Overcoming the Limitations of γ- and δ-C-H Arylation of Amines through Ligand Development

被引:154
作者
Chen, Yan-Qiao [1 ]
Wang, Zhen [1 ]
Wu, Yongwei [1 ]
Wisniewski, Steven R. [2 ]
Qiao, Jennifer X. [3 ]
Ewing, William R. [3 ]
Eastgate, Martin D. [2 ]
Yu, Jin-Quan [1 ]
机构
[1] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA
[2] Bristol Myers Squibb, Chem & Synthet Dev, 1 Squibb Dr, New Brunswick, NJ 08903 USA
[3] Bristol Myers Squibb, Discovery Chem, POB 4000, Princeton, NJ 08543 USA
关键词
TRANSIENT DIRECTING GROUP; C(SP(3))-H ARYLATION; FUNCTIONALIZATION; BENZALDEHYDES; BONDS; INHIBITOR; SITE; ALKENYLATION; OLEFINATION; POSITIONS;
D O I
10.1021/jacs.8b07109
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
引用
收藏
页码:17884 / 17894
页数:11
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