Bases Lithium isopropyl amide

Even with fairly strong bases such as hydroxides or alkoxides, most carbonyl compounds are converted to their enolates only to a very small extent. A typical p Ta for the protons next to a carbonyl group is 20-25, while the pKa of methoxide is around 16, so we can only hope for about 1 part enolate in 104 parts carbonyl compound. With a much stronger base, this all changes, and the enolate is formed quantitatively from the carbonyl compound. This is a very important result which we shall capitalize on in Chapters 26 and 27. The base usually used is LDA (Lithium Di-isopropyl Amide), and it works like this. 

Substituted sulfinyl esters (6) have also been prepared by this reaction using the same base or lithium cyclohexyl-(isopropyl)amide, which gives higher yields. 

To form an enolate in essentially 100% yield, a much stronger base such as lithium diisopropyl-amide, Li NrCH(CHn)2l7. abbreviated as LDA, is used (entry 5). LDA is a strong nonnucleo-philic base. Like the other nonnucleophilic bases (Sections 7.8B and 8.1), its bulky isopropyl groups make the nitrogen atom too hindered to serve as a nucleophile. It is stUl able, though, to remove a proton in an acid-base reaction. 

What is needed for the alkylation is rapid conversion of the ester into a reasonably stable enolate, so rapid in fact that there is no unenolised ester left. In other words the rate of proton removal must be faster than the rate of combination of enolate and ester. These conditions are met when lithium enolates are made from esters with lithium amide bases at low temperature, often 78 °C. Hindered bases must be used as otherwise nucleophilic displacement will occur at the ester carbonyl group to give an amide. Popular bases are LDA (Lithium Di-isopropyl Amide, 66), lithium hexamethyldisilazide 67, and lithium tetramethylpiperidide 68, the most hindered of all. These bases are conveniently prepared from the amine, e.g. 65 for LDA, and BuLi in dry THF solution. 

As can be seen in the Table, lithium di isopropyl amide (LOA) is a satisfactory base in cases where the carbon group (R) of a methyl ketone (RCOCH3) either is bulky or does not contain an a-niethylene or a-methine group. In the other cases, LDA Is relatively ineffective. In such cases, however, the use of lithium 2,2,6,6-tetramethylpiperidide (LTMP) in place of LDA gives satisfactory results. The LTMP procedure appears to be the only documented method that is satisfactory for the conversion of the above-mentioned type. 

The aldol reaction of 2,2-dimethyl-3-pentanone, which is mediated by chiral lithium amide bases, is another route for the formation of nonracemic aldols. Indeed, (lS,2S)-l-hydroxy-2,4,4-trimethyl-l-phenyl-3-pentanone (21) is obtained in 68% ee, if the chiral lithiated amide (/ )-A-isopropyl-n-lithio-2-methoxy-l-phenylethanamine is used in order to chelate the (Z)-lithium cnolate, and which thus promotes the addition to benzaldehyde in an enantioselective manner. No anti-adduct is formed25. 

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