Direct synthesis of N-perfluoro-tert-butyl secondary amines from N-trifluoromethyl secondary amines†

Abstract

N-Perfluoro-tert-butyl (N-PFtB) secondary amines, harboring a unique ¹⁹F-reporting moiety linked directly to nitrogen, are highly attractive due to their diverse potential applications. However, their mild and facile synthesis remains a significant challenge. Herein, we present a safe and efficient strategy for the direct synthesis of N-perfluoro-tert-butyl secondary amines from readily available N-trifluoromethyl secondary amines. Experiments and theoretical calculations demonstrate that this novel protocol encompasses three main processes: the elimination of hydrogen fluoride from the N-trifluoromethyl precursor, consecutive addition–elimination conversion of difluoromethyl imine (R–NCF₂) to hexafluoropropyl imine (R–NC(CF₃)₂), and final addition of R–NC(CF₃)₂ with the in situ generated fluoroform (HCF₃). Key advantages of this reaction include the utilization of a single trifluoromethyl source and the N-trifluoromethyl starting material itself as the hydrogen source. Notably, the elimination of hydrogen fluoride, facilitated by CsF, is critical for the success of this approach. This method is compatible with a broad range of functional groups, including heterocyclic compounds. ¹⁹F MRI experiments suggest promising prospects for PFtB-labeled secondary amines as ¹⁹F MRI contrast agents.