Michael reactions enamine catalysis

A wide variety of carbon nucleophiles have been successfully used in the organocatalytic asymmetric inter- and intramolecular Michael addition to different a,p-unsaturated systems. Among them, the addition of aldehydes to diverse Michael acceptors such as, a,p-unsaturated ketones, alkylidene malonates, P-nitrostyrenes, and vinyl sulfones, is one of the most studied reactions. Enamine catalysis is the most frequently employed chiral activation found in the literature. 

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. 

A bifunctional mechanism involving enamine catalysis [55, 58, 77] was clearly indicated in the Michael reactions promoted by catalyst 101. The observed... 

Evidence for the intermediacy of the enamine has also been confirmed in some examples involving synthetic utilization of thiazolium salts, for example in the catalysis by thiazolium salts of Michael reactions between aldehydes and a,/ -unsaturated compounds58 (equation 6). 

Chen and coworkers have reported a new domino Michael-Michael addition reaction between a,a-dicyanoalkene [26] derived from cyclohexanone and benzyli-deneacetone, resulting in a stepwise [4 + 2]-type cycloaddition to afford almost enantiopure bicyclic adduct 15. In contrast to the completely inert function of secondary ammonium salt, a primary amine, 9-amino-9-deoxyepiquinine lo [27], in combination with trifluoroacetic acid, was found to be highly efficient in the activation of the a, 3-unsaturated ketone by tandem iminium-enamine catalysis (Scheme 10.21) [28],... 

A variety of a,a-dicyanoalkenes derived from aryl ketones have also been extensively explored under the same catalytic conditions, and in general the vinylogous Michael adducts were obtained due to the steric hindrance in the following enamine catalysis by primary amine lo [28]. Nevertheless, an interesting domino Michael-Michael-retro-Michael reaction was observed for a,a-dicyanoalkenes derived from acetophenone and propiophenone, giving a facile process to chiral 2-cyclohexen-l-one derivatives. It was noteworthy that a kinetic resolution was observed in the intramolecular Michael addition step (Scheme 10.22). 

Sequential Iminium-Enamine Catalysis. Directed Electrostatic Activation. A comparison of the standard catalytic cycles for enamine activation (Scheme 2.1) and for iminium ion activation (Scheme 2.12) show that iminium catalysis proceeds, after the addition of the nucleophile, via an ( )-enamine. In the presence of a suitable electrophile, this enamine gives rise to an iminium ion that after hydrolysis can give rise to an a,p-diftmctionalyzed carbonyl (Scheme 2.13) [85]. Scheme 2.13 also shows that when using a chiral 2-substituted pyrrohdine or an imidazolidinone as the catalyst, the sequential apphcation of the steric model for Michael addition to iminium ions (Figure 2.15) and of the steric model for electrophilic attack to enamines (Figure 2.IB) predicts the absolute stereochemistry of the major isomer obtained in the reaction. 

Intramolecular Michael Reaction of Aldehydes. Imidazolidinone catalyst 1 mediates the asymmetric intramolecular Michael addition of simple aldehydes to enones at rt (eq 15). The reaction is thought to proceed via an enamine mechanism but a dual-activation mechanism involving both enamine and iminium catalysis can also be considered. When a catalytic amount of 1 was used, products were obtained in excellent yield although in low enantioselectivity (eq 15). Better selectivity was observed, however, when catalyst 2 was used (eq 15). 

Many important intramolecular reactions, such as aldol reaction, Michael addition, transannular reaction, and a-alkylation reaction, could be reaUzed via enamine catalysis. 

Enamine catalysis provided the synthetic platform for a second example of asymmetric MCR. In 2001, Barbas and colleagues described a Knoevenagel/Michael reaction sequence between acetone, benzaldehyde (14), and diethyl malonate (15) catalyzed by the chiral secondary amine 16 (Scheme 42.4). Despite the moderate level of enantioselectivity, this reaction was engineered upon rather sophisticated catalytic machinery [21]. The catalyst promoted both individual steps of the MCR, although only the second enamine-catalyzed process was stereo-determining. The... 

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