Synthesis and Physicochemical Characterization of 5 Trifluoromethyl-Substituted Saturated O- and S-Heterocycles

Fluorinated saturated heterocycles are valuable yet underexplored motifs in drug design. Here we present a scalable strategy for the synthesis of fluorinated tetrahydrofuran (THF) and tetrahydrothiophene (THT) building blocks from simple and readily available starting materials. The optimized conditions enabled access to CF₃-substituted ketones and the corresponding stereodefined alcohol, amine, and amino acid derivatives on decagram scale. Physicochemical profiling established clear structure–property relationships. pKₐ and pI values were affected by strong inductive effects of heteroatoms and SO₂ groups, with CF₃ substitution consistently enhancing the compound’s acidity and lowering isoelectric points. LogP measurements highlighted scaffold- and substituent-dependent lipophilicity, with sulfur-containing motifs being most lipophilic and sulfone derivatives – least. Overall, this work delivers a robust platform for accessing versatile fluorinated building blocks (including noncanonical amino acids) for drug discovery.