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

Journal of the American Chemical Society
Melissa A AshleyMathew J Vetticatt

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 (13)C 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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Citations

May 5, 2017·The Journal of Physical Chemistry. B·Ellen V DalessandroJosefredo R Pliego
May 25, 2016·Organic & Biomolecular Chemistry·Ciril Jimeno
Mar 26, 2019·The Journal of Organic Chemistry·Charitha GurugeNasri Nesnas
Dec 7, 2021·Journal of the American Chemical Society·Harvey J A DaleGuy C Lloyd-Jones

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