Reversing conventional site-selectivity in C(sp3)–H bond activation

Abstract

AbstractOne of the core barriers to developing C–H activation reactions is the ability to distinguish between multiple C–H bonds that are nearly identical in terms of electronic properties and bond strengths. Through recognition of distance and molecular geometry, remote C(sp2)–H bonds have been selectively activated in the presence of proximate ones. Yet achieving such unconventional site selectivity with C(sp3)–H bonds remains a paramount challenge. Here we report a combination of a simple pyruvic acid-derived directing group and a 2-pyridone ligand that enables the preferential activation of the distal γ-C(sp3)–H bond over the proximate β-C(sp3)–H bonds for a wide range of alcohol-derived substrates. A competition experiment between the five- and six-membered cyclopalladation step, as well as kinetic experiments, demonstrate the feasibility of using geometric strain to reverse the conventional site selectivity in C(sp3)–H activation.Conventional regioselectivity in Pd-catalysed C(sp3)–H activation is dictated by the formation of a five-membered palladacycle. Now, it has been shown that the combination of a simple directing group and a 2-pyridone ligand favours six-membered cyclopalladation, demonstrating the feasibility of using geometric strain to reverse conventional site selectivity in these reactions.\n