Alkylation of Simple Carbanion-Enolates

Carbanion-enolates are nucleophiles that react with alkyl halides (or sulfonates) by typical S 2 reactions, Carbanion-enolates are best formed using lithium diisopropylamide (lda), (r-Pr)2N Li, in tetrahydrofuran. This base is very strong and converts all the substrate to the anion. Furthermore, it is too sterically hindered to react with RX. 

Ketones, esters and nitriles but not aldehydes, which take a different route also can be reacted with LDA. See Table 17-1(6) for stabilization of negative charge on a C a to a C N group. 

Since the carbanion-enolates are ambident ions with two different nucleophilic sites, they can be alkylated at C or at O. 

O-alkylation reduces the yield of the more usually desired C-alkylation product. Other drawbacks to the synthetic utility of this reaction are (1) di- and tri-alkylation produces mixtures if more than a single H is present on the a C (2) ketones with H s on more than one a C will give a mixture of alkylation products. 

Problem 17.10 (a) Use carbanion-enolate alkylations to synthesize (i) 2-ethylbutanenitrile, (ii) 3-phenyl-2-pentanone, (iii) 2-benzylcyclopentanone. (6) Why can the unsymmetrical ketone in part (ii) be alkylated in good yield 4 

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While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

A complete understanding of enolate chemistry must include knowledge of the aggregation of the enolate species involved [5]. Consider the reaction of an enolate with an alkyl halide as it may have been depicted over the years (Scheme 3.3), progressing from the simple carbanion alkylation to the reaction of supramolecular aggregates. 

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

Alkylations occur in the reaction of carbanions with simple primary or secondary alkyl chlorides, bromides, iodides, or tosylates. For the reaction in Equation 7.5, a weak base was used to generate a small concentration of the resonance delocalized enolate anion [14], In this case, the electrophile, methyl iodide, is present from the initial stage. The least hindered side of the carbanion attacked to give the diastereomer shown. 

Ordinarily nucleophilic addition to the carbon-carbon double bond of an alkene is very rare It occurs with a p unsaturated carbonyl compounds because the carbanion that results IS an enolate which is more stable than a simple alkyl anion... 

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