Halogen Bond-catalyzed Pictet-Spengler Reaction

We report an efficient halogen bond-catalyzed Pictet-Spengler reaction using diaryliodonium salts as catalysts as a metal-free alternative to traditional acid catalysis. Through systematic optimization, exceptional catalytic activity was achieved with only 0.5 mol-% of a simple dibenzoiodolium with a perfluorinated borate counterion. The protocol demonstrates a broad substrate scope, converting various N-protected tryptamines and diverse carbonyl compounds (aromatic, heteroaromatic, and aliphatic aldehydes) to the corresponding tetrahydro-β-carbolines (THβCs) in up to 98% yield. The reaction versatility was further demonstrated by a successful oxa-variant using tryptophol. Control experiments revealed the crucial role of halogen bonding in promoting both the initial condensation and the final cyclization steps.