Dakin–West reaction

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The Dakin–West reaction is a chemical reaction that transforms an amino-acid into a keto-amide using an acid anhydride and a base, typically pyridine.[1][2][3][4][5]

It is named for Henry Drysdale Dakin (1880–1952) and Randolph West (1890–1949). Of special note, the keto-amide product is always racemic. However, in 2016 Schreiner and coworkers reported the first asymmetric variant of this reaction.[6]

The Dakin–West reaction

With pyridine as a base and solvent, refluxing conditions are required.[7] However, with the addition of 4-dimethylaminopyridine (DMAP) as a catalyst, the reaction can take place at room temperature.[8]

With some acids, this reaction can take place even in the absence of an α-amino group.

This reaction should not be confused with the Dakin reaction.

Reaction mechanism[edit]

The reaction mechanism involves the acylation and activation of the acid 1 to the mixed anhydride 3. The amide will serve as a nucleophile for the cyclization forming the azlactone 4. Deprotonation and acylation of the azlactone forms the key carbon-carbon bond. Subsequent ring-opening of 6 and decarboxylation give the final keto-amide product.[9][10]

The mechanism of the Dakin-West reaction

General ketone synthesis[edit]

Modern variations on the Dakin–West reaction permit many enolizable carboxylic acids – not merely amino acids – to be converted to their corresponding methyl ketones. For example, β-aryl carboxylic acids can be efficiently converted to β-aryl ketones by treatment of an acetic anhydride solution of the acid with catalytic N-methylimidazole. This reactivity is attributed in part to generation of acetylimidazolium, a powerful cationic acetylating agent, in situ.[11]

Modified Dakin-West reaction

See Also[edit]

References[edit]

  1. ^ Dakin, Henry Drysdale; West, Randolph (1928). "A General Reaction of Amino Acids". The Journal of Biological Chemistry 78 (1): 91–104. 
  2. ^ Dakin, Henry Drysdale; West, Randolph (1928). "A General Reaction of Amino Acids. II". The Journal of Biological Chemistry 78 (3): 745–756. 
  3. ^ Dakin, Henry Drysdale; West, Randolph (1928). "Some Aromatic Derivatives of Substituted Acetylaminoacetones". The Journal of Biological Chemistry 78 (3): 757–764. 
  4. ^ Wiley, Richard H. (1947). "The Conversion of Amino Acids to Oxazoles". The Journal of Organic Chemistry 12 (1): 43–46. doi:10.1021/jo01165a006. 
  5. ^ Buchanan, G. L. (1988). "The Dakin–West reaction". Chemical Society Reviews 17: 91–109. doi:10.1039/CS9881700091. 
  6. ^ Wende, Raffael C.; Seitz, Alexander; Niedek, Dominik; Schuler, Sören M. M.; Hofmann, Christine; Becker, Jonathan; Schreiner, Peter R. (2016). "The Enantioselective Dakin-West Reaction". Angewandte Chemie International Edition 55: 2719-2723. doi:10.1002/anie.201509863. 
  7. ^ Wiley, Richard H.; Borum, O. H. (1953). "3-Acetamido-2-butanone". Organic Syntheses 33: 1. doi:10.15227/orgsyn.033.0001. 
  8. ^ Höfle, Gerhard; Steglich, Wolfgang; Vorbrüggen, Helmut (1978). "4-Dialkylaminopyridines as Highly Active Acylation Catalysts. [New synthetic method (25)]". Angewandte Chemie International Edition in English 17 (8): 569–583. doi:10.1002/anie.197805691. 
  9. ^ Knorr, Rudolf; Huisgen, Rolf (1970). "Zum Mechanismus der Dakin-West-Reaktion, I Die Reaktion von N-Acyl-sek.-aminosäuren mit Acetanhydrid". Chemische Berichte 103 (8): 2598–2610. doi:10.1002/cber.19701030831. 
  10. ^ Allinger, Norman L.; Wang, Grace L.; Dewhurst, Brian B. (1974). "Kinetic and mechanistic studies of the Dakin-West reaction". The Journal of Organic Chemistry 39 (12): 1730–1735. doi:10.1021/jo00925a029. 
  11. ^ Tran, Khanh-Van; Bickar, David (2006). "Dakin−West Synthesis of β-Aryl Ketones". The Journal of Organic Chemistry 71 (17): 6640–6643. doi:10.1021/jo0607966.