The Direct, Enantioselective, One‐Pot, Three‐Component, Cross‐Mannich Reaction of Aldehydes: The Reason for the Higher Reactivity of Aldimine versus Aldehyde in Proline‐Mediated Mannich and Aldol Reactions

Abstract

In the proline-mediated Mannich and aldol reactions of propanal as a nucleophile, the aldimine prepared from benzaldehyde and p-anisidine is about 7 times more reactive than the corresponding aldehyde, benzaldehyde, as an electrophile. This higher reactivity of aldimine over aldehyde is attributed to the carboxylic acid of proline protonating the basic nitrogen atom of the aldimine more effectively than the oxygen atom of the aldehyde, an explanation which has been both experimentally and theoretically verified.

Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and Selectivities

“…Hayashi and co-workers have suggested that the more basic imines are more readily activated by the carboxylic acid of proline. 47 …”

Direct Organocatalytic Mannich Reaction of Acetaldehyde: An Improved Catalyst and Mechanistic Insight from a Computational Study

“…In general, it is quite difficult to control the high reactivity of acetaldehyde. An acid activates the imine selectively rather than the aldehyde8c and promotes the Mannich reaction efficiently, whereas the reactivity of the enamine is reduced with suppression of the generation of an enamine from the product, which reduces the overall reactions, because of the bulkiness of catalyst 1 . The Mannich reaction catalyzed by bulky organocatalyst 1 , combined with acid additives, distinguishes it from the proline‐mediated reaction 7a…”

Diarylprolinol Silyl Ethers: Development and Application As Organocatalysts

“…In our work [27][28][29][30][31][32][33], reactions were conducted using acetaldehyde and N-benzoyl-Nbenzylidene amine (29) as model substrates, and a diarylprolinol silyl ether as the key catalyst; the resulting b-amino aldehyde product 30 was isolated by its conversion into the corresponding alcohol by reduction with LiAlH 4 . When proline 16 was employed as the catalyst, excellent enantioselectivity was obtained in CH 3 CN with moderate yield, due to competitive hydrolysis of the imine under the acidic conditions.…”