Michael additions of aldehydes

Direct catalytic Michael addition of aldehydes to nitrostyrenes proceeds in good yield, syn diastereoselectivity, and enantioselectivity (up to 82/90/99%, respectively) using a recyclable dendritic catalyst bearing chiral pyrrolidine moieties.200 High-yielding enantio- and diastereo-selective direct Michael addition of ketones to nitroalkenes to give aldol products employ modular acyclic primary amino acid derivatives as catalysts.201... 

Enantioselective Michael additions of aldehydes to enones using imidazolidinones as organocatalysts show evidence of enamine intermediates.217 Several co-catalysts -mainly phenols - raise the yield and/or ee. 

Organocatalyst (56), a pyrrolidine sulfonamide derived from L-proline, catalyses the direct Michael addition of aldehydes to nitrostyrene with high ee and de, apparently exploiting its bifunctional (acid-base) nature.220 ... 

An intramolecular asymmetric Michael addition of aldehydes and ketones - to give cyclopentanals - gives the otherwise disfavoured d.v-producls when catalysed with (f) antibody 38C2, the first commercially available catalytic antibody 222 One case gave 99% de, 98% ee. ... 

An enantioselective intermolecular Michael addition of aldehydes (138) to enones (139), catalysed by imidazolidinones (140), has been reported. Chemoselectivity (Michael addition versus aldol) can be controlled through judicious choice of hydrogen bond-donating co-catalysts. The optimal imidazolidinone-hydrogen bond donor pair affords Michael addition products in <90% ee. Furthermore, the enamine intermediate was isolated and characterized and its efficacy as a nucleophile in the observed Michael addition reactions was demonstrated.172... 

A novel antibody-catalysed intramolecular Michael addition of aldehydes and ketones to enones [(148) -> (149)] has been accomplished. The reaction is enantio- and diastereo-selective with a high ee and cis/trans ratio. Antibody 38C2 is the only catalyst to date capable of generating this selectivity in Michael addition products.177... 

Scheme 2.48 The Michael addition of aldehydes on nitroolefins, catalyzed by 45a and 45b.

Chi Y, Gellman SH (2005) Diphenylprolinol methyl ether a highly enantioselective catalyst for Michael addition of aldehydes to simple enones. Qrg Lett 7 4253 1256... 

Peelen TJ, Chi Y, Gellman SH (2005) Enantioselective organocatalytic Michael additions of aldehydes to enones with imidazolidinones cocatalyst effects and evidence for an enamine intermediate. J Am Chem Soc 127 11598— 11599... 

Wang W, Wang J, Li H (2005) Direct, highly enantioselective pyrrolidine sulfonamide catalyzed Michael addition of aldehydes to nitrostyrenes. Angew Chem Int Ed Engl 44 1369-1371... 

The use of thiazolium salts enables the benzoin condensation to proceed at room temperature. It can also be performed in dipolar aptotic solvents or under phase transfer conditions. Thiazolium salts such as vitamin Bi, thiazolium salts attached to y-cyclodextrin, macrobicyclic thiazolium salts, thiazolium carboxylate, ° naphtho[2,l-d]thiazolium and benzothiazolium salts catalyze the benzoin condensation and quaternary salts of 1-methylbenzimidazole and 4-(4-chlorophenyl)-4//-1,2,4-triazole are reported to have similar catalytic activity. Alkylation of 2-hydroxyethyl-4-methyl-l,3-thiazole with benzyl chloride, methyl iodide, ethyl bromide and 2-ethoxyethyl bromide yields useful salts for catalyzing 1,4-addition of aldehydes to activated double bonds. Insoluble polymer-supported thiazolium salts are catalysts for the benzoin condensation and for Michael addition of aldehydes. Electron rich al-kenes such as bis(l,3-dialkylimidazolidin-2-ylidenes) bearing primary alkyl substituents at the nitrogen atoms or bis(thiazolin-2-ylidene) bearing benzyl groups at the nitrogen atoms are examples of a new class of catalyst for the conversion of ArCHO into ArCHOHCOAr. 

Recently, Zhao et al. reported the use of 2-trimethylsilanyloxy-methyl-pyrrolidine functionalized chiral dendrimer catalysts (Figure 4.20) for catalytic enantio- and diastereoselective Michael addition of aldehydes to nitrostyrenes (Scheme 4.15)... 

General comments about the Michael reaction procedures are analogous to those developed in the aldol and Mannich reactions.For example, the O-TMS-protected diphenylprolinol compound 20 in cooperation with benzoic acid catalyses the asymmetric Michael addition of aldehydes to nitroalkenes, in a simple, practical and efficient procedure. Benzoic acid promotes the rapid formation of the enamine intermediate and the reaction takes place in the highly concentrated organic phase of the aqueous biphasic system. 

Reproduced with permission Horn Veverkov E, PoUckovi V. Liptakov L. K menov E MeSarov M. Toma 5, Sebesta R. Orgarocataiyst efficiency in the Michael additions of aldehydes to nitroaikenes in water and in a bal-mii. ChemCatChem 2012 4 101 -8. Copyright (2012), Wiley. 

Veverkova E, Polackova V, Liptakovi L, Kazmerova E, Meciarovi M, Toma S, Sebesta R. Organocatalyst efficiency in the michael additions of aldehydes to nitroalkenes in water and in a ball-mill. ChemCatChem 2012 4 1013-8. 

Scheme 2.12 Enantioselective Michael addition of aldehydes to nitroalkenes catalyzed by 31a and 3a.

Scheme 2.15 Enantioselective Michael addition of aldehydes with functionalized nitroalkenes and an application to the total synthesis of densely functionalized homoprolines and natural product (-)-botryodipIodin.

Figure 2.8 Some active catalysts in the Michael addition of aldehydes or ketones to nitroolefins in aqueous media.

For example, the addition to vinyl sulfones has attracted a lot of attention mainly because of the synthetic possibilities that the sulfone group affords in terms of its wide possibilities to undergo a wide variety of transformations. iPBP 15a and prolinal-deiived aminal 12b catalysts have proved their usefulness in the Michael addition of aldehydes to this particular class of Michael acceptors, showing that good yields of the desired Michael adducts could be obtained under the optimized conditions, although with moderate enantios-electivities (Scheme One of the main problems of this particular... 

Alkylidenemalonates and malononitriles constitute another class of doubly activated olefins that can be used as highly electrophilic Michael acceptors in this reaction. For example, the Michael addition of aldehydes with these compounds has been reported to proceed with very good yields and enantioselectivities using 0-TMS diphenylprolinol 31a as catalyst (Scheme 2.29). On the other hand, the Michael addition of ketones to alkylidenemalonates has... 

Importantly, prolinamide catalysts (Figure 6.3) work well in Michael addition reactions using nitro-olefins as acceptors. iV-Tritylprolinamide 33 and aminonaphthyridine-derived ProNap 34 served as organocatalysts in asymmetric Michael additions of aldehydes and cyclohexanone to nitro-alkenes. Proline-functionalised C3-symmetric 1,3,5-triallq lbenzene 35 was screened in the reaction of cyclohexanone to nitrostyrene to afford the Michael adducts in good yields and diastereoselectivity but low enantioselectivity. 

Sugar-hased prolinamide 16m has also been employed as catalyst for the asymmetric Michael addition of cyclohexanones to p-nitroslyrenes. During optimisation of the reaction conditions, the authors found that the polarity of the solvent does not modify the yield or stereoselectivity, but the best ee was obtained under neat conditions at -20 °C. Ammonium ionic liquids 41a,b are also efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitro-olefins giving the adducts with excellent yields and enantioselectivities and modest to high diastereoselectivities. 

Scheme 7.28 Asymmetric Michael addition of aldehydes with methyl or ethyl vinyl ketones catalysed hy (S)-diphenylprolinol methyl ether.

Addition of benzoic acid enhanced the reactivity of the catalyst in the Michael addition of aldehydes. Therefore, less reactive trisubstituted nitroalkenes could also be used. Acetic acid as acidic additive also helped in the addition of unsaturated aldehydes to nitroalkenes (Scheme 8.3). This reaction proceeds via dienamine activation of unsaturated aldehydes. 

The Michael addition of aldehydes to indolylnitroalkenes led to chiral indol-substituted 4-nitro-2-allq lbutanals in high yield and diastereo- and enantiomeric purities.In our laboratory, we have investigated Michael additions of ojyacetaldehydes to nitroalkenes. ... 

Replacement of phenyl groups with AT-methyl imidazole moieties in the catalyst Cl structure led to catalyst C4 (Figure 8.2). ° This catalyst worked efficiently in aqueous media. Catalyst C4 catalysed Michael additions of aldehydes to nitroalkenes in a mixture of brine and NaHCOs. 

Michael additions of aldehydes to nitroalkene with catalyst Cl can also be performed under solvent-free conditions in a ball-mill. The reaction was considerably more efficient under ball-milling conditions than with conventional stirring. Ball-milling reactions proceeded faster and afforded the... 

Ma and coworkers described the first organocatalytic asymmetric Michael addition of aldehydes to a,p-unsaturated thiol esters promoted by catalyst Cla. The reaction proceeded with good yields, diastereoselectivity and excellent enantioselectivity. 

Paixao and coworkers showed that a sulfur-modified catalyst C5 was able to efficiently catalyse the Michael addition of malonates to enals in EtOH/ brine mixture (Scheme 8.7). The sulfur-containing catalyst was efficient for the Michael addition of aldehydes to nitroalkenes in polyethylene glycol (PEG). The most important feature of this system was its reusability. After extraction of the reaction products, the PEG solution containing the organocatalyst was reused at least four times with no adverse effects on yield or enantioselectivity. ... 

If an unsaturated aldehyde was combined with a 1,3-dinitro compound, chiral cyclohexanes were formed by a nitro-Michael/Heniy reaction sequence. Miehael addition followed by double Heniy reaction also led to ehiral eyelohexane derivatives. In another application of the Henry re-aetion, Hayashi used nitroalkenes with pentane-l,5-dial (generated in situ) to form ehiral eyelohexane carboxaldehydes. Chiral cyclopentanes were also eonstrueted in another manner. Enamine-mediated Michael addition of aldehydes to 5-iodo-l-nitropent-l-ene led to an intermediate enamine, which underwent intramoleeular cyclisation via iodide displacement. ... 

Scheme 9.12 Diamine Ic-catalysed asymmetric Michael addition of aldehydes.

A series of aminal-pyrrolidine-derived organcatalysts was synthesised by Alexakis and coworkers. ° Initially, this family of aminal catalysts was evaluated for catalysing the Michael addition of aldehydes to nitro-olefins. When Ik was used, the products obtained had moderate to good stereoselectivities (up to 79% ee) at ambient temperature (Scheme 9.17). The reaction of vinyl-sulfone with linear aldehydes yielded more satisfactory results. Impressive reactivity and good enantioselectivities were obtained when only 10 mol% of Ik was used and representative examples are presented in Scheme 9.17. The stereocontrol exhibited by the catalyst was possibly associated with the strong interaction between the sulfonyl group and the aminal catalyst. 

Peng and coworkers reported an example of the Michael addition of aldehydes to ot-substituted nitro-olefins in the presence of sulfonamide-derived organocatalyst 3a. A wide range of y-nitro carbonyl products were... 

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