Iminium species Michael addition

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

The first highly regio-, chemo-, diastereo-, and enantio-selective vinylogous Michael addition of oqa-dicyanoalkenes to oq/S-unsaturated aldehydes employs salts of a,a-diarylprolinol (103) (20 mol%) as organocatalysts. The reaction presumably involves the formation of an iminium species from the aldehyde as the first step of the cascade.153... 

Increasing importance has to be attributed to modem tandem (or cascade ) techniques—reaction sequences that can be performed as a one-pot procedure because the first reaction step creates the arrangement of functional groups needed for the second to occur. Schemes 5-7 present some in situ preparations for iminium species, which can then react further with appropriate nucleophiles that are already present (preferably in the same molecule). Most elegantly, in situ generation of iminium ions for tandem processes was performed by a 3,3-sigmatropic (aza-Cope-type) rearrangement (Scheme 5), but also by initial Michael-type addition reactions to vinyl-substituted Atio... 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

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