[¹⁸F]Fluorophenols from non-activated [¹⁸F]fluorobenzaldehydes by Baeyer-Villiger oxidation

Objectives The oxidation of [¹⁸F]fluorobenzaldehydes to [¹⁸F]fluorophenols offers a very useful tool for radiosyntheses since several potential radiopharmaceuticals contain this structural motive. Unfortunately this strategy has been confined to aldehydes bearing electron donating substituents leaving non-activated [¹⁸F]fluorobenzaldehydes aside. Recently, such aldehydes were converted into phenols by Baeyer-Villiger oxidation using a hypervalent aryl-λ³-bromane [1]. However, the synthesis of this reagent is hardly amenable, thereby limiting its application. Thus, the synthesis of [¹⁸F]fluorophenols from non-activated [¹⁸F]fluorobenzaldehydes using commercially available reagents was investigated here as an alternative.

Methods 2- and 4-[¹⁸F]fluorobenzaldehyde served as model compounds. They were prepared from either (2- and 4-formylphenyl)trimethylammonium triflate or 2- and 4-fluorobenzaldehyde. Several parameters like oxidant, additive, reagent concentration, reaction time and solvent were examined in order to optimize the synthesis of 2- and 4-[¹⁸F]fluorophenols. The optimized conditions were then applied to the synthesis of 4-[¹⁸F]fluoro-3-methylphenol, 5-bromo-2-[¹⁸F]fluorophenol and 4-bromo-2-[¹⁸F]fluorophenol from their respective [¹⁸F]fluorobenzaldehydes.

Results The best radiochemical yield (RCY) and selectivity with respect to the formation of [¹⁸F]fluorophenols were obtained with 2,2,2-trifluoroethanol as solvent. Under the optimized conditions of 80 °C and 30 min reaction time, 2-[¹⁸F]fluorophenol, as an example, was obtained with a RCY of 97 ± 3 %. The studies showed that the addition of H₂SO₄ is necessary and it seems to have a dual effect as catalyst and desiccant. Further, the efficiency of the oxidant decreased following the order: Oxone® > peracetic acid > m-CPBA > H₃BO₃/H₂O₂. Even the strongly deactivated bromo-2-fluorobenzaldehydes could be converted to the corresponding phenols with a RCY of 50 %.

Conclusions The Baeyer-Villiger oxidation method was successfully modified to convert non-activated [¹⁸F]fluorobenzaldehydes to [¹⁸F]fluorophenols with high RCY.