Synthesis of 5‑(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes

A comprehensive
study on the synthesis of 5-fluoroalkyl-substituted
isoxazoles starting from functionalized halogenoximes is reported.
One-pot metal-free [3 + 2] cycloaddition of CF3-substituted
alkenes and halogenoximes bearing ester, bromo, chloromethyl, and
protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles.
The target 3,5-disubstituted derivatives were obtained in a regioselective
manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl-
and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination
of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively,
in turn prepared via metal-free cycloaddition of halogenoximes and
propargylic alcohol. An alternative approach based on nucleophilic
substitution in 5-bromomethyl derivatives was found to be more convenient
for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes
with the Ruppert–Prakash reagent was used for the preparation
of (β,β,β-trifluoro-α-hydroxyethyl)­isoxazoles.
Utility of described approaches was shown by multigram preparation
of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles,
for example, fluorinated analogues of ABT-418 and ESI-09.