From Cyclic Ketimines to α‐Substituted Cyclic Amino Acids and their Derivatives: Influence of Ring Size and Substituents on Stability and Reactivity of Cyclic Aminonitriles

Abstract

A general route to alpha‐substituted cyclic amino acids was elaborated. The approach is based on Strecker reaction with cyclic ketimines. The influence of ring size and substituent at the alpha‐position of cyclic ketimine on the hydrocyanation was studied. It was found that five‐membered aminonitriles have a tendency to eliminate HCN very easily, especially in the case of aryl‐substituted derivatives. A series of 5–7 membered amino nitriles with different substituents was prepared. Subsequent hydrolysis allows the preparation of alpha‐substituted pipecolic acids. In the case of seven‐membered derivatives, it was necessary to use a formylation‐hydrolysis sequence. Synthesis of alpha‐substituted prolines and their amides was elaborated starting from the corresponding five‐membered ketimines through a benzylation‐hydrolysis‐hydrogenation sequence.