Fine-Tuning of Physicochemical Properties of 3,3-Disubstituted Oxetanes Introducing Fluorine Atom(s) on the Building...

Fluorinated oxetane derivatives garner significant attention due to their unique physicochemical properties and diverse bioisosteric possibilities for potential applications in medicinal chemistry. We developed robust methodologies for the synthesis of 3-fluoroalkyl-substituted oxetanes, leveraging nucleophilic substitution, deoxy- and deoxofluorination, as well as fluoroiodination as key steps of introduction of fluorine atoms directly to the oxetane core or adjacent alkyl groups. Optimized reaction sequences enabled the gram-scale synthesis of various small building blocks, i.e., amines, carboxylic acids, alcohols, etc. Physicochemical studies revealed that fluorination significantly impacts acidity, with oxetane derivatives demonstrating the decrease of pK_a values on up to three units in the case of replacement of gem-dimethyl, cyclopropyl- or cyclobutylidene moieties. These findings underscore the utility of fluorinated oxetanes as versatile building blocks for future applications in drug design and advanced materials.