Organic Letters
Letter
only successful example of catalytic enantioselective variants is
electron-withdrawing group at the ortho- or meta-position
underwent the reaction smoothly to afford products in good
yields with excellent stereoselectivities (entries 5−8). The
reactions of 2-naphthyl- and 1-naphthyl-substituted α-
fluoroalkenes (1i and 1j) also proceeded well in high yields.
Further investigation of the substrate scope with respect to
the reaction using α-alkyl-substituted styrene derivatives
15
catalyzed by a chiral phosphoric acid. The introduction of
another functional group to the carbon−carbon double bond,
instead of the alkyl substituent, leads to further utilization of
the enantioenriched dihydro-4H-1,3-oxazines thus formed. α-
Fluoroalkenes are ideal to access a variety of dihydro-4H-1,3-
oxazine derivatives in an enantioenriched form, because the
fluorine substituent not only provides sufficient reactivity in
the [4 + 2] cycloaddition reaction but also is transformable
while maintaining the 5,6-dihydro-4H-1,3-oxazine frame-
2
imine 2, having a series of aryl substituents Ar , was conducted
(entries 11−17). The reaction of imines having a substituent at
2
the para-position of Ar , 2bd−2dd, afforded 4a-bd−4a-dd in
moderate yields (entries 11−13), whereas imines having meta-
substituted aryl moieties, 2ed−2gd, also underwent the
reaction to generate products in good yields with excellent
stereoselectivities (entries 14−16). The use of 2hd having a 2-
thienyl group as the heteroaryl substituent resulted in the
formation of a product with excellent enantioselectivity, albeit
with low yield presumably because of low electrophilicity of
2hd (entry 17).
1
6
work. Herein, we describe an enantioselective reaction of
α-fluorostyrenes 1 with N-benzoyl imines 2 in the presence of
chiral phosphoric acid catalyst 3 (Scheme 1). The present [4 +
2
] cycloaddition reaction efficiently provided fluorine-contain-
ing 5,6-dihydro-4H-1,3-oxazines 4 in excellent diastereo- and
enantioselectivities. We also demonstrated that further treat-
ment of 4 with silyl enol ether in the presence of BiCl catalyst
As shown in the initial screening for the reaction conditions
(Table 1, entries 6 and 7), it was anticipated that the
substituent on Ar of the benzoyl group of imine 2 would
3
resulted in the formation of a substitution product through a
selective C−F bond cleavage without any loss of enantiomeric
excess.
3
tolerate the present reaction under the optimal conditions,
3
Our initial attempt commenced with the reaction of α-
fluorostyrene 1a with 2 equiv of N-benzoyl imine 2aa using 5
mol % of chiral phosphoric acid (R)-3a in CH Cl at room
although the electronic property of the substituent on the Ar
group would affect the progress of the reaction. In fact, the
introduction of an electron-donating group at the para-position
2
2
1
7
3
temperature. As shown in Table 1, entry 1, [4 + 2]
cycloaddition reaction product 4a-aa was formed in moderate
yield with excellent diastereoselectivity, albeit moderate
enantioselectivity. To improve both yield and enantioselectiv-
ity, the substituent effect of the benzoyl group of 2 was
investigated (entries 2−4). Although the introduction of
electron-withdrawing groups at 3- and 5-positions of the aryl
group reduced the yields (entries 2 and 3), the use of 2ad
having a 4-trifluoromethylphenyl group afforded 4a-ad in good
yield with a marked improvement of enantioselectivity (entry
of Ar , 2ae and 2af, led to a decrease in yields but had a
minimal influence on the stereoselectivities (Scheme 2). In
3
Scheme 2. Substituent Effect on Ar Group of Imine 2
4
). Screening for the solvent established that the use of toluene
enhanced both yield and enantioselectivity (entry 5). Further
optimization revealed that the amount of imine 2ad could be
reduced to 1.2 equiv without any loss of enantioselectivity
(
entry 6). The reaction of 2aa, instead of 2ac, under the
optimal conditions (entry 6) afforded corresponding product
a-aa with excellent stereoselectivities, even though there was a
contrast, other Ar3 groups having fluorine atom(s) as
substituents, 2ac and 2ag, exhibited the marked positional
effect of the fluorine substituent(s). The use of 2ac having the
4
1
8
slight decrease in the yield (entry 7). The use of
representative chiral phosphoric acid catalysts, such as (R)-
3
3
b and (R)-3c, resulted in marked decreases in yields and
3,5-difluoro substituent on the Ar group resulted in the
enantioselectivities (entries 8 and 9). Consequently, chiral
phosphoric acid (R)-3a having a pentafluorophenyl group as
aryl unit G was identified as the optimal catalyst. Either imine
detrimental effect on yield and enantioselectivity. While the
introduction of the fluorine atom to the ortho-position, 2ag,
facilitated the reaction to afford 4a-ag in fairly good yield with
excellent enantioselectivity.
2
ad having a 4-trifluoromethylphenyl group or 2aa having a
simple phenyl group was useful for the present reaction,
Finally, to confirm the potential use of α-fluoroalkenes as the
carbon nucleophile, derivatization of the cycloaddition product
was conducted to demonstrate the synthetic utility of α-
whereas imine 2 having the 4-trifluoromethylphenyl group as
3
the Ar group was employed for further investigations because
19
its reaction furnished a product that had the highest yield and
stereoselectivity among the combinations tested (entry 6).
With optimal catalyst (R)-3a and reaction conditions in
hand, the substrate scope for the present [4 + 2] cycloaddition
reaction was examined (Table 2). The reaction of α-
fluorostyrenes having a substituent at the para-position of
the aryl group (1b−1d) afforded the corresponding products
in high yields with excellent stereoselectivities (entries 1−3).
In addition, this transformation was sufficiently reliable,
permitting the synthesis of 4 on a gram scale, and the reaction
of 1d (4.0 mmol) with 2ad afforded 1.9 g of 4d-ad (entry 4).
α-Fluorostyrenes having an electron-donating group or an
fluoroalkenes. As shown in Scheme 3, the reaction of 4d-ad
with silyl enol ether 5 in the presence of BiCl catalyst
3
provided substitution product 6 as a single diastereomer with
retention of the 5,6-dihydro-4H-1,3-oxazine skeleton in
5
moderate yield. In addition, no loss of enantiomeric excess
was observed during the course of the derivatization.
In conclusion, we have developed an enantioselective [4 +
2] cycloaddition reaction of α-fluorostyrenes with N-benzoyl
imines using a chiral phosphoric acid catalyst. The present
reaction afforded enantioenriched 5,6-dihydro-4H-1,3-oxazines
having a fluorine substituent at the 6-position in good yields
with excellent diastereo- and enantioselectivities. The sub-
C
Org. Lett. XXXX, XXX, XXX−XXX
Terada, Masahiro
