Enamine catalysis, conjugate addition

The best alternatives to enamines for conjugate addition of aldehyde, ketone, and acid derivative enols are silyl enol ethers, Their formation and some uses were discussed in Chapters 21 and 26-28, but these stable neutral nueleophiles also react very well with Michael acceptors either spontaneously or with Lewis acid catalysis at low temperature,... 

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). 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

If you want to do a conjugate addition of a carbonyl compound without having a second anion-stabilizing group, you need some stable and relatively unreactive enol equivalent. In Chapters 27 and 28 you saw how enamines are useful in alkylation reactions. These neutral species are also perfect for conjugate addition as they are soft nucleophiles but are more reactive than ends and can be prepared quantitatively in advance. The reactivity of enamines is such that heating the reactants together, sometimes neat, is all that is required. Protic or Lewis acid catalysis can also be used to catalyse the reaction at lower temperature. 

An alternative and useful method for intramolecular conjugate addition when the Michael donor is a ketone is the formation of an enamine and its reaction with a Michael acceptor. This can be advantageous as enamine formation occurs under reversible conditions to allow the formation of the product of greatest thermodynamic stability. Treatment of the ketone 40 with pyrrolidine and acetic acid leads to the bicyclic product 41, formed by reaction of only one of the two possible regio-isomeric enamines (1.51). Such reactions can be carried out with less than one equivalent of the secondary amine and have recently been termed organo-catalysis (as opposed to Lewis acid catalysis with a metal salt). The use of chiral secondary amines can promote asymmetric induction (see Section 1.1.4). 

With respect to the covalent activation in conjugate additions, the catalyst, usually a primary or a secondary amine, can reversibly form a chiral enamine [ 11 ] to activate the nucleophile (D, Fig. 2.2) or a chiral iminium ion [12] to activate the acceptor (E, Fig. 2.2). The detection of enamine intermediates in asymmetric oiganocatalysis has been for a long time the missing piece of evidence for the commonly accepted mechanism of enamine catalysis. This gap has been recently solved with the first detection and structnral characterization of enamine intermediates in proUne-cata-lyzed aldol reactions by real-time NMR spectroscopy [13] and the direct observation of an enamine intermediate in the crystal strnctnre of an aldolase antibody [14]. 

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