Green synthesis of 2-trifluoromethylquinoline skeletons via organocatalytic N-[(α-trifluoromethyl)vinyl]isatins CN bond activation

The Pfitzinger reaction has long served as a notable synthesis pathway for quinoline-4-carboxylic acids. Although recognized for its synthetic potential since its discovery >138 years ago, a truly catalytic variant has remained elusive until now. Herein, we present a novel 2‑tert‑butyl‑1,1,3,3-tetramethylguanidine (BTMG)-catalyzed Pfitzinger reaction that employs N-[(α-trifluoromethyl)vinyl]isatins with amines and alcohols, providing direct routes to 2-CF₃-quinoline-4-carboxamides and carboxylic esters. This method is not only green and environmentally benign but also accommodates the introduction of other functional groups like CF₂H and CO₂Me at the C2 position of quinoline skeleton. The utility of this methodology was demonstrated by the broad substrate scope, the late-stage modification of commercial drugs, and the diverse derivatization of quinoline framework. More importantly, this work not only opens up a new avenue for the activation of amide CN bonds in catalytic reaction development, but also unlocks the huge potential of some 2-trifluoromethyl quinolines with strong inhibitory activity against PTP1B or optoelectronic application in organic light-emitting diodes.