Synthesis and Diels–Alder Reactivity of 4-Fluoro-4-Methyl-4<i>H</i>-Pyrazoles

• Main Authors: Nile S. Abularrage, Brian J. Levandowski, Ronald T. Raines
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: International Journal of Molecular Sciences
• Subjects: antiaromaticity; click chemistry; cycloaddition; 4H-pyrazole; hyperconjugation
• Online Access: https://www.mdpi.com/1422-0067/21/11/3964
• ISSN: 1661-6596; 1422-0067

4<i>H</i>-Pyrazoles are emerging scaffolds for “click” chemistry. Late-stage fluorination with Selectfluor^® 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.