Triton b-assisted, efficient, and convenient synthesis of 3-indolyl-3-hydroxy oxindoles in aqueous medium

Article abstract of DOI:10.1080/00397910902916072

An efficient and convenient synthesis of 3-indolyl-3-hydroxy oxindole is described by the reaction of isatin with indole in the presence of Triton B in an aqueous medium.

Full text of DOI:10.1080/00397910902916072

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Triton B–Assisted, Efficient, and
Convenient Synthesis of 3-Indolyl-3-
hydroxy Oxindoles in Aqueous Medium
H. M. Meshram a , D. Aravind Kumar a , P. Ramesh Goud a & B.
Chennakesava Reddy a
a Organic Chemistry Division I , Indian Institute of Chemical
Technology , Hyderabad , India
Published online: 09 Dec 2009.
To cite this article: H. M. Meshram , D. Aravind Kumar , P. Ramesh Goud & B. Chennakesava Reddy
(2009) Triton B–Assisted, Efficient, and Convenient Synthesis of 3-Indolyl-3-hydroxy Oxindoles in
Aqueous Medium, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:1, 39-45, DOI: 10.1080/00397910902916072
To link to this article: http://dx.doi.org/10.1080/00397910902916072
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Synthetic Communications1, 40: 39–45, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902916072
TRITON B–ASSISTED, EFFICIENT, AND CONVENIENT
SYNTHESIS OF 3-INDOLYL-3-HYDROXY OXINDOLES
IN AQUEOUS MEDIUM
H. M. Meshram, D. Aravind Kumar, P. Ramesh Goud,
and B. Chennakesava Reddy
Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, India
An efficient and convenient synthesis of 3-indolyl-3-hydroxy oxindole is described by the
reaction of isatin with indole in the presence of Triton B in an aqueous medium.
Keywords: Aqueous medium; indole; isatin; oxindole; Triton B
The indole ring is found in many biologically active molecules as well as in
natural products.[1] Isatin derivatives are also useful intermediates in the synthesis
of natural products.[2] The hybrid molecules of isatin and indole possess a wide spec-
trum of biological activity such as anti-inflammatory activites.[3] They can be used as
hormone secretagogue[4] and for cancer chemotherapy.[5] Some of the derivatives are
also useful for the synthesis of chiral ligands.[6] Because of the medical importance of
indolyl oxindoles,[7] there is interest in developing a simple and efficient method for
the synthesis of indolyl oxindoles. These compounds are synthesized by the reaction of
isatin with indole in the presence of dimethyl amine.[6] Recently, b-cyclodextrin (b-CD)
has been used as an inclusion complex for the synthesis of oxindole in neutral
conditions.[8] However, longer reaction time and difficulties in the separation of
the product are some of the drawbacks of these reactions.
In recent years, the use of Triton B has received considerable attention in
organic synthesis because of its nonmetallic nature, efficiency, and easy availability.
Triton B has been used as a phase-transfer catalyst as well as reagent for Micheal
addition,[9] nitro aldol,[10] C-alkynylation,[11] and carbamate formation.[12] Our inter-
est in the development of nonmetallic reagents[13] prompted us to explore the basic
activity of Triton B. Herein, we report the results of a Triton B–mediated reaction
of isatin with indole, which led to 3-indolyl-3-hydroxy oxindole (Scheme 1).
We screened various quaternary ammonium hydroxides (10 mol%) and found
that benzyltrimethyl ammonium hydroxide was the best choice of base for optimum
conversion in the shortest reaction time (Table 1). Next, we focused our efforts on
optimizing the molar ratios of Triton B (Table 2). During the investigation, we
Received January 7, 2009.
Address correspondence to H. M. Meshram, Organic Division I, Indian Institute of Chemical
Technology, Hyderabad 500 007, A.P., India. E-mail: hmmeshram@yahoo.com
39

40
H. M. MESHRAM ET AL.
Scheme 1. Synthesis of 3-hydroxy-3-indolylindolin-2-ones in the presence of Triton B.
observed that 7 mol% of Triton B was sufficient for a high degree of conversion
within a short time. Further addition of Trion B did not show any remarkable
improvement in the yield.
The efficiency of the Triton B–catalyzed system for the synthesis of 3-indolyl-
3-hydroxy oxindole was further extended to a variety of substrates, and results are
summarized in Table 3.
From Table 3, we see that halogen-substituted isatins react smoothly with
indole and lead to good yield of the expected product. The order of reactivity is
I > F > Br > Cl. The counterpart-substituted indoles also react rapidly with isatins
and give the product in good yield. Notably, it was observed that the methyl substi-
tutent on the indole ring shows an increase in the rate of reactivity and results in
good yield of product. It is worth mentioning that azaindole also reacts with isatin
in identical conditions and forms a single product with a high degree of conversion.
The present protocol has advantages over earlier methods in terms of rapid reaction
and comparable yields.
Table 1. Screening of different bases
Amount
(mol%)
Time
(min)
Yield
(%)
Base
Tetramethyl ammonium hydroxide
Tetraethyl ammonium hydroxide
Tetrabutyl ammonium hydroxide
Trimethyl benzyl ammonium
hydroxide (Triton B)
7
7
7
7
60
50
48
15
70
73
77
93
Table 2. Different mol% ratio of Triton B
Ratio of Triton B (mol%)
Time (min)
Yield (%)
3
4
5
6
7
8
9
30
27
23
20
15
15
15
80
86
82
90
93
94
94

SYNTHESIS OF 3-INDOLYL-3-HYDROXY OXINDOLES
41
Table 3. Synthesis of 3-hydroxy-3-indolylindolin-2-ones in the presence of Triton B
Time
(min)
Yield
(%)b
Entry
Istain (1)
Indole (2)
Product (3)a
a
15
93
95
90
84
92
b
10
12
25
20
c
d
e
f
15
20
94
90
g
(Continued )

42
H. M. MESHRAM ET AL.
Table 3. Continued
Time
(min)
Yield
(%)b
Entry
Istain (1)
Indole (2)
Product (3)a
h
35
20
15
15
85
90
92
90
i
j
k
l
30
20
86
93
m
n
15
95
(Continued )

SYNTHESIS OF 3-INDOLYL-3-HYDROXY OXINDOLES
43
Table 3. Continued
Time
(min)
Yield
(%)b
Entry
Istain (1)
Indole (2)
Product (3)a
o
p
18
25
90
85
aAll the products exhibited physical and spectral (NMR, mass, IR) properties in accordance with the
assigned struture.
bIsolated.
In conclusion, we have demonstrated an efficient and convenient method for
the synthesis of oxindole. The use of nonmetallic base and aqueous medium supports
the environmental friendliness of the method. In addition, the method is applicable
for substituted isatins as well as indoles.
GENERAL PROCEDURE
A mixture of indole (1 equiv.), Triton B (7 mol% in H2O), and isatin was stirred
at room temperature for the stipulated time (see Table 3). After completion of the
reaction, the mixture was extracted with ethyl acetate and dried over Na2SO4.
Removal of solvent under reduced pressure gave the corresponding 3-indolyl-
3-hydroxy oxindole, which was purified through a column using hexane=ethanol.
SPECTRAL DATA FOR SELECTED PRODUCTS
Entry 3a
1
Solid; 294–295ꢀC; H NMR (300 MHz, CDCl3, Me4Si) d (ppm) 5.96 (s, 1H),
6.71–7.42 (m, 8H), 7.46–7.62 (m, 1H), 10.03 (s, 1H), 10.41 (s, 1H). IR (KBr)
n ¼ 3401, 3054, 2926, 1706 cmꢁ1. EIMS m=z 287 (M þ Na)þ.
Entry 3c
1
Solid; 315–317ꢀC; H NMR (300 MHz, CDCl3, Me4Si) d (ppm) 6.28 (s, 1H),
6.85–7.06 (m, 4H), 7.15–7.35 (m, 2H), 7.93 (d, 1H, J ¼ 6.67 Hz), 8.13 (d, 1H,

44
H. M. MESHRAM ET AL.
J ¼ 3.70 Hz), 10.18 (s, 1H), 11.35 (s, 1H). IR (KBr) n ¼ 3210, 3164, 2924, 1712 cmꢁ1
EIMS m=z 266 (M þ 1)þ.
.
Entry 3g
Solid; 138–143ꢀC; 1H NMR (300 MHz, CDCl3, Me4Si) d (ppm) d 7.13 (m, 2H),
7.4 (s, 1H), 7.99 (m, 2H), 7.45 (m, 3H), 8.05 (m, 2H). IR (KBr) n ¼3455, 3242, 2924,
1711, 799 cmꢁ1. EIMS m=z 302, 300 (M þ 1), 222, 181.
Entry 3h
Solid; 247–250ꢀC; 1H NMR (300 MHz, CDCl3, Me4Si) d (ppm) d 5.51 (bs, 2H),
6.55 (s, 1H), 7.03 (t, 2H), 7.68 (m, 2H). IR (KBr) n ¼ 3422, 3262, 2924, 1704, 1617,
1456, 673 cmꢁ1. EIMS m=z 401 (M þ Na), 361, 222.
Entry 3j
1
Solid; 227–229ꢀC; H NMR (300 MHz, CDCl3, Me4Si) d 2.22 (s, 3H), 2.41 (s,
3H), 5.96 (s, 1H), 6.66–7.05 (m, 5H), 7.08–7.24 (m, 2H), 10.05 (s, 1H), 10.51 (s, 1H).
IR (KBr) n ¼ 3328, 3200, 1709 cmꢁ1. EIMS m=z 315 (M þ Na)þ.
Entry 3k
1
Solid; 170–172ꢀC; H NMR (300 MHz, CDCl3, Me4Si) d 2.27 (s, 3H), 6.14 (s,
1H), 6.71–6.82 (m, 1H), 6.84–7.15 (m, 4H), 7.92 (d, 1H, J ¼ 8.15 Hz), 8.13 (d, 1H,
J ¼ 4.44 Hz), 10.01 (s, 1H), 11.24 (s, 1H). IR (KBr) n ¼ 3248, 2922, 1695 cmꢁ1. EIMS
m=z 280 (M þ 1)þ.
Entry 3o
Solid; 397–399ꢀC; 1H NMR (300 MHz, CDCl3, Me4Si) d 6.43 (s, 1H),
6.79–7.15 (m, 5H), 7.94 (d, 1H, J ¼ 8.59 Hz), 8.14 (d, 1H, J ¼ 4.68 Hz), 10.20 (s,
1H), 11.36 (s, 1H). IR (KBr) n ¼ 3219, 2923, 1709 cmꢁ1. EIMS m=z 284 (M þ 1)þ.
Entry 3p
1
Solid; 92–94ꢀC; H NMR (300 MHz, CDCl3, Me4Si) d 6.27 (s, 1H), 6.76–7.30
(m, 5H), 7.49–7.73 (m, 1H), 7.86 (s, 1H), 10.10 (s, 1H), 10.76 (s, 1H). IR (KBr)
n ¼ 3312, 2926, 1719 cmꢁ1. EIMS m=z 383 (M þ Na)þ.
ACKNOWLEDGMENTS
D. A., P. R. G., and B. C. K. R. thank the Council of Scientific and Industrial
Research for the award of a fellowship and J. S. Yadav, director, Indian Institute of
Chemical Technology, for his support and encouragement.

SYNTHESIS OF 3-INDOLYL-3-HYDROXY OXINDOLES
45
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