Michael addition, acidic solvents

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. 

Since mild activation conditions appear to be important, a number of solution activation conditions were tested. PAMAM dendrimers are comprised of amide bonds, so the favorable conditions for refro-Michael addition reactions, (low pH, high temperature and the presence of water) may be able to cleave these bonds. Table 1 shows a series of reaction tests using various acid/solvent combinations to activate the dendrimer amide bonds. Characterization of the solution-activated catalysts with Atomic Absorption spectroscopy, FTIR spectroscopy and FTIR spectroscopy of adsorbed CO indicated that the solution activation generally resulted in Pt loss. Appropriate choice of solvent and acid, particularly EtOH/HOAc, minimized the leaching. FTIR spectra of these samples indicate that a substantial portion of the dendrimer amide bonds was removed by solution activation (note the small y-axis value in Figure 4 relative... 

There are only few examples of organic reactions catalysed effectively by Lewis acids which can be carried out in pure water without any organic co-solvent. While water can be used successfully for the uncatalysed Michael addition of 1,3-diketones (Table 4, entry D)22, the corresponding reaction of /i-kctocsters does not give satisfactory results. On the other hand, the Yb(OTf)3 catalysed Michael reaction of various /i-ketoesters (Table 21, entry A)257 and a-nitroesters (Table 21, entry B)258 takes place. 

The fluoride ion is an effective catalyst for Michael additions involving relatively acidic carbon compounds.85 The reactions can be done in the presence of excess fluoride, where the formation of the [F—H—F ] ion occurs, or by use of a tetraalkylammonium fluoride in an aprotic solvent. 

Williams group observed low enantioselectivities for the Michael addition of a prochiral nucleophile, ethyl 2-cyanopropionate 623, to methyl vinyl ketone 624 catalyzed by chiral platinum complexes (Scheme 8.196)." The NMR analysis indicated that these cationic Pt complexes act as Lewis acids toward nitriles. The X-ray crystal structure as well NMR analysis showed that the solvent ligand that is readily displaced by an organic substrate is situated cis to the nitrogen donor in the Pt complex and, therefore, is in a chiral pocket created by the oxazoline ring. 

As is to be expected, an alkynic ketone undergoes a Michael addition with a carbanion, leading eventually to a pyranone (50JA1022). Using malonic esters, a 3-alkoxycarbonyl derivative results, which is hydrolyzed to the 2-oxopyran-3-carboxylic acid under alkaline conditions, but to the pyranone by sulfuric acid. Rapid ester exchange is observed with the initial products, the alcohol used as solvent determining the nature of the alkyl group in the 3-carboxylic esters (Scheme 90). 

The reaction of 3-(3,4-dimethoxyphenyl)propanoic acid with thallium(III) trifluoroace-tate in the presence of boron trifluoride etherate leads to a mixture of the dihydrocoumarin (574) and the spirolactone (572) (78JOC3632). It is suggested that these products arise through an initial one-electron oxidation to the radical cation, the fate of which may vary. Thus, intramolecular reaction with the carboxyl group gives the radical (571) and eventually the spirolactone. Alternatively, capture of the radical ion by solvent and further oxidation affords the radical (573), whereupon an intramolecular Michael addition to the carboxyl group and aromatization lead to the dihydrocoumarin (Scheme 218) (81JA6856). 

Kotsuki et al.909 have developed a method to effect the Michael addition of [3-ketoesters with ethyl acrylate in the presence of triflic acid under solvent-free conditions [Eq. (5.335)]. Nonactivated cyclohexanones as Michael donors and a,/3-unsaturated ketones as acceptors are also reactive. The use of menthyl acrylates did not result in any significant asymmetric induction. 

A hydroxyapatite-bound La complex (LaHAP), prepared by using a cation-exchange method, has been reported to function as an efficient heterogeneous catalyst for the Michael addition of 1,3-dicarbonyls to enones under aqueous or solvent-free conditions. Further application to an asymmetric version by a fluoroapatite-bound La complex catalyst modified with (R,R)-tartaric acid has also been described.171... 

The amino benzopyran of step 5 (2.0 g) and dimethyl acetylene dicarboxylate (1.24 g 1.01 ml) were refluxed in ethanol (30 ml) for 26 hours. The reaction mixture was cooled to 0°C and the insoluble yellow-brown solid was collected by filtration and washed with a little ethanol and dried to give 2.0 g of a product which was a mixture of maleic and fumaric esters obtained by Michael addition of the amine to the acetylene. This mixture of esters (2.0 g) was treated with polyphosphoric acid (30 ml) and heated on the steam bath with stirring for 20 minutes. The reaction mixture was then poured onto ice and stirred with ethyl acetate. The organic layer was separated, washed with water and dried. The solvent was evaporated to leave 1.6 g of a yellow orange solid. Recrystallisation of this solid from ethyl acetate gave the required product as fluffy orange needles, mp 187°-188°C. 

To the extent that the enolate resulting from conjugate addition at the (3-carbon can be stabilized, the rate of this reaction pathway is enhanced. For example, (3-Michael additions are observed for MVK, acrolein, and acetylenic electrophiles even without the presence of a Lewis acid. Furthermore, MVK reacts with the 2,5-dimethylpyrrole complex (22) to form a considerable amount of (3-alkylation product, whereas only cycloaddition is observed for methyl acrylate. The use of a Lewis acid or protic solvent further enhances the reactivity at the (3-position relative to cycloaddition. While methyl acrylate forms a cycloadduct with the 2,5-dimethylpyrrole complex (22) in the absence of external Lewis acids, the addition of TBSOTf to the reaction mixture results in exclusive conjugate addition (Tables 3 and 4). 

Several iodine-catalyzed organic transformations have been reported. Iodine-catalyzed reactions are acid-induced processes. Molecular iodine has received considerable attention because it is an inexpensive, nontoxic and readily available catalyst for various organic transformations under mild and convenient conditions. Michael additions of indoles with unsaturated ketones were achieved in the presence of catalytic amounts of iodine under both solvent-free conditions and in anhydrous EtOH (Scheme 19) [85,86]. l2-catalyzed Michael addition of indole and pyrrole to nitroolefins was also reported (Scheme 20) [87]. 

The lanthanide triflate remains in the aqueous phase and can be re-used after concentration. From a green chemistry viewpoint it would be more attractive to perform the reactions in water as the only solvent. This was achieved by adding the surfactant sodium dodecyl sulfate (SDS 20 mol%) to the aqueous solution of e.g. Sc(OTf)3 (10 mol%) [145]. A further extension of this concept resulted in the development of lanthanide salts of dodecyl sulfate, so-called Lewis acid-surfactant combined catalysts (LASC) which combine the Lewis acidity of the cation with the surfactant properties of the anion [148]. These LASCs, e.g. Sc(DS)3, exhibited much higher activities in water than in organic solvents. They were shown to catalyze a variety of reactions, such as Michael additions and a three component a-aminophosphonate synthesis (see Fig. 2.44) in water [145]. 

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