Regio- and Stereoselective Deprotonation and Functionalization of Strained 1‑Aza[n.1.0]bicycles

Journal article

Strained 1-aza­[n.1.0]­bicycles 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 azabicyclo[2.1.0]­pentane (ABP) and azabicyclo[3.1.0]­hexane (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.

Authors: Xie, T; Plowright, T; Somper, JD; Fairchild, M; Soler, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Journal of the American Chemical Society
• Volume: 148
• Issue: 17
• Pages: 18296-18304
• Publication date: 2026-04-22
• Acceptance date: 2026-04-13
• DOI: 10.1021/jacs.6c03462
• EISSN: 1520-5126
• ISSN: 0002-7863
• Language: English
• Keywords: Stereoselectivity; Surface modification; Deprotonation; Aliphatic compound; Surface (topology)