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

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 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.

A General and Modular Approach to BCP Alkylamines via Multicomponent Difunctionalization of [1.1.1]Propellane

“…Considering the emerging importance of BCP as a para -phenyl ring bioisostere, it is not surprising that the introduction of fluoroalkyl groups to the BCP structure is also a highly sought-after goal. Traditionally, the synthesis of fluoroalkyl-substituted BCPs typically proceeds with a multistep sequence through radical addition of fluoroalkyl halides to [1.1.1]­propellane (Figure C) . However, the reaction of gaseous CF 3 I, CF 2 HI, or other fluoroalkyl iodides requires the use of steel cylinders or the advance preparation of gaseous solutions, leading to inconvenient practical applications.…”

A General Organophotoredox Strategy to Difluoroalkyl Bicycloalkane (CF2‐BCA) Hybrid Bioisosteres**

“…The method is general and extendable to highly diversified scaffolds, including complex bioactive ingredients [9] . The synthetic versatility of the CF 2 −BCA 7 was proved with various manipulations.…”

“…The method is general and extendable to highly diversified scaffolds, including complex bioactive ingredients. [9] The synthetic versatility of the CF 2 À BCA 7 was proved with various manipulations. To evaluate the structural features of the hybrid bioisosteres in the solid state, we performed single crystal X-ray analysis on selected products.…”

Theoretical Underpinning of Synergetic Ir/Cu-Metallaphotoredox Catalysis in Multicomponent C–N Cross-Coupling Reactions

“…Multicomponent reactions (MCRs) provide a unique efficient tool for multiple bond formation, allowing one to access in a single reaction complex chemical compounds from simple and readily available substrates. , During the past few decades MCRs have been widely used in both academic and industrial synthetic organic chemistry. , However, this method typically requires harsh reaction conditions, heating with organometallic reagents, or high-pressure mercury lamp irradiations as an example. − To overcome these limitations, the application of recently developed photoredox-transition metal dual catalysis under mild reaction conditions has gained remarkable attention in synthetic chemistry. − …”