Base-catalyzed C-alkylation of potassium enolates with styrenes via a Metal-ene Reaction: A Mechanistic Study

Base-catalyzed, C-alkylation of potassium enolates with styrenes (CAKES) has recently emerged as a highly practical and convenient method for elaboration or synthesis of pharmaceutically-relevant cores. Potassium enolate-type precursors such as alkyl-substituted heterocycles (pyradines, pyrazines and thiophenes), ketones, imines, nitriles and amides undergo C-alkylation reactions with styrene in the presence of KOtBu or KHMDS. Surprisingly, no studies have probed the reaction mechanism beyond the likely initial formation of a potassium enolate. Herein, a synergistic approach of computational (DFT) and kinetic studies rationalizes various experimental observations and supports a metal-ene-type reaction for amide CAKES. Moreover, our approach explains experimental observations in other reported C-alkylation reactions of other enolate-type precursors, thus implicating a general mechanism for CAKES.