Iron-Catalyzed Enantioselective Multicomponent Cross-Couplings of α-Boryl Radicals.

Despite recent interest in the development of iron-catalyzed transformations, methods that use iron-based catalysts capable of controlling the enantioselectivity in carbon-carbon cross-couplings are underdeveloped. Herein, we report a practical and simple protocol that uses commercially available and expensive iron salts in combination with chiral bisphosphine ligands to enable the regio- and enantioselective (up to 91:9) multicomponent cross-coupling of vinyl boronates, (fluoro)alkyl halides, and Grignard reagents. Preliminary mechanistic studies are consistent with rapid formation of an α-boryl radical followed by reversible radical addition to monoaryl bisphosphine-Fe(II) and subsequent enantioselective inner-sphere reductive elimination. From a broader perspective, this work provides a blueprint to develop asymmetric Fe-catalyzed multicomponent cross-couplings via the use of alkenes as linchpins to translocate alkyl radicals, modify their steric and electronic properties, and induce stereocontrol.

General method for iron-catalyzed multicomponent radical cascades-cross-couplings.

Transition metal­catalyzed cross-coupling reactions are some of the most widely used methods in chemical synthesis. However, despite notable advantages of iron (Fe) as a potentially cheaper, more abundant, and less toxic transition metal catalyst, its practical application in multicomponent cross-couplings remains largely unsuccessful. We demonstrate 1,2-bis(dicyclohexylphosphino)ethane Fe­catalyzed coupling of α-boryl radicals (generated from selective radical addition to vinyl boronates) with Grignard reagents. Then, we extended the scope of these radical cascades by developing a general and broadly applicable Fe-catalyzed multicomponent annulation­cross-coupling protocol that engages a wide range of π-systems and permits the practical synthesis of cyclic fluorous compounds. Mechanistic studies are consistent with a bisarylated Fe(II) species being responsible for alkyl radical generation to initiate catalysis, while carbon-carbon bond formation proceeds between a monoarylated Fe(II) center and a transient alkyl radical.

Fe-catalyzed three-component dicarbofunctionalization of unactivated alkenes with alkyl halides and Grignard reagents.

A highly chemoselective iron-catalyzed three-component dicarbofunctionalization of unactivated olefins with alkyl halides (iodides and bromides) and sp2-hybridized Grignard reagents is reported. The reaction operates under fast turnover frequency and tolerates a diverse range of sp2-hybridized nucleophiles (electron-rich and electron-deficient (hetero)aryl and alkenyl Grignard reagents), alkyl halides (tertiary alkyl iodides/bromides and perfluorinated bromides), and unactivated olefins bearing diverse functional groups including tethered alkenes, ethers, protected alcohols, aldehydes, and amines to yield the desired 1,2-alkylarylated products with high regiocontrol. Further, we demonstrate that this protocol is amenable for the synthesis of new (hetero)carbocycles including tetrahydrofurans and pyrrolidines via a three-component radical cascade cyclization/arylation that forges three new C-C bonds.