Pd(II)-Catalyzed Hydroxyl-acyloxylation of <i>gem</i> -Dimethyl Groups via Dual C(sp ³ )–H Activation

Herein, we report a one-pot dual oxyfunctionalization reaction of ubiquitous gem -dimethyl groups using a single Pd(II)/Pd(IV) catalytic system, achieving both hydroxyl-acyloxylation and diacetoxylation by employing N -pyridine ylide as a directing group. This strategy exhibits remarkable generality, tolerating a wide range of functional groups and enabling the late-stage modification of complex drug derivatives. Mechanistic studies, including 18 O-labeling experiments, kinetic analysis, and DFT calculations, unveil a pathway involving sequential C–H activations. The observed heteroselectivity is governed by kinetic preferences, stemming from distinctive noncovalent interactions in key transition states. This work provides a novel solution to the intermolecular 1,3-heterodifunctionalization of C(sp 3 )–H bonds, offering a powerful and versatile toolkit for molecular construction.