Nickel-catalyzed radical relay enabled chemoselective fluoroalkyl-borylation of [1.1.1]propellane under kinetic control.

Recently, fluoroalkyl-substituted bicyclo[1.1.1]pentanes (BCPs) have attracted considerable attention from the medicinal chemistry community due to their superior physicochemical properties as pharmaceutical bioisosteres of benzene rings. However, related early medicinal research is hampered by a number of challenges, including insufficient and lengthy construction of valuable fluoroalkyl BCP building blocks. Here, we report a general approach to fluoroalkyl-substituted BCP-BPins in a single step using [1.1.1]propellane and economical B2Pin2 in which fluoroalkylhalides serve as radical precursors in conjunction with C─C/C─B couplings featuring mild conditions, easy setup, and broad scope. The diverse transformation of active boryl is applicable to the synthesis of valuable fluorinated bicyclic building blocks, including a commercial drug analog. Detailed mechanism and kinetic studies suggest that the key to the excellent three-component coupling selectivity of the reaction is the different tendencies of BCP-nickel and fluoroalkyl-nickel species to undergo C─Ni bond cleavage or reductive elimination.