Radical Sampling Enabled Saturated N-Heterocycle Cyclization

High Resolution Image Download MS PowerPoint Slide Nitrogen-containing saturated heterocycles are essential structural motifs in many small molecule drugs, and the development of methods to rapidly access these scaffolds remains highly desirable. A modular and streamlined strategy for accessing these motifs involves in situ condensation of an aldehyde and an amine, followed by radical generation and cyclization to afford the desired heterocycle. Current applications of this strategy are limited in scope and efficiency, requiring amines that are prefunctionalized with the radical progenitor. Expansion of this approach to unfunctionalized amines, by using native C–H bonds as radical precursors, would greatly expand the scope, modularity, and expediency toward heterocycles. However, the selective C–H bond activation required to effect cyclization is challenging. Radical sampling, characterized by net-reversible hydrogen atom transfer (HAT) processes, addresses this issue by deploying cyclization as the product-determining step. This strategy leverages kinetic differences among competing cyclization pathways to selectively quench undesired radical intermediates with slower rates of cyclization while allowing the rapidly cyclizing radical to form the target six-membered ring. Herein, we report a general cyclization strategy that constructs versatile saturated heterocycles directly from aldehydes and amines through a radical sampling mechanism.