Michael addition of active methylene compounds

Fig. 13.67. Mechanism of the base-catalyzed Michael addition of active-methylene compounds (top) and of ketones (bottom), respectively. Subst refers to a substituent, and EWG stands for electron-with-drawing group.

Moreno-Manas et al. [98] reported on a similar effect of triphenylphosphine for the Michael addition of active methylene compounds to n-acceptor olefins such as methyl vinyl ketone, acrylonitrile, and 2-vinylpyridine and dialkyl azodi-carboxylates. They compared the reactivity of RuH2(PPh3)4, RuCl2(PPh3)3, and PPh3 and concluded that for /5-diketones, ketoesters, and ketoamides, triphenylphosphine released from the ruthenium complexes contributes totally or partially to the catalysis. 

The RuH2(PPh3)4-catalyzed addition of active methylene compounds can also be applied to conjugate additions to a,/3-unsaturated carbonyl compounds (Michael additions). In 1989, Murahashi reported the first example of the transition metal-catalyzed Michael addition of active methylene compounds [74]. One of the notable advances of this catalytic reaction is that the addition of C-H bonds to a,/3-unsaturat-ed carbonyl compounds give Michael adducts without contamination by the corresponding aldol products (Eq. 9.56) [74]. Recently, Murahashi applied their aldol and Michael addition reactions to a solid-phase synthesis using polymer-supported nitriles (Scheme 9.12) [76]. In this case, four component reactions took place with high diastereoselectivity. 

Ranu BC, Baneijee S (2005) Ionic liquid as catalyst and reaction medium. The dramatic influence of a task-specific ionic liquid, bmim][OH], in Michael addition of active methylene compounds to conjugated ketones, carboxylic esters, and nitriles. J Oig Lett 7 3049-3052... 

Depending on the catalyst, either subst. quinolizidines or 4-ketoquino-lizidines may be obtained by reductive cyclization of pyridine derivatives, prepared by Michael addition of active methylene compounds to 2-vinylpyridine. E A mixture of diethyl / -(2-pyridyl)ethylmalonate, Raney-Ni, and ethanol heated 1 hr. at 145° under a H2-pressure of 200 atm. —> 3-earbethoxy-4-ketoquinolizidine. Y 97%. (V. Boekelheide and S. Rotehild, Am. Soc. 71, 879 (1949).)... 

Pyranones can also be prepared from the Michael addition of active methylene compounds to the appropriate enaminones. Additions of methylene nitriles to the enaminones 364 and 366 under strongly basic conditions followed by acidification give the 2-pyranones 365 and 367, respectively. Scheme 103 (81S225 85JHC713). Additions of ethyl acetoacetate to enaminones are also reported to afford 2-pyranones (91CPB1655). 

Furthermore, this catalyst promotes asymmetric Mannich reactions [31] and Michael addition of active methylene compounds to a,p-unsaturated imides [32]. 

Inokuma, T, Hoashi, Y. and Takemoto, Y. (2006) Thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to a,P-unsaturated imides Dual activation of imide by intra- and intermolecular hydrogen bonding. Journal of the American Chemical Society, 128, 9413-9419. 

Fig. 13. Michael additions of activated methylene compounds to olefins.

Michael additions of active methylene compounds (e.g. 1,3-dicarbonyls, /3-keto-esters, and malonates) to a,/3-unsaturated esters, leading to 5-keto-ester derivatives, can be effected very efficiently and under near neutral conditions by using Ni(acac)2 as catalyst. The Michael addition of O-silyl ester enolates to cycloalkenones to give 5-keto-esters can be carried out in the absence of a catalyst if the two reactants are simply heated together in acetonitrile (Scheme 20) Yields with simple models are 90% not only is this method a... 

The addition of active methylene compounds (ethyl malonate, ethyl aoeto-acetate, ethyl plienylacetate, nltromethane, acrylonitrile, etc.) to the aP-double bond of a conjugated unsaturated ketone, ester or nitrile In the presence of a basic catalyst (sodium ethoxide, piperidine, diethylamiiie, etc.) is known as the Michael reaction or Michael addition. The reaction may be illustrated by the addition of ethyl malonate to ethyl fumarate in the presence of sodium ethoxide hydrolysis and decarboxylation of the addendum (ethyl propane-1 1 2 3-tetracarboxylate) yields trlcarballylic acid ... 

Selected examples of the Michael-type addition of activated methylene compounds with electron-... 

The asymmetric Michael addition of active methylene or methine compounds to electron-deficient olefins, particularly o,[l-unsaturated carbonyl compounds, represents a fundamental - yet useful - approach to construct functionalized carbon frameworks [36]. 

The prerequisite 1,5-dicarbonyl compounds and their equivalents can be formed in situ by a Michael addition of activated methylene groups onto O Ji-unsaturated systems <1996CHEC-II>. In this manner, 5-alkylidene-2-thioxo-dihydropyrimidincM,6(l //,5//)-dione 84 reacts with ethyl 3-oxobutanoate under microwave irradiation to from the intermediate 1,5-dicarbonyl compound 85, which spontaneously cyclize to afford the corresponding 4//-pyrans in high yield (Scheme 28) <2003SC3747>. 

The asymmetric Michael addition of active methylene or methyne compounds to electron deficient olefins, particularly a,P-unsaturated carbonyl compounds, represents a fundamental and useful approach to construct functionalized carbon frameworks [51]. The first successful, phase-transfer-catalyzed process was based on the use of well-designed chiral crown ethers 69 and 70 as catalyst. In the presence of 69, P-keto ester 65 was added to methyl vinyl ketone (MVK) in moderate yield but with virtually complete stereochemical control. In much the same way, crown 70 was shown to be effective for the reaction of methyl 2-phenylpropionate 67 with methyl acrylate, affording the Michael adduct 68 in 80% yield and 83% ee (Scheme 11.15) [52]. 

A similar dramatic influence of ionic liquid was also reported by Ranu s group in the Michael reaction of active methylene compounds with methyl vinyl ketone and methyl acrylate in the presence of an ionic liquid, 1-butyl-3-methylimidazolium hydroxide ([bmImjOH). Interestingly, open-chain 1,3-dicarbonyl compounds reacted with methyl vinyl ketone and chalcone to give the usual monoaddition products, whereas the same reactions with methyl acrylate or acrylonitrile provided exclusively bis-addition products (Scheme 5.55). 

The Michael addition of active methylene (and methine) compounds to activated 7t-systems is one of the more useful C—C bond-forming reactions (Scheme 5.10). Classical basic activation of the nucleophile can generate by-products from competing side reactions. Therefore, much effort has been dedicated to the development of catalysts for Michael reactions, mainly transition metals and lanthanides [92], The current challenge is the development of heterogeneous catalytic systems. 

Michael condensation reactions (base-catalyzed addition of active methylene compounds to activated unsaturated systems) were reported in 1887." This reaction has been used to prepare... 

The use of C-H bonds is obviously one of the simplest and most straightforward methods in organic synthesis. From the synthetic point of view, the alkylation, alkenylation, arylation, and silylation of C-H bonds are regarded as practical tools since these reactions exhibit high selectivity, high efficiency, and are widely applicable, all of which are essential for practical organic synthesis. The hydroacylation of olefins provides unsymmetrical ketones, which are highly versatile synthetic intermediates. Transition-metal-catalyzed aldol and Michael addition reactions of active methylene compounds are now widely used for enantioselective and di-astereoselective C-C bond formation reactions under neutral conditions. 

All conjugate additions add the elements of H and Nu across the a and P carbons. In the Michael reaction, the nucleophile is an enolate. Enolates of active methylene compounds are particularly common. The a,p-unsaturated carbonyl component is often called a Michael acceptor. 

The Michael-type addition reaction of a carbonucleophile with an activated olefin constitutes one of the most versatile methodologies for carbon-carbon bond formation [1]. Because of the usefulness of the reaction as well as the product, many approaches to the asymmetric Michael-type addition reactions have been reported, especially using chirally modified olefins [2-8]. However, the approach directed towards the enantioselective Michael-type addition reaction is a developing area. In this Chapter, the recent progress of the enantioselective Michael-type addition reaction of active methylene compounds and also organometallic reagents with achiral activated olefins under the control of an external chiral ligand or chiral catalysts will be summarized [9]. 

The recent progress in the Michael addition reaction of active methylene compounds with a, -unsaturated carbonyl compounds has been characterized by the... 

Remu BC, Baneijee S, Jana R (2007) Ionic Uquid as catalyst and solvent the remarkable effect of a betsic ionic liquid, [bmim][OH] on Michael addition and alkylation of active methylene compounds. Tetiahedron 63 776-782... 

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