A novel one pot four-component reaction for the efficient synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-3′-carboxylate and trifluoromethylated spiro[indole-3,4′-pyrano[2,3-c]pyrazole] derivatives using recyclable PEG-400

Article abstract of DOI:10.1039/c5nj01448d

A novel, simple and efficient synthetic protocol has been developed for the synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-3′-carboxylate and trifluoromethylated spiro[indole-3,4′-pyrano[2,3-c]pyrazole] derivatives via a one pot, four-component r

Full text of DOI:10.1039/c5nj01448d

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PAPER
A Novel One pot four-component reaction for the efficient synthesis of
spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylate and
trifluoromethylated spiro[indole-3,4'-pyrano[2,3-c]pyrazole] derivatives
using recyclable PEG-400
5
K. Karnakar, K. Ramesh, K. Harsha Vardhan Reddy, B. S. P. Anil Kumar, Jagadeesh Babu Nanubonula
and Y. V. D. Nageswar*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A novel, simple and efficient synthetic protocol has been developed for the synthesis of spiro[indoline-3,4'-pyrano[2,3-
10 c]pyrazole]-3'-carboxylate and trifluoromethylated spiro[indole-3,4'-pyrano[2,3-c]pyrazole] derivatives via a one pot, four-
component reaction using recyclable polyethylene glycol (PEG-400). This new protocol produces novel spiro pyranopyrazole
derivatives in good to excellent yields, with operational simplicity and recycling of PEG-400. The remarkable features of this
methodology are high yields, easy work-up process, and a greener method by avoiding toxic catalyst and hazardous solvents.
Introduction
15
The design of multicomponent reactions (MCRs) is a
significant field of research from the point of view of
combinatorial chemistry.1 Multiꢀcomponent reactions, involving
the intrinsic formation of several bonds in one step, have proven
to be efficient and a powerful tool for the rapid formation of
medium but has been used as
a support for various
50 transformations.9 Polyethylene glycol (PEG) and modified
polyethylene glycol derivatives have been admired as efficient
alternate reaction media, due to their remarkable features like
nonꢀtoxicity, low cost, recoverability, bioꢀdegradability and bioꢀ
compatibility when compared to other “neoteric solvents” such as
55 ionic liquids, superꢀcritical fluids and micellar systems.10 PEG is
most commonly employed as a phaseꢀtransfer catalyst in various
organic transformations.11 PEG is also used as a recyclable
reaction medium in various substitution reactions,12 oxidation and
reduction reactions,13 asymmetric dihydroxylation,14 Heck
60 reaction,15 Wacker reaction,16 Suzuki crossꢀcoupling reaction,17
and partial reductions of alkynes.18
20 complex heterocyclic compounds in recent years.2 MCR strategy
is an important approach utilized by researchers worldwide, to
create several libraries of molecules of miscellaneous biological
activities and has gained prominence in organic, medicinal and
combinatorial chemistry.3 In most of the cases, a single product
25 was obtained from three or more different substrates by reacting
in a wellꢀdefined manner through MCRs.4 These timeꢀefficient
reactions are environmentally benign and atom economic. MCRs
are costꢀeffective since the expensive purification processes as
well as protectionꢀdeprotection steps are nonꢀexistent.5 Although
30 the first MCR dates back to the Strecker synthesis6 of αꢀamino
acid in 1850, the MCR strategy has been utilized successfully in
Hantsch’s synthesis of 1,4ꢀdihydropyridines7 and Robinson’s
synthesis of alkaloid tropinone.8 Consequently, rapid
development is observed in threeꢀ and fourꢀcomponent reactions.
35
Polyethylene glycol (PEG), a biologically acceptable
polymer used widely in drug delivery and in bioconjugates as tool
for diagnostics, has hitherto not been broadly used as a solvent
Fig. 1 Some biologically active important molecules containing
65
Spirooxindole motif.
40 MCP Division, Indian Institute of Chemical Technology,
Hyderabad 500607, India
Fax: +91ꢀ40ꢀ27160512
Potential biological activities and widespread synthetic
utilities of spirocyclic compounds have led to their identification
as a class of heterocyclic compounds, which has created
considerable interest in the pharmaceutical industry and in the
70 diversified field of organic synthesis due to their steric strain
associated with the quaternary carbon.19 Moreover, increased
Eꢀmail: dryvdnageswar@gmail.com
† Electronic Supplementary Information (ESI) available: [details of any
45 supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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DOI: 10.1039/C5NJ01448D
potentiality is generally observed when two or more different
heterocyclic moieties exist in a single molecule.20 Isatin based
spiro compounds or spirooxindoles are important core structures
found in many natural alkaloids as well as synthetic
pharmaceuticals21 such as spirotryprostatin (A & B), NTD609,
Pteropodine and strychnofoline,22 (Fig.1). Recent development of
new protocols for the construction of spirocyclic compounds is an
interesting and challenging task in organic synthesis. Moreover,
dihydropyrano[2,3ꢀc]pyrazole skeleton is an important core unit
5
55
10 to exhibit a wide range of biological activities such as antiꢀ
inflammatory, antimicrobial, anticancer and molluscicidal
activities.23
Scheme
1
Synthesis of spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀ
carboxylate derivatives using PEGꢀ400
It is well known that the fluorine containing heteroꢀ
cyclic compounds often results in dramatic modification of their
15 physical, chemical and biological properties.24 Especially, the
trifluoromethyl group is a key structural unit in many fluorinated
compounds of biological and pharmaceutical significance. As a
result, trifluoromethyl substituted organic molecules exhibit
interesting biological activities with potential for applications in
20 the medicinal and agricultural fields.25 Due to their significant
and diverse biological activities design and widening the scope of
novel methods for the construction of trifluoromethylated
compounds are the challenging task for researchers involved in
this particular field.
Results and Discussion
60
Initially, a model reaction was conducted by taking
isatin (1.0 mmol), malononitrile (1.0 mmol), dimethyl
acetylenedicarboxylate (DMAD) (1.0 mmol) and hydrazine
hydrate (1.0 mmol) at 40ꢀ50 0C and the desired product was
obtained in 30% yield, along with the unreacted starting
65 materials, even after prolonged reaction time (24 h). To explore
the ideal reaction conditions to get maximum product yield
several reactions were conducted. During this optimization study,
it was observed that 100ꢀ110 0C is ideal temperature for the
reaction. After optimizing the experimental conditions, 5ꢀ
70 methoxy isatin (1.0 mmol), malononitrile (1.0 mmol) dimethy
acetylene dicarboxylate(DMAD) (1.0 mmol) and hydrazine
hydrate (1.0 mmol) were reacted in the presence of recyclable
polyethylene glycol (PEG)ꢀ400, resulting in the formation of the
desired spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀcarboxylate
75 derivative in excellent yield (Table 1, Entry 1). To expand the
scope of this protocol, different experiments were conducted with
various substituted isatins and these results were tabulated in
Table 1. It was observed that this protocol was also effective with
Nꢀsubstituted isatins such as NꢀCH3, NꢀPh, NꢀBenzyl isatins
80 resulting in good yields. Apart from malononitrile, reactions with
methyl cyanoacetate and ethyl cyanoacetates were also conducted
resulting in corresponding spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀ
c]pyrazole]ꢀ3'ꢀcarboxylate derivatives in moderate yield. Scope
of the protocol was also extended with diethyl
85 acetylenedicarboxylate under similar reaction conditions and the
results are summarized in Table 1. This protocol was also
extended a step further, using phenyl hydrazine in place of
hydrazine component, providing the desired spiro[indolineꢀ3,4'ꢀ
pyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀcarboxylate derivatives in good yield.
90
25
Herein, we sought to develop a single structural
framework by combining spirooxindole, pyran, and pyrazole
motifs for emergent interest in designing novel polycyclic
heterocycles by combining various structurally diverse motifs.
Recently, Choudhury et al., developed spiro[indolineꢀ3,4'ꢀ
30 pyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀcarboxylate derivatives in the presence
of triethylamine and ethanol.26 Song et al., synthesized
trifluoromethylated spiro pyranopyrazole derivatives from isatin,
malononitrile,
hydrazine
hydrate
and
ethyl
4,4,4ꢀ
trifluoroacetoacetate as a starting materials.27 Very recently, Pore
35 et al., reported novel spiro pyranopyrazole derivatives from
isatin, malononitrile, hydrazine hydrate and dialkyl
acetylenedicarboxylates in the presence of ethanol and water
mixture.28
Despite the importance of these reported protocols,
40 many suffer from drawbacks such as use of expensive reagents,
prolonged reaction times, harsh reaction conditions, cumbersome
product isolation procedures, and low yields. Sustainable
chemistry has gained prominence recently due to its
environmental compatibility. To explore a mild, efficient and
45 environmentally benign recyclable synthetic protocol, we have
demonstrated the synthesis of Pyrazolo[3,4ꢀb]quinoline
derivatives in the presence of PEGꢀ400.29 In our continued quest
for the development of ecoꢀfriendly protocols30 and considering
the significant biological activities of spirooxindoles, herein, we
50 report a oneꢀpot fourꢀcomponent reaction for the synthesis of
novel spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀcarboxylate
derivatives using recyclable PEGꢀ400 as a reaction medium
(Scheme 1).
Scheme
2
Synthesis of trifluoromethylated spiro[indolineꢀ3,4'ꢀ
pyrano[2,3ꢀc]pyrazole] derivatives using PEGꢀ400
95
2
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DOI: 10.1039/C5NJ01448D
b
R3
R4
Yield (%)
S.No.
13
1
3
Product
NH
Time(h)
3
We further synthesized a variety of trifluoromethylated
spiro[indoleꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole] derivatives (Scheme 2)
using ethyl 4,4,4ꢀtrifluoroacetoacetate in place of dialkyl
acetylenedicarboxylate affording products in good yields. In
continuation of further explorations of this method, several
reactions were also conducted with various substituted isatins and
these results were tabulated in Table 2. All these products were
characterized by spectroscopic and analytical methods.
O
O
COOMe
NH2NH2.H2O
Me
86
CN
NC
O
O
NH
N
H
N
H2N
O
O
NH
O
COOEt
5
14
Et
3
82
CN
Ph NHNH2
NC
N
N
H
N
H2N
O
Ph
Me
O
N
O
COOMe
NH2NH2.H2O
NH2NH2.H2O
15
16
CN
CN
Me
Me
3
3
83
81
NC
O
O
NH
Ph
N
N
H2N
O
O
Me
10 Table 1: Synthesis of spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀ
carboxylate derivatives using PEGꢀ400a .
O
N
O
COOMe
NC
NH
N
N
H2N
Ph
NH
O
F
F
O
COOMe
17
18
Ph NHNH2
Ph NHNH2
Me
Me
3.5
78
84
CN
CN
NC
O
N
N
H
N
H2N
O
Ph
O
NH
Me
Me
O
COOMe
3
O
NC
N
N
H
N
Ph
H2N
O
NH
O
O
COOEt
19
20
NH2NH2.H2O
NH2NH2.H2O
Et
3
3
87
86
CN
NC
O
NH
N
H
N
H2N
O
NH
O
O
COOMe
COOMe
Me
MeOOC
H2N
O
NH
N
H
N
O
a
Reaction conditions: Isatin (1.0 mmol), Malononitrile (1.0 mmol),
Dialkyl acetylene dicarboxylate (1.0 mmol), Hydrazine hydrate (1.0
20 mmol) and PEGꢀ400 at 110ꢀ110 0C. b Isolated yields.
Table 2: Synthesis of trifluoromethylated spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀ
c]pyrazole] derivatives using PEGꢀ400a .
15
25
a Reaction conditions: Isatin (1.0 mmol), Malononitrile (1.0 mmol), Ethyl
4,4,4ꢀtrifluoroacetoacetate (1.0 mmol), Hydrazine hydrate (1.0 mmol) and
PEGꢀ400 at 110ꢀ110 0C. b Isolated yields.
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A plausible mechanism was proposed for the general
of spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀ
synthesis
carboxylates using this present protocol in scheme 3. Initially,
Knoevenagel condensation occurs between isatin and
malononitrile, forming the adduct (A), which reacts with the
pyrazolone intermediate (B) formed by the condensation of
dialkyl acetylene dicarboxylate and hydrazine hydrate. This
crucial step involves Michael addition of B onto intermediate (A),
followed by enolization and ring closure providing the desired
5
10 product (C) as reported in the literature and it was further
supported by Xꢀray crystallography 31 (Figure 2).
25
Scheme 3: Plausible mechanism
Conclusions
In conclusion, we have developed a simple and highly
efficient greener approach for the oneꢀpot, fourꢀcomponent
30 synthesis
of
spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀ
carboxylate and trifluoromethylated spiro[indoleꢀ3,4'ꢀpyrano[2,3ꢀ
c]pyrazole] derivatives by using PEGꢀ400 as inexpensive,
biodegradable, and reusable reaction medium. This novel
protocol generates five new bonds in one sequence. The salient
35 features of this methodology are efficiency, environmentally
benign nature and high yield, wider scope of substrate choice,
ease of product purification, nonꢀinvolvement of hazardous
catalysts or toxic solvents.
Experimental Section
40 General procedure for the synthesis of spiro[indoline-3,4'-
pyrano[2,3-c]pyrazole]-3'-carboxylate / trifluoromethylated
spiro[indole-3,4'-pyrano[2,3-c]pyrazole] derivatives:
To a stirred solution of polyethylene glycol (PEG)ꢀ400
(5 mL), isatin (1.0 mmol), and malononitrile (1.0 mmol) were
45 added and stirred at 100 ꢀ 110 °C for 20 min. Then a solution of
hydrazine hydrate (1.0 mmol) and dialkyl acetylenedicrboxylate /
ethyl 4,4,4ꢀtrifluoroacetoacetate (1.0 mmol) in PEGꢀ400 was
added to it. The whole reaction mixture was stirred until the
reaction was complete as indicated by TLC. After completion of
50 the reaction, ether (5mL) was added and stirred for a 5ꢀ10 mins
and cooled to ꢀ50 o C. At this temperature PEG became solid and
the ether layer saturated with product was separated and
evaporated. The crude product was purified by column
chromatography, using hexane and EtOAc as eluent to provide
55 the title compound. The recovered PEG was reused for further
cycles. For the NMR spectroscopic analysis the title compound
was dissolved in the ratio of solvents Acetoneꢀd6 and DMSOꢀd6 is
4:1.
Figure 2. ORTEP diagram of compound Table 1 Entry 3 with the atomꢀ
15 numbering scheme. Displacement ellipsoids are drawn at the 30%
probability level and H atoms are shown as small spheres of arbitrary
radii. The solvent of crystallization acetone was also included in the
crystal lattice. The asymmetric unit containing 1:1 stoichiometric ratio of
compound and acetone is shown. Only major component of the
20 disordered atoms is shown for clarity.
Characterization of selected compounds:
60
Methyl
6'ꢀaminoꢀ5'ꢀcyanoꢀ5ꢀmethoxyꢀ2ꢀoxoꢀ2'Hꢀ
spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀcarboxylate (Table
1, Entry 1): IR (KBr) 3445, 3275, 3185, 2933, 2192, 1710,
1635, 1494, 1222, 1089 cmꢀ1; 1H NMR (300 MHz, Acetoneꢀ
4
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Weinhein, 2006; (d) A.; de Meijere, P. von Zezschwitz and S. Brase,
Acc. Chem. Res. 2005, 38, 413. and references cited therein.
d6+DMSOꢀd6) δ 9.83 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.80ꢀ6.76
(m, 1H), 6.74 – 6.70 (m, 1H), 6.67 (s, 2H), 3.69 (s, 3H), 3.52 (s,
3H) ppm. 13C NMR (75 MHz, Acetoneꢀd6+DMSOꢀd6) δ 177.3,
161.3, 158.0, 155.9, 135.8, 135.3, 129.2, 128.7, 117.5, 113.4,
110.6, 109.7, 101.1, 58.7, 55.0, 51.0, 48.3 ppm. ESIꢀMS: 368
(M+H) +; C17H14N5O5.
60 3. (a) H. Bienayme, C. Hulme, G.; Oddon and P. Schmitt, Chem. Eur. J.
2000, 6, 3321ꢀ3329; (b) G. Balme, E. Bossharth and N. Monteiro,
Eur. J. Org. Chem. 2003, 21, 4101ꢀ4111; (c) S. Brase, C. Gil and K.
Knepper, Bioorg. Med. Chem. 2002, 10, 2415ꢀ2437; (d) A. Domling
and I. Ugi, Angew. Chem. Int. Ed. 2000, 39, 3168ꢀ3210.
65 4. (a) P. A. Tempest, Curr. Opin. Drug Discovery 2005, 8, 776; (b) H.
Fujioka, K. Murai, O. Kubo, Y. Ohba and Y. Kita, Org. Lett. 2007, 9,
1687; (c) N. M. Evdokimov, A. S. Kireev, A. A. Yakovenko, M. Y.
Antipin, I. V. Magedov and A. Kornienko, J. Org. Chem. 2007, 72,
3443; (d) X. S. Wang, Q. Li, J. R. Wu, Y. L. Li, C. S. Yao, S. J. Tu,
5
Methyl 6'ꢀaminoꢀ5ꢀchloroꢀ5'ꢀcyanoꢀ2ꢀoxoꢀ2'Hꢀspiro[indolineꢀ
3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀcarboxylate (Table 1, Entry 2):
IR (KBr) 3442, 3275, 3180, 2933, 2185, 1710, 1622, 1494, 1222,
1
10 1089 cmꢀ1; H NMR (300 MHz, Acetoneꢀd6+DMSOꢀd6) δ 10.60
(s, 1H), 7.26ꢀ7.23 (m, 1H), 7.10ꢀ7.14 (m, 3H), 6.97 (d, J = 8.3
Hz, 1H), 3.55 (s, 3H) ppm. 13C NMR (75 MHz, Acetoneꢀ
d6+DMSOꢀd6) δ 177.2, 161.2, 157.9, 156.3, 141.5, 136.1, 128.9,
128.4, 126.3, 124.1, 117.6, 110.7, 100.3, 57.1, 51.2, 48.0 ppm.
15 ESIꢀMS: 372 (M+H) +; C16H11ClN5O4.
70
Synthesis 2008, 1902.
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Wender, S. T. Handy and D. L. Wright, Chem. Ind. 1997, 765.
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148; (b) A. Haimov, R. Neumann, Chem. Commun. 2002, 876–877;
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(d) T. J. Dickerson, N. N. Reed and K. D. Janda, Chem. Rev. 2002,
Methyl
6'ꢀaminoꢀ5ꢀbromoꢀ5'ꢀcyanoꢀ2ꢀoxoꢀ1'ꢀphenylꢀ1'Hꢀ
spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀcarboxylate (Table
1, Entry 3): IR (KBr) 3444, 3273, 3180, 2930, 2182, 1715, 1622,
1494, 1220, 1085 cmꢀ1; 1H NMR (300 MHz, Acetoneꢀd6+DMSOꢀ
20 d6) δ 10.34 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.64 (t, J = 8.1 Hz,
1H), 7.34 (t, J = 7.5 Hz, 1H), 7.19ꢀ7.16 (m, 3H), 7.10 (d, J = 7.1
Hz, 1H), 6.98ꢀ6.92 (m, 2H), 3.48 (s, 3H) ppm. 13C NMR (75
MHz, Acetoneꢀd6+DMSOꢀd6) δ 177.8, 160.6, 159.0, 142.4,
138.3, 137.5, 134.0, 129.5, 128.7, 128.1, 125.4, 124.0, 122.4,
25 122.0, 121.8, 117.2, 109.5, 59.2, 51.0, 48.5 ppm. ESIꢀMS: 492
(M+H) +; C22H15BrN5O4.
80
85
90
102, 3325–3344.
10. J. Chen, S. K. Spear, J. G. Huddleston and R. D. Rogers, Green.
Chem., 2005, 7, 64
11. K. Z. Andrade and L. M. Alves, Curr. Org. Chem. 2005, 9, 195.
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Synth. Commun., 1987, 17, 1569.
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Reddy, Org. Lett., 2002, 4, 4399.
16. A. Haimov and R. Neumann, Chem. Commun., 2002, 876.
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Shyamsundar, Tetrahedron Lett. 2004, 45, 2421.
95 19. S. T. Hilton, T. C. T. Ho, G. Pljevalijcic and K. Jones, Org. Lett.
2000, 17, 2639.
20. R. Balini, G. Bosica, M. Conforti, R. Magi, A. Mazzacannt, P. Righi
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21. (a) T. H. Kang, K. Matsumoto, Y. Murakami, H. Takayama, M.
Methyl
6'ꢀaminoꢀ5'ꢀcyanoꢀ5ꢀmethoxyꢀ2ꢀoxoꢀ1'ꢀphenylꢀ1'Hꢀ
spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ3'ꢀcarboxylate (Table
1, Entry 5): IR (KBr) 3440, 3278, 3180, 2933, 2185, 1710, 1622,
30 1494, 1222, 1089 cmꢀ1; 1H NMR (300 MHz, Acetoneꢀd6+DMSOꢀ
d6) δ 9.93 (s, 1H), 7.43 (m, 3H), 7.28 (m, 2H), 6.91 (d, J = 8.4
Hz, 1H), 6.82ꢀ6.79 (m, 1H), 6.74 – 6.70 (m, 1H), 6.64 (s, 2H),
3.71 (s, 3H), 3.52 (s, 3H) ppm. 13C NMR (75 MHz, Acetoneꢀ
d6+DMSOꢀd6) δ 177.2, 160.4, 159.9, 155.5, 146.3, 138.0, 137.0,
100
Kitajima, N. Aimi and H. Watanabe, Eur. J. Pharmacol. 2002, 444,
39; (b) S. Edmondson, S. Danishefsky, L. Seppꢀlorenzinol and N.
Rosen, J. Am. Chem. Soc. 1999, 121, 2147.
35 135.8, 135.0, 129.3, 127.9, 121.6, 117.1, 113.2, 110.7, 109.6,
+
99.1, 59.0, 55.0, 50.6, 48.6 ppm. ESIꢀMS: 444 (M+H)
C23H18N5O5.
;
22. (a) C. B. Cui, H. Kakeya and H. Osada, Tetrahedron 1996, 52,
12651–12666; (b) C. B. Cui, H. Kakeya and H. Osada, J. Antibiot.
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B. Lakshminarayana, A. Goh, R. Suwanarusk, T. Jegla, E. K.
Schmitt, H.ꢀP. Beck, R. Brun, F. Nosten, L. Renia, V. Dartois, T. H.
Keller, D. A. Fidock, E. A. Winzeler and T. T. Diagana, Science
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Naturforsch. 2006, 61, 1–5; (b) E. H. Elꢀ Tamany, F. A. ElꢀShahed
and B. H. Mohamed, J. Serb. Chem. Soc. 1999, 64, 9–18; (c) J. L.
Wang, D. Liu, Z. J. Zhang, S. Shan, X. Han, S. M. Srinivasula, C. M.
Croce, E. S. Alnemri and Z. Huang, Proc. Natl. Acad. Sci. U.S.A.
2000, 97, 7124–7129; (d) F. M. Abdelrazek, P. Metz, N. H. Metwally
and S. F. ElꢀMahrouky, Arch. Pharm. 2006, 339, 456–460; (e) F. M.
Abdelrazek, P. Metz, O. Kataeva, A. Jaeger and S. F. ElꢀMahrouky,
Arch. Pharm. 2007, 340, 543–548.
24. R. E. Bank, Organofluorine Chemistry: Principles and Commercial
Application, Plenum and Elsevier, New York, 1994. R. E. Filler,
Organic Chemistry in Medicinal Chemistry and Biochemical
Applications, Plenum and Elsevier, Amsterdam, 1993. (a) B. E.
Smart, J. Fluorine Chem., 2001, 109, 3–11; (b) N. Iwai, R. Sakai, S.
Tsuchida, M. Kitazume and T. Kitazume, J. Fluorine Chem., 2009,
130, 434–437; (c) W. R. Dolbier Jr., J. Fluorine Chem., 2005, 126,
157–163;
6'ꢀAminoꢀ5ꢀmethoxyꢀ2ꢀoxoꢀ3'ꢀ(trifluoromethyl)ꢀ2'Hꢀ
105
110
115
120
125
spiro[indolineꢀ3,4'ꢀpyrano[2,3ꢀc]pyrazole]ꢀ5'ꢀcarbonitrile (Table
40 2, Entry 1): IR (KBr) 3470, 3311, 3175, 3105, 2205, 1711, 1648,
1501, 1402, 1336, 1146, 1018 cmꢀ1. 1H NMR (300 MHz, acetoneꢀ
d6) δ= 9.51 (s, 1H), 6.94ꢀ6.83 (m, 3H), 6.66 (s, 2H), 3.72 (s, 3H)
ppm. 13C NMR (75 MHz, acetoneꢀd6): δ 49.6, 56.9, 60.6, 112.1,
113.2, 116.3, 118.6, 123.2, 130.5, 135.6, 136.7, 136.8, 158.1,
45 163.0, 178.7 ppm. ESIꢀMS: 378 (M+H) +; C16H11F3N5O3.
Acknowledgments
We thank CSIR, New Delhi, India, for fellowships to K.K,
K.H.V.R, B.S.P, K. D. and UGC for fellowship to K.R.
50 References
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New Journal of Chemistry
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K. A. Undale; Tetrahedron Lett. 2013, 54, 5876.
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31. Crystal data for Table 1 Entry 3: The compound was crystallized
from acetone solvent using the slow evaporation method. The acetone
was included in the crystal lattice. The asymmetric unit contains the
compound and acetone in 1:1 ratio. Molecular formula,
C22H14BrN5O4·C3H6O, M = 550.37, colourless block, 0.42 x 0.38 x
0.29 mm3, triclinic, space group P (No. 2), a = 10.107(3), b =
11.058(3), c = 12.667(3)Å, α = 71.325(4), β = 71.161(4), γ =
78.620(4)°, V = 1262.4(6) Å3, Z = 2, Dc = 1.448 g/cm3, F000 = 560,
CCD area detector, MoKα radiation, λ = 0.71073 Å, T = 293(2)K,
35
40
45
2θmax = 56.56°, 14880 reflections collected, 5935 unique (Rint
=
0.022), Final GooF = 1.038, R1 = 0.0468, wR2 = 0.1409, R indices
based on 4013 reflections with I >2σ(I) (refinement on F2), 378
parameters, 34 restraints, ꢁ = 1.673 mmꢀ1, minimum and maximum
residual density, ꢀ0.24 and 0.67 e/Å3. CCDC 982356 contains
supplementary crystallographic data for the structure. These data can
be
obtained
free
of
charge
at
www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44(0) 1223 336 033; email:
deposit@ccdc.cam.ac.uk. The full details of crystal data collection
and refinement was provided in supporting information.
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 7
New Journal of Chemistry
View Article Online
DOI: 10.1039/C5NJ01448D
Graphical Abstract
A Novel One pot four-component reaction for the efficient synthesis
of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylate and
trifluoromethylated spiro[indole-3,4'-pyrano[2,3-c]pyrazole]
derivatives using recyclable PEG-400.
K. Karnakar, K. Ramesh, K. Harsha Vardhan Reddy, B. S. P. Anil Kumar, Jagadeesh
Babu Nanubonula and Y. V. D. Nageswar*
A novel, simple and efficient synthetic protocol has been developed for the synthesis of
spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylate and trifluoromethylated spiro[indole-
3,4'-pyrano[2,3-c]pyrazole] derivatives via a one pot, four-component reaction using recyclable
PEG-400.
R2
R1
N
O
COOR4
NH2NH2.H2O
R3
NH
N
H2N
R1
O
O
COOR4
COOR4
PEG-400
R3
R1
R2
O
100-1100C
CN
N
R2
N
O
COOR4
R3
Ph NHNH2
R1 =CH3, OCH3, Cl, Br, F; R2 = H, CH3, Ph, Benzyl
R3 = CN, COOCH3, COOEt; R4 = CH3, Et
N
N
Ph
H2N
R1
O
R2
N
O
O
O
O
R3
CF3
NH
PEG-400
100-1100C
R3
R1
NH2NH2.H2O
O
CN
F3C
OEt
N
R2
N
H2N
O