Ac-l-methionine-catalyzed, nitrite-triggered cycloaddition reactions between bromides and alkynes/alkenes: step-economical reactions for modular synthesis

Abstract

The development of modular, chemically diverse and regioselective reactions for expanding the cycloaddition reaction toolbox hinges heavily on a strict functional 1,3-dipole and dipolarophile pairing exploration. In this study, we disclose a step-economical, nitrite-triggered cycloaddition reaction between bromide and alkyne/alkene for the modular assembly of isoxazoles (or isoxazolines). This process involves in situ Ac-L-methionine (S11)-catalyzed sulfur ylide generation, nitrite-triggered generation of a sulfonium masked 1,3-dipole, and subsequent cascade cycloaddition with an alkyne (or alkene) by the simultaneous release of Ac-L-methionine (S11). With the intrinsic advantages of high regio-selectivity, excellent efficiency, wide functionality tolerance, biocompatible conditions and operational simplicity, this reaction is robust for the direct diversification of pharmaceuticals and bio-relevant motifs. Moreover, this intermolecular cycloaddition reaction could be well expanded to the intramolecular cycloaddition for fused-ring isoxazoles and proximity-triggered sulfide-induced cycloaddition for specific methionine modification.