Abstract

The use of F-based decorations in drug discovery started from the development of fluorocorticoids and fluorochinolones (1950s and 1980s respectively) and it resulted in about 20% of approved drugs on the Market containing fluorine. From a medicinal chemistry perspective, the installation of F-based small groups (e.g. -CF₃, -CF₂H, -OCF₃, -OCF₂H, -SCF₃, - SCF₂H) necessarily impacts on physicochemical, pharmacokinetics, pharmacodynamics and toxicological properties of small molecules. Accordingly, a huge interest on this topic is constantly arising in the medicinal chemistry community. Focusing on heteroarenes, the synthetic access to these substitutions is guaranteed by a number of effective reactions, such as Miniscitype reaction, photochemistry or electrochemistry C-H activation. The aim of this work is to analyze the rational in using these groups in medicinal chemistry and to highlight the current available synthetic toolbox of C-H activation for their introduction on heteroarenes of pharmaceutical interest. A particular focus has been given to those procedures amenable at late-stage functionalisation process.

Keywords: Late stage functionalisation, LSF, fluoro-based small groups, C-H activation, OCF₃, OCF₂H, CF₂H, SCF₃, SCF₂H.

Graphical Abstract