Robinson-Gabriel synthesis

The Robinson-Gabriel cyclodehydration of 2-acylamidoketones 1 is one of the oldest yet most versatile synthesis of 2,5-di- and 2,4,5-trialkyl, aryl, heteroaryl-, and aralkyloxazoles 2.  

In 1909, Robinson demonstrated the utility of acylamidoketones as intermediates to aryl-and benzyl-substituted 1,3-oxazoles through cyclization with sulfuric acid. Extension of sulfuric acid cyclization conditions to alkyl-substituted oxazoles can give low yields, for example 10-15% for 2,5-dimethyl-l,3-oxazole. Wiegand and Rathbum found that polyphosphoric acid can provide alkyl-substituted oxazoles 4 in yields equal to or greater than those obtained with sulfuric acid. Significantly better yields are seen in the preparation of aryl- and heteroaryl-substituted oxazoles. For example, reaction of ketoamides 5 with 98% phosphoric acid in acetic anhydride gives oxazoles 6 in 90-95% yield.  

Wasserman demonstrated with 0 labeling studies that the amide carbonyl oxygen is incorporated into the oxazole ring upon cyclization 

Wipf and Miller have reported side-chain oxidation of 3-hydroxy amides with the Dess-Martin periodinane, followed by immediate cyclodehydration with triphenylphosphine-iodine, which provides a versatile extension of the Robinson-Gabriel method to substituted oxazoles. Application of this method was used to prepare the oxazole fragment 10 in 55% overall yield from 3-hydroxy amide 8. 

More recent examples have employed a milder reagent system, triphenyl-phosphine and dibromotetrachloroethane to generate a bromo-oxazoline, which is subsequently dehydrohalogenated. Wipf and Lim utilized their method to transform intermediate 11 into the 2,4-disubstituted system of (+)-Hennoxazole k Subsequently, Morwick and coworkers reported a generalized approach to 2,4-disubstituted oxazoles from amino acids using a similar reagent combination, triphenylphosphine and hexachloroethane.  

Meguro, K. Tawada, H. Sugiyama, Y. Fujita, T. Kawamatsu, Y. Chem. Pharm. 

Turchi, 1. J. In The Chemistry of Heterocyclic Compounds, 45 Wiley New York, 1986 pp 1-342. (Review). 

Brooks, D. A. Robinson-Gabriel Synthesis in Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 249-253. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 220, Springer-Verlag Berlin Heidelberg 2009 

CjBraCU, CH2CI2 2,6-di-tert-butylpyridine NaHCOj, CHjClj, 0 °C 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 235, Springer International Publishing Switzerland 2014 

CaBrjCU. CH2CI2 2,6-dl-fe/t-butylpyridine NaHCOj, CH2CI2, 0 C 

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Ring transformations heterocyclic compounds reviews, 1, 70 Ring-chain tautomerism polyheteroatom six-membered rings, 3, 1056 Ripariochromene A synthesis, 3, 751, 755 Robinson-Gabriel synthesis oxazoles, 6, 216... 

Onaka demonstrated the utility of a modified Fisher method in the one-step synthesis of oxazole alkaloid Halfordinol (16) in higher overall yield than previously reported by Robinson-Gabriel synthesis. ... 

Preparation of oxazole Cyclocondensation of amides, through dehydration, leads to the formation of corresponding oxazoles. This synthesis is known as Robinson-Gabriel synthesis. A number of acids or acid anhydrides, e.g. phosphoric acid, phosphorus oxychloride, phosgene and thionyl chloride, can bring about this dehydration. 

Oxazoles may be similarly prepared in good yields. Thus, 5-ethoxy-4-methyloxazole (173) was obtained by treating ethyl 2-formamide propionate (172) with phosphorus pentoxide in chloroform at 55°C (72JCS(P1)909,914). Known collectively as the Robinson-Gabriel synthesis, these cyclodehydrations can be effected by sulfuric acid or anhydrous hydrogen fluoride (cf CHEC 4.18). 

Similar tautomerisation of the enol group gives an actual intermediate 3.13, and disconnection of the amide linkage reveals aminoketone 3.15 and an acylating species 3.14 such as an acid chloride. The forward process, cyclocondensation of amides 3.13 to yield oxazoles 3.10, is known as the Robinson-Gabriel synthesis. 

One of the most reliable methods for constructing the oxazole ring is the cyclodehydration of a-acylamino ketones, the Robinson-Gabriel synthesis (1909/1910) (equation 93). The reaction is usually conducted in the presence of sulfuric add or phosphorus pentachloride and more recently polyphosphoric add, phosgene or anhydrous hydrogen fluoride have... 

Angew. Chem. Int. Ed. Engl. 44, 3668-3688, 2005 Kent, M. and Tepe, J.J., One-pot Friedel-Crafts/ Robinson-Gabriel synthesis of oxazoles using oxazolone templates, J. Org. Chem. 70, 4211 213, 2005 Movassaghi, M. and Ondrus, A.E., Enantioselective total synthesis of tricyclic myrmicarin alkaloids, Org. Lett. 7, 4423 426, 2005 Paizs, C., Katona, A., and Retey, J., The interaction of heteroaryl-acrylates and alanines with phenylalanine ammonia-lyase form parsley. Chemistry 12, 2739-2744, 2006. Cuprous ions have been observed to promote a Friedel-Crafts acylation reaction (Kozikowski, A.P. and Ames, A., Copper(l) promoted acylation reactions. A transition metal-mediated version of the Friedel-Crafts reaction, J. Am. Chem. Soc. 102, 860-862, 1980). 

The classical method for making oxazoles, the Robinson-Gabriel synthesis, which is formally analogous to the cyclising dehydration of 1,4-dicarbonyl compounds to furans (18.13.1.1), is the acid-catalysed closure of a-acylamino-carbonyl-compounds and a simple example is shown below. ... 

A convenient route to polysubstituted oxazoles was developed through a variation on the Robinson-Gabriel synthesis in which the key 1,4-dicarbonyl compounds were obtained by a rhodium carbene N-H insertion reaction. Dirhodium tetraacetate catalysed reaction of primary amides 103 and diazocarbonyl compounds 107 gave a-acylaminoketones 108, which were converted into 109 by cyclodehydration using the Wipf and Miller protocol <04T3967>. 

A. From o-Acylamino Carbonyl Compounds (The Robinson-Gabriel Synthesis)... 

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