Stereoretentive Radical Cross-Coupling

Free radicals were first discovered over 120 years ago by Gomberg and the first radical cross-couplings demonstrated by Kochi in the 1970's. Fueled by the need for general methods to couple C(sp3)-fragments, this area has seen an explosion of renewed interest. In contrast to widely employed polar cross-coupling chemistry to forge C(sp2)–C(sp2) bonds (Suzuki, Negishi, Kumada, etc.), radical cross-coupling is advantageous when applied to the coupling of saturated systems due to the mild conditions employed and enhanced chemoselectivity associated with single electron chemistry. Indeed, the ability to employ ubiquitous carbon-based fragments (carboxylic acids, alcohols, amines, olefins, etc.) in cross-coupling has dramatically simplified access to a variety of complex molecules. Despite these advantages, enantiospecific coupling reactions involving free radicals are unknown and generally believed to be impossible due to their near-instantaneous racemization (picosecond timescale). As a result, controlling the stereochemical outcome of radical cross-coupling can only be achieved on a case-by-case basis using bespoke chiral ligands or in a diastereoselective fashion guided by nearby stereocenters. Here we show how readily accessible enantioenriched sulfonylhydrazides and low loadings of an inexpensive achiral Ni-catalyst can be enlisted to solve this vexing challenge for the first time thereby enabling enantiospecific, stereoretentive radical cross-coupling between enantioenriched alkyl fragments and (hetero)aryl halides without exogenous redox chemistry or chiral ligands. Calculations support the intermediacy of a unique Ni-bound diazene-containing transition state with C–C bond formation driven by loss of N2.