Use of trifluoroacetaldehyde N-tfsylhydrazone as a trifluorodiazoethane surrogate and its synthetic applications

Abstract

Trifluorodiazoethane (CF₃CHN₂), a highly reactive fluoroalkylating reagent, offers a useful means to introduce trifluoromethyl groups into organic molecules. At present, CF₃CHN₂ can only be generated by oxidation of trifluoroethylamine hydrochloride under acidic conditions; due to its toxic and explosive nature, its safe generation and use remains a prominent concern, hampering wider synthetic exploitation. Here we report the development of trifluoroacetaldehyde N-tfsylhydrazone (TFHZ-Tfs) as a CF₃CHN₂ surrogate, which is capable of generating CF₃CHN₂ in situ under basic conditions. The reaction conditions employed in this chemistry enabled a difluoroalkenylation of X–H bonds (X = N, O, S, Se), affording a wide range of heteroatom-substituted gem-difluoroalkenes, along with Doyle-Kirmse rearrangements and trifluoromethylcyclopropanation reactions, with superior outcomes to approaches using pre-formed CF₃CHN₂. Given the importance of generally applicable fluorination methodologies, the use of TFHZ-Tfs thus creates opportunities across organic and medicinal chemistry, by enabling the wider exploration of the reactivity of trifluorodiazoethane.

Since fluoro-compounds are popular in industrial settings, efficient methods for incorporation of fluoride into organic molecules are desirable. Here, the authors developed trifluoroacetaldehyde N-tfsylhydrazone (TFHZ-Tfs) as a CF₃CHN₂ surrogate that generates CF₃CHN₂ in situ under basic conditions.