Alkylation, enolate ions basicity

Mazur " obtained 2a-alkyl-5a-H (3) or 4 -alkyl-5 -H products (6) by direct alkylation of either 5a-H (1) or 5 -H-3-keto steroids (4) with alkyl halides under basic conditions. In general, formation and alkylation of the more stable enolate ion is observed in this procedure. 

The enolate ions of esters or ketones can also be alkylated with alkyl halides to create larger carbon skeletons [Following fig.(b)]. The most successful nucleophilic substitutions are with primary alkyl halides. With secondary and tertiary alkyl halides, the elimination reaction may compete, particularly when the nucleophile is a strong base. The substitution of tertiary alkyl halides is best done in a protic solvent with weakly basic nucleophiles. However, yields may be poor. 

Alkylation of disubstituted acetic esters has become an important new route to trisubstituted acetic acids and their derivatives. Sodium tri-phenylmethide or potassium triphenylmethide is used to convert the ester to its enolate ion, which, in turn, is allowed to react with an alkyl iodide to form the trialkylated ester. The yields are in the range of 42-61%. Potassium hydroxide in acetal solvents serves as basic reagent in the alkylation of certain esters by reactive halides. An interesting preparation of diethyl tetramethylsuccinate involves alkylation of ethyl isobutyrate with ethyl a-bromoisobutyrate. The yield is 30%. ... 

Two of the four general carbonyl-group reactions—carbonyl condensations and a substitutions—take place under basic conditions and involve enolate ion intermediates. Since the experimental conditions for the two reactions are so similar, how can we predict which will occur in a given case When we generate an enolate ion with the intention of carrying out an < alkylation, how can we be sure that a carbonyl condensation reaction won t occur instead ... 

The enolate ion is nucleophilic at the alpha carbon. Enolates prepared from aldehydes are difficult to control, since aldehydes are also very good electrophiles and a dimerization reaction often occurs (self-aldol condensation). However, the enolate of a ketone is a versatile synthetic tool since it can react with a wide variety of electrophiles. For example, when treated with an unhindered alkyl halide (RX), an enolate will act as a nucleophile in an Sn2 mechanism that adds an alkyl group to the alpha carbon. This two-step a-alkylation process begins by deprotonation of a ketone with a strong base, such as lithium diisopropylamide (LDA) at -78°C, followed by the addition of an alkyl halide. Since the enolate nucleophile is also strongly basic, the alkyl halide must be unhindered to avoid the competing E2 elimination (ideal RX for Sn2 = 1°, ally lie, benzylic). 

We also know that hydroxide ion or alkoxide ions are not basic enough to form the enolate ion in high concentration. Hence, the hydroxide ion or alkoxide ion would substitute for the halide ion of the alkyl halide to give an alcohol or ether. However, strong bases, such as potassium hydride or LDA, yield stoichiometric quantities of the enolate. An alkyl halide is then added to the solution of the enolate to give the a-alkylated product. 

The synthetic chemistry of enolate anions is centered on their nucleophilic and basic properties. Accordingly these ions participate in SN2 reactions with suitable alkyl compounds ... 

Reactions with stabilized enolate species such as malonate ions also lead to alkylation, but because of the requisite basic conditions, the initial alkylation products are subsequently converted to secondary products [289]. 

Interestingly, no correlation could be observed from their monomer ion-pair acidities (pAT0 in THF) and the second-order rate constant for the monomer in their reaction with m-chlorobenzyl bromide (Table 2, right), a linear relationship occurs when the corresponding cesium salts are alkylated with methyl tosylate. On the other hand according to the authors, this accounts for the fact that the lithium cation is as important as the basicity of the enolate. 

Ambient nucleophiles ( S-diketones or jS-ketoesters) are known to attack always by the more basic y-carbon atom. A difficulty, frequently encountered in intramolecular alkylation of S-dicarbonyl compounds, is the concurrent formation of both C- and 0-alkylated products. It is, however, normally possible to direct the alkylation toward carbon or oxygen by proper selection of (1) the solvent, (2) the enolate counter ion, and (3) the leaving group. 

In the presence of a very strong base, such as amide ion or an organolithium reagent, it is possible to convert dicarbonyl compounds to their dianions. Subsequent alkylation of such dianions leads to alkylation at the more strongly basic enolate site, rather than at the carbon atom between the two carbonyl carbons. The more acidic methylene group activated by two carbonyl substituents is the preferred site in the monoanion, as discussed earlier. The ability to determine the site of monoalkylation by choice of the amount and nature of the basic catalyst has significantly expanded the synthetic utility of enolate alkylations. Scheme 1.7 gives some examples of formation and alkylation of dianions. 

Alkylation of j8-diketones using polymers as supports for the intermediate enolate anion has also been reported (Gelbard and Colonna, 1977). Reaction of several cyclohexyl j3-diketones with Amberlite IRA-9(K) formed a resin-linked j8-diketonate that could be readily alkylated. Similarly, it was shown that alkylation of phenoxide anions can be readily effected when the anions are supported via an ionic bond with the resin (Gelbard and Colonna, 1977). Alkylations of /3-diketones were also shown to occur if a fluoride-substituted, strongly basic resin (Amberlyst A26, A27, or Dowex MSA-1) is used (Miller et at., 1978). In this case, the presence of the fluoride ion was necessary before reaction would proceed. Considering the report on the use of Amberlite IRA-900— a very similar resin— the necessity for a fluoride ion is puzzling. In the same publication, the 0-alkylation of phenols, the sulfenylation of /3-diketones, and the Michael addition of a thiol to an ot,/8-unsaturated ketone were also investigated. 

We recall that enolates undergo condensation reactions with the carbonyl carbon atom of aldehydes (Section 21.7). Enolates tend to react to give alkylation at carbon. A similar reaction occurs between the phenolate ion and formaldehyde. Because both C-2 and C-4 are nucleophilic, two possible condensation products may result. The following reaction shows condensation at C-4, producing a conjugation-extended enolate. Subsequent tautomerization generates the enol form, which is a phenol. Solvent-mediated proton transfer also occurs, giving a phenoxide rather than the more basic (and less stable) alkoxide ion. 

---