Supramolecular synthesis of 3-indolyl-3-hydroxy oxindoles under neutral conditions in water

Article abstract of DOI:10.1021/jo702496s

(Chemical Equation Presented) Various 3-indolyl-3-hydroxy oxindoles were prepared for the first time by supramolecular catalysis involving the reaction of β-CD:isatin complexes with indoles under neutral conditions in water. β-Cyclodextrin can be recovered and reused a number of times without loss of activity.

Full text of DOI:10.1021/jo702496s

SCHEME 1
Supramolecular Synthesis of 3-Indolyl-3-hydroxy
Oxindoles under Neutral Conditions in Water
V. Pavan Kumar, V. Prakash Reddy, R. Sridhar, B. Srinivas,
M. Narender, and K. Rama Rao*
Organic Chemistry DiVision-I, Indian Institute of Chemical
Technology, Hyderabad-500 007, India
molecular recognition ability and catalysis by cyclodextrins in
the exclusive formation of 3-indolyl-3-hydroxy oxindoles from
isatins and indoles under neutral conditions in water.
drkrrao@yahoo.com
Isatins are familiar for their manifold biological activity and
indole fragment is featured widely in a wide variety of
biologically active compounds.4 Some derivatives of isatin are
key intermediates in the synthesis of natural products.5 Isatin
and its derivatives possess a reactive keto-carbonyl group that
readily undergoes condensation reactions under mild conditions.6
Different derivatives of isatin have been synthesized to study
their bioactivity. Oxindoles are well-known among these
compounds. Oxindoles are useful as antibacterial, anti-inflam-
matory,7 laxative,8 Growth hormone secretagogue,9 and new
targets for cancer chemotherapy.10 These intermediates are also
useful in the synthesis of chiral ligands to obtain high enanti-
oselectivities in numerous catalytic reactions.11
In spite of different biological activities associated with
various oxindole derivatives,12 the synthesis of monosubstituted
3-indolyl-3-hydroxy oxindoles by Friedel-Crafts reaction of
indoles with electron-deficient carbonyl compounds such as
isatins will be one of the synthetically useful transformations
since this reaction usually results in 3,3′-biindolyl oxindoles.13
Thus, there is need to develop a generally applicable, mild and
environmentally benign practical methodology for 3-indolyl-3-
hydroxy oxindoles from isatin and indoles under neutral
conditions with a recyclable catalyst especially in water for
reasons of safety, economical and environmental concerns. This
becomes further sophisticated if these reactions can be per-
formed under supramolecular catalysis. We have attempted the
ReceiVed NoVember 21, 2007
Various 3-indolyl-3-hydroxy oxindoles were prepared for the
first time by supramolecular catalysis involving the reaction
of â-CD:isatin complexes with indoles under neutral condi-
tions in water. â-Cyclodextrin can be recovered and reused
a number of times without loss of activity.
Supramolecular chemistry involves noncovalent intermolecu-
lar forces and has profound influence on the catalysis of a variety
of organic reactions. It involves reversible formation of host-
guest complexes by molecular recognition as seen in enzymes.
Among various supramolecular hosts, cyclodextrins have excited
much interest as enzyme models.1 The most accessible â-cy-
clodextrin (â-CD) is a cyclic oligosaccharide consisting of seven
glucose units. The cavity size and the inner hydrophobicity are
suitable for encapsulating a variety of guests such as aromatic
compounds.2 The improvement of the reaction rate and selectiv-
ity with â-CD inclusion complexes has been reported in a
number of organic reactions.3 The complex formation with â-CD
could alter product distribution in the organic reactions. These
characteristics arise from the geometrical constraint of the guest
molecules on inclusion into â-CD. Herein, we demonstrate the
(4) Sundberg, R. J. The Chemistry of Indoles; Academic: NewYork,
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Germany, 2005. (b) Mateos-Timoneda, M. A.; Crego-Calama, M.; Rein-
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Komiyama, M. Cyclodextrin Chemistry; Springer-Verlag: New York, 1978.
(3) (a) Narender, M.; Reddy, M. S.; Pavan Kumar, V.; Reddy, V. P.;
Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem., 2007, 72, 1849. (b) Surendra,
K.; Krishnaveni, N. S.; Mahesh, A.; Rao, K. R. J. Org. Chem. 2006, 71,
2532. (c) Krishnaveni, N. S.; Surendra, K.; Rao, K. R. Chem. Commun.
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Y. V. D.; Rao, K. R. J. Org. Chem. 2003, 68, 2058. (e) Ravichandran, R.;
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10.1021/jo702496s CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/23/2008
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J. Org. Chem. 2008, 73, 1646-1648

TABLE 1. Synthesis of 3-Hydroxy-3-indolylindolin-2-ones in the
Presence of â-Cyclodextrin in Water
FIGURE 1. Supramolecular synthesis of 3-indolyl-3-hydroxy oxin-
doles.
by the addition of indole (2) and stirring for 1-3 h at 40 °C to
give the corresponding products (3) (Scheme 1). The reaction
proceeds smoothly with a high degree of conversion without
the formation of any byproducts. This methodology is also
compatible with various substituted isatins and indoles. No
asymmetric induction was observed in these reactions. Several
examples illustrating this simple and practical methodology are
summarized in Table 1. However, this reaction did not proceed
when the nitro group was present in the 5-position of the indole
ring. All the products were characterized by 1H NMR, IR, mass
spectroscopy, and elemental analysis. The catalyst â-CD can
be easily recovered and reused.
The reaction also occurs at room temperature, but longer
reaction times (>50 h) are required and the isolated yields of
products are also low (15-25%). The substantial role of â-CD
is illustrated by performing the reaction in water without using
â-CD at 40 °C, where the formation of biindolyl products was
identified. Use of a catalytic amount of â-CD (0.1 mmol per
mole of the substrate) at 40 °C also has no impact and only
gives biindolyl products. These experiments clearly demonstrate
the significance of 1:1 complexation of â-CD with isatin in the
catalysis of the reaction.
We propose a supramolecular catalysis for the formation of
monosubstituted product by rigid complex formation between
isatin and â-CD (Figure 1). The formation of complex can be
1
explained by H NMR studies. NMR spectroscopy is one of
the most important techniques used for characterization of
inclusion complexes. The formation of inclusion complex results
in the shift changes in the resonances of the host cyclodextrin
and the guest protons.14
A comparison of the 1H NMR spectra (D2O) of â-CD, â-CD:
isatin complex, and freeze-dried reaction mixture of â-CD:isatin
complex with the indole was studied. It is observed from Figure
2 that there is an upfield shift of H3 (0.02 ppm) and H5 (0.02
ppm) protons of cyclodextrin in the â-CD:isatin complex as
compared to â-CD, indicating the formation of an inclusion
complex of isatin with â-CD from the secondary side of
cyclodextrin. It is further observed from the spectra of the
reaction mixture of â-CD:isatin complex with the indole at 30
min that there is also an upfield shift of H6 proton by 0.07 ppm.
This indicates the complexation of the indole from the primary
side of cyclodextrin for the reaction to proceed (Figure 2). This
clearly demonstrates that the isatin is elegantly set for the
a All products were identified by IR, NMR, mass spectroscopy, and
elemental analysis. b Yields of products isolated after column chromatog-
raphy.
synthesis of 3-indolyl-3-hydroxy oxindoles from isatins and
indoles by utilizing â-cyclodextrin in water under neutral
conditions.
In general, the reactions were carried out by the in situ
formation of 1:1 â-CD complex with isatin (1) in water followed
(14) (a) Jia, S.-Y.; Hao, Y.-Q.; Li, L.-N.; Chen, K.; Wu, Y.; Liu, J.;
Wu, L. Ding, Y.-H. Chem. Lett. 2005, 34, 1248. (b) Schneider, H. J.; Hacket,
F.; Rudiger, V.; Ikeda, H. Chem. ReV. 1998, 98, 1755. (c) Demarco, P. V.;
Thakkar, A. L. J. Chem. Soc., Chem. Commun. 1970, 2.
J. Org. Chem, Vol. 73, No. 4, 2008 1647

Experimental Section
General Procedure for the Synthesis of 3-Indolyl-3-hydroxy
Oxindoles. â-CD (1mmol) was dissolved in water (15 mL) by
warming to 50 °C until a clear solution was formed. Then, isatin
(1 mmol) dissolved in methanol (0.5 mL) was added dropwise
followed by indole (1 mmol) and the mixture was stirred at 40 °C
until the reaction was complete (as monitored by TLC) (Table 1).
The mixture was extracted with ethyl acetate, and the extract was
filtered. The organic layer was dried over anhydrous Na2SO4, the
solvent was removed under reduced pressure, and the resulting
product was further purified by column chromatography. The
aqueous layer was cooled to 5 °C to recover â-CD by filtration.
The recovered â-CD was reused for five consecutive runs in this
reaction without any change in the yield and purity.
Preparation of â-CD:Isatin Inclusion Complex. â-CD (1
mmol) was dissolved in water (15 mL) by warming to 50 °C until
a clear solution was formed, and then isatin (1 mmol) dissolved in
methanol (1.0 mL) was added dropwise and the solution was
allowed to come to room temperature. It was cooled to 5 °C for 12
h and the white precipitate was filtered and dried.
FIGURE 2. 1H NMR spectra (200 MHz) of (a) â-CD, (b) â-CD:isatin
complex, and (c) reaction mixture after 30 min. The spectra were
obtained in D2O at 25 °C.
Acknowledgment. We thank CSIR, New Delhi, India, for
fellowships to V.P.K., V.P.R., R.S., B.S., and M.N.
addition reaction with the indole in the hydrophobic microen-
vironment of â-cyclodextrin cavity.
Note Added after ASAP Publication. An author name was
spelled wrong in ref 6b in the version published ASAP January
23, 2008; the corrected version was published ASAP January
25, 2008.
Thus, we have demonstrated, for the first time, an operation-
ally simple and efficient aqueous phase synthesis of 3-indolyl-
3-hydroxy oxindoles by using â-cyclodextrin under neutral
conditions. â-Cyclodextrin, apart from being nontoxic, is also
considered as metabolically safe.15 This method is very simple,
high yielding. and environmentally friendly. Further potential
applications of this reaction are under study.
Supporting Information Available: Characterization data for
all compounds including 1H NMR spectra and IR. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Uekama, K.; Hirayama, F.; Irie, T. Chem. ReV. 1998, 98, 2045.
JO702496S
1648 J. Org. Chem., Vol. 73, No. 4, 2008