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

Area of Science:

• Organic Chemistry
• Catalysis
• Radical Chemistry

Background:

• Multicomponent reactions offer efficient synthesis pathways.
• Radical-mediated reactions are valuable tools in organic synthesis.
• Existing methods for alkene difunctionalization often require harsh conditions or specific initiators.

Purpose of the Study:

• To develop a novel, streamlined method for the multicomponent difunctionalization of styrenes.
• To utilize α-aminoalkyl radical-mediated halogen-atom transfer (XAT) with copper catalysis.
• To avoid the need for external peroxides or photoredox conditions.

Main Methods:

• Integration of α-aminoalkyl radical-mediated halogen-atom transfer (XAT) with copper catalysis.
• Utilizing air-equilibrated conditions and inexpensive CuCl2 as a catalyst.
• Mechanism studies involving tertiary amine oxidation to generate α-aminoalkyl radicals.

Main Results:

• Efficient synthesis of β-(fluoro)alkylated ketones from styrenes and alkyl halides.
• Broad substrate scope including various alkyl radical precursors and styrenes.
• Excellent functional group tolerance under mild reaction conditions.
• Demonstrated utility in late-stage functionalization of bioactive molecules.

Conclusions:

• A mechanistically distinct and efficient approach to alkene difunctionalization has been established.
• The copper catalyst plays a unique role in initiating the radical chain via amine oxidation.
• This method provides a practical and modular route to complex molecules, including pharmaceuticals.