Synthesis of 3-Amino-4-fluoropyrazoles Using Selectfluor

Significance

Reported is the synthesis of 3-amino-4-fluoro-5-substituted pyrazoles, initiated by electrophilic fluorination of β-methylthio-β-enamino ketones via NFSi (difluorination, one example) or Selectfluor (monofluorination) to give fluorinated enamino ketones in mediocre to good yields. These were further treated with hydrazine in refluxing isopropanol to afford the desired pyrazoles in synthetically useful yields. Two examples of monosubstituted hydrazines were tested (not shown in scheme): MeNHNH₂ led to a 1:1 mixture of pyrazoles, and PhNHNH₂ led to the formation of a single product. Additionally, debenzylation (R^² = Bn) via hydrogenation without the loss of ­fluorine was demonstrated. A reasonable substrate scope was studied.