Radical-Based Catalytic Transformations of 1-Azabicyclo[1.1.0]butanes: Opportunities and Future Directions

Abstract 1-Azabicyclo[1.1.0]butanes (ABBs) have emerged as versatile strained precursors to saturated, three-dimensional azetidine scaffolds that are increasingly valuable in modern drug discovery. This Perspective contends that the recent proliferation of radical-based catalytic platforms, encompassing photoredox, metallaphotoredox, energy-transfer, and electrochemical manifolds, serves as an effective complement to classical polar chemistry, enabling diverse transformations and the construction of sterically congested carbon–carbon and carbon–heteroatom bonds through distinct reactivity profiles. We illustrate how open-shell intermediates enable the precise, regiodivergent, and multicomponent construction of sterically congested azetidines and azabicyclo[n.1.1]alkanes. We argue that while several mechanistic patterns have now been proposed, their underlying reactivity principles remain incompletely understood, and the broader synthetic potential remains largely underexplored. We therefore chart a forward-looking agenda: the development of alternative radical transformations, the expansion of radical coupling partners to include abundant and readily available feedstocks, the integration of electrochemistry for scalable and catalyst-free processes, and the design of radical relay sequences that access architecturally complex bridged azabicycles beyond simple azetidines. By framing these frontiers as both timely and achievable, we aim to catalyze the evolution of radical ABB chemistry from a specialized tool into a broadly enabling strategy for constructing the nitrogen-containing, sp3-rich chemical space that next-generation drug discovery demands.