Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N–X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up).

亲电卤化是药物化学家广泛使用的工具，可以对分子进行预功能化以进一步实现多样性，或者将卤素原子掺入药物或类药物化合物中以解决代谢问题或调节脱靶效应。目前提高卤化能力的方法依赖于新试剂的发明或使用各种添加剂（例如路易斯或布朗斯台德酸、路易斯碱和氢键活化剂）活化市售试剂。人们对能够在温和条件下卤化原本不活泼的化合物的新试剂有很高的需求。在这里，我们报告了一类基于异头酰胺的卤化试剂的发明，利用存储在N-X异头酰胺的金字塔形氮中的能量作为驱动力。这些稳健的卤化方法与各种官能团和杂环兼容，如 50 多种化合物（包括 13 克规模的示例和 1 个流动化学放大）的示例。