Nucleophilic, Anionic C(sp³)-Fluorination via Catalytic Methodologies

Fluorine has quickly become an atom of great importance in pharmaceutical development. Fluorine, being the element with the highest electronegativity,  can impart substantial changes to a molecule’s chemical and physical properties. Incorporation of fluorine into a given framework can be divided into both nucleophilic and electrophilic fluorinating reagents. Particularly, nucleophilic fluorination has the distinct advantage over electrophilic fluorination when accessing radioactive [¹⁸F] labeled substances. Such substances have their applications in positron emission tomography (PET) that allows the radiolabeled substrates to be visualized in medical settings. However, accessing C(sp³)-fluorinated compounds can be challenging due to inherit low nucleophilicity of fluoride and substrate specific obstacles. As such, several modern strategies have been developed to overcome some of the barriers preventing access to further fluorinated chemical space [1].

The pioneering work of the Groves lab in 2015 describes the first decarboxylative fluorination via fluoride. Such reactivity is shown to proceed by manganese porphyrin catalysis and is expanded to radiofluorination [2]. Further work in the field by Doyle in 2020 saw the group using iridium based photocatalysis on substrate-bound redox active esters circumventing the need for superstoichiometric oxidant [3]. From the same group in 2021, a photocatalyzed C(sp³)–H nucleophilic fluorination method was described. Such a transformation is powerful for diversification not requiring prefunctionalization [4]. Recently in 2024, the Gouverneur group sought to improve this methodology by using TEMPO-bound starting materials that, upon cleavage, result in substrate-based carbocations susceptible to fluoride trapping. This strategy bypasses the need for the oxidation of substrate-based radicals described by the Doyle group above, simplifying the process [5].

Overall, the field of nucleophilic fluorination is being explored by many groups in recent years. Many of the methods being developed have also been shown to expand the field of radiofluorination, freeing chemical space previously inaccessible by traditional methods.

[1] Doyle, A. J. Am. Chem. Soc. 2023, 145, 9928-9950.

[2] Groves, J. Angew. Chem. Int. Ed. 2015, 54, 5241-5245.

[3] Doyle, A. J. Am. Chem. Soc. 2020, 142, 9493-9500.

[4] Doyle, A. Nature Communications 2021, 12, 6950.

[5] Gouverneur, V. J. Am. Chem. Soc. 2024, 146, 11599-11604