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

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.