Chalcone Michael reactions

Keywords active methylene compound, chalcone, Michael reaction, alumina, microwave irradiation... 

Heterobimetallic asymmetric complexes contain both Bronsted basic and Lewis acidic functionalities. These complexes have been developed by Shibasaki and coworkers and have proved to be highly efficient catalysts for many types of asymmetric reactions, including catalytic asymmetric nitro-aldol reaction (see Section 3.3) and Michael reaction. They have reported that the multifunctional catalyst (f )-LPB [LaK3tris(f )-binaphthoxide] controls the Michael addition of nitromethane to chalcones with >95% ee (Eq. 4.140).205... 

The reactivity of phenylacetic esters with electron-deficient alkenes is generally fairly poor, even under phase-transfer catalytic conditions. The reaction with cinnamic esters is often accompanied by hydrolysis and the yield of the adduct with chalcone is generally <60% [10]. The activity of the methylene group towards alkylation has been enhanced by the initial complexation of the phenyl ring with chromium tricarbonyl (see Section 6.2), but this procedure has not been applied to the Michael reaction. 

Rare earth-Li-binaphthooxides Aza-Michael reaction on chalcone High (+)-NLE 55... 

Sods [80] reported novel thiourea catalyst 134 in an efficient Michael reaction between nitromethane and chalcones to access chiral nitrocarbonyls in high enan-tioselectivity (Scheme 30). 

The activated Ba(OH)2 catalyst was successfully used for the Michael reactions of chalcone with active methylene compounds 290), as well as for the Michael reaction of other benzylidene derivatives of acetone, butanone, 3-methylbutanone, 4-methyl-2-pentanone, and 3,3-dimethylbutanone with ethyl acetoacetate and diethyl malonate. The reaction with diethyl malonate gave good yields of the Michael adduct (between 65 and 93%), whereas with ethyl acetoacetate various products were obtained, depending on temperature and amount of catalyst (Scheme 43) 291). Thus, by varying the reaction conditions, it was possible to obtain a single product with practically 100% selectivity, the yields being higher than those obtained with soluble catalysts, such as KOH, NaOH, or piperidine. 

Scheme 6.139) [293]. Ricci and co-workers explained the outcome of their aza-Michael reaction with the mechanistic picture visualized in Scheme 6.140 C9-epi-QN -derived thiourea 121 displayed a bifunctional mode of catalysis, which simultaneously activated both the chalcone Michael acceptor and the donor O-benzylhydroxylamine through explicit hydrogen bonding. 

Thiourea catalyst 139 was also screened in the asymmetric Friedel-Crafts reaction between 2-naphthol trans-nitrostyrene (73% yield 0% ee 18 h in toluene at -20 °C and 10 mol%) [277], in the asymmetric aza-Michael reaction of O-benzyl-hydroxylamine to chalcone (72% conv. 19% ee 72 h in toluene at 20 °C and 20mol% catalyst loading) [293], and in the asymmetric Morita-BayUs-HiUman [176, 177] reaction between cyclohexenecarbaldehyde and 2-cyclohexene-l-one (20% yield 31% ee 46 h at rt and 20mol% DABCO and 139) [310]. In aU these transformations, thiourea 139 proved to be not competitive to the organocatalysts probed for these transformations under identical screening conditions and thus was not employed in the optimized protocols. 

Complex LSB 9 is readily prepared either by the reaction of La(0 Pr)3 with 3 equiv. of B1NOL followed by the addition of NaO Bu (3 equiv.) or by the reaction of LaCl nfLO with sodium binaphthoxide. The complex 9 is stable to oxygen and moisture and has been proven to be effective in the catalytic Michael reaction of various enones with either malonates or p-keto esters. The Michael adducts with up to 92% ee were obtained in almost quantitative yield. Typical results with malonates are summarized in Table 8D.1 (Ln = lanthanide) [18], In general, the use of THF as solvent gave the best results except for the case of the LSB-catalyzed reaction of rmns-chalcone with dimethyl malonate, wherein the use of toluene was essential to give the adduct with good enantiomeric excess. The effects of the central metal (La, Pr, and Gd) on asymmetric induction were also examined in the same reaction, and LSB was found to be the best catalyst. 

Protected glycine derivatives have been used as the nucleophilic partner in enantioselective syntheses of amino acid derivatives by chiral PTC (Scheme 10.9). Loupy and co-workers have reported the addition of diethyl acetylaminomalonate to chalcone without solvent with enan-tioselectivity up to 82% ee [44]. The recent report from the Corey group, with catalyst 8a used in conjunction with the benzophenone imine of glycine t-butyl ester 35, discussed earlier, results in highly enantioselective reactions (91-99% ee) with various Michael acceptors (2-cyclo-hexenone, methyl acrylate, and ethyl vinyl ketone) to yield products 71-73 [21], Other Michael reactions resulting in amino acid products are noted [45]. 

Keywords chalcone, iV-acetylaminomalonate, Michael reaction, phase transfer reaction... 

Copper(II) tetrafluoroborate Cu(BF4)2xH20 has been identified as a new and highly efficient catalyst for Michael addition of thiols to o ,/5-unsaturated carbonyl compounds under solvent-free conditions and in H20 at room temperature. The reactions are very fast and are completed within 2 min to 1 h. The rate of thiol addition is dependent on the steric hindrance at the /3-carbon of the o ,/3-unsaturated carbonyl substrate. In the case of chalcones, the reactions are best carried out in MeOH as solvent.237... 

Apart form the aforementioned highly enantioselective hetero-Diels-Alder reactions, that proceed with very low catalyst loadings, the catalytically accessible enolates have also been used for related intramolecular Michael reactions (Philips et al. 2007) and for the desym-metrization of 1,3-diketones yielding cyclopentenes via an intramolecular aldol reaction (Wadamoto et al. 2007). The formation of cyclopentenes, however, presents a special case, so—depending on the stereochemical nature of the enone substrates (s-cis or s-trans) and the stereochemistry of the final products—two different mechanisms are discussed in the literature. Whereas /ran.v-cycl open (cries are proposed to be available upon conjugate addition of a homoenolate to chalcones,... 

Benzylquininium chloride has been studied as a catalyst for the asymmetric Michael reaction. Reaction of amidoma-lonate (5) and chalcone (4) with catalytic base and a variety of chiral, nonracemic ammonium salts in the absence of solvent produced (6) in yields of 41-68% and 20-68% ee (eq 2). The quinine-derived salt (1) was of intermediate effectiveness (38% ee, 47% yield) when compared to ephedrine-based catalysts. Although (1) was not specifically tested with regard to solvation effects, it is suggested that increased aggregation of reactive species under solid-liquid PTC conditions leads to enhanced organization and selec-... 

Whereas a stoichiometric amount of TiCU was used in the original liquid-phase reactions [87], it was found that a catalytic amount of Sc(OTf)3 was effective in solid-phase Michael reactions of PSSEEs with a,/3-unsaturated ketones [88], Whereas the 1,5-dicarbonyl compound was obtained in 38 % yield in the model reaction of PSSEE 5 with chalcone and a stoichiometric amount of TiCU, the yield was improved to 93 % by use of 20 mol % Sc(OTf)3 as a catalyst in the same reaction. In addition to improvement of the yield, it should be noted that after the reaction Sc(OTf)3 was readily removed from the product resins by filtration because it is soluble in water the insoluble titanium residue which appeared after quenching the reaction by addition of water in the TiCU-mediated reaction was often difficult to remove and would contaminate the product resins. 

Michael reactions. The addition of amines to chalcones can be accomplished in aqueous suspensions of the reactants in the presence of cetyltrimethylammonium halides, i.e., organic solvents are not required. 

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 )... 

A similar dramatic influence of ionic liquid was also reported by Ranu s group in the Michael reaction of active methylene compounds with methyl vinyl ketone and methyl acrylate in the presence of an ionic liquid, 1-butyl-3-methylimidazolium hydroxide ([bmImjOH). Interestingly, open-chain 1,3-dicarbonyl compounds reacted with methyl vinyl ketone and chalcone to give the usual monoaddition products, whereas the same reactions with methyl acrylate or acrylonitrile provided exclusively bis-addition products (Scheme 5.55). 

Some more significant applications. Aldol reaction in ionic liquids is catalyzed by 0-silylserines. Michael reaction between malonitrile and chalcones proceeds without the usual catalysts using ionic liquids as reaction media, presumably the acidity of the carbon acid is enhanced/... 

Asymmetric nitro-Michael reactions of methyl vinyl ketone (MVK) in the presence of bicyclic guanidine with a benzhydryl group led, disappointedly, to low asymmetric induction (9-12%) [21a] Trials for the reaction of 0 ,p-unsaturated y- or 8-lactones with pyrrolidine in the presence of the conjugate acids of a bicyclic guanidine [50] or the Murphy s guanidine [24a] (R = Me in Scheme 4.7) resulted in the production of racemic compounds. The latter phase transfer catalyst (PTC) catalyses the nitro-Michael addition of chalcone but with limited range (70% yield, 23% ee) [24c]. 

Excellent conversions and selectivities were observed both with respect to the alkene and the primary oxidant [62]. In nitro-Michael reaction it was noted that the Murphy s PTC does not work as a good chiral catalyst for the Michael reaction of chalcone, but the same PTC effectively catalyses the epoxidation of chalcones with sodium hypochlorite (NaOCl) [24c]. Trials for the epoxidation of chalcone in the combination of hydroperoxides and modified guanidines 19 [27b] resulted in less effective asymmetric induction compared to the Murphy s PTC [53] (Scheme 4.21). 

Kumamoto, T., Rhine, K., Endo, M. et al. (2005) Guanidine-catalysed asymmetric addition reactions Michael reaction of cyclopentenone with dibenzyl malonates and epoxidation of chalcone. Heterocycles, 66, 347-359. 

Phenols have been condensed with alkenoylesters to give chromans by an oxa-Michael addition/electrophilic aromatic addition sequence with magnesium(II)- or copper(II)-bis-oxazoline complexes as chiral Lewis acid catalysts (Scheme 17b) [97]. This reaction may be initiated by an oxa-Michael reaction, followed by a hydroarylation of a carbonyl group. The authors suggest that the initial stereodetermining oxa-Michael addition is followed by a fast diastereoselective aromatic substimtion [97]. A nickel Lewis acid, derived from Ni(hfacac)2 (hfacac = 1,LL5,5,5-hexafluoro-3,5-dioxopentane enolate) and chiral Al-oxide ligands, catalyzes the enantioselective oxa-Michael cyclization of 2-tert-butyloxycarbonyl-2 -hydroxy-chalcones to 3-ferf-butoxycarbonyl flavanones, which can be decarboxylated to flavanons in a separate step (Scheme 17c) [98]. A Lewis acid activation of the unsaturated p-ketoester unit can be assumed. 

Zhang Z, Dong Y-W, Wang G-W, Komatsu K. Mechanochemical Michael reactions of chalcones and azachalcones with ethyl acetoacetate catalyzed by K2CO3 under solvent-free conditions. Chem Lett 2004 33 168-9. 

Scheme 5.7 Enantioselective Michael reaction of nitromethane to chalcones applied to the enantioselective synthesis of baclofen.

Wang et al. further used pyrrolidine-sulfonamide 3a to develop a highly enantioselective Michael reaction of cyclic ketones to a,p-unsaturated ketones (chalcones). The synthetically useful 1,5-dicarbonyl compounds were obtained in good yields and with high stereoselectivities (>40 1 dr, up to 97% ee). The most satisfactory results were achieved for six-membered cyclic ketones, whereas cyclopentanone appeared to be a more challenging substrate for this reaction (Scheme 9.26). A possible transition-state model was presented to rationalise the stereochemical outcome in which hydrogen-bond formation between the NH in 3a and the carbonyl group of chalcone caused the increase in reactivity. 

TABLE 5.11. Effect of Ligand on the Asymmetric Michael Reaction Between Chalcone and Dimethyl Malonate Catalyzed by NAP-MgO at 25 °C... 

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