The rapid diversification of core ring structures in complex molecules through switchable skeletal editing is valuable in the drug discovery process. However, controllable methods for chemically divergent modifications of azaarene frameworks using common substrates are challenging, despite the potential to maximize structural diversity and complexity. Here we report the tunable skeletal editing of quinolines through Brønsted acid-catalysed multicomponent reactions of quinoline N-oxides, dialkyl acetylenedicarboxylates and water to generate nitrogen-containing heteroaromatic compounds together with linear compounds in a modular fashion. Specifically, in a one-pot procedure, after cyclization and sequential rearrangement processes, the quinoline N-oxides are easily converted into unique 2-substituted indolines. These then undergo acid-promoted fragmentation to give indoles, base-facilitated ring-opening to afford 2-alkenylanilines and oxidative cyclization to yield isoquinolinones. Catalytic asymmetric skeletal editing of quinolines is also realized, providing enantioenriched benzazepines bearing quaternary stereocentres, and late-stage skeletal modification of quinoline cores in several drugs is demonstrated.

通过可切换的骨骼编辑使复杂分子中的核心环结构快速多样化，这在药物发现过程中很有价值。然而，尽管有可能最大限度地提高结构多样性和复杂性，但使用常见基材对 Azaarene 框架进行化学发散修饰的可控方法具有挑战性。在这里，我们报道了喹啉 N-氧化物、二烷基乙酰炔二羧酸盐和水的 Brønsted 酸催化多组分反应对喹啉的可调谐骨架编辑，以模块化方式生成含氮杂芳烃化合物和线性化合物。具体来说，在一锅法中，经过环化和连续重排过程后，喹啉 N-氧化物很容易转化为独特的 2-取代吲哚啉。然后，它们经过酸促进的碎裂得到吲哚，碱促进的开环得到 2-烯基苯胺，并发生氧化环化得到异喹啉酮。还实现了喹啉的催化不对称骨骼编辑，提供带有四元立体中心的对映体富集的苯氮卓类药物，并且证明了几种药物中喹啉核心的后期骨骼修饰。