General and Practical Route to Diverse 1-(Difluoro)alkyl-3-aryl Bicyclo[1.1.1]pentanes Enabled by an Fe-Catalyzed Multicomponent Radical Cross-Coupling Reaction

Bicyclo[1.1.1]pentanes (BCPs) are of great interest to the agrochemical, materials, and pharmaceutical industries. In particular, synthetic methods to access 1,3-dicarbosubsituted BCP-aryls have recently been developed, but most protocols rely on the stepwise C-C bond formation via the initial manipulation of BCP core to make the BCP electrophile or nucleophile followed by a second step (e.g., transition-metal-mediated cross-coupling step) to form the second key BCP-aryl bond. Moreover, despite the prevalence of C-F bonds in bioactive compounds, one-pot, multicomponent cross-coupling methods to directly functionalize [1.1.1]propellane to the corresponding fluoroalkyl BCP-aryl scaffolds are lacking. In this work, we describe a conceptually different approach to access diverse (fluoro)alkyl BCP-aryls at low temperatures and fast reaction times enabled by an iron-catalyzed multicomponent radical cross-coupling reaction from readily available (fluoro)alkyl halides, [1.1.1]propellane, and Grignard reagents. Further, experimental and computational mechanistic studies provide insights into the mechanism and ligand effects on the nature of C-C bond formation. Finally, these studies are used to develop a method to rapidly access synthetic versatile (difluoro)alkyl BCP halides via bisphosphine-iron catalysis.

Automated summary

This study presents a conceptually different approach to access diverse (fluoro)alkyl BCP-aryls through an iron-catalyzed multicomponent radical cross-coupling reaction. Experimental and computational mechanistic studies provide insights into the mechanism and ligand effects on C-C bond formation.