Palladium-Catalyzed α-Arylation of Cyclic β-Dicarbonyl Compounds for the Synthesis of CaV1.3 Inhibitors

Jisu Yun, Dayeon Jeong, Zhong Xie, Sol Lee, Jiho Kim, D. James Surmeier, Richard B. Silverman, Soosung Kang

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4 Scopus citations


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 CaV1.3 Ca2+channel inhibitors. Among the synthesized molecules, 14e was the most potent CaV1.3 inhibitor with an IC50of 1.42 μM.

Original languageEnglish
Pages (from-to)14252-14263
Number of pages12
JournalACS Omega
Issue number16
StatePublished - 26 Apr 2022

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants funded by MSIT (NRF-2018R1A5A2025286; NRF-2019M3E5D4065251; NRF-2019R1A2C2004142). This work was also supported by grants from the Michael J. Fox Foundation and the JPB Foundation to DJS.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.


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