Pyridine halogenation reactions are crucial for obtaining the vast array of derivatives required for drug and agrochemical development. However, despite more than a century of synthetic endeavors, halogenation processes that selectively functionalize the carbon–hydrogen bond in the 3-position of a broad range of pyridine precursors remain largely elusive. We report a reaction sequence of pyridyl ring opening, halogenation, and ring closing whereby the acyclic Zincke imine intermediates undergo highly regioselective halogenation reactions under mild conditions. Experimental and computational mechanistic studies indicate that the nature of the halogen electrophile can modify the selectivity-determining step. Using this method, we produced a diverse set of 3-halopyridines and demonstrated late-stage halogenation of complex pharmaceuticals and agrochemicals.

中文翻译：

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通过锌亚胺中间体卤化吡啶的3位

吡啶卤化反应对于获得药物和农用化学品开发所需的大量衍生物至关重要。然而，尽管经过一个多世纪的合成努力，选择性官能化多种吡啶前体 3 位碳氢键的卤化过程在很大程度上仍然难以捉摸。我们报道了吡啶基开环、卤化和闭环的反应序列，其中无环锌亚胺中间体在温和条件下经历高度区域选择性卤化反应。实验和计算机理研究表明，卤素亲电子试剂的性质可以改变选择性决定步骤。使用这种方法，我们生产了多种 3-卤代吡啶，并演示了复杂药物和农用化学品的后期卤化。