Pentanidium-catalyzed enantioselective α-hydroxylation of oxindoles using molecular oxygen

Article abstract of DOI:10.1021/ol302030v

Pentanidium-catalyzed α-hydroxylation of 3-substituted-2-oxindoles using molecular oxygen has been developed with good yields and enantioselectivities. This reaction does not require an additional reductant such as triethyl phosphite, which was typically added to reduce the peroxide intermediate. The reaction was demonstrated to consist of two-steps: an enantioselective formation of hydroperoxide oxindole and a kinetic resolution of the hydroperoxide oxindole via reduction with enolates generated from the oxindoles.

Full text of DOI:10.1021/ol302030v

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4762–4765
PentanidiumÀCatalyzed Enantioselective
r‑Hydroxylation of Oxindoles Using
Molecular Oxygen
Yuanyong Yang,† Farhana Moinodeen,† Willy Chin,† Ting Ma,† Zhiyong Jiang,*,‡ and
Choon-Hong Tan*,‡,§
Department of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543, Key Laboratory of Natural Medicine and Immuno-Engineering of
Henan Province, Henan University, Kaifeng, Henan, China, 475004, and Division of
Chemistry and Biological Chemistry, Nanyang Technological University,
21 Nanyang Link, Singapore 637371
choonhong@ntu.edu.sg; chmjzy@henu.edu.cn
Received July 22, 2012
ABSTRACT
Pentanidium-catalyzed r-hydroxylation of 3-substituted-2-oxindoles using molecular oxygen has been developed with good yields and
enantioselectivities. This reaction does not require an additional reductant such as triethyl phosphite, which was typically added to reduce
the peroxide intermediate. The reaction was demonstrated to consist of two-steps: an enantioselective formation of hydroperoxide oxindole and a
kinetic resolution of the hydroperoxide oxindole via reduction with enolates generated from the oxindoles.
Molecular oxygen can be obtained at almost no cost
and as a reagent, produces no environmentally hazardous
byproduct and is thus considered by many to be the ideal
oxidant. In the past few decades, several transition metal-
catalyzed oxidations of organic substrates with molecular
oxygen have been developed.1 The insertion of hydroxy
groups, particularly to the R-position of functional groups
is an important transformation,2 as many compounds of
biological importance and synthetic interest consist of
oxygenated carbon skeletons. It is known that many
carbonyl compounds react rapidly with molecular oxygen
under basic conditions.3
Phase-transfer catalysis has the advantages of hav-
ing simple experimental procedures and mild reaction
conditions.4 It was demonstrated that R-hydroxylation
of achiral ketones can be achieved with molecular oxygen
as oxidant in the presence of Cinchona alkaloid-derived
phase-transfer catalysts.5 R-Hydroxy ketones with moderate
† National University of Singapore
‡ Henan University
§ Nanyang Technological University
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r
10.1021/ol302030v
Published on Web 09/04/2012
2012 American Chemical Society

enantioselectivities were obtained, and triethyl phosphite
was added to reduce the peroxide intermediate. Optically
activecrown etherswerealsoshowntobeeffective asphase
transfer catalysts for R-hydroxylation of cyclic ketones
with molecular oxygen.6
the enantioselective Michael reactions of tert-butyl
glycinate-benzophenone Schiff base with high enantio-
selectivities and low catalyst loading.10 In this comm-
unication, we wish to report that R-hydroxylation of
3-substituted-2-oxindoles can be efficiently conducted
using pentanidium ascatalyst with high enantioselectivities.
Molecular oxygen was used as the oxidant, and contrary to
all previous reports, no reductant such as triethyl phosphite
was required (Figure 1, eq 2).
Figure 1. Enantioselective R-hydroxylation of 3-substituted-
2-oxindoles (1) with (EtO)3P as reductant (known),9b (2) without
reductant (this work).
Figure 2. Various chiral pentanidiums.
The oxidation of 3-methyl-2-oxindole 2a with air in the
presence of 5 mol % pentanidium 1a was initially con-
ducted with 2 equiv of triethyl phosphite as the reductant.
The solvent used was toluene with 50% aq KOH (v/v = 10:1)
and at a reaction temperature of À20 °C. The reac-
tion proceeded smoothly to afford 3-hydroxy-2-oxindole
3a with 52% yield and 56% ee in 12 h (Table 1, entry 1).11
We found that in the absence of triethyl phosphite, the
reaction also proceeded well. We were pleasantly surprised
when we found that the ee of 3a was increased to 67%.
However, significant amount of hydroperoxide oxindole
4a was detected as a side product (3a/4a = 70:30, entry 2).
Next, we tried to determine if the steric and electronic
properties of pentanidiums 1 (Figure 2) would alter the
product ratio and enantioselectivities. The use of more bulky
and electron-deficient benzylic groups on pentanidiums 1
improved the enantioselectivities (entries 3À5); pentanidium
1d afforded 3a with 92% ee (entry 5).11 Further optimization
of the reaction conditions were carried out by examining
different solvents with 1d as catalyst (entries 6À7); toluene
was identified as the ideal solvent.11 Lower reaction tem-
perature (À60 °C) improved the ee to 97% without loss of
reaction rate, but the ratio of 3a/4a was decreased to 43:57
(entry 9). We observed that the amount of molecular
oxygen affects the ratio of 3a/4a. When the amount of
air was restricted to 0.55 equiv of O2, the ratio of 3a/4a was
enhanced to 91:9, and ee of 3a was slightly decreased to
95% (entry 10). The hydroperoxide oxindole 4a could be
isolated and determined to have an ee of 36% ee (entry 10).
When a slightly lesser amount of O2 was used (0.4 equiv),
the ratio of 3a/4awasevenbetter, but the enantioselectivity
suffered slightly (82% ee, 3a/4a >95:5, entry 11). The ab-
solute configuration of 3a was designated as R by compar-
ing with an example in the literature, and the absolute
configuration of 4a was determined to be S via reduction.11
3-Substituted-3-hydroxy-2-oxindole is the core struc-
ture of a number of several natural products with a broad
spectrum of biological activities, and it is the focus of a
number of medicinal chemistry programs.7 The 3-hydroxy
position greatly affects the biological activities and
developing an efficient method to obtain enantiopure
3-hydroxy-2-oxindoles is critical for further investiga-
tions of these compounds.8 Shibata, Toru and co-workers
demonstrated the enantioselective R-oxidation of
3-substituted-2-oxindole using DBFOX-Zn(II) catalyst
and oxaziridine as oxidant.9a Subsequently, Itoh and co-
workers investigated the reaction under phase transfer con-
dition using molecular oxygen in the presence of Cinchona
alkaloid-derived catalyst (Figure 1, eq 1).9b Moderate to
good enantioselectivities were observed. More recently,
Barbas and co-workers utilized a dimeric quinidine to cat-
alyze the aminooxygenation of 3-substituted-2-oxindole with
nitrosobenzene as an approach toward chiral 3-hydroxy-
2-oxindoles.9c
Previously, we disclosed a new class of phase transfer
catalysts, pentanidiums, and showed that it can catalyze
(6) (a) Eckehard, V. D.; Volker, K. Liebigs Ann. Chem. 1992, 283–
285. (b) Vries, E. F. J.; Ploeg, L.; Colao, M.; Brussee, J.; Van der Gen, A.
Tetrahedron: Asymmetry 1995, 6, 1123–1132.
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Piyasena, H.; Nicholas, A. M. Bioorg. Med. Chem. Lett. 1997, 7, 1255–
1260. (c) Zhang, H.; Kamano, Y.; Yoshitatsu, I.; Haruhisa, K.; Kanki,
K.; Hideji, L.; George, R. P. Tetrahedron 1995, 51, 5523–5528.
(d) Teruhisa, T.; Hume, W. E.; Takashi, U.; Kazuhiko, O.; Yasuyuki,
U.; Kazuo, K.; Shinji, H.; Jun, N.; Hitoshi, S.; Mutsuo, T.; Hiroshi, N.;
Ryu, N. J. Med. Chem. 2001, 44, 4641–4649. (e) Piyasena, H.; Matthew,
E.; Sandra, L. M.; Jay, K.; Harvey, W.; Christopher, G. B.; Debra, J. P.;
Gao, Q.; Stella, H.; Valentin, K. G.; Nicholas, A. M. J. Med. Chem.
2002, 45, 1487–1499. (f) Teruhisa, T.; Hume, W. E.; Nagamine, J.;
Kawamura, T.; Mutsuo, T.; Nagata, R. Bioorg. Med. Chem. Lett. 2005,
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Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488–16489. (b) Sano, D.;
Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593–1595. (c) Bui, T.; Candeias,
N. R.; Barbas, C. F., III J. Am. Chem. Soc. 2010, 132, 5574–5575.
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C.-H. J. Am. Chem. Soc. 2011, 133, 2828–2831.
(11) See the Supporting Information for details.
Org. Lett., Vol. 14, No. 18, 2012
4763

Table 1. Optimizing Conditions for Pentanidium-Catalyzed
R-Hydroxylation of 3-Methyl-2-oxindole 2aa
Table 2. Pentanidium-Catalyzed R-Hydroxylation of
3-Substituted-2-Oxindoles 2 with Molecular Oxygena
entry
1
solvent temp (°C) ee of 3a (%)b ratio of 3a/4ab
1
2
3
4
5
6
7
8
9
1a toluene
1a toluene
1b toluene
1c toluene
1d toluene
1d THF
À20
À20
À20
À20
À20
À20
À20
À40
À60
À60
À60
56c
67
78
86
92
38
87
93
97
95
82
>95:5
70:30
69:31
72:28
71:29
51:49
66:34
62:38
43:57
91:9
1d ether
1d toluene
1d toluene
10d,e,f 1d toluene
11e,g
1d toluene
>95:5
a Unless otherwise noted, the reaction was carried out with 0.05
mmol 2a, 0.3 mL of 50% aq KOH and 0.0025 mmol catalyst 1 in 3.0 mL
of solvent, and the conversions of all reactions were determined as 100%
by 1H NMR analysis. b Determined by HPLC analysis on a chiral
stationary phase. c Yield = 52%, 12 h, 2 equiv of (EtO)3P. d 0.55 equiv
of O2 (2.9 mL air, calculated at 25 °C, 1 atm, 21% v/v of O2 in air) was
used, introduced to reaction via a syringe. e Reaction time was 3 days.
f The ee of 4a is 36%. g 0.4 equiv of O2 (2.1 mL of air) was used, and 83%
conversion was observed.
a Unless otherwise noted, the reaction was carried out with 0.05
mmol 2, 0.3 mL of 50% aq KOH and 0.0025 mmol catalyst 1d in 3.0 mL
of toluene. b Isolated yields of 3. c Enantiomeric excesses of 3 determined
by HPLC analysis on a chiral stationary phase.
which configuration is controlled by pentanidium 1.
The hydroperoxide oxindoles 4 are subsequently reduced
by the enolates of 3-substituted-2-oxindoles, generated in
situ under the basic reaction condition. This kinetic resolu-
tion step further improved the enantiopurity of the hydroxyl-
oxindole obtained.
With the optimized reaction condition on hand, the
R-hydroxylation could be extended to a variety of 3-
substituted-2-oxindoles to give 3-hydroxyl-2-oxindoles
3bÀk in 85À98% ee and 83À93% yield (Table 2). Studies
showed that the introduction of various substituents onto
the phenylgroupofoxindolesdid not affect theee (Table 2,
entries 1À3). When the substitutent at C3-position of 2 was
an n-butyl group, the ee was slightly decreased to 85%
(entry 4). It was also found that benzyl, allyl and alkynyl-
substituted oxindoles were hydroxylated in high yields
and with excellent enantioselectivities (entries 5À10).
In all reactions, the ratios of 3/4 were satisfactory,
and the side product 4 could be readily removed by
chromatography.11
We found that, from the optimization studies, the amount
of hydroperoxide oxindoles obtained was related to amount
of molecular oxygen in the reaction. When 3-methyl-2-
oxindole 2a was oxidized using an O2 balloon instead of
air, hydroperoxide oxindole 4a could be obtained in high
yield and good enantioselectivity (85% yield, 80% ee,
eq 3). A mixture of toluene and THF was helpful to
increase the yield of 4a; it was observed that polar solvent
promoted the formation of the hydroperoxide oxindole. It
is interesting to note that the absolute configuration of 4a
obtained in this experiment is R, opposite to that when 4a
was obtained as a minor product and air was used as the
oxidant (Table1, entry 10). Therefore, we proposed thatthe
R-hydroxylation should be a two-step reaction (Figure 3).
First, 3-substituted-2-oxindoles 2 react with O2 in an en-
antioselective fashion to give the hydroperoxide oxindoles 4,
Figure 3. Proposed reaction pathway.
A simple isotope labeling experiment was conducted
with 18O2 (eq 4) to verify the role of molecular oxygen as
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Org. Lett., Vol. 14, No. 18, 2012

oxidant.12 It was observed that [18O]-3a was obtained with
84% level of 18O incorporation, as determined by mass
spectroscopy.
molecular oxygen has been developed using pentanidium
as the chiral phase-transfer catalyst. Several 3-hydroxyl-
2-oxindoles with excellent enantioselectivities (85%À98% ee)
were obtained. This reaction was demonstrated to be
a two-step reaction: an enantioselective formation of
hydroperoxide oxindole followed by kinetic resolution
of the hydroperoxide oxindole. We are currently using
this protocol to prepare enantiopure biologically active
3-hydroxyl-2-oxindoles. Further mechanistic studies will
be carried out, and results will be reported in due course.
Under strongly basic condition and at low temperature,
racemic hydroperoxide oxindole 4a can be obtained as a
major product by treating 2a under O2 atmosphere (eq 5).
Pure rac-4a can be obtained through recrystallization. In
order to elucidate the second step of the R-hydroxylation,
we utilized 5 mol % of pentanidium 1d as catalyst and
2 equiv of rac-4a as oxidant. In the absence of air,
3-methyl-2-oxindole 2a can be hydroxylated to (R)-3a with
76% ee, and the remained hydroperoxide oxindole was
determined to be (S)-4a with 51% ee (eq 6).11 The selectiv-
ity factor S (or Krel) was determined to be 5 on the basis of
this result.11,13 This result demonstrated that the pentani-
dium catalyst has a bias for selecting (R)-4a (match case)
and used it to form (R)-3a preferentially.
Acknowledgment. Financial support from ARF grant
(R-143-000-461-112 to C.-H.T.) from NUS and the
National Natural Science Foundation of China (21072044
to Z.J.) is greatly appreciated.
In summary, a highly enantioselective reductant-
free R-hydroxylation of 3-substituted-2-oxindoles using
Supporting Information Available. General informa-
tion, typical experimental procedures, characterization
and NMR spectra of the compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org
(12) (a) Zhu, M.-K.; Zhao, J.-F.; Loh, T.-P. J. Am. Chem. Soc. 2010,
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Chem. Soc. 2011, 133, 1760–1762. (c) Chiba, S.; Zhang, L.; Lee, J.-Y.
J. Am. Chem. Soc. 2010, 132, 7266–7267. (e) Zhang, C.; Jiao, N. J. Am.
Chem. Soc. 2010, 132, 28–29.
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7725–7726. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307–1315.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
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