F- and F-Arene Deoxyfluorination via Organic Photoredox-Catalysed Polarity-Reversed Nucleophilic Aromatic Substitution.

Nucleophilic aromatic substitution (SAr) is routinely used to install F and F in aromatic molecules, but is typically limited to electron-deficient arenes due to kinetic barriers associated with C-F bond formation. Here we demonstrate that a polarity-reversed photoredox-catalysed arene deoxyfluorination operating via cation radical-accelerated nucleophilic aromatic substitution (CRA-SAr) enables the fluorination of electron-rich arenes with F and F under mild conditions, thus complementing the traditional arene polarity requirements necessary for SAr-based fluorination. The utility of our radiofluorination strategy is highlighted by short reaction times, compatibility with multiple nucleofuges, and high radiofluorination yields, especially that of an important cancer positron emission tomography (PET) agent [F]5-fluorouracil ([F]FU). Taken together, our fluorination approach enables the development of fluorinated and radiofluorinated compounds that can be difficult to access by classical SAr strategies, with the potential for use in the synthesis and discovery of PET radiopharmaceuticals.