1,4-Pd Migration-Enabled Synthesis of Fused 4-Membered Rings

Abstract

1,4-Palladium migration has been widely used for the functionalization of remote C-H bonds. However, this mechanism has been limited to aryl halide precursors. This work reports an unprecedented Pd0-catalyzed cyclobutanation protocol producing valuable fused cyclobutanes starting from cycloalkenyl (pseudo)halides. This reaction takes place via alkenyl-to-alkyl 1,4-Pd migration, followed by intramolecular Heck coupling. The method performs best with cyclohexenyl precursors, giving access to a variety of substituted bicyclo[4,2,0]octenes. Reactants containing an N-methyl or methoxy group give rise to fused azetidines or oxetanes, respectively, via the same mechanism. Kinetic and deuterium-labeling studies point to a rate-limiting C(sp3)-H activation step.