Alkylation preformed lithium enolates

A number of methods have been developed for accomplishing aldol addition reactions in a stereoselective manner. The preformed lithium enolates of alkyl esters normally react with aldehydes to give mixtures of the two diastereomeric g-hydroxy esters (eq 1). However, the enolates derived from... 

Several examples of conjugate addition of carbanions carried out under aprotic conditions are given in Scheme 2.24. The reactions are typically quenched by addition of a proton source to neutralize the enolate. It is also possible to trap the adduct by silylation or, as we will see in Section 2.6.2, to carry out a tandem alkylation. Lithium enolates preformed by reaction with LDA in THF react with enones to give 1,4-diketones (Entries 1 and 2). Entries 3 and 4 involve addition of ester enolates to enones. The reaction in Entry 3 gives the 1,2-addition product at —78°C but isomerizes to the 1,4-product at 25° C. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,(3-unsaturated esters (Entry 5). Entries 6 to 8 show cases of... 

The extra ester group is not normally added to the preformed ketone as ethyl acetoacetate 41 is available and the diester is available diethyl malonate 59. If it is necessary to make the 1,3-dicarbonyl compound, this can be done by methods described in chapters 19 and 20. The carboxylic acid 56 can be disconnected at the branchpoint to an alkyl halide and the synthon 58 that could be realised as the anion of diethyl malonate 59 or the lithium enolate of ethyl acetate. 

Seebach has also studied the utility of esters in organometallic acylation. In this case, preformed ester enolates of 2,6-di(t-butyl)-4-methylphenyl esters (BHT esters) were slowly warmed above -20 C to form the corresponding ketene. If this was done in the presence of an ad tional equivalent of alkyl-lithium the ketene was trapped to give a ketone enolate in high yield. The same reaction failed to give any product when simple esters such as methyl, ethyl or Nbutyl were uscd. Scheme 17 is illustrative of the method. 

Stereoselective aldol condensation. Aldol condensation has been shown to be subject to kinetic stereoselection, with (Z)-enolates giving mainly the erythro-aldol and (E)-enolates giving mainly the (Areo-aldol. This observation has been extended to preformed (Z)- and (E)-lithium enolates generated under kinetic control with LDA in THF or ether at — 72°. When one of the alkyl groups is sterically demanding, complete kinetic stereospecificity can be obtained. As the bulk of the alkyl group decreases, stereoselection also decreases. Thus the kinetic enolate of ethyl /-butyl ketone (1) is the (Z)-isomer a, and it reacts with benzalde-hyde to form the erythro-aldol (2) with no detectable amounts of the threo-aldol. 

The Tsuji-Trost protocol has been successfiilly employed for the allyUc alkylation of preformed lactone enolates. It has been demonstrated that this Pd-catalysed reaction can be carried out in an enantio- and diastereo-selective manner. The use of additives, such as LiCl, was found to be crucial for reaching high levels of product selectivity. Among the five pathways investigated by DFT methods, the reaction between an (allyl)Pd(BINAP) (2,2 -bis(diphenylphosphino)-1,1 -binaphthyl) complex and a LiCl-lithium enolate adduct was predicted to be the most likely route for C-C bond formation. 

The simple lithium tetraorganoaluminates including LiAlEt4 are known to polymerize methyl methacrylate monomers [222]. This is, however, only possible at the very low temperature of -78°C. In contrast, preformation of the i-Bu2Al(BHT)-t-BuLi complex, then treatment of methyl methacrylate at 0°C afforded PMMA with a molecular weight of 28400 (Scheme 6.174) [223]. NMR analysis revealed that the alkyl group bonded to the end of the polymer chain is the t-Bu moiety derived from t-BuLi and not alkyl groups from aluminum. The contribution of two enolate intermediates, monomeric and dimeric aluminum species, was invoked to account for the structure of the initiation species. 

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