Palladium-Catalyzed Functionalization of C-H Bonds and Alkenes.

Abstract

A highly regio- and chemoselective methodology for the ligand-directed palladium-catalyzed C-H activation/acetoxylation of sp3 C-H bonds was developed. The reaction was found to be general with a variety of directing groups such as oxime ethers, isoxazolines and pyridines. In addition, the reaction exhibited high selectivity for the acetoxylation of 1° sp3 C-H bonds. The ligand directed palladium-catalyzed C-H activation/acetoxylation of sp2 and sp3 C-H bonds was shown to be effective with alternative oxidants such as Oxone and K2S2O8 in place of PhI(OAc)2. The use of these peroxide based oxidants over PhI(OAc)2 is advantageous because they are cheaper and do not release toxic byproducts such as iodobenzene. A comprehensive investigation to elucidate the factors affecting the C-H activation/acetoxylation by one ligand over another was conducted. It was determined that in the presence of multiple chelating functionalities in a reaction, the substrate bearing the most basic ligand would lead to the predominant product under our reaction conditions. These transformations are believed to proceed via a PdII/IV catalytic cycle. Mechanistic studies implicate that ligand directed palladium mediated C-H activation is the rate-limiting step in these reactions. Finally, Pd-alkyl intermediates generated via aminopalladation were intercepted using strong oxidants such as PhI(OAc)2 to afford 1,2-difunctionalized products. Under our optimal conditions, the use of alkenes bearing tethered alcohols, acids, or amines led to the formation of substituted tetrahydrofuran rings, lactones, or pyrrolidines.