Oxalic amides are usually widely concerned due to their various biological activities. For example, monomethyl oxalate can be used as chemical hybridization reagent for Cicer arietinum, and oxalate aryldiamide compounds are useful as glycogen phosphorylase inhibitors, or as a small molecule modulator that acts on the CD4-gp120 protein. Until recently, the team led by Dawei Ma uses oxalate 2,6-dimethylphenyl monoamide carboxylic acid as a ligand for copper-catalyzed C—N coupling reaction of aryl iodides and bromides with amines, thus opening up new uses of these compounds. However, this reaction is mainly applicable to the coupling reaction of aryl iodides and bromides.
The transition metal-catalyzed coupling reaction of aryl halides with suitable nucleophiles, such as amines, active methylene compounds, alkynes, phenols, alcohols, thiophenols, sodium sulfinics, sodium sulfides, phosphates and the like, is very efficient for the formation of C—N, C—C, C—O, C—S, and C—P bonds. Generally, due to the high reactivity of aryl iodides and aryl bromides, the corresponding coupling reaction proceeds well under the catalysis of transition metals such as palladium, copper and nickel. Aryl chlorides are cheaper and more readily available, and have more application prospects compared with aryl bromides (iodides). However, high energy of C—Cl bond makes the oxidative addition of transition metal to aryl chlorides hardly occur, and the coupling reaction is more difficult than that of aryl bromides and iodides. Palladium and nickel catalyzed C—N coupling reactions of aryl chlorides have been reported by using sterically hindered phosphine ligands. In 2005, Hartwig and coworkers described the coupling reaction of (hetero)aryl chlorides with primary amines was promoted by a large sterically hindered phosphine ligand with a ferrocene structure. The loading of catalysts and ligands in this system can even be reduced to one hundred thousandth molar equivalent. Such reaction can be accomplished at room temperature for some particular heteroaryl substrates. In addition, a wide range of functionalized (hetero)aryl chlorides were compatible for this transformation.
In 2011, Buchwald's group found that the use of different phosphine ligands allowed the coupling reaction of aryl chlorides with primary and secondary amines respectively. The system has a very wide compatibility with substrates. In addition to common aliphatic amines, the aromatic amines with heterocyclic rings also are suitable nucleophiles.
Although the catalysis of metallic palladium and nickel are highly efficient in the amination of aryl chlorides, there are still some problems in large-scale applications: 1. it is required to add large sterically hindered and complex phosphine ligands or N-heterocyclic carbenes ligands; 2. palladium catalyst is expensive, and for zero-valent nickel catalyzed reaction, the operation is quite harsh. In contrast, copper catalysts are cheap, stable and readily available, and the useful ligands are simple. However, the substrates of copper-catalyzed coupling reaction reported so far are mostly limited to aryl iodides and bromides.
In 2007, Pellón's group reported the coupling of 2-chlorobenzoic acid and aliphatic amines with assistance of ortho-substituent effect and ultrasound. Both primary and secondary amines can provide the corresponding coupling products in good yields. However, only aryl chlorides with ortho-carboxyl substituent are suitable for this transformation (Docampo, M. L.; Pellón, R. F.; Estevez-Braun, A.; Ravelo, A. G. Eur. J. Org. Chem. 2007, 4111.). This reaction should undergo a nucleophilic substitution process rather than a coupling reaction. In addition, the high reaction temperature is still required. A schematic of this reaction is shown in FIG. 1.
Another report on Ullmann coupling reaction of aryl chlorides came from Taillefer's group. They used 2,2,6,6-tetramethyl-3,5-heptanedione as a ligand to achieve C—O coupling of benzyl chlorides with phenols. However, the addition of large amount ligand as much as 0.8 equivalents made the reaction less economically (Xia, N.; Taillefer, M. Chem. Eur. J. 2008, 14, 6037.). A schematic of this reaction is shown in FIG. 2.
In summary, there is no catalytic system for copper-catalyzed coupling reaction of aryl chlorides in the art that enables the reaction to be carried out efficiently.