3-Fluoroalkyl (CF₃, CHF₂, CH₂F) Cyclobutane-Derived Building Blocks for Medicinal Chemistry: Synthesis and Physicochemical Properties

Synthesis and physicochemical characterization of all possible cis- and trans-1,3-disubstituted cyclobutane-derived amines and carboxylic acids bearing mono-, di- and trifluoromethyl groups at the C-3 position is disclosed. Tetramethylammonium fluoride (TMAF)- or morpholinosulfur trifluoride (Morph-DAST)-mediated nucleophilic fluorination of appropriate cis- and trans-diastereomeric substrates was used as the key step for the preparation of CH₂F- and CHF₂-substituted derivatives. To obtain the corresponding cis- and trans-isomeric CF₃-substituted derivatives, resolution of known 3-(trifluoro­methyl)cyclobutanecarboxylic acid (obtained as a mixture of dia­stereomers) was applied. The proposed procedures were suitable for the preparation of corresponding fluoroalkyl-substituted cyclobutane-derived amines and carboxylic acids on up to 50 g scale. All 12 building blocks obtained were characterized by measuring dissocia­tion constants (pKa) and lipophilicities (LogP, for model derivatives) to evaluate the effect of the fluoroalkyl substituents on their physico­chemical properties relevant to further drug discovery applications.