In Situ Electrophilic Activation of Hydrogen Peroxide for Catalytic Asymmetric α-Hydroxylation of 3-Substituted Oxindoles

Article abstract of DOI:10.1055/s-0036-1558958

Peroxy trichloroacetimidic acid, in situ generated from aqueous hydrogen peroxide and trichloroacetonitrile, was found to act as a competent electrophilic oxygenating agent for the direct α-hydroxylation of oxindoles. The use of chiral 1,2,3-triazolium sa

Full text of DOI:10.1055/s-0036-1558958

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In Situ Electrophilic Activation of Hydrogen Peroxide for Catalytic
Asymmetric α-Hydroxylation of 3-Substituted Oxindoles
Kohsuke Ohmatsua
Yuichiro Andoa
Takashi Ooi*a,b
a Institute of Transformative Bio-Molecules (WPI-ITbM)
and Department of Applied Chemistry,
Graduate School of Engineering, Nagoya University,
Nagoya 464-8601, Japan
tooi@apchem.nagoya-u.ac.jp
b CREST, Japan Science and Technology Agency (JST),
Nagoya 464-8601, Japan
Received: 29.12.2016
Accepted after revision: 06.02.2017
Published online: 27.02.2017
source.7 In conjunction with these studies, we became in-
terested in the possibility of exploiting the reactivity of the
peroxy imidic acid as an electrophilic oxygenating agent to
directly install a hydroxyl group at the α-position of car-
bonyl compounds using hydrogen peroxide as a terminal
oxidant (Scheme 1 C).
DOI: 10.1055/s-0036-1558958; Art ID: st-2016-b0882-c
Abstract Peroxy trichloroacetimidic acid, in situ generated from aque-
ous hydrogen peroxide and trichloroacetonitrile, was found to act as a
competent electrophilic oxygenating agent for the direct α-hydroxyl-
ation of oxindoles. The use of chiral 1,2,3-triazolium salt as a phase-
transfer catalyst enabled rigorous absolute stereocontrol in the carbon–
oxygen bond-forming reaction. The present study provides a new, yet
practical method for straightforward access to optically active α-hy-
droxycarbonyl compounds.
A) Activation of alcohols using trichloroacetonitrile
NH
Cl3CCN
Nu
R
OH
R
Nu
R
O
CCl3
Key words hydroxylation, carbonyl compound, hydrogen peroxide,
imidic acid, oxindole, chiral ion pair, 1,2,3-triazolium ion
trichloroacetimidate
B) Payne-type oxidation
Conversion of the hydroxyl group into a better leaving
group, such as acetoxy or sulfonyloxy, represents one of the
most fundamental and versatile activation processes for
implementing the subsequent bond-forming reactions. Fac-
ile generation of trichloroacetimidates from alcohols by the
treatment with trichloroacetonitrile is a particularly unique
example (Scheme 1 A),1,2 which has been classically utilized
for glycosylation reactions.3 The trichloroacetimidate is a
reactive electrophile, yet compatible with Brønsted acid or
hydrogen-bond donor catalysis. The groundwork for this
hydroxyl-group activation tactic was laid by Payne through
the development of the epoxidation of alkenes by peroxy
trichloroacetimidic acid, which was generated in situ from
hydrogen peroxide and trichloroacetonitrile under basic
conditions (Scheme 1 B).4,5 The potential applicability of
this mode of peroxy imidic acid generation to asymmetric
catalysis was demonstrated by our group in the develop-
ment of the enantioselective Payne-type oxidation of N-sul-
fonyl imines.6 On the other hand, we recently established a
catalytic system for the direct asymmetric α-amination of
carbonyl compounds based on the activation of hydroxyl-
amines with trichloroacetonitrile as an electrophilic amine
R1
Cl3CCN
NH
HO
X
O
X
HO OH
R1
O
CCl3
(X = CR22 or NR2)
peroxy imidic acid
C) Asymmetric α-hydroxylation of carbonyl compounds
O
O
Cl3CCN
R1
HO
R1 R2
HO OH
+
R3
R3
R2
Scheme 1 Transformations based on the activation of hydroxyl group
with trichloroacetonitrile
Asymmetric α-hydroxylation of carbonyls is an efficient
and straightforward method to access chiral tertiary α-hy-
droxycarbonyl compounds, which constitute structural
components of many biologically active organic molecules
and serve as versatile synthetic intermediates.8 There have
been various successful examples that relied on the com-
bined use of effective catalysts and appropriate oxygenating
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reagents such as alkyl hydroperoxide,9 dimethyldioxirane,10
oxaziridine,11 nitrosoarene,12 and molecular oxygen.13 How-
ever, reliable catalytic systems that can use abundant and
safe-to-handle hydrogen peroxide as an oxidant are ex-
tremely scarce because of its low electrophilicity.14 Here, as
our solution to this problem, we report the development of
a highly enantioselective direct α-hydroxylation of 3-sub-
stituted oxindoles under the catalysis of chiral 1,2,3-tri-
azolium salts.15
We initially attempted the reaction of N-Boc-3-phenyl-
oxindole (2a) with excess 30% aqueous solution of hydro-
gen peroxide (20 equiv) in the presence of trichloroacetoni-
trile (1.0 equiv), potassium carbonate (1.0 equiv), and a cat-
alytic quantity of L-alanine-derived chiral 1,2,3-triazolium
bromide 1a·Br (5 mol%) in toluene at 0 °C under argon at-
mosphere (Table 1, entry 1). The carbon–oxygen bond for-
mation proceeded smoothly, and the desired α-hydroxyox-
indole 3a was obtained with moderate enantioselectivity. It
should be noted that no oxidation products were detected
in the absence of trichloroacetonitrile and substrate 2a was
recovered quantitatively (Table 1, entry 2). This observation
emphasizes the critical importance of the combination of
hydrogen peroxide and trichloroacetonitrile in promoting
direct α-hydroxylation. For improving the stereoselectivity,
we evaluated the effect of the catalyst structure, specifically
that of the aliphatic substituent (R) on the stereogenic cen-
ter of amino acid origin, and identified the L-leucine-de-
rived triazolium salt 1c·Br as an optimal catalyst (Table 1,
entry 4). Subsequent screening of the solvents revealed the
significant influence on the reactivity and selectivity pro-
files (Table 1, entries 6–9). In particular, diethyl ether
proved to be the solvent of choice, making it feasible to at-
tain high reaction efficiency and enantioselectivity (Table 1,
entry 7). An additional insight gained from a control exper-
iment was that the present hydroxylation could occur in the
absence of the triazolium catalyst to give the racemic prod-
Table 1 Optimization of Reaction Conditionsa
Table 2 Scope of Oxindolesa
Ph
1·Br (5 mol%)
Ph
OH
Cl3CCN (1 equiv)
O +
30% aq H2O2
1c·Br (5 mol%)
O
R1
N
R1
K2CO3 (1 equiv)
solvent, Ar
N
30% aq H2O2 (5 equiv)
Cl3CCN (1 equiv)
(X equiv)
OH
Boc
Boc
R2
R2
2a
3a
0 °C, 15 h
O
O
K2CO3 (1 equiv)
Et2O, Ar
N
N
Boc
Boc
R
Ph
2
3
–10 °C, 24 h
Ph
N
N
Ph
1a·Br (R = Me)
N
N
H
O
Entry
R1
4-MeC6H4
R2
3
Yield (%)b ee (%)c
1b·Br (R = CH2Ph)
1c·Br (R = CH2i-Pr)
1d·Br (R = n-Pr)
H
1
2
H
3b
3c
3d
3e
3f
86
80
81
89
90
67
93
58
71
87
96
97
96
89
90
89
71
93
92
93
90
93
92
90
94
89
94
95
97
94
98
94
94
90
Ph
Ph
4-MeOC6H4
4-FC6H4
3-MeC6H4
3-MeOC6H4
1-Naph
2-Naph
Et
H
Br
Solvent
3
H
Entry
1
H2O2 (X equiv) Yield (%)b
ee (%)c
4
H
1
2d
3
1a
1a
1b
1c
1d
1c
1c
1c
1c
1c
1c
1c
toluene
toluene
toluene
toluene
toluene
CH2Cl2
Et2O
20
20
20
20
20
20
20
20
20
5
65
0
65
–
5
H
6
H
3g
3h
3i
77
66
82
49
80
10
54
83
57
97
79
83
79
61
90
24
75
92
92
94
7
H
4
8
H
5
9
n-Bu
H
3j
6
10
11
12
13
14
15
16
17
c-HexCH2
CH2=CHCH2
Bn
H
3k
3l
7
H
8
THF
H
3m
3n
3o
3p
3q
3r
9
EtOAc
Et2O
4-MeOC6H4CH2
4-FC6H4CH2
Ph
H
10
11
12e
H
Et2O
2
Me
MeO
F
Et2O
5
Ph
a Unless otherwise noted, reaction was conducted with 2a (0.1 mmol), 30%
aq solution of H2O2, Cl3CCN (1 equiv), K2CO3 (1 equiv), and 1·Br (5 mol%) in
solvent (1 mL) at 0 °C for 15 h under Ar.
Ph
a Reaction was conducted with 2 (0.1 mmol), 30% aq solution of H2O2 (5
equiv), Cl3CCN (1 equiv), K2CO3 (1 equiv), and 1c·Br (5 mol%) in Et2O (1 mL)
at –10 °C for 24 h under Ar.
b Isolated yield.
c Determined by HPLC with chiral column.
d Without Cl3CCN.
b Isolated yield.
c Determined by HPLC with chiral column.
e Reaction was performed at –10 °C for 24 h.
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uct (data not shown). We assumed that this competitive
background pathway could be suppressed by reducing the
amount of hydrogen peroxide. Indeed, the use of five equiv-
alents of hydrogen peroxide enabled higher enantiocontrol
without notable rate retardation (Table 1, entry 10). Finally,
lowering the temperature to –10 °C with prolonged reac-
tion time resulted in an almost quantitative formation of 3a
with a satisfactory level of enantiomeric purity (Table 1, en-
try 12).
References and Notes
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The scope of 1c·Br-catalyzed asymmetric direct α-hy-
droxylation of 3-substituted oxindoles 2 was explored un-
der the optimized conditions, and the representative re-
sults are summarized in Table 2.16 Generally, 5 mol% of 1c·Br
was sufficient to control the hydroxylation of a range of N-
Boc oxindoles, giving rise to the corresponding chiral hy-
droxyoxindoles 3 with uniformly high enantioselectivity.
With respect to 3-aryl oxindoles, this protocol tolerated the
incorporation of both electron-donating and electron-with-
drawing substituents (Table 2, entries 1–5). The reaction
with 3-(1-naphthyl)oxindole showed slightly lower conver-
sion (Table 2, entry 6), whereas the product was isolated in
excellent yield in the oxidation of 2 having 2-naphthyl sub-
stituent (Table 2, entry 7). 3-Alkyl oxindoles also appeared
to be suitable nucleophiles, and a similar degree of reactivi-
ty and selectivity was observed (Table 2, entries 8–14).
Moreover, this catalytic system well accommodated differ-
ently 5-substituted 3-phenyloxindoles (Table 2, entries 15–
17).
In conclusion, we have developed a catalytic enantiose-
lective α-hydroxylation of 3-substituted oxindoles using
aqueous hydrogen peroxide as a terminal oxidant. The judi-
cious use of trichloroacetonitrile and the chiral 1,2,3-tri-
azolium salt for the electrophilic activation of hydrogen
peroxide and the stereocontrol of carbon–oxygen bond for-
mation, respectively, allows for the direct asymmetric
transfer of hydroxyl group into the α-position of carbonyls.
We believe that this operationally simple, yet powerful
method will be further applied to the development of syn-
thetically valuable asymmetric hydroxylation reactions.
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70, 1691. (c) Tsutsumi, R.; Kim, S.; Uraguchi, D.; Ooi, T. Synthesis
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Lian, M.; Li, Z.; Wang, Y.; Meng, Q. J. Org. Chem. 2012, 77, 9601.
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Acknowledgment
Financial support was provided by CREST (JST), JSPS KAKENHI Grant
Number JP16H01015 in Precisely Designed Catalysts with Custom-
ized Scaffolding, and the Program for Leading Graduate Schools ‘Inte-
grative Graduate Education and Research Program in Green Natural
Sciences’ at Nagoya University.
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Chem. Soc. 2009, 131, 4562.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1558958.
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(14) Li, Z.; Lian, M.; Yang, F.; Meng, Q.; Gao, Z. Eur. J. Org. Chem. 2014,
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the mixture was stirred for 24 h. The reaction was quenched
with a sat. aq solution of NH4Cl, and the extractive workup was
performed with EtOAc. The organic extracts were dried over
Na2SO4, filtered, and concentrated. The crude residue was puri-
(16) In the present system, the N-Boc group on the oxindole nitrogen
seemed crucial for achieving high efficiency and enantioselec-
tivity. For instance, attempted reaction of N-4-methoxyphenyl
3-phenyloxindole under identical conditions described in Table
2 afforded the corresponding α-hydroxyoxindole in moderate
yield with low enantioselectivity (45% yield, 28% ee).
(17) Representative Procedure for Catalytic Asymmetric α-
Hydroxylation of Oxindoles
fied by column chromatography on silica gel (hexane–CHCl3 =
3:1 as eluent) to afford 3a (31.5 mg, 0.097 mmol, 97% yield, 94%
ee).
Compound 3a: [α]D23 = +45.6 (c = 3.0, CHCl3) for 94% ee. 1H NMR
(400 MHz, CDCl3): δ = 7.94 (1 H, d, J = 8.2 Hz), 7.40 (1 H, td, J =
8.0, 1.2 Hz), 7.36–7.29 (6 H, m), 7.20 (1 H, t, J = 7.8 Hz), 3.42 (1
H, s), 1.63 (9 H, s). 13C NMR (101 MHz, CDCl3): δ = 176.0, 149.2,
139.9, 139.8, 130.3, 128.8, 128.7, 125.7, 125.4, 125.2, 115.6,
85.0, 77.8, 28.2, one peak for aromatic carbon was not found
probably due to overlapping. IR (film): 3456, 3001, 2978, 1788,
1609, 1479, 1342, 1285, 1146, 908, 719 cm-1. HRMS (ESI+): m/z
calcd for C19H19NO4Na+ [M + Na]+: 348.1206; found: 348.1206.
HPLC (ID3, hexane–i-PrOH = 10:1, flow rate = 0.5 mL/min, λ =
210 nm): t = 15.8 min (major isomer); 17.5 min (minor isomer).
A solution of 1c·Br (3.76 mg, 0.005 mmol), oxindole 2a (30.9 mg,
0.10 mmol), and K2CO3 (13.8 mg, 0.10 mmol) in Et2O (1.0 mL)
was degassed by alternating vacuum evacuation/argon backfill.
Then, the resulting mixture was cooled to –10 °C. To this solu-
tion were successively added a 30% aq solution of H2O2 (50 μL,
0.50 mmol) and trichloroacetonitirile (10 μL, 0.10 mmol), and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D