Oxidative desulfurization-fluorination of thioethers. Application for the synthesis of fluorinated nitrogen containing building blocks

Organic & Biomolecular Chemistry
Verena HugenbergGünter Haufe

Abstract

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.

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Citations

Feb 10, 2016·Organic & Biomolecular Chemistry·Dirk UlbrichGünter Haufe
Feb 13, 2013·Chemistry : a European Journal·Bernd M SchmidtHidehiro Sakurai
May 1, 2020·European Journal of Organic Chemistry·Shyam S Samanta, Stéphane P Roche

Related Concepts

Nitrogen
Oxidation-Reduction
Thioethers
Sulfur
Fluorine Compounds
Fluorination
Carbon
Imino Acids
Nitrogen
Oxidation

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