Cu(II)-Mediated direct F-dehydrofluorination of phosphine oxides in high molar activity.

BACKGROUND

The F/F-isotope exchange method employing P(V)-centered prosthetic groups demonstrates advantages in addressing mild one-step aqueous F-labeling of peptides and proteins. However, the molar activity (A) achieved through isotope exchange remains relatively low, unless employing a high initial activity of [F]F. To overcome this drawback, our work introduces a novel approach through a Cu-mediated direct F-dehydrofluorination of phosphine oxides. This method leverages the straightforward separation of the F-labeled product from the phosphine oxide precursors, aiming to primarily increase A.

RESULTS

Through a F-dehydrofluorination efficiency test, Cu(OAc) was identified as the optimal oxidative metal salt, exhibiting a remarkable 100% conversion within one hour. Leveraging the straightforward separation of phosphine oxide precursors and phosphinic fluoride products, the A of an activated ester, [F]4, sees an impressive nearly 15-fold increase compared to the F/F-isotope exchange, with the same initial activity of [F]F. Furthermore, this Cu(II)-mediated F-dehydrofluorination approach demonstrates tolerance up to 20% solvent water content, which enables the practical radiosynthesis of F-labeled water-soluble molecules under non-drying conditions.

CONCLUSIONS

The direct F-dehydrofluorination of phosphine oxide prosthetic groups has been successfully accomplished, achieving a high A via Cu(II)-mediated oxidative addition and reductive elimination.