Key words hydroxylation - carbonyl compound - hydrogen peroxide - imidic acid - oxindole - chiral
ion pair - 1,2,3-triazolium ion
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. Facile 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 development of the enantioselective
Payne-type oxidation of N -sulfonyl 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 hydroxylamines with trichloroacetonitrile
as an electrophilic amine source.[7 ] In conjunction with these studies, we became interested 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 carbonyl compounds using hydrogen
peroxide as a terminal oxidant (Scheme [1 ] C).
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-hydroxycarbonyl 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 combined use of effective
catalysts and appropriate oxygenating reagents such as alkyl hydroperoxide,[9 ] dimethyldioxirane,[10 ] oxaziridine,[11 ] nitrosoarene,[12 ] and molecular oxygen.[13 ] However, reliable catalytic systems that can use abundant and safe-to-handle hydrogen
peroxide as an oxidant are extremely 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-substituted oxindoles under the catalysis of chiral 1,2,3-triazolium
salts.[15 ]
Table 1 Optimization of Reaction Conditionsa
Entry
1
Solvent
H2 O2 (X equiv)
Yield (%)b
ee (%)c
1
1a
toluene
20
65
65
2d
1a
toluene
20
0
–
3
1b
toluene
20
77
79
4
1c
toluene
20
66
83
5
1d
toluene
20
82
79
6
1c
CH2 Cl2
20
49
61
7
1c
Et2 O
20
80
90
8
1c
THF
20
10
24
9
1c
EtOAc
20
54
75
10
1c
Et2 O
5
83
92
11
1c
Et2 O
2
57
92
12e
1c
Et2 O
5
97
94
a Unless otherwise noted, reaction was conducted with 2a (0.1 mmol), 30% aq solution of H2 O2 , Cl3 CCN (1 equiv), K2 CO3 (1 equiv), and 1 ·Br (5 mol%) in solvent (1 mL) at 0 °C for 15 h under Ar.
b Isolated yield.
c Determined by HPLC with chiral column.
d Without Cl3 CCN.
e Reaction was performed at –10 °C for 24 h.
Table 2 Scope of Oxindolesa
Entry
R1
R2
3
Yield (%)b
ee (%)c
1
4-MeC6 H4
H
3b
86
93
2
4-MeOC6 H4
H
3c
80
92
3
4-FC6 H4
H
3d
81
93
4
3-MeC6 H4
H
3e
89
90
5
3-MeOC6 H4
H
3f
90
93
6
1-Naph
H
3g
67
92
7
2-Naph
H
3h
93
90
8
Et
H
3i
58
94
9
n -Bu
H
3j
71
89
10
c -HexCH2
H
3k
87
94
11
CH2 =CHCH2
H
3l
96
95
12
Bn
H
3m
97
97
13
4-MeOC6 H4 CH2
H
3n
96
94
14
4-FC6 H4 CH2
H
3o
89
98
15
Ph
Me
3p
90
94
16
Ph
MeO
3q
89
94
17
Ph
F
3r
71
90
a Reaction was conducted with 2 (0.1 mmol), 30% aq solution of H2 O2 (5 equiv), Cl3 CCN (1 equiv), K2 CO3 (1 equiv), and 1c ·Br (5 mol%) in Et2 O (1 mL) at –10 °C for 24 h under Ar.
b Isolated yield.
c Determined by HPLC with chiral column.
We initially attempted the reaction of N -Boc-3-phenyloxindole (2a ) with excess 30% aqueous solution of hydrogen peroxide (20 equiv) in the presence
of trichloroacetonitrile (1.0 equiv), potassium carbonate (1.0 equiv), and a catalytic
quantity of l -alanine-derived chiral 1,2,3-triazolium bromide 1a ·Br (5 mol%) in toluene at 0 °C under argon atmosphere (Table [1 ], entry 1). The carbon–oxygen bond formation proceeded smoothly, and the desired
α-hydroxyoxindole 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 center of amino acid origin, and identified the l -leucine-derived 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 profiles (Table [1 ], entries 6–9). In particular, diethyl ether proved to be the solvent of choice,
making it feasible to attain high reaction efficiency and enantioselectivity (Table
[1 ], entry 7). An additional insight gained from a control experiment was that the present
hydroxylation could occur in the absence of the triazolium catalyst to give the racemic
product (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
equivalents of hydrogen peroxide enabled higher enantiocontrol without notable rate
retardation (Table [1 ], entry 10). Finally, lowering the temperature to –10 °C with prolonged reaction
time resulted in an almost quantitative formation of 3a with a satisfactory level of enantiomeric purity (Table [1 ], entry 12).
The scope of 1c ·Br-catalyzed asymmetric direct α-hydroxylation of 3-substituted oxindoles 2 was explored under the optimized conditions, and the representative results 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 hydroxyoxindoles 3 with uniformly high enantioselectivity. With respect to 3-aryl oxindoles, this protocol
tolerated the incorporation of both electron-donating and electron-withdrawing substituents
(Table [2 ], entries 1–5). The reaction with 3-(1-naphthyl)oxindole showed slightly lower conversion
(Table [2 ], entry 6), whereas the product was isolated in excellent yield in the oxidation
of 2 having 2-naphthyl substituent (Table [2 ], entry 7). 3-Alkyl oxindoles also appeared to be suitable nucleophiles, and a similar
degree of reactivity and selectivity was observed (Table [2 ], entries 8–14). Moreover, this catalytic system well accommodated differently 5-substituted
3-phenyloxindoles (Table [2 ], entries 15–17).
In conclusion, we have developed a catalytic enantioselective α-hydroxylation of 3-substituted
oxindoles using aqueous hydrogen peroxide as a terminal oxidant. The judicious use
of trichloroacetonitrile and the chiral 1,2,3-triazolium salt for the electrophilic
activation of hydrogen peroxide and the stereocontrol of carbon–oxygen bond formation,
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 synthetically valuable asymmetric hydroxylation
reactions.
