Chemical Technology Division, CSIR-Institute of Himalayan Bioresource and Technology, Palampur 176061, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
Org Biomol Chem. 2021 Nov 18;19(44):9675-9687. doi: 10.1039/d1ob02000e.
Herein, regioselective -C-H halogenation of -pyrimidyl (hetero)aromatics through SAr (electrophilic aromatic substitution) type reaction is disclosed. SAr type reaction has been utilized for the C5-bromination of indolines (-selective) with -bromosuccinimide under metal and additive-free conditions in good to excellent yields. The developed methodology is also applicable for iodination and challenging chlorination. The pyrimidyl group is identified as a reactivity tuner that also controls the regioselectivity. The present method is also applicable for selective halogenation of aniline, pyridine, indole, oxindole, pyrazole, tetrahydroquinoline, isoquinoline, and carbazole. DFT studies such as Fukui nucleophilicity and natural charge maps also support the observed -selectivity. Post-functionalization of the title compound into the corresponding arylated, olefinated, and dihalogenated products is achieved in a one-pot, two-step fashion. Late-stage C-H bromination was also executed on drug/natural molecules (harmine, etoricoxib, clonidine, and chlorzoxazone) to demonstrate the applicability of the developed protocol.
本文揭示了通过 SAr（亲电芳香取代）型反应实现嘧啶基（杂）芳基芳烃的区域选择性 -C-H 卤化。SAr 型反应已被用于在无金属和添加剂条件下，通过 -溴代琥珀酰亚胺实现吲哚啉的 C5-溴化（ -选择性），产率良好至优秀。所开发的方法也适用于碘代和挑战性的氯化。嘧啶基被确定为一种反应性调谐器，也控制着区域选择性。本方法也适用于苯胺、吡啶、吲哚、吲哚酮、吡唑、四氢喹啉、异喹啉和咔唑的选择性卤化。密度泛函理论（DFT）研究，如亲核性和自然电荷映射，也支持观察到的 -选择性。标题化合物可以一锅两步的方式转化为相应的芳基化、烯基化和二卤代产物。药物/天然分子（哈尔明、依托考昔、可乐定和氯唑沙宗）的晚期 C-H 溴化也已完成，以证明所开发方案的适用性。
