1,4-Michael addition reactions nitroalkanes

The Michael addition of nih oalkanes to alkenes substituted with two elecbon-withdrawing groups at the a- and 3-positions provides a new method for the preparation of functionalized alkenes. Although reactions are not new, Ballini and coworkers have used this sbategy in the synthesis of polyfunctionalized unsaturated carbonyl derivatives by Michael addition of nih oalkanes to enediones as shown in Eqs. 7.124-7.126. Success of this type of reaction depends on the base and solvent. They have found that DBU in acetonihile is the method of choice for this puipose. This base-solvent system has been used widely in Michael additions of nitroalkanes to elechon-deficient alkenes (see Section 4.3, which discusses the Michael addition). ... 

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... 

The Michael addition of nitro compounds is a useful method for the preparation of various natural products. The Michael addition of nitroalkanes to dehydroalanines gives y-nitro-a-amino acids, which provides a convenient synthesis of side-chain modified a-amino acids (Eq. 4.114).152 Transformations of y-nitro-a-amino acid derivatives into a-amino acids occur by reductive denitration (see Section 7.2) into y-oxygenated a-amino acids by the Nef reaction (Eq. 

The Michael addition of nitroalkanes to a,P-unsaturated ketones followed by the Nef reaction has been extensively used as a method for the conjugated addition of acyl anions to enones (see Section 6.1, Nef Reaction). This strategy is one of the best methods for the preparation of 1,4-dicarbonyl compounds.156a h Various natural products have been prepared via this route.157 For example, r/.v-jasmone is prepared from readily available materials, as shown in Scheme 4.19.156f... 

The Nef reaction can also be carried out with reducing agents. Aqueous titanium chloride reduces nitro compounds to imines, which are readily hydrolyzed to carbonyl compounds (Eq. 6.17).28 The Michael addition of nitroalkanes to enones followed by reaction with TiCl3 provides an excellent route to 1,4-diketones and hence to cyclopentenones. For example, cw-jasmone is readily obtained,28 as shown in Eq. 6.18. 

Alumina-supported KF is an effective reagent for Michael addition of nitroalkanes to electron-deficient olefins. Subsequent cycloalkylations afford cyclopropanes.37 However, the reaction of a, 3-unsaturated ketones with nitroalkanes in the presence of KF-A1203 in acetonitrile gives 4,5-dihydrofuranes (Eq. 7.39).40... 

The synthetic methods which are illustrated in this section are (a) the formation of symmetrical 1,4-diketones from 1,3- (or / -)keto esters (Expt 5.104), and (b) a Michael addition reaction involving nitroalkanes and a, /f-unsaturated ketones (Expt 5.105). The synthesis of symmetrical 1,4-diketones from the sodio derivatives of /f-keto esters, or their mono-alkyl derivatives, by treatment with iodine [Method (a)], may be formulated in the following general manner. 

The Michael addition of nitroalkanes to a,f -unsaturated enones, catalysed by the novel chiral imidazolidine-2-yltetrazole (151), has been investigated. The new, more soluble organocatalyst decreases reaction times and improves enantioselectivities com- pared with other catalysts. The Michael addition adducts were obtained with up to 92% ee.179... 

Self-catalysed Michael Addition reactions of selected nitroalkanes (427) with dicyclohexylammonium 2-(diethoxyphosphoryl)acrylate (428) afforded 4-nit-roalkanoates (429) (Scheme 101). It was also demonstrated that the Nef reaction on the resulting primary and secondary 4-nitroalkanoates involved intramolecular catalysis by the carboxylic acid group. ... 

Similar reactions could also be carried out with ketene diethyl dithioacetal S-monooxide (251). The Michael addition of nitroalkanes 246 to 251 afforded the selective monoadducts 252, but that to 247 (R = H) yielded a mixture of the mono- (248) and diadducts. 

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... 

The Michael addition reaction is commonly recognized as one of the most important carbon-carbon bond-forming reactions in organic synthesis, and major efforts have been made to develop efficient catalytic systems for this type of transformation. In particular, the Michael addition of a carbon nucleophile to nitroalkenes is a useful synthetic method for the preparation of nitroalkanes [76], which are versatile synthetic intermediates owing to the various possible easy transformations of the nitro group into other useful functional groups, such as amino groups and nitrile oxides. 

In addition, it has been shown that the catalytic use of PS-N3PAPT (10 mol%) was very effective for Michael addition reactions of a variety of Michael donors such as p-ketoesters, ot-nitroketones and nitroalkanes with activated olefins such as methyl acrylate and methyl vinyl ketone [41] (Scheme 6.9). The recyclability of the catalyst was established after it had been used 12 times. When diethyl malonate or ethyl cyanoacetate was used as the Michael donor substrate, the expected disubstituted adducts were obtained in moderate to good yields. 

Michael addition is one of the most efficient and effective routes to C-C bond formation[127]. This reaction is widely applied in organic synthesis and several new versions of it have been introduced recently. The commonly employed anionic alkyl synthons for Michael addition are those derived from nitroalkanes, ethyl cyanocarboxylates, and malonates, and their limitations have been largely overcome by newer methodologies. However, the newer approaches are by no means devoid of drawbacks such as long reaction times, modest product yields in many cases, and the requirement for excess nitroalkane. Michael addition reactions of Schiff s bases have long been known to constitute a convenient method for functionalizing a-amino esters at the a position and the ratio of Michael addition to cycloaddition product has been found to depend upon the metal ion employed to chelate the enolate produced upon deprotonation (see below). 

We found that Michael addition of nitroalkanes had limited success with nitromethane owing to its nitroaldol reaction with the products formed from methyl vinyl ketone and cyclohexenone, for example. (It may be noted in this regard that although the product obtained in the reaction of methyl vinyl ketone with nitromethane was achieved in 78% yield [127], a recent report [128] described a 98 % yield by employing the less basic catalyst TBD at a higher temperature 0°C). However, 2-nitropropane and nitrocyclohexane were much better candidates for pro-azaphosphatrane-catalyzed reactions for which DBU and TMG typically require longer reaction times and afford only poor to modest product yields [127]. 

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... 

H-Phe-His-OH, H-His-Phe-OH, H-Lys-Phe-OH, H-Leu-Arg-OH, H-Val-Arg-OH, H-Lys-Arg-OH, H-Lys-iyr-OH, H-Lys-His-OH, H-His-Leu-OH, H-Leu-His-OH) along with different amine additives 25 and 26, it was found that H-Leu-His-OH dipeptide 24 in combination with (1J ,2J )-1,2-diphenylethylenediamine (26) in a suitable ratio (0.3 equiv. each) is a new primary amine-based catalytic system for the nitroalkane-Michael addition reaction (Scheme 13.17). 

After the preliminary studies on the reaction, a wide variety of efficient chiral organocatalysts has been developed by dilferent groups for the Michael addition of nitroalkanes to enones. For instance, Jprgensen s group has reported that imidazolidine catalyst 106 (Scheme 2.54), easily prepared from phenylalanine, promotes the conjugate addition of acyclic- and cyclic nitroalkanes with a wide variety of acyclic... 

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). 

Michael addition reactions generally involve the addition of an active methylene, such as a malonate or nitroalkane, to activated olefins, such as a,p-unsaturated carbonyl compounds, in the presence of a base. 

Alumina can be impregnated with potassium fluoride, creating a solid, basic catalyst [145]. This solid has a wide range of catalytic applications involving elimination, condensation and addition reactions. Included in this group are the Michael additions of nitroalkanes to a, 3-unsaturated carbonyls (equation 4.35) [80]. 

Lubineau and Aug reported the beneficial effect of using water as the solvent in the Michael addition of nitroalkanes to methyl vinyl ketone under neutral conditions. Moreover, addition of glucose or saccharose increased the rate of the reaction. Various nitroalkanes were condensed with different electrophilic alkenes in NaOH (0.025-0.1 m), without any added organic solvent, affording the corresponding adducts with moderate to good yields when a catalytic amoimt of cetyltrimethylammonium chloride (CTACl) was used (Scheme 8.12). ... 

Lubineau, A. and Aug6, J., Water-promoted organic reactions. Michael addition of nitroalkanes to methyvinylketone under neutral conditions. Tetrahedron Lett., 1992, 33, 8073-8074. 

Kitazume and coworkers used microreactors with microchaimels 100 pm wide and 40 pm deep for the synthesis of a series of organofluorine compounds [19,20]. The silylation of4,4,4-trifluorobutan-2-one and the Mukaiyama-type aldol reaction of the resulting enol silyl ether with acetals gave good yields of the desired products [20]. They also described nitro-aldol reactions of 2,2-difluoro-l-ethoxyethanol and Michael additions of nitroalkanes to ethyl 4,4,4-trifluorocrotonate and ethyl 4,4-difluorocrotonate [19,20]. Reactions were carried out at room temperature, and... 

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-... 

The enantioselective Michael addition of nitroalkanes to enones provides an attractive synthetic route towards chiral pyrrolidines, y-lactams, and y-amino acids. Du and coworkers have developed a squaramide-catalyzed Michael addition reaction of nitroalkanes to chalcones (Scheme 10.20) [98]. The authors noted that electron-withdrawing substituents on the aryl portion of squaramide enhanced the activity of the catalyst owing to the increased acidity of the squaramide N-H. Interestingly, the yield and enantioselectivity both increased when the reaction was performed at an elevated temperature. The reactions between nitromethane and various chalcones afforded the Michael adducts in high yields and high enantioselectivities at 80 °C. Varying the substituents on chalcones showed some effect on... 

An effective asymmetric synthesis of optically active 1,3-dinitro compounds via the Michael addition of nitroalkanes to nitroalkenes has been described to afford the corresponding adducts with 72 8 dr and up to 94% eeP The catalytic system, a modified cinchona alkaloid derivative (9), performs well with a broad variety of substrates, and the catalyst loading can be decreased to 2 mol% without compromising the asymmetric induction or the reaction rate. 

---