Tang et al.
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SCHEME 1. Conventional Synthesis of the 2-Isoxazolines
for β-hydroxy ketones,5 β-hydroxy nitriles,6 β-amino acids,7
and γ-amino alcohols,8 etc. Therefore, numerous synthetic
methods have been developed to produce 2-isoxazolines of
which the 1,3-dipolar cycloaddition of nitrile oxides to alkenes9
(Scheme 1, reaction a) and the reaction of R,β-unsaturated
carbonyl compounds with hydroxylamine are the most impor-
tant1 (Scheme 1, reaction b). Although these transformations
are widely used, some challenges still remain especially for
regio- and stereoselectivities.10,11
Recently, we reported an efficient and regioselective app-
roach for the preparation of a series of 3-substituted and
3,5-disubstituted isoxazoles (eq 1).12 In this transformation,
it was proposed that the
FIGURE 1. 5-Hydroxy-2-isoxazolines as versatile synthons.
work on the reaction of N-hydroxy-4-toluenesulfonamide 1
(TsNHOH)13 with R,β-unsaturated aldehydes/ketones,
providing a very facile and highly regioselective tactic to
5-hydroxy-2-isoxazolines, which would be versatile synthons
for isoxazoles 12 (Figure 1, path a),14 β-hydroxy oximes 13,15
β-lactams 15 (Figure 1, path b),16 and γ-amino alcohols 2,17
especially chiral 3-amino-3-phenylpropan-1-ol 2a, a valuable
intermediate for the synthesis of (S)-dapoxetine (Figure 1,
path c).18,19
Results and Discussion
Synthesis of 5-Hydroxy-2-isoxazolines. 5-Hydroxy-2-is-
oxazolines were commonly obtained as intermediates in the
synthesis of isoxazoles from 1,3-dicarbonyl compounds and
hydroxylamine.14b However, this approach was usually hard
to control, leading to low regioselectivity.20 While the 1,3-
cycloaddition of nitrile oxides with enolates appeared to be
an especially versatile route to the 5-hydroxy-2-isoxazolines,
this method bore some disadvantages due to the high reac-
tivity of reactants and harsh reaction conditions.9,21 Thus,
the development of facile and regioselective methods for the
synthesis of 5-hydroxy-2-isoxazolines is desirable. We envi-
sioned that condensation between hydroxylamine 113 with a
leaving group (Ts) and R,β-unsaturated aldehydes/ketones
would be a suitable strategy to achieve this goal (Scheme 2).
isoxazoles were formed via dehydration of 5-hydroxy-2-
isoxazolines. Herein, we provide a full account of our
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