Synthesis of Highly Functionalized Tetrahydropyridines by Ring Opening of [3.3.1]-Heterobicyclic Compounds with Grignard Reagents

Abstract

We herein report our study about the ring opening of 1,3-diaza-4-oxa-[3.3.1]-nonene derivatives with organometallic reagents leveraging on their inherent ring strain and presence of reactive functionalities. The ring-opening occurs with Grignard reagents at the carbon bearing the two nitrogen atoms affording unconventional functionalized trans-2,3-disubstituted 1,2,3,6-tetrahydropyridines that are important structural frameworks due to their synthetic versatility and presence in bioactive molecules. The possibility to prepare enantioenriched tetrahydropyridines was also formally explored with success. A computational DFT study points to the formation of a transient iminium ion intermediate in which the coordination of magnesium to the oxygen of the carbonyl and the N−O endocyclic oxygen promotes the ring-opening process at the gem-diamine carbon atom.