Michael reactions iminium catalysis

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

Scheme 7.66 Cascade triple Michael/Michael/aldol reaction combining H-bonding activation and iminium catalysis.

Anthrones [204] and 3-substituted oxindoles [205] possess activated methylenes which have been able to react under asymmetric iminium catalysis with a,p-unsaturated aldehydes. The reaction with 3-substituted oxindoles is especially attractive, since chiral quaternary stereocenters are generated. For this purpose, chiral primary amine thiourea catalyst 132 has been demonstrated as a very efficient promoter for the addition of 3-alkyl substituted oxindoles to P-aryl substituted enals in the presence of benzoic acid as cocatalyst in toluene at rt to afford the corresponding Michael adducts in good diastereoselectivities (dr up to >19/1) and good enantioselectivities (73-93% ee) (Scheme 2.75) [205a], P-Alkyl substituted enals are not suitable partners for the reaction affording very low diastereo- and enanti-... 

Woodward probably conducted the most outstanding work on iminium catalysis before its rebirth in 2000. In this work. Woodward applied proUne catalysis in a triple organocascade reaction consisting of a deracemization (via aretro-Michael, Michael addition) and an intramolecular aldol reaction that determine the stereochemical outcome of the reaction (Scheme 1.5), leading to the synthesis of erythromycin [13]. 

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. 

In 2010, Chen and co-workers [134] developed the first organocatalytic asymmetric conjugate addition of a, 3-unsaturated aldehydes via iminium catalysis. In the presence of diarylprolinol silylether 7 and o-fluorobenzoic acid (OFBA), the reaction proceeded well to afford the highly valued adducts with excellent enantioselectivities and with up to outstanding diastereoselectivities (Scheme 5.67). To emphasize the synthetic utility of the reaction, a number of natural-product-like or drug-like molecules with versatile skeletons have been efficiently constructed from the corresponding Michael adducts. 

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... 

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). 

In addition, sUyl enol ethers of substituted acetophenones [93] or thioesters [94] react with a,P-unsaturated aldehydes under iminium-catalysis conditions in the sense of a Mukaiyama-Michael reaction (Scheme 4.24). Apphcations of this transformation can be found in the total syntheses of compactin [95] and ho mod trie acid lactone and its homolog [96]. 

In conclusion, Kappe s group demonstrated the absence of any differences between conventional and microwave heating in proline-catalyzed Mannich and aldol reactions as well as no evidence for specific or non-thermal microwave effects. In all cases, in contrast to the previous literature reports, the results obtained with microwave irradiation could be reproduced by conventional heating at the same reaction temperature and time in an oil bath. The differences observed in previous publications could be a result of incorrect temperature measurements [36]. After Kappe s [35] publication several articles appeared in the literature concerning the application of microwaves in asymmetric organocatalysis, mostly in aldol and Michael type reactions operating via enamine as well as iminium catalysis. 

---