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.
Rationale: α-Substituted cyclic amino nitriles show different reactivity and stability in solution depending on their ring size. Mass-spectrometric modeling of the reactions, which normally take place in solution, may shed light on the nature of the studied compounds and explain some observations.
Methods:The stability of the nitriles in an acidic solution was studied by adding glacial acetic acid. Gas-phase modelling was conducted by gas chromatography/mass spectrometry (GC/MS) with electron ionization mass spectrometry and direct inlet electrospray ionization. QqQ and Orbitrap analyzers were used to carry out tandem mass spectrometry (MS/MS) experiments.
Results:The obtained data show that the elimination of HCN from α-substituted cyclic amino nitriles occurs in the same way for an acidic solution, thermolysis and electrospray ionization. According to GC, the most stable were N-formylated nitriles compared with N-benzylated or N-unsubstituted ones. Electrospray ionization demonstrated its advantages for the routine identification of cyclic amino nitriles due to milder conditions than in electron ionization. Fragmentations of cyclic ketimines, formed from N-unsubstituted amino nitriles, are discussed in particular.
Conclusions: Similarities in the behavior of the α-substituted cyclic amino nitriles under electron ionization, electrospray ionization, thermolysis and reaction in solution under acidic catalysis were discovered and confirmed by MS/MS experiments. Fragmentation schemes of the studied nitriles and corresponding imines are proposed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.