Mono-Endo-6-N,N-Diethylcarbamoyl And Bis-Endo,Endo-6,12-N,N-Diethylcarbamoyl Derivatives Of Troger'S Base. Synthesis And Exo-Endo Isomerization Study

An efficient synthetic route to the mono-endo-6-N,N-diethylcarbamoyl and bis-endo,endo-6,12-N,N-diethylcarbamoyl derivatives of Troger's base (TB), endo-7 and endo-8, is reported. Studies of reaction time, proton source, and additive allowed establishment of optimized conditions for the conversion of exo-7 into the corresponding isomer endo-7. With a longer reaction time, the exo,exo-6,12 bis-carbamoyl derivative exo-8 was converted into the corresponding endo,endo-bis-carbamoyl product endo-8. Single crystal X-ray crystallographic analysis confirmed the structural and stereochemical assignments made on the basis of H-1 NMR, mechanistic, and computational studies. Deuterium quench experiments using LDA, CD3ONa/CD3OD and DCl/CD3OD conditions of both exo-7 and exo-8 afforded exo-7d(1) and exo-8d(2), respectively (> 95% deuterium incorporation), supporting an enolate mechanism for the isomerization. In contrast, when repeating the experiment with DCl/CD3OD, no deuterium was incorporated, suggesting the traditional ring-opening mechanism involving an iminium ion.[GRAPHICS]