Copper-Promoted Difluorocarbene Insertion Reaction

Introducting fluoro-containning groups on molecule could obviously change its lipophilic property,metabolic stability and cell membrame penetration ability.The organic compounds containing difluoromethyl or difluoromethylene groups play an important role in the field of pesticides,pharmaceuticals and materials.However,the natural organic compound containing difluoromethyl or difluoromethylene groups is rare.Compared with trifluoroalkylation,difluoroalkylation has been relatively less developed.In the past few years transition-metal-mediated difluoroalkylation became a hot research topic in organofluorine chemistry.In this dissertation,the four major contents are summarized as followed,(1)1,3-cyclohexanedione which prones to enolization in the presence of base was chosen as a model substrate for optimization of the reaction conditions.ClCF2COOEt was chosen as the sources of difluorocarbene.The effects of base,temperature,reaction time and solvent on the reaction were explored.The reaction showed the best reactivity with 1.5 equiv of ClCF2COOEt,and 3 equiv of NaOH in DMF at 60? for 7h.With the optimum conditions in hand,we studied the generality of this O-regioselective difluoromethylation using various 1,3-dion substrates.A series of 1,3-cyclopentanediones and 1,3-cyclohexanedions with different functional groups were subjected for the reaction to provide the corresponding difluoromethyl enol ethers in good to excellent yields.The products were characterized by NMR,IR,mass spectra and HRMS.Furthermore,in order to demonstrate the practicality of the method,a gram-scale reaction was carried out.A plausible mechanism for O-difluoromethylation of 1,3-diones is shown at the end of the chapter.(2)The copper(?)chlorodifluoroacetate complexes[L2Cu][O2CCF2Cl](4a-c,L =bpy,Me2bpy,phen,respectively),synthesized from the readily available and inexpensive chlorodifluoroacetic acid,have been reported.These complexes are fully characterized by NMR,IR,X-ray crystallography and HRMS in the solid state and detailed solution-phase methods.Then 4c was used as an efficient difluorocarbene reagent for the difluoromethylation of phenols.The effects of base,temperature,reaction time,solvent and different ligands on the reaction were examined.With the optimum conditions in hand,we focused on expanding the reaction substrate scope.This method displays good functional group tolerance,along with moderate to good yields.The desired products were determined by NMR,IR,mass spectra and HRMS.It is also possible to prepare difluoroalkylated products on a gram scale.The intermedicate product of folumilast were synthesized under the optimum conditions.The mechanistic investigation reveals that the difluoromethylation proceeds through the initial copper-mediated formation of difluorocarbene and subsequent concerted addition of difluorocarbene to phenol to form a three-center transition state.(3)Copper(I)chlorodifluoroacetate complexes(4a or 4c)have been applied as trifluoromethylation precursor.The complexes[L2Cu][O2CCF2Cl](L = bpy or phen)reacted with(hetero)aryl iodides and bromides in the presence of 3 equiv CsF in DMF at 750C to afford the trifluoromethylarenes in good to excellent yields.High compatibility with various chemical functions or(hetero)cycles was also observed in the reaction.The expected products were determined by NMR,IR,mass spectra and HRMS.We also carried out a gram-scale reaction.A reaction mechanism involving a difluorocarbene intermediate,along with a subsequent formation of LnCuCF3 was proposed.(4)In the last chapter we explore the S-difluoromethylation of tert-butyl 3-(phenylthio)propanoate.ClCF2COONa was used as difluorocarbene source and the effects of base,temperature,reaction time and solvent on the reaction were investigated.The reaction get the best result in the presence of 7.5 equiv NaOH,1.25 equiv ClCF2COONa and 1 equiv zinc powder in NMP at 60? for 4h.A series of tert-butyl 3-(phenylthio)propanoate with different functional groups reacted to furnish the corresponding difluoromethylthiolated arens(ArSCF2H)in good to excellent yields.Then the effects of different electron-withdrawing groups on the reaction was discussed.We also proposed a plausible mechanism for S-difluoromethylation of tert-butyl 3-(phenylthio)propanoate according to the deuterium labeling experiment.