A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles

Article abstract of DOI:10.1016/j.tetlet.2012.11.083

A mild, high yielding approach to C-3 hydroxylated oxindoles using catalytic quantities of tetrabutylammonium fluoride and air as the stoicheiometric oxidant is reported over a wide range of substitution patterns.

Full text of DOI:10.1016/j.tetlet.2012.11.083

Tetrahedron Letters 54 (2013) 843–846
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Tetrahedron Letters
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A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of
oxindoles
⇑
Benjamin R. Buckley , Beatriz Fernández D.-R.
Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, high yielding approach to C-3 hydroxylated oxindoles using catalytic quantities of tetrabutylam-
monium fluoride and air as the stoicheiometric oxidant is reported over a wide range of substitution
patterns.
Received 10 October 2012
Revised 7 November 2012
Accepted 21 November 2012
Available online 29 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Oxindole
TBAF
Oxidation
Catalysis
Welwitindoline
Cl
Methods for functionalization of the oxindole nucleus are of sig-
nificant value in medicinal chemistry and natural product synthe-
sis.1 Due to their unprecedented structural diversity, biological
activity and structural challenge, oxindoles continue to attract
the interest of chemists and biologists alike. For example, the con-
volutamydines,2 and the 3-hydroxywelwitindolinones are part of a
growing list of biologically active 3-hydroxyoxindoles (Fig. 1).3 3-
Hydroxyoxindoles with a quaternary benzylic centre are a useful
class of compounds also found in several drug candidates, includ-
ing the potent, orally active growth hormone secretagogue SM-
130686,4 a drug that currently is under investigation for the treat-
ment of growth hormone deficiency and other medical conditions
(Fig. 1).5
Me
Me
Me
OH
SCN
O
O
N
Me
3-hydroxy-N-methylwelwitindolinone C isothiocyanate
Cl
R
Br
HO
CF3
OH
There are a number of reports on the enantioselective formation
of quaternary carbon centres at the 3-position of oxindoles.6 For
example, Hartwig first reported the palladium-catalysed synthesis
O
O
N
H2N
Br
N
H
of oxindoles by amide a
-arylation with ees of up to 67%.7 This was
O
convolutamydine A, R = COMe
convolutamydine E, R = CH2OH
NEt2
SM-130686
HO
later improved upon by Kündig using modified N-heterocyclic
carbenes8 and Marsden has reported several methods for the syn-
thesis of 3-hydroxy- and 3-amino-oxindoles.9
Copper-mediated processes have also recently been employed
to prepare quaternary C-3 oxindoles by both the Kündig10 and Tay-
lor groups.11 Also of note are the recent reports by Franz,12 who has
reported the asymmetric direct addition of nucleophiles to isatins
using chiral Lewis acids, and Shibata and Toru who have reported
the asymmetric C-3 hydroxylation of oxindoles also using chiral
S
NHMe
HO
Cl
HN
SMe
HO
N
N
O
O
N
H
N
H
ciclazindol
dioxibrassine
donaxaridine
Figure 1. Exemplar biologically active C-3 hydroxy oxindoles and
compound.
a related
⇑
Corresponding author. Tel.: +44 (0)1509 22 8752; fax: +44 (0)1509 22 3925.
E-mail address: b.r.buckley@lboro.ac.uk (B.R. Buckley).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.083

844
B. R. Buckley, B. Fernández D.-R. / Tetrahedron Letters 54 (2013) 843–846
Table 1
Application to a range of substratesa,b
Scheme 1. Gassman’s and Halweg’s route to isatins.
Me
Me
OH
H
Me
Me
TBAF (1.1 equiv.)
THF, 0 °C
O
O
N
N
Me
Me
TMS
Me
2
, 76%
H
1
(R)-
Me
(racemic)
82% ee
O
N
Me
not observed
Scheme 2. Curran’s attempted removal of the trimethylsilyl group from 1.
Lewis acids, with an oxaziridine as the stoicheiometric oxidant.13
Thus owing to the significance of the oxindole structural motif,
the development of catalytic methods for the synthesis of oxin-
doles bearing a C-3 hydroxy quaternary centre is highly desirable.
Gassman and Halweg reported the air oxidation of oxindoles to
isatins (Scheme 1) through treatment of 3-methylthiooxindoles
with a strong stoicheiometric base and air; strict anhydrous condi-
tions were required in order to prevent degradation of the isatin to
the corresponding anthranilic acid.14 We also noted the recent re-
port from Curran and co-workers,15 where the attempted removal
of the trimethylsilyl (TMS) group from 1 resulted in 3-hydroxy-1,3-
dihydroindol-2-one 2 being the sole product of the reaction
(Scheme 2). Careful investigation of Curran’s reaction conditions
revealed the use of 1.1 equiv of tetrabutylammonium fluoride
(TBAF); as 1.0 equiv was required to fully desilylate the aryl ring
we postulated that in order for 3-hydroxy-1,3-dihydroindol-2-
one to be the sole product of the reaction, base-catalysed aerial
oxidation must occur. We believed that this interesting unwanted
side reaction could be a practical, mild solution to the synthesis of
a
General conditions: TBAF (1 M in THF, 0.2 equiv), THF (2 mL), open vessel, rt,
24 h.19
b
Percentage yields shown refer to the isolated yield after chromatography.
is present in a variety of natural products and biologically impor-
tant molecules (see Fig. 1 for example); again we observed an
excellent conversion into the hydroxylated products 4k–4p. These
results are important when considering the recent report in which
Itoh and co-workers described the asymmetric aerial phase-trans-
fer oxidation of oxindoles (using aq KOH as a stoicheiometric
base): they noted that benzyl protected oxindoles gave poor yields
of C-3 hydroxylated products, also that the Boc protecting group
was not tolerated under their reaction conditions; further they
did not report the oxidation of oxindoles with aromatic groups at
C-3.20 Jiang and Tan have also reported the molecular oxygen oxi-
dation of oxindoles employing a stoicheiometric base and a chiral
pentadinium salt, but the substrate screen was narrow with the
only group at nitrogen studied being p-methoxybenzyl.21 Our pro-
cedure appears quite general with the protecting group on nitro-
gen having little influence on the reaction, however, a group at
nitrogen is essential for the reaction to occur (see 4b, Table 1 for
example, this is presumably due to deprotonation of the nitrogen
in preference to enolate formation).
Intrigued by these findings we also carried out a competition
experiment through the addition of an electrophile to the reaction.
For example, when 3g is treated with TBAF (0.2 equiv) in THF the
oxidized oxindole 4g is the sole product (Table 1), however, if
1,3-dichloro-5,5-dimethylhydantoin (DCDMH) is added prior to
the addition of TBAF then chlorination at C-3 is observed (to afford
5 along with recovered starting material 3g, Scheme 3), with no C-
3 hydroxylated product 4g being detectable by 1H NMR spectros-
copy or TLC analysis. Suggesting that quenching of the enolate with
3-hydroxyoxindoles using
a readily available organocatalyst
(TBAF) and a benign oxidant (air). This is even more important
when one considers that from both an economic and environmen-
tal viewpoint there is currently an urgent need for more atom effi-
cient systems that employ environmentally benign oxidants such
as H2O2, or more preferably, O2.16
We started our investigation by looking at the aerial oxidation
of 1,3-dimethyl-1,3-dihydroindol-2-one (3a) using varying equiva-
lents of TBAF in tetrahydrofuran as the solvent.17 We were de-
lighted to find that the reaction was extremely rapid at room
temperature and excellent yields of the hydroxylated oxindole 4a
were observed with catalyst loadings as low as 10 mol %. Below
this level we observed a poor conversion into the desired product
perhaps due to the breakdown of catalyst–counterion pairs at a
low catalyst concentration.18
Using our optimized conditions (THF, 20 mol % TBAF)19 we
screened a range of 3-alkyloxindoles, and again we were delighted
to find that excellent yields of the corresponding 3-hydroxyoxin-
doles 4c–4j were achieved (Table 1). We were also interested to
see if our system was able to oxidize 3-aryl oxindoles as this motif

B. R. Buckley, B. Fernández D.-R. / Tetrahedron Letters 54 (2013) 843–846
845
Cl
O
N
N
Cl
Bn
Bn
Bn
OH
O
H
Cl
(DCDMH 1.1 equiv.)
O
O
O
N
N
TBAF (0.2 equiv.)
THF, r.t., 24 h
N
Bn
Bn
Bn
5 15% conversion
4g not observed
3g
Scheme 3. Competition experiment by addition of DCDMH to the reaction.
A proposed catalytic cycle is outlined in Scheme 4. Treatment of
oxindole 3 with TBAF affords tetrabutylammonium enolate 6 plus
HF, following Path A addition of O2 affords peroxide anion 7 and
recombination with a molecule of HF affords peroxide 8 plus TBAF
which can re-enter the catalytic cycle.22 In order to break down
peroxide 8 we propose that another molecule of enolate 6 inter-
cepts 8 (Path B) and affords two molecules of the hydroxylated
product 4 plus another molecule of TBAF.
Recently Garg and co-workers23 and Rawal and co-workers24
both independently described their routes to (À)-3-hydroxy-N-
methylwelwitindolinone C isothiocyanate employing a strong
base, and in the case of Garg, air and Rawal an oxaziridine as oxy-
gen sources for the C-3 hydroxylation reaction (Scheme 5).
Employing our TBAF conditions to a model substrate 9, shown in
Scheme 6, which was prepared by analogy to that reported previ-
ously by Garg and co-workers,17,25 we were able to establish that
an excellent yield of the C-3 hydroxylated product 10 could be
achieved.
In conclusion, we have developed a mild catalytic process for
the hydroxylation of oxindoles at the C-3 position using an envi-
ronmentally benign terminal oxidant that appears to be of general
use to a wide range of protected oxindoles. The protocol is also
effective for hindered substrates such as the welwitindolinone
model 9. In addition stoicheiometric TBAF is an effective base for
halogenation at the C-3 position of oxindoles.
Scheme 4. Proposed catalytic cycle.
Acknowledgments
Cl
Cl
Ref. 23 LiHMDS, air
THF, 23ºC, 48%.
Me
Me
The authors would like to thank Eli Lilly Co. for a generous
equipment donation, Research Councils UK for a RCUK fellowship
(to B.R.B.), the EU Lifelong Learning Programme for support (to
B.F.D.-R.), the Royal Society for a Research Grant (RG100494) and
Loughborough University for funding.
H
H
or
Me
Me
Me
Me
SCN
SCN
Ref. 24 KHMDS, THF,
O
O
H
OH
–78ºC, then
O
O
O
Ph
67%.
NSO2Ph
N
N
Supplementary data
Me
Me
Supplementary data (synthetic details along with 1H and 13C
NMR spectra for all novel compounds) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.11.083.
Scheme 5. Garg and Rawal’s independent routes to 3-hydroxywelwitindoline.
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