Copper-Catalyzed Enantioconvergent Radical C(sp<sup>3</sup>)–N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)aromatic Amines under Ambient Conditions
Ji‐Jun Chen, Jiayong Zhang, Jia‐Heng Fang, Xuan‐Yi Du, Hai‐Dong Xia, Bin Cheng, Nan Li, Zhang‐Long Yu, Jun-Qian Bian, Fuli Wang, Jingjing Zheng, Weilong Liu, Qiang‐Shuai Gu, Zhong‐Liang Li, Xin‐Yuan Liu
Abstract
The enantioconvergent C(sp 3 )–N cross-coupling of racemic alkyl halides with (hetero)aromatic amines represents an ideal means to afford enantioenriched N -alkyl (hetero)aromatic amines yet has remained unexplored due to the catalyst poisoning specifically for strong-coordinating heteroaromatic amines. Here, we demonstrate a copper-catalyzed enantioconvergent radical C(sp 3 )–N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. The key to success is the judicious selection of appropriate multidentate anionic ligands through readily fine-tuning both electronic and steric properties for the formation of a stable and rigid chelating Cu complex. Thus, this kind of ligand could not only enhance the reducing capability of a copper catalyst to provide an enantioconvergent radical pathway but also avoid the coordination with other coordinating heteroatoms, thereby overcoming catalyst poisoning and/or chiral ligand displacement. This protocol covers a wide range of coupling partners (89 examples for activated racemic secondary/tertiary alkyl bromides/chlorides and (hetero)aromatic amines) with high functional group compatibility. When allied with follow-up transformations, it provides a highly flexible platform to access synthetically useful enantioenriched amine building blocks.