Substitution Reactions of Enolates

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both stable enolates, such as those derived from 6-ketoesters, 6-diketones, and malonate esters, as well as less stable enolates of monofunctional ketones, esters, nitriles, etc., are reactive. Many aspects of the relationships among reactivity, stereochemistry, and mechanism have been clarified. The starting point for the discussion of these reactions is the structure of the enolates. Studies of ketone enolates in solution indicate that both tetrameric and dimeric clusters can exist. THF, a solvent in which many synthetic reactions are performed, favors tetrameric structures for the lithium enolate of isobutyrophenone, for example.  

Several ester enolates have also been examined by X-ray crystallography. The enolates of r-butyl propionate and f-butyl 3-methylpropionate were obtained as TMEDA solvates of enolate dimers. Methyl 3,3-dimethylbutanoate was obtained as a THF-solvated tetramer. 

Because of the delocalized nature of enolates, an electrophile can attack either at oxygen or at carbon. Soft electrophiles prefer carbon and it is found experimentally that most alkyl halides react to give C-alkylation. Because of the tt character of the HOMO of the anion, there is a stereoelectronic preference for attack of the electrophile approximately perpendicular to the plane of the enolate. The frontier orbital is i 2 with electron density mainly at O and C(2). The TS for an S 2 alkylation of an enolate can be represented as below. 

The leaving group in the alkylating reagent has a major effect on whether C- or O-alkylation occurs. The C- versus O-alkylation ratio has been studied for the potassium salt of ethyl acetoacetate as a function of both solvent and leaving 

Leaving group X Solvent C 0 ratio Leaving group X Solvent C 0 ratio 

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Negishi, E.-i. Palladium-catalyzed cross-coupling involving 3-hetero-substituted compounds. Palladium-catalyzed a-substitution reactions of enolates and related derivatives other than the Tsuji-Trost allylation reaction. Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 693-719. 

III.2.14.1 Palladium-Catalyzed of-Substitution Reactions of Enolates and Related Derivatives Other than the Tsuji-Trost Allylation Reaction... 

In this section, attention is focused on the Pd-catalyzed a-substitution reactions of enolates and related derivatives represented by Method I in Scheme 1, other than Tsuji-Trost allylation and propargylation. Additionally, its charge-affinity inverted version represented by Method II in Scheme 1 is also discussed. In general, it is advisable to consider simultaneously various other alternatives including those shown in Scheme 1, especially Method III. Indeed, Method III discussed in the following section provides the currently most... 

The acyl addition and acyl substitution reactions of enolate anions presented in this chapter clearly show that enolate anions are nucleophiles. In Chapter 11 (Section 11.3), various nucleophiles reacted with primary and secondary alkyl halides via Sn2 reactions. Enolate anions also react with alkyl halides via 8 2 reactions in what is known as enolate alkylation. 

V.2.1.4 Palladium-Catalyzed Allylation and Related Substitution Reactions of Enolates and Related Derivatives of Ordinary Ketones, Aldehydes, and Other Carbonyl Compounds... 

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