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

Diisopropylethylamine mono(hydrogen fluoride) (8), which can be prepared by addition of two equivalents of diisopropylethylamine to the complex diisop ropylethylamine tris(hydrogen fluoride) (7). is shown to be an effective an d selective nucleophilic fluorinating reagent when applied to halogen-excha nge reactions of chloromethyl ethers, in particular the conversion of 1,1,1 ,3,3,3-hexafluoroisopropyl chloromethyl ether (3) to the volatile anestheti c sevoflurane (1, 1, 1,3,3,3-hexafluoroisopropyl fluoromethyl ether). The a mine portion of the reagent does not react with the starting material to gi ve a troublesome quaternary ammonium salt, as is the case for the species f ormed 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. (C) 2001 Elsevier Scien ce B.V. All rights reserved.