δ-C(sp3)H Activation of Free Alcohols Enabled by Rationally Designed H-Bond-Acceptor Ligands

Abstract

The ability to employ a wide range of native substrates is essential for the broad application of transition-metal-catalyzed C–H activation. Recent advances have made native carboxylic acids, ketones, and amines amenable to C(sp3)–H activation, but alcohols, perhaps the most common functionality in organic chemistry, have remained intractable due to their low affinity for late-transition-metal catalysts. Herein we describe the rational development of ligands to overcome this challenge and enable alcohol-directed -C(sp3)–H arylation reactions. Our ligand design strategy employs charge balance and a secondary-coordination-sphere H-bonding interaction—evidenced by SAR studies, computational modelling, and crystallographic data—to stabilize L-type hydroxyl coordination to palladium, thereby facilitating the assembly of the key C–H cleavage transition state. In contrast to prior studies in C–H activation, where secondary interactions were used to control selectivity in the context of established reactivity, this report demonstrates the feasibility of employing secondary interactions to enable challenging novel reactivity by enhancing substrate-catalyst affinity.