Stork reaction

What is Stork reaction?

The Stork reaction was initially discovered by Stork et al. in 1954. This reaction involves the use of an enamine, which acts as an effective enol synthon, to mediate the alkylation or acylation at the α-carbon of carbonyl compounds such as aldehydes or ketones.

The Stork alkylation and Stork acylation refer to the enamine-based reactions that allow for this type of synthesis. Additionally, the Stork addition, Stork enamine addition, or Michael-Stork addition all refer to enamine-mediated addition or conjugated addition.

Stork reaction - general reaction scheme
Stork reaction
  • R1, R2 = alkyl or R1R2NH = pyrrolidine, piperidine, morpholine
  • R = alkyl, benzyl, allyl, acyl
  • X = halogen, TfO, etc. (see list of acronyms)

The rate of alkylation depends on the basicity and steric environment of the secondary amine. Cyclic enamines with six-membered rings are slightly stronger bases than saturated tertiary amines, while those with five- and seven-membered rings are much stronger bases. To prepare enamines from ketones or aldehydes, cyclic secondary amines such as pyrrolidine, piperidine, or morpholine are typically used under mild conditions.

The use of enamine as an enol synthon can effectively reduce the possibility of overalkylation, although overreaction is still a major issue. Enamines can also undergo double acylation, forming β-diketones or triketones upon hydrolysis. Hexamethylenimine produces a high yield of monoalkylated ketones, while piperidine-derived enamines give a low yield. Moreover, the nitrogen atom of enamine may participate in the alkylation, even when pyrrolidine is replaced with piperidine.

Interestingly, the morpholine enamine of cyclohexanone reacts with phenyl isocyanate at the other α-carbon, not belonging to the enamine moiety. It is important to note that the reaction between carbonyl compounds and primary amines typically gives imines, while secondary amines yield enamines. However, the presence of α-substituents can affect this trend. For example, α-cyano groups favor the formation of enamines, while amino or dialkylamino groups stabilize the imine structure.

References

A new synthesis of 2-alkyl and 2-acyl ketones
Gilbert Stork, Ross Terrell, and Jacob Szmuszkovicz
Journal of the American Chemical Society 1954 76 (7), 2029-2030
DOI: 10.1021/ja01636a103

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