The Stability of Imidazolidinones is the Primary Influence on the Catalytic Activity of Proline Amides and Proline Sulfonamides in Enamine Catalysis Using Alkyl Aldehyde Substrates

Some N‐substituted proline derivatives catalyse the reactions of alkyl aldehydes with electrophilic partners, and others give negligible amounts of product. The key reaction between the aldehyde and the proline derivative has been studied, and a rationale for the reactivity observed is presented. Si...

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Bibliographic Details
Published in:European journal of organic chemistry 2013-01, Vol.2013 (1), p.141-147
Main Authors: Tin, Sergey, Fuentes, José A., Lebl, Tomas, Clarke, Matthew L.
Format: Article
Language:English
Subjects:
Aldehydes
Enamines
Enzymes
Michael addition
Organocatalysis
Reaction mechanisms
Reactive intermediates
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Summary:Some N‐substituted proline derivatives catalyse the reactions of alkyl aldehydes with electrophilic partners, and others give negligible amounts of product. The key reaction between the aldehyde and the proline derivative has been studied, and a rationale for the reactivity observed is presented. Simple proline amides derived from aromatic amines (poor catalysts) form stable imidazolidinones quite rapidly at the expense of enamines, the latter being detected, if at all, for less than an hour. Less basic proline amides form a kinetic diastereomer of an imidazolidinone that very slowly inverts its stereochemistry to give a final thermodynamic product. The stereochemistry of these diastereomers was fully assigned by 1H NMR, NOE, and TOCSY experiments. A proline amide derived from an alkylamine (good catalyst) forms high concentrations of enamine that is only slowly (days) converted into a single diastereomer of an inert imidazolidinone. In contrast, another good catalyst, a proline sulfonamide, immediately forms a reactive imidazolidinone, that rapidly ring‐opens and exchanges with other aldehydes. This presumably drip‐feeds iminium ions and enamines into the catalytic cycle. Thus, there are two quite different mechanistic regimes that lead to efficient catalysis. These mechanistic insights should now allow some element of rational design of prolinamides for enamine reactions using aldehydes. Some proline amides are poor catalysts when aldehydes are used as substrates since the catalysts irreversibly form imidazolidinones. Proline amides with more basic amide groups form long‐lived enamines, which allows catalysis to proceed. Proline sulfonamides only form imidazolidones, but these are unstable.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.201201174