Synthesis and Physicochemical Characterization of 6‐Trifluoromethyl Spiro[3.3]Heptane Building Blocks

Decagram-scale synthesis of functionalized CF₃-containing spiro[3.3]heptane building blocks (including alcohols, amines, boronates, carboxylic acid, and amino acids) starting from the commercially available materials is developed. Using model derivatives, the effects of the CF₃ group on physicochemical and conformational properties of the title scaffold are elucidated and compared to those of nonfluorinated, monofluorinated, and gem-difluorinated counterparts.

A practical synthesis of 6-(trifluoromethyl)spiro[3.3]heptane-derived building blocks is developed. Starting from a commercially available cyclobutanone derivative, a key building block—1,1-bis(bromomethyl)-3-(trifluoromethyl)cyclobutane—is prepared on a 0.5 kg scale in a single run. Further construction of the spiro[3.3]heptane core is achieved via double alkylation of TosMIC or malonate diester on up to 120 g scale. Simple functional group transformation provides access to a wide range of mono- and bifunctional spiro[3.3]heptane-derived building blocks, including alcohols, amines, boronate esters, carboxylic acids, and amino acids on a gram to multigram scale. Physicochemical properties (i.e., acidity pK _a and lipophilicity LogP) are experimentally determined and compared to those for non-, mono-, and gem-difluorinated counterparts, as well as cyclohexane and cycloheptane derivatives. The spatial structure of the obtained compounds is evaluated by X-ray diffraction studies and characterized by exit vector plot analysis.