Palladium-Catalyzed α-Arylation of Cyclic β-Dicarbonyl Compounds for the Synthesis of Ca_V1.3 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. The coupling reactions of various para- or meta-substituted aryl halides occurred efficiently when Pd(t-Bu₃P)₂, Xphos, and Cs₂CO₃were 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_V1.3 Ca²⁺channel inhibitors. Among the synthesized molecules, 14e was the most potent Ca_V1.3 inhibitor with an IC₅₀of 1.42 μM.