Robinson–Gabriel synthesis
The Robinson–Gabriel synthesis is an organic reaction in which a 2-acylamino-ketone reacts intramolecularly followed by a dehydration to give an oxazole. A cyclodehydrating agent is needed to catalyze the reaction[1] [2][3] It is named after Sir Robert Robinson and Siegmund Garbriel who described the reaction in 1909 and 1910 respectively.
2-Acylamino-ketones can be synthesized using the Dakin–West reaction.
Reaction Mechanism
The first part of this reaction is the cyclization of an 2-acylamidoketone that contains all three oxazole substituents. The second part is a dehydration, removing water from the molecule [4]. Labeling studies have determined that the amide oxygen is the most Lewis basic and therefore is the one included in the oxazole [5].
Modifications
Recently, a solid-phase version of the Robinson-Gabriel synthesis has been described. The reacton requires trifluoroacetic anhydride to be used as the cyclodehydrating agent in etheral solvent and the 2-acylamidoketone be linked by the nitrogen atom to a benzhydrylic-type linker.
A one-pot diversity-oriented synthesis has been developed via a Friedel-Crafts/Robinson-Gabriel synthesis using a general oxazolone template. The combination of aluminum chloride as the Friedel-Craft Lewis acid and trifluoromethanesulfonic acid as the Robinson-Gabriel cyclodehydrating agent were determined to generate the desired products. [6]
A popular extension of the Robinson-Gabriel cyclodehydration has been reported by Wipf et al. to allow the synthesis of substituated oxazoles from readily available amino acid derivatives. This is achieved through the side-chain oxidation of β-keto amides with the Dess-Martin reagent followed by the cyclodehydration of intermediate β-keto amides with triphenylphosphine, iodine, and triethylamine. [7]
Cyclodehydrating Agents
Many cyclodehydrating agents have been discovered to be of use in the Robinson-Gabriel synthesis. Historically, the dehydration agent is concentrated sulfuric acid. To date, the reaction has been shown to proceed with a variety of other agents including phosphorous pentachloride, phosphorous pentoxide, phosphoryl chloride, thyonyl chloride, phosphoric acid-acetic anhydride, polyphosphoric acid, and anhydrous hydrogen fluoride [8]
Applications
Oxazoles have been found to be common substructures in multiple naturally isolated compounds and have thus garnered attention within the chemical and pharmaceutical community. The Robinson-Gabriel synthesis has been used during multiple studies dealing with molecules that incorporate an oxazole, among them Diazonamide A [9], Diazonamide B [10], bis-phosphine platinum (II) complexes[11], Mycalolide A[12]
Eric Biron et. al. developed a solid-phase synthesis of 1,3-oxazole-based peptides on solid phase from dipeptides by oxidation of the side-chain followed by Wipf and Miller's cyclodehydration of β-ketoamides described above [13].
Lilly Research Laboratories has disclosed the structure of a described dual PPARα/γ agonist that has possible beneficial impact on type 2 diabetes. The Robinson-Gabriel cyclodehydration is the second part of a two reaction synthesis of the agonist. Starting with aspartic acid β esters undergoing acylation to differentiate the first substituent, linked to carbon-2, followed by Dakin-West conversion to keto-amide to introduce the second substituent, and ending with the Robinson-Gabriel cyclodehydration at 90°C for 30 minutes with either phosphorus oxychloride in DMF or catalytic sulfuric acid in acetic anhydride. [14]
References
- ^ Robinson, R. J. Chem. Soc. 1909, 95, 2167.
- ^ Gabriel, S. Ber. 1910, 43, 134.
- ^ Gabriel, S. Ber. 1910, 43, 1283.
- ^ Turchi, I. (Sept 15, 2009). Heterocyclic Chemistry in Drug Discovery. John Wiley & Sons. p. 235. ISBN 978-1-118-14890-7.
{{cite book}}: Check date values in:|date=(help) - ^ Wasserman, H. J. Org. Chem 1973, 38, 2407-2408.
- ^ Keni, M. J. Org. Chem. 2005, 70, 4211-4213
- ^ Wipf, P. J. Org. Chem. 1993, 58, 3604-3606
- ^ Turchi, I. (Sept 15, 2009). The Chemistry of Heterocyclic Compounds, Oxazoles. John Wiley & Sons. p. 3. ISBN 9780471869580.
{{cite book}}: Check date values in:|date=(help) - ^ Nicolaou, K. J. Am. Chem. Soc. 2004, 126 (40), 12897-12806
- ^ Zhang, J. Org. Lett. 2011, 13 (3), 390-393
- ^ Kindahl, T. J. Phys.Chem. 2012, 116 (47), 11519-11530
- ^ Hoffman, T. Org. Lett. 2010, 12 (15), 3348-3351
- ^ Biron, e. Org. Lett. 2006, 8 (11), 2417-2420
- ^ Godfrey, A. J. Org. Chem. 2002, 68, 2623-2632
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