Overcoming the limitations of directed C-H functionalizations of heterocycles.
Overcoming the limitations of directed C-H functionalizations of heterocycles.
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DOI：
10.1038/nature13885
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发表时间：
2014-11-20
期刊：
影响因子：
64.8
通讯作者：
Yu, Jin-Quan
中科院分区：
文献类型：
--
作者：
Liu, Yue-Jin;Xu, Hui;Kong, Wei-Jun;Shang, Ming;Dai, Hui-Xiong;Yu, Jin-Quan
在定向C-H活化反应中，杂环底物中的氮和硫原子与金属催化剂发生强烈的配位反应。这种配位可能导致催化剂中毒或C-H官能化，限制了C-H活化反应在杂环药物开发中的应用。在这里，我们报告了一个强大的和合成有用的反应，克服了与在杂环上进行C-H官能化反应相关的并发症。我们的方法使用了一个简单的N-甲氧基酰胺基团，它既是一个直接基团，也是一个阴离子配体，以空气为唯一氧化剂，促进了Pd(0)源中反应性PdX2(X=ArCONOMe)物种的原位生成。通过这种方式，PdX2物种固有地锚定在邻近ConHome基团的目标C-H键附近，从而避免了各种杂环的干扰。值得注意的是，该反应覆盖了用含有强配位杂原子的底物观察到的传统位置选择性模式，包括氮、硫和磷。因此，这种操作简单的好氧反应证明了绕过长期困扰药物化学中定向C-H活化应用的基本限制的可行性。
In directed C–H activation reactions, nitrogen and sulfur atoms present in heterocyclic substrates coordinate strongly with metal catalysts. This coordination, which can lead to catalyst poisoning or C–H functionalization at an undesired position, limits the application of C–H activation reactions in heterocycle-based drug discovery. Herein, we report a robust and synthetically useful reaction that overcomes the complications associated with performing C–H functionalization reactions on heterocycles. Our approach employs a simple N-methoxy amide group, which serves as both a directing group and an anionic ligand to promote the in situ generation of the reactive PdX2 (X = ArCONOMe) species from a Pd(0) source using air as the sole oxidant. In this way, the PdX2 species is inherently anchored in close proximity with the target C–H bond adjacent to CONHOMe group, thus avoiding the interference from various heterocycles. Remarkably, this reaction overrides the conventional positional selectivity patterns observed with substrates containing strongly coordinating heteroatoms, including nitrogen, sulfur, and phosphorus. Thus, this operationally simple aerobic reaction demonstrates the feasibility of bypassing a fundamental limitation that has long plagued applications of directed C–H activation in medicinal chemistry.
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影响因子：
64.8
作者：
Leow, Dasheng;Li, Gang;Mei, Tian-Sheng;Yu, Jin-Quan
通讯作者：
Yu, Jin-Quan
影响因子：
15
作者：
ITO, Y;SUGINOME, M;MURAKAMI, M
通讯作者：
MURAKAMI, M
影响因子：
15
作者：
Kwak, Jaesung;Kim, Min;Chang, Sukbok
通讯作者：
Chang, Sukbok
影响因子：
62.1
作者：
Colby, Denise A.;Bergman, Robert G.;Ellman, Jonathan A.
通讯作者：
Ellman, Jonathan A.
影响因子：
18.3
作者：
Daugulis O;Do HQ;Shabashov D
通讯作者：
Shabashov D