4.7 Article

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

Journal

Publisher

MDPI
DOI: 10.3390/ijms21113964

Keywords

antiaromaticity; click chemistry; cycloaddition; 4H-pyrazole; hyperconjugation

Funding

  1. NSF
  2. NIH [F32 GM137543, R01 GM044783]
  3. NSF [ACI-1548562]

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4H-Pyrazoles are emerging scaffolds for click chemistry. Late-stage fluorination with Selectfluor((R)) 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.

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