Synthesis of 3,5-Disubstituted Isoxazoles via 1,3-Dipolar Cycloaddition Reaction between Alkynes and Nitrile Oxides generated from O-Silylated Hydroxamic Acids

Laure-Elie Carloni, Stefan Mohnani, Davide Bonifazi
Eur. J. Org. Chem.2019: 7322-7334
DOI: 10.1002/ejoc.201901045


In this paper, we report the regioselective synthesis of 3,5-disubstituted isoxazoles by 1,3-dipolar cycloaddition between alkynyl dipolarophiles and nitrile oxide dipoles generated in-situ from O-silylated hydroxamic acids in the presence of trifluoromethanesulfonic anhydride and NEt3. Thanks to the mild, metal-free and oxidant-free conditions that this strategy offers, the reaction was successfully applied to a wide variety of alkynyl dipolarophiles, demonstrating the tolerance of this approach to diverse functional groups. In particular, we have shown that the method was compatible with biological molecules such as peptides and peptide nucleic acids (PNA). This protocol constitutes another example of metal-free 1,3-dipolar cycloaddition leading to the regioselective formation of isoxazoles.

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