Aza-Friedel–Crafts Cyclization vs Plancher Rearrangement in the Acid-Catalyzed Reaction of 3-Benzylindolenines

Exposure of 3-benzylindolenines to acidic conditions typically triggers the classical Plancher rearrangement, wherein the benzylic group undergoes a 1,2-migration to furnish 3-substituted 2-benzylindoles. Under identical conditions, however, these substrates have the potential to engage in an aza-Friedel-Crafts (aza-FC) cyclization involving the aryl ring of the benzylic group. Herein, we present the first systematic study delineating the competition between aza-FC cyclization and the Plancher rearrangement across a series of 3-benzylindolenines. Our studies reveal that the reaction outcome is highly dependent on the electronic nature of the benzylic aryl ring. Specifically, 3,5-dimethoxy- and 3-aminobenzyl substituents exclusively promote aza-FC cyclization. A 3,4,5-trimethoxybenzyl motif also favors this pathway, albeit not with complete selectivity. In contrast, all other benzylic substituents examined exclusively undergo the 1,2-Plancher rearrangement. Notably, indolenines bearing a two- or three-atom tether between an aryl ring and the indolenine C3 position uniformly undergo aza-FC cyclization.