Synthesis and Physicochemical Properties of Functionalized cis– 2‐((Fluoro)Alkyl)Cyclobutanes

Efficient decagram-scale synthesis of (fluoro)alkyl-containing cis-1,2-disubstituted cyclobutane-derived building blocks is described. Starting from commercially available chemicals, target cyclobutylamines, carboxylic acids, and other valuable derivatives are obtained in 3-8 steps on up to a 39 g scale. Physicochemical characterization of the prepared compounds and their model derivatives reveal the distinct features of cis-1,2-disubstituted cyclobutanes (namely, significantly lowered lipophilicity) as compared to their previously reported trans-isomeric counterparts. Computational analysis, along with experimentally obtained structural properties, suggest the decisive influence of the compounds' conformation on the discussed properties.