Practical difluoroethylation reactions of amines using difluoroacetic acid Oska Pugh, Alex Uner, Conor Nolan, Ross Denton Glaxo Smith Kline Carbon Neutral Laboratory, University of Nottingham, UK
While trifluoroethylamines have been well studied in the literature and well represented in the pharmaceutical industry. Less well studied are difluoroethylamines which unlike trifluoroethylamines retain some basicity at nitrogen. Because of this retention of basicity routes difluoroethylamines represent an attractive form of mildly basic amines. Classical methods to produce difluoroethylamines often employ derivatives of difluoroacetic acid such as 2,2-difluoroethanol, 2,2-difluoroethyl trifluoromethanesulfonate or 2,2-difluoroacetaldehyde. 1 In this work we have developed a mild metal free approach to tertiary difluoroethylamines taking advantage of inexpensive difluoroacetic acid as the starting material. Starting with a silane mediated amidation reaction we can produce a diverse array of difluoroacetamides with good functional group tolerance. From these amide intermediates we can reduce the amide to the corresponding amine with additional silane and a strong Brønsted acid, in this case benzene sulfonic acid was employed. This procedure takes advantage of the in situ generation of a silyl sulfonate as the active reducing agent. This procedure offers good yields and is tolerant to other sensitive functional groups such as esters and nitriles and has been further developed to allow for in situ Boc deprotections in the generation of unsymmetrical piperazines. References 1. M. Epifanov, P. J. Foth, F. Gu, C. Barrillon, S. S. Kanani, C. S. Higman, J. E. Hein and G. M. Sammis, J. Am. Chem. Soc. , 2018, 140 , 16464–16468.
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