Organic Letters
Letter
a
desired products 3ea−ga in high yields with excellent
diastereo- and enantioselectivities.
Scheme 2. Scope of Propargylic Acetates 2
2-Naphthyl substrate 1h was also suitable to the reaction,
giving 3ha in 89% yield and a dr of 12:1 with >99% ee.
Heteroaromatic substrate 1i served well for the reaction,
leading to the corresponding 3,3-disubstituted oxindole 3ia in
high yield, and excellent diastereo- and enantioselectivity. The
aliphatic substituent was well tolerated in this reaction. Thus,
the product 3ja bearing a 3-methyl group was obtained in 76%
yield and a dr of >20:1 with >99% ee. The substituent at the
phenyl ring of the oxindole skeleton was also examined. The
results revealed that the substituent at the 5- or 6-position
displayed little effect on the reaction performance. In contrast,
the substituent at the 7-position resulted in the dramatically
reduced reactivity. Thus, 7-CF -substituted substrate 1m gave
3
the desired product 3ma in only 39% yield albeit in >20:1 dr
with 95% ee. Besides the methyl group, other substituents
(1n−q) at the N-position of oxindoles were also tolerated in
the reaction but did not improve the reaction performance.
The absolute configuration of 3,3-disubstituted oxindoles was
unambiguously determined by X-ray structure analysis of 3ga,
to which a (R,R)-configuration was assigned (CCDC
Next, the substrate scope with respect to propargylic acetates
was investigated, and the results are listed in Scheme 2. The
results revealed that all aromatic substrates tested gave rise to
perfect enantioselectivity, regardless of the substitution pattern
and electronic property of the substituent. The reaction was
somewhat sensitive to the substitution pattern on the phenyl
ring. Thus, both 3- and 4-chloro-substituted substrates 2c and
2
d gave similar perfect results; in contrast, the 2-chloro-
substituted substrate 2b led to a significant decrease in the
yield and diastereoselectivity presumably due to the steric
hindrance. The substituent at the para position of the phenyl
ring showed an observed effect on the reactivity but less
affected the diastereo- and enantioselectivity. 1-(Naphth-2-
yl)prop-2-yn-1-yl acetate 2j was not so compatible with the
present catalytic system in terms of yield, in which 3aj was
obtained in only 43% yield but with perfect diastereo- and
enantioselectivity. 2-Thienyl substrate 2k proceeded smoothly,
giving the product 3ak in 89% yield and a dr of >20:1 with
a
Reaction conditions: 1a (0.3 mmol), 2 (0.36 mmol), Cs CO (0.36
2
3
mmol), Cu(MeCN) PF (5 mol %), (S ,R )-L4 (5.5 mol %) in
4
6
c
p
MeOH (3 mL) at −40 °C for 10 h. Isolated yield was provided. The
1
dr value was determined by H NMR. The ee value was determined
by chiral HPLC analysis.
>
99% ee. However, aliphatic substrate 2l was not tolerated in
Scheme 3. Synthetic Applications
the reaction.
To demonstrate the utility of this type of product, some
synthetic transformations of 3aa were carried out as shown in
Scheme 3. The scalability of this process was verified by
performing the reaction of 1a and 2a on a gram-scale, in which
3
aa was isolated in 90% yield and >20:1 dr with >99% ee even
at a reduced catalyst loading of 2.5 mol %. The hydrogenation
of 3aa with Lindlar catalyst selectively reduced the alkyne
moiety to the alkene 5 in 94% yield without any loss in the
diastereo- and enantioselectivity. A click reaction of 3aa with
tosyl azide via the copper-catalysis resulted in 1,2,3-triazole 4
in 81% yield with fully maintained diastereo- and enantiose-
lectivities.
A transition state of Cu−allenylidene complex with chiral
ligand (S ,R )-L4 is proposed to explain the observed
c
p
stereoselectivities as shown in Scheme 4. Due to the edge-to-
face aromatic interaction and the steric hindrance, the
nucleophilic attack of oxindoles from the S face at the Si
i
face of the γ-carbon atom of the Cu−allenylidene complex is
favored, thus leading to the propargylic alkylation product with
a (R,R)-configuration.
C
Org. Lett. XXXX, XXX, XXX−XXX
Xia, Jin-Tao
