Chiral amines are widely used in the fields of medicine, pesticides, and catalysis. The large demand for chiral amines has made the field of asymmetric synthesis of chiral amines a research hotspot. Hofmann N-alkylation reaction can directly synthesize more valuable amines from inexpensive and readily available industrial amines, and is a commonly used and efficient method for synthesizing high value-added amines.
Researchers have developed the strategy of copper/chiral anionic catalysts as new single electron transfer catalysts in the field of free radical asymmetric catalysis, providing a new strategy for free radical asymmetric catalytic reactions. Recently, researchers have reported the stereoconvergent N-alkylation of alkylamines catalyzed by copper/chiral tridentate anionic ligands. This method can directly convert various industrial raw materials such as amines, amine containing drug molecules, and even ammonia into unnatural chirality in one step under mild conditions α-Amino acid derivatives with excellent enantioselectivity and functional group tolerance. This reaction is highly practical, and chiral ligands can be synthesized in large quantities on a hundred-gram scale without the need for purification.
Chiral unnatural α- amino acid derivatives have been widely used in various fields such as organic synthesis, biology, pharmaceuticals, and materials science. Researchers first studied the N-alkylation reaction of benzylamine and racemization α-carbonyl alkyl chloride. The researchers successfully obtained the target product with a yield of 68% and enantioselectivity of 87% using their copper catalyst and a ligand derived from cinchona alkaloids. Subsequently, researchers improved the yield and enantioselectivity of the target product by screening ligands.
Through further detailed optimization, the optimal reaction conditions were finally obtained as follows: 1 and 1.5 equivalents of substrate, 10 mol% copper iodide, 15 mol% ligands and 3.0 equivalents of Cs2CO3, 1,4-dioxane as solvent, reacting at 45 ℃ for 72 hours.
This method achieves the rapid construction of a series of α-chiral amino acid derivatives with high chemical selectivity and high enantioselectivity, and the substrate has a wide range of applications (>180 examples), which can be applied to various types of alkylamines, including primary and secondary chain like, cyclic alkyl amines, bulk commercial alkylamines, and amine containing drug molecules.
In order to prove the application value of this reaction, researchers conducted a series of conversion applications. Six drugs can be rapidly prepared through simple transformation, and post modification of drug molecules can also be carried out. In addition, this reaction can also be applied to the synthesis of the commercial drug Xadago and active molecule γ-Secretase inhibitor.
Chiral amines are widely used in the fields of medicine, pesticides, and catalysis, with a large demand but limited synthesis strategies. This method is simple and efficient, with mild conditions, wide substrate compatibility, and strong practicality. It provides an effective and practical tool for pharmaceutical research and development and other fields.
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Reference
- Enantioconvergent Cu-catalyzed N-alkylation of aliphatic amines
Ji-Jun Chen, Jia-Heng Fang, Xuan-Yi Du, Jia-Yong Zhang, Jun-Qian Bian, Fu-Li Wang, Cheng Luan, Wei-Long Liu, Ji-Ren Liu, Xiao-Yang Dong, Zhong-Liang Li, Qiang-Shuai Gu, Zhe Dong and Xin-Yuan Liu
