Synthesis Of α-Hydroxycarboxylic Acid Anilides Via Copper-catalyzed Selective C–N Coupling Reaction

α-Hydroxycarboxylic acid anilides are widely used in medical field and agricultural chemical field because of their good biological activities.There are many synthetic methods of α-hydroxycarboxylic acid anilides. For example, transformation of α-hydroxycarboxylic acid with halogenation reagents, and then condensation of the resulting acyl halides and anilines; or condensation of α-hydroxycarboxylic acid and anilines with assistance of certain condensation reagents and additives.Therefore, in continuation of our studies on coupling reactions, and in view of the importance of α-hydroxycarboxylic acid anilides and the practicality of Ullmann-type C-N coupling reaction, we have investigated chemoselective C-N cross-coupling reactions of α-hydroxyamides for the synthesis of α-hydroxycarboxylic acid anilides. But the α-hydroxyamides contain a hydroxyl group and an acylamino group. Therefore, we need to find a suitable reaction conditions to make the reaction to carry out selectively in the acylamino group.Firstly, we selected mandelamide and p-bromotoluene as substrates to investigate the ratio of reactants, solvent, catalyst and ligand, alkali, temperature, time and other coupling reaction conditions. Finally, we obtained the optimal experimental conditions that the ratio of α-hydroxyamides and aryl halides was 1.2:1, CuI was used as the catalyst with DMEDA as ligand, weak base K₂CO₃（2 equiv.） was added, and the reactions were performed in toluene（5 mL） for 24 h under 110 °C.And then, with the optimized reaction conditions at hand, reactions of various aryl halides and mandelamide were performed. The results show that chlorobenzene achieved much lower yield than bromobenzene, while iodobenzene obtained better results. The aryl halides with a strong electron-donating group such as methoxyl gave a little lower yield than those with a weak one. The aryl halides with electronwithdrawing groups such as 4-nitrophenyl bromide gave nearly no product. The position of substituents on the aromatic ring of aryl bromide influences the results obviously. Generally, yields with para substituents are highest, and yields with ortho substituents are the lowest.Next, various α-hydroxyamides were examined to react with iodobenzene. Most substrates gave high yields. Especially, the yield of phenyllactamide is up to 96%. The position of substituents on the phenyl ring of the α-hydroxyamides influences the results.Finally, we take the L-phenyllactamide and DL-phenyllactamide as raw materials to react with iodobenzene, respectively. p-Iodotoluene, p-iodoanisole were examined for the influence of chirality on the reactions. The results show that under the reaction conditions, not only they got high yields, but also no racemization occurred, the ee value was obtained as high as 96%.In a word, we have developed a novel protocol for efficient synthesis of α-hydroxycarboxylic acid anilides via CuI-catalyzed selective C-N cross coupling reaction, and the method has wide scope of substrates.