Site-selective C-H arylation of primary aliphatic amines enabled by a catalytic transient directing group
Site-selective C-H arylation of primary aliphatic amines enabled by a catalytic transient directing group
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DOI：
10.1038/nchem.2606
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发表时间：
2017-01-01
期刊：
影响因子：
21.8
通讯作者：
Ge, Haibo
中科院分区：
文献类型：
--
作者：
Liu, Yongbing;Ge, Haibo
过渡金属催化的脂肪胺C-H键直接官能化反应在有机化学和药物化学研究中具有重要意义。已经开发了几种用于脂肪族仲胺和脂肪族叔胺的直接sp（3）C-H官能化的方法，但是脂肪族伯胺在远程位置的位点选择性官能化仍然是一个挑战。在这里，我们报告了直接的，高度位点选择性的γ-芳基化的伯烷基胺通过钯催化的C-H键功能化的过程中未活化的sp（3）碳。使用乙醛酸作为廉价的、催化的和瞬时的导向基团，在没有任何保护或脱保护步骤的情况下制备了广泛的γ-芳基化伯烷基胺。这种方法提供了直接获得有机和药物化学中的重要结构基序，而不需要预官能化的底物或化学计量的导向基团，并在这里证明了直接从市售的2-氨基-2-丙基丙烷-1，3-二醇合成免疫调节药物芬戈莫德的类似物。
Transition-metal-catalysed direct C-H bond functionalization of aliphatic amines is of great importance in organic and medicinal chemistry research. Several methods have been developed for the direct sp(3) C-H functionalization of secondary and tertiary aliphatic amines, but site-selective functionalization of primary aliphatic amines in remote positions remains a challenge. Here, we report the direct, highly site-selective gamma-arylation of primary alkylamines via a palladium-catalysed C-H bond functionalization process on unactivated sp(3) carbons. Using glyoxylic acid as an inexpensive, catalytic and transient directing group, a wide array of gamma-arylated primary alkylamines were prepared without any protection or deprotection steps. This approach provides straightforward access to important structural motifs in organic and medicinal chemistry without the need for pre-functionalized substrates or stoichiometric directing groups and is demonstrated here in the synthesis of analogues of the immunomodulatory drug fingolimod directly from commercially available 2-amino-2-propylpropane-1,3-diol.