Synthesis and Physicochemical Characterization of 6-Trifluoromethyl Spiro[3.3]heptane Building Blocks

A practical synthesis of 6-(trifluoromethyl)spiro[3.3]hep¬tane-derived building blocks was developed. Starting from a commercially available cyclobutanone derivative, a key building block – 1,1-bis(bromomethyl)-3-(trifluoromethyl)cyclobutane – was prepa¬red on a 0.5 kg scale in a single run. Further construction of the spiro[3.3]heptane core was achieved via double alkylation of TosMIC or malonate diester on up to 120 g scale. Simple functional group transformation provided 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 pKa and lipophilicity LogP) were experimentally determined and compared to those for non-, mono-, and gem-difluorinated counterparts, as well as cyclohexane and cycloheptane derivatives. Spatial structure of the obtained compounds was evaluated by X-ray diffraction studies and characterized by exit vector plot (EVP) analysis.