A Titanium(III)-Catalyzed Reductive Umpolung Reaction for the Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines.

A catalytic reductive C1-acylation of 3,4-dihydroisoquinolines is presented that gives direct access to 1,1-disubstituted tetrahydroisoquinolines. The reaction is a titanium(III)-catalyzed reductive umpolung process in which nitriles act as effective acylation agents. The method is highly chemo- and regioselective and is demonstrated in 20 examples. It is well-suited for the large-scale synthesis of functionalized tetrahydroisoquinoline products, which is exemplified in the form of a six-step synthesis of (±)-3-demethoxyerythratidinone.