Copper Catalyzed C-O Coupling Reaction And Its Applications

Aryl ethers and the phenols are not only important intermediates in organic synthesis, but also frequently emerged as drugs and biologically active natural products. Copper-catalyzed C-O coupling reaction is one of the most important means of preparing such compounds. Although many efforts have been taken in this field and many useful methods have been developed, there are still some drawbacks which can’t be ignored, such as limited catalyst types to monovalent copper salt, and much cheaper, more stable divalent copper salts are not reported; limited substrate scope to iodides and activated bromides while the bromides and chlorides are more economical and more abundant; many methods require the participation of a large number of expensive ligand, which greatly increased the cost of the reaction. Therefore, a more moderate and economical C-O coupling reactions with broader range of substrates scope is of great significance.An exposure of aryl bromide and diols to the catalyst system consisting of copper chloride (5 mol%) at 130° C can efficiently generate aryloxy alcohols. It is the first report for the coupling reaction of aryl bromides and aliphatic diols, and also the first report for the application of divalent copper salts in C-O coupling reaction. The reaction system used weak base potassium carbonate to avoid the possible destruction of the substrates in strong alkaline environment, and does not require any ligand or solvent, not only avoiding the tedious experimental operation, and also greatly reducing the cost, constructing an economical and green reaction protocol. Further studies showed that the reaction product aryloxy alcohols can provide phenols in the presence of KOH in DMSO via intramolecular nucleophilic substitution reaction, allowing the important conversion from aryl bromides to phenols. Second, aryloxy alcohols can be facially converted to benzofuran-3(2H)-ones and chroman- 4-ones by Jones oxidation and the followed acid-catalyzed intramolecular Friedel-Crafts acylation. Such structures themselves not only have a wide range of biological activity, and are often used as important organic synthesis intermediates for the synthesis of drugs and biologically active compounds.When we studied the C-O coupling reaction of aryl halides and glycolic acid, we found a selective synthesis of phenoxy acetic acids and phenols can be achieved by slightly adjusting the catalyst and base in the reaction system. When cuprous iodide was used as catalyst and cesium carbonate as base, the reaction system tends to form phenoxyacetic acid compounds, thereby avoiding the oxidation step in the synthesis of phenoxyacetic acid.When the copper hydroxide was used as catalyst and sodium hydroxide as base, the reaction system can provide phenols in excellent yields, where glycolic acid played its role as a ligand with the amount of only 30 mol%. Compared with other reported methods, glycolic acid represent an more economical and efficient ligand, by which, the reaction time can be shortened to only 3-6 hours. The characters combined with rapid conversion, simple workup and low cost, allowed our protocol to apply in large-scale industrialized production.Research in the synthesis of phenols from aryl bromides revealed that 8-hydroxyquinoline can serve as an effective ligand in the hydroxylation reaction of the aryl bromide, thus allowing the direct conversion from aryl bromides to phenols.8-Hydroxyquinoline mediated phenol synthesis is highly efficient, economical, and possesses wide substrate scope, so it has good application prospects in phenol synthesis. We also found that the reaction system can be easily applied to the synthesis of benzofuran compounds, which are famous for a wide range of biological activity and rich existence in nature world.