Transition-Metal-Free Reductive Hydroxymethylation of Isoquinolines

Abstract

A transition-metal-free reductive hydroxymethylation reaction has been developed, enabling the preparation of tetrahydroisoquinolines bearing C4-quaternary centers from the corresponding isoquinolines. Deuterium labelling studies and control experiments enable a potential mechanism to be elucidated which features a key Cannizzaro-type reduction followed by an Evans–Tishchenko reaction. When isoquinolines featuring a proton at the 4-position are used, a tandem methylation-hydroxymethylation occurs, leading to the formation of 2 new C−C bonds in one pot.