The synthesis of 3-azabicyclo[3.2.0]heptyl boropinacolates and trifluoroborates via the [2 + 2] photocycloaddition of the corresponding alkenyl boronic derivatives and maleimides or maleic anhydride is described. Optimization of the reaction conditions (i.e., wavelength, concentration of the reagents, photosensitizer) was carried out, and the scope and limitations of the method were studied. Alkenyl boronic acid pinacolates were found to be more suitable for the [2 + 2] cycloaddition, providing better reaction outcomes compared to the trifluoroborates. The utility of this approach was shown by the preparation of bi-and trifunctional building blocks (21 examples), which could be easily synthesized on up to 60 g scale. These cycloadducts provide a convenient entry into the 3-azabicyclo[3.2.0]heptane scaffold through the C−C coupling or oxidative deborylation reactions.
Synthesis of previously unavailable 1,2‐disubstituted cyclobutane building blocks bearing mono‐, di‐ and trifluoromethyl groups are disclosed. The key steps included deoxofluorination or TMAF‐mediated nucleophilic substitution in the appropriate bifunctional cyclobutanes; for the CF3‐substituted derivatives, alternative methods based on cyano‐ or azidotrifluoromethylation of cyclobutene using the Togni reagent II were also proposed. All methods provided trans diastereomers of the target primary amines and carboxylic acids (6 representatives) and were suitable for their multigram preparation. Furthermore, dissociation constants (pKa) and lipophilicity (logP) values were measured to evaluate the effect of the fluoroalkyl substituents on acidity/basicity and lipophilicity of the building blocks obtained.
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