meta-Nitration of Pyridines and Quinolines through Oxazino Azines

Abstract

meta-Nitration of azines (pyridines and quinolines) serves as a powerful method for the prompt construction and derivatization of several pharmaceuticals, agrochemicals, and materials. However, due to the inherent electronic properties of pyridines, achieving direct selective meta–C–H nitration under mild conditions has been a long-standing challenge in synthetic chemistry. Currently, there is no adequate strategy for late-stage meta–C–H nitration of pyridine-containing drugs and drug precursors. To address this void, we introduce a practical protocol for the highly regioselective meta-nitration of pyridines using a dearomatization-rearomatization strategy. The introduced method provides a diversification platform for selective nitration at the meta-position of azines via a radical pathway. This mild, open-air, one-pot, scalable, and catalyst-free process is employed for the late-stage meta-nitration of pyridine containing drugs, drug precursors, and ligands using pyridines as the limiting reagents. Consecutive C3 and C5 difunctionalization of pyridines is also achieved with complete regiocontrol relying on sequential addition, which further highlights the potential of the presented work. Additionally, the obtained products could be transformed into meta-amino azine products and other valuable building blocks. Incorporating N-heterocyclic amine structures through amidation into ibuprofen has significantly improved the drug’s clinical success, highlighting the importance of this work.