Indium trichloride catalysed domino reactions of isatin: A facile access to the synthesis of spiro(indoline-3,4′-pyrano[2,3- c ]pyrazol)-2-one derivatives

Article abstract of DOI:10.1055/s-0033-1340666

A versatile high-yielding indium trichloride mediated one-pot regioselective synthesis of spiroxindoles via domino one-pot, three-component reaction of isatins, pyrazoles, and (E-)-N-methyl-1-(methylthio)-2- nitroethenamine is described. This reaction presumably occurs via domino Knoevenagel condensation-?Michael addition-intramolecular O-cyclization sequence. The salient features of the methodology are its clean reaction conditions, the eco-friendly medium, low cost, easy isolation, and excellent yields without column chromatographic purification. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340666

708▌
LETTER
lIenttedr ium Trichloride Catalysed Domino Reactions of Isatin: A Facile Access to
the Synthesis of Spiro(indoline-3,4′-pyrano[2,3-c]pyrazol)-2-one Derivatives
Synthesis of Spiropyranopyrazoles
Nataraj Poomathi, Jayabal Kamalraja, Sivakalai Mayakrishnan, D. Muralidharan, Paramasivan T. Perumal*
Organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, Chennai 6000 20, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received: 21.11.2013; Accepted: 31.12.2013
their relatively low toxicity, their stability in air and water
Abstract: A versatile high-yielding indium trichloride mediated
at ambient temperature, and the fact that they can be han-
one-pot regioselective synthesis of spiroxindoles via domino one-
dled safely without any apparent toxicity.
pot, three-component reaction of isatins, pyrazoles, and (E-)-N-
methyl-1-(methylthio)-2-nitroethenamine is described. This reac-
tion presumably occurs via domino Knoevenagel condensation–
Michael addition–intramolecular O-cyclization sequence. The sa-
often enhances the biological profile remarkably, we con-
lient features of the methodology are its clean reaction conditions,
the eco-friendly medium, low cost, easy isolation, and excellent
Guided by the observation that the presence of two or
more different heterocyclic moieties in a single molecule
tinued our work on the synthesis of novel heterocycles12
employing domino protocols. Recently, Shestopalov et
al.13 reported the synthesis of spiro(indoline-3,4′-pyra-
no[2,3-c]pyrazol)-2-ones via one-pot, two-step reaction
of isatin, hydrazine, malanonitile, and β-keto ester cata-
lyzed by Et3N.
yields without column chromatographic purification.
Key words: domino reaction, spiroxindole, indium trichloride,
Michael addition, regioselective synthesis
Considering the above reports, the development of new
and simple synthetic methods for the efficient preparation
of the spiroxindoles will be a beneficial and interesting
challenge as a part of our research study, which aims to
develop new selective and environmentally friendly
methodologies for the preparation of heterocyclic com-
pounds.14 In this paper, we report a rapid, one-pot synthe-
sis of spiro(indoline-3,4′-pyrano[2,3-c]pyrazol)-2-one
derivatives through domino Knoevenagel condensation–
Michael addition–intramolecular O-cyclization sequence
of reactions in a single step with improved efficiency al-
lowing the rapid isolation of products. In addition, we de-
scribe the optimum reaction conditions in terms of rate
and yield.
Multicomponent reactions (MCR) are chemical transfor-
mations in which three or more starting materials combine
together via a one-pot procedure to give a final complex
product. Such reactions have emerged as powerful and
bond-forming efficient tools in organic, combinatorial,
and medicinal chemistry for their facileness and efficien-
cy as well as their economy and ecology in organic syn-
thesis.1 In the past decade, there have been tremendous
developments in three- and four-component reactions and
significant efforts are made to develop new MCR.2
The spiroxindole system is the core structure of many
pharmacological agents, natural alkaloids,3 and their de-
rivatives and occupies a special place in organic and me-
dicinal chemistry because these compounds are well-
known as microtubule assembly inhibitors (spirotrypros-
tatin A and B),4 muscarinic M1, and serotonin receptor
modulators (pteropodine and isopteropodine),5 and non-
peptidyl growth-hormone secretagogues (MK-0677).6
Considerable attention has been focused on the develop-
ment of new methodologies to synthesize novel spiroxin-
dole ring systems because of their interesting biological
and pharmacological properties, such as vasodilatory, hy-
poglycemic, anti-inflammatory, analgesic, and antipyretic
activities.7 Some indole and oxindoles that were fused
with different heterocycles have recently received atten-
tion due to their useful biological properties.8 These fused
heterocyclic systems seem to be promising candidates for
biological responses since they incorporate both indole
and other heterocycles moieties simultaneously.
Initial reaction was carried out with isatin 1, pyrazole 2,
and
(E-)-N-methyl-1-(methylthio)-2-nitroethanamine
(NMSM, 3) leading to the formation of spiroxindole 4a
(Scheme 1). This reaction was chosen as model reaction
to investigate the feasibility of the strategy and to opti-
mize the reaction conditions (Table 1). To begin with, the
reaction was performed in the absence of base in ethanol
which failed to yield the product even after eight hours ei-
ther at ambient temperature or reflux conditions. When
this reaction was tested in the presence of bases such as
pyridine, pyrrolidine, piperidine, L-proline, DBU, K2CO3,
Na2CO3, NaOH, and DMAP in refluxing ethanol traces of
4a were obtained at longer reaction time, but in the pres-
ence of DABCO, 4a was obtained in 70% yield at three
hours.
The feasibility of the reaction was further examined with
various Lewis acids, such as SnCl2·2H2O, PTSA·H2O,
FeCl3, In(OTf)3, AlCl3, and BiCl3 in refluxing ethanol but
these Lewis acids could not promote the reaction effi-
ciently even after prolonged reaction times (Table 1). In
the presence of indium trichloride in ethanol, 4a was ob-
Recently, the synthetic utility of indium(III) Lewis acids
in organic synthesis9–11 has received great attention due to
SYNLETT 2014, 25, 0708–0712
Advanced online publication: 31.01.2014
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3
6
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5
2
1
4
1
4
3
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2
0
9
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DOI: 10.1055/s-0033-1340666; Art ID: ST-2013-D1053-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Spiropyranopyrazoles
709
R2
N
O
R1
Me
O
NO2
NO2
SMe
Me
+
InCl3, EtOH
reflux
R1
O
+
O
N
N
R2
N
R3
MeHN
NHMe
N
O
N
R3
1
2
3
4a–z
Scheme 1 Synthesis of spiro(indoline-3,4′-pyrano[2,3-c]pyrazol)-2-one derivatives 4a–z
tained in 94% yield (Table 1, entry 12). Subsequently, in The optimal conditions thus established were then applied
effect of solvents (EtOH, MEOH, and MeCN) and cata- to the synthesis of novel spiroxindoles via the one-pot,
lyst loading, 5 mol%, 10 mol%, 15 mol%, 20 mol%, and three-component domino reaction of isatin 1, pyrazole 2,
25 mol% of indium trichloride were tested, respectively.
and NMSM (3), respectively (Table 2). A total of 26 novel
spiroxindoles were synthesized15 in excellent yields. To
the best of our knowledge, there is no report on the syn-
thesis of spiroxindoles through the MCR of isatin, pyr-
azole, and NMSM. Therefore, such a synthesis can be
considered as a powerful and practical method for the
preparation of a new class of pyrazoles and NMSM-fused
isatin heterocyclic derivatives.
Table 1 Optimization of the Reaction Conditions
Entry Catalyst (mol%)
Time (h)Yield (%)a,b
MeOH EtOH MeCN Neat
1
2
InCl3 (20)
10
70
10
20
15
20
25
20
50
45
30
70
72
65
65
92
25
10
10
30
5
50
15
10
30
SnCl2·2H2O (20) 10
10
On the basis of the above results a plausible mechanism
for the formation of spiroxindole is proposed in Scheme 2.
The first step is the Knoevenagel condensation between
active methylene compound 2 and spiroxindole 1 that
leads to the adduct 5, which acts as a Michael acceptor.
3
PTSA·H2O (20)
BiCl3 (20)
AlCl3 (20)
FeCl3 (20)
In(OTf)3 (20)
InCl3 (15)
InCl3 (10)
InCl3 (5)
10
10
10
10
10
10
10
10
10
7
trace
4
trace trace
10 30
trace 12
5
The adduct 5 immediately undergoes Michael-type addi-
tion with NMSM (3) to generate the open-chain interme-
diate 6. The intermediate 6 undergoes intramolecular O-
cyclization via path I to give compound 6 with elimination
of MeSH. The intermediate 6 may exist in another tauto-
meric form 6′ which could undergo N-cyclization via path
II to give compound 4′. During our investigations, we did
not observe even traces of 4′ and only 4 was obtained ex-
clusively, suggesting O-cyclization through route I, mak-
ing the protocol highly chemo and regioselective. The
scope of the reaction was further studied with various isat-
in derivatives under optimized conditions. All the reac-
tions proceeded smoothly to provide spiro(indoline-3,4′-
pyrano[2,3-c]pyrazol)-2-one derivatives 4a–z in good
yields (80–94%). The results are summarized in Table 2.
The structures of the products were identified by their FT-
IR, 1H NMR, and 13C NMR spectroscopic and mass spec-
trometric data. Furthermore, the structure was finally
ascertained by single-crystal X-ray diffraction data (Fig-
ure 1).16 Compound 4b (CCDC-964326, Figure 1) crystal-
lized in the monoclinic space group P2(1)/c with the
following unit cell parameters a = 10.7871(18) Å, α = 90°,
b = 20.851(3) Å, β = 99.028(5)°, c = 8.0231(13) Å, γ =
90°.
6
7
10
80
60
40
92
94
85
70
20
45
30
25
45
52
40
35
35
30
20
15
25
35
20
15
8
9
10
11
12
13
14
InCl3 (25)
InCl3 (20)
InCl3 (20)
5
InCl3 (20)
3
a The reaction was performed with isatin 1 (1 mmol), pyrazole 2
(1 mmol), NMSM (3, 1 mmol), catalyst, reflux.
b Isolated yields.
The results summarized in Table 1 show that 20 mol%
loading of indium trichloride was optimal. Higher
amounts of indium trichloride did not lead to significant
change in the reaction yields (Table 1, entry 11). From the
data in Table 1, ethanol was found to be the ideal solvent
for the domino reaction which afforded the maximum
yield of 4a (94%, Table 1, entry 12). From the above re-
sults, indium trichloride emerged as the ideal choice of
Lewis acid for these domino reactions. Further, the prod-
uct was precipitated in the reaction vessel and hence no
column chromatographic purification was required. After
completion of the reaction the product was filtered and
washed with ethanol to obtain pure 4a.
In summary, we have demonstrated a simple and efficient
route for the one-pot, three-component synthesis of spi-
ro(indoline-3,4′-pyrano[2,3-c]pyrazol)-2-one derivatives
regioselectively in almost quantitative yields using readi-
ly available starting materials. It is noteworthy that this
domino reaction results in the formation of three new
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 708–712

710
N. Poomathi et al.
LETTER
Table 2 Synthesis of Spiro(indoline-3,4′-pyrano[2,3-c]pyrazol)-2-one Derivatives by One-Pot, Three-Component Reactions
R2
O
N
Me
NO2
SMe
R1
Me
O
InCl3, EtOH
reflux, 5–7 h
NO2
R1
O
+
O
+
N
N
R2
N
R3
MeHN
NHMe
3
N
O
N
R3
1
2
4a–z
Entry
R1
R2
R3
Time (h)
Yield (%)a–c
Product 4
1
2
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
6
94
90
92
88
85
89
84
86
90
93
80
85
89
84
91
87
90
92
89
94
93
92
88
92
88
90
4a
4b
4c
4d
4e
4f
Cl
Br
NO2
Me
H
H
7
3
H
5.5
6.5
6
4
H
5
H
6
Me
Et
All
7
7
H
7
4g
4h
4i
8
H
6.5
7
9
H
propargyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
H
Bn
5
4j
F
H
6
4k
4l
Cl
Cl
Cl
NO2
Cl
H
Me
7
propargyl
6.5
6
4m
4n
4o
4p
4q
4r
4s
Et
Et
7
Bn
5
H
6
Cl
NO2
Me
H
H
H
5
H
H
6.5
5
H
H
4t
propargyl
Me
H
5.5
5
4u
4v
4w
4x
4y
4z
Cl
H
H
Et
H
6
Cl
Br
Br
propargyl
propargyl
Bn
H
5
H
7
H
5.5
a.The reaction was performed with isatin 1 (1 mmol), pyrazole 2 (1 mmol), NMSM (3, 1 mmol), InCl3 (0.20 mmol), EtOH (3 mL), reflux.
b Reaction progress was followed by TLC analysis.
c Yields of isolated products.
bonds (two C–C and one C–O) in a single operation. The product is obtained in pure form just by filtration. Further
significant features of this method are simple practical investigations pertaining to the synthesis of several other
workup, high yields of the products, operational simplici- novel heterocycles using (E)-N-methyl-1-(methylthio)-
ty, and no column chromatographic purification as the 2-nitroethanamine are currently in progress in our lab.
Synlett 2014, 25, 708–712
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Spiropyranopyrazoles
711
Me
InCl3
O
O
H
O
H
N
O
N
N
N
+
O
NO2
N
NO2
N
H
path II
1
Me
H
Me
Me
Me
S
Me
S
H
Me
N
InCl3
N
N
2
N
O:
N
O
Me
Me
InCl3
InCl3
EtOH
reflux
Knoeveanagel
condensation
6
6'
N-attack
O-attack
H
N
path I
– MeSH
O
H
N
NO2
H
Me
N
O
+
O
NO2
H
NO2
N
O
S
N
N
Me
Me
H
InCl3
H
S
Me Me
N
Me
N
N
InCl3
N
3
O
N
N
O
Me
H
5
– H2O
H
N
H
O
NO2
N
O
NO2
Me
Me
S
Me
N
N
N
N
N
H
O
Me
N
4
4'
Scheme 2 Proposed mechanism for the domino reaction
entist Scheme (WOS-A) and the Council of Scientific and Industrial
Research (CSIR) under Open Source Drug Discovery (OSDD)
Scheme, New Delhi.
References and Notes
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Figure 1 The molecular structure of 4b
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Acknowledgment
We gratefully acknowledge the generous financial support from the
Department of Science and Technology (DST) under Women Sci-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 708–712

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LETTER
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(15) General Procedure for the Preparation of
Spiro(indoline-3,4′-pyrano[2,3-c]pyrazol)-2-one
Derivatives by a One-Pot, Three-Component Reaction of
Isatin, Pyrazole, and NMSM
A mixture of isatin 1 (1 mmol), pyrazole 2 (1 mmol), NMSM
(3, 1 mmol), and InCl3 (0.20 mmol) in EtOH (3 mL) were
charged in a 25 mL round-bottomed flask, and the mixture
was heated at reflux. The resulting solution was stirred for 5–
7 h. The consumption of the starting material was monitored
by TLC. The precipitated solid was filtered, washed with
EtOH (5–7 mL), and dried under vacuum to obtain pure 4a–
z in good yields (80–94%). The identities of products 4a–z
were confirmed by FTIR, NMR, and ESI-Mass, giving good
agreement with the assigned structures.
Compound 4a: white solid, 94%; mp 275–278 °C. IR (KBr):
ν = 3356, 2344, 1725, 1652, 1130, 1068, 924.91, 753.0 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 10.78 (br S, 1 H, NH),
10.75–10.76 (d, 1 H, J = 4.96 Hz, NH), 7.75–7.77 (d, 2 H, J
= 8.04 Hz, ArH), 7.53–7.57 (t, 2 H, J = 7.78 Hz, ArH), 7.36–
7.40 (t, 1 H, J = 7.38 Hz, ArH), 720–7.24(t, 1 H, J = 7.64 Hz,
ArH), 7.13–7.15 (d, 1 H, J = 7.28 Hz, ArH), 6.91–6.95 (t, 2
H, J = 7.62 Hz, ArH), 3.20–3.21 (d, 3 H, J = 4.72 Hz,
NHCH3), 1.63 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
DMSO-d6): δ = 176.5, 159.5, 144.6, 142.9, 142.9, 137.2,
132.1, 130.0, 128.8, 127.5, 123.6, 122.4, 121.1, 109.7,
107.5, 98.3, 50.0, 36, 29, 15, 12.0 ppm. ESI-MS: m/z =
404.07 [M + 1]+.
Compound 4q: white solid, 90%; mp >350 °C. IR (KBr): ν
= 3275, 1708, 1647, 1467, 1355, 1171, 1054, 1020, 921, 738
cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 12.5 (br s, 1 H,
NH), 10.7 (br s, 1 H, NH), 10.6 (s, 1 H, NH), 7.15–7.19 (t, 1
H, J = 7.52 Hz, ArH), 6.90–7.00 (d, 1 H, J = 7.36 Hz, ArH),
6.87–6.90 (t, 2 H, J = 6.72 Hz, ArH), 3.17 (br s, 3 H,
NHCH3), 1.61 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
DMSO-d6): δ = 176.8, 160.5, 153.7, 142.7, 136.0, 132.7,
128.5, 123.6, 122.36, 109.60, 107.35, 96.70, 49.54, 28.90,
9.36 ppm. ESI-MS: m/z = 328.50 [M + 1]+.
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(16) Crystallographic data for compound 4b has been deposited
with the Cambridge Crystallographic Data Center as
supplementary publication number CCDC-964326. Copy of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(1223)762911 or e-mail: deposit@ccdc.cam.ac.uk].
Synlett 2014, 25, 708–712
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