Synthesis Of Phosphorylated Heterocycles Via Radical Cascade Reactions

Heterocycles are widely found in natural products and pharmacologically active molecules.Recently,radical cascade cyclization reaction has been recognized as one of the most efficient synthetic strategy for the construction of a heterocyclic skeleton with step-and atom-economy,which could complete the construction of multiple chemical bonds through multiple consecutive reaction steps in one-pot without the tedious separation of intermediates.Moreover,organophosphorus compounds have broad applications in multiple research areas including organic synthesis,pesticide,pharmaceutical,functional materials and so on.In this thesis,we have developed novel and powerful strategies for the synthesis of phosphorylated heterocycles via phosphoryl radical-initiated cascade reaction.Phosphoryl radical generated from organophosphorus reagents in the presence of silver salts or under the irradiation of visible light could trigger the cyclization of N-allylbenzamides or methylthiolated alkynones effectively for the preparation of phosphorylated heterocycles dihydroisoquinolones or thioflavones,respectively.The research contents are as follows:(1)Silver-mediated radical phosphorylation/cyclization to access phosphoryl-substituted dihydroisoquinolones:An efficient silver-mediated radical cascade cyclization strategy was developed,by which a series of phosphoryl-substituted dihydroisoquinolones were prepared in one pot via reaction of unactivated alkene N-allylbenzamides with phosphine oxides under mild reaction conditions.This protocol features experimental simplicity,step economy,and broad substrate scope,diarylphosphonate oxides and H-phosphonates can be applied to the reaction.(2)Visible-light-promoted cyclization towards phosphoryl-substituted dihydroisoquinolones:A visible-light-promoted radical cascade cyclization of easily available N-allylbenzamides with diarylphosphonate oxides for the synthesis of phosphoryl-substituted dihydroisoquinolones was developed under room temperature.This reaction employs an inexpensive and commercial organic photocatalyst,which shows its eminent merits such as mild reaction conditions,transition-metal-free,broad substrate scope,and easily scale up.(3)Visible-light-induced synthesis of phosphorylated thioflavones in water:A metal-free visible-light-induced radical cascade cyclization was developed for the preparation of phosphorylated thioflavones from methylthiolated alkynones and diarylphosphonate oxides in the presence of 4Cz IPN(2,4,5,6-tetrakis(carbazol-9-yl)-1,3-dicyanobenzene)and LPO(dilauroyl peroxide)in water.With this green and sustainable strategy,a wide range of phosphorylated thioflavones were prepared with satisfactory yields.Moreover,some phosphorylated N-heterocycles,including phosphorylated oxindole,phosphorylated quinoline-2,4(1H,3H)-dione,and phosphorylated benzothiazole,could be smoothly synthesized in good isolated yields by using this green and sustainable strategy.In addition,the employment of water as green medium avoid the waste and toxicity issues of organic solvents,and the aqueous medium could be recycled and reused.