Enantioselective Continuous-Flow Production of 3-Indolylmethanamines Mediated by an Immobilized Phosphoric Acid Catalyst

A polystyrene-supported 1,1'-bi-2-naphthol derived phosphoric acid has been synthesized and applied in the enantioselective Friedel-Crafts reaction of indoles and sulfonylimines. The immobilized catalyst was highly active and selective, and gave rise to a broad range of 3-indolylmethanamines (19 examples) in high yields and excellent enantioselectivities (up to 98% enantiomeric excess) after short reaction times under very convenient reaction conditions (RT in dichloromethane). Moreover, repeated recycling (14 cycles) was possible with no substantial loss in catalytic performance and the system could be adapted to a continuous-flow operation (6h). Finally, the applicability of the system was further confirmed by rapid access to a library of compounds with three points of diversity in a single continuous-flow experiment that involved sequential pumping of different substrate combinations.