Controllable Diverse Construction of gem-Difluoroallylated Bicyclo[1.1.1]pentanes and Cyclobutanes from [1.1.1]Propellane via Copper Catalysis

Abstract

A controllable strategy using [1.1.1]propellane (TCP) for the selective synthesis of gem-difluoroallylated bicyclo[1.1.1]pentanes (BCPs) and cyclobutanes (CyBus) with electrophilic fluoroalkylating reagents, 3,3-difluoroallyl sulfonium salts (DFASs), and organometallic reagents, including Grignard and organozinc reagents, has been developed. In this strategy, a stepwise procedure by nucleophilic addition of organometallic reagents to TCP, followed by copper-catalyzed cross-coupling with DFASs, favors the formation of fluoroalkylated BCPs. A one-pot copper-catalyzed three-component carbene transfer reaction of organozinc reagents and DFASs with TCP as the precursor prefers the generation of fluorinated CyBus, featuring the formation of two C−C bonds and a quaternary carbon center. This innovative carbene transfer reaction also leads to a unique and unexpected BCP and CyBu-connected structure. Applying these approaches leads to the diversified synthesis of complex fluorinated strained rings, rendering this strategy attractive for applications in medicinal chemistry.