Process Development of the Copper(II)-Catalyzed Dehydration of a Chiral Aldoxime and Rational Selection of the Co-Substrate

The access towards chiral nitriles remains crucial in the synthesis of several pharmaceuticals. One approach is based on metal-catalyzed dehydration of chiral aldoximes, which are generated from chiral pool-derived aldehydes as substrates, and the use of a cheap and readily available nitrile as co-substrate and water acceptor. Dehydration of N-acyl α-amino aldoximes such as N-Boc-l -prolinal oxime catalyzed by copper(II) acetate provides access to the corresponding N-acyl α-amino nitriles, which are substructures of the pharmaceuticals Vildagliptin and Saxagliptin. In this work, a detailed investigation of the formation of the amide as a by-product at higher substrate loadings is performed. The amide formation depends on the electronic properties of the nitrile co-substrate. We could identify an acceptor nitrile which completely suppressed amide formation at high substrate loadings of 0.5 m even when being used with only 2 equivalents. In detail, utilization of trichloroacetonitrile as such an acceptor nitrile enabled the synthesis of N-Boc-cyanopyrrolidine in a high yield of 92 % and with full retention of the absolute configuration.     

超声辐射下水溶液中芳醛肟的合成

在没有催化剂条件下, 芳香醛与盐酸羟胺的水溶液经超声辐射于室温反应, 可以72%～98%收率得到肟. 该方法具有操作简便、反应条件温和、反应时间短、对环境友好等优点.