Michael trans-chalcone

Scheme 6.119 Michael adducts from the asymmetric addition of nitromethane to trans-chalcones catalyzed by 122.

In 2007, Chen and co-workers reported the 122-catalyzed (10mol% loading) enantioselective Michael addition [149-152] of ethyl a-cyanoacetate to various electron-rich and electron-deficient trans-chalcones [283]. The reaction was performed for a broad spectrum of chalcones and gave the corresponding adducts in yields of 80-95% and in ee values of 83-95%, but at low sy /a ti-diastereoselectiv-ities as shown for representative products 1-8 in Scheme 6.125. 

Scheme 7.8 Enantioselective Michael addition of malononitrile to trans-chalcones catalysed by prolinol Ij.

The enantioselective Michael addition of malononitrile CH2(CN)2 to trans-chalcones R CH=CHCOR catalysed by diarylprolinols (151), has been studied in detail. Both experimental and computational results are consistent with a bifunctional non-covalent activation of the reactants (152). The latter mechanism correctly predicts formation of the (R)-configured products (<75% eef- but is in conflict with the generally accepted iminium mechanism. Furthermore, (151) is likely to form the corresponding oxazolidine derivative as an intermediate, which has not been taken into account. 

Experiment 38 involves the reaction between ethyl acetoacetate and trans-chalcone in the presence of base. Under the conditions of this experiment, a sequence of three reactions takes place a Michael addition followed by an internal aldol reaction and a dehydration. 

Michael Addition Reaction Involving trans-Chalcones... 

Enantioselective Michael reactions of thiols provide a convenient route to diverse chiral sulfides. Chen and coworkers have demonstrated that a chiral squaramide catalyst was effective in promoting a sulfa-Michael conjugated addition of various aromatic and aliphatic thiols to a wide range of trans-chalcones (Scheme 10.19) [97]. Moderate to excellent yields and enantioselectivities were achieved. Notably, the reactions between various benzylthiol and trans-chalcones bearing electron-donating or electron-withdrawing substituents proceeded with high enantioselectivities. 

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. 

Optically pure (+)-(i )-3-phenylsulfanyl-l,3-diarylpropan-l-ones are readily available by the enantioselective Michael addition of thiophenols to chalcones. After reduction, acidic dehydration of the racemic alcohol affords a mixture of the racemic cis- and trans- 2,4-disubstituted thiochromans (Scheme 164). A detailed consideration of the stereochemical outcome of the reaction with unsymmetrically substituted diaryl derivatives suggests the involvement of a [1,3] PhS shift via a four-membered sulfonium intermediate and this is backed up by theoretical calculations <2003T3621>. 

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,... 

Enantioselective epoxidation of a chalcone analogue (75) and t-BuOOH with 10 mol% of (72) gave trans-(2R,3S -(76) in up to 80% ee. Soluble polyethylene glycol (PEG)-bound catalyst (73) was also developed to recover and reuse the ligand for Michael and epoxidation reactions, but the enantioselectivity was low despite the high yield. 

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