Direct Spirocyclization of Tryptamines with Dearomatized Phenols Enables Catalyst-Free Access to C3-Spirocyclic Indolenines

This study presents a fluorinated alcohol-mediated strategy for the regioselective spirocyclization of tryptamines, enabling efficient synthesis of C3-spirocyclic indolenines with an all-carbon quaternary center. The catalyst-free protocol affords the desired products in excellent yields while exhibiting broad substrate scope and high functional-group tolerance. Mechanistic investigations, supported by density functional theory calculations, suggest that the reaction proceeds via formation of a ketimine intermediate. Computational studies further reveal that the C3 cyclization pathway is energetically more favorable than the competing C2 cyclization pathway. In addition, gram-scale synthesis and subsequent synthetic transformations highlight the practicality and synthetic utility of the developed cyclization methodology.