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Eur. J. Org. Chem. 2023, 26, 24, e202300292

DOI: 10.1002/ejoc.202300292

Demchuk O.; Bobovskyi B.; Vashchenko B.; Hryshchuk O.; Skreminskyi A.; Chernykh A.; Moskvina V.; Hordiyenko O.; Volochnyuk D.; Grygorenko O.

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.

 

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