Iminium ions Knoevenagel reactions

Iminium ions are intermediates in a group of reactions that form ,( -unsaturated compounds having structures corresponding to those formed by mixed aldol addition followed by dehydration. These reactions are catalyzed by amines or buffer systems containing an amine and an acid and are referred to as Knoevenagel condensations,2U The reactive electrophile is probably the protonated form of the imine, since it is a more reactive electrophile than the corresponding carbonyl compound.212... 

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

Iminium catalysis directly utilizes the higher reactivity of the iminium ion in comparison to the carbonyl species and facilitates Knoevenagel-type condensations, cyclo- and nucleophilic additions, and cleavage of cr-bonds adjacent to the a-carbon. Enamine catalysis on the other hand involves catalytically generated enamine intermediates that are formed via deprotonation of an iminium ion, and react with various electrophiles or undergo pericyclic reactions. ... 

The Mannich reaction is very closely related to the Knoevenagel condensation reaction in that it involves iminium intermediates. The reaction, which is carried out in mildly acidic solution, effects a-alkylation of ketones and aldehydes with dial-kylaminomethyl groups. The electrophilic species is the iminium ion derived from... 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

On the basis of the proposed catalytic cycle, aldehyde 9 reacts with 1,3-indandione 178 by amine-catalyzed Knoevenagel condensation to provide the benzylidene-indandione B via iminium ion A, which is an excellent organic Lewis acid. This intermediate thns undergoes a Diels-Alder or a double Michael reaction with the soft nucleophile 2-amino-1,3-butadiene C generated in situ from enone 84 and the amine catalyst to produce the... 

A Mannich-type condensation mechanism involving an iminium ion electrophile similar to the aminocatalytic Knoevenagel reaction has recently been proposed for the amine-catalyzed self-aldolization of propionaldehyde (Eq. (6)) [55]. Although this mechanism is not unreasonable it should be... 

A domino reaction of an aldehyde (R -CHO) with nitromethane followed by a second aldehyde (R -CH2CHO) yields a functionalized two-stereocentre product (74). Using a simple proline derivative, diphenylprolinol TMS ether, des typically over 95% and ees of 99% were obtained. This amine serves as a multiple-hydrogen-bond-donor (MHBD) catalyst, and is proposed to act in iminium mode for the Knoevenagel-type reaction of nitromethane ion, and then as an enamine catalyst of the second step. ... 

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