Michael donors malonates

In the presence of 10 mol% of this catalyst, the malonates 56 could be added to several nitroolefins 57 with up to 93% ee. Apolar solvents such as toluene are crucial for high ee values. It is also noteworthy that (i) good ee can be achieved with catalyst 55 even in the absence of solvents, i.e. with a mixture of the neat starting materials 56 and 57, and that (ii) the range of Michael donors/acceptors includes aryl- and alkyl-substituted nitroolefins and 2-alkylated malonates. 

Next, the mechanism of the Type II reactions is discussed. To discriminate one of the enantiofaces of the acceptor it is desirable to place and to activate the electrophiles in a chiral environment. At the same time, effective activation of the Michael donor is required. In Shibasaki s ALB-catalyzed reaction (Scheme 3), it was proposed that the aluminum cation functioned as a Lewis acid to activate enones at the center of the catalyst, and that the Li-naphthoxide moiety deproton-ated the a-hydrogen of malonate to form the Li enolate (Scheme 9). Such simultaneous activation of both reactants at precisely defined positions became feasible by using multifunctional heterobimetallic complexes the mechanism is reminiscent of that which is operative in the active sites of enzymes. The observed absolute stereochemistry can be understood in terms of the proposed transition state model 19. Importantly, addition of a catalytic amount of KOt-Bu (0.9equiv. to ALB) was effective in acceleration of the reaction rate with no deterioration of the... 

Michael additions are useful in acetoacetic ester syntheses and malonic ester syntheses because the enolate ions of both of these esters are good Michael donors. As an example, let s consider the addition of the malonic ester enolate to methyl vinyl ketone (MVK). The crucial step is the nucleophilic attack by the enolate at the carbon. The resulting enolate is strongly basic, and it is quickly protonated. 

Michael addition-alkylation pathway has to be considered because simple methylene active compounds such as dimethyl malonate or methylcyanoac-etate were found to be good Michael donors with /1-substituted unsaturated esters such as 5-phenyl-2-pentenoate in the reaction conditions. However, when the reaction was quenched before completion, a substantial amount of product resulting from attack onto the zr-allylPd complex was isolated, bringing an evidence for the alkylation/Michael addition pathway. 

In place of active methylene compounds having a nitrile group, malonates, 13-ketoesters, 1,3-diketones, 1,1-disulfones, nitro compounds, Mel drum acid, and anthrone can also be used as the Michael donors for these ruthenium-catalyzed aldol and Michael reactions. The reaction proceeds well in acetonitrile under mild and neutral conditions (Eq. 9.59) [83]. 

The mechanism is illustrated with the addition of a malonate anion across the double bond of ethyl cinnamate. The reaction is reversible in protic solvents and the thermodynamically most stable product usually predominates. When organometallic reagents are used as Michael donors (e.g., copper-catalyzed organomagnesium additions) SET-type mechanisms may be operational. 

The epi-quinine urea 81b was also found by Wennemers to promote an asymmetric decarboxylation/Michael addition between thioester 143 and 124 to afford the product 144 in good yield and high enantioselectivity (up to 90% ee) (Scheme 9.49). Here, malonic acid half-thioesters serve as a thioester enolate (i.e., enolate Michael donors). This reaction mimics the polyketide synthase-catalyzed decarboxylative acylation reactions of CoA-bound malonic acid half-thiesters in the biosynthesis of fatty adds and polyketides. The authors suggested, analogously with the enzyme system, that the urea moiety is responsible for activating the deprotonated malonic add half-thioesters that, upon decarboxylation, read with the nitroolefin electrophile simultaneously activated by the protonated quinuclidine moiety (Figure 9.5) [42]. 

In addition, it has been shown that the catalytic use of PS-N3PAPT (10 mol%) was very effective for Michael addition reactions of a variety of Michael donors such as p-ketoesters, ot-nitroketones and nitroalkanes with activated olefins such as methyl acrylate and methyl vinyl ketone [41] (Scheme 6.9). The recyclability of the catalyst was established after it had been used 12 times. When diethyl malonate or ethyl cyanoacetate was used as the Michael donor substrate, the expected disubstituted adducts were obtained in moderate to good yields. 

Michael s original (non-biological) donors were carbanions derived from an activated methylene-group as in diethyl malonate, but the most likely Michael donors in enzymes are the anions of either the NH— group in imidazole (as in Bloch s original discovery), or the hydroxy-group of serine, or the mercapto-group of cysteine. 

Bis(phenylsulfonyl)methane has also been employed as an acidic carbon pronucleophile related to malonates and 1,3-diketones with success in the Michael reaction with ot,p-unsaturated aldehydes using 31c as catalyst (Scheme 3.6). The reaction showed a remarkable substrate scope when alkyl-substituted enals were employed but failed when cinnamaldehyde was tested as Michael acceptor. Alternatively, a more acidic cyclic gem-bissulfone has been used as Michael donor, keeping the high yields and enantioselectivities observed for the reaction and also allowing to expand the scope of the reaction to several aromatic enals.In all cases, the chemistry of the sulfonyl group was employed to generate a methyl group after metal-mediated desulfuration or, alternatively. 

The higher activity of primary amines in the reaction involving enones as Michael acceptors has also been extended to the use of different bifunctional catalysts (Scheme 3.19), which usually contain a primary amine functionality connected to a basic site by means of a chiral scaffold, as is the case in the use of 280 and 55. These diamine catalysts have been found to be excellent promoters of the Michael reaction of enones with cyclic 1,3-dicarbonyl compounds and malonates respectively, the tertiary amine basic site present at the catalyst structure being responsible for assisting in the deprotonation of the Michael donor in order to increase the concentration of the nucleophile species. In a different approach, bifunctional thiourea-primary amine catalyst 56a has also... 

Cyclic ketones or acetone react with nitro-olefins, giving the corresponding -adducts hy action of the potassium salt of chiral p-chlorophenyl amino acid catalyst (18 examples, 40-99% anti syn 42 58-4 96 ee 61-95%). Malonates,2-nitroalkanes or p-ketoesters are useful Michael donors and can react with enones in the presence of lithium salts of primary amino acids to create a new carhon-carhon hond at the p-position of the ketone (Scheme 12.9). However in some cases p-amino acids were more efficient than the a-amino acids. ... 

S. Danishefsky [17] has shown, how to effect ring expansion of the three-membered ring compound 1 (Fig. 9) starting with inversion displacement at the stereogenic center. When 1 was treated with the enolate anion of dimethyl ethyl malonate (2), a product was obtained which, after hydrolysis and decarboxylation, furnished a mixture of diastereomers 4 and 5 in 44% overall yield. Under the appropriate conditions, both the five-membered ring compounds give the Michael donor D of Fig 7. 

In the Michael reaction, an enolate acts as a nucleophile and adds 1,4 to an a,P-unsaturated carbonyl compound (Section 22.12). 1,3-Dicarbonyl compounds firequently provide the enolate, called the Michael donor. Three a,p-unsaturated carbonyl compounds are commonly used as Michael acceptors 3-buten-2-one (methyl vinyl ketone), 2-propenal (acrolein), and methyl 2-propenoate (methyl acrylate). For example, dimethyl malonate reacts with 3-buten-2-one in a base-catalyzed reaction. 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

A Michael reaction involves the conjugate addition of a stable enolate ion donor to an o,/3-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product. Usually, the stable enolate ion is derived from a /3-diketone, jS-keto ester, malonic ester, or similar compound. The C—C bond made in the conjugate addition step is the one between the a carbon of the acidic donor and the (3 carbon of the unsaturated acceptor. 

Scheme 6.61 Mechanistic proposals of the 12-catalyzed asymmetric Michael addition of diethyl malonate to trans-P-nitrostyrene proposed by the Takemoto group (A, B, and C) and initial enolate complex (D) with the ammonium group as additional hydrogen-bond donor initiating an alternative mechanism suggested by Sods, Ptipai, and coworkers.

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