Michael condensation reaction

Michael condensation reaction Arthur Michael (U.S.) discovers the Michael condensation reaction, the transformation of an unsaturated compound into a saturated compound with an additional carbon atom. [1887]... 

Cellulose ethers are prepared by nucleophilic reactions, Michael condensation reactions and epoxidations. The most commonly used nucleophilic reaction is the reaction of alkali cellulose with alkyl halide (equation 4)... 

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... 

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). 

The best method to achieve a high regioselectivity is the use of preformed enolates. A double annulation reaction is possible if, for example, a diketone such as 11 is used as starting material. The product of the Michael addition 12 can undergo two subsequent aldol condensation reactions to yield the tricyclic dienone 13 ... 

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,... 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

Stork reaction (Section 23.11) A carbonyl condensation between an enamine and an a,/3-unsaturated acceptor in a Michael-like reaction to yield a 1.5-dicarbonyl product. 

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]. 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

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... 

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%). 

With a.-bromo Michael acceptors. Condensation reaction of 2-aminothiazoline with a-bromo-a,/3-unsaturated compounds, commercially available or generated in situ, provided a route to functionalized 2,3,5,6-tetrahydro-imidazo[2,l-3]thiazoles 411 (Equation 187) <1994H(38)2593>. 

Another advantage of this method is that no catalyst is needed for the addition reaction this means that the base-catalyzed polymerization of the electrophilic olefin (i.e., a,j8-unsaturated ketones, esters, etc.) is not normally a factor to contend with, as it is in the usual base-catalyzed reactions of the Michael typCi It also means that the carbonyl compound is not subject to aldol condensation which often is the predominant reaction in base-catalyzed reactions. An unsaturated aldehyde can be used only in a Michael addition reaction when the enamine method is employed. 

Scheme 43 Multicomponent Michael/Michael/aldol condensation reaction...

Michael Addition (Condensation, Reaction) The addition of a carbon nucleophile to an activated unsaturated system. 

The Michael-induced condensation reaction between acrylates and aldehydes is dramatically accelerated by high pressure, cutting the reaction time from several days to a few minutes. ... 

C.4. Sti/le Couplings, Knoevenagel Condensations, and Michael Addition Reactions... 

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. 

Closure of the nonaromatid ring of the anthracycline system has been effected by condensation of a 2-(3-oxobutyl)anthraquinone with nitromethane [135]. After the initial Henry reaction, a Michael-type reaction is induced by the quinone carbonyl in spite of the high electron density of the aromatic ring to be attacked, and the site of attack being a donor. 

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... 

The pentane-1,5-dione is usually formed in situ by aldol- or Michael-type reactions (203 — 204 — 200). Thus, acetaldehyde (203 R = H, R = Me) and ammonia give 4-picoline and 3-ethyl-4-methylpyridine by formation of the intermediate (205), condensation with another molecule of MeCHO, and subsequent dehydrogenation. The same reaction also yields 2-picoline and 5-ethyl-2-methylpyridine via the intermediate (206). Such reactions are used industrially. 

A very useful method for generating 3 (2H)- dihydrofuranones is based on the Michael addition of anions derived from a-hydroxyesters to a,/3-unsaturated substrates (Scheme 82). The intermediate anion attacks the adjacent ester moiety via a Dieckmann condensation reaction to produce a substituted furanone ring which usually bears useful functionality. Overall yields of 45-60% have been obtained for this reaction. 

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