Umpolung Asymmetric 1,5‐Conjugate Addition via Palladium Hydride Catalysis

Electronically matched nucleophilic 1,6‐conjugate addition has been well studied and widely applied in synthetic areas. In contrast, nucleophilic 1,5‐conjugate addition represents an electronically forbidden process and is considered unfeasible. Here, we describe modular protocols for 1,5‐conjugate addition reactions via palladium hydride catalysis. Both palladium and synergistic Pd/organocatalyst systems are developed to catalyze 1,5‐conjugate reaction, followed by inter‐ or intramolecular [3+2] cyclization. A migratory 1,5‐addition protocol is established to corroborate the feasibility of this umpolung concept. The 1,5‐addition products are conveniently transformed into a series of privileged enantioenriched motifs, including polysubstituted tetrahydrofuran, dihydrofuran, cyclopropane, cyclobutane, azetidine, oxetane, thietane, spirocycle and bridged rings. Preliminary mechanistic studies corroborate the involvement of palladium hydride catalysis. An unconventional umpolung protocol was demonstrated for novel 1,5‐conjugate additions via palladium hydride catalyst. Three catalytic reaction modes including 1,5‐addition cascade with inter‐ and intramolecular [3+2] cyclization and migratory 1,5‐addition were established via palladium or palladium/organo‐cocatalysis.