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-[(alpha-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. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.