An efficient and rapid synthesis of 3-hydroxy-3-alkyl-2-oxindoles via Zn-mediated barbier-type reaction under aqueous conditions

Article abstract of DOI:10.1007/s12039-017-1329-8

A robust and rapid synthesis of 3-hydroxy-3-alkyl-2-oxindoles from isatins is described. This method introduces an ecofriendly, un-activated Zn dust, solid NH ₄Cl and substrates under aqueous conditions, which has produced the product in modera

Full text of DOI:10.1007/s12039-017-1329-8

J. Chem. Sci.
© Indian Academy of Sciences
DOI 10.1007/s12039-017-1329-8
RAPID COMMUNICATION
An efficient and rapid synthesis of 3-hydroxy-3-alkyl-2-oxindoles
via Zn-mediated barbier-type reaction under aqueous conditions
L RAJU CHOWHANa,∗, MARRI SAMEER REDDYb and NANDIGAMA SATISH KUMARa
aCentre for Applied Chemistry, Central University of Gujarat, Gandhinagar, Gujarat 382 030, India
bSchool of Chemical Sciences, Central University of Gujarat, Gandhinagar, Gujarat 382 030, India
E-mail: rchowhan@cug.ac.in
MS received 4 March 2017; revised 22 May 2017; accepted 10 June 2017
Abstract. Arobustandrapidsynthesisof3-hydroxy-3-alkyl-2-oxindolesfromisatinsisdescribed. Thismethod
introduces an ecofriendly, un-activated Zn dust, solid NH4Cl and substrates under aqueous conditions, which
has produced the product in moderate to good yields. Without using column chromatography, majority of the
compounds were isolated in analytically pure form. The progress of the reaction could be visualized by naked
eye.
Keywords. Allyl halides; barbier reaction; ecofriendly synthesis; isatin; oxindoles; green synthesis;
water-mediated reaction.
drug Efavirenz which is an anti-HIV drug.11 Interesting
1. Introduction
biological activities including antimicrobial,12 antitu-
mor,13 and oviposition-stimulant14 activities have been
reported for brassinin and its analogues. There are a few
reports in the literature for the synthesis of 3-hydroxy-
3-alkyl-2-oxindoles.15 However, these methods involve
the usage of toxic metals, costly and air sensitive cat-
alysts and usage of volatile organic solvents. Based
on these facts, it is necessary to develop a simple and
eco-friendly protocol for the synthesis of 3-hydroxy-3-
alkyl-2-oxindoles.
Organic reactions performed under aqueous conditions
have attracted much attention in organic chemistry.
These methods are greener, easy to handle and economi-
cally viable1 making it as sustainable method which can
be scaled up for industrial level applications. Many reac-
tions including metal-catalyzed reactions for C-N,2 C-C
bond formation as well as catalytic asymmetric trans-
formations3 and numerous other reactions have been
successfully carried out under aqueous conditions with
no or minimal amount of solvents. This information
clearly proves the diverse utility of this methodology.
On the other hand, 3-hydroxy-3-alkyl-2-oxindoles
were found to be important core motifs of many nat-
ural products and biologically important molecules
(Figure 1).4 For example, TMC-95 acts as a pro-
teomes inhibitor,5 Celogentins were used for treatment
2. Experimental
Isatins, Ammonium chloride, alkyl halides were acquired
from Sigma Aldrich and Merck, and used without further
purification. N-substituted Isatins were synthesized as per
literature16 and characterized by 1H NMR to confirm the for-
of liver and eye diseases,6 Convolutamydines possess mation. Solvents used were acquired from Merck and SD
anti-inflammatory activity7 and its artificial analogues
Fine. Analytical thin layer chromatography was performed
were found to show anti-cancer8 and anti-convalescent
with the help of pre-coated silica gel plate (200 μm) which
were acquired from Sigma Aldrich matrix gel on Aluminium
activities.9 Welwitindolinones have shown multi-drug
with no fluorescent indicator. Zinc used was of laboratory
resistant activity.10 3-(cyclopropylethynyl)-3-hydroxy-
grade reagent. Column chromatography was performed over
silica gel of 60–120 mesh, both acquired from Rankem fine
chemicals.
1,5-dimethylindolin-2-one has shown HIV reverse tran-
scriptase inhibition activity and it is more active than the
To a solution of isatins (1 mmol), zinc dust (5 mmol),
alkyl halide (3 mmol) in THF was added saturated NH4Cl
*
For correspondence
Electronic supplementary material: The online version of this article (doi:10.1007/s12039-017-1329-8) contains supplementary material,
which is available to authorized users.

L Raju Chowhan et al.
Figure 1. Natural products with 3-hydroxy-3-substituted-2-oxindoles core.
(37 mmol) and stirred at rt for 20 min. The reaction mixture not one-pot reactions and involve the preparation of
was extracted with EtOAc (3×10 mL), the combined organic
nucleophilic species separately under inert condition,
layer was washed with brine (5 mL) and dried over anhydrous
followed by addition to carbonyl compound. There-
Na2SO4. Concentration in vacuum gave the corresponding 3-
fore, development of one-pot reaction under aqueous
hydroxy-3-alkyl-2-oxindoles as white solid in pure form. All
condition for addition of carbonyls are assumed to be
3-benzylated products were purified with column chromatog-
important and will be useful in green chemistry per-
raphy by using hexanes and ethyl acetate.
spective.
As a part of our ongoing research work on the syn-
3. Results and Discussion
thesis of biologically active compounds,19 here we
report a simple, mild and rapid method as an alter-
native to existing synthetic routes for the synthesis
of 3-hydroxy-3-alkyl-2-oxindoles under aqueous con-
ditions. We employed isatin 1a and allyl bromide 2a
as model substrates for optimization of reaction con-
Modified Barbier reaction protocol has gained much
attention due to its operational simplicity and
rapidness.17 Addition of organometallic to carbonyl
compounds are known.18 However, these methods are
Table 1. Optimization study.
Entry Allyl bromide (equivalent)a Zinc (equivalent) Time (min) Yield (%)b
1
2
1
1
2
3
20 30
20 50
3
4
5
6
2
2
3
5
4
5
5
8
20
20
15
20
72
80
95
95
aReaction conditions; all reactions were carried out at 1mmol of Isatin and 37
equiv. of sat. NH4Cl at rt. bIsolated yield.

An efficient and rapid synthesis of 3-hydroxy-3-alkyl-2-oxindoles
Scheme 1. Barbier-type reaction with unactivated Zn dust.
ditions. Initially, we performed a reaction with isatin Table 2. Scope of substrates.
1a (1 equiv.), allyl bromide 2a (1 equiv.) and Zn dust
(2 equiv.) by stirring for 20 minutes (Table 1, entry 1)
which formed the corresponding hydroxyoxindole in
30% yield, Scheme 1. Increase in the quantity of Zn
increased the yield up to 50%. Further increase in the
stoichiometric equivalents of allyl bromide and Zn dust,
surprisinglyincreasedtheproductyieldupto72%(entry
3, Table 1). Finally, we identified the best optimized
reaction condition as isatin 1a (1 equiv.), allyl bromide
2a (3 equiv.), Zn dust (5 equiv.) and saturated NH4Cl
(37 equiv.) and stirring for 15 minutes at rt (entry 5,
Table 1). The structure of the product was confirmed by
using 1H-NMR, 13C-NMR and ESI-HRMS spectrome-
try studies.
We applied this protocol successfully to a vari-
ety of alkyl halides and isatins affording the desired
product in good to excellent yields, as shown in
Table 2. We used propargyl, benzyl and substituted
allyl bromides (2a–2g) fruitfully with Isatin (1a) to
prepare the corresponding hydroxyl oxindole deriva-
tives (3b–3o), Scheme 2. The results are summarised
in Table 2.
To increase the substrate scope, we have used 5-
substituted (1b) and N-alkylated isatins (1c, 1d). How-
ever, in the case where N-substituted isatins were
employed as substrates, yield was lower compared with
simple isatin (Table 2, 3k–3o). We were delighted
to find that many products were found to be pure
enough (confirmed through NMR) after the workup
and hence chromatographic purification was not nec-
essary.
aReaction conditions: all reactions were carried out at 1mmol
of Isatin and saturated aqueous NH4Cl at rt. bIsolated yield.
c1:1 diastereomeric ratio. d1:2 diastereomeric ratio.
The progress of the reaction could be visualized by
naked eye; as the reaction progresses, the colour of the
reaction mixture turns into pale yellow from orange red.
We are interested to develop this protocol in gram
scale. We performed the reaction between isatin (1a,
1.47 g), zinc dust (4 g), benzyl bromide (2c, 3 mL) and
NH4Cl (5 g) under optimized reaction conditions. After
completion of the reaction, the product was purified by
column chromatography (yield, 1.9 g) (Scheme 2).
The limitation of this method was that it could not
be extended to inactivated alkyl and aryl halides. More-
over, generation of nucleophile is not feasible under this
condition. Allyl halide 2d and 2f afforded 3d and3f,
respectively, in 1:1 ratio of diastereomers, whereas
the benzylic halide 2g yielded 3g in 1:2 diastere-
omeric ratio, Table 2. We observed no isomerisation of
propargylic alcohols (3b, 3i, 3l) to the corresponding
allenes.20

L Raju Chowhan et al.
Scheme 2. Reaction of Isatin with various alkyl halides.
4. Conclusions
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In conclusion, a rapid and eco-friendly method for
the synthesis of 3-Hydroxy-3-alkyl-2-Oxindoles was
developed under aqueous conditions. Without using any
previously activated zinc or solid support, the method
has yielded the desired product in moderate to excel-
lent yields. No isomerisation of propargylic alcohols to
the corresponding allenes was observed. The method
described here is simple, economical, and environmen-
tally benign as it avoids purification in many cases.
Efforts are being made to increase the scope of this
method.
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Characterization data and spectra for all the compounds are
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Acknowledgements
L. R. C thanks DST-SERB (SB/EMEQ-304/2014) for funding
and M. S. R thanks UGC for Non-NET fellowship. Authors
are grateful to Prof. S. A Bari Hon’ble Vice-Chancellor, CUG
for his kind support and encouragement.
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