One pot four-component reaction for the efficient synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-3′-carboxylate derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.07.117

A novel one pot protocol has been developed to synthesize various spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-3′-carboxylate derivatives from the four-component reaction of isatin, malononitrile, hydrazine derivatives and dialkyl acetylenedicarboxylates. In this process two C-C bonds, two C-N bonds and one C-O bond have formed in one pot. The notable features of this protocol are simple and environmentally benign reaction condition, easy isolation of products, applicable to a wide range of readily available starting materials and good yields.

Full text of DOI:10.1016/j.tetlet.2013.07.117

Accepted Manuscript
One pot four-component reaction for the efficient synthesis of spiro[indo‐
line-3,4’-pyrano[2,3-c]pyrazole]-3’-carboxylate derivatives
Suman Pal, Nasim Khan, Shaik Karamthulla, Sk Jahir Abbas, Lokman H.
Choudhury
PII:
S0040-4039(13)01285-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.117
TETL 43315
Reference:
To appear in:
Tetrahedron Letters
Please cite this article as: Pal, S., Khan, N., Karamthulla, S., Abbas, S.J., Choudhury, L.H., One pot four-component
reaction for the efficient synthesis of spiro[indoline-3,4’-pyrano[2,3-c]pyrazole]-3’-carboxylate derivatives,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.117
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Graphical abstract
Leave this area blank for abstract info.
One pot four-component reaction for the efficient
synthesis of spiro[indoline-3,4'-pyrano[2,3
c]pyrazole]-3'-carboxylate derivatives
Suman Pal, Md. Nasim Khan, Shaik Karamthulla, Sk Jahir Abbas
and Lokman H. Choudhury*
1

One pot four-component reaction for the efficient synthesis of
spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylate
derivatives
Suman Pal, Md. Nasim Khan, Shaik Karamthulla, Sk Jahir Abbas
and Lokman H. Choudhury*
Department of Chemistry, Indian Institute of Technology Patna, Patna-800 013, INDIA
E-mail: lokman@iitp.ac.in ; Tel: +916122552038 ; Fax: +916122277383
Abstract: A novel one pot protocol has been developed to synthesize various spiro[indoline-
3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylate derivatives from the four-component reaction of
isatin, malononitrile, hydrazine derivatives and dialkyl acetylenedicarboxylates. In this
process two C-C bonds, two C-N bonds and one C-O bond have formed in one pot. The
notable features of this protocol are simple and environmentally benign reaction condition,
easy isolation of products, applicable to a wide range of readily available starting materials
and good yields.
Keywords: Multicomponent reaction, Domino reaction, Isatin, Malononitrile, Hydrazine
hydrate, Dialkyl acetylenedicarboxylate.
Spirocyclic compounds are considered as important building blocks for the easy access of a
variety of cyclic products by rearrangement reaction due to their steric strain associated with
the quaternary carbon.1 Development of new methods for the construction of spirocyclic
compounds is an interesting and challenging task in organic synthesis.2 Isatin, a bioactive
natural product having a benzylic ketone and a -lactam moiety attached with the arene ring
is a widely used building block for the construction of spirooxindole derivatives.3 Isatin based
spiro compounds or spirooxindoles are important subunit found in many natural products as
well as in synthetic pharmaceuticals such as spirotryprostatin B,4 NITD609,5 cyclopiamine
B,6 strychnofoline,7 elacomine,8 horsfiline9 etc. (Fig. 1). Due to their significant and varied
biological activities design and development of novel methods for the construction of
2

functionalized spirooxindoles have drawn remarkable interest from the synthetic organic as
well as medicinal chemists.10
Figure 1. Some biologically important molecules containing spirooxindole motif
From the literature we realized that dihydropyrano[2,3-c]pyrazole scaffolds exhibit a wide
range of biological activities such as antimicrobial11, anticancer12, anti-inflammatory13 and
molluscicidal activities.14,15Considering their clinical significance, development of efficient
methods for the synthesis of dihydropyrano[2,3-c]pyrazole scaffolds have gained
considerable attention from the synthetic community.16 Although a number of methods are
known for the construction of dihydropyrano[2,3-c]pyrazole and spirooxindole derivatives,
however to our best of knowledge there is no method reported for the one-pot synthesis of
spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylate
derivatives
from
the
multicomponent reaction of isatin, malononitrile, hydrazine hydrate and dialkyl
acetylenedicarboxylates. In continuation of our efforts towards the development of
functionalized heterocycles using multicomponent domino reactions17 we envisioned that
spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylate derivatives could be synthesized
by four-component reaction of isatin, malononitrile and hydrazine hydrate and dialkyl
acetylenedicarboxylate in presence of a base (Scheme 1).
3

Scheme 1. Proposed strategy for the synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-
3'-carboxylate derivatives
Recently we have demonstrated that the four-component reaction of amine, aromatic
aldehyde, dimethyl acetylenedicarboxylate (DMAD) and malononitrile in presence of PEG as
medium provides highly functionalized dihydropyridines and exhibit DNA cleavage
properties.18 Similarly, we have reported multicomponent reaction of malononitrile, aldehyde
and thiols to provide highly functionalized amino pyridines with interesting photophysical
properties.19 In continuation of our work on multicomponent reactions, and considering the
significant biological activities of spirooxindoles, we turned our attention towards isatin
based MCRs.
For our initial investigation the reaction of isatin, malononitrile, hydrazine hydrate and
diethyl acetylenedicarboxylate in ethanol was chosen as a model reaction. At room
temperature and in the absence of any base or catalyst we could not isolate our desired four-
component product even after 12 h stirring. After 24 h of stirring very trace amount of
corresponding product was obtained. Next, the same set of reaction was performed in
presence of one equivalent of mild base K2CO3. Within 8 h the corresponding four-
component product 5a was isolated in 52% yield. Product 5a was characterized by usual
spectroscopic techniques and elemental analysis. Encouraged by this result we attempted to
optimize the yield of the reaction by screening the same set of reaction with various widely
explored organic bases such as DBU, DABCO, DMAP and Et3N and the results are
summarized in Table 1. Among all the screened bases Et3N was found superior with respect
to reaction time and yield obtained. The same reaction was also tested using varying the
4

amount of Et3N and one equivalent was found to be the optimum amount required for this
reaction. Then we investigated the influence of different organic solvents in this reaction.
Among the various solvents such as EtOH, CH2Cl2, CH3CN, THF and DMF, EtOH was
found the best solvent for this multicomponent reaction.
Table 1
Optimization of reaction conditiona
Entry
Base
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
THF
Time (h)
Yield(%)b
trace
52
1
2
3
4
5
6
7
8
9
10
No catalyst
K2CO3
DBU
24
8
8
8
8
6
6
6
6
6
36
DABCO
DMAP
Et3N
48
44
79
Et3N
trace
56
Et3N
Et3N
CH3CN
58
Et3N
DMF
51
aReaction conditions: Isatin (1.0 mmol), malononitrile (1.0 mmol), hydrazine
hydrate (1.1 mmol), diethyl acetylenedicarboxylate (1.1 mmol), and base (1.0
mmol) at rt. b Isolated yield
With the optimized reaction condition in hand, the substrate scope, generality and versatility
of this multicomponent reaction was investigated. A series of substituted isatin derivatives
such as 5-Cl, 5-Br, 1-Me, 1-Ph, 7-Cl were found applicable for the synthesis of corresponding
spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylates in good yields. Similar to
malononitrile, ethyl cyanoacetate also participated in this multicomponent reaction to afford
the corresponding spirooxindole derivatives in good yields. We also tested the variability of
5

diethyl acetylenedicarboxylate by replacing it with dimethyl acetylenedicarboxylate under the
similar reaction condition and the results are summarized in Table 2. Next, applicability of
phenyl hydrazine in place of hydrazine hydrate was examined under the optimized reaction
condition. The compounds 5r and 5s were obtained in good yields using phenyl hydrazine in
place of hydrazine hydrate. It is evident from these results that the present protocol is highly
versatile as all the four starting materials can be varied independently and bond-forming
efficiency, i.e., total number of new bonds formed in one pot is five for this multicomponent
1
reaction. All the products were fully characterized by IR, H NMR, 13C NMR spectra and by
elemental analysis. The molecular structure of a representative compound 5i was established
unambiguously by single crystal X-ray diffraction (Fig. 2). The compound 5i was
recrystallized from the mixture of MeOH and MeCN and the crystal belongs to Triclinic, P-1
space group with Z = 2. In this molecule intra molecular hydrogen bonding has been
observed between the CO of ethyl ester moiety and the NH2 of the pyran ring due to their
close proximity. Similarly intermolecular hydrogen bonding also exists between the NH2
present in the pyran ring and the amide carbonyl (CONH) of oxindole moiety. The crystal
structure (5i) also shows the inclusion of solvent molecule (MeOH) and showing hydrogen
bonding with the 5i (Fig. 3). It is noteworthy to mention that in all the cases the reactions
were found remarkably clean except a few cases all the products were purified by
recrystallization.20
Table 2
Synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-carboxylate derivativesa
Entry
Time(hr)
Product
Yieldb
(%)
1
2
3
6

1
2
3
4
5
6
6
79
70
68
71
68
66
10
10
8
10
10
7
6
84
7

8
6
6
8
8
8
8
83
80
79
76
78
74
9
10
11
12
13
8

14
15
16
10
10
10
64
62
65
17
10
66
aReaction conditions: Isatin (1.0 mmol), malononitrile or its derivative (1.0 mmol), hydrazine
hydrate (1.1 mmol), dialkyl acetylenedicarboxylate (1.1 mmol), and Et3N (1.0 mmol) in
ethanol at rt. bisolated yield.
9

Figure 2. ORTEP diagram of compound 5i.MeOH (CCDC 950299)
Figure 3. The hydrogen bonding pattern in molecule 5i
On the basis of the above results a plausible reaction mechanism is shown in Scheme 2.
We believe that the initial step is formation of intermediate A by Knoevenagel condensation
of 1 and 2. Next step is the formation of pyrazolone B from the reaction of dialkyl
acetylenedicarboxylate (3) and hydrazine hydrate (4). Then the intermediate B undergoes
10

Michael addition to A in the presence of a base followed by enolization affording
intermediate C which undergoes intramolecular cyclization to form D. In the final step D
undergoes tautomerization and transforms into the desired product E.
Scheme 2. Proposed mechanism for the synthesis of spiro[indoline-3,4'-pyrano[2,3-
c]pyrazole]-3'-carboxylate derivatives.
In conclusion, we have developed a simple and efficient four-component domino reaction
mediated by Et3N for the easy access of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3'-
carboxylate derivatives under mild reaction condition from the readily available starting
materials. Considering the presence of spirooxindole and pyranopyrazole moiety in the
products, this type of molecule may become useful in medicinal chemistry. Further efforts to
see the scope and diversity of this multicomponent domino is currently underway and will be
reported in due course.
Acknowledgements
L.H.C. is grateful to DST, New Delhi for financial assistance under the fastrack scheme with
sanction No. SR/FT/CS-042/2009. S.P. is thankful to UGC for his research fellowship.
11

M.N.K. and S.K. are grateful to CSIR for their research fellowships. The authors are also
grateful to SAIF, Panjab University, SAIF, IIT Madras and IIT Kanpur for providing
analytical facilities for characterization of compounds.
Supplementary data
Supplementary data associated with this article can be found in the online version at
doi:xxxxxxxxxxxxxx
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20. General procedure for the synthesis of spiro[indoline-3,4'-pyrano[2,3-
c]pyrazole]-3'-carboxylate derivatives: A mixture of isatin (1.0 mmol),
malononitrile or its derivative (1.0 mmol) and Et3N (1.0 mmol) in 3.0 mL ethanol
were stirred at room temperature for 0.5h. Then a solution of hydrazine hydrate
(1.1 mmol) and dialkyl acetylenedicarboxylate (1.1 mmol) in 2.0 mL ethanol was
added to it. The whole solution was stirred at room temperature for stipulated time
as indicated in Table 2. The progress of the reaction was monitored by TLC. After
completion of the reaction, the resulting precipitates were collected by filtration
and the crude product was recrystallized from the mixture of methanol and
acetonitrile (7:3). In some cases the crude product were purified by column
chromatography using silica gel (60-120 mesh) and 50% ethyl acetate in hexane
as eluent.
14

Graphical abstract
Leave this area blank for abstract info.
One pot four-component reaction for the efficient
synthesis of spiro[indoline-3,4'-pyrano[2,3
c]pyrazole]-3'-carboxylate derivatives
Suman Pal, Md. Nasim Khan, Shaik Karamthulla, Sk Jahir Abbas
and Lokman H. Choudhury*