Nitroalkanes Michael addition acceptors

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... 

Yamaguchi and coworkers have found that proline rubidium salts catalyze the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When (25)-L-prolines are used, acyclic ( )-enones give (S)-adducts. Cyclic (Z)-enones give (R)-adducts predominantly (Eq. 4.139).203 Recently, Hanessianhas reported that L-proline (3 7% mol equiv) and 2,5-dimethylpiperazine are more effective to induce catalytic asymmetric conjugate addition of nitroalkanes to cycloal-kanones.204... 

The product of a Michael addition depends on the number of acidic protons present in the nitroalkane substrate. Nitroform, which has one acidic proton, can only react with one equivalent of Michael acceptor. Nitroform is a strong acid and sufficiently dissociated in solution so that it can be used in addition reactions without a base catalyst. The reaction of nitroform with unsaturated ketones has been investigated by Gilligan and Graff and used to synthesize a number of trinitromethyl-based explosives. 

Chiral crown ether phosphine-palladium complexes have been used to catalyse the alkylation of carbanions derived from a-nitro ketones and a-nitro esters,63 and proline rubidium salts have been used to catalyse asymmetric Michael addition of nitroalkanes to prochiral acceptors 64 80% enantioselectivity can be achieved in each case. 

A rubidium salt of proline (5-10 mol%) has been reported to catalyse the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When L-proline was used, acyclic (I )-enones produced (.S )-adducts. whereas cyclic (Z)-enones gave (R )-adducts.88... 

The 1,4-addition (or conjugate addition) of resonance-stabilized carbanions. The Michael Addition is thermodynamically controlled the reaction donors are active methylenes such as malonates and nitroalkanes, and the acceptors are activated olefins such as a,P-unsaturated carbonyl compounds. 

A Michael addition consists of the addition of the enolate of an active-methylene compound, the anion of a nitroalkane, or a ketone enolate to an acceptor-substituted alkene. Such Michael additions can occur in the presence of catalytic amounts of hydroxide or alkoxide. The mechanism of the Michael addition is shown in Figure 13.67. The addition step of the reaction initially leads to the conjugate base of the reaction product. Protonation subsequently gives the product in its neutral and more stable form. The Michael addition is named after the American chemist Arthur Michael. 

Michael addition. Ostaszynski and Wielgat 58] used potassium (luoride as j talysi for the Michael addition of nitromethane to a double bond. (Alkali lorides were originally suggested by Yasuda ct al. [59] as catalysts foi the chael addition reactions.) The work of addition of nitroalkanes was continued J]- Various acceptors, for example, methylacrylate and acrylonitrile, were fd. Among nitroalkanes gem-dinitroalkancs were applied as donors. Nitro-ICS readily formed double salts with KHFj, RbHFj and CsHFj. The yield Ihe adducts of such salts with compounds containing a double bond varied reen 60 and 90%, viz. (5) ... 

In 2008, Ye and coworkers also developed a new type of multifunctional cinch-onidine-based catalyst, such as 119 having an additional primary amine moiety, for the Michael addition of nitroalkane to cydic enones [32], In the presence of an acid cocatalyst, the primary amine moiety of 119 can act as a Lewis base to activate the Michael acceptor via iminium formation. The catalysts 119a and 119b (5 mol%) provided quite excellent enantioselectivity (up to 98% ee) for the Michael addition of nitroalkanes to cyclohexenone (Scheme 9.40). The observed retardation of the reaction rate and the opposite sense of enantioselectivity obtained with the catalyst 119b indicated the importance of the configuration of the cydohexane... 

Mechanistically related are the reactions of nitroalkane anions with strongly electron-deficient olefins21"25. Following Michael addition, a cycloalkylation, under nitrite expulsion, produces cyclopropane derivatives with acceptor groups. At least in certain examples, the configuration of the precursor olefin is reflected in the stereochemistry of the resulting cyclopropane22. 

It has already been mentioned that one of the first examples in which the catalytic use of chiral amines was suggested for the activation of Michael acceptors in Michael addition reactions were the early reports by Yamaguchi, which focused on the conjugate addition of malonates and nitroalkanes to... 

S.2.3.2. 0L, -Unsaturatecl Aldehydes as Acceptors. As an alternative strategy for the synthesis of y-nitro aldehyde compounds, the asymmetric Michael addition of nitroalkanes to a,(3-unsaturated aldehydes was also investigated in recent years. Due to the high reactivity of aldehydes, the competitive 1,2-addition reaction is the major limitation for the development of such a reaction. Disubstituted prolinol silyl ether derivatives [72] proved to be effective catalysts to tackle this synthetic challenge, and excellent results were obtained with 7 in the presence of acid or base additive (Scheme 5.35). 

Nitroalkenes as Acceptors. The organocatalytic asymmetric Michael addition of activated methylenes to nitroalkenes is an important carbon-carbon bond-forming reaction, which provides access to synthetically useful enantioen-riched nitroalkanes. In 2003, Takemoto and co-workers [77] disclosed the first highly... 

Carbon-carbon bond forming reactions between carbanionic nucleophiles like enolates or deprotonated nitroalkanes and electron deficient alkenes and alkynes belong to the oldest and most versatile transformations known today (225-229). Moreover, stereoselective variants have proven to possess an enormous potential in the syntheses of complex molecules as already exemplified in Sect. 2.4. Whereas the applications depicted in this previous section utilized nucleophiles activated by enamine formation with a chiral secondary amine catalyst to achieve these highly selective C-C bond formations, the present discussirai will focus on the addition of carbon nucleophiles to iminium-activated Michael acceptors. Herein traditional Michael additions using e.g. enolate nucleophiles will be described whereas the use of aromatic Michael donors with iminium-activated acceptors in Friedel-Crafts type reactions will be discussed separately subsequently. 

In 2009, Zhu and Lu reported organocatalytic asymmetric Michael additions of nitroalkanes to another Michael acceptor such as vinyl sulfone mediated by another cinchona alkaloid-derived thiourea catalyst, which afforded the desired Michael products with good enantioselectivities of up to 84% ee (Scheme 1.20). This method in combination with a ready desulfonation represented a new approach to access a-alkylated chiral amines. 

Du and coworkers have developed a stereoselective direct Michael addition of nitroalkanes to nitroalkenes catalyzed by quinine-derived dimeric squaramide 21 [93]. This transformation provided facile access to 1,3-dinitro compounds in high diastereo- and enantioselectivities starting from aryl-substituted nitroalkenes (Scheme 10.18). However, the use of an aliphatic nitroalkene as Michael acceptor resulted in a low yield and diminished enantioselectivity. While nitroethane and 1-nitropropane are excellent substrates, branched 2-nitropropane did not undergo the Michael addition reaction. The authors also noted that slightly reduced dias-... 

Fig. 5 Catalysts for the conjugate addition of nitroalkanes to acyclic Michael acceptors...

Nitroolefins are excellent Michael acceptors which react with a broad range of nucleophiles in a Michael fashion. The resulting functionalized nitroalkanes can be readily converted into amines by reduction reactions or to carbonyl compounds by a Nef reaction . The addition of nucleophiles to nitroolefins is complicated by the subsequent addition of the resulting nitronate to remaining nitroolefin. Whereas such a side-reaction is quite fast for lithium and magnesium nitronates. it is slow for zinc... 

Michael condensations, together with the Diels-Alder cycloaddition and the aldol reactions, are the most powerful and useful bond-fonning reactions in synthetic organic chemistry. Like the nitro-aldol (Henry) additions, nitroalkanes are particularly appropriate reagents in Michael reactions they act as a-hydrogen donors. Nitroalkanes react easily with typical Michael acceptors such as a,p-unsaturated aldehydes or ketones under base or Lewis acid catalysis. ... 

In a typical work, the Michael reaction of several 1,3-dicarbonyl compounds, nitroalkanes and thiols as donors with various a,j3-unsaturated carbonyl acceptors on the surface of alumina in dry media have been described [23]. It was concluded that a dramatic improvement was obtained using this process when compared to the existing methods. The important features of this methodology are (a) no need for base, (b) no undesirable side reaction, (c) extremely fast addition, (d) mild reaction conditions, (e) easy set-up and work-up, (f) no toxic and expensive materials involved, and (g) high yields. 

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