Synthesis and Diels–Alder Reactivity of 4-Fluoro-4-Methyl-4H-Pyrazoles
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ijms-21-03964-v2.pdf
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Author(s)
Abularrage, Nile S.
Levandowski, Brian J.
Raines, Ronald T
Date Issued
May 2020
Journal
International Journal of Molecular Sciences
Publisher
Multidisciplinary Digital Publishing Institute
Citation
Abularrage, Nile S., Brian J. Levandowski, and Ronald T. Raines. "Synthesis and Diels–Alder Reactivity of 4-Fluoro-4-Methyl-4H-Pyrazoles." International Journal of Molecular Sciences 21, 11 (May 2020): 3964 ©2020 Author(s)
Version
Final published version
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: antiaromaticity; click chemistry; cycloaddition; 4H-pyrazole; hyperconjugation
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.3390/ijms21113964
