Michael addition of ketones

Annulation reaction of (benzotriazol-l-yl)acetone 531 with chalcones provides an efficient route to 3,5-diarylphenols 538. The reaction is catalyzed by NaOH in ethanol. In the first step, Michael addition of ketone 531 to the C=C bond of a chalcone gives diketone 532. In the second step, condensation between the carbonyl... 

Michael additions of ketone enolates. The stereochemistry of Michael additions of lithium enolates of ketones to a,(3-enones is controlled by the geometry of the enolate. Addition of (Z)-enolates results in anti-products with high diaster-eoselectivity, which is not changed by addition of HMPT. Reaction of (E)-enolates is less stereoselective but tends to favor syn-selectivity, which can be enhanced by addition of HMPT. 

Figure 6.32 Proposed intermediates in the 100-catalyzed Michael addition of ketones to nitroalkenes favored Z-enamine (A) and disfavored E-enamine (B).

Scheme 6.177 Typical products obtained from the 208-catalyzed asymmetric Michael addition of ketones to nitroalkenes.

The advancements in supramolecular catalysis are not limited to transitions-metal catalyzed reactions. Clarke and coworkers recently reported the preparation of a library of organocatalysts and their application in the asymmetric Michael addition of ketones to nitroalkenes [37]. They proposed use of a supramolecular catalyst formed... 

CsF in the presence ol tetraalkoxysilanes also effects Michael addition of ketones lo a,/ -unsaturaied ketones, esters, and nitriles. Presumably the enolate is generated and is converted by Si(OR)a into the silyl enol ether, which reacts in situ.2 Examples ... 

Michael addition to unsaturated amides. This system (1 equiv. of each) effects Michael addition of ketones, nitro compounds, ethyl cyanoacetate, and diethyl malonate to a,(3-unsaturated amides. Addition to methacrylamides is interesting because the final products are glutarimides or dihydropyridinones. 

Direct catalytic Michael addition of aldehydes to nitrostyrenes proceeds in good yield, syn diastereoselectivity, and enantioselectivity (up to 82/90/99%, respectively) using a recyclable dendritic catalyst bearing chiral pyrrolidine moieties.200 High-yielding enantio- and diastereo-selective direct Michael addition of ketones to nitroalkenes to give aldol products employ modular acyclic primary amino acid derivatives as catalysts.201... 

L-Prolinamides (71) with a pendant alcohol act as recoverable bifunctional catalysts of direct nitro-Michael addition of ketones to -nitrostyrenes, giving syn-de s up to 94% and ees up to 80%.204 The pyrrolidine provides enamine catalysis, and the side-chain donors can hydrogen-bond the nitro oxygens. 

Thiourea-Mediated Michael Addition of Ketones to Nitroolefins [29] (pp. 82-83)... 

Enders D, Seki A (2002) Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett 2002 26-28 Enders D, Vrettou M (2006) Asymmetric synthesis of (+)-polyoxamic acid via an efficient organocatalytic Mannich reaction as the key step. Synthesis 13 2155-2158... 

Enders D, Seki A (2002) Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett 2002 26-28... 

TABLE 8. Conditions for the Michael addition of ketone enolates to a, 6-unsaturated esters, according to equation 37... 

PEG-supported proline 92 was designed to catalyze the asymmetric Michael addition of ketones to nitrostyrene (Scheme 3.26) [53]. Using 5mol% of the polymeric catalyst, the Michael adduct 95 was obtained in good yields (up to 94%) and moderate to good enantioselectivities (up to 86% ee). A high level of diastereose-lectivities (>98/2, syn/anti) was also observed. The enantiomeric excesses obtained... 

The thiourea functionality, inserted on the most frequently used chiral pyrrolidine scalTold, works excellently as reactivity and enantioselectivity control co-factor by chelating the nitro group of the acceptor. This solution, adopted in 25, provides a family of robust catalysts that afford high yields (up to 98%) and great stereoselectivities (up to 99 1 dr and 99% ee) in direct Michael additions of ketones to various nitroolefins in water. ... 

Highly substituted 6-keto-esters [e.g. (215)] having vicinal quaternary centres can be prepared by Michael additions of ketone enolates to highly active acceptors containing two electron withdrawing groups.200 Substituted 6-keto-esters (218) have been obtained with good to excellent enantiomeric enrichments by Michael... 

Scheme 2.10 Enantioselective Michael addition of ketones to nitroalkenes catalyzed by primary amine-sulfonamide catalysts 27a-b and by 9-epi amino cinchona alkaloid 28a.

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

Alkylidenemalonates and malononitriles constitute another class of doubly activated olefins that can be used as highly electrophilic Michael acceptors in this reaction. For example, the Michael addition of aldehydes with these compounds has been reported to proceed with very good yields and enantioselectivities using 0-TMS diphenylprolinol 31a as catalyst (Scheme 2.29). On the other hand, the Michael addition of ketones to alkylidenemalonates has... 

Various i-prolinamides, derived from chiral p-amino alcohols, are active hifunctional catalysts for nitro-Michael additions of ketones to p-nitrostyr-enes. In particular, catalyst 25e exhibits the highest catalytic performance working in polar aprotic solvents. 

Wang and coworkers synthesised recyclable and reusable pyrrolidine-fluorosulfonamide organocatalysts 3b,c. The fluorous sulfonamide organocatalyst 3b was used for the Michael addition of ketones and aldehydes to nitro-olefins in water, and the reaction gave products with high enantio- and diastereomeric purity. Robust organocatalyst 3b was easily separated from... 

Ley and coworkers also used tetrazole 5a to catalyse the asymmetric Michael addition of a ketone to an aromatic nitro-olefin in a 1 1 mixture of ethanol and isopropanol. The products obtained had moderate to good diastereoselectivities (up to >19 1 dr) and moderate enantioselectivities (up to 73% ee). Further, a homoproline tetrazole derivative (5b) was prepared and used for asymmetric Michael reaction. Catalysts 5a and 5b gave similar diastereoselectivities however, the catalyst 5b produced products with higher enantioselectivities in the Michael addition of ketones to aromatic nitro-olefins (Scheme 9.34). Ley and coworkers explained that the side chain of the homotetrazole was responsible for the increased enantioselectivity. 

Scheme 12.10 Michael addition of ketones with maleimides.

L-2-Chlorophenylglycine has been used as a cocatalyst with quinidine thiourea for the Michael addition of ketones or aldehydes with iV-phe-nylmaleimide (15 examples, 71-99%, dr 78 22-99 1, ee 89-99%). ... 

Oxazole-containing molecules found several applications in catalysis and materials chemistry. Pyrrolidinyl-oxazole-carboxamide catalysts 140 were reported as new chiral bifunctional organocatalysts effective in the asymmetric Michael addition of ketones to nitroolefins (140BC8008). Compound 141 exhibits different spectral properties (both in absorption and emission) in response to external stimuli, such as pressure and protonation, and it is therefore promising for the realization of piezofluorochromic materials (14CC2569). 

Scheme 2.40 Asymmetric Michael addition of ketones to p-nitrostyrenes catalyzed by ionic self-assembled organocatalysts...

The different solvents, additives, and cosolvents present in the reaction media can assist in the stabilization of the transition state and favor one facial preference for the approaching of the substrates as depicted in proposed transition state D [52b] (Fig. 2.10) for the 32-catalyzed Michael addition of ketones to nitrostyrene. In this case, a cooperative hydrogen-bond solvent participation (represented by H O) takes place resembling the oxyanion hole commonly found in enzymes for stabilizing transition states. It seems then very clear that intra- and intermolecular hydrogenbonding interactions play a key role in the organocatalytic cycle. 

Scheme 2.43 Organocatalyzed stereoselective Michael addition of ketones to alkylidene malonates...

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