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

Abstract A straightforward approach to α‐CF 3 ‐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 AlMe 3 ‐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 ., p K a and Log P ) 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 CF 3 group (Δp K a ≈4), while the lipophilicity increased (by ca. 0.5 Log P units). The summarized data provides a convenient guideline for application of the synthesized compounds in drug discovery programs.