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

Expedient gram- to decagram-scale synthesis of cis-1,2-disubstited (fluoro)alkyl cyclobutanes—valuable small building blocks for medicinal chemistry—is developed. Physicochemical evaluation of the title compounds through the pK _a and LogP measurements reveal interesting trends affected by the compound's fluorination pattern and stereochemistry, which is rationalized through molecular electrostatic potential surface (MEPS) and conformational analysis.

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.

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