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.