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B. Li et al. / Tetrahedron Letters xxx (2018) xxx–xxx
in asymmetric hydroxylation of N-protected 3-substituted oxin-
doles with oxaziridine as the oxidant.12
in the presence of 5 mol% catalyst 2c with cyclohexane as solvent.
The desired oxindole products 4a–4k were afforded in excellent
yields (94–99%) and moderate to excellent level of enantioselectiv-
ities of 30–94% ee. Generally, N-Boc-protected 3-aryloxindole
derivatives gave satisfactory results of both reactivity and enan-
tioselectivity (4a–4j; Scheme 1). N-Cbz-protected product of 4k
was produced efficiently in 98% yield under the optimal conditions,
however, the enantioselectivity were decreased to 30% ee in com-
parison of 4a (Scheme 1, 85% ee of 4a vs 30% ee of 4k).
When the optimized reaction conditions were applied to 3-ben-
zyl substituted N-Boc-oxindole of 1l, the enantioselectivity was
very poor (20% ee) although with excellent yield of 99% after 24
h (Table 2, entry 1). Thus, the catalysts 2a–2e were screened again
with the hydroxylation reaction of 1l with 3d in cyclohexane as
solvent. It was found that the catalyst 2d achieved the best enan-
tioselectivity (58% ee) with the desired product 5a (Table 1, entries
1–5). By using 5 mol% 2d as catalyst, the solvent effect was inves-
tigated (Table 1, entries 6–10), toluene as solvent gave comparable
results in comparison of cyclohexane (Table 2, 57% ee of entry 6 vs
58% ee of entry 4). In order to improve the enantioselectivity,
changing the reaction temperature from 25 °C to À20 °C led to a
significant increase in enantioselectivity to 77% ee (Table 2, entry
11). Further decreasing the temperature to À30 °C did not give bet-
ter results (Table 2, entry 12).
After optimizing the reaction conditions, we started to evaluate
the substrate scope of this reaction by varying the structure of 3-
benzyl substituted N-Boc-oxindoles. As shown in Scheme 3, the
desired oxindole products 5a–5l were afforded in excellent yields
(91–99%) and moderate to good enantioselectivities of 23–78% ee
were achieved. As can be seen, a number of substituted N-Boc-
oxindoles regardless of the electronic nature of the substituents,
such as methyl, fluoro or methoxy on the aryl groups of both oxin-
dole skeleton and the 3-arylmethylene substituents, reacted effi-
ciently with 3d to afford the desired products 5b–5l efficiently
(Scheme 3).
In conclusion, we have developed an iminophosphorane cat-
alyzed enantioselective hydroxylation of N-protected 3-substi-
tuted oxindoles by using oxaziridines as the hydroxyl reagents.
The reaction proceeded smoothly under mild conditions, and the
desired oxindole products were obtained in excellent yields of
91–99% and moderate to excellent level of enantiomeric excess
We began the study with the hydroxylation reaction of N-Boc-
protected 3-phenyl-2-oxindole 1a with racemic 3a (N-3-(4-nitro-
phenyl)-2-(phenylsulfonyl)-1,2-oxaziridine) as the model reaction
to investigate the reaction conditions and to optimize the catalyst
at room temperature. We first attempted the reaction by using
toluene as solvent to screen the catalysts 2a–2e. It was found that
catalyst 2c was the most suitable catalyst in this reaction and the
product 4a was achieved in the highest enantioselectivity with
excellent yield after 3 h (98% yield, 60% ee; Table 1, entry 3). Of
note, Mannich adducts of 1a with aryl sulfonimines were not
observed by thin-layer chromatography experiments since the
aryl sulfonimines can be generated from oxaziridines as byprod-
ucts in this reaction. Then we examined the oxidants of oxaziri-
dine derivatives with 10 mol% catalyst 2c in toluene (Table 1,
entries 6–9), it was found that 3d with pentafluorophenyl substi-
tuted oxaziridine improved the enantioselectivity without loss in
efficiency (95% yield, 75% ee). After that we optimized the reaction
conditions by screening solvents at room temperature (Table 1,
entries 10–18). As shown in Table 1, the results showed that
tetrahydrofuran (THF) and mesitylene gave comparable enan-
tiomeric excess of 76% and 73%, respectively (Table 1, entries 14
and 18). We were delighted to observe that non-polar solvent of
cyclohexane led to 4a in 99% yield with good enantioselectivity
of 83% ee (Table 1, entry 16). The protic solvent of isopropanol
gave 4a in 35% yield with 54% ee (Table 1, entry 17). Further study
of catalyst loading showed that 5 mol% catalyst 2c was enough to
afford 4a in 99% yield with 85% ee (Table 1, entry 19). However,
less catalyst loading results in very sluggish reaction (Table 1,
entry 20). Of note, the absolute configuration of compound 4a
was determined to be ‘‘(S)” by comparison of the optical rotation
3
value to the reported literature value. Furthermore, two equiva-
lents of racemic 3d were employed in this reaction, 4a was
obtained in 99% yield with 83% ee. The recovered 3d were
obtained in 87% yield and 15% enantiomeric excess were deter-
mined by HPLC (Table 1, entry 21).
With the optimized reaction conditions in hand, we then
explored the generality of the reaction scope with various N-pro-
tected 3-aryloxindole derivatives. The reaction scope was summa-
rized in Scheme 2, all reactions were completed within 3 h at 25 °C
Table 2
Screening of reaction conditions for asymmetric hydroxylations.a
Entry
Cat. 2
Solvent
Temp. [°C]
Yield [%]b
ee [%]c
1
2
3
4
5
6
7
8
9
2c
2a
2b
2d
2e
2d
2d
2d
2d
2d
2d
2d
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Toluene
25
25
25
25
25
25
25
25
99
99
99
99
99
99
99
99
99
99
99
95
20
51
11
58
40
57
47
55
40
45
77
71
EtOAc
DCM
2
Et O
25
25
1
1
1
0
1
2
THF
Toluene
Toluene
À20
À30
a
b
c
Reactions were performed on a 0.1 mmol scale of N-Boc-protected oxindole 1l using oxaziridine 3d (0.1 mmol, 1.0 equiv.) and 5 mol% catalyst in solvent (2 mL) for 24 h.
Isolated yield.
Determined by HPLC analysis on a chiral stationary phase.
Li, Baocheng
