Direct C3−H Alkylation and Alkenylation of Quinolines with Enones

Conversion of quinoline C-H bonds into C-C bonds is essential for obtaining the enormous array of derivatives required for pharmaceutical and agrochemical development. Despite over a century of synthetic efforts, direct alkylation and alkenylation at C3-H positions in a wide array of quinoline precursors remain predominantly challenging and elusive. This report outlines the first successful quinoline C3-H alkylation and alkenylation reactions, exhibiting exceptional regio- and stereoselectivity, all achieved under redox-neutral and transition-metal-free conditions. The method involves a three-step, one-pot or two-pot sequence, including 1,4-dearomative addition, functionalization at C3, and elimination or transalkylation to produce 3-alkylated/alkenylated quinolines. The presence of a carbonyl group in these products allows for further synthetic manipulations, enabling the production of cyanides, amides, amines, and simple alkyl derivatives.