Why pyrrolidines did not work in the alkylation–cyclization–isomerization–3-aza-Cope cascade?

Alkylation–cyclization–isomerization–3-aza-Cope cascade is a powerful method for constructing fused nitrogen heterocycles bearing tetrasubstituted carbons. Despite this, the use of pyrrolidines as starting substrates in these reactions remains limited. In our study, we conducted a detailed analysis of the cascade product using OTBS-substituted pyrrolidine. Our findings revealed that the main product was a nine-five-membered bicyclic enamine, which formed through a 3-aza-Cope rearrangement from syn-vinylammonium. Further, our comprehensive DFT calculations of the transition states of the 3-aza-Cope rearrangement from both anti- and syn-dienolates and vinylammoniums demonstrated that the rearrangement from syn-vinylammonium was more favorable. This preference stems from its progression through a late transition state that minimizes distortion of the pyrrolidine ring. These findings enhance our understanding of the mechanism and facilitate the prediction of outcomes of future cascade reactions.