We use density functional methods to model a tandem aza-Cope – Mannich reaction where ZnCl<sub>2</sub> is the catalyst. We delineate the energy profile leading to the four possible pyrrolidine stereoisomers in an effort to determine the reaction’s stereoselectivity. We consider a substrate that lacks a protecting group at the nitrogen center and that is where the Lewis acid catalyst coordinates. Consequently, the cyclization step occurs in conjunction with an intramolecular proton transfer leading to a thermodynamically more stable deprotonated carbonyl. This results in significantly higher activation barriers for the Mannich cyclization step when compared to substrates with either electron-withdrawing or electron–donating protecting groups.

Effect of omitting a protecting group at the nitrogen center of a pyrrolidine on the energy profile of the reaction

256th National Meeting (2018)

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