Stork enamine alkylation
The Stork enamine alkylation involves the addition of an enamine to a Michael acceptor or other electrophile to give an alkylated iminium product, which is hydrolyzed by dilute aqueous acid to give the alkylated ketone or aldehyde. Since enamines are generally produced from ketones or aldehydes, this overall process constitutes a selective monoalkylation of a ketone or aldehyde, a process that may be difficult to achieve directly.
The reaction is named after its inventor, Gilbert Stork.
Scope
The most reliable Stork enamine synthesis adds the enamine to a Michael acceptor:- formation of an enamine from a ketone
- addition of the enamine to an alpha, beta-unsaturated aldehyde or ketone
- hydrolysis of the enamine back to a ketone
However, the reaction applies to a wide variety of electrophiles. Acyl halides result in the formation of 1,3-diketones ; and benzylic, allylic/propargylic, α-carbonyl, and α-alkoxy halides alkylate the enamine.
However, the mechanism of the Stork reaction is not entirely straightforward. Enamines are stronger nucleophiles at the nitrogen atom, and initially react there before undergoing Hofmann-type rearrangement to the product. Thus methyl and other primary alkyl halides generally only give low to moderate yields of the desired alkylation product.
An anionic enamine, known as an azaenolate or metalloenamine, enables alkylation with less-reactive alkyl halides:
[Image:Stork C alkylation.png|center|400px|Stork enamine reaction with alkyl halides]
In this method a carbonyl compound is condensed to a Schiff base. The imine then reacts with a Grignard reagent to the corresponding Hauser base. The chelating effect of the magnesium ion and the species' negative charge shifts the primary site of nucleophilicity to carbon, and enables displacing a less reactive alkyl halide. Hydrolysis then yields the alkylated ketone.
In the Enders SAMP/RAMP hydrazone-alkylation reaction, a hydrazone replaces the amine for enantioselection.