Copper-catalysed oxy-alkylation of styrenes enabled by halogen-atom transfer.

Herein, we present a mechanistically distinct approach to the multicomponent difunctionalisation of styrenes with alkyl halides and oxygen by integrating α-aminoalkyl radical-mediated halogen-atom transfer (XAT) with copper catalysis under air-equilibrated conditions. This strategy eliminates the need for external peroxides or photoredox conditions, offering a streamlined and efficient alternative. Mechanism studies uncover a unique role for the copper catalyst: instead of directly activating alkyl halides, inexpensive CuCl oxidizes a tertiary amine to generate an α-aminoalkyl radical, which then drives XAT to release alkyl radicals. These radicals subsequently add to alkenes, facilitating efficient difunctionalisation. This method accommodates a broad range of alkyl radical precursors, including fluoroalkyl- and alkyl halides, and demonstrates compatibility with diverse styrenes, enabling the modular synthesis of β-(fluoro)alkylated ketones with excellent functional group tolerance under mild conditions. Notably, the strategy's practical utility is exemplified through the late-stage functionalisation of biologically active molecules and pharmaceuticals, showcasing its potential for rapid, efficient access to structurally complex molecules.