Palladium-Catalyzed α-Arylation of Cyclic β-Dicarbonyl Compounds for the Synthesis of Ca V 1.3 Inhibitors

Cyclic α-aryl β-dicarbonyl derivatives are important scaffolds in medicinal chemistry. Palladium-catalyzed coupling reactions of haloarenes were conducted with diverse five- to seven-membered cyclic β-dicarbonyl derivatives including barbiturate, pyrazolidine-3,5-dione, and 1,4-diazepane-5,7-dione....

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Veröffentlicht in:ACS omega 2022-04, Vol.7 (16), p.14252-14263
Hauptverfasser: Yun, Jisu, Jeong, Dayeon, Xie, Zhong, Lee, Sol, Kim, Jiho, Surmeier, D James, Silverman, Richard B, Kang, Soosung
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Sprache:eng
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Zusammenfassung:Cyclic α-aryl β-dicarbonyl derivatives are important scaffolds in medicinal chemistry. Palladium-catalyzed coupling reactions of haloarenes were conducted with diverse five- to seven-membered cyclic β-dicarbonyl derivatives including barbiturate, pyrazolidine-3,5-dione, and 1,4-diazepane-5,7-dione. The coupling reactions of various para- or meta-substituted aryl halides occurred efficiently when Pd( -Bu P) , Xphos, and Cs CO were used under 1,4-dioxane reflux conditions. Although the couplings of ortho-substituted aryl halides with pyrazolidine-3,5-dione and 1,4-diazepane-5,7-dione were moderate, the coupling with barbiturate was limited. Using the optimized reaction conditions, we synthesized several 5-aryl barbiturates as new scaffolds of Ca 1.3 Ca channel inhibitors. Among the synthesized molecules, was the most potent Ca 1.3 inhibitor with an IC of 1.42 μM.
ISSN:2470-1343
2470-1343
DOI:10.1021/acsomega.2c00889