Electrostatic Effects Accelerate Decatungstate-Catalyzed C-H Fluorination Using [18F]- and [19F]NFSI in Small Molecules and Peptide Mimics

The site-selective fluorination of unactivated C(sp(3))-H bonds provides unique opportunities to rapidly alter drug properties or generate radiotracers for positron emission tomography (PET) imaging. Toward this goal, photoactivated decatungstate (DT) is capable of generating carbon radicals through hydrogen atom transfer that subsequently undergo fluorination by reaction with N-fluorobenzenesulfonimide (NFSI) or [F-18]NFSI. This process enables C(sp(3))-H fluorination of a wide range of aliphatic compounds, though reaction rates can be highly variable and limit applications in radiotracer synthesis. Here, we demonstrate that cationic ammonium functions in aliphatic molecules promote formation of a precursor complex with DT that significantly increases the rate of C-H abstraction. The general utility of this rate-accelerating electrostatic effect is demonstrated on more than 30 ammonium-containing molecules, including amino acids, heterocycles, and pseudopeptides. Moreover, this effect is highlighted in the rapid production of [F-18]Glu-U-FHLeu, a F-18-labeled prostate specific membrane antigen (PSMA)-binding ligand.