Photoinduced copper-catalysed asymmetric amidation via ligand cooperativity

The substitution of an alkyl electrophile by a nucleophile is a foundational reaction in organic chemistry that enables the efficient and convergent synthesis of organic molecules. Although there has been substantial recent progress in exploiting transition-metal catalysis to expand the scope of nucleophilic substitution reactions to include carbon nucleophiles(1-4), there has been limited progress in corresponding reactions with nitrogen nucleophiles(5-8). For many substitution reactions, the bond construction itself is not the only challenge, as there is a need to control stereochemistry at the same time. Here we describe a method for the enantioconvergent substitution of unactivated racemic alkyl electrophiles by a ubiquitous nitrogen-containing functional group, an amide. Our method uses a photoinduced catalyst system based on copper, an Earth-abundant metal. This process for asymmetric N-alkylation relies on three distinct ligands-a bisphosphine, a phenoxide and a chiral diamine. The ligands assemble in situ to form two distinct catalysts that act cooperatively: a copper/bisphosphine/phenoxide complex that serves as a photocatalyst, and a chiral copper/diamine complex that catalyses enantioselective C-N bond formation. Our study thus expands enantioselective N-substitution by alkyl electrophiles beyond activated electrophiles (those bearing at least one sp- or sp(2)-hybridized substituent on the carbon undergoing substitution)(8-13) to include unactivated electrophiles.

Automated summary

The study describes a method for enantioselective substitution of unactivated alkyl electrophiles using a copper-based photoinduced catalyst system, expanding the scope of enantioselective N-substitution reactions to include unactivated electrophiles.