General and Practical Route to Diverse 1,3-(Difluoro)alkyl bicyclo[1.1.1]-Aryl Pentanes Enabled by an Fe-Catalyzed Multicomponent Radical Coupling

Abstract

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 stepwise C-C bond formation via 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 prevalence of C-F bonds in bioactive compounds, one pot, multicomponent cross-coupling methods to directly functionalize BCP to the corresponding fluoroalkyl BCP-aryl scaffolds are lacking. In this work, we describe a conceptual 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, bicyclo[1.1.1]pentane, and Grignard reagents. Further, experimental and computational mechanistic studies provide insights into mechanism and ligand effects on the nature of C-C bond formation. Finally, these studies are used to develop a new method to rapidly access synthetic versatile 1-(fluoro)alkyl,3-bromo and -iodo BCPs via bisphosphine iron catalysis.

General and Modular Route to (Halo)alkyl BCP-Heteroaryls Enabled by α-Aminoalkyl Radical-Mediated Halogen-Atom Transfer

“…5 In the same year, Gutierrez et al reported an iron-catalyzed multicomponent radical cross-coupling reaction from [1.1.1]propellane, (fluoro)alkyl halides, and Grignard reagents, offering access to diverse 1-(difluoro)alkyl-3-aryl bicyclo[1.1.1]pentanes (Figure 1C, down). 6 Despite their utilities, both methodologies are limited to tertiary alkyl radicals and prefunctionalized (het)arenes because they rely on the combination of singleelectron transfer (SET) and reductive elimination mechanisms in which the generated primary and secondary alkyl radicals through the SET process will directly attack the metal catalyst, leading to a two-component side product. In this context, the development of a new strategy that would tolerate diverse kinds of alkyl radicals would be of importance to the synthetic industry.…”

Photocatalyzed 1,3-Bromodifluoroallylation of [1.1.1]Propellane with α-Trifluoromethylalkenes and KBr Salts

“…11 Another synthetic approach to 1bromo-3-alkyl BCPs from difluoroalkyl bromides enabled by bisphosphine-iron catalysis was documented by the group of Gutierrez. 12 A photocatalytic 1,3-bromoalkylatio of [1.1.1]propellane was disclosed by Anderson and co-workers, in which the substrates are also limited to electron-poor alkyl bromides. 6 Mechanistic studies suggest that the aforementioned three transformations are predominantly initiated through the formation of alkyl radicals.…”