Heterogeneous Michael reaction

The Michael reaction involving addition to carbon-carbon double bonds containing an electron-withdrawing group is catalysed by base. A variety of heterogeneous bases which can be reused are known, including alumina, KF on alumina and phenolates supported on silica, the last having proved particularly effective for addition of /3-keto esters to enones (Scheme 1.7). 

The first investigations on iron-catalyzed Michael reactions utilized Fe(acac)3 as catalyst. However, this metal complex is itself catalytically almost inactive. Yields of only up to 63% could be achieved, if BF3OEt2 is used as a co-catalyst [55], Polystyrene-bound Fe(acac)3 catalysts were also reported to give yields up to 63% [56], FeCl3 was used as a co-catalyst for clay-supported Ni(II). Yields achieved with this heterogeneous system ranged from 40 to 98% [57]. The double Michael addition of acrylonitrile to ethyl cyanoacetate is smoothly catalyzed by a complex generated from [Fe(N2) (depe)2] [depe = l,2-bis(diethylphosphano)ethane]. At 23 °C and after 36h, an 88% yield is obtained with 1 mol% of this Fe(0) catalyst [58]. 

Michael Reactions in Ionic Liquids and Heterogeneous Catalysis... 

Corma, A., Iborra, S., Rodriguez, I., Iglesias, M. and Sanchez, F.MCM-41 heterogenized chiral amines as base catalysts for enantioselective Michael reaction, Catal. Lett., 2002, 82, 231-242. 

Recently, a new one-pot process for the sequence (i)-(iii) has been realized under heterogeneous catalysis (Ballini et al 2007b). In fact, treating at room temperature according to the reaction in Figure 2.20 one equivalent of primary haloalkanes (57) and one equivalent of aldehyde, or conjugate enone, in the presence of IR A-402 nitrite and Amberlyst A-21, the nitroalkanols (60) or y-nitro ketones (61) were obtained, respectively, in a one-pot SN2-nitroaldol (Henry) or SN2-Michael reactions. 

Ballini, R., Barboni, L., and Palmieri, A. 2007b. A new heterogeneous one-pot process for both nitroaldol (Henry) and Michael reactions from primary haloalkanes via nitroalkanes. Synlett, 19 3019-21. 

One synthesis approach towards y-hydroxylated ionic liquids is a Michael-type addition of a protonated ammonium salt to a a, /l-an sal uni led carbonyl compound such as methylvinyl ketone yielding an oxobutyl functionalized cation. Intrinsically unstable due to retro-Michael reaction, this OS could however be transformed by a heterogeneous catalyzed hydrogenation reaction yielding a hydroxyl functionalized TSIL [24] (Fig. 7). 

As described in Sections 2.3.1.2 and 2.2.3, Choudary et al. recently revealed nanocrystalline magnesium oxide (NAP-MgO) as a recyclable heterogeneous catalyst [40, 45]. These authors extended the use of this new type of heterogeneous catalyst for the asymmetric Michael reaction of different acyclic enones with nitromethane and 2-nitropropane [69a]. In a Michael reaction of chalcone with nitromethane in THF solvent at -20°C, NAP-MgO/(lR,2R)-(-)-diaminocyclohexane (DAC) was found to be an excellent catalyst system (96% ee, 95% yield) (Scheme 2.32). This Michael reaction proceeds via the dual activation of both substrates (nucleophiles and electrophiles) by NAP-MgO. The Lewis basic site (O /O ) of the NAP-MgO activates the nitroalkanes, while the Lewis acid moiety (Mg /Mg )... 

The heterogeneity of the catalysis was confirmed by an investigahon of the liquid-phase supernatants over the solid-state catalysts after a catalytic cycle. Neither the ligand nor catalyst achvity in the Michael reaction were observed in the supernatant solution for the catalyst 3d. The heterogenized ALB catalyst 3d was recovered by syringe removal of the supernatant and rinsing with fresh solvent... 

The activation of enoxysilanes by fluoride ions provides a general method for carbon-carbon bond formation. The most extensively studied reactions are the cross-aldolization and the Michael reactions (see Scheme 23). These reactions can be activated, as noted earlier, by CsF in heterogeneous conditions or by NR4F in homogeneous... 

Traditionally, the Michael reaction is catalyzed by mild to moderately strong bases such as potassium t-butoxide, diisopropylamine [38], and tetramethylguani-dine [39] as homogeneous catalysts. The main disadvantages of this type of catalyst are the production of significant amounts of multiple Michael adducts, which are difficult to separate, and problems associated with catalyst recovery. These problems, plus recent interest in environmentally friendly solid catalysts, has led to the development of heterogeneous catalytic systems for this reaction. Examples of heterogeneous catalysts are those based on CsF and KF on alumina... 

The Michael addition of active methylene (and methine) compounds to activated 7t-systems is one of the more useful C—C bond-forming reactions (Scheme 5.10). Classical basic activation of the nucleophile can generate by-products from competing side reactions. Therefore, much effort has been dedicated to the development of catalysts for Michael reactions, mainly transition metals and lanthanides [92], The current challenge is the development of heterogeneous catalytic systems. 

Alkylamine and dialkylaminopyridine immobilized on acidic SA surfaces also act as a heterogeneous catalyst for the Michael reaction of nitrile compounds with electron-withdrawing alkenes (Scheme 6.18) [122, 123]. Doubly alkylated products were obtained with nitrile compounds possessing two a-hydrogen atoms (Scheme 6.19). 

Amorphous SA treated with 3-aminopropyltriethoxysilane (tertiary amine) and 3-(diethylamino) propyltrimethoxysilane (primary amine) acts as a heterogeneous catalyst for the one-pot synthesis of 1,3-dinitroalkanes from aldehydes and nitromethane (Scheme 6.21) [133]. Trifunctionality of the catalyst surface has been proposed. Aldehydes are activated by surface acid sites and they react with secondary amino group to form imine intermediates. The proton of nitromethane is abstracted by a tertiary amine group accompanied by nucleophilic attack of the deprotonated nitromethane on the imine, which is also assisted by a surface acid site, resulting in nitroalkenes. Another nitromethane is activated by the tertiary amine group, and the Michael reaction with nitroalkenes occurs to give the 1,3-dinitroalkanes. 

Quite recently, cross-linked dendrimer was also found to be a good support for Sc(III) catalyst [101]. The resultant material could be used in water as a catalyst for three-component Mannich-type reactions and Mukaiyama aldol reactions. A simple immobilization method of Sc species by using montmorillonite as a support has also been reported recently [102]. This method provides a highly active heterogeneous catalyst for Michael reactions under aqueous or solvent-free conditions. 

Mirza-Aghayan et al. [51] reported a heterogeneous Michael addition of N-acetylaminomalonate to chalcone, in the presence of a chiral phase-transfer catalyst (N-benzyl-N-methylephedrinium bromide) and potassium hydroxide. The reaction was realized in toluene as well as in the absence of the solvent The authors observed that sonication enhances the rate of the reaction by 4—5 times with no loss of enantioselectivity compared to conventional stirring. For the reaction carried out without solvent at 60 °C for 5 min the product was isolated in 82% yield and 40% ee. This phenomenon is connected to homogenization of the reaction mixture and mass transfer enhancement. 

Poly(vinyl alcohol) undergoes Michaels addition with compounds containing activated double bonds, including acrylonitrile (145—150), acrylamide (151—153), A/-methylolacrylamide (154—156), methyl vinyl ketone (157,158), acrolein (157), and sodium 2-acrylamido-2-methylpropanesulfonate (159). The reactions have been carried out under conditions spanning from homogeneous reactions in solvent to heterogeneous reactions occurring in the swollen powder or fiber. 

The Michael addition of nitroalkanes to election-deficient alkenes provides a powerful synthetic tool in which it is perceived that the nitro group can be transformed into various functionalities. Various kinds of bases have been used for this transformation in homogeneous solutions, or, alternatively, some heterogeneous catalysts have been employed. In general, bases used in the Henry reaction are also effective for these additions (Scheme 4.18).133... 

The heterogeneous catalytic systems have some advantages over homogeneous reactions. Chemical transformations under heterogeneous conditions can occur with better efficiencies, higher purity of products, and easier work-up. Ballini and coworkers have found that commercial amberlyst A-27 is the best choice for the Michael addition of nitroalkanes with [ substituted alkene acceptors (Eq. 4.111).150 The reaction is also carried out by potassium carbonate in the presence of Aliquat 336 under ultrasonic irradiation (Eq. 4.112).151... 

Several examples exist of the application of chiral natural N-compounds in base-catalyzed reactions. Thus, L-proline and cinchona alkaloids have been applied [35] in enantioselective aldol condensations and Michael addition. Techniques are available to heterogenize natural N-bases, such as ephedrine, by covalent binding to mesoporous ordered silica materials [36]. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

Silica-supported Lewis acids are useful catalysts with microwave irradiation for conjugate additions. The silica-supported catalysts are obtained by treatment of silica with ZnCh [Si(Zn)], Et2AlCl [Si(Al)] or TiCl4 [Si(Ti)] [ 150-152], The Michael addition of methyl a-acetamidoacrylate (196) with indole (2) under Si(M) heterogeneous catalysis assisted by microwave irradiation afforded the alanine derivative 197 within 15 min and/or bis-indolyl 198, depending on the reaction conditions (Scheme 45) [153]. While the bis-indolyl product 198 is only formed when Si(Zn) was used as catalyst, the alanine derivative 197, as a single product is formed under thermal heating in a yield of 12%. The best yields were observed with Si(Al) (Table 5). The product 198 was obtained by elimination of acetamide followed by a-Michael addition between intermediate 199 with a second mole of indole. 

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