Synthesis of Axially Chiral Vinyl Halides via Cu(I)-Catalyzed Enantioselective Radical 1,2-Halofunctionalization of Terminal Alkynes

Abstract

Organohalides are crucial in modern organic synthesis, thanks to their robust and versatile reactivity in cross-coupling and other key transformations. However, catalytic asymmetric methods for producing enantioenriched organohalides, particularly axially chiral vinyl halides, remain underdeveloped. Here, we present a Cu(I)-catalyzed, highly enantioselective radical alkyne 1,2-halofunctionalization, utilizing custom-designed tridentate anionic N,N,N-ligands with bulky peripheral substituents. This method efficiently employs (hetero)aryl and alkyl sulfonyl chlorides, as well as α-carbonyl alkyl bromides, as radical precursors and utilizes a diverse range of 2-amino and 2-oxy aryl terminal alkynes as substrates to produce highly enantioenriched axially chiral vinyl halides. The reaction is scalable to gram quantities, and the vinyl halides can be further transformed into axially chiral thiourea, pyridyl carboxamide, and quinolyl sulfonamide compounds, some of which show significant potential in asymmetric catalysis. Both experimental and theoretical mechanistic studies support an enantioselective halogen atom transfer mechanism. This method opens an avenue for accessing axially chiral organohalides, facilitating their broad applications in various related fields.