Deprotonation of Carbonyl Compounds by Lithium Dialkylamides

The intermediate formed in the nucleophilic addition step abstracts a proton from the solvent to give the observed product. 

After isolation, the Michael addnct may be subjected to ester hydrolysis and decarboxylation. When a,(3-nnsaturated ketones are carried through this sequence, the final prodncts are 5-keto acids (8-keto acids). 

Ethyl 2-carboethoxy-5-oxohexanoate (from diethyl malonate and methyl vinyl ketone) 

PROBLEM 21.13 Ethyl acetoacetate behaves similarly to diethyl malonate in its reactivity toward a,(3-unsaturated carbonyl compounds. Give the structure of the product of the following reaction sequence  

Most of the reactions of ester enolates described so far have centered on stabilized eno-lates derived from 1,3-dicarbonyl componnds snch as diethyl malonate and ethyl acetoacetate. Althongh the synthetic valne of these and related stabilized enolates is clear, chemists have long been interested in extending the nsefnlness of nonstabilized enolates derived from simple esters. Consider the deprotonation of an ester as represented by the acid-base reaction 

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Deprotonation of carbonyl compounds by lithium dialkylamide bases is the single most common method of forming alkali enolates. Four excellent reviews have already been published. " Sterically hindered amide bases are employed to retard nucleophilic attack on the carbonyl group. The most common and generally useful bases are (i) lithium diisopropylamide (LDA 5) (ii) lithium isopropylcyclo-hexylamide (LICA 6) (iii) lithium 2,2,6,6-tetramethylpiperidide (LITMP 7) (iv) lithium hexamethyldisilylamide (LHMDS 8) and (v) lithium tetramethyldiphenyldisilylamide (LTDDS 9). Bases that are not amides include sodium hydride, potassium hydride and triphenylmethyllithium. 

Metallated imines can be formed from imines derived from enolizable carbonyl compounds by deprotonation with Grignard reagents or organolithium reagents, but more recent studies have generally involved the use of lithium dialkylamides, e.g. LDA, as the base. Alternative methods of producing metallated imines, e.g. addition of r-butyllithium to the imine double bond of 2-azadienes, are known. 

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