Study On Selective Coupling Of Diaryliodonium Salts And Amino Acid Amides

N-aryl-?-amino acid amides including chiral isomers have demonstrated their extensive and important applications as clinic medicines.There are many methods for the synthesis of racemic N-aryl-?-amino acid amide,but like most chiral drugs,their chirality has an important effect on the biological activity of the drug.Racemic N-aryl-?-amino acid amide may be resolved by chiral HPLC using a certain chiral stationary phase,but racemic synthetic method at most gives 50% yield of the desired product.It does not meet the requirements of atomic economy and green chemistry.Our group had reported the synthesis of N-(2-halide aryl)amino acid amide with aryl ortho-dihalides and amino acid amide by CuI catalyst.But direct synthesis ofN-aryl-?-amino acid amideis still unsolved research topic.Diaryliodonium salts are a class of highly reactive aromatic electronphiles that can react with many types of nucleophiles.They are used innon-catalyst C-N coupling reactions,C-H activation,phenylene formation,and dearomatization of phenols.Considering the chemicalproperty of the diaryliodonium salts,C-N coupling of diaryliodonium saltswith amino acid amideswereexploredto obtain N-aryl-?-amino acid amide.In this paper,benzene and iodine were used to synthesize dibenzyliodonium salt.Thenthe C-N coupling reaction of diphenyliodonium triflate and L-phenylalaninamide was tried.Fortunately,the desired product N-phenyl-L-phenylalaninamide was obtained.Then catalysts,solvents,bases,temperature,reaction time and the ratio of substrates were screened.The optimized condition was as follows: a mixture ofdiphenyliodonium triflate and L-phenylalaninamide(molar ritio: 2:1),Cu(OAc)2(as catalyst),K3PO4(as base),and 1,4-dioxane(as solvent)was stirred at room temperature for 24 h.Under the optimized condition,the reactions of diphenyliodonium triflate with various amino acid amides were screened.And thenthe effect of differentdiaryliodonium salts were studied.All the desired products were obtained.In order to verify whether the product was racemized during the reaction,we carried out chiral HPLC analysisand found that the chirality was kept.Finally,diphenyliodonium triflate with other dinucleophileswere researched.For some dinucleophiles,such as aminobenzamides,amino imidazole,and aminophenol,all of the reactionswere selectively carried out at the relatively strong alkaline position.Interestingly,our cheap copper-catalyzed synthetic method withdiaryliodonium salts as substrates afford the same coupling products as Buchwald's expensive palladium-catalyzed approach with aryl halides as substrates.All compounds in this article were characterized by 1H NMR,13 C NMR,andmass spectrometer.