Enhanced Selectivity in 4-Quinolone Formation: A Dual-Base System for Palladium-Catalyzed Carbonylative Cyclization with Fe(CO) 5

• Published in: Molecules (Basel, Switzerland) Switzerland), 2024-02, Vol.29 (4), p.850
• Main Authors: Guo, Meng, Wu, Dou, Yang, Hongyu, Zhang, Xiao, Xue, Dong-Xu, Zhang, Weiqiang
• Format: Article
• Language: English
• Subjects: 4-quinolone; Carbon monoxide; carbonylation; CO-releasing molecule; Efficiency; High temperature; Investigations; Ligands; mechanism; NMR; Nuclear magnetic resonance; Palladium; Pd catalysis; Potassium
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29040850

The use of gaseous CO in Pd-catalyzed carbonylative quinolone synthesis presents challenges related to safety and precise pressure control. In response, a streamlined non-gaseous synthesis of 4-quinolone compounds has been developed. This study introduces a tunable CO-releasing system utilizing Fe(CO) activated by a dual-base system of piperazine and triethylamine. This alternative liquid CO resource facilitates the palladium-catalyzed carbonylative C-C coupling and subsequent intramolecular cyclization. By tuning the tandem kinetics of carbonylation and cyclization, this non-gaseous method achieves the successful synthesis of 22 distinct 4-quinolones with excellent yields. This is achieved through the three-component condensation of sub-stoichiometric amounts of Fe(CO) with 2-iodoaniline and terminal alkynes. Operando mechanistic studies have revealed a novel CO transfer mechanism that facilitates homogeneous carbonylative cyclization, distinguishing this method from traditional techniques. In addition to addressing safety concerns, this approach also provides precise control over selectivity, with significant implications for pharmaceutical research and the efficient synthesis of pharmaceutical and bioactive compounds.