Bicyclic Isosteres of Pyridine/Piperidine: From Synthesis to Applications

2-Azabicyclo[2.2.2]octanes have been designed, synthesized, and validated biologically as isosteres of piperidine/pyridine. The key reaction step was the cyclization of cyclic alkenyl amines with the KOtBu/I₂/CO₂ combination. The method proved to be scalable (up to 20 g) and general: it was also applied for the synthesis of 2-azabicyclo[2.1.1]hexanes, 2-azabicyclo[3.1.1]heptanes, 2-azabicyclo[2.2.1]heptanes, 7-azabicyclo[2.2.1]heptanes, and 6-azabicyclo[3.2.1]octanes. Finally, combined with the nitrogen deletion tactic, this method also opened a practical way toward the previously hardly accessible 1,2-disubstituted bicyclo[1.1.1]pentanes—saturated analogues of ortho-benzenes.