The selective installation of azide groups into C­(sp3)–H bonds is a priority research topic in organic synthesis, particularly in pharmaceutical discovery and late-stage diversification. Herein, we demonstrate a generalized manganese-catalyzed oxidative azidation methodology of C­(sp3)–H bonds using nucleophilic NaN3 as an azide source under electrophotocatalytic conditions. This approach allows us to perform the reaction without the necessity of adding an excess of the substrate and successfully avoiding the use of stoichiometric chemical oxidants such as iodine­(III) reagent or NFSI. A series of tertiary and secondary benzylic C­(sp3)–H, aliphatic C­(sp3)–H, and drug-molecule-based C­(sp3)–H bonds in substrates are well tolerated under our protocol. The simultaneous gram-scale synthesis and the ease of transformation of azide to amine collectively advocate for the potential application in the preparative synthesis. Good reactivity of the tertiary benzylic C­(sp3)–H bond and selectivity of the tertiary aliphatic C­(sp3)–H bond in substrates to incorporate nitrogen-based functionality at the tertiary alkyl group also provide opportunities to manipulate numerous potential medicinal candidates. We anticipate our synthetic protocol, consisting of metal catalysis, electrochemistry, and photochemistry, would provide a new sustainable option to execute challenging organic synthetic transformations.

Direct electrochemical oxidative functionalization of caffeine under metal‐free and external‐oxidant‐free conditions was achieved. Nucleophiles such as various substituted pyrazoles, alcohols, and sodium trifluoromethanesulfonate can be utilized with high diastereoselectivity for the dearomatizative functionalization of caffeine. In addition, selective C2 functionalization of caffeine has also been realized with the modification of solvent and reaction time. A gram‐scale experiment demonstrates the potential application in the derivatization of caffeine.