The significance of chelation-assisted C–H functionalization stands upon the superior site-selectivity, easy synthesis, and diverse product utility. In this work, we design a meta-directing scaffold by tuning the side chain of a pyrimidine-based template to attain unconventional site-selectivity in anilines. A simple methyl substitution at the side chain enhances the directing group (DG) efficacy significantly, leading to an almost exclusive meta-selectivity. The current DG further enables a meta-selective cyanation of aniline and its higher homologues irrespective of the substrate electronic bias. The synthetic impact of the methodology is further highlighted with late-stage functionalizations of two very popular local anesthetics butamben and benzocaine. A thorough experimental and in silico study further unfolds the importance of the substitution effect in attaining superior site-selectivity and the role of silver carbonate in the mechanistic cycle.

中文翻译：

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利用“甲基效应”开发新型 C-H 氰化元导向模板

螯合辅助的 C-H 官能化的重要性在于其优越的位点选择性、易于合成和多样化的产品用途。在这项工作中，我们通过调整基于嘧啶的模板的侧链来设计元定向支架，以获得苯胺中非常规的位点选择性。侧链上的简单甲基取代可显着增强导向基团 (DG) 功效，从而导致几乎唯一的间位选择性。目前的DG进一步实现了苯胺及其高级同系物的间位选择性氰化，而与底物电子偏压无关。两种非常流行的局部麻醉剂丁苯苯和苯佐卡因的后期功能化进一步凸显了该方法的合成影响。彻底的实验和计算机研究进一步揭示了取代效应在获得优异的位点选择性方面的重要性以及碳酸银在机械循环中的作用。