title: Synthesis of 4-substituted 3,3-difluoropiperidines.
abstract: Synthetic strategies toward 4-substituted 3,3-difluoropiperidines were evaluated. 4-Alkoxymethyl- and 4-aryloxymethyl-3,3-difluoropiperidines were synthesized via 1,4-addition of ethyl bromodifluoroacetate to 3-substituted acrylonitriles in the presence of copper powder, followed by borane reduction of the cyano substituent, lactamization, and reduction of the lactam. This method was applied to establish the synthesis of N-protected 3,3-difluoroisonipecotic acid, a fluorinated gamma-amino acid. 4-Benzyloxy-3,3-difluoropiperidine was prepared using an analogous methodology and was converted to N-protected 3,3-difluoro-4,4-dihydroxypiperidine, a compound with high potential as a building block in medicinal chemistry.
authors.affiliation: Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Gent, Belgium.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Surmont
authors.forename: Guido
authors.initials: G
authors.lastname: Verniest
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Thuring
authors.forename: Gregor
authors.initials: G
authors.lastname: Macdonald
authors.forename: Frederik
authors.initials: F
authors.lastname: Deroose
authors.forename: Norbert
authors.initials: N
authors.lastname: De Kimpe
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000596:Amino Acids; D006845:Hydrocarbons, Fluorinated; D010880:Piperidines; D003300:Copper