Mono-endo-6-N,N-diethylcarbamoyl and bis-endo,endo-6,12-N,N-diethylcarbamoyl derivatives of Tröger’s base. Synthesis and exo-endo isomerization study

Abstract

An efficient synthetic route to the mono-endo-6-N,N-diethylcarbamoyl and bis-endo,endo-6,12-N,Ndiethylcarbamoyl derivatives of Tröger'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 1 H NMR, mechanistic, and computational studies. Deuterium quench experiments using LDA, CD 3 ONa/CD 3 OD and DCl/CD 3 OD 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/CD 3 OD, no deuterium was incorporated, suggesting the traditional ring-opening mechanism involving an iminium ion.