Copper-Catalyzed Site-Specific α-Azidation of Ibuprofen and Naproxen Analogs

Ibuprofen and Naproxen analogs serve as nonsteroidal anti-inflammatory drugs and are the main drugs used to reduce pain, fever, and inflammation. Herein, we report a copper-catalyzed method for the first site-specific α-C(sp 3 )-H azidation reaction of Ibuprofen and Naproxen analogs. Controlled experiments suggested a unique copper-catalyzed chelation-assisted proton-coupled electron transfer mechanism. The gram-scale synthesis and the ease of nitrogen-based functionalization at the α-site of Ibuprofen and Naproxen analogs provide opportunities to manipulate numerous potential medicinal candidates. Compared to parent Ibuprofen, the α-azido Ibuprofen amide and α-phosphoramidate-substituted Ibuprofen amide showed both higher anti-inflammatory and analgesic activity (statistically significant difference, p < 0.01) in in vivo experiments. Simultaneously, this unique copper-catalyzed chelation-assisted proton-coupled electron transfer strategy paves the way for α-C(sp 3 )-H activation of ubiquitous carboxylic acids, amides, esters and so on.