The Difluoromethyl Group as a Masked Nucleophile: A Lewis Acid/Base Approach.

Autor: Geri JB; Department of Chemistry , University of Michigan , 930 N. University , Ann Arbor , Michigan 48109 , United States., Wade Wolfe MM; Department of Chemistry , University of Michigan , 930 N. University , Ann Arbor , Michigan 48109 , United States., Szymczak NK; Department of Chemistry , University of Michigan , 930 N. University , Ann Arbor , Michigan 48109 , United States.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2018 Aug 01; Vol. 140 (30), pp. 9404-9408. Date of Electronic Publication: 2018 Jul 24.
DOI: 10.1021/jacs.8b06093
Abstrakt: The difluoromethyl group (R-CF 2 H) imparts desirable pharmacokinetic properties to drug molecules and is commonly targeted as a terminal functional group that is not amenable to further modification. Deprotonation of widely available Ar-CF 2 H starting materials to expose nucleophilic Ar-CF 2 - synthons represents an unexplored, yet promising route to construct benzylic Ar-CF 2 -R linkages. Here we show that the combination of a Brønsted superbase with a weak Lewis acid enables deprotonation of Ar-CF 2 H groups and capture of reactive Ar-CF 2 - fragments. This route provides access to isolable and reactive Ar-CF 2 - synthons that react with a broad array of electrophiles at room temperature. The methodology is highly general in both electrophile and difluoromethyl (hetero)arene and can be applied directly to the synthesis of benzylic difluoromethylene (Ar-CF 2 -R) linkages, which are useful lipophilic and metabolically resistant replacements for benzylic linkages in medicinal chemistry.
Databáze: MEDLINE
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