Study On The Reaction And Mechanism Of Nickel-catalyzed Selective Monoarylation Of Polyfluoroaromatics

Polyfluoroarene compounds remain not only the main parts of liquid crystal material and fundamental skeletons of organic electronic material,but also tend to be applied in the area of disease treatment and biological function molecules.The improvement of preparation methods lies in one of the most important research areas in fluoriated organic chemistry.However,as the influence of fluorine substituent,high temperature,such as 100 ? or even higher,is in great need to facilitate the reductive elimination of hypervalent metal complex to generate polyfluorobiaryl compounds.Under high temperature and alkaline conditions,polyfluoroarene with multiple reactive sites could react many times.Bisarylation product is very hard to isolate,which depreciates the value of direct arylation strategy.Based on the study of polyfluorophenyl Grignard reagent,the nickel-catalyzed highly selective monoarylationmethods of polyfluoroarene via Kumada coupling and Negishi coupling are established in this thesis..Part one:Nickel-Catalyzed Highly Selective Monoarylation of Polyfluoroarene via Kumada couplingIt' s proved that the diphosphine ligand based on diphenyl ether skeleton couldfacilitate the Kumada cross coupling process between polyfluorophenyl Grignard reagent and aryl triflates at room temperature.In the mixed solvents of THF/dioxane/DME(4:6:1),the scale of substrates is studied thoroughly,which is as follows:1)Under this condition,sensitive functional groups,such as ester,cyano,ketone and chloride are tolerated;2)The coupling of heterocyclic aryl triflates,based on thiophene,indole and quinoline coupled well with tetrafluorophenyl Grignard reagent.3)It is also available for alkenyl triflate.According to 19F NMR and GC analysis,no obvious biarylation products were generated,while the monoarylation products were dominate with momo/bis ratio above 99%.Under this catalysis condition,the Kumada coupling reactions with polyfluoroarenes containing similar reactive sites have been studied.It is demonstrated that the nickel catalyst is effective for such kind of polyfluoroarenes.And for polyfluoroarenes with one reactive site,the catalytic system shows a great ability too.In order to display the potentiality of newly developed nickel catalytic system,many asymmetrical fluoriated polyaryls were prepared,which are the source of flexible functional material areas.Last but not least,the reaction mechanism is under in-depth research,especially the arrest state of catalyst.The stable(DPEPhos)Ni(II)(ArF4)2 is synthesized successfully.This complex is stable enough for column chromatography.With DPEPhos as the phosphine ligand,this complex was detected in the solution by the tracking the reaction mixture with HRMS and 19F NMR.It was demonstrated that the aryl group on nickel(II)complex has been exchanged with tetrafluorophenyl Grignard reagent as time went by,and the stable(DPEPhos)Ni(?)(ArF4)2 was generated gradually as the catalyst arrest state.Part two:Nickel-Catalyzed Highly Selective Monoarylation of Polyfluoroarene via Negishi couplingThe nucleophilic ability of polyfluorophenyl Grignard reagent makes the aryl exchange(second transmetalation)with the nickel(?)complex possible.Subsequently,the stable nickel(?)complex with two polyfluoroarene units is generated at a competitive way,which makes catalyst inactive.So we are trying to use a weaker reagent--polyfluorophenyl zinc reagent to inhibit the second transmetalation.Experiment results have confirmed our hypothesis.It was found that in THF solution,the catalyst derived from DPEPhos and Ni(cod)2 not only catalyzes the coupling between aryl triflates and polyfluorophenyl zinc reagents,but also aryl bromides and aryl iodides including electrically-rich,neutral and poor substrates.The Negishi coupling conditions have greatly simplified the catalytic system and increased synthetic value of nickel catalyst.With this efficient coupling condition in hand,the Negishi coupling between heterocyclic aryl bromides and polyfluorophenyl zinc reagents has also been studied.This system still works well for these challenging and important substrates,which provides a very efficient and practical strategy for composing critical fluoro-containing drug molecules.The great advantage was further demonstrated by the gram-scale synthesizing key intermediate of tedizolid phosphate.