LAUSR

Carbon-hydrogen (C−H) functionalization of pyridines is a powerful tool for the rapid construction and derivatization of many agrochemicals, pharmaceuticals, and materials. Because of the inherent electronic properties of pyridines, selective meta-C−H functionalization is challenging. Here, we present a protocol for highly regioselective meta-C−H trifluoromethylation, perfluoroalkylation, chlorination, bromination, iodination, nitration, sulfanylation, and selenylation of pyridines through a redox-neutral dearomatization-rearomatization process. The introduced dearomative activation mode provides a diversification platform for meta-selective reactions on pyridines and other azaarenes through radical as well as ionic pathways. The broad scope and high selectivity of these catalyst-free reactions render these processes applicable for late-stage functionalization of drugs. Description Activating pyridine’s 3-position Numerous pharmaceutical compounds contain aromatic heterocycle components such as pyridine. Chemists therefore prize reactions that selectively append substituents to particular sites on these rings. Boyle et al. report that upon opening pyridine rings to form linear imines, the distinct characteristics of these intermediates strongly favored halogenation at the carbon in the otherwise unreactive 3-position. Recyclization then yielded a selectively halogenated ring. A complementary approach by Cao et al. relies on a reversible reaction of the pyridines with an alkyne and ester, disrupting the electronic structure to activate the 3-position for halogenation as well as trifluoromethylation (see the Perspective by Joo). —JSY Opening and reclosing pyridines enables selective halogenation at the 3-position of the ring.