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

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

Authors

Keith G. Andrews

Radmilla Faizova

ROSS DENTON ross.denton@nottingham.ac.uk
Professor of Organic Chemistry



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, 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 http://eprints.nottingham.ac.uk/id/eprint/43664
Publisher URL https://www.nature.com/articles/ncomms15913
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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