Michael acceptors iminium activation

Activation of Michael Acceptors by Iminium Ion Formation, Activation of Carbonyl Donors by Enamine Formation... 

In 2008, Ye and coworkers also developed a new type of multifunctional cinch-onidine-based catalyst, such as 119 having an additional primary amine moiety, for the Michael addition of nitroalkane to cydic enones [32], In the presence of an acid cocatalyst, the primary amine moiety of 119 can act as a Lewis base to activate the Michael acceptor via iminium formation. The catalysts 119a and 119b (5 mol%) provided quite excellent enantioselectivity (up to 98% ee) for the Michael addition of nitroalkanes to cyclohexenone (Scheme 9.40). The observed retardation of the reaction rate and the opposite sense of enantioselectivity obtained with the catalyst 119b indicated the importance of the configuration of the cydohexane... 

This dual enamine/iminium activation profile in cascade Michael/aldol reactions can also be found even in some early reports, mostly focused on the self-dimerization of enals catalyzed by proline or analogues derived thereof, which generally proceeded with low enantioselect vities. There is not a clear and definitive mechanistic pathway confirmed for these reactions, although the most widely accepted proposal for the dimerization of enals (Scheme 7.4) ° involved sequential activation of one molecule of the substrate as a dienamine (Michael donor) and another molecule as iminium ion (Michael acceptor). 

E-ajp-unsaturated ester was employed, while a single diastereoisomer was obtained using the corresponding Z substrate. This reaction design has also been extended to the use of an a,p-unsaturated aldehyde as the initial Michael acceptor, in this case it being necessary to consider the possible dual activation of the Michael donor and acceptor by the catalyst through the formation of the corresponding enamine and iminium intermediates. ... 

On the other hand, a triple Michael/Michael/Aldol cascade sequence has been developed for the synthesis of highly substituted cyclohexanes starting from dimethylmalonate, an a,p-unsaturated aldehyde and a nitroalkene in which H-bonding catalysis and iminium activation were jointly employed for the simultaneous activation of the two Michael acceptors involved in the... 

Although organocatalytic intramolecular conjugate additions have been reported (see Sect 1.3.1.3), the Michael acceptor is almost always either a ketone or an aldehyde, since the coimnon mode of activation for these systems is through iminium ion... 

Amine Catalysis (Via Iminium Ion Activation). a,p-Unsaturated aldehydes and ketones are common Michael acceptors susceptible to be activated by an amine catalyst via ion iminium formation [64]. This general activation strategy for enals and enones has been applied to aza-Michael reactions with relative success [65]. One complication of the approach is that both the catalyst and the nucleophile are amine species that could mix their preconceived roles and lead to either catalyst... 

Compared with unsaturated aldehydes, enones tend to be less reactive Michael acceptors. However, the addition of nitrogen-centered nucleophiles to enones can be promoted by certain primary amine catalysts by means of an iminium activation mechanism. Specifically, 9-amine-9-deoxy-epi cinchone derivatives (catalysts 9,36/37), in the presence of organic acids, have proven their usefiilness in catalyzing the addition of carbamate derivatives [75], protected hydroxylamine derivatives [76], and A/-heterocycles to acyclic [77, 78] and cychc unsaturated ketones [79] (Scheme 11.21). In general, aromatic ketones were less reactive and led to lower yields. 

Carbon-carbon bond forming reactions between carbanionic nucleophiles like enolates or deprotonated nitroalkanes and electron deficient alkenes and alkynes belong to the oldest and most versatile transformations known today (225-229). Moreover, stereoselective variants have proven to possess an enormous potential in the syntheses of complex molecules as already exemplified in Sect. 2.4. Whereas the applications depicted in this previous section utilized nucleophiles activated by enamine formation with a chiral secondary amine catalyst to achieve these highly selective C-C bond formations, the present discussirai will focus on the addition of carbon nucleophiles to iminium-activated Michael acceptors. Herein traditional Michael additions using e.g. enolate nucleophiles will be described whereas the use of aromatic Michael donors with iminium-activated acceptors in Friedel-Crafts type reactions will be discussed separately subsequently. 

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