Isotopologues of potassium 2,2,2-trifluoroethoxide for applications in positron emission tomography and beyond

Abstract

The 2,2,2-trifluoroethoxy group increasingly features in drugs and potential tracers for biomedical imaging with positron emission tomography (PET). Herein, we describe a rapid and transition metal-free conversion of fluoroform with paraformaldehyde into highly reactive potassium 2,2,2-trifluoroethoxide (CF₃CH₂OK) and demonstrate robust applications of this synthon in one-pot, two-stage 2,2,2-trifluoroethoxylations of both aromatic and aliphatic precursors. Moreover, we show that these transformations translate easily to fluoroform that has been labeled with either carbon-11 (t_1/2 = 20.4 min) or fluorine-18 (t_1/2 = 109.8 min), so allowing the appendage of complex molecules with a no-carrier-added ¹¹C- or ¹⁸F- 2,2,2-trifluoroethoxy group. This provides scope to create candidate PET tracers with radioactive and metabolically stable 2,2,2-trifluoroethoxy moieties. We also exemplify syntheses of isotopologues of potassium 2,2,2-trifluoroethoxide and show their utility for stable isotopic labeling which can be of further benefit for drug discovery and development.

The 2,2,2-trifluoroethoxy group features in drugs and potential tracers for biomedical imaging with positron emission tomography. Herein, the authors report the conversion of fluoroform into potassium 2,2,2-trifluoroethoxide isotopologues and their applications in late stage 2,2,2-trifluoroethoxylations of aromatic and aliphatic substrates for positron emission tomography and stable isotope labeling.