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Site selectivity represents a key challenge for non-directed C−H functionalization, even when the C−H bond is intrinsically reactive. Here, we report a copper-catalyzed method for benzylic C−H azidation of diverse molecules. Experimental and density functional theory studies suggest the benzyl radical reacts with a Cu II -azide species via a radical-polar crossover pathway. Comparison of this method with other C−H azidation methods highlights its unique site selectivity, and conversions of the benzyl azide products into amine, triazole, tetrazole, and pyrrole functional groups highlight the broad utility of this method for target molecule synthesis and medicinal chemistry.

Azoles are important motifs in medicinal chemistry, and elaboration of their structures via direct N−H/C−H coupling could have broad utility in drug discovery. The ambident reactivity of many azoles, however, presents significant selectivity challenges. Here, we report a copper-catalyzed method that achieves site-selective cross-coupling of pyrazoles and other N−H heterocycles with substrates bearing (hetero)benzylic C−H bonds. Excellent N-site selectivity is achieved, with the preferred site controlled by the identity of co-catalytic additives. This cross-coupling strategy features broad scope for both the N−H heterocycle and benzylic C−H coupling partners, enabling application of this method to complex molecule synthesis and medicinal chemistry.

Copper-catalyzed radical-relay reactions provide a versatile strategy for selective C–H functionalization; however, reactions with peroxide-based oxidants often require excess C–H substrate. Here, we report a photochemical strategy to overcome this limitation by using a Cu/2,2′-biquinoline catalyst that supports benzylic C–H esterification with limiting C–H substrate. Mechanistic studies indicate that blue-light irradiation promotes carboxylate-to-copper charge transfer, reducing resting-state CuII to CuI, which activates the peroxide to generate an alkoxyl radical hydrogen-atom-transfer species. This “photochemical redox buffering” introduces a unique strategy to sustain the activity of Cu catalysts in radical-relay reactions.

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