C–H Alkenylation of Heteroarenes: Mechanism, Rate, and Selectivity Changes Enabled by Thioether Ligands

Abstract

Thioether ancillary ligands have been identified that can greatly accelerate the C–H alkenylation of <i>O</i>-, <i>S</i>-, and <i>N</i>-heteroarenes. Kinetic data suggest thioether–Pd-catalyzed reactions can be as much as 800× faster than classic ligandless systems. Furthermore, mechanistic studies revealed C–H bond cleavage as the turnover-limiting step, and that rate acceleration upon thioether coordination is correlated to a change from a neutral to a cationic pathway for this key step. The formation of a cationic, low-coordinate catalytic intermediate in these reactions may also account for unusual catalyst-controlled site selectivity wherein C–H alkenylation of five-atom heteroarenes can occur under electronic control with thioether ligands even when this necessarily involves reaction at a more hindered C–H bond. The thioether effect also enables short reaction times under mild conditions for many <i>O-</i>, <i>S</i>-, and <i>N</i>-heteroarenes (55 examples), including examples of late-stage drug derivatization