Palladium-Catalyzed Synthesis Of Flavonoids

Chromone frameworks are frequently found in a diverse array of compounds,including ubiquitous natural flavone and isoflavone products in plants,biologically and therapeutically active drugs such as anti-inflammatory,antiplatelet,antimicrobial,antiobesity and anticancer agents,and drug candidates for neurodegenerative diseases and adenosine receptors.Chromones as a privileged scaffold in drug discovery and development have received considerable attention over the past years.Consequently,much effort has been focused on the development of new synthetic methods and the evaluation of biological properties of chromone derivatives.Transition metal-catalyzed C-H bond activation C-C bond coupling reactions is an effective method of organic synthesis for the formation of C-C bonds.The method consists of inert material to obtain the desired product directly,thus simplifying the preparation of raw materials,saving energy and time to improve the synthesis efficiency,also reduce the impact on the environment during the reaction of.Therefore,C-H bond activation palladium catalyzed reaction is one of the hot spots in recent years.Despite the significant progress made in the palladium-catalyzed synthesis of chromones,novel synthetic approaches,with enhanced reaction efficiency,milder reaction conditions as well as improved availability of starting materials,are still desirable.In this paper,we report on a new and efficient entry to 4H-chromen-4-one derivatives through Pd-catalyzed intramolecular acylation of ether-tethered alkenyl bromides and aldehydes,readily accessible starting material from regio-and stereoselective nucleophilic addition of salicylaldehydes to alkynyl bromides in DMF.With Pd(PPh3)4(5 mol%)as a catalyst,Xphos(15 mol%)as the ligand,K2CO3(3.0 eq.)as a base,and 1,4-dioxane as a reaction medium,at 140 ℃ for 24 h,the corresponding product can be obtained in 80% isolated yield.The scope of this acylation process for the synthesis of chromones was then examined.A variety of diversely substituted chromone derivatives was obtained in moderate to good yields with both electron-donating and electron-withdrawing group.In addition,a wide array of alkenyl bromides with simple linear alkyl substitutions was amenable to the protocol,delivering 4H-chromen-4-one derivatives in 60-78% yields.Alkenyl bromide that contained a protected alcohol functionality is also tolerated.The result presented here should be of considerable interest for valuable synthetic targets for medicinal chemistry.