In(OTf)3-Catalyzed (3 + 3) Dipolar Cyclization of Bicyclo[1.1.0]butanes with N-Nucleophilic 1,3-Dipoles: Access to 2,3-Diazabicyclo[3.1.1]heptanes, 2,3-Diazabicyclo[3.1.1]heptenes, and Enantiopure 2-Azabicyclo[3.1.1]heptanes

The investigation into the synthesis of azabicyclo[3.1.1]heptanes (azaBCHeps) as bioisosteres to flat aza-aromatics has garnered increasing attention, while it encounters significant challenges. Herein, we have demonstrated the In(OTf)₃-catalyzed (3 + 3) dipolar cyclization of bicyclo[1.1.0]butanes (BCBs) with hydrazones and π-allyl-iridium 1,3-dipoles, engendering a diverse array of azaBCHeps. The cyclization of hydrazones and BCBs furnished densely substituted 2,3-diazabicyclo[3.1.1]heptanes and 2,3-diazabicyclo[3.1.1]heptenes under nitrogen and oxygen atmospheres, respectively. A combination of experimental and computational investigations lends robust support for the proton-transfer-interposed sequential mechanism. More importantly, by integrating In(OTf)₃/iridium relay catalysis, enantiopure 2-azabicyclo[3.1.1]heptanes were constructed through the (3 + 3) cyclization of BCBs with aza-π-allyl-iridium 1,3-dipoles, in situ generated from N-allyl carbonates. Both methodologies exhibit mild reaction conditions and good tolerance for various functional groups. Moreover, the copious derivatization of products highlights the utility of the newly synthesized heterobicyclic motifs as versatile building blocks in synthetic chemistry.