Low‐Temperature Nickel‐Catalyzed C−N Cross‐Coupling via Kinetic Resolution Enabled by a Bulky and Flexible Chiral N‐Heterocyclic Carbene Ligand

The transition‐metal‐catalyzed C−N cross‐coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low‐temperature enantioselective amination of aryl halides remain a coveted targ...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2021-07, Vol.60 (29), p.16077-16084
Main Authors: Wang, Zi‐Chao, Xie, Pei‐Pei, Xu, Youjun, Hong, Xin, Shi, Shi‐Liang
Format: Article
Language:English
Subjects:
Amination
Amines
Aromatic compounds
asymmetric catalysis
Catalysts
Chemical reactions
Computer applications
Cross coupling
C−N coupling
Enantiomers
Halides
Ligands
low-temperature reactions
NHC ligands
Nickel
Sigma factor
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Summary:The transition‐metal‐catalyzed C−N cross‐coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low‐temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low‐temperature (as low as −50 °C), enantioselective Ni‐catalyzed C−N cross‐coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N‐heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ‐bonds on the C2‐symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal‐catalyzed asymmetric cross‐coupling reactions. An unprecedented low‐temperature, asymmetric Ni‐catalyzed C−N cross‐coupling of sterically hindered secondary amines with aryl chlorides via kinetic resolution is reported. A bulky yet flexible, chiral NHC ligand enables both low barrier oxidative addition and reductive elimination and high levels of enantiocontrol. Computational studies indicate that multiple σ‐bond rotations of the C2‐symmetric chiral NHC adapt to the changing needs of catalytic processes.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202103803