Alkylation of Carbon Nucleophiles by Conjugate Addition

SECTION 1.10. ALKYLATION OF CARBON NUCLEOPHILES BY CONJUGATE ADDITION 

The previous sections have dealt primarily with reactions in which the new carbon-carbon bond is formed by an SN2 reaction between the nucleophilic carbanions and the alkylating reagent. Another important method for alkylation of carbon involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,/i-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. Other kinds of nucleophiles such as amines, alkoxides, and sulfide anions also react similarly, but we will focus on the carbon-carbon bondforming reactions. 

In contrast to the reaction of an enolate anion with an alkyl halide, which requires one equivalent of base, conjugate addition of enolates can be carried out with a catalytic amount of base. All the steps are reversible. 

The fluoride ion is an effective catalyst for Michael additions involving relatively acidic carbon compounds.85 The reactions can be done in the presence of excess fluoride, where the formation of the [F—H—F ] ion occurs, or by use of a tetraalkylammonium fluoride in an aprotic solvent. 

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON. ENOLATES AND ENAMINES 

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Alkylation of Carbon Nucleophiles by Conjugate Addition General References... 

Reactions of chiral allylic boranes with carbonyl compounds Reactions of chiral allyl boranes with imines Asymmetric Addition of Carbon Nucleophiles to Ketones Addition of alkyl lithiums to ketones Asymmetric epoxidation with chiral sulfur ylids Asymmetric Nucleophilic Attack by Chiral Alcohols Deracemisation of arylpropionic acids Deracemisation of a-halo acids Asymmetric Conjugate Addition of Nitrogen Nucleophiles An asymmetric synthesis of thienamycin Asymmetric Protonation... 

Acyclic stereocontrol remains a challenging problem in synthesis. While enan-tiomerically pure sulfoxides are valuable synthetic intermediates for enantiocon-trolled carbon-carbon bond formation by conjugate addition in cyclic cases, their usefulness for such alkylations in acyclic cases has not been firmly established. Moreover, most sulfoxide directed alkylation protocols utilize the valuable sulfur auxiliary just once, which limits the synthetic versatility of the process. Marino et al. have recently reported SN2 displacements of acyclic allylic mesyloxy vinyl sulfoxides with organocopper reagents (Scheme 10).33 In addition to the excellent observed stereoselectivities, the newly created chiral center is adjacent to a vinyl sulfoxide which should allow for subsequent chirality transfer operations. On treatment with organocopper nucleophiles, both sulfoxide diastereoisomers 40b and 43b underwent SN2 displacements with high Z selectivity to yield products 42b and 45b, respectively (Table 2). The oxidation state on the sulfur was varied... 

The most common method for the synthesis of phosphinopeptides is the addition of a nucleophilic, trivalent phosphorus species to a carbon electrophile, including conjugated double bonds, alkylating agents, imines, and carbonyl compounds. By analogy with the phosphite ester additions described above, the nucleophilic form of a phosphinic acid is the trivalent species, generated from the more stable, pentavalent PH derivative by deprotonation or by silylation (cf. Scheme 2). 

In most cases98 conjugate addition-enolate alkylation reaction sequences do not exhibit particular sensitivity with respect to the identity of the alkyl group present in the alkyl alkenoate substrate. When a Michael donor has been chosen that reacts in both the 1,4- and 1,2-addition modes, it may be possible to choose an alkyl group for the ester substrate that forces the Michael donor to undergo exclusive 1,4-addition by sterically shielding the carbonyl carbon from attack by the nucleophile (equation 23)."... 

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... 

There are two major reactions of organocuprates, and both give products reminiscent of a carbon nucleophile (1) reaction with alkyl halides and (2) conjugate addition with a,p-unsaturated ketones. Conjugate addition to a, 3-unsaturated ketones is promoted when ether is used as a solvent.381 The substitution reaction is promoted by the use of THF or ether-HMPA as a solvent. l As mentioned earlier, the mechanism of these reactions probably involves a one-electron transfer, although other mechanistic proposals are in the literature,but the synthetic result is that expected of a carbon nucleophile. 85 The general reactivity of organocuprates with electrophiles follows the order ... 

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