Saturated aza-cycles are foundational to drug discovery, and methods for the production of complex motifs including bridged, fused, and spirocyclic amines have the potential to significantly accelerate medicinal chemistry efforts. Constrained amines, in comparison to their simpler monocyclic counterparts, often exhibit higher sp<sup>3</sup> content, improved metabolic stability, and favorable physicochemical properties. We herein report a unified strategy to accessing bicyclic amines via intramolecular C–H bond amination under Hofmann-Löffler-Freytag (HLF) conditions. Mechanistically, we uncovered a synergistic effect of light and heat activation on our cyclization and applied these findings to decagram scale synthesis of such architectures. Evaluation of a small representative set of bicyclic compounds revealed improved microsomal stability and differentiated lipophilicities.

Disruptive chemistry at Merck: Synthetic innovations in bicyclic amine synthesis and beyond

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.