Alkylating the α-carbon via enolate formation
Alkylating the α-carbon via enolate formation
Putting an alkyl group on the α-carbon of a carbonyl compound is one way of important reaction to form a carbon–carbon bond.
- First, the strong base, such as LDA, removes the proton from the α-carbon.
- Then, alkyl halide (best with primary alkyl halides) is added and alkylation proceeds in the SN2 reaction.
LDA (lithium diisopropylamide)
- LDA (lithium diisopropylamide) is used to remove
the α-hydrogen, essentially all the carbonyl compound is converted to the enolate ion. - The product acid (diisopropylamine, or DIA) is a much weaker acid than the reactant acid (the ketone).
- LDA is easily prepared by adding butyllithium to diisopropylamine in THF at -78℃ (that is, at the temperature of a dry ice/acetone bath.)
Alkylating unsymmetrical ketones
If the ketone is unsymmetrical and has hydrogens on both
α-carbons, two monoalkylated products can be obtained.
The relative amounts of the two products depend on the reaction conditions.
The reaction is carried out with a kinetic enolate ion
- Under irreversibly conditions (-78°C).
- Using a bulky base such as LDA.
The reaction is carried out with a thermodynamic enolate ion
- Under reversibly conditions.
- More alkyl substituents (due to increased alkene stability).
Alkylating the α-carbon using an Enamine
Alkylate an aldehyde or a ketone is that it forms a monoalkylated product without having to use a strong base (LDA).
Enamines react with electrophiles in the same way that enolate ions do.
Mechanism of the alkylation of an a-carbon via an enamine
- Cyclohexanone (carbonyl compound) is converted to enamine by treatment with Pyrrolidine (secondary amine) in the presence of a trace amount of acid.
- The enamine reacts with the alkyl halide in an SN2 reaction.
- The imine is hydrolyzed to an α-alkylated ketone and the secondary amine that was used to form the enamine.
