Michael additions allyl anions

The TT-allylpalladium complexes 241 formed from the ally carbonates 240 bearing an anion-stabilizing EWG are converted into the Pd complexes of TMM (trimethylenemethane) as reactive, dipolar intermediates 242 by intramolecular deprotonation with the alkoxide anion, and undergo [3 + 2] cycloaddition to give five-membered ring compounds 244 by Michael addition to an electron-deficient double bond and subsequent intramolecular allylation of the generated carbanion 243. This cycloaddition proceeds under neutral conditions, yielding the functionalized methylenecyclopentanes 244[148], The syn-... 

Another domino cuprate 1,4-addition-initiated threefold anionic domino sequence was developed by Chemla and coworkers (Scheme 2.93) [214]. Michael addition of the a, 3-unsaturated ester 2-387 with PhCu(CN)ZnBr was followed by a carbocyclization to give the zinc species 2-388 which can be intercepted by iodine or an allyl bromide affording substituted pyrrolidines 2-389 and 2-390, respectively. 

The group ofWalborsky probably has described one of the first true anionic/radi-cal domino process in their synthesis of the spirocyclopropyl ether 2-733 starting from the tertiary allylic bromide 2-730 (Scheme 2.161) [369]. The first step is a Michael addition with methoxide which led to the malonate anion 2-731. It follows a displacement of the tertiary bromide and a subsequent ring closure which is thought to involve a SET from the anionic center to the carbon-bromine anti bonding orbital to produce the diradical 2-732 and a bromide anion. An obvious alternative Sn2 halide displacement was excluded due to steric reasons and the ease with which the reaction proceeded. 

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

The synthesis of 4-alkyl thioketones is possible by exploiting the stabilizing effect of a sulfur atom upon an adjacent carbanionic center. Ambident allylic anions react so that conjugate addition proceeds exclusively with the a-carbon of the nucleophile,129 243 244 as illustrated in equation (S3) 245 arylsulfinyl and arylsulfonyl groups normally246 behave similarly.247-249 Sulfur-stabilized vinylic carbanions can be prepared and function as Michael donors in difunctionalization sequences.250... 

A limited number of other anionic species have been employed as Michael donors in tandem vicinal difunctionalizations. In a manner similar to sulfur ylides described above, phosphonium ylides can be used as cyclopropanating reagents by means of a conjugate addition-a-intramolecular alkylation sequence. Phosphonium ylides have been used with greater frequency261-263 than sulfur ylides and display little steric sensitivity.264 Phosphorus-stabilized allylic anions can display regiospecific 7-1,4-addition when used as Michael donors.265... 

Ethyl-2-(sulfonylmethyl)- and 2-(cyanomethyl)-allyl carbonates133 as well as (methoxycarbo-nyl)methylallyl carbonates136 serve as substrates for the [3 + 2] cycloaddition. Oxidative addition into the allylic C—O bond of the carbonate, followed by decarboxylation, gives a 2-substituted allylpalladium al-koxide. The alkoxide then deprotonates the C—H a to the electron-withdrawing substituent at the 2-position of the allyl. This anion then undergoes a Michael addition to an a,(3-unsaturated ketone or ester, followed by intramolecular allylation of the anion of the Michael product (Scheme 2). 

One potential problem in the reactions of stabilized allylic or propargylic carb-anions is the dimerization of the starting material if the carbanions are not formed stoichiometrically. Alkenes substituted with electron-withdrawing groups are good Michael acceptors, to which nucleophiles will undergo conjugate addition. For instance, the Baylis-Hillman reaction of allyl cyanide with benzaldehyde requires careful optimization of the reaction conditions to avoid dimerization of the nitrile (Scheme 5.12). This problem is related to a common side reaction of Michael additions reaction of the product with the Michael acceptor (Scheme 10.21). 

The reaction of vinylic phenyliodium salts (57) with cyanide anions could be mistaken for a simple substitution reaction.59 However, the presence of both allylic (58) and vinylic (59) nitrile products suggests a more complex picture. Deuterium labelling experiments show that the allylic product is formed via the Michael addition of cyanide to the vinylic iodonium salt, followed by elimination of iodobenzene and a 1,2-hydrogen shift in the 2-cyanocycloalkylidene intermediate (60). H-shift occurs from the methylene carbon in preference to the methine carbon. The effects of substitution and different nucleophiles were examined. 

In the catalytic presence of tetrabutylammonium fluoride, a trimethylsilyl group is cleaved from AKtrimethylsilyl)rnethylbenzylimine to form the resonance-stabilized 2-aza-allyl anion which undergoes a Michael addition reaction with, for example, methyl acrylate, giving y-aminoesters.333 These types of aminoesters serve as a starting material for the elaboration of diversely substituted pyrrolidones.334... 

On the basis of these findings, a combination of this intramolecular crosscoupling with an initial intermolecular Michael addition was reported by Singer in order to afford cyanobenzofulvene acetal 85 which was an intermediate of the synthesis of a benzazepine [81]. Thus, Michael addition of 2-halophenylacetonitrile derivatives of 86 to ethoxy acrylate performed in the presence of a large excess of base leads to the corresponding conjugated allylic anion 87. The crucial issue in this process is the oxidative addition of the palladium to the electron-rich arene. This problem was solved... 

The nucleophilic addition of lithiated allyl phenyl sulfone to nitrones at 0 °C afforded 4-(phenylsulfonyl)isoxazol-idines as major products. The process probably involves the isomerization of the allylsulfonyl moiety of the initially formed hydroxylamine anion to vinylsulfone which then undergoes intramolecular Michael addition. For example, the chiral nitrone 536 afforded isoxazolidine 537 with high diastereoselectivity (Equation 88) <2005T3335>. When the same reaction was carried out in the presence of hexamethylphosphoramide (HMPA) at —80°C, the anti-a-sulfonyl homoallyl hydroxylamine was obtained. 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

Direct generation of a cyclopropoxy anion from a siloxycyclopropane and fluoride ion has been applied to seven-membered ring formation. Michael addition of the resulting allyl anion can account for the cyclization. An uncyclized i ,y-unsaturated ketone with the E configuration is also formed as a byproduct. 

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

Figure 5.10. Auxiliaries for asymmetric Michael addition of allyl anions (a) [195]. (b)...

Renewed efforts have been made to sterically control the Michael addition of allylic phosphonate carbanions to cyclic enones. The anions generated by the... 

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