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

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.