Merging Photoredox PCET with Ni-Catalyzed Cross-Coupling: Cascade Amidoarylation of Unactivated Olefins

Article abstract of DOI:10.1016/j.chempr.2018.11.014

The integration of amidyl radicals with cross-coupling chemistry opens new avenues for reaction design. However, the lack of efficient methods for the generation of such radical species has prevented many such transformations from being brought to fruition. Herein, the amidoarylation of unactivated olefins by a cascade process from non-functionalized amides is reported by merging, for the first time, photoredox proton-coupled electron transfer (PCET) with nickel catalysis. This new technology grants access to an array of complex molecules containing a privileged pyrrolidinone core from alkenyl amides and aryl- and heteroaryl halides in the presence of a visible light photocatalyst and a nickel catalyst. Notably, the reaction is not restricted to amides—carbamates and ureas can also be used. Mechanistic studies, including hydrogen-bond affinity constants, cyclization rate measurements, quenching studies, and cyclic voltammetry, were central to comprehend the subtleties contributing to the integration of the two catalytic cycles. A rapid, highly diastereoselective amidoarylation of unactivated olefins was achieved to render medicinally privileged pyrrolidinone structures. Taking advantage of a photoredox proton-coupled electron transfer process, amidyl radicals were obtained from non-prefunctionalized N–H bonds under mild conditions, which were subsequently trapped by pendant olefins, delivering alkyl radicals for nickel-catalyzed cross-coupling. Mechanistic studies revealed the key balance between thermodynamically-driven radical generation and kinetically-driven cyclization, which led to expanding the scope toward urea and carbamate substrates. Rapid generation of molecular complexity and access to novel 3D chemical space is pivotal for successful and efficient drug discovery. Nickel/photoredox dual catalysis has arisen as an appealing strategy toward such a goal by rapidly introducing C_sp3 centers under mild reaction conditions. By taking advantage of a native amide group, we achieved an amidoarylation reaction of unactivated olefins, rendering a series of medicinally privileged structures in a highly atom-economical way. The reaction takes advantage of a photoredox proton-coupled electron transfer event to cleave the strong amidyl N–H bond homolytically. Subsequent regiospecific 5-exo-trig cyclization generates an alkyl radical. High functional group tolerance was achieved with excellent diastereoselectivities owing to the reaction's mild nature. Mechanistic studies showed the intricate relationship between the base stoichiometry and the N–H donor, as well as the key balance between kinetic and thermodynamic factors.