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

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.

SUBMITTER: Abularrage NS

PROVIDER: S-EPMC7312747 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Abularrage Nile S NS Levandowski Brian J BJ Raines Ronald T RT

International journal of molecular sciences 20200531 11

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 antia ...[more]

PMID: 32486503

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