Synthesis and Diels–Alder Reactivity of 4-Fluoro-4-Methyl-4<i>H</i>-Pyrazoles
4<i>H</i>-Pyrazoles are emerging scaffolds for “click” chemistry. Late-stage fluorination with Selectfluor<sup>®</sup> is found to provide a reliable route to 4-fluoro-4-methyl-4<i>H</i>-pyrazoles. 4-Fluoro-4-methyl-3,5-diphenyl-4<i>H</i>-pyrazole (MFP...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-05-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/11/3964 |
| Summary: | 4<i>H</i>-Pyrazoles are emerging scaffolds for “click” chemistry. Late-stage fluorination with Selectfluor<sup>®</sup> is found to provide a reliable route to 4-fluoro-4-methyl-4<i>H</i>-pyrazoles. 4-Fluoro-4-methyl-3,5-diphenyl-4<i>H</i>-pyrazole (MFP) manifested 7-fold lower Diels–Alder reactivity than did 4,4-difluoro-3,5-diphenyl-4<i>H</i>-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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| ISSN: | 1661-6596 1422-0067 |