Oxidative desulfurization-fluorination of thioethers. Application for the synthesis of fluorinated nitrogen containing building blocks.
An oxidative desulfurization-fluorination protocol has been used to synthesize (2S)-2-(difluoromethyl)-N-tosylpyrrolidine (6a) and (2S)-2-(trifluoromethyl)-N-tosylpyrrolidine (7a) from the (2S)-prolinol-derived (2S)-2-(4-chlorophenylthiomethyl)-N-tosylpyrrolidine (9) or (2S)-2-(dithian-2-yl)-N-tosylpyrrolidine (5). Efforts to prepare 3,3-difluoroalanine similarly from an N-protected S-aryl-cysteine ester 17 gave only traces of the target compound 18. Instead, an unique N-(α,α-difluorobenzyl)-N-α',α'-dibromoglycine ester 19 was formed by an unprecedented sequence of reaction steps. A plausible mechanism is suggested involving a sulfur-assisted deoxygenation-difluorination of an imino oxygen and a haloform reaction like carbon-carbon bond fission as key-steps. Efforts to prepare (2S)-2-(fluoromethyl)-N-tosylpyrrolidine (12) from (2S)-N-tosylprolinol (3) by treatment with Fluolead™ (1-tert-butyl-4-trifluorosulfanyl-3,5-dimethylbenzene) gave only 5% of the target compound, but 95% of (3R)-3-fluoro-N-tosylpiperidine (11a) by ring enlargement.
Organisch-Chemisches Institut and European Institute for Molecular Imaging, Westfälische Wilhelms-Universität, Münster, Germany.
Verena
V
Hugenberg
Roland
R
Fröhlich
Günter
G
Haufe
D017611:Fluorine Compounds / Q000138:chemical synthesis*; D054879:Halogenation; D008958:Models, Molecular; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D010084:Oxidation-Reduction; D013440:Sulfides / Q000737:chemistry*; D013455:Sulfur / Q000737:chemistry*
D017611:Fluorine Compounds; D013440:Sulfides; D013455:Sulfur; D009584:Nitrogen