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Palladium‐Catalyzed C(sp(3))−H Arylation of Primary Amines Using a Catalytic Alkyl Acetal to Form a Transient Directing Group

C−H Functionalization of amines is a prominent challenge due to the strong complexation of amines to transition metal catalysts, and therefore typically requires derivatization at nitrogen with a directing group. Transient directing groups (TDGs) permit C−H functionalization in a single operation, w...

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Detalles Bibliográficos
Autores principales: St John‐Campbell, Sahra, Ou, Alex K., Bull, James A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391947/
https://www.ncbi.nlm.nih.gov/pubmed/30255961
http://dx.doi.org/10.1002/chem.201804515
Descripción
Sumario:C−H Functionalization of amines is a prominent challenge due to the strong complexation of amines to transition metal catalysts, and therefore typically requires derivatization at nitrogen with a directing group. Transient directing groups (TDGs) permit C−H functionalization in a single operation, without needing these additional steps for directing group installation and removal. Here we report a palladium catalyzed γ‐C−H arylation of amines using catalytic amounts of alkyl acetals as transient activators (e.g. commercially available (2,2‐dimethoxyethoxy)benzene). This simple additive enables arylation of amines with a wide range of aryl iodides. Key structural features of the novel TDG are examined, demonstrating an important role for the masked carbonyl and ether functionalities. Detailed kinetic (RPKA) and mechanistic investigations determine the order in all reagents, and identify cyclopalladation as the turnover limiting step. Finally, the discovery of an unprecedented off‐cycle free‐amine directed ϵ‐cyclopalladation of the arylation product is reported.