In Michael addition

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). ... 

Lactones have been ultilized as donors, as well as acceptors, in Michael additions giving products with excellent diastereoselectivity. Once the 7>faces of the enolate or the oi,/ -unsatu-rated lactone are effectively shielded by an appropriate substituent at a stereogenic center a to the olefin moiety, this results in the exclusive formation of the Irons-adduct. 

Example The use of orgaiio copper compounds in Michael additions (p T 118) has a disadvantage in that one of the two starting R groups in (1) is wasted. 

Oare, D. A., Stereochemistry of the Base-Promoted Michael Addition Reaction, 19, 227 Acyclic Stereocontrol in Michael Addition Reactions of Enamines and Enol Ethers, 20, 87 Okamoto, Yoshio, Optically Active Polymers with Chiral Recognition Ability, 24, 157. 

Some chiral quaternary ammonium salts are also effective in Michael addition reactions. The Merck catalysts 7 (R=4-CF3, X=Br) and 9 (R=4-CF3, X=Br, 10,11-dihydro) were used tor the Michael additions of 59,61, and 64 to vinyl ketones to give the adducts 60,62, and 65 (isolated as 66), respectively,148,491 with excellent enantioselectivity, as shown in Scheme 19. The Michael addition of the O Donnell imine 23 to the a,(3-unsaturated carbonyl compounds also efficiently proceeded by use of the N-anthracenyl-methyl catalyst 12 (R=allyl, X=Br), giving the Michael adducts 67 (Scheme 20).1251... 

Usually, the diastereoselectivity in Michael additions is the one predicted by the Felkin-Anh model.57 However, it was discovered that in the case of the addition of highly hindered nucleophiles, as potassium phthalimide and succinimide, the major product has the opposite configuration to the one predicted by this model, because of the presence of steric hindrance interactions.58... 

Like oxygen nucleophiles, phosphorus and selenium nucleophiles have been employed rarely in Michael additions to activated dienes. The reaction of phosphites with acceptor-substituted dienes was studied by several Russian groups116-118 again, 1,6-adducts and 2 1 addition products were formed (equation 37). The acid-catalyzed reaction of selenourea with sorbic acid was also reported to provide a 1,6-addition product119 (equation 38). 

Typical acceptors in Michael additions are reducible and their radical anions often undergo dimerization (hydrodimerizations). Either the radical anions or more likely the dimer dianions can act as EGBs toward the donor in the Michael addition. Since the reaction is catalytic in base when the product anion is more basic than the donor anion, the Michael addition can take place by reduction of a small fraction (2-10%) of the acceptor [129]. The reaction takes place in 20 to 77% yield... 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

An efficient asymmetric Michael addition of thiols to cycloalkenones (103) (56-90% ee) and an effective asymmetric protonation in Michael additions of thiols to non-cyclic enones (104) (75-90% ee), catalysed by LaNas tris(binaphthoxide) (105) and SmNas-tris(binaphthoxide) (106) complexes, respectively, has been reported. ... 

Following work on Michael addition of triazoles to nitro-olefins (discussed in Sect. 2.5), bifunctional chiral thiourea catalysts were used in the addition of triazoles to chalcones [83]. The catalytic system was applicable to enones bearing aromatic groups of varying electronic natures to provide good yields and moderate selectivity. a-Cyanoacetates [84] were also applied in Michael addition to chalcones under similar catalytic conditions (Scheme 33). 

Lieby-Muller F, Simon C, Constantieux T, Rodriguez J (2006) Current developments in Michael addition-based multicomponent domino reactions involving 1,3-dicarbonyls and derivatives. QSAR Comb Sci 25 432 38... 

Starting material for the synthesis is the enaminoaldehyde obtainable by some version of the Villsmeyer reaction on pi coline derivative 9. Condensation of that with cyanoacetamide in the presence of methoxide leads to pyridone J. The reaction can be rationalized by assuming that the initial step consists in Michael addition of the anion from acetamide to the acrolein elimination of dimethyl amine would afford the intermediate Conden-... 

These a,/l-unsaturated ketones and aldehydes are used as reactants in Michael additions (Section 1.10) and Robinson annulations (Section 2.1.4), as well as in a number of other reactions that we will encounter later. Entries 8 and 9 in Scheme 2.11 illustrate Michael reactions carried out by in situ generation of a,/ -unsaturated carbonyl compounds from Mannich bases. 

In contrast, phosphine oxides were later applied in Michael additions of silyl ketene acetals to cycHc and acychc a,P-unsaturated ketones promoted by 59a as scavengers of any catalytically active Me3Si species formed during the reaction (Scheme 5.80) [151]. Further, this methodology now allows the realization of an... 

The nucleophilicity of the carbon of enamines makes them particularly useful reagents in organic synthesis because they can be acylated, alkylated, and used in Michael addition. 

A variety of nucleophilic agents can be used propanedinitrile, 3-oxo-butanoate esters, and cyanoethanoate esters all form relatively stable car-banions and function well in Michael addition reactions. Obviously, if the carbanion is too stable, it will have little or no tendency to attack the double bond of the a./8-unsaturated acid derivative. The utility of the Michael addition for preparing 1,5-dicarbonyl compounds is illustrated by the examples in Exercise 18-49. 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

Crown ethers have given impressive enantioselectivites in Michael additions (Chart 10.2). Purely synthetic chiral crowns are of limited use on large scale based on cost although, in general, the crowns are less susceptible to catalyst degradation and, therefore, have higher catalyst turnover numbers than the chiral quaternary ammonium salts. Of interest are crowns with symmetry, aza-crowns, and those with sugars or other chiral-pool units as sources of chirality (Charts 2 and 4). 

Organolithiums have been shown to add to a variety of trithiocarbonate oxides exclusively in a thiophilic maimer, as a consequence of the electrophilic character of the sulfine sulfur, to give an intermediate carbanion stabilized by three sulfur atoms the soft carbanion, which forms trithioorthoester oxide on quenching with water, acts as the equivalent of the (alkylthio)carbonyl anion in Michael addition.98... 

Lactam 45 (R = H) was used, in base as a nucleophile in Michael addition, to yield iV-alkyl derivatives in good to high yields (73-90%), <1995TL829, 1995JME5045, 2000BMC1111> however, when ethylenediamine was reacted with artemisinin, dimer 46 was isolated in low yield (Equation 6) <2003MOL901>. 

These mixed cuprates undergo conjugate addition to mono-, di-, and trisubstituted enones in good to excellent yield. Additives such as S(CH3)2 and R3P, which are sometimes necessary in Michael additions of R2CuLi, are not necessary.9... 

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

Bismuth-metal complexes, characteristics, 2, 34 Bismuth(III) nitrate, in Michael additions, 9, 442 Bismuth nucleophiles, in conjugate additions, 10, 395... 

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