Methylene compound Michael reaction

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 ... 

Michael condensations are catalyzed by alkaU alkoxides, tertiary amines, and quaternary bases and salts. Active methylene compounds and aUphatic nitro compounds add to form P-substituted propionates. These addition reactions are frequendy reversible at high temperatures. Exceptions are the tertiary nitro adducts which are converted to olefins at elevated temperatures (24). 

As far as the stereochemistry concerns, when the cyclization occurs through a Michael reaction, the thermodynamic product is generally obtained, but some exceptions have been observed such as that of A-acetyl glucosamine protected as 4,6-benzylidene, the reaction of which with [(ethoxycarbonyl)methylene]triphenylphosphorane afforded the ot-C-glycosyl compound stereoselectively.28... 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

There are some examples of pyran synthesis by Method 2, which involves the reactions of unsaturated ketones with methylene-active nitriles. In a typical case of Method 2, the Michael reaction of a,j5-unsaturated carbonyl compounds 26 (77TL1835, 78JHC57,... 

The activated Ba(OH)2 catalyst was successfully used for the Michael reactions of chalcone with active methylene compounds 290), as well as for the Michael reaction of other benzylidene derivatives of acetone, butanone, 3-methylbutanone, 4-methyl-2-pentanone, and 3,3-dimethylbutanone with ethyl acetoacetate and diethyl malonate. The reaction with diethyl malonate gave good yields of the Michael adduct (between 65 and 93%), whereas with ethyl acetoacetate various products were obtained, depending on temperature and amount of catalyst (Scheme 43) 291). Thus, by varying the reaction conditions, it was possible to obtain a single product with practically 100% selectivity, the yields being higher than those obtained with soluble catalysts, such as KOH, NaOH, or piperidine. 

The addition of nitromethane (56% yield/168h 87% ee) or methyl a-cyanoacetate (94% yield/52h 82% ee) as alternative CH-acidic methylene compounds required increased reaction temperatures (60 to 80 °C) to furnish the adducts 7 and 8. As exemplarily depicted in Scheme 6.69 for benzylic alcohol thiourea 12 catalyzes the transformation of the obtained malononitrile Michael products to the respective carboxyhc acid derivatives (89% yield/88h). This method of derivatization also described for methanol (87% yield/24h rt), benzyl amine (77% yield/3h rt), and N,0-dimethylhydroxyamine (75% yield/20h 60°C) as nucleophiles was reported to be feasible as a one-pot strategy without isolation of the initially formed Michael adduct [222]. 

Methylene iodide, 300 Michael reaction, 912, 913, 914 Michler s ketone, 982 Mixed melting point, 34, 229, 1028 Mixtures of organic compounds, qualitative analysis of, 1090 -1100 preliminary examination, 1093, 1094 ... 

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. 

Keywords active methylene compound, chalcone, Michael reaction, alumina, microwave irradiation... 

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>. 

The application of achiral cationic zirconocene compounds for methyl methacrylate polymerisation, e.g. a mixture of [Cp 2ZrMe(THF)]+[BPh4] and Cp 2ZrMe2 in methylene chloride solution, leads to the formation of syndio-tactic poly(methyl methacrylate). The species responsible for propagation are believed to be the bimetallic ones, involving cationic zirconium enolate and neutral zirconocene, which facilitates the process. Propagation is postulated to occur via the Michael reaction between the coordinating monomer and the cationic enolate [537] ... 

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. 

Interestingly, the reaction of active methylene compounds having a nitrile group with a,/l-unsaturated carbonyl compounds give Michael adducts without contamination by the corresponding aldol products (Eq. 61) [89-92]. Murahashi and coworkers [89-91] proposed that the addition of the C-H bond to a low-valent ruthenium constitutes the initial step. Recently, Takaya and Murahashi [94] applied their aldol and Michael addition reactions to solid-phase synthesis using polymer-supported nitriles. 

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. 

Cyclic active-methylene compounds react in Michael reactions not only with a,/J-unsaturated acceptors, but also with acetylene dicarboxylates, propiolates, and their derivatives (Scheme IV/8). If, for instance, acetylene carboxylic esters are added to a variety of cyclic-active methylene compounds, ring-expanded products generally are formed directly. In other cases, it is possible to isolate the intermediate cyclobutene derivatives, which can be converted to the ring enlarged compounds in a second reaction step. 

Enones like this, with two hydrogen atoms at the end of the double bond, are called exo-methylene compounds they are very reactive, and cannot easily be made or stored. They certainly cannot be made by aldol reactions with formaldehyde alone as we have seen. The solution is to make the Mannich base, store that, and then to alkylate and eliminate only when the enone is needed. We shall see how useful this is in the Michael reaction in Chapter 29. 

An unusual methylene-transfer reaction along with [4-I-4] cyclodimerization was observed, when 5,A-d5-tert-butylthiophene 1-oxide was refluxed in toluene with 2-methylene-l,3-dimethylimidazolidine <2001GL758>. Initially a Michael adduct is formed by the addition of 104 to 103. This adduct upon intramolecular cyclization gives the cyclopropyl compound with elimination of a carbene. This on further oxygen-transfer reaction gives products 105 and 106. The 1,4-Michael adduct on further Michael reaction with 103 produces another adduct, which on cyclization followed by elimination of 104 gives 107 (Scheme 25). 

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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