Taming Azide Radicals for Catalytic C–H Azidation

Reactions that directly transform aliphatic C–H bonds into alkyl azides are noticeably lacking in the repertoire of synthetic reactions, despite the importance of molecules containing C–N3 bonds in organic synthesis, chemical biology, and drug discovery. Harnessing the ubiquity of C–H bonds in organic molecules and the versatility of the azide functional group, such transformations could have broad applications in various disciplines. Radical C–H activation represents an appealing strategy to achieve aliphatic C–H azidation, as it overcomes many drawbacks of conventional organometallic approaches in activating inert aliphatic C–H bonds. Novel C–H azidation methodologies could be realized by combining radical C–H activation via hydrogen atom abstraction with suitable azide-transfer reagents. In this perspective, we survey the history of radical C–H azidation and summarize several significant recent advances in the field. All radical C–H azidations to date follow a general approach comprising an initial radical C–H abstraction step and a subsequent azide transfer to the incipient carbon-centered radicals. A particular focus of this perspective is on the beneficial effects of using transition-metal catalysts in C–H azidation reactions, which have "tamed" azide radicals and led to reactions that proceed efficiently under much milder conditions and provide broader substrate scope and higher regioselectivities and stereoselectivities, compared to previous approaches.