Synthesis Of 4-Quinolone Derivatives Through Sequential Michael Addition-elimination/Pd- Catalyzed Buchwald-Hartwig Amination Reaction

Quinolone derivatives is an important nitrogen-containing six-membered heterocyclic compounds, which are widely present in a large number of the basic framework of biologically active molecules, natural products and organic functional materials. Such as 4-quinolones are an important class of pharmacophore, many derivatives have shown a wide range of biological activity, have therapeutic active molecules, such as anti-bacterial, anti-tumor, anti-malarial, anti-mitotic, HIV-1 integrase inhibitors, etc. physiological activity. Has a very important role in the design and synthesis of the drug molecule. The traditional method for the synthesis of these substances are generally based on the ring condensation reactions, such as Conrad-Limbach and Nirvana door Rostov Chomsky condensation reaction. Although these methods have been widely used in the preparation of quinolones, but due to harsh (high temperature or strong base) which reaction conditions, limiting their application, and therefore,4-quinolones efficient, simple and high selectivity skeletal structure Synthesis method of important scientific value and potential applications, causing research interests in organic synthesis, medicinal chemistry and materials chemistry and other fields workers.In this paper, a halogenated benzoyl chloride with terminal alkynes nucleophilic addition reaction, to give (Z)-β-vinyl aryl ketone intermediate product, on this basis, by Michael addition to eliminate/palladium-catalyzed Buchwald-Hartwig N-arylation by way of "one-pot" reaction synthesized 4-quinolone derivative. Studies have shown that the "one pot synthesis" optimum conditions:a:Pd (PPh3) 4 (5 mol%), ligand Davephos (10 mol%), KOtBu(3.0equiv), was added directly to THF (2 mL) at 110℃with the time of 24 h, the target product can be obtained in good yields; b:For aromatic primary amine as a substrate, with K2CO3 as base in THF (2 mL) at 110 for 12h, after elimination of the Michael addition reaction product is generated, and then the catalyst Pd (PPh3) 4 (5 mol%), ligand Davephos (10 mol%), the base KOtBu were added in for 12h more, then obtained 4-quinolones product. To gain insight into the mechanism of the reaction, some designed control experiments were conducted, and a proposed reaction mechanism was shown..In short, this paper reported the palladium-catalyzed Buchwald-Hartwig amination synthesis methods 4-quinolone derivative practical, simple operation and high efficiency, etc., for the metal palladium-catalyzed synthesis of nitrogen-containing heterocyclic compounds adds a new effective way.