Concerted nucleophilic aromatic substitution with (19)F(-) and (18)F(-).
Concerted nucleophilic aromatic substitution with (19)F(-) and (18)F(-).
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DOI：
10.1038/nature17667
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发表时间：
2016-06-16
期刊：
影响因子：
64.8
通讯作者：
Ritter T
中科院分区：
文献类型：
--
作者：
Neumann CN;Hooker JM;Ritter T
亲核芳族取代（SNAr）被有机化学家广泛用于芳族分子的官能化，并且它是生成用于PET成像的含有18F的芳烃的最常用方法。各种亲核试剂都表现出SNAr反应性，反应的操作简单性意味着转化可以可靠地大规模进行。在SNAr过程中，亲核试剂攻击带有“离去基团”的碳原子，导致带负电荷的中间体，称为迈森海默络合物。只有具有吸电子取代基的芳烃才能在迈森海默络合物形成期间充分稳定所产生的负电荷积累，限制了SNAr反应的范围：最常见的SNAr底物在邻位和/或帕拉含有强π受体。在这篇手稿中，我们提出了一个不寻常的协同亲核芳香取代反应（CSNAr），不限于电子贫乏的芳烃，因为它不通过迈森海默中间体进行。我们展示了一个苯酚脱氧核糖核酸反应，CSNAr是一个逐步取代的青睐。机理的见解使我们能够开发一个功能基团耐受的18F-deoxynucleotide反应的酚，它可用于合成18F-PET探针。选择性18F引入，而不需要常见的，但繁琐的，共沸干燥的18F，现在可以完成从苯酚作为起始材料，并提供了18F标记的化合物无法通过常规化学。
Nucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain a 18F for use in PET imaging. A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales. During SNAr, attack of a nucleophile at a carbon atom bearing a ‘leaving group’ leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of SNAr reactions: the most common SNAr substrates contain strong π-acceptors in the ortho and/or para position(s). In this manuscript, we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CSNAr is favored over a stepwise displacement. Mechanistic insights enabled us to develop a functional group–tolerant 18F-deoxyfluorination reaction of phenols, which can be used to synthesize 18F-PET probes. Selective 18F introduction, without the need for the common, but cumbersome, azeotropic drying of 18F, can now be accomplished from phenols as starting materials, and provides access to 18F-labeled compounds not accessible through conventional chemistry.