Lithium dialkylamides ester enolization

A further improvement utilizes the compatibility of hindered lithium dialkylamides with TMSC1 at —78 °C. Deprotonation of ketones and esters with lithium dialkylamides in the presence of TMSC1 leads to enhanced selectivity (3) for the kinetically generated enolate. Lithium t-octyl-t-butyl-amide (4) appears to be superior to LDA for the regioselective generation of enolates and in the stereoselective formation of (E) enolates. 

Kinetic enolates. The kinetic enolate of a ketone or ester is generated with enhanced selectivity by a lithium dialkylamide in the presence of chlorotrimethylsilane. In addition, LOBA is superior to LDA for regioseicctivc generation of enolates and for stereoselective formation of (E)-enolatfes. 

In 1972, a further brilliant improvement on the Claisen rearrangement was realized by Ireland and co-woikers. Ester enolization wiA lithium dialkylamide bases, followed by silylation with TMS-Cl, generated reactive silyl ketene acetals at -78 °C or lower temperatures. Sigmatropic rearrangement to easily hydrolyzable 7,8-unsaturated silyl esters occurred at ambient tempontures (15 16 17 equa-... 

Deprotonation of esters with lithium dialkylamides gives rise to ( )-enolates. However, with normal alkyl propionates there is little or no stereoselectivity in additions to aldehydes (equation 65). It was found by Meyers and Reider that certain esters that contain additional ether oxygens in the alcohol moiety give reasonably high anti selectivity (equation 66). Unfortunately, this high selectivity is not general, as is shown by the example in equation (67). ... 

Zinc ester enolates may also be obtained by the addition of ZnX2 to lithium or sodium enolates as first described by Hauser and Puterbaugh (equation 6)P This approach has so far received little attention but similar reactions have been used to obtain zinc ketone enolates. In this regard, it should be noted that Heathcock and coworkers have shown that deprotonation reactions of ketones with zinc dialkylamide bases reach equilibrium at only about 50% conversion (equation 7). This result implies that attempts to prepare zinc enolates from solutions of amide-generated lithium enolates will be successful only when the lithium enolate is made amine-free. 

In 1972, Ireland and Mueller reported the transformation that has come to be known as the Ireland-Claisen rearrangement (Scheme 4.2) [1]. Use of a lithium dialkylamide base allowed for efficient low temperature enolization of the allyUc ester. They found that sUylation of the ester enolate suppressed side reactions such as decomposition via the ketene pathway and Claisen-type condensations. Although this first reported Ireland-Claisen rearrangement was presumably dia-stereoselective vide infra, Section 4.6.1), the stereochemistry of the alkyl groups was not an issue in its application to the synthesis of dihydrojasmone. 

The reactions discussed in section 4.1 obviously describe enolate anion reactions. The reactions in this section involve malonate derivatives that react with bases such as sodium hydride or lithium dialkylamides to generate the malonate anion, a highly stabilized enolate. This section also includes reactions of enolate anions derived from mono-esters and other acid derivatives. 

Trimethylsilylacetate esters may he converted to the enolate by treatment with lithium dialkylamide bases (LDA in Eq. 7.28) in THF at -78°C. These will add to ketones or aldehydes quickly at -78°C, followed by elimination of MOjSiOLi and formation of a,p-unsaturated esters in high yields, uncontaminated by p,y-unsaturated isomers [47]. This is known as the Peterson reaction [48, 49]. The requisite ethyl trimethylsilylacetate is made by the reaction of cldorotrimethylsilane, ethyl bromoacetate, and zinc [50]. Esters of longer-chain acids give mostly 0-silylation under these conditions, but diphenylmethylchlorosilane gives C-silylation selectively. These diphenyl-methylsilylated esters also give the Peterson reaction (Eq. 7.29) [51]. 

The reaction of lithium enolates with molecular oxygen has been used for the a-hydroxylation of several substrates. The carbanion generated in the reaction of N,N-dialkylamides or esters with alkyl lithium reagents undergoes rapid oxidation under mild conditions when treated with molecular oxygen. The reaction produces an a-hydroperoxide intermediate which is cleanly reduced with sodium sulphite to the a-hydroxo derivatives" (equation 1). 

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