Carbonylative cycloaddition of alkenes and imines to β-lactams enabled by resolving the acid-base paradox

Abstract

Catalytic carbonylative cycloaddition of alkenes and imines is an ideal and unprecedented transformation for the synthesis of β-lactams; however, such a process remains largely elusive and presents onerous challenge. The main hurdle is basically due to the acid-base paradox imparted by the proton-addition and -elimination elementary steps required in the catalytic process. We report herein a strategy to resolve the acid-base paradox by identifying an appropriate basic solvent, which can accommodate both acid and base for sustaining the palladium catalysis. Such a strategy enabled an efficient Pd-catalyzed hydrocarbonylative cycloaddition reaction, which can transfer a wide variety of electron-deficient alkenes, dienes, cyclic alkenes, styrenes, and imines in the presence of CO into a large set of nitrile-containing, allylic, and spirocyclic β-lactams. Mechanistic studies disclosed that this success can be ascribed to the basic solvent N-methyl-2-pyrrolidone (NMP), which can sustain the generation of HPdX species in presence of acid and base.