Pd-catalysed direct β-C(sp3)–H fluorination of aliphatic carboxylic acids

Abstract

The ever-increasing demand for fluorinated molecules due to their widespread applications has raised substantial interest in the development of new synthetic methodologies that selectively introduce fluorine into molecular scaffolds. While transition-metal-catalysed fluorination reactions in principle provide a direct means to convert inert C–H bonds into C–F bonds, fundamental challenges such as the high energetic barriers associated with the formation of C–F bonds by reductive elimination, among others, remain to be systematically addressed. Carboxylic acids, owing to their versatile synthetic utility in organic synthesis, serve as ideal model substrates in this context. Here we report a protocol that enables the β-C(sp3)–H fluorination of free carboxylic acids, giving access to a wide range of fluorinated carboxylic acids. The rational design of the oxidizing reagent proved to be crucial in establishing the protocol and introduces an additional design dimension to the field of C–H activation. C–F bond formation using transition-metal catalysis is a challenge owing to the high energy barrier associated with reductive elimination. Now the direct β-C(sp3)–H fluorination of aliphatic carboxylic acids with a broad substrate scope is reported, using rational oxidant design to facilitate the reductive elimination step.