| N-Aryl a-amino acid amides including N-(2-haloaryl) a-amino acids are the core structures of a number of bioactive compounds, for example, Loviride and other anti-HIV compounds, lead compounds for anti-cancer drugs or pharmaceutical agents.A number of methods were developed for synthesis of racemic N-(2-haloaryl) and N-aryl a-amino acid amides. For example, Ghosez disclosed electrophilic amination of2-azadienes with arylnitroso to give adducts, which may be transformed into racemic N-aryl a-amino acid amides. Recently Beller developed a ruthenium-catalyzed amination of a-hydroxy amides.Like most chiral bioactive compounds, chirality of N-(2-haloaryl) and N-aryl a-amino acid amides has an important influence on the bioactivity of these drugs. The eutomer generally has much higher bioactivity than the corresponding racemic one,Racemic N-(2-haloaryl) and N-aryl a-amino acid amides may be resolved by chiral HPLC using a certain chiral stationary phase. Racemic synthetic method at most gives50%yield of the desired product, so it contradicts the rule of atom economy and green chemistry.Thus developing one step synthe of enantiomer-rich N-(2-haloaryl) and N-aryl a-amino acid amides is of importance.Some activated haloarenes such as some fluoroarenes with nitro or cyano groups may directly react with aliphatic amino group of chiral α-amino acid amides to produce chiral N-(2-haloaryl) a-amino acid amides. For non-activated haloarenes, it is reported that a chiral reagent synthetic procedure by addition of the isocyanate Me3SiNCO to optically pure complicated zirconaaziridine epimers as chiral reagents, which after protonolysis gave (S)-N-phenyl-phenylglycinamide with less50%yield. However, this method has shortcomings such as low yield, difficulty in preparation of chiral zirconaaziridine epimers, harsh reaction condition and complex operation procedures, thus this protocol is impractical.Although copper-and palladium-catalyzed C-N coupling of amides and amino acids and their derivatives are extensively studied, selective C-N coupling of primary amino group of a-amino acid amides with primary amide group is still unresolved.In this paper, the main research is synthesis of N-(2-halide aryl) amino acid amide with aryl ortho-dihalides and amino acid amide by CuI catalytic without Ligand-join.This paper is divided into three parts:First,1-bromo-2-iodobenzene and L-alaninamide hydrochloride was used as the model substrate for the optimization of reaction conditions. The catalysts, reaction temperatures, base types, solvents, reaction time and ligands were investigated. Ultimately the optimal reaction conditions were obtained, that is, in the presence of CuI and K2CO3,1-bromo-2-iodobenzene and L-alaninamide in DMF were performed under argon at90℃for48hours.Secondly, after the optimal reaction conditions at hand, we investigated the reactions of1-bromo-2-iodobenzene with L-valinamide hydrochloride, L-leucinamidehydrochloride, glycinamide hydrochloride, L-phenylglycinamide hydrochloride, L-phenylalaninamide hydrochloride, L-threolinamide hydrochloride,2-aminobutyramide respectively. Except L-threolinamide hydrochloride, other amino acid amides gave good yields and high optical activity.Finally, we evaluated the reactions of1-bromo-2-iodo-4-methyl-benzene,1-chloro-2-bromo-4-methoxybenzene,1-chloro-2-iodo-4-nitrobenzene,1-chloro-2-iodo-4-(trifluoromethyl) benzene,1-chloro-2-bromo-4-nitrobenzene,1,2,4,5-bromophenyl,2-bromo-3,5-dichloro-pyrimidine and four amino acid amides. The results demonstrates that activity of halogen atom I has highest, Br second, Cl the poorest; aryl ortho-dihalides containing electron-donating groupaffords higher yield, while substrates with electron-withdrawing groupsgave lower yields. Generally, most of the substrates had good results.In a word, we developed an efficient, cost-saving protocol of ligand-free copper-catalyzed synthesis of N-(2-haloaryl) amino acid amides. |
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