ChemMedChem

Cover image for Vol. 12 Issue 4

Editorial Board Chairs: Antonello Mai, Rainer Metternich. Assoc. Editors: David Peralta, Scott Williams (Sr)

Impact Factor: 2.98

ISI Journal Citation Reports © Ranking: 2015: 18/59 (Chemistry Medicinal); 77/255 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

February 06, 2017

VIP: Aqueous Instability of δ-Fluorobutylpiperidines

VIP: Aqueous Instability of δ-FluorobutylpiperidinesRaffael Vorberg, Erick M. Carreira, Klaus Müller*

Partially fluorinated alkyl groups have been explored successfully over the past few years as potentially interesting modulators of compound properties in medicinal chemistry. Fluorinated alkyl groups are chemically quite robust, in general. However, when carrying a single fluorine atom four carbon centers away from an amine nitrogen center, a fluoroalkyl group may become labile under very mild assay conditions, such as for the determination of lipophilicity. Such δ-fluoroalkyl amines suffer fluorine expulsion through intramolecular attack by the amine nitrogen atom to form cyclic products. This reactivity is extraordinary, as such fluorinated N-alkylamine derivatives are otherwise fully stable in various organic solvents during synthesis, isolation, and purification. Their reactivity arises in the presence of a mixture of organic solvents and water, the latter promoting the cleavage of the C–F bond through strong fluoride solvation. Further investigations showed that a second fluorine substituent at the same position fully restores stability of the N-alkylamine derivatives, but cannot fully abrogate the reactivity when placed at an adjacent position. These findings constitute an important caveat to molecular design in drug discovery.

Dr. Klaus Müller is Professor emeritus from the University of Basel and formerly Distinguished Scientist at F. Hoffmann-La Roche AG, Basel, Switzerland. After retirement he was appointed Senior Research Associate at the Laboratory for Organic Chemistry at the ETH Zürich, where he continues his research in organofluorine chemistry, building block design, and investigations into molecular structure, property, and recognition.

Received January 12, 2017; accepted manuscript online January 31, 2017, DOI: 10.1002/cmdc.201700027.

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