Michael reaction partners

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

The previous sections dealt with reactions in which the new carbon-carbon bond is formed by addition of the nucleophile to a carbonyl group. Another important method for alkylation of carbon nucleophiles involves addition to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,(3-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. 

Protected glycine derivatives have been used as the nucleophilic partner in enantioselective syntheses of amino acid derivatives by chiral PTC (Scheme 10.9). Loupy and co-workers have reported the addition of diethyl acetylaminomalonate to chalcone without solvent with enan-tioselectivity up to 82% ee [44]. The recent report from the Corey group, with catalyst 8a used in conjunction with the benzophenone imine of glycine t-butyl ester 35, discussed earlier, results in highly enantioselective reactions (91-99% ee) with various Michael acceptors (2-cyclo-hexenone, methyl acrylate, and ethyl vinyl ketone) to yield products 71-73 [21], Other Michael reactions resulting in amino acid products are noted [45]. 

The Michael reaction involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic partners are typically a,fi-unsaturated ketones, esters or nitriles, but other electron-withdrawing substituents can be used to activate the carbon—carbon double bond to nucleophilic attack. A tandem aldol-Michael reaction has been recently described. Wachter-Jurcsak and coworkers66 reported that the reactions involving 2-pyridinecarboxaldehyde, 71, and 2-quinolinecarboxaldehyde with the enolates of acetophenone, 70, afforded the unexpected symmetric l,5-diphenyl-3-(2-heteroaryl)-1,5-pentanediones (Scheme 24). 

Tsuchii et al. reported a very interesting four-component domino process where an alkyne, two olefins and diphenyl diselenide sequentially react to form a highly functionalized cyclopentane derivative, after a linear addition sequence and 5-exo-trig cyclization [136]. This reaction can be seen as an interrupted polymerization process initiated by the addition of selenyl radical to an electron-deficient alkyne in the presence of a large excess of a Michael acceptor. The identity of each reaction partner is important for the outcome of the reaction. For instance, use of (PhS)2 instead of (PhSe)2 leads to the polymerization product rather than to the cyclization one, while (PhTe)2 did... 

The [2+2] cycloaddition is the main method for the synthesis of cyclobutanes and 4-membered ring heterocycles. The thermal reaction between two alkenes is not a synchronous, pericyclic process, which is symmetry forbidden, but is a two-step, Lewis acid-catalysed procedure involving a Michael reaction between an electron-rich alkene and an electron-poor partner followed by cyclisation (Figure 8.7). 

Recently, there has been considerable progress in the synthesis of nitrogen-containing heterocycles based on (ox)indole skeleton. Oxindole derivatives serve as useful reaction partners in various domino transformations. Michael addition of aliphatic aldehydes to electron-deficient olefinic oxindole motifs gave chiral intermediates, which were further combined with diverse activated olefins or imines to afford spirocyclic oxindoles with high molecular complexity (Scheme 8.27). Spiro-oxindole derivatives were also assembled by a Michael/Michael/aldol cascade of oxindole and two equivalents of enal. " ... 

Next to an oxa-Michael addition, an aza-Michael reaction is a suitable partner for a CM event in a domino process, too [40]. On heating the unsaturated carbamates... 

Chiral tetrahydrothiophenes are compounds displaying important biological activities. They were obtained also through an enantioselective domino sulfa-Michael-Michael process of a,(3-unsaturated aldehydes with ethyl 4-mercapto-2-butenoate [47]. While catalyst 17a turned out to be ineffective, the diarylprolinol silyl ether 17b afforded cyclic products with high to excellent enantio- and diastereoselectivity (Scheme 14.16a). A closely related sulfa-Michael aldol process was developed by using 3-mercapto a-carbonyl esters as reaction partners. The best stereoselectivity and yield were obtained with diaryl prolinol 17c in the presence of small amounts of H2O (Scheme 14.16b) [48]. 

P-, and S-Heterocycles The reaction of two similar or dissimilar aryl aldehydes 250/251 with malonodi-nitrile 21 or ethyl 2-cyanoacetate 175 catalyzed by Af-hetero-cyclic carbenes (NHCs) has been demonstrated to provide fully substituted furans 252 in good to high yields (74-90%), within short reaction times up to 5 h under solvent-free conditions (Scheme 13.59) [97]. This transformation is based on the umpolung of one of the aldehydes by the NHC, while the other one undergoes a Knoevenagel condensation with the CH-acidic reaction partner. The Breslow intermediate then attacks the condensation product in fashion of a Michael addition. After elimination of the NHC, base-catalyzed cyclization provides the desired products. Five different NHCs have been tested catalyzing this reaction. 

Alkylideneindolones are particularly good electrophiles, especially toward Michael additions, and therefore constitute excellent starting materials for the synthesis of spirooxindoles by multiple bond-forming approaches. The general strategy of the cascade reactions consists of an initial Michael reaction followed by a nucleophilic addition of the in situ formed enolate intermediate to various electrophiles. In the last years, several electrophilic partners with different scaffolds that lead to formal cyclizations, such as [3+2] cycloadditions [8a], Diels-Alder reactions [8b], and cyclopropanation [8c], have been used to afford a plethora of new spirooxindole scaffolds with excellent stereocontrol. 

---