Overcoming the Limitations of γ- and δ-C-H Arylation of Amines through Ligand Development
Overcoming the Limitations of γ- and δ-C-H Arylation of Amines through Ligand Development
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DOI：
10.1021/jacs.8b07109
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发表时间：
2018-12-26
影响因子：
15
通讯作者：
Yu, Jin-Quan
中科院分区：
文献类型：
--
作者：
Chen, Yan-Qiao;Wang, Zhen;Yu, Jin-Quan
基于可逆亚胺键的L、x型瞬态定向基团（TDG）已成为酮和游离胺C-H活化的广泛有用的工具。然而，多种反应组分（TDG本身、底物和底物-TDG加合物）与钯催化剂之间的竞争性结合相互作用通常会导致多种非反应性配合物的形成，这使得配体的开发极具挑战性。本文中，我们报告了一种多功能2-吡啶酮配体的发现，该配体解决了这些问题，并显著改善了烷基胺的γ -亚甲基芳基化，将偶联伙伴扩展到广泛的医学上重要的杂芳基碘化物，甚至是以前不反应的杂芳基溴。适当的瞬态导向基团和吡啶酮配体的结合也使烷基胺的三角芳化成为可能。值得注意的是，我们的瞬时导向基团设计揭示了与不同的瞬时导向基团匹配Pd-螯合的大小以及由γ -c - h键和δ c - h键产生的环的大小的重要性：与Pd（II）配合形成六元螯合物的tdg对γ -c - h键具有选择性，而通过五元螯合物与Pd（II）配合的tdg倾向于激活δ c - h键。这些发现为利用瞬时定向基团策略开发无保护基团和选择性C-H功能化提供了途径。
L,X-type transient directing groups (TDG) based on a reversible imine linkage have emerged as broadly useful tools for C-H activation of ketones and free amines. However, competitive binding interactions among multiple reaction components (TDG itself, substrate, and substrate-TDG adduct) with the palladium catalyst often lead to the formation of multiple unreactive complexes, rendering ligand development extremely challenging. Herein we report the finding of versatile 2-pyridone ligands that addresses these problems and significantly improves the gamma-methylene arylation of alkyl amines, extending the coupling partners to a wide range of medicinally important heteroaryl iodides and even previously unreactive heteroaryl bromides. The combination of an appropriate transient directing group and pyridone ligand has also enabled the delta-arylation of alkyl amines. Notably, our transient directing group design reveals the importance of matching the size of the Pd-chelation with different transient directing groups and the size of palladacycles generated from gamma- and delta-C-H bonds: TDGs that coordinate with Pd(II) to form a six-membered chelate are selective toward gamma-C-H bonds, whereas TDGs that coordinate with Pd(II) via a five-membered chelate tend to activate delta-C-H bonds. These findings provide an avenue for developing protecting group free and selective C-H functionalization using the transient directing group strategy.