Synthesis And Application Of BippyPhos Analogues

In the synthesis of aromatic amines,C-N bond is mainly established by coupling reaction,among which Buchwald-Hartwig cross coupling reaction is an important method to construct C-N bond.However,most of these coupling reactions have many disadvantages,such as large amount of catalyst,complex ligand structure and difficult synthesis.Although there are many catalytic systems with high catalytic efficiency and good selectivity,some of them are sensitive to water and air,which is not conducive to the reaction.Therefore,the development trend of C-N coupling reaction is to prepare catalyst system with high selectivity,low toxicity and recycling.In this paper,five new ligands containing phosphine have been synthesized with bippyphos as template and some of them have been applied to palladium catalyzed C-N coupling reaction of amides with haloarenes.1.Synthesis of new ligands containing phosphineFirstly,1-（1,3,5-triphenyl-1H-pyrazol-4-yl）-1H-pyrazole（L₁-A for short）were synthesized by three steps one pot method.The intermediate（L₁-A）was synthesized from dibenzoylmethane by bromination,pyrazole alkylation and phenylhydrazine cyclization.The purity of the intermediate（L₁-A）was 98%after recrystallization.Similarly,4-methyl-1-（1,3,5-triphenyl-1h-pyrazol-4-yl）-1H pyrazol（L₂-A for short）and 3-methyl-1-（1,3,5-triphenyl-1h-pyrazol-4-yl）-1H pyrazol（L₃-A for short）were synthesized by using 4-methylpyrazol and 3-methylpyrazol instead of pyrazol.Then,the intermediate（L₁-A,L₂-A,L₃-A）was extracted with n-butyl lithium under the protection of nitrogen,and the phosphine was added with di-tert-butylchlorophosphane or dicyclohexylchlorophosphine.The temperature was controlled at about-15℃during the reaction.After one hour of reaction,it gradually rose to room temperature.The following five ligands were obtained by crystallization or column chromatography:L₁:5-（di-tert-butyl phosphine）-1-（1,3,5-triphenyl-1h-pyrazol-4-yl）-1H-pyrazol（Bippy Phos）L₂:5-（di-tert-butylphosphine）-4-methyl-1-（1,3,5-triphenyl-1h-pyrazol-4-yl）-1H-pyrazolL₃:5-（di-tert-butylphosphine）-3-methyl-1-（1,3,5-triphenyl-1h-pyrazol-4-yl）-1H-pyrazolL₄:5-（dicyclohexylphosphine）-1-（1,3,5-triphenyl-1h-pyrazol-4-yl）-1H-pyrazolL₆:5-（dicyclohexylphosphine）-3-methyl-1-（1,3,5-triphenyl-1h-pyrazol-4-yl）-1H-pyrazol2.Ligands participate in palladium catalyzed C-N coupling reaction of amides with aryl halidesTaking 3-（difluoromethyl）-1-methyl-1H-pyrazole-4-carboxamide and 1-chloro-3,4-dimethylbenzene as substrates,and using ligand L₁as an example,the type of bases,solvents,the type and amount of the catalysts were investigated,and the best conditions were found:tert-butanol as solvent,K₂CO₃ as base,2 mol%Pd（dba）₂,2 mol%ligand.The conversion of the model can reach 99%at 95℃for 16hours.The catalytic system reacts well with bromobenzene and chlorobenzene,but iodobenzene does not react;the catalytic system has good applicability and can be applied to various of aryl chlorides.Secondly,the C-N coupling reactions of acetamide,benzamide,phenylacetamide and nicotinamide with various of aryl chlorides were investigated.Among them,the conversion of chloroaromatics with electron withdrawing group is higher than that with electron supplying group,and the conversion of chloroaromatics with pyridine chloride and larger steric hindrance is lower.