Difluoromethyl pyridines have gained significant attention in medicinal and agricultural chemistry. The direct C−H-difluoromethylation of pyridines represents a highly efficient economic way to access these azines. However, the direct meta-difluoromethylation of pyridines has remained elusive and methods for site-switchable regioselective meta- and para-difluoromethylation are unknown. Here, we demonstrate the meta-C−H-difluoromethylation of pyridines through a radical process by using oxazino pyridine intermediates, which are easily accessed from pyridines. The selectivity can be readily switched to para by in situ transformation of the oxazino pyridines to pyridinium salts upon acid treatment. The preparation of various meta- and para-difluoromethylated pyridines through this approach is presented. The mild conditions used also allow for the late-stage meta- or para-difluoromethylation of pyridine containing drugs. Sequential double functionalization of pyridines is presented, which further underlines the value of this work.

二氟甲基吡啶在医药和农业化学领域引起了广泛关注。吡啶的直接CH-二氟甲基化代表了获取这些吖嗪的高效经济方法。然而，吡啶的直接间二氟甲基化仍然难以捉摸，并且位点可切换的区域选择性间二氟甲基化和对二氟甲基化的方法尚不清楚。在这里，我们通过使用恶嗪吡啶中间体（很容易从吡啶中获得），通过自由基过程演示了吡啶的间-C−H-二氟甲基化。通过酸处理后恶嗪基吡啶原位转化为吡啶鎓盐，选择性可以容易地转变为对位。介绍了通过这种方法制备各种间二氟甲基化吡啶和对二氟甲基化吡啶。所使用的温和条件还允许含吡啶药物的后期间二氟甲基化或对二氟甲基化。吡啶的连续双官能化被提出，进一步强调了这项工作的价值。