Copper-Catalyzed Selective Mononitration of Unbiased ortho -C–H Bonds in Arenes Using a Ball Mill in Air: Excellent Compatibility with Heterocycles

We describe the first copper-catalyzed, amide–oxazoline-directed, highly regioselective mono- ortho -C–H nitration of arenes and heteroarenes conducted under ambient air using ball milling at room temperature. This newly developed method affords novel nitroarenes in high yields with excellent regioselectivity between the two unbiased ortho -C–H bonds. Importantly, this work constitutes the first example of C–H bond nitration achieved under mechanochemical conditions as well as the first successful implementation of ball milling in amide–oxazoline-directed transformations. Moreover, the nitration of heteroaromatic systems directed by an amide–oxazolione group had not been previously reported, which has been accomplished in the present study. The developed methodology exhibits a broad substrate scope and high tolerance toward diverse functional groups, including heterocycles, and allows for facile directing group removal from the products. Its practical utility was further demonstrated through gram-scale reaction and various subsequent C–H functionalization and further transformations of the mononitrated products. The practical applicability of this strategy was further illustrated through the late-stage functionalization of telmisartan drug, a well-known antagonist for the angiotensin II receptor. In addition, several control experiments were performed to obtain mechanistic insight and to elucidate the proposed catalytic cycle.