Synthesis Of Chiral Amino Acid Anilides By Copper-Catalyzed Selective N-Arylation Of Amino Acid Amides And Naphthol Derivatives By Protecting-group-free Palladium Catalysis

Chiral amino acid anilides are a subclass of amino acid derivatives and have extensive and important applications. They are essential core structures in a number of bioactive compounds, such as clinical antiarrythmic agent tocainide, histone deacetylases(HDACs) inhibitors, pH-controlled light-activated reagents for cancer therapy, cold menthol receptor antagonists, and antimalarial agents. Chiral amino acid anilides are also found as chiral ligands used in catalytic asymmetric Mannich-type reactions, ruthenium(II)-catalyzed asymmetric transfer hydrogenation of ketones and chiral organocatalysts for asymmetric aldol reactions. Besides, they are used as organic synthesis intermediates and utilized in the synthesis of peptides and peptidomimetics.Chiral amino acid anilides are typically synthesized via three-step synthetic routes. The first step is protection of l-, d-and dl-amino acids with CbzCl, Boc2O, phthalic anhydride or ethyl thioltrifluoroacetate. The second step is condensation of N-protected amino acids and anilines in the presence of carboxylic activating agents. The last step is removal of the protecting groups to furnish the chiral amino acid anilides. All of these approaches involve multiple step synthetic routes, thus resulting in low atom economy, high cost, tedious work-up and potential environmental pollution. So there is an important need to search for an efficient, atom-economic, inexpensive synthetic protocol of chiral amino acid anilides. But there are two amino groups in an amino acid amide molecule, so control of the selective C-N cross coupling of these compounds is unavoidable. Fortunately, we occasionally found the synthesis of chiral amino acid anilides by copper-catalyzed selective N-arylation of amino acid amides.Firstly, L-phenylalaninamide and bromobenzene were selected as reaction substrate to optimize reaction conditions. The types and amount of catalyst, the types and amount of ligand, reaction time, temperature, bases, reaction time, and solvents has been researched. The optimizing condition is:5mol%Cul as catalyst,10mol%DMEDA as ligand,110℃as reaction temperature,24hours as reaction time, K2CO3as base, toluene as solvent, feed molar ratio is amides:aryl halides:catalyst:ligand: base=1.2:1.0:0.05:0.1:2(mol).Secondly, the reactions of L-phenylalaninamide and aryl halides, the reaction of various amino acid amides and bromobenene/iodobenzene have been researched. Results showed that catalytic system used in this paper was fit for aryl bromide and aryl iodides, aryl iodides had much higher reactivity than the corresponding aryl bromides. Especially bromides with electron withdrawing group, the product (S)-N-(2-amino-3-phenylpropanoyl)benzamide produced a high yield of up to86%. In order to verify whether racemization occurred during the C-N cross-coupling, the enantiomericexcess of the products (S)-N-(2-amino-3-phenylpropanoyl)benzamide and (S)-N-(2-amino-3-phenylethanoyl)benzamide were analyzed by chiral HPLC on a Daicel Chiralcel OD-H column. The chiral HPLC results demonstrated the ee value as high as99%. In summary, we have discovered a direct, practical, cost-effective and atom-economic protocol for chemically selective copper-catalyzed selective C-N coupling of chiral amino acid amides and aryl halides to synthesize chiral amino acid anilides.BINOL and its derivatives are widely used as a class of chiral ligands for transition metal-catalyzed homogeneous and heterogeneous asymmetric organic reactions, but the BINOL derivatives synthesized by the process of hydroxy protection and deprotection, thus resulting in low atom economy, high cost, tedious work-up and potential environmental pollution. Inspired by the research of protecting group free Suzuki coupling reactions, a straightforward, protecting group free protocol for the synthesis of chiral6-substituted and6,6’-disubstituted binols with good yields by palladium-catalyzed hydroxylation, C-N and C-O coupling of chiral6-bromo-and6,6’-dibromo-1,1’-binaphthols was developed. All compounds were characterized by1H NMR,13C NMR, and IR spectroscopy.