Synthesis and Diels-Alder Reactivity of 4-Fluoro-4-Methyl-4 H-Pyrazoles

Int J Mol Sci. 2020 May 31;21(11):3964. doi: 10.3390/ijms21113964.

Abstract

4H-Pyrazoles are emerging scaffolds for "click" chemistry. Late-stage fluorination with Selectfluor® is found to provide a reliable route to 4-fluoro-4-methyl-4H-pyrazoles. 4-Fluoro-4-methyl-3,5-diphenyl-4H-pyrazole (MFP) manifested 7-fold lower Diels-Alder reactivity than did 4,4-difluoro-3,5-diphenyl-4H-pyrazole (DFP), but higher stability in the presence of biological nucleophiles. Calculations indicate that a large decrease in the hyperconjugative antiaromaticity in MFP relative to DFP does not lead to a large loss in Diels-Alder reactivity because the ground-state structure of MFP avoids hyperconjugative antiaromaticity by distorting into an envelope-like conformation like that in the Diels-Alder transition state. This predistortion enhances the reactivity of MFP and offsets the decrease in reactivity from the diminished hyperconjugative antiaromaticity.

Keywords: 4H-pyrazole; antiaromaticity; click chemistry; cycloaddition; hyperconjugation.

MeSH terms

  • Chemistry Techniques, Synthetic
  • Cycloaddition Reaction*
  • Fluorine / chemistry
  • Glutathione / chemistry
  • Kinetics
  • Models, Molecular
  • Molecular Conformation*
  • Molecular Structure
  • Organic Chemicals / chemistry
  • Pyrazoles / chemistry*
  • Stereoisomerism
  • Thermodynamics
  • Ultraviolet Rays

Substances

  • Organic Chemicals
  • Pyrazoles
  • Fluorine
  • pyrazole
  • Glutathione