Remote Construction of N‐Heterocycles via 1,4‐Palladium Shift‐Mediated Double C−H Activation

• Published in: Angewandte Chemie Vol. 134; no. 17
• Main Authors: Miyakoshi, Takeru, Niggli, Nadja E., Baudoin, Olivier
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 19-04-2022
• Subjects: Bonding; Chemistry; Coupling; C−H Activation; Demethylation; Isoindolines; N-Heterocycles; Nitrogen; Palladium; Selectivity; β-Lactams
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202116101

In the past years, Pd0‐catalyzed C(sp3)−H activation provided efficient and step‐economical methods to synthesize carbo‐ and heterocycles via direct C(sp2)−C(sp3) bond formation. We report herein that a 1,4‐Pd shift allows access to N‐heterocycles which are difficult to build via a direct reaction. It is shown that o‐bromo‐N‐methylanilines undergo a 1,4‐Pd shift at the N‐methyl group, followed by intramolecular trapping by C(sp2)−H or C(sp3)−H activation at another nitrogen substituent and remote C−C bond formation to generate biologically relevant isoindolines and β‐lactams. The product selectivity is influenced by the employed ligand, with NHCs favoring the product of remote C−C coupling against products arising from direct C−C coupling and N‐demethylation.
A ligand‐controlled 1,4‐palladium shift onto an N‐methyl group enables the construction of C−C bonds in a remote position to the initial C−Br bond, leading to valuable isoindoline and β‐lactam products. The reaction proceeds via trapping of the σ‐alkylpalladium intermediate by C−H activation at another nitrogen substituent.