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

In the past years, Pd-0-catalyzed C(sp(3))-H activation provided efficient and step-economical methods to synthesize carbo- and heterocycles via direct C(sp(2))-C(sp(3)) 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(sp(2))-H or C(sp(3))-H activation at another nitrogen substituent and remote C-C bond formation to generate biologically relevant isoindolines and beta-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.

Automated summary

In the past years, Pd-0-catalyzed C(sp(3))-H activation has provided efficient and economical methods for synthesizing carbo- and heterocycles via direct C(sp(2))-C(sp(3)) bond formation. This study reports a 1,4-Pd shift that enables the synthesis of N-heterocycles, which are difficult to build through direct reactions. The reaction involves the 1,4-Pd shift of o-bromo-N-methylanilines at the N-methyl group, followed by intramolecular trapping and remote C-C bond formation, resulting in the formation of biologically relevant isoindolines and beta-lactams. The selectivity of the reaction is influenced by the choice of ligand, with NHCs favoring the formation of products through remote C-C coupling.