),
7.33–7.40 (1H, m, ArH), 7.34 (1H, s, ArH), 7.52–7.57 (2H, m,
The nitroketene dithioacetals, isatin derivatives, various
amines, various active methylene compounds and solvents were ArH), 7.72 (2H, d, 3JHH ¼ 8.1 Hz, ArH), 10.74–10.76 (1H, m, NH),
obtained from Sigma Aldrich and Fluka Co., which were used 10.90 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 12.1 (CH3),
without further purication. IR spectra: Bruker Tensor 27 29.3 (CH3N), 49.9 (Cspiro), 98.7 (C–NO2), 107.4 (C]C–N), 109.7,
spectrometer. NMR spectra: Bruker DRX-300 Avance instrument 119.4, 120.8, 122.4, 123.6, 127.2, 128.9, 131.8, 131.9, 134.3,
(300 MHz for 1H and 75.4 MHz for 13C) with DMSO-d6 as 138.4, 142.9 (Ar), 143.2 (C]N), 145.3 (N–N–C–O), 159.3 (O–C–
N), 176.4 (CO). Anal. calcd for C21H16ClN5O4 (437.09): C, 57.61;
H, 3.68; N, 16.00. Found C, 57.50; H, 3.92; N, 16.41.
solvents. Chemical shis are expressed in parts per million
(ppm), and coupling constant (J) are reported in hertz (Hz).
Mass spectra: Agilent 5975C VL MSD with Triple-Axis detector
5-Bromo-30-methyl-60-(methylamino)-50-nitro-10-phenyl-10H-
operating at an ionization potential of 70 eV. Elemental anal- spiro[indoline-3,40-pyrano[2,3-c]pyrazol]-2-one
(5c).
White
yses for C, H and N: Heraeus CHNO-Rapid analyzer. Melting powder, mp: 280–282 ꢀC, yield 0.375 g (78%); IR (KBr) (nmax
/
points: electrothermal 9100 apparatus.
cmꢁ1): 3340, 3170 (NH), 1687 (C]O), 1489 and 1370 (NO2), 1245
(C–N), 1035 (C–O) 776 (Ar), 524 (C–Br). 1H NMR (300 MHz,
3
DMSO): d 1.62 (3H, s, CH3), 3.16 (3H, d, JHH ¼ 5.1 Hz, NCH3),
General procedure for the synthesis of 5a–h and 5n–q
3
6.85 (1H, d, JHH ¼ 8.1 Hz, ArH), 7.32–7.42 (3H, m, ArH), 7.46
A mixture of amine (1 mmol), 1,1-bis(methylthio)-2-nitro
ethylene (0.165 g, 1 mmol), and 10 mL EtOH was taken in
a 50 mL round-bottomed ask, and was stirred for 4 h. Then,
isatin derivatives (1 mmol) and active methylene compounds (1
mmol) were added to the reaction mixture, and was stirred for
a period of time shown in Table 1, which was monitored by TLC
(ethyl acetate/n-hexane, 6 : 4). The reaction mixture was cooled
to room temperature and the precipitate was ltered to obtain
the crude product. The solid was washed with 96% ethanol and
dried in an oven at 150 ꢀC to yield product 5 and analyzed by 1H
NMR and 13C NMR spectroscopy. Only in the case of 5n, the
round-bottom ask was tted with a reux condenser and
heated with stirring in an oil-bath at reux temperature.
(1H, s, ArH), 7.62 (1H, d, 3JHH ¼ 8.4 Hz, ArH), 7.73 (1H, d, 3JHH
¼
8.4 Hz, ArH), 10.74–10.76 (1H, m, NH), 10.90 (1H, s, NH). 13C
NMR (75.4 MHz, DMSO): d 12.1 (CH3), 29.4 (CH3N), 50.1 (Cspiro),
97.7 (C–NO2), 107.2 (C]C–N), 111.6, 114.2, 121.2, 126.7, 127.6,
129.4, 130.1, 131.6, 131.8, 134.6, 137.2, 142.2 (Ar), 143.1 (C]N),
144.5 (N–N–C–O), 159.4 (O–C–N), 176.2 (CO).
10-(3-Chlorophenyl)-30-methyl-60-(methylamino)-50-nitro-10H-
spiro[indoline-3,40-pyrano[2,3-c]pyrazol]-2-one (5d). White
powder, mp: 272–275 ꢀC, yield 0.375 g (86%); IR (KBr) (nmax
/
cmꢁ1): 3130, 3052 (OH), 1701 (C]O), 1584 and 1397 (NO2), 1217
(C–N), 1026 (C–O) 772 (Ar), 542 (C–Cl). 1H NMR (300 MHz,
3
DMSO): d 1.60 (3H, s, CH3), 3.17 (3H, d, JHH ¼ 6.3 Hz, NCH3),
3
6.87–6.93 (2H, m, ArH), 7.10 (1H, d, JHH ¼ 7.2 Hz, ArH), 7.17–
7.22 (1H, m, ArH), 7.43 (1H, d, 3JHH ¼ 8.1 Hz, ArH), 7.57 (1H, d,
3JHH ¼ 8.1 Hz, ArH), 7.78 (1H, d, 3JHH ¼ 7.2 Hz, ArH), 7.84 (1H, s,
ArH), 10.70–10.72 (1H, m, NH), 10.75 (1H, s, NH). 13C NMR (75.4
MHz, DMSO): d 12.2 (CH3), 29.4 (CH3N), 50.2 (Cspiro), 97.7 (C–
NO2), 107.2 (C]C–N), 111.1, 121.1, 121.2, 124.0, 126.5, 127.6,
128.7, 130.0, 130.1, 134.2, 141.8 (Ar), 143.1 (C]N), 144.5 (N–N–
C–O), 159.4 (O–C–N), 176.4 (CO); MS (EI, 70 eV): m/z (%) ¼ 438
(1) [M + 1]+, 437 (3) [M]+, 391 (25), 376 (100), 363 (23), 209 (24),
111 (32).
General procedure for the synthesis of 5i–m
In the case of the synthesis of compounds 5i–m, H2O was used
as the reaction medium and the round-bottom ask was tted
with a reux condenser and heated with stirring in an oil-bath
at reux temperature for a period of time shown in Table 1.
30-Methyl-60-(methylamino)-50-nitro-10-phenyl-10H-spiro
[indoline-3,40-pyrano[2,3-c]pyrazol]-2-one (5a). White powder,
mp: 268–272 ꢀC, yield 0.342 g (85%); IR (KBr) (nmax/cmꢁ1): 3186,
3060 (NH), 1686 (C]O), 1532 and 1386 (NO2), 1223 (C–N), 1015
(C–O) 766 (Ar). 1H NMR (300 MHz, DMSO): d 1.58 (3H, s, CH3),
3.17 (3H, d, 3JHH ¼ 4.8 Hz, NCH3), 6.87–6.93 (2H, m, ArH), 7.11
5-Bromo-10-(3-chlorophenyl)-30-methyl-60-(methylamino)-50-
nitro-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazol]-2-one (5e).
White powder, mp: 268–271 C, yield 0.386 g (75%). H NMR
1
ꢀ
3
3
3
(1H, d, JHH ¼ 7.2 Hz, ArH), 7.18 (1H, d, JHH ¼ 7.5 Hz, ArH),
(300 MHz, DMSO): d 1.62 (3H, s, CH3), 3.26 (3H, d, JHH
¼
7.34–7.39 (1H, m, ArH), 7.51–7.57 (2H, m, ArH), 7.73 (2H, d, 3JHH
4.5 Hz, NCH3), 6.85 (1H, d, 3JHH ¼ 7.8 Hz, ArH), 7.38 (1H, d, 3JHH
¼ 8.1 Hz, ArH), 10.71–10.73 (1H, m, NH), 10.74 (1H, s, NH). 13
C
3
¼ 8.1 Hz, ArH), 7.45 (1H, d, JHH ¼ 8.1 Hz, ArH), 7.50 (1H, s,
3
NMR (75.4 MHz, DMSO): d 12.2 (CH3), 29.4 (CH3N), 50.0 (Cspiro),
98.3 (C–NO2), 107.5 (C]C–N), 109.7, 121.1, 121.2, 122.4, 122.6,
123.6, 127.5, 128.9, 130.0, 130.1, 132.1, 137.3 (Ar), 142.9 (C]N),
144.7 (N–N–C–O), 159.4 (O–C–N), 176.6 (CO); MS (EI, 70 eV): m/z
(%) ¼ 403 (9) [M]+, 387 (32), 342 (78), 303 (67), 274 (67), 115 (35),
91 (55), 77 (100). Anal. calcd for C21H17N5O4 (403.13): C, 62.53;
H, 4.25; N, 17.36. Found C, 62.11; H, 3.90; N, 17.18.
ArH), 7.56–7.61 (1H, m, ArH), 7.72 (1H, d, JHH ¼ 8.1 Hz, ArH),
7.83 (1H, s, ArH), 10.74–10.83 (1H, m, NH), 10.90 (1H, s, NH).
13C NMR (75.4 MHz, DMSO): d 12.2 (CH3), 29.4 (CH3N), 50.0
(Cspiro), 98.2 (C–NO2), 107.2 (C]C–N), 111.7, 114.2, 119.4, 120.8,
126.7, 127.2, 131.7, 131.8, 134.3, 134.4, 138.3, 142.2 (Ar), 143.4
(C]N), 145.2 (N–N–C–O), 159.3 (O–C–N), 176.1 (CO); MS (EI, 70
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eV): m/z (%) ¼ 517 (6) [M + 2]+, 515 (5) [M]+, 501 (24), 456 (100), 9.31 (1H, s, NH), 9.80 (1H, s, NH), 9.90 (1H, s, NH). 13C NMR
342 (38), 125 (46), 111 (84).
(75.4 MHz, DMSO): d 11.3 (CH3), 20.8 (CH2), 41.0 (NCH2), 56.5
(Cspiro), 77.2 (C–NO2), 84.0 (C]C–O), 110.5, 123.3, 125.2, 126.1,
(5f). 127.6, 130.1 (Ar), 139.3 (NCON), 141.6 (N–C–O), 151.9 (O–C–
5-Chloro-10-(3-chlorophenyl)-30-methyl-60-(methylamino)-50-
nitro-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazol]-2-one
1
ꢀ
White powder, mp: 254–258 C, yield 0.376 g (80%). H NMR NCH3), 152.2 (CO), 179.5 (CO); MS (EI, 70 eV): m/z (%) ¼ 419
3
(300 MHz, DMSO): d 1.65 (3H, s, CH3), 3.18 (3H, d, JHH
¼
(0.01) [M]+, 181 (47), 153 (100), 128 (53), 90 (19), 63 (40).
3.6 Hz, NCH3), 6.90 (1H, d, 3JHH ¼ 8.4 Hz, ArH), 7.25 (1H, d, 3JHH
5-Chloro-70-(isopropylamino)-60-nitrospiro[indoline-3,50-pyr-
3
¼ 8.1 Hz, ArH), 7.32 (1H, s, ArH), 7.45 (1H, d, JHH ¼ 7.5 Hz, ano[2,3-d]pyrimidine]-2,20,40(10H,30H)-trione
(5k).
White
3
ArH), 7.55–7.61 (1H, m, ArH), 7.71 (1H, d, JHH ¼ 8.4 Hz, ArH), powder, mp: 270–272 ꢀC, yield 0.318 g (76%); IR (KBr) (nmax
/
7.83 (1H, s, ArH), 10.68–10.79 (1H, m, NH), 10.89 (1H, s, NH). cmꢁ1): 3161, 3046 (NH), 1729, 1650, 1601 (C]O), 1466 and 1373
13C NMR (75.4 MHz, DMSO): d 12.2 (CH3), 29.4 (CH3N), 50.0 (NO2), 1239 (C–N), 1021 (C–O) 758 (Ar), 550 (C–Cl). 1H NMR (300
(Cspiro), 98.1 (C–NO2), 107.2 (C]C–N), 111.1, 119.5, 120.9, 124.0, MHz, DMSO): d 1.12 (6H, d, 3JHH ¼ 6.6 Hz, CH3), 3.19–3.28 (1H,
126.5, 127.3, 128.8, 131.8, 134.1, 134.3, 138.3, 141.8 (Ar), 143.4 m, CH), 6.61 (1H, d, 3JHH ¼ 8.1 Hz, ArH), 6.92 (1H, s, ArH), 7.03
(C]N), 145.2 (N–N–C–O), 159.3 (O–C–N), 176.2 (CO); MS (EI, 70 (1H, d, 3JHH ¼ 8.1 Hz, ArH), 7.42–7.68 (1H, m, NH), 9.36 (1H, s,
eV): m/z (%) ¼ 472 (5) [M + 1]+, 471 (7) [M]+, 425 (20), 410 (100), NH), 9.82 (1H, s, NH), 9.88 (1H, s, NH). 13C NMR (75.4 MHz,
336 (17), 192 (22), 166 (24), 125 (33), 111 (66).
DMSO): d 20.8 (CH3), 43.5 (CH), 77.2 (C–NO2), 83.9 (C]C–O),
110.5, 123.3, 125.2, 127.6 (Ar), 139.3 (NCON), 141.6 (N–C–O),
152.2 (O–C–NCH3), 152.2 (CO), 179.5 (CO); MS (EI, 70 eV): m/z
5-Bromo-10-methyl-60-(methylamino)-50-nitro-30-(tri-
uoromethyl)-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazol]-2-
one (5g). White powder, mp: 298–301 ꢀC, yield 0.292 g (62%). 1H (%) ¼ 419 (0.01) [M]+, 181 (48), 153 (100), 128 (53), 110 (4), 90
NMR (300 MHz, DMSO): d 3.20 (3H, d, 3JHH ¼ 3.6 Hz, NHCH3), (18), 63 (36).
3.86 (3H, s, NCH3), 7.04 (1H, d, 3JHH ¼ 7.2 Hz, ArH), 7.34 (1H, d,
5-Bromo-60-nitro-70-(propylamino)spiro[indoline-3,50-pyrano
3JHH ¼ 7.5 Hz, ArH), 7.39 (1H, s, ArH), 10.71–10.76 (1H, m, NH), [2,3-d]pyrimidine]-2,20,40(10H,30H)-trione (5l). White powder,
10.80 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 29.2 (CH3), mp: 235–239 ꢀC, yield 0.328 g (71%). 1H NMR (300 MHz, DMSO):
35.6 (CH3N), 49.9 (Cspiro), 96.1 (C–NO2), 107.5 (C]C–N), 125.0, d 0.90 (3H, t, 3JHH ¼ 8.1 Hz, CH3), 1.47–1.54 (2H, m, CH2), 2.65–
111.5, 113.6, 126.6, 131.7, 134.5, 142.7 (Ar), 134.0 (C]N), 145.2 2.73 (2H, m, NCH2), 6.57 (1H, d, 3JHH ¼ 8.1 Hz, ArH), 7.03 (1H, s,
3
(N–N–C–O), 158.5 (O–C–N), 176.1 (CO).
ArH), 7.16 (1H, d, JHH ¼ 8.1 Hz, ArH), 7.38–7.78 (1H, m, NH),
9.30 (1H, s, NH), 9.81 (1H, s, NH), 9.90 (1H, s, NH). 13C NMR
Red (75.4 MHz, DMSO): d 11.3 (CH3), 20.9 (CH2), 41.0 (NCH2), 56.7
60-(Benzylamino)-5-chloro-30-methyl-50-nitro-10-phenyl-10H-
spiro[indoline-3,40-pyrano[2,3-c]pyrazol]-2-one
(5h).
powder, mp: 271–274 ꢀC, yield 0.328 g (58%). 1H NMR (300 (Cspiro), 77.2 (C–NO2), 83.8 (C]C–O), 111.0, 112.8, 125.5, 126.0,
3
MHz, DMSO): d 3.10 (3H, d, JHH ¼ 4.2 Hz, NHCH3), 3.33–3.45 130.4 (Ar), 139.9 (NCON), 142.0 (N–C–O), 143.8 (O–C–NCH3),
(2H, m, CH2), 7.14–7.64 (8H, m, ArH), 11.20–11.31 (1H, m, NH), 152.1 (CO), 179.3 (CO).
12.53 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 25.6 (CH2),
5-Bromo-70-(isopropylamino)-60-nitrospiro[indoline-3,50-pyr-
(5m). White
47.9 (Cspiro), 99.2 (C–NO2), 117.0 (C]C–N), 119.8, 120.2, 121.0, ano[2,3-d]pyrimidine]-2,20,40(10H,30H)-trione
123.5, 130.7, 131.5, 132.2, 132.6, 134.2, 135.7, 136.7 (Ar), 149.9 powder, mp: 260–262 ꢀC, yield 0.333 g (72%). 1H NMR (300
(C]N), 156.9 (N–N–C–O), 164.7 (O–C–N), 176.0 (CO).
MHz, DMSO): d 1.12 (6H, d, 3JHH ¼ 6.3 Hz, CH3), 3.21–3.33 (1H,
5-Chloro-70-(methylamino)-60-nitrospiro[indoline-3,50-pyr-
m, CH), 6.67 (1H, d, 3JHH ¼ 8.1 Hz, ArH), 7.03 (1H, s, ArH), 7.16
ano[2,3-d]pyrimidine]-2,20,40(10H,30H)-trione
(5i).
White (1H, d, 3JHH ¼ 8.1 Hz, ArH), 7.55–7.81 (1H, m, NH), 9.32 (1H, s,
powder, mp: 287–293 ꢀC, yield 0.254 g (65%); IR (KBr) (nmax
/
NH), 9.82 (1H, s, NH), 9.89 (1H, s, NH). 13C NMR (75.4 MHz,
cmꢁ1): 3410, 3196 (NH), 1730, 1653 (C]O), 1472 and 1371 DMSO): d 20.8 (CH3), 43.5 (CH), 44.3 (Cspiro), 77.2 (C–NO2), 83.9
(NO2), 1241 (C–N), 1126 (C–O) 768 (Ar), 560 (C–Cl). 1H NMR (300 (C]C–O), 111.1, 112.9, 117.2, 124.0, 126.1, 130.4 (Ar), 139.7
MHz, DMSO): d 3.08 (3H, d, 3JHH ¼ 4.8 Hz, NCH3), 6.96 (1H, d, (NCON), 142.0 (N–C–O), 152.1 (O–C–NCH3), 162.0 (CO), 179.3
3JHH ¼ 8.1 Hz, ArH), 7.11 (1H, d, 3JHH ¼ 8.1 Hz, ArH), 7.34 (1H, s, (CO).
ArH), 10.51–10.53 (1H, m, NH), 10.66 (1H, s, NH), 11.23 (1H, s,
250-Chloro-2-(methylamino)-3-nitro-5H-spiro[indeno[1,2-b]
NH), 12.52 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 29.3 pyran-4,30-indoline]-20,5-dione (5n). Red powder, mp: 238–
1
ꢀ
(CH3N), 48.7 (Cspiro), 88.9 (C–NO2), 107.5 (C]C–O), 110.1, 123.8, 240 C, yield 0.265 g (65%). H NMR (300 MHz, DMSO): d 3.39
125.4, 128.3, 133.2, 143.9 (Ar), 149.4 (NCON), 152.0 (N–C–O), (3H, d, 3JHH ¼ 7.2 Hz, CH3), 7.11–7.63 (7H, m, ArH), 11.21–11.32
157.0 (O–C–NCH3), 161.3 (CO), 176.6 (CO). Anal. calcd for (1H, m, NH), 12.53 (1H, s, NH). 13C NMR (75.4 MHz, DMSO):
C
15H10ClN5O6 (391.03): C, 45.99; H, 2.57; N, 17.88. Found C, d 25.6 (CH3), 48.0 (Cspiro), 89.8 (C–NO2), 99.1 (C]C–O), 119.7,
46.11; H, 2.38; N, 18.01. 120.2, 120.9, 127.9, 129.0, 131.5, 132.2, 134.5, 135.8, 136.3, 149.8
5-Chloro-60-nitro-70-(propylamino)spiro[indoline-3,50-pyrano (Ar), 156.9 (O–C–N), 164.7 (C]C–O), 174.9 (NCO), 188.6 (CO).
[2,3-d]pyrimidine]-2,20,40(10H,30H)-trione (5j). White powder,
2-(Benzylamino)-3-nitrospiro[benzo[g]chromene-4,30-indo-
mp: 240–242 ꢀC, yield 0.314 g (75%); IR (KBr) (nmax/cmꢁ1): 3393, line]-20,5,10-trione (5o). Red powder, mp: >300 ꢀC, yield 0.311 g
1
3140 (NH), 1702 (C]O), 1607 (C]O), 1472 and 1372 (NO2), (65%). H NMR (300 MHz, DMSO): d 4.79–4.89 (2H, m, CH2),
1179 (C–N), 1040 (C–O), 599 (C–Cl). 1H NMR (300 MHz, DMSO): 6.76–6.81 (1H, m, ArH), 7.13 (1H, d, JHH ¼ 6.6 Hz, ArH), 7.32
3
d 0.87 (3H, t, 3JHH ¼ 7.8 Hz, CH3), 1.44–1.57 (2H, m, CH2), 2.68– (1H, d, 3JHH ¼ 6.3 Hz, ArH), 7.37–7.41 (1H, m, ArH), 7.58 (1H, d,
2.74 (2H, m, NCH2), 6.60 (1H, d, 3JHH ¼ 8.1 Hz, ArH), 6.92 (1H, s, 3JHH ¼ 7.5 Hz, ArH), 7.71–7.84 (2H, m, ArH), 8.05 (1H, d, 3JHH
¼
3
ArH), 7.03 (1H, d, JHH ¼ 8.1 Hz, ArH), 7.41–7.69 (1H, m, NH), 6.9 Hz, ArH), 10.74 (1H, s, NH), 10.92–11.03 (1H, m, NH). 13C
16532 | RSC Adv., 2019, 9, 16525–16533
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NMR (75.4 MHz, DMSO): d 45.6 (CH3), 50.2 (Cspiro), 107.5 (C–
NO2), 109.4 (C]C–O), 121.7, 124.1, 126.5, 126.8, 128.2, 129.1,
9 B. M. Trost and M. K. Brennan, Synthesis, 2009, 2009, 3003–
3025.
129.3, 131.2, 131.3, 135.4, 137.9, 144.7 (Ar), 148.6 (O–C–N), 156.3 10 A. Velazquez-Campoy, M. J. Todd and E. Freire, Biochemistry,
(C]C–O), 176.2 (NCO), 176.5 (CO), 181.4 (CO).
2000, 39, 2201–2207.
11 T. Ponpandian and S. Muthusubramanian, Synth. Commun.,
2014, 44, 868–874.
50-Chloro-3-nitro-2-(propylamino)spiro[benzo[g]chromene-
4,30-indoline]-20,5,10-trione (5p). Red powder, mp: >300 ꢀC,
yield 0.288 g (62%); IR (KBr) (nmax/cmꢁ1): 3214, 3061 (NH), 1731, 12 R. C. Cioc, E. Ruijter and R. V. Orru, Green Chem., 2014, 16,
1651, 1605 (C]O), 1524 and 1352 (NO2), 1214 (C–N), 1067 (C–O)
2958–2975.
1
768 (Ar), 542 (C–Cl). H NMR (300 MHz, DMSO): d 0.85 (3H, t, 13 X. B. Chen, Z. C. Liu, L. F. Yang, S. J. Yan and J. Lin, ACS
3JHH ¼ 8.1 Hz, CH3), 1.50–1.60 (2H, m, CH2), 2.62–2.77 (2H, m,
Sustainable Chem. Eng., 2014, 2, 1155–1163.
14 R. Ghahremanzadeh, T. Amanpour and A. Bazgir, J.
Heterocycl. Chem., 2009, 46, 1266–1270.
3
3
NCH2), 6.88 (1H, d, JHH ¼ 8.4 Hz, ArH), 7.30 (1H, d, JHH
¼
8.4 Hz, ArH), 7.41 (1H, s, ArH), 7.60 (1H, d, 3JHH ¼ 7.8 Hz, ArH),
7.67–7.72 (2H, m, ArH), 7.82 (1H, d, 3JHH ¼ 7.8 Hz, ArH), 10.28– 15 K. Rad-Moghadam and L. Youseabar-Miri, Tetrahedron,
10.67 (1H, m, NH), 10.89 (1H, s, NH). 13C NMR (75.4 MHz,
2011, 67, 5693–5699.
DMSO): d 11.5 (CH3), 21.1 (CH2), 41.2 (NCH2), 55.0 (Cspiro), 104.2 16 Y. Zou, Y. Hu, H. Liu and D. Shi, ACS Comb. Sci., 2011, 14, 38–
(C–NO2), 112.7 (C]C–O), 125.7, 126.1, 128.1, 131.4, 131.8, 43.
133.4, 134.5 (Ar), 147.6 (O–C–N), 155.5 (C]C–O), 176.5 (NCO), 17 A. Bazgir, G. Hosseini and R. Ghahremanzadeh, ACS Comb.
177.0 (CO), 182.0 (CO).
Sci., 2013, 15, 530–534.
50-Bromo-3-nitro-2-(propylamino)spiro[benzo[g]chromene-4,30-
indoline]-20,5,10-trione (5q). Red powder, mp: >300 ꢀC, yield
18 G. Mohammadi Ziarani, N. Hosseini Mohtasham,
N. Lashgari, A. Badiei, M. Amanlou and R. Bazl, J.
Nanostruct., 2012, 2, 489–500.
1
3
0.305 g (60%). H NMR (300 MHz, DMSO): d 0.82 (3H, t, JHH
¼
8.4 Hz, CH3), 1.50–1.60 (2H, m, CH2), 2.62–2.80 (2H, m, NCH2), 19 T. He, Q. Q. Zeng, D. C. Yang, Y. H. He and Z. Guan, RSC
6.83 (1H, d, 3JHH ¼ 8.4 Hz, ArH), 7.43 (1H, d, 3JHH ¼ 8.4 Hz, ArH),
Adv., 2015, 5, 37843–37852.
7.53 (1H, s, ArH), 7.55 (1H, d, 3JHH ¼ 7.5 Hz, ArH), 7.62–7.72 (2H, 20 K. Niknam and P. Abolpour, Monatsh. Chem., 2015, 146, 683–
m, ArH), 7.82 (1H, d, 3JHH ¼ 7.2 Hz, ArH), 10.28–10.65 (1H, m, NH),
690.
10.90 (1H, s, NH). 13C NMR (75.4 MHz, DMSO): d 11.4 (CH3), 20.2 21 C. Wang, Y. H. Jiang and C. G. Yan, Chin. Chem. Lett., 2015,
(CH2), 41.0 (NCH2), 56.5 (Cspiro), 101.9 (C–NO2), 112.7 (C]C–O),
26, 889–893.
125.7, 126.1, 128.1, 131.4, 131.8, 133.4, 134.5 (Ar), 142.8 (O–C–N), 22 K. Niknam, A. Piran and Z. Karimi, J. Iran. Chem. Soc., 2016,
155.2 (C]C–O), 173.0 (NCO), 176.5 (CO), 207.0 (CO).
13, 859–871.
23 J. Xie, X. Y. Xing, F. Sha, Z. Y. Wu and X. Y. Wu, Org. Biomol.
Chem., 2016, 14, 8346–8355.
Conflicts of interest
24 P. Muthuraja, S. Prakash, G. Siva, S. Muthusubramanian and
P. Manisankar, ChemistrySelect, 2017, 2, 10071–10075.
25 M. Zhang, Q. Y. Fu, G. Gao, H. Y. He, Y. Zhang, Y. S. Wu and
Z. H. Zhang, ACS Sustainable Chem. Eng., 2017, 5, 6175–6182.
26 A. Hasaninejad, F. Mandegani, M. Beyrati, A. Maryamabadi
and G. Mohebbi, ChemistrySelect, 2017, 2, 6784–6796.
27 T. Liu, Y. H. Lai, Y. Q. Yu and D. Z. Xu, New J. Chem., 2018, 42,
1046–1051.
The authors declare no competing nancial interest.
Acknowledgements
Financial support of this research from Imam Khomeini
International University, Iran is gratefully acknowledged.
28 F. A. Tameh, J. Safaei-Ghomi, M. Mahmoudi-Hashemi and
H. Shahbazi-Alavi, RSC Adv., 2016, 6, 74802–74811.
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