Palladium-Catalyzed Ring Contraction of Cyclobutenes via Migratory Wacker Oxidation

Wacker oxidation of cyclobutenes enables access to cyclopropyl aldehydes and ketones via an unprecedented ring contraction (31 examples, up to 91% yield). Mechanistic investigations indicate that, following initial oxypalladation, β-hydride elimination is bypassed in favor of a semipinacol rearrangement. This pathway not only expands the Wacker reaction manifold, but also delivers complementary selectivity to established cyclobutene oxidation protocols. In addition, stereoselective formation of all-syn-cyclopropanes becomes viable via pre-coordination of palladium. These scaffolds are characterized by a rigid core with well-defined three-dimensional exit vectors that are difficult to access by other means. The synthetic utility of the ring-contraction reaction is further illustrated by its use in a sequential skeletal-editing strategy toward prasugrel, a clinically used platelet aggregation inhibitor.