Stork enamine alkylation
The Stork enamine alkylation involves the addition of an enamine to a Michael acceptor (e.g., an α,β -unsaturated carbonyl compound) or other electrophile to give an alkylated iminium product, which is hydrolyzed by dilute aqueous acid to give the alkylated ketone or aldehyde.[1] Since enamines are generally produced from ketones or aldehydes, this overall process (known as the Stork enamine synthesis) 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 (Columbia University).
Scope
[edit]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 (Stork acylation);[2] and benzylic, allylic/propargylic, α-carbonyl (e.g., bromoacetone), and α-alkoxy (e.g., methoxymethyl chloride) 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.[3] Thus methyl and other primary alkyl halides generally only give low to moderate yields of the desired alkylation product.[4]
An anionic enamine, known as an azaenolate or metalloenamine, enables alkylation with less-reactive alkyl halides:[5]
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.
References
[edit]- ^ McMurry, John (21 March 2003). Organic Chemistry (Hardcover) (6th ed.). Belmont, CA: Thomson-Brooks/Cole. ISBN 0-534-38999-6.
- ^ March, Jerry (1985). Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.). New York: Wiley. ISBN 9780471854722. OCLC 642506595.
- ^ Mayr, Herbert (2011). "Farewell to the HSAB Treatment of Ambident Reactivity". Angewandte Chemie International Edition. 50 (29): 6481–6483. Bibcode:2011ACIE...50.6470M. doi:10.1002/anie.201007100. PMID 21726020, an excerpt from Breugst, Robert Martin (2010). A Marcus-Theory-Based Approach to Ambident Reactivity (PDF) (PhD dissertation). Ludwig Maximilian University of Munich. pp. 340–343.
- ^ Stork, Gilbert.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. (January 1963). "The Enamine Alkylation and Acylation of Carbonyl Compounds". Journal of the American Chemical Society. 85 (2): 207–222. Bibcode:1963JAChS..85..207S. doi:10.1021/ja00885a021. ISSN 0002-7863.
- ^ A New Method for the Alkylation of Ketones and Aldehydes: the C-Alkylation of the Magnesium Salts of N-Substituted Imines Gilbert Stork and Susan R. Dowd J. Am. Chem. Soc.; 1963; 85(14) pp 2178–80; doi:10.1021/ja00897a040