Practical and innate carbon-hydrogen functionalization of heterocycles

摘要

Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and patho-physiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications-such as aqueous solubility and their ability to act as ligands-render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 ℃ or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.%富含氮的杂环在制药领域很多，它们的合成已rn通过在由过渡金属介导的交叉耦合反应方面所rn取得的一系列进展而得到简化。然而，不依靠rn预先功能化的起始材料的实用的、具有选择性rn的C-H功能化方法的开发却是一个欠发展的领rn域。本文作者报告，亚磺酸锌盐可被用来将烷rn基转移到杂环上，从而允许在药学上有用的rnC-C键以一种温和的、直接的和操作简单的方rn式形成，同时又能以一种正交方式对其他固有rn的C-H功能化方法做出反应。