Michael addition reaction malonate

The Michael Addition Reaction consists in the addition of the sodio-derivative of ethyl acetoacetate, ethyl malonate or ethyl cyanoacetate to an olefine group... 

In the Michael addition reaction depicted in eq. [146] the diastereomeric sulfoxides 312 are formed under kinetic control conditions, therefore, the addition of sodium diethyl malonate is an irreversible process. On the contrary, addition of sodium methoxide to the sulfoxide 311 is a thermodynamically controlled process and leads to a mixture of diastereomeric ]3-methoxysulfoxides 313 in a 31 69 ratio (320). 

Shibasaki made several improvements in the asymmetric Michael addition reaction using the previously developed BINOL-based (R)-ALB, (R)-6, and (R)-LPB, (R)-7 [1]. The former is prepared from (R)-BINOL, diisobutylaluminum hydride, and butyllithium, while the latter is from (R)-BINOL, La(Oz -Pr)3, and potassium f-butoxide. Only 0.1 mol % of (R)-6 and 0.09 mol % of potassium f-butoxide were needed to catalyze the addition of dimethyl malonate to 2-cy-clohexenone on a kilogram scale in >99% ee, when 4-A molecular sieves were added [15,16]. (R)-6 in the presence of sodium f-butoxide catalyzes the asymmetric 1,4-addition of the Horner-Wadsworth-Emmons reagent [17]. (R)-7 catalyzes the addition of nitromethane to chalcone [18]. Feringa prepared another aluminum complex from BINOL and lithium aluminum hydride and used this in the addition of nitroacetate to methyl vinyl ketone [19]. Later, Shibasaki developed a linked lanthanum reagent (R,R)-8 for the same asymmetric addition, in which two BINOLs were connected at the 3-positions with a 2-oxapropylene... 

Recently, Maruoka and coworkers addressed the importance of dual-functioning chiral phase-transfer catalysts such as 70a for obtaining a high level of enantio-selectivity in the Michael addition of malonates to chalcone derivatives (Scheme 5.35) [37]. For instance, the reaction of diethyl malonate with chalcone in... 

Different cyclic products are formed in the double Michael addition of malonic acid ethyl methyl ester to ( vE)-l,5-diphenylpenta-l,4-dien-3-one under basic conditions. Label the stereogenic units in the reaction products with the appropriate stereodescriptors. 

In recent years the use of tandem reaction sequences to create complex cyclic systems in a single reaction has blossomed587-604. Although this area is beyond the scope of the present work, one such process will serve as illustration. Thus, a Michael addition of malonate to... 

The mechanism of the Michael addition reaction using ester 3.3 and mesityl oxide is shown in Scheme 3.13. The enolate A derived from the malonic ester (3.3) attacks the (3-carbon... 

The first chiral aluminum catalyst for effecting asymmetric Michael addition reactions was reported by Shibasaki and coworkers in 1986 [82], The catalyst was prepared by addition of two equivalents of (i )-BINOL to lithium aluminum hydride which gave the heterobimetallic complex 394. The structure of 394 was supported by X-ray structure analysis of its complex with cyclohexenone in which it was found that the carbonyl oxygen of the enone is coordinated to the lithium. This catalyst was found to result in excellent induction in the Michael addition of malonic esters to cyclic enones, as indicated in Sch. 51. It had previously been reported that a heterobimetallic catalyst prepared from (i )-BINOL and sodium and lanthanum was also effective in similar Michael additions [83-85]. Although the LaNaBINOL catalyst was faster, the LiAlBINOL catalyst 394 (ALB) led to higher asymmetric induction. 

The Michael addition reaction in water suspension medium is also applicable to carbon-carbon bond formation. A mixture of 70a, methyl acetylacetate (76), 72 and water was stirred for 5 h at room temperature, then the reaction product was filtered and dried to give the addition product 77 in 98% yield [34]. Although a similar solvent-free Michael addition reaction of 70a with diethyl malonate at 60 °C has been reported, organic solvent was still necessary to isolate the product from the reaction mixture [36]. 

The stereochemical course of the subsequent Michael addition of malonic ester to the unsaturated ketone (23) proved to be unexpected. The kinetically controlled product 27 of addition was obtained in the presence of sodium methoxide and an excess of dimethyl malonate however, the thermodynamically preferred ester 28, also obtainable by base-catalyzed equilibration of 27, was the major product of the reaction. According to the IR (absence of Bohlmann bands) and NMR spectra, both 27 and 28 contained cis-quinolizidine ring systems formed possibly by reversible retro-Michael cleavage of the C-3 to Aj, bond in 23. This possibility explains the observed rapid destruction of 23 in the presence of very strong base with simultaneous appearance of a UV maximum at 410 nm presufiaably due to the conjugated enone system present in 29. 

An example illustrating the synthetic possibilities arising from the Michael addition reaction with these carbon-11 labelled vinyl cyanides is their addition to the carbanion formed from dimethyl malonate (equation 72). These compounds are useful from a... 

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 addition is one of the most efficient and effective routes to C-C bond formation[127]. This reaction is widely applied in organic synthesis and several new versions of it have been introduced recently. The commonly employed anionic alkyl synthons for Michael addition are those derived from nitroalkanes, ethyl cyanocarboxylates, and malonates, and their limitations have been largely overcome by newer methodologies. However, the newer approaches are by no means devoid of drawbacks such as long reaction times, modest product yields in many cases, and the requirement for excess nitroalkane. Michael addition reactions of Schiff s bases have long been known to constitute a convenient method for functionalizing a-amino esters at the a position and the ratio of Michael addition to cycloaddition product has been found to depend upon the metal ion employed to chelate the enolate produced upon deprotonation (see below). 

It has already been mentioned that one of the first examples in which the catalytic use of chiral amines was suggested for the activation of Michael acceptors in Michael addition reactions were the early reports by Yamaguchi, which focused on the conjugate addition of malonates and nitroalkanes to... 

Lattanzi and coworkers disclosed that L-diaiyl prolinols served as suitable catalysts in one of the most popular Michael addition reaction, i.e. the reaction of malonate esters and cyclic p-ketoesters to nitroalkenes to generate functionalised products amenable to further manipulation (Scheme 7.7). 

Paixao and coworkers showed that a sulfur-modified catalyst C5 was able to efficiently catalyse the Michael addition of malonates to enals in EtOH/ brine mixture (Scheme 8.7). The sulfur-containing catalyst was efficient for the Michael addition of aldehydes to nitroalkenes in polyethylene glycol (PEG). The most important feature of this system was its reusability. After extraction of the reaction products, the PEG solution containing the organocatalyst was reused at least four times with no adverse effects on yield or enantioselectivity. ... 

Kumaraswamy et al. prepared a calcium-BINOL catalyst 132 and applied it in asymmetric Michael and epoxidation reactions. At the outset of their study, they found the choice of calcium salt was important for the enan-tioselectivity. After optimisation, they prepared 132 by the reaction of calcium chloride with potassium-BINOL. Using this catalyst, moderate yields and enantioselectivities were obtained for the Michael addition of malonates 4 or p-ketoesters 101 to enones 10, giving products 136 and 137. The same authors extended this work to the epoxidation of enones using tert-butyl hydroperoxide 102 again with moderate results (Scheme 3.42). 

Subsequently, the highly enantioselective Michael addition of malonates and 1,2,4-triazole to cyclic and acyclic enones, as well as the first phospha-Michael reaction of cyclic enones and diaryl phosphine oxides was reported using a similar catalyst.In 2012, Huang, Wang and coworkers demonstrated that primary amine-thiourea 39 can efficiently catalyse the... 

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