Michael addition, acidic double

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 ... 

Another impo2rtant P—C-hond-forming reaction is the base-cataly2ed Michael addition to activated double bonds. For example, dimethyl phosphite can be added to dimethyl maleate to yield tetramethylphosphonosucciaate [2788-26-3] (TMPS), an iatermediate ia the synthesis of 2-phosphonobutane-l,2,4-tricarboxyhc acid [37971-36-1] (PBTC) with 98% yield (20). 

A surprising exception has been reported with evidence for a cleavage reaction in the case of divinyl sulphone. In non-aqueous and slightly acidic media, the behaviour of a., ji-unsaturated aromatic sulphones is also complex (see Table 7) since the cleavage and the saturation may compete. Strongly electrophilic double bonds undergo Michael additions in aprotic solvents by slowly protonated anions. Transfer of labile hydrogen may also lead to unactivated bases. It is noteworthy that in numerous cases (Table 6) the saturation is the preferred route. 

Double Michael additions of nitro compounds bearing tethered acidic carbons to 3-butyn-2-one under NaH catalysis give nitrocyclohexanes with high stereoselectivity. The products are transformed into traws-fused bicyclic compounds via the Dickmann reaction on treatment with base. (Eq.4.129).176... 

An acid-catalyzed double-Michael addition of water to the bridged bis-dioxine moiety in a larger macrocyclic framework has been described by the Kollenz group (Scheme 6.134) [269]. While conventional reaction conditions failed to provide any of the desired functionalized 2,4,6,8-tetraoxaadamantane product, microwave heating of the hydrophobic macrocyclic bisdioxine in a 1 1 mixture of 1,2-dichloroethane and acetic acid containing excess concentrated hydrochloric acid at 170 °C for 40 min provided a 35% isolated yield of the desired oxaadamantane compound. 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

Dimerization of methyl crotonate has been carried out with alkaline earth metal oxides as basic catalysts 15). The reaction proceeds by Michael addition, which is initiated by abstraction of an allylic hydrogen of methyl crotonate by the basic site to form the allylic carbanion, which attacks a second methyl crotonate molecule at the jS-position to form a methyl diester of 3-methyl-2-vinylglutaric acid. The diester undergoes a double bond migration to form the final E- and Z- isomers of 3-ethylidene-3-methylglutaric acid dimethyl ester (MEG) (Scheme 22). 

APROTIC DOUBLE MICHAEL ADDITION PREPARATION OF 1,3-DIMETHYL-5-OXOBICYCLO[2.2.2]OCTANE-2-CAR80XYLIC ACID... 

In addition to these extensive studies on electrophile-mediated intramolecular peroxydation of electron-rich C=C bonds, some examples of intramolecular hydroperoxide addition to electron-poor C=C bonds have been described. For example, several racemic analogues 371 of the naturally occurring plakinic acid were readily obtained by peroxymercuration followed by hydridodemercuration of the dienic acids 370 (Scheme 95 f °. Intramolecular Michael addition of hydroperoxide function to the double... 

This procedure is an excellent method to prepare 1,4-dicarbonyl compounds 163 (Scheme 7.48) and, using triethylamine, has been extended to include other activated double bonds.Thus, the starting a-amino acids can be considered as nucleophilic acyl equivalents. Representative examples of 5(47/)-oxazolones prepared via Michael additions are shown in Table 7.18 (Fig. 7.20). 

Forsyth, C.J. Hao, J. Aiguade, J. (2001) Synthesis of the (-i-)-C26-C40 domain of the azaspiric acids by a novel double intramolecular hetero-Michael addition strategy. Angew. Che. Int. Ed. Engl., 40, 3663-7. 

Primary amines may interact with double bonds in a reaction analogous to a Michael addition reaction (e.g., fluvoxamine maleate, where the fluvoxa-mine primary amine group can interact with the double bond in the maleic acid counterion). Examples of excipients that contain double bonds include sodium stearyl fumarate and sorbitan monooleate. 

In a closely related asymmetric reaction, the required absolute stereochemistry at C-4 was established via a Michael addition of a cuprate reagent to a dihydropiperidinone (Scheme 12). The stereochemistry at C-3 was introduced in the form of piperidinone 61, a compound readily available from (5)-glutamic acid. Protection of both the amino and alcohol functionalities was achieved using standard reaction conditions to give 62. Introduction of the A -double bond was accomplished via phenylselenation of the lithium... 

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