Isotope Effects Reveal the Mechanism of Enamine Formation in l -Proline-Catalyzed α-Amination of Aldehydes

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Abstract

The mechanism of l-proline-catalyzed α-amination of 3-phenylpropionaldehyde was studied using a combination of experimental kinetic isotope effects (KIEs) and theoretical calculations. Observation of a significant carbonyl 13C KIE and a large primary α-deuterium KIE support rate-determining enamine formation. Theoretical predictions of KIEs exclude the widely accepted mechanism of enamine formation via intramolecular deprotonation of an iminium carboxylate intermediate. An E2 elimination mechanism catalyzed by a bifunctional base that directly forms an N-protonated enamine species from an oxazolidinone intermediate accounts for the experimental KIEs. These findings provide the first experimental picture of the transition-state geometry of enamine formation and clarify the role of oxazolidinones as nonparasitic intermediates in proline catalysis.

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Ashley, M. A., Hirschi, J. S., Izzo, J. A., & Vetticatt, M. J. (2016). Isotope Effects Reveal the Mechanism of Enamine Formation in l -Proline-Catalyzed α-Amination of Aldehydes. Journal of the American Chemical Society, 138(6), 1756–1759. https://doi.org/10.1021/jacs.5b10876

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