Nickel-catalyzed radical relay enabled chemoselective fluoroalkyl-borylation of [1.1.1]propellane under kinetic control.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41481729.
- Also identified by DOI 10.1126/sciadv.aea8588 and PMC identifier 12758546.
- Licence recorded as CC BY-NC.
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Abstract
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 B<sub>2</sub>Pin<sub>2</sub> 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.