Polyethylene glycol (PEG-400): A mild and efficient reaction medium for one-pot synthesis of 3-hydroxy-3-(pyridin-2-ylmethyl)indolin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2013.04.089

3-(Pyridylmethyl)-3-hydroxy-2-oxindole derivatives were synthesized in high yields under mild, and catalyst-free conditions using polyethylene glycol (PEG-400) as a solvent. The use of low cost PEG-400 makes it simple, convenient, and environmentally beni

Full text of DOI:10.1016/j.tetlet.2013.04.089

Tetrahedron Letters 54 (2013) 3503–3506
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Polyethylene glycol (PEG-400): a mild and efficient reaction medium
for one-pot synthesis of 3-hydroxy-3-(pyridin-2-ylmethyl)indolin-2-ones
M. Raghu a, M. Rajasekhar b, B. Chandra Obula Reddy a, C. Suresh Reddy b, B. V. Subba Reddy a,
⇑
a Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, India.
a r t i c l e i n f o
a b s t r a c t
Article history:
3-(Pyridylmethyl)-3-hydroxy-2-oxindole derivatives were synthesized in high yields under mild, and
catalyst-free conditions using polyethylene glycol (PEG-400) as a solvent. The use of low cost PEG-400
makes it simple, convenient, and environmentally benign.
Received 14 November 2012
Revised 18 April 2013
Accepted 20 April 2013
Available online 28 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Isatin
2-Methyl pyridine
Catalyst-free conditions
Polyethyleneglycol
The 3-hydroxyoxindole nucleus is found in various biologically
active molecules such as convolutamydines1 and TMC-95A2,3 and
also exists in various alkaloids such as donaxaridine,4 dioxibrassi-
nine,5 welwitindolinone C6, and 3-hydroxyglucoisatisin (Fig. 1).7
These compounds are known to exhibit potent biological and
pharmaceutical activities such as anticancer, anti-HIV, antioxidant,
and neuroprotective properties.8 Indeed, a substituent at C-3 posi-
tion of the oxindole plays a key role in biological activity.9 There-
fore, there is sustained interest in developing simple and efficient
methods for the preparation of 3-hydroxyindolin-2-ones. In partic-
ular, 3-hydroxy-3-(pyridin-2-ylmethyl)indolin-2-ones are attrac-
tive intermediates for the synthesis of biologically active
compounds.10 Generally, 3-hydroxy-3-(pyridin-2-ylmethyl)indo-
lin-2-ones are prepared by acid catalyzed addition of 2-methylpyr-
idine to isatin.11–13 Recently, microwave irradiation has also been
used to enhance the reaction rates.14
In recent years, the use of alternative solvents such as ionic liq-
uids, polyethylene glycol, and super critical fluids has gained
importance as green reaction media in view of environmental per-
ception.15,16 Though water is a safe alternative, it is not always pos-
sible to use water as a solvent due to hydrophobic nature of the
reactants and the sensitivity of many catalysts to aqueous condi-
tions.17 In this context, PEG has become an alternative reaction
media to perform organic synthesis due to its inherent advantages
over toxic solvents. Furthermore, PEG is inexpensive, easy to han-
dle, thermally stable, non-toxic, and recyclable. To the best of our
knowledge, there are no reports for the synthesis of 3-hydroxy-
3-(pyridin-2-ylmethyl)indolin-2-ones using PEG-400 as a reaction
medium under catalyst-free conditions.
In continuation of our interest on PEG mediated organic trans-
formations,18 we, herein, report a simple and efficient approach
for the synthesis of 3-hydroxy-3-(pyridin-2-ylmethyl)indolin-2-
ones under catalyst-free conditions using PEG-400 as an eco-
friendly and recyclable medium (Scheme 1).
S
Cl
S
HN
O
HN
Me
SCN
H
Me
HO
HO
OH
O
Me
N
H
O
N
H
N
Me
Dioxibrassinine
Donaxaridine
Welwitindolinone
O
HO
N
O
HO
HO
H
N
NH
O
OSO3H
HO
O
O
N
N
H
O
S
O
H
O
HO
HO
HN
O
OH
NH2
Me
O
HO
HN
3-Hydroxyglucoisatisin
Me
TMC-95A
O
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
Figure 1. Biologically active 3-hydroxy-2-oxindole derivatives.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.089

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M. Raghu et al. / Tetrahedron Letters 54 (2013) 3503–3506
HO
R3
N
R3
O
PEG-400
R1
R1
+
°
O
60 C, 8h
O
N
N
N
1
R2
R2
3
2
R1 = CH3,
R2 = H, Ph, C3H5
R3 H, F, Cl, Br, I, NO2, OCH3
Scheme 1. Preparation of 3-hydroxy-2-oxindoles.
HO
4
7
4
7
O
3
N
3
In order to illustrate the products, the structure, and numbering
of isatin and oxindole are shown in Figure 2.
5
6
5
2
2
1
1
6
O
O
N
N
In general, all the reactions were clean affording the 3-hydroxy-
2-oxindole derivatives in good yields under the above conditions
(Table 1). The substituent had shown some effect on conversion.
For instance, 5-methoxyisatin gave the desired product in high
yield in short reaction time (entries d, e, and q, Table 1) compared
to electron-deficient counterparts. Halogen substituted isatins
H
H
3-Hydroxy-3-(pyridin-2-ylmethyl)
indolin-2-one
Indoline-2,3-dione
Figure 2. Chemical structure and numbering of isatin and oxindole.
Table 1
PEG mediated synthesis of 3-hydroxy-2-oxindoles via the condensation of isatins with alkyl pyridines
Entry
Methylpyridine (1)
Isatin (2)
Product (3)a
Time (h)
6.0
Yield (%)b
O
HO
N
Br
Br
N
N
a
75
N
N
O
O
O
O
3a
H3C
H3C
O
HO
N
Br
Br
Br
N
N
b
c
7.0
5.0
4.0
70
79
83
O
3b
Ph
Ph
O
HO
Br
N
N
N
N
H
O
N
H
3c
O
HO
O
O
N
d
N
O
N
O
3d
H3C
H3C
O
HO
O
O
N
e
f
3.0
5.0
85
80
N
N
N
H
O
N
H
O
N
3e
O
HO
N
O
N
O
3f
O
HO
Cl
Cl
N
g
7.0
6.0
77
80
N
O
N
O
N
N
3g
3h
H3C
H3C
O
HO
Cl
Cl
h
N
N
H
O
N
H
O

M. Raghu et al. / Tetrahedron Letters 54 (2013) 3503–3506
3505
Table 1 (continued)
Entry
Methylpyridine (1)
Isatin (2)
Product (3)a
Time (h)
6.0
Yield (%)b
O
HO
I
I
i
82
78
75
N
N
N
H
O
N
H
O
O
N
3i
3j
O
HO
j
5.0
7.0
N
H
O
N
H
N
N
Br
HO
O
O
Br
N
k
N
H
N
H
O
Br
3k
Br
HO
O
N
l
5.0
6.0
6.0
82
78
82
N
N
N
N
N
H
O
N
H
O
3l
F
HO
O
O
F
N
m
n
N
H
N
H
O
3m
Cl
HO
O
Cl
N
N
O
N
H
OH
N
H
3n
O
HO
N
N
O
o
5.0
75
O
3o
Ph
Ph
Br
HO
O
O
Br
N
p
q
6.0
4.0
8.0
80
85
60
N
N
N
N
N
H
O
O
O
H
3p
O
HO
O
O
N
N
O
N
H
HO
H
3q
O2N
O
O
O2N
N
r
N
N
H
H
3r
a
Reaction conditions: isatin (1 mmol), methylpyridine (3 mmol), PEG (5 ml), 60 °C.
Isolated yield.
b
afforded products reasonably in good yields (entries a–c, g–i, k, m,
n, and p, Table 1). However, 5-nitroisatin afforded the product in a
relatively low yield (entry r, Table 1). The reaction was also suc-
cessful with 4-methylpyridine (entries g–j, Table 1). Next, we at-
tempted the coupling of isatins with 2,6-dimethylpyridine.
Interestingly, mono-aldol reaction was observed in case of 2,6-
dimethylpyridine. No bis-adduct was isolated under the present
reaction conditions (entries l–r, Table 1). The structures of all the
products were determined from their spectral (IR, 1H NMR, 13C
NMR, and ESI-MS) data and also by direct comparison with authen-
tic samples.14 The scope of this process was illustrated with respect
to various isatins and alkylpyridines (Table 1). In order to assess
the efficiency of PEG-400, the reaction of 2,6-dimethylpyridine
with isatin was also carried out in polar solvents such as DMF,
DMSO, NMP, and ethyleneglycol. Of these solvents, PEG-400 was
found to be superior to provide the corresponding product 3l and
the results are presented in Table 2.
The generality of this reaction was investigated and the results
are presented in Table 1. As seen in Table 1, a variety of isatins
underwent smooth condensation with alkyl pyridines in PEG-400
at 60 °C to provide
a
diversified 3-hydroxy-3-(pyridin-2-
ylmethyl)indolin-2-ones (Table 1)19
.
A plausible reaction mechanism is depicted in Scheme 2. PEG-
400 activates both picoline and isatin by protonation. Subsequent
attack of the methylene group on isatin gave the desired 3-hydro-
xy-3-(pyridin-2-ylmethyl)indolin-2-one derivative (Scheme 2).
In conclusion, we have developed an efficient approach for the
synthesis of various 3-hydroxy-3-(pyridin-2-ylmethyl)indolin-2-
one derivatives using PEG-400 without the need of any additive
or acid catalyst. The mild reaction conditions, inexpensive reaction

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M. Raghu et al. / Tetrahedron Letters 54 (2013) 3503–3506
6. Jimenez, J. I.; Huber, U.; Moore, R. E.; Atterson, G. M. L. J. Nat. Prod. 1999, 62,
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Comparison of solvents in the synthesis of 31
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Entry
Solvent
Amount (mL)
Time (h)
Yield (%)
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1
2
3
4
DMF
DMSO
NMP
Ethyeleglycol
5
5
5
5
12
10
10
10
58
60
57
65
9. Satyamaheshwar, P. Curr. Bioact. Compd. 2009, 5, 20.
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H
H
N
N
O
O
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+
+
N
CH3
N
CH2
O
H
O
O
H
H
H
O
PEG
O
O
PEG
O
H
H
N
14. Meshram, H. M.; Rao, N. N.; Rao, L. C.; Kumar, N. S. Tetrahedron Lett. 2012, 53,
3963.
N
OH
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Scheme 2. A plausible reaction pathway.
medium, operational simplicity, and high yields are the advantages
of this protocol.
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Acknowledgements
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19. Typical procedure for the synthesis of 3-hydroxy-3-(6-methylpyridin-2-
yl)methyl)indolin-2-one derivative: a mixture of isatin (147 mg, 1 mmol) and
2,6-dimethylpyridine (321 mg, 3 mmol) was taken in 5 mL polyethylene
glycol-400. The resulting mixture was allowed to stir at 60 °C for 5.0 h. After
completion of the reaction, as monitored by TLC, the reaction mixture was
poured into water and extracted with ethyl acetate. The organic layer was
removed under reduced pressure, and the crude product was purified by
column chromatography on silica gel using ethyl acetate:hexane mixture (3:7)
as eluent to yield (208 mg 82%) the desired product 3l.
The authors are thankful to Dr. J.S. Yadav, Director, IICT, for his
kind support.
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