Methylenes Michael addition acceptors

Another important reaction in synthetic chemistry leading to C-C bond formation is the Michael addition. The reaction typically involves a conjugate or nucleophilic 1,4-addition of carbanions to a,/l-unsaturated aldehydes, ketones, esters, nitriles, or sulfones 157) (Scheme 21). A base is used to form the carbanion by abstracting a proton from an activated methylene precursor (donor), which attacks the alkene (acceptor). Strong bases are usually used in this reaction, leading to the formation of byproducts arising from side reactions such as condensations, dimerizations, or rearrangements. 

Michael acceptors which carry a good leaving group at the a-carbon atom or whose electron-withdrawing group itself can serve as the leaving group may be cyclopropanated by active methylene compounds under basic conditions via a prototropic shift subsequent to the Michael addition as outlined in equation 139. Thus, the basicity of the carbanions involved must be balanced to allow the requisite prototropic shift otherwise, the reaction will be very slow or will not work. 

The 1,4-addition (or conjugate addition) of resonance-stabilized carbanions. The Michael Addition is thermodynamically controlled the reaction donors are active methylenes such as malonates and nitroalkanes, and the acceptors are activated olefins such as a,P-unsaturated carbonyl compounds. 

Both 1,3- and 1,4- bis[2-(2-arylethenesulfonyl)vinyl]benzenes, synthesized by a Knoevenagel reaction between the appropriate benzenedicarbaldehyde and 2-arylethenesulfonylacetic acid, behave as Michael acceptors and undergo double Michael addition reactions with activated methylene compounds. The products are phenylene-bis(tetrahy-drothiopyran 1,1-dioxides) 460 (Scheme 158) <2005JHC255>. 

A Michael addition consists of the addition of the enolate of an active-methylene compound, the anion of a nitroalkane, or a ketone enolate to an acceptor-substituted alkene. Such Michael additions can occur in the presence of catalytic amounts of hydroxide or alkoxide. The mechanism of the Michael addition is shown in Figure 13.67. The addition step of the reaction initially leads to the conjugate base of the reaction product. Protonation subsequently gives the product in its neutral and more stable form. The Michael addition is named after the American chemist Arthur Michael. 

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. 

A series of heterocycle derivatives of 1,1-bis-phosphonate (222), (223), (224) and (225) has been synthesized by Michael addition of 1,1-methylene bis-phosphonate to acceptors such as 5-arylidene rhodamines, 5-benzylidene-2-thiohydantoin, benzylidene or 2(2 -furyliden)-cyanomethyl-l,3-benzothiazoles... 

The synthesis of dialkyl 3-cyanopropylphosphonates by Michael reaction can be effected by two different routes, the phosphorns reagent being the nucleophile or the Michael acceptor. The Michael addition of compounds containing active methylene groups such as cyanomethylphosphonate, ... 

Several structurally different diketones (acetylacetone, methyl 2-oxocyclohex-ane carboxylate) and active methylene compounds (diethyl malonate, ethyl aceto-acetate) and thiols (methyl thioglycolate) underwent clean, fast, and efficient Michael addition with methyl vinyl ketone, acrolein, and methyl acrylate over NaY and Na beta zeolites [88] in high yield (70-80%). The reactions were performed in the absence of solvent, at room temperature, with 1 g catalyst per mmol donor. When HY zeolite was used instead of NaY formation of the desired Michael adduct was low and polymerization of Michael acceptor was the main reaction. 

Oxa- and aza-Michael additions followed by intramolecular cyclizations occur when propargyl alcohols are treated with a, -unsaturated nitroalkenes in the presence of t-BuOK in THF. Although exo-3-methylene tetrahydrofurans are usually the major products of these reactions, 3,4-dihydropyrans are also obtained in some cases, depending upon the substituents present within the donor and acceptor. Equation 59 shows the results of the reactions of propargyl alcohol with four nitroalkenes. Similar reactions of methyl propargylamine with these same acceptors give exclusively 3-methylenepyrrolidines."... 

The enantioselective phase-transfer catalyzed Michael addition of A-(diphenyl-methylene)glycine fert-butyl ester to several Michael acceptors such as methyl acrylate, cyclohex-2-enone and ethyl vinyl ketone was initially studied by Corey et al. employing 0(9)-aUyl-Af-9-anlhraceny]melhylcinchonidimum bromide (173) (Fig. 2.24) as catalyst and cesium hydroxide as base [272]. Different studies followed this pioneering woik, presenting diverse modifications over the standard procedure such as the employment of non-ionic bases [273], variations of the nucleophile functionality [274], and using new chiral phase-transfer catalysts, the most attention paid to this latter feature. For instance, catalyst 173 was successfully employed in the enantioselective synthesis of any of the isotopomers of different natural and unnatural amino acids... 

Nitroalkenes as Acceptors. The organocatalytic asymmetric Michael addition of activated methylenes to nitroalkenes is an important carbon-carbon bond-forming reaction, which provides access to synthetically useful enantioen-riched nitroalkanes. In 2003, Takemoto and co-workers [77] disclosed the first highly... 

Michael Addition. The Michael addition is a conjugate nucleophilic addition of a carbanion to electron-deficient olefins (Fig. 13) (54). A base is used to form the carbanion by abstraction of protons from activated methylene donors which attack the olefin acceptor forming an enolate ion. The mechanism is 1,4-addition of a nucleophile to the conjugated system. 

The nucleophilic properties of groups such as -NHR and -SH have been reported in natural Michael acceptor systems present in many natural products. Typical examples are the addition of the sulfhydryl groups of glutathione to the exocyclic methylene of sesquiterpene lactones (Fig. 6.7).14,41 Such interactions have been considered as responsible for the biological activity observed in many natural products, and this is again the case in Zwanenburg s hypothesis for strigolactones. 

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. 

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