The Direct β-C(sp3)–H Fluorination of Carboxylic Acids

Abstract

Due to their widespread applications fluorine-containing compounds have become indispensable in various areas of our everyday lives. The ever-increasing demand for complex fluorinated molecules has raised a significant interest to develop new synthetic methodologies that selectively introduce fluorine into molecular scaffolds. While functional group interconversion approaches are well-established in this regard, their reliance on pre-installed reactive handles has encouraged organic chemists to investigate new strategies to enable a direct conversion of inert C–H bonds into C–F bonds. Transition-metal-catalyzed fluorination reactions have been recognized as a promising tool in this context, but fundamental challenges, such as the very high energetic barriers associated with the formation of C–F bonds by reductive elimination, amongst other reasons, remain to be addressed systematically. Arguably, research towards new concepts in fluorination chemistry should be conducted with substrates that are of immediate utility and imply a generalizability of the respective strategies. Carboxylic acids, owing to their versatile synthetic utility in organic synthesis and their comparably challenging use in C–H activation ideally fulfill these criteria. Herein, we here report a protocol that for the first time enables the β-C(sp3)–H fluorination of free carboxylic acids. The rational design of the oxidizing reagent proved to be crucial in establishing the protocol and introduces a new dimension to the rational design of synthetic methods in the field of C–H activation. The reported protocol gives access to a wide range of fluorinated carboxylic acids without the need to introduce an exogenous directing group.