Synthesis Of Fluorinated Quinoxalines,Imidazoles,Quinolones And Quinolines Using Fluoroalk-2-Ynoates As Fluorinated Building Blocks

In this paper,a study on the reaction of fluoroalkynoates as fluorine-containing building blocks was carried out to synthesize series fluoroalkylated heterocyclic compounds,including quinoxalines,imidazoles,quinolones and quinolines.The main contents are summarized as follows:Part 1A convenient and practical cascade method was developed to synthesize fluoroalkylated quinoxalines using anilines and fluoroalkynoates as starting materials.Firstly,aniline and electron-deficient fluoroalkylated alkyne reacted in Me OH at rt to form Michael addition adduct,which was re-dissolved in DMSO after evaporating the solvent.In the presence of TMSN₃,PIDA and KI,quinoxaline was efficiently formed at rt.Under this mild and metal-free condition,a bis-imine intermediate?2-4a?was detected and isolated for the first time.KI played a crucial role in this reaction.The structures of the products were confirmed by ¹H NMR,¹⁹F NMR,¹³C NMR,UPLC-MS,HR-MS,IR,X-ray,etc.The reaction mechanism was described.This method has the advantages of mild condition,broad scope of substrates and up to 95%isolated yield.Part 2A convenient and practical cascade method was developed to synthesize fluoroalkylated imidazoles using amines with?-hydrogen and fluoroalkynoates as starting materials.Amines with?-hydrogen reacted with electron-deficient fluoroalkylated alkynes to form Michael addition product in DMSO solution at rt.And then,in the presence of Na N₃,KI and PIDA,fluoroalkylated imidazoles were efficiently synthesized at rt.The structures of the products were confirmed by ¹H NMR,¹⁹F NMR,¹³C NMR,LC-MS,HR-MS,IR,etc.The reaction mechanism was proposed.This method has the advantages of easy operation,short reaction time and up to 94%isolated yield.This method was successfully applied to synthesize the key intermediate of Du P-532?angiotensin II receptor antagonist?with 52% isolated yield in one step,which was much higher than original scheme with 32% overall yield in five steps.Part 3An efficient and mild cascade synthesis of 3-carbonyl-2-fluoroalkylated4-quinolones using fluoroalk-2-ynoates as fluorinated building blocks and commercially available isatins as starting materials without transition-metal catalyst was developed.The reaction proceeded smoothly at room temperature in one pot within a short time to afford structurally diverse desired products.The control experiments demonstrated two possible pathways for their formation.The structures of the products were confirmed by ¹H NMR,¹⁹F NMR,¹³C NMR,UPLC-MS,HR-MS,IR,X-ray,etc.The reaction mechanism was described.This method has the advantages of easy operation,short reaction time and up to 91%isolated yield.Part 4An efficient and mild cascade synthesis of perfluoroalkylated quinolines using perfluoroalk-2-ynoates as fluorinated building blocks and commercially available isatins and alcohols as starting materials without transition-metal catalyst was achieved.The reaction proceeded smoothly at room temperature in one pot within a short time to afford structurally diverse desired products.The control experiments demonstrated this transformation involving Michael addition/intramolecular rearrangement process.The structures of the products were confirmed by ¹H NMR,¹⁹F NMR,¹³C NMR,UPLC-MS,HR-MS,IR,etc.The reaction mechanism was proposed.This method has the advantages of readily available starting materials,practical operation,short reaction time and up to 91% isolated yield.