InCl3-catalyzed efficient one-pot synthesis of 2-pyrrolo-3′-yloxindoles

Article abstract of DOI:10.1016/j.tetlet.2009.04.089

An InCl₃-catalyzed one-pot synthesis of 2-pyrrolo-3′-yloxindoles was achieved via three-component reaction of 3-phenacylideneoxindole, β-keto ester, and ammonium acetate at reflux by a sequential Michael addition followed by Paal-Knorr condensa

Full text of DOI:10.1016/j.tetlet.2009.04.089

Tetrahedron Letters 50 (2009) 3959–3962
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
InCl3-catalyzed efficient one-pot synthesis of 2-pyrrolo-30-yloxindoles
*
Gnanamani Shanthi, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
An InCl3-catalyzed one-pot synthesis of 2-pyrrolo-30-yloxindoles was achieved via three-component
reaction of 3-phenacylideneoxindole, b-keto ester, and ammonium acetate at reflux by a sequential
Michael addition followed by Paal–Knorr condensation.
Article history:
Received 2 December 2008
Revised 17 April 2009
Accepted 22 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
InCl3
Three component
3-Phenacylideneoxindole
b-Keto ester
Paal–Knorr condensation
Multicomponent reactions (MCRs) are special types of synthet-
ically useful organic reactions in which three or more different
starting materials react to give a final product in a one-pot proce-
dure. MCRs are powerful tools in the modern drug discovery pro-
cess and allow the fast, automated, and high-throughput
generation of organic compounds.1 In the past decades, there have
been tremendous developments in three- and four-component
reactions and great efforts have been and still are being made to
find and develop new MCRs.2
Pyrroles are one of the most prevalent heterocyclic compounds,
which are present as the basic cores in many natural products,3 po-
tent pharmaceutical compounds,4 and various kinds of functional
materials.5 Despite numerous diverse approaches toward the syn-
thesis of pyrroles developed so far,6 it is still challenging to prepare
polysubstituted pyrroles with various substituents from readily
available building blocks. In addition, oxindoles are attractive tar-
gets in organic synthesis because of their significant biological
activities as well as wide-ranging utility as synthetic intermediates
for alkaloids, drug candidates, and clinical pharmaceuticals.7 To the
best of our knowledge, there have been only two reports on the
synthesis of pyrrolo oxindoles. Previously, Bergmann et al.8 re-
ported the synthesis of pyrrolo oxindoles from 3-acetonylideneox-
indole and 3-amino crotonates in toluene under reflux for several
hours. Muthusamy et al.9 synthesized less substituted 2-pyrrol-
30-yloxindoles from 3-diazooxindoles and pyrroles in the presence
of rhodium(II) acetate catalyst. In view of their importance, the
development of a new and simple method for the synthesis of
highly substituted pyrrole moiety is of importance.
Lately, the utility of indium(III) Lewis acids10 in organic synthe-
sis has received a great deal of interest due to their relatively low
toxicity, stability in air and water and recyclability. As part of our
current studies on the design of new routes for the preparation
of biologically active heterocyclic compounds and in the applica-
11
tion of InCl3 in organic synthesis, we herein disclose a simple
and improved method for the synthesis of 2-pyrrolo-30-yloxindoles
using a catalytic amount of InCl3 (20 mol %) in ethanol at reflux in a
shorter reaction time (10–15 min). To the best of our knowledge,
this is the first report for the synthesis of 2-pyrrolo-30-yloxindoles
from 3-phenacylideneoxindole, b-keto ester, and ammonium ace-
tate (Scheme 1).
H
CH3
N
O
O
CH3
OMe
InCl3 (20 mol%)
EtOH, reflux
CO2CH3
NH4OAc
+
+
O
O
N
H
O
N
H
1a
4a
3
2a
keto-enol
tautomerism
H
CH3
N
CO2CH3
OH
N
H
* Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.089

3960
G. Shanthi, P. T. Perumal / Tetrahedron Letters 50 (2009) 3959–3962
Table 1
Table 2 (continued)
Catalytic activity of various Lewis acids on the three-component reactiona
S.no
Product (4) (keto:enol)a
Time (min)
Yieldb (%)
Entry
Catalyst
Time (h)
Yield (%)
H
CH3
N
1
2
3
4
5
6
7
8
None
2.5
1.5
1.5
1.0
1.0
1.0
20
48
45
40
56
60
85
92
SnCl2.H2O
NH2SO3H
CAN
Bi(OTf)3
BiCl3
CO2CH2CH2OCH
3
5
15
91
O
N
H
4e
In(OTf)3
InCl3
0.50
0.25
(7:1)
a
Reaction of phenacylideneoxindole, methyl acetoacetate, and ammonium ace-
tate in ethanol at reflux.
H
N
CH3
Cl
CO2CH3
In order to study the scope and limitations of the three-compo-
nent reaction, various Lewis acid catalysts, including SnCl2ꢀH2O,
NH2SO3H, CAN, Bi(OTf)3, BiCl3, In(OTf)3, and InCl3 were investigated
(Table 1). The best overall yield (92%) was obtained with InCl3 in eth-
anol. Optimum results were obtained using 20 mol % of InCl3.
6
7
8
10
15
15
15
93
92
88
90
O
N
H
4f
(9:1)
The reaction was carried out with 3-phenacylideneoxindole12
1
H
N
(1 equiv), b-keto ester 2 (1 equiv), and ammonium acetate 3
(2.5 equiv) catalyzed by InCl3 (20 mol %) in ethanol and was re-
fluxed for 10–15 min. The product precipitated from the reaction
mixture.13 This protocol is remarkably simple and requires no puri-
fication technique like column chromatography.
Table 2 summarizes our results on the one-pot reaction of
various 3-phenacylideneoxindole and b-keto ester with ammo-
nium acetate. All the reactions went smoothly and afforded the
CH3
Cl
CO2CH2CH3
O
N
H
4g
(8:1)
H
N
CH3
Table 2
Cl
Synthesis of 2-pyrrolo-30-yloxindoles 4a–i
CO2CH2Ph
S.no
Product (4) (keto:enol)a
Time (min)
Yieldb (%)
O
N
H
4h
H
CH3
N
(10:1)
CO2CH3
O
1
10
92
H
N
CH3
N
H
Cl
4a
CO2CH2CH2OCH3
(10:1)
9
O
N
H
4i
H
CH3
N
(8:1)
CO2CH2CH3
a
Ratio obtained from 1H NMR analysis of the NH protons.
Isolated yield.
2
3
4
10
15
10
93
90
94
b
O
N
H
4b
(10:1)
H
N
H
CH3
CH3
N
O
CO2CH2CH3
O
CH3
CH3
InCl3 (20 mol%)
EtOH, reflux
O
O
NH4OAc
O
+
+
O
N
H
N
H
N
4c
O
H
4j
(8:1)
keto-enol
tautomerism
H
CH3
N
H
CH3
CH3
N
CO2CH2Ph
O
O
N
H
4d
OH
N
H
(9:1)
Scheme 2.

G. Shanthi, P. T. Perumal / Tetrahedron Letters 50 (2009) 3959–3962
3961
O
O
OH
O
R'
R''
R'
R''
2
5
R
..
OH
O
O
OH
H
H
R'
CO2R''
HO
R'
N
R'
O
5
R
CO2R''
OR''
InCl3
O
NH3
+
O
R
H
O
InCl3
O
N
N
H
6
H
N
H
1
-2H2O
R'
H
N
H
R'
N
R
R
CO2R''
CO2R''
keto-enol
O
OH
tautomerism
N
N
H
H
4
Scheme 3.
corresponding highly substituted 2-pyrrolo-30-yloxindoles in good
yields.
Supplementary data
The structures of compounds 4a–i were confirmed by IR, 1H and
13C NMR spectroscopy, mass spectrometry, and elemental analy-
sis.14 The IR spectrum of 4a showed absorptions at 3356, 3207,
1694, and 1671 cmꢁ1 indicating the presence of –NH and –C@O
groups, respectively. In the 1H NMR spectrum, aromatic signals
were seen at d 6.79–7.52, methyl and methoxy protons at d 2.40
and 3.17, methine proton was observed at d 4.55, and two broad
singlets at d 10.32 and 11.61 showed the presence of two –NH
groups (D2O exchangeable). Carbonyl carbons resonated at d
164.4 (ester carbonyl) and 178.5 (oxindole carbonyl) in the 13C
NMR spectrum. The mass spectrum of 4a displayed the molecular
ion (M+) peak at m/z 360.
This method offers several advantages such as milder reaction
condition, shorter reaction time, high yield, and simple experimen-
tal and isolation procedures making it an efficient route to the syn-
thesis of 2-pyrrolo-30-yloxindoles.
To further explore the potential of this protocol for the synthe-
sis of pyrrolo oxindoles, we also investigated the one-pot reaction
involving 3-phenacylideneoxindole, acetylacetone, and ammo-
nium acetate and the corresponding pyrrolo oxindole 4j (keto:e-
nol = 7:1) was obtained in 93% yield (Scheme 2).
The proposed mechanism involves the Michael addition of enol
5 onto the 3-phenacylideneoxindole 1 as shown in Scheme 3, then
in situ generated 1,4-dicarbonyl compound 6 undergoes Paal–
Knorr condensation with ammonium acetate to afford product 4.
In summary, we have demonstrated an improved, one-pot,
three-component reaction that offers a simple and clean method
for the synthesis of 2-pyrrolo-30-yloxindoles from 3-phenacylid-
eneoxindole, 1,3-dicarbonyl, and ammonium acetate catalyzed by
indium(III) chloride. Further, development of new multicomponent
reactions using indium(III) chloride as a catalyst is in progress.
Biological evaluation of these derivatives is underway.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.089.
References and notes
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13. General procedure for the synthesis of 2-pyrrolo-30-yloxindoles 4a–j: To a stirred
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Acknowledgment
One of the authors, G.S. thanks the Council of Scientific and
Industrial Research, New Delhi, India, for the research
fellowship.

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G. Shanthi, P. T. Perumal / Tetrahedron Letters 50 (2009) 3959–3962
(1 equiv), and ammonium acetate 3 (2.5 equiv) in ethanol, catalytic amount of
J = 6.9 Hz), 2.46 (s, 3H), 3.69 (m, 2H), 4.59 (s, 1H), 6.76 (m, 3H), 6.97 (m, 1H),
7.09 (m, 5H), 10.35 (s, 1H, NH, D2O exchangeable), 11.63 (s, 1H, NH, D2O
exchangeable). 13C NMR (125 MHz, DMSO-d6): d 13.1, 13.9, 44.7, 57.8, 108.7,
109.7, 113.7, 120.8, 122.4, 126.9, 127.3, 127.7, 127.8, 128.8, 131.6, 131.7,
131.8, 136.6, 142.9, 163.9, 178.4. MS (m/z): 360 (M+). Anal. Calcd for
C22H20N2O3: C, 73.32; H, 5.59; N, 7.77. Found: C, 73.27; H, 5.52; N, 7.70.
2-Methyl-3-acetyl-5-phenyl-4-(2-oxo-2,3-dihydro-1H-indol-3-yl)-1H-pyrrole
4j (Scheme 3): White solid. mp: 334–335 °C. IR (KBr): 3331, 3149, 1690,
InCl3 (20 mol %) was added and refluxed for 10–15 min as mentioned in Table
2. Upon cooling, the product precipitated from the reaction mixture, which was
filtered, dried, and recrystallized from ethanol.
14. Methyl 2-methyl-5-phenyl-4-(2-oxo-2,3-dihydro-1H-indol-3-yl)-1H-pyrrole-3-
carboxylate 4a: White solid. mp: 316–317 °C. IR (KBr): 3357, 3207, 1694,
1671, 1463, 1103, 696 cmꢁ1 1H NMR (500 MHz, DMSO-d6): d 2.40 (s, 3H), 3.17
.
(s, 3H), 4.55 (s, 1H), 6.79 (m, 3H), 7.08 (m, 1H), 7.31 (t, 1H, J = 7.7 Hz), 7.42 (t, 2H,
J = 7.7 Hz), 7.52 (d, 2H, J = 7.7 Hz), 10.32 (s, 1H, NH, D2O exchangeable), 11.61
(s, 1H, NH, D2O exchangeable). 13C NMR (75 MHz, DMSO-d6): d 12.9, 44.6, 49.2,
108.6, 109.4, 113.9, 120.9, 122.4, 127.0, 127.3, 128.8, 131.5, 131.7, 131.8, 136.5,
142.9, 164.4, 178.5. MS (m/z): 346 (M+). Anal. Calcd for C21H18N2O3: C, 72.82; H,
5.24; N, 8.09. Found: C, 72.75; H, 5.16; N, 8.01.
1621, 1467, 1213, 697 cmꢁ1 1H NMR (500 MHz, DMSO-d6): d 2.08 (s, 3H),
.
2.50 (s, 3H), 4.44 (s, 1H), 6.74 (m, 3H), 7.05 (m, 1H), 7.31 (t, 1H, J = 6.9 Hz),
7.44 (t, 2H, J = 6.9 Hz), 7.47 (d, 2H, J = 7.7 Hz), 10.18 (s, 1H, NH, D2O
exchangeable), 11.54 (s, 1H, NH, D2O exchangeable). 13C NMR (125 MHz,
DMSO-d6): d 14.6, 29.9, 44.8, 108.5, 114.2, 120.1, 120.5, 121.9, 126.7, 127.4,
127.8, 128.8, 131.0, 131.6, 131.9, 135.4, 143.4, 178.0, 191.7. MS (m/z): 330
(M+). Anal. Calcd for C21H18N2O2: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.27;
H, 5.40; N, 8.41.
Ethyl 2-methyl-5-phenyl-4-(2-oxo-2,3-dihydro-1H-indol-3-yl)-1H-pyrrole-3-
carboxylate 4b: White solid. mp: 317–318 °C. IR (KBr): 3354, 3211, 1700,
1668, 1465, 1100, 699 cmꢁ1 1H NMR (300 MHz, DMSO-d6): d 0.84 (t, 3H,
.