6.2 Direct Alkylation of Simple Enolates

6.2 Direct Alkylation of Simple enolates

Ester enolates: ester (pKa ~25) do not form high concentration of enolates when treated with alkoxides (alcohol pKa 16-18). Therefore, strong, non- nucleophilic bases, such as LDA (pKa =36), are required to rapidly and quantitatively deprotonate them at -78oC in THF. (Kinetic condition)

HMPA may be added to ester enolate alkylation to improve the yields.

If the ester possesses a β-stereocenter and the β-substituents are of widely different size, then alkylation of the enolate derived from such an ester usually leads to high diastereoselectivity. For example, to minimize the A1,3 strain the enolate adopts a conformation in which the smallest group (H) is nearly eclipsing with double bond. The nucleophile, MeI, then approaches the enolate from the side

opposite the larger group (phMe2Si).

1 Dilithio dianions of carboxylic acids can be prepared in THF-HMPA solution using LDA as the base. These anions are more stable than α-ester anion but can still be readily C-alkylated.

N,N-disubstituted amides are efficiently α-alkylated by treatment with a strong base followed by reaction with an alkyl halide.

Ketone Enolates

Ketone requires a strong base than NaOEt or NaOCH3 to convert them into enolate anions in high enough concentration to be useful for subsequent alkylation.

2 Common base used to generate ketone enolates for alkylation (1) t-BuOK in DMSO, t-BuOH, THF, or DME (2) NaH in THF or DME

(3) NaNH2 in Et2O, THF, or DME (4) Or lithium dialkylamide (R2NLi)

Regioselective Enolate Formation via Deprotonation

Thermodynamic enolates are generated at room temperature or reflux by conducting the deprotonation in the presence of a small amount of a weak acid. Lithiated bases are preferred for thermodynamic enolate generation because lithium enoates have a fairly covalent oxyfgen-lithium bond. Consequently, the most stable enolates will be those that have the most highly substituted double bond.

3 The ratio can be measured by reacting the enolates with R3SiCl. Silyl halide such Me3SiCl are oxophilic and react nearly exclusively via O-silylation, forming an oxygen-silicon bond (142 kcal/mol) rather than a carbon silicon-bond (85 kcal/mol)

4 Kinetic enolates are obtained by slow addition of the ketone (1.00 eq.) to an excess of a hindered strong base at low temperature in an aprotic solvent.

5 Since conjugated enolates react almost exclusively at the α-position, low temperature protonation of a conjugated enolate provides the β,γ-undaturated ketone.

6 Via Cleavage of Silyl Enol Ethers

Regioselectively generated silyl enol ethers react with methyllithium to afford regiochemically pure lithium enolates.

Via-metal-ammonia reduction of enones

Vis conjugate addition reactions

Trapped by silyl chloride, acyl halide, dialkyl carbonates

7 Conjugate reduction of enones with K-selectride (K[sec-Bu3BH]) is valuable method for regiospecifically generating enolate anions.

Via introduction of Activating group

Intermolecular Alkylation of Ketone Enolates

Several factors must be adjusted to maximize the C-alkylation of ketone enolates.

8 If di- or polyalkylation is a problem, the addition of triethanolamine borate to the reaction mixture will suppress overalkylation. Likewise, enolates formed in the presence of Et3B reacts smoothly to form mono-alkylation products.