Dakin–West reaction explained

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). In 2016 Schreiner and coworkers reported the first asymmetric variant of this reaction employing short oligopeptides as catalysts.^[6]

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

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]}

General ketone synthesis

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]

See also

• Robinson–Gabriel synthesis - A process for converting the keto-amide products of this reaction into oxazoles

Notes and References

1. Dakin. Henry Drysdale. West. Randolph. A General Reaction of Amino Acids. The Journal of Biological Chemistry. 1928. 78. 1. 91–104. 10.1016/S0021-9258(18)84021-2. free.
2. Dakin. Henry Drysdale. West. Randolph. A General Reaction of Amino Acids. II. The Journal of Biological Chemistry. 1928. 78. 3. 745–756. 10.1016/S0021-9258(18)83978-3. free.
3. Dakin. Henry Drysdale. West. Randolph. Some Aromatic Derivatives of Substituted Acetylaminoacetones. The Journal of Biological Chemistry. 1928. 78. 3. 757–764. 10.1016/S0021-9258(18)83979-5. free.
4. Wiley. Richard H.. The Conversion of Amino Acids to Oxazoles. The Journal of Organic Chemistry. 1947. 12. 1. 43–46. 10.1021/jo01165a006. 20280736.
5. Buchanan. G. L.. The Dakin–West reaction. Chemical Society Reviews. 1988. 17. 91–109. 10.1039/CS9881700091.
6. Wende. Raffael C.. Seitz. Alexander. Niedek. Dominik. Schuler. Sören M. M.. Hofmann. Christine. Becker. Jonathan. Schreiner. Peter R.. The Enantioselective Dakin-West Reaction. Angewandte Chemie International Edition. 2016. 55. 8. 2719–2723. 10.1002/anie.201509863. 26804727.
7. Wiley. Richard H.. Borum. O. H.. 3-Acetamido-2-butanone. Organic Syntheses. 1953. 33. 1. 10.15227/orgsyn.033.0001.
8. Höfle. Gerhard. Steglich. Wolfgang. Vorbrüggen. Helmut. 4-Dialkylaminopyridines as Highly Active Acylation Catalysts. [New synthetic method (25)]. Angewandte Chemie International Edition in English. 1978. 17. 8. 569–583. 10.1002/anie.197805691.
9. Knorr. Rudolf. Huisgen. Rolf. Zum Mechanismus der Dakin-West-Reaktion, I Die Reaktion von N-Acyl-sek.-aminosäuren mit Acetanhydrid. Chemische Berichte. 1970. 103. 8. 2598–2610. 10.1002/cber.19701030831. 5448834.
10. Allinger. Norman L.. Wang. Grace L.. Dewhurst. Brian B.. Kinetic and mechanistic studies of the Dakin-West reaction. The Journal of Organic Chemistry. 1974. 39. 12. 1730–1735. 10.1021/jo00925a029.
11. Tran. Khanh-Van. Bickar. David. Dakin−West Synthesis of β-Aryl Ketones. The Journal of Organic Chemistry. 2006. 71. 17. 6640–6643. 10.1021/jo0607966. 16901161.