An improved catalytic method for the synthesis of 3,3-di(indolyl)oxindoles using Amberlyst 15 as a heterogeneous and reusable catalyst in water

Article abstract of DOI:10.1007/s00706-012-0723-7

Amberlyst 15 efficiently catalyzed the electrophilic substitution reaction of indoles with isatin derivatives to afford 3,3-di(indolyl)oxindoles in water. An important feature of this protocol is the reaction of 3-methyl-1H-indole with isatins to give the corresponding 3,3-diaryloxindole derivatives in high yields. The catalyst exhibited remarkable reusable activity. Springer-Verlag 2012.

Full text of DOI:10.1007/s00706-012-0723-7

Monatsh Chem
DOI 10.1007/s00706-012-0723-7
ORIGINAL PAPER
An improved catalytic method for the synthesis
of 3,3-di(indolyl)oxindoles using Amberlyst 15
as a heterogeneous and reusable catalyst in water
•
Yaghoub Sarrafi Kamal Alimohammadi
•
•
Marzieh Sadatshahabi Nasibeh Norozipoor
Received: 5 February 2011 / Accepted: 9 January 2012
Ó Springer-Verlag 2012
Abstract Amberlyst 15 efficiently catalyzed the electro-
philic substitution reaction of indoles with isatin
derivatives to afford 3,3-di(indolyl)oxindoles in water. An
important feature of this protocol is the reaction of
3-methyl-1H-indole with isatins to give the corresponding
3,3-diaryloxindole derivatives in high yields. The catalyst
exhibited remarkable reusable activity.
transformations [24, 25]. The solid acids generally have
high turnover numbers that can be easily separated from
reaction mixtures [26]. Amberlyst 15, a macro reticular
sulfonic acid-based polystyrene cation exchange resin, is
an insoluble polymeric catalyst that can replace most sol-
uble strong acids. During recent years, Amberlyst 15 has
attracted much attention as an easily available and non-
hazardous catalyst, or an effective promoter that can
enhance the reactivity and selectivity of various organic
reactions [27–31].
Keywords 3,3-Di(indolyl)oxindoles Á
Amberlyst 15 Á Water Á Isatin Á Indole
With an increasing awareness of the need for more
sustainable strategies for synthetic chemistry across aca-
demic laboratories and industry, several eco-friendly
strategies have been recognized: to carry out solvent-free
reactions, to replace the use of stoichiometric reagents with
catalysts, to use biocatalytic processes, and finally to per-
form reactions in aqueous media or other nonclassical
reaction solvents [32, 33]. With this emphasis on the use of
cleaner green chemistry processes, recently the uses of
organic reactions in water have received considerable
attention. Being abundant, economical and safe, water
has naturally become a benign solvent in organic synthesis
[34, 35].
Introduction
Indoles are important compounds in organic chemistry
because of their widespread occurrence in nature and
diversified biological and pharmacological activities [1, 2].
The oxindole framework is a privileged heterocyclic motif
that constructs the core of a large family of bioactive
natural products and a series of pharmaceutically active
compounds [3–10]. Several methods have been developed
for the synthesis of oxindoles, including approaches based
on the condensation of arenes with isatins in different
reaction conditions [11–23].
Recently, great attention has also been focused from
both environmental and economical points on the use of
heterogeneous solid acid catalysts for various organic
Results and discussion
In connection with our ongoing work on oxindoles [36–38],
we report an efficient and clean route for the synthesis of
some new oxindole derivatives from isatins and indoles
using Amberlyst 15 as a green and reusable catalyst in water
(Scheme 1).
Y. Sarrafi (&) Á M. Sadatshahabi Á N. Norozipoor
Division of Organic Chemistry, Faculty of Chemistry,
University of Mazandaran, 47416 Babolsar, Iran
e-mail: ysarrafi@umz.ac.ir
Initially, when the reaction of indole (1 mmol) and
isatin (0.5 mmol) with a catalytic amount of Amberlyst 15
(0.3 g) was heated in water at 70 °C as a simple model
K. Alimohammadi
Tarbiat moallem of Dr. Shariaty, University of Payambare
Aazam, Sari, Iran
123

Y. Sarrafi et al.
Scheme 1
3-methyl-1H-indole with 5-bromo and 5-nitroisatin under
similar conditions, and all of the new products were
characterized by 1H, 13C NMR, IR, and mass spectral data.
It is noteworthy that the 1H NMR spectrum of 3,3-
bis(3-methylindolyl)oxindole (2a) showed a singlet at
d = 1.94 ppm for two methyl groups of the indole rings,
and one signal at 8.66 ppm appeared for two NHs of the
indole moieties. In contrast to 2a, in the 1H NMR spectrum
of 3,3-bis(3-methylindolyl)-5-bromooxindole (2b), two
different signals appeared for two NHs at 9.73 and
10.20 ppm, and two signals at 1.70 and 1.98 ppm appeared
for two methyl groups of the indole rings. Similarly, the 1H
NMR spectrum of 3,3-bis(3-methylindolyl)-5-nitrooxin-
dole (2c) showed two different signals for two NHs as well
as for two methyl groups (1H, 13C). Presumably, the
appearance of two different signals for two NHs and
methyl groups in compounds 2b and 2c results from the
steric hindrance (methyl-bromine or methyl-nitro interac-
tion), which restrained the free rotation of the
diastereotopic indole rings around carbon–carbon bonds.
The reaction of 3-methyl-1H-indole with isatin derivatives
required a longer time to produce comparable yields with
respect to compounds 1 (Table 2).
Table 1 The reaction of isatins with 2-substituted indoles catalyzed
by Amberlyst 15 in water (Scheme 1)
Prod. R1 R2 R3
R4
Yielda/%
94, 91, 89b 311–313 312–314 [27]
M.p./°C Lit. m.p./°C
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2 89
297–298 298–299 [27]
309–310 310–311 [27]
287–289 288–289 [27]
291–292 292–293 [27]
301–302 300–301 [27]
272–274 272–273 [27]
212–213 212–214 [27]
334–336 [300 [28]
331–333 232-234 [29]
331–332 332–333 [36]
325–326 324–325 [36]
223–225 223–224 [36]
241–244 –
H
Br
H
H
H
H
H
H
H
90
91c
92
93
91
92c
95
90
PhCH2
Me
Me H
1g
1h
1i
Me Me
Me PhCH2
Me H
H
1j
Me H Me
1k
1l
Me H
Me H
H
H
NO2 88
Br
H
92
90c
1m
1n
1o
a
Me H PhCH2
H
H
Me H
Me H
NO2 89
Br 92
201-203
–
Yields of pure isolated product based on isatin
b
c
The same Amberlyst 15 was used for each of the three runs
Reaction conducted in water/acetone (4/1)
The reaction of isatin with pyrrole was also studied
under the reaction conditions, but a black compound was
obtained that was shown to be a mixture of mono- and
disubstituted oxindoles in 37% yield together with 67% of
the unreacted isatin.
substrate, the reaction proceeded rapidly to give the cor-
responding 3,3-di(indolyl)oxindole in high yield after a
relatively short reaction time.
To clarify the generality of this reaction, several isatin
derivatives were treated with different indoles in water to
afford the corresponding 3,3-di(heteroaryl)oxindoles 1.
The results are shown in Table 1. All known compounds
were characterized by comparison of their physical and
spectroscopic data with authentic samples. We found that
the presence of electron-withdrawing groups on the aro-
matic ring of isatin or electron-donating groups on the
isatin nitrogen did not affect the reaction time and yields.
Since only a few reports on the reaction of isatin with
3-substituted indoles have so far appeared in the literature
[5, 7], we examined the effect of 3-methyl-1H-indole on
this conversion. We were pleased to find that the reaction
of 3-methyl-1H-indole with isatin in the presence of Am-
berlyst 15 in water proceeded to give the corresponding
3,3-di(heteroaryl)oxindole in excellent yield (Scheme 2).
Encouraged by this result, we extended the reaction of
The catalyst can be easily recycled by filtering and
reused at least three times without significant loss of yield
and reactivity (Table 1). However, when the reaction of
isatin and indole was conducted in the absence of the
catalyst under the same reaction conditions, no product was
formed, and only the starting materials were collected. In
general, the suggested mechanism for the reaction of in-
doles with isatin derivatives is patterned in Scheme 3.
In summary, we have described a simple, convenient,
and environmental protocol for the preparation of 3,3-
di(indolyl)oxindoles from different indoles and isatins
using Amberlyst 15 in water. The notable features of this
method are mild reaction conditions, simplicity in opera-
tion, cleaner reaction profiles, low cost, and reusability of
the catalyst, which make it an attractive and very useful
process for the synthesis of important biological oxindoles.
123

An improved catalytic method for the synthesis of 3,3-di(indolyl)oxindoles
Scheme 2
by TLC, the precipitated solid and the Amberlyst were fil-
tered off and washed with water (2 9 20 cm3). To the
residue under the filter was added 20 cm3 acetone, and after
dissolution of the product, the resin was removed by filtra-
tion, and the resulting solution was evaporated under reduced
pressure. The pure product was obtained by recrystallization
from ethanol. The catalyst could be recovered after filtration.
The residue was then washed with acetone, dried at 130 °C
for 1 h, and reused in another reaction. The recycled catalyst
was used for three consecutive reactions without observation
of appreciable loss in its catalytic activities.
Table 2 The reaction of isatins with 3-methyl-1H-indole catalyzed
by Amberlyst 15 in water (Scheme 2)
Prod.
R
Time/h
Yielda/%
M.p./°C
2a
2b
2c
a
H
8
93
89
88
300–302
260–265
283–286
Br
12
12
NO2
Yields of pure isolated product based on isatin
Experimental
Chemicals were obtained from Fluka and Merck, and used
without further purification. All known products were
identified by comparison of their physical and spectral data
with those of authentic samples. Melting points were
measured on an Electrothermal 9100 apparatus. Infrared
spectra were recorded on a Shimadzu IR-8300 series
3,3-Bis(2-methyl-1H-indol-3-yl)-5-nitrooxindole
(1n, C26H20N4O3)
1
M.p.: 241–244 °C; IR (KBr):m = 1,698, 3,383 cm-1; H
ꢀ
NMR (500 MHz, DMSO-d6): d = 1.99 (s, 3H, Me), 2.17
(s, 3H, Me), 6.53 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.8 Hz,
2H), 6.88 (d, J = 7.8 Hz, 1H), 7.00 (m, 3H), 7.23 (bs, 2H),
8.10 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 8.78 (s, 1H, NH),
8.82 (s, 1H, NH), 10.18 (s, 1H, NH) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 13.84, 14.04, 53.32, 108.58,
109.78, 110.81, 111.54, 111.58, 119.28, 119.47, 119.75,
120.79, 121.04, 121.09, 126.28, 127.53, 128.24, 133.01,
135.20, 135.81, 135.91, 137.15, 142.32, 142.74, 148.61,
180.23 ppm; MS: m/z = 436 (M?).
1
FT–IR spectrophotometer. H and 13C NMR spectra were
recorded on a Bruker 500 MHz instrument in CDCl3 with
TMS as a standard. Mass spectra were recorded on a Jeol
DX303 HF mass spectrometer.
General procedure for the preparation
of 3,3-di(heteroaryl)oxindoles
A mixture of indole (1 mmol) and isatin (0.5 mmol) in
10 cm3 water in the presence of 0.3 g Amberlyst-15 was
stirred at 70 °C for 0.5 h (for reaction times for compounds
2, see Table 2). After completion of the reaction, as indicated
3,3-Bis(2-methyl-1H-indol-3-yl)-5-bromooxindole
(1o, C26H20BrN3O)
1
M.p.: 201–203 °C; IR (KBr):m = 1,718, 3,403 cm-1; H
ꢀ
NMR (500 MHz, DMSO-d6): d = 1.98 (s, 3H, Me), 2.12
Scheme 3
123

Y. Sarrafi et al.
(s, 3H, Me), 6.53 (d, J = 7.9 Hz, 1H), 6.73 (d, J = 8.1 Hz,
1H), 6.82 (t, J = 6.7 Hz, 2H), 6.98 (d, J = 8.0 Hz, 1H),
7.05 (d, J = 6.7 Hz, 2H), 7.22 (d, J = 7.7 Hz, 2H), 7.30 (t,
J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.86 (s, 1H, NH), 7.93 (s,
1H, NH), 8.69 (s, 1H, NH) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 13.87, 14.07, 53.76, 109.48, 110.68,
110.77, 110.98, 111.84, 115.53, 119.81, 119.90, 120.19,
120.47, 121.25, 121.48, 127.64, 128.45, 129.56, 131.37,
132.05, 135.02, 135.39, 135.45, 137.61, 139.37,
180.52 ppm; MS: m/z = 469 (M?).
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3,3-Bis(3-methyl-1H-indol-2-yl)-5-bromooxindole
(2b, C26H20BrN3O)
1
M.p.: 260–265 °C; IR (KBr):m = 1,657, 3,423 cm-1; H
ꢀ
NMR (500 MHz, DMSO-d6): d = 1.70 (s, 3H, Me), 1.98
(s, 3H, Me), 6.33 (s, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.76
(m, 2H), 6.87 (t, J = 7.3 Hz, 1H), 6.92 (m, 2H), 7.00 (t,
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J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 9.73 (s, 1H,
NH), 10.20 (s, 1H, NH), 11.80 (s, 1H, NH) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 9.04, 22.91, 52.79, 95.29,
109.15, 110.78, 110.9, 111.78, 113.76, 118.50, 119.43,
121.94, 123.20, 123.31, 123.33, 125.22, 125.98, 128.70,
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1
ꢀ
NMR (500 MHz, DMSO-d6): d = 1.66 (s, 3H, Me), 2.00
(s, 3H, Me), 6.72 (d, J = 8.5 Hz, 1H), 6.82 (t, J = 7.3 Hz,
2H), 6.96 (t, J = 6.8 Hz, 3H), 7.08 (t, J = 7.5 Hz, 1H),
7.15 (d, J = 7.4 Hz, 1H), 7.30 (bs, 1H), 7.40 (d,
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123.34, 123.49, 123.68, 128.69, 130.02, 135.88, 141.00,
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Acknowledgments We are grateful to the Research Councils of
Mazandaran University for their partial financial support.
123