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.