Nature2014-06-24 4:34 PM

点选择性远端碳-氢键激发 Conformation-induced remote meta-C–H activation of amines

论文摘要 

为了充分实现碳-氢键激发在有机化学中的合成潜力,开发能在相对于已有官能团的各种不同位置选择性激发碳-氢键的新方法很重要。在这篇论文中,Jin-Quan Yu及同事利用一个可再生的模板来引导苯胺和苄胺的远距离(在3到11个键之外)间位碳-氢键的烯化和乙酸化反应。这个模板能够引导四氢喹啉、苯并恶嗪、苯胺、苄胺、2-苯基吡咯烷和2-苯基-哌啶的间位选择性碳-氢键功能化,而所有这些药物在药物发现中都常用作构造单元。

Abstract 

Achieving site selectivity in carbon–hydrogen (C–H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C–H bonds in any given organic molecule can lead to the activation of undesired C–H bonds by a non-selective catalyst. One solution to this problem is to distinguish C–H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C–H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied. However, the directed activation of C–H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C–H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation. Here we report a recyclable template that directs the olefination and acetoxylation of distal meta-C–H bonds—as far as 11 bonds away—of anilines and benzylic amines. This template is able to direct the meta-selective C–H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho- to meta-selectivity.

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