Michael condensation

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). 

Warfarin [81-81-2] (6) is prepared by the Michael condensation of benzyHdene acetone with 4-hydroxycoumarin (86). It is used as a rodenticide (see Poisons, commercial) and in anticoagulant therapy. 

Michael condensation is the addition of a compound with an active methylene group to an a, p-unsaturated keto-compound... 

Thus, condensation of isoniazide with acetone at the basic nitrogen gives the corresponding Shiff base (8). Catalytic reduction affords the antidepressant, iproniazid (9). Addition of the same basic nitrogen to methyl acrylate by Michael condensation leads to the 3-amino ester (10). This is converted to the amide, nialamide (11), on heating with benzylamine. 

Further work in this area showed that only one of the cou-marin rings was needed for biologic activity. Condensation of the hydroxyacetophenone, 4, with diethyl carbonate affords 4-hydroxycoumarin (2). The reaction may involve the 3-ketoester (5) cyclization of this would afford 2. Alternately, the reagent may first give the 0-acyl derivative cyclization as above will give the same product. Michael condensation of the coumarin with benzalacetone (6) affords the anticoagulant warfarin (named after its place of origin Wisconsin Alumni Research Foundation,... 

Anionic Diels-Alder reactions have been studied less extensively with the interest having been focused mainly on the cycloaddition of enolates of a,/l-unsaturated ketones with electron-poor olefins [24] (Equations 1.8 and 1.9). These reactions are fast and stereoselective and can be regarded as a sequential double Michael condensation, but a mechanism involving a Diels-Alder cycloaddition seems to be preferred [24b,f, 25]. 

An impressive diastereoselective domino Mannich/Michael condensation of polymer-bound (polystyrene) glycosylimines 10-32 with 1,3-butadiene 10-33 has been reported by Kunz and coworkers [11]. These authors obtained dihydropiperid-inones 10-34 in good yield and high diastereoselectivity (Scheme 10.8). 

The pyrrolo[2,3-c/]pyrimidine anticancer agent is prepared utilizing, as a key sequence, Michael condensation of 2,6-diamino-4(.37/)-pyrimidinone with nitroalkenes, followed by the Nef reaction that leads to the annulated pyrrole ring (Eq. 10.67).98... 

A very interesting organocatalyzed one-pot Michael addition/aldol condensation/Darzens condensation has been reported for the asymmetric synthesis of epoxy-ketones <06JA5475>. An initial asymmetric Michael condensation between 16 and 17 is catalyzed by proline derivative 18. Intermediate 19 then undergoes an aldol condensation followed by a stereoselective Darzens condensation to provide epoxy-ketone 20 in moderate yield and with surprisingly good enantiomeric excess. 

One-pot syntheses of diaryl-a-tetralones by Michael condensation and subsequent Robinson annulation reactions of isophorone with chalcones were performed efficiently in a solvent-free PTC system under the action of MW irradiation. Compared with conventional heating substantial rate enhancements were observed, within very short reaction times, by use of microwaves (Eq. 59 and Tab. 5.31). They were far better than those achieved by the classical method (NaOEt in EtOH under reflux for 24 h 40-56%). 

N-Methyb/>-toluenesulfonamide, 34, 97 /3-Methyl-S-valerolactone, 35, 87 Methyl vinyl ether, 34, 29 Methyl vinyl ketone, 37, 19 Michael condensation between 3-nitropro-pane and methyl acrylate, 32, 86 Monochlorourea, 30, 24, 25, 26 Monoethanolamine, 32, 19 Monoethyl malonate, 37, 34 Mucobromic acid, 32, 95... 

An alternative solution to blocking groups, is the introduction of an activating group at the less reactive position in order to favour the attack of the reagent at this site of the molecule. Such is the case, for instance, in the synthesis of helminthosporal by Corey [24]. In the first step of the synthesis, which involves a Michael condensation of carvomenthone (36) with methyl vinyl ketone to give the... 

Several condensation routes to 2,3 -bipyridinones have been reported. Thus 3-acetylpyridine and nicotinaldehyde were condensed to the a,/ -unsat-urated ketone 45, which reacted in a Michael condensation with l-(car-bamoylmethyl)pyridinium chloride (46) to give 2,4-di(3-pyridyl)-6-pyridone (47). Compound 47 was converted to the alkaloid nicotelline 10 by replacement of the hydroxyl group of 47 by chlorine, followed by reductive dehalogenation. Related condensations have been described, including the synthesis of 4,6-diphenyl-2,3 -bipyridine. Similarly, aldehyde 48 was condensed with cyanoacetamide (49) to afford 2-(3-pyridyl)-5-cyano-6-pyridone (50), the cyano group of which was hydrolyzed and decarbox-ylated to 2,3 -bipyridin-6-one. Several modifications and extensions of... 

N-Alkylation of oxazolo[4,5-4]pyridines can be achieved in a number of ways. Viaud et al. have reported direct N-alkylation by reaction with alkyl halides (Equation 27 Table 23) or Michael condensation with a range of olefins (Equation 28 Table 24) <1996TL2409>, both methods affording the desired products in good yields. 

Table 24 Michael condensation of oxazolo[4,5-fa]pyridines (Equation 28) <1996TL2409>...

An elegant extension of this approach is the combination of the nitroalkanes to ketone reaction with prior EGB-catalysed Michael condensation involving nitronate anions. Azobenzene works well as the catalyst probase and the condensation and... 

Jeio and Kalad4 have developed another, more efficient, route to 1-hydroxymethylpyrrolizidine. A two-step Michael condensation of nitromethane with ethylmethoxycrotonate and then with ethyl acrylate resulted in ethyl j8-methoxymethyI-y-nitropimelate (74). The latter yields 2-(2-carboethoxy-l-methoxymethylethyl)pyrrolid-5-one (75) on hydrogenation over Raney nickel and 2-(3-hydroxy-1-... 

Reaction of carbanions with dialkynic ketones, the so-called skipped diynes, can produce pyranones through an initial Michael condensation. It should be noted however that diynones are vulnerable to attack at several sites and that mixed products can be formed. Addition of the anions derived from diethyl malonate and ethyl cyanoacetate to hepta-2,5-diyn-4-one (313 R1 = Me) gives the pyranones (314 R2 = C02Et or CN Scheme 91) (74JOC843). The former carbanion reacts similarly with the diynone (313 R1 = Bun) (68T4285). The second alkyne moiety appears to have little effect on the course of the reaction, which parallels the synthesis of pyranones from monoalkynic ketones. 

In the case of a ketone with two active methylene groups, such as dibenzylketone, the reaction can take two courses. The pyranone results from Michael addition to the alkyne followed by normal ring closure. The second product, a resorcinol, arises from either Michael condensation followed by an intramolecular Claisen condensation or the order of these two reactions may be reversed (60JCS5153). 

A Michael condensation also features in a synthesis of 4-substituted 3-cyanocoumarins (81ZOR2630). 

The use of ethyl acetoacetate in this route allows the formation of a 3-ethoxycarbonyl-pyrylium salt (68JOC1102). Some care is appropriate in this type of reaction in the absence of an added hydride acceptor, however, since the chalcone may undergo a Michael condensation with the intermediate 1,5-dione, leading to side products. 

In general, the mechanisms of nucleophilic additions to double bonds have not been as much studied or systemized as those of electrophilic addition. Reactions 7.51 and 7.52 are examples of the very useful Michael condensation, in which a carbanion adds to an a,/ -unsaturated carbonyl or nitrile compound. The usefulness of these reactions arises from the fact that the number of ways of building longer carbon chains from smaller ones is limited. 

The mechanism of the Michael condensation is not actually a 1,2-addition as implied in Equations 7.51 and 7.52, but rather a 1,4-addition as shown in Equation 7.54. Protonation occurs first on the oxygen atom because 64b contributes more to the overall structure of the anion than 64a. The stereochemistry of 1,2-addition in the Michael condensation is therefore irrevelant to the mechanism of the condensation.124 Other nucleophilic additions to alkenes125 and alkynes126 go either syn or anti depending on the particular reaction. 

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