Diisopropylethylamine mono(hydrogen fluoride) for nucleophilic fluorination of sensitive substrates: synthesis of sevoflurane

Abstract

Diisopropylethylamine mono(hydrogen fluoride) ( 8), which can be prepared by addition of two equivalents of diisopropylethylamine to the complex diisopropylethylamine tris(hydrogen fluoride) ( 7), is shown to be an effective and selective nucleophilic fluorinating reagent when applied to halogen-exchange reactions of chloromethyl ethers, in particular the conversion of 1,1,1,3,3,3-hexafluoroisopropyl chloromethyl ether ( 3) to the volatile anesthetic sevoflurane (1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether). The amine portion of the reagent does not react with the starting material to give a troublesome quaternary ammonium salt, as is the case for the species formed by addition of two equivalents of triethylamine to triethylamine tris(hydrogen fluoride). These particular chloromethyl ether substrates require a 1:1 stoichiometry of diisopropylethylamine to hydrogen fluoride to give useful rates of reaction and yields when solventless conditions are desired. Two other complexes, diisopropylethylamine bis(hydrogen fluoride) and 7, are ineffective for conversion of 3 to sevoflurane.