Enantioseparation and racemization of α-aryl-α-fluoroacetonitriles

The 2-Aryl-2-fluoroacetonitriles have garnered increasing interest as versatile building blocks in asymmetric synthesis. However, the configurational stability of these organofluorines is poorly understood and analytical methods that can be used to differentiate between their enantiomers remain underdeveloped. In this study, baseline high performance liquid chromatography (HPLC) enantioseparation of ten 2-aryl-2-fluoroacetonitriles was achieved by screening frequently used chiral stationary phases. While Chiralcel OD, Chiralpak AD, and Chiralpak AS proved to be most broadly useful, preparative separation of the enantiomers of 2-(2-naphthyl)-2-fluoroacetonitrile was possible on Chiralcel OJ. This enabled racemization studies at various temperatures and in the presence of organic bases which showed that this compound is configurationally stable under neutral conditions upon heating to 130°C for 6 h but undergoes complete racemization within 10 h in the presence of stoichiometric amounts of a guanidine base at room temperature. The racemization is likely to proceed via formation of an achiral keteniminate intermediate and obeys reversible first-order reaction kinetics with a half-life time of 87.7 min in ethanolic hexanes at 23.2°C. Racemization is significantly slower and occurs with a half-life time of 23.1 h at 22.4°C when the guanidine is replaced with a weaker amidine base.