Synthesis of 4-substituted 3,3-difluoropiperidines.
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.
Surmont
Riccardo
R
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Gent, Belgium.
Verniest
Guido
G
Thuring
Jan Willem
JW
Macdonald
Gregor
G
Deroose
Frederik
F
De Kimpe
Norbert
N
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
D000596:Amino Acids; D006845:Hydrocarbons, Fluorinated; D010880:Piperidines; D003300:Copper