-CF₃-Substituted Saturated Bicyclic Amines: Advanced Building Blocks for Medicinal Chemistry

A straightforward approach to alpha-CF3-substituted saturated bicyclic amines starting from commercially available compounds is proposed. The key steps include addition of the Ruppert-Prakash reagent to imine moiety and AlMe3-promoted intramolecular heterocyclization. The reaction sequence provides access to fluorine-containing azabicyclo[n.2.1]alkane (n=1-3) or azabicyclo[2.2.2]octane derivatives in 10-42 % overall yield. The physicochemical properties of the prepared compounds or their model derivatives (i. e., pK(a) and LogP) were measured and compared to those for the parent monocyclic or non-fluorinated saturated heterocycles. As expected, amine basicity was lowered considerably upon introduction of the CF3 group (Delta pK(a)approximate to 4), while the lipophilicity increased (by ca. 0.5 LogP units). The summarized data provides a convenient guideline for application of the synthesized compounds in drug discovery programs.