A scalable protocol demonstrates N-selective difluoromethylation, tolerating multiple functional groups.
N-selective difluoromethylation of 4-hydroxyquinolines is a formidable challenge due to competing N- and O-difluoromethylation pathways. Herein, we present a mild, efficient, and scalable protocol using BrCF2CO2H and LiOtBu for the selective N-difluoromethylation of 4-hydroxyquinolines. This method tolerates reactive functional groups such as carboxylic acid, ester, and amide. A series of N-deuterodifluoromethyl analogues (−CF2D) is also synthesized.
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Kumawat et al. (2025) studied this question.
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