Efficient and General Aerobic Oxidative Cross-Coupling of THIQs with Organozinc Reagents Catalyzed by CuCl₂: Proof of a Radical Intermediate

A general new method for the highly concise synthesis of C-1-alkylated tetrahydroisoquinolines (THIQ) is reported. The CuCl₂-catalyzed procedure is based on a coupling of nonfunctionalized THIQs with organozinc reagents under aerobic conditions. It proceeds in high yields and is broadly applicable to a wide range of substrates. It relies on a regioselective sp³ C-H bond activation allowing for an sp³-sp³ bond union under mild reaction conditions in a rapid and effective manner. Mechanistically it involves an iminium ion intermediate that is formed via an organic radical involving a single-electron-transfer process. For the first time for this type of reaction a radical intermediate has been proven by EPR spectroscopy.