C Alkylation of Enolate Anions

Cyclization of 47 discussed in Section 9.2.E showed an intramolecular alkylation reaction of enolates to give 49, but the formation of 50 illustrated an important competing reaction in the alkylation of enolates. An enolate anion is a bidentate nucleophile because it contains two nucleophilic centers, the carbanionic center and the oxygen, as illustrated by 90. Reaction of the O nucleophile in 90 with an alkyl halide leads to the vinyl ether 91. Reaction at the C nucleophile of 90 generates the usual alkylation product 92. Since a carb-anion is usually more nucleophilic than an alkoxy anion for common electrophiles, 92 tends to be the major product. There are several factors that can influence the relative proportion of these products, however. When 

Treatment of ketone 93 with dimsyl anion generates enolate 94, but this can potentially form a mixture of E)- and (Z)-isomers. Reaction of 94 with various alkyl halides led to the 0-alkylation product (95) and the C-alkylation product (96). In DMSO, the ratio of O- to C-alkylation is relatively insensitive to changes in the gegenion (the metal), suggesting that the enolate is an unencumbered anion in this cation solvating medium. Note that C-alkylation is preferred except when the steric bulk at the nucleophilic carbon becomes too great (R, = Ph, Ph or Et, Et). For PhCOCHPh2 (93, r1 = r2 = Ph), O-alkylation is effectively the only process. 

This reaction can sometimes be useful in synthesis. In the Honda et al. formal synthesis of securinine,2h N-benzylamino-ketone (97) was treated with lithium hexamethyldisilazide and then sorbic anhydride. This gave dienyl ester 98 by O-alkylation of the initially formed enolate anion. When the nitrogen protecting group was 

In ether and THF, 0-alkylation is a much less serious problem in reactions with alkyl halides. With the possible exception of iodomethane, the use of lithium enolates in ether solvents leads to C-alkylation as the major product in virtually all cases. When the enolate carbanion center is sterically hindered, however, O-alkylation can be a problem, even in THF or ether. There are some reagents that prefer 0-alkylation, with silyl halides, and anhydrides being the most common. Both of these O-alkylation reactions will be discussed in Section 9.3.C. 

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The heats of reaction for O-alkylation and C-alkylation of enolate anions clearly show that the latter reactions lead to the thermodynamically more stable products 12). 

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