A practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid

Andrews, Keith G.; Faizova, Radmilla; Denton, Ross M.

Abstract

Amines are a fundamentally important class of biologically active compounds and the ability to manipulate their physicochemical properties through the introduction of fluorine is of paramount importance in medicinal chemistry. Current synthesis methods for the construction of fluorinated amines rely on air and moisture sensitive reagents that require special handling or harsh reductants that limit functionality. Here we report practical, catalyst-free, reductive trifluoroethylation reactions of free amines exhibiting remarkable functional group tolerance. The reactions proceed in conventional glassware without rigorous exclusion of either moisture or oxygen, and use trifluoroacetic acid as a stable and inexpensive fluorine source. The new methods provide access to a wide range of medicinally-relevant functionalized tertiary beta-fluoroalkylamine cores, either through direct trifluoroethylation of secondary amines or via a three-component coupling of primary amines, aldehydes and trifluoroacetic acid. A reduction of in situ-generated silyl ester species is proposed to account for the reductive selectivity observed.

Citation

Andrews, K. G., Faizova, R., & Denton, R. M. (in press). A practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid. Nature Communications, 8, Article 15913. https://doi.org/10.1038/ncomms15913

• Journal Article Type: Article
• Acceptance Date: May 9, 2017
• Online Publication Date: Jun 26, 2017
• Deposit Date: Jul 19, 2017
• Publicly Available Date: Jul 19, 2017
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Article Number: 15913
• DOI: https://doi.org/10.1038/ncomms15913
• Public URL: https://nottingham-repository.worktribe.com/output/868307
• Publisher URL: https://www.nature.com/articles/ncomms15913
• Contract Date: Jul 19, 2017