Regio- and Stereoselective Deprotonation and Functionalization of Strained 1-Azan.1.0bicycles

Strained 1-azan.1.0bicycles offer unique opportunities to rapidly assemble complex 3D heterocycles via strain-release reactivity. However, access to functionalized variants is limited by their innate instability and challenging assembly. Herein, we report a regio- and stereoselective lithiation strategy for azabicyclo2.1.0pentane (ABP) and azabicyclo3.1.0hexane (ABH), enabling direct functionalization of the strained framework. In contrast to predictions based on conventional acidity models, lithiation occurs exclusively at the exo-C2-H position in both heterocycles. The resulting organolithium intermediates undergo efficient trapping with a diverse array of electrophiles, providing access to C2/C3-substituted pyrrolidines and piperidines with full diastereocontrol upon subsequent ring-opening. Notably, upon trapping with boronic esters, ABH boronates undergo strain-promoted migration, while ABP analogues favor elimination. Extensive experimental and computational studies reveal that the exo-C2-H bond is the thermodynamic site of deprotonation and that the ABP 1,2-boronate rearrangement is outcompeted by deleterious C3 intermolecular nucleophilic addition. This work expands the synthetic utility of azabicyclic scaffolds and provides a blueprint for exploiting strained heterocycles for stereoselective synthesis.