ROBINSON-GABRIEL Oxazole Synthesis

ROBINSON-GABRIEL Oxazole Synthesis Synthesis of oxazoles from amides of a-aminoketones (see 1st edition). 

ROBINSON - FOULDS Quinoline synthesis 322 ROBINSON - GABRIEL Oxazole synthesis 323 ROELEN Carbonylation 323 ROSENMUND - von BRAUN Aromatic cyanation 324... 

Other references related to the Robinson-Gabriel oxazole synthesis are cited in the literature. 

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. ... 

Nicolaou and co-workers established the severely strained A-ring oxazole (21) in their total synthesis of antitumor agent diazonamide A through initial oxidation of the hindered alcohol of intermediate 20 with TPAP and subsequent Robinson-Gabriel cyclodehydration of the resultant ketoamide with a mixture of POCI3 and pyridine (1 2) at 70°C. ... 

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>. 

Synthesis. The preparation of these heterocycles was accomplished using traditional methodology. 2,4-Disubstituted and 2,4,5-trisubstituted compounds were prepared via the Hantzsch (21) synthesis. The Gabriel (22) and Robinson-Gabriel (23) syntheses were used to prepare the 2,5-disubstituted thiazoles and oxazoles, respectively. The intermediate keto-amides could be converted into thiazoles by heating with P4S] q pyridine or with Lawesson s reagent (24). 

Oxazoles are a common structural motif foxmd in numerous molecules that display antiviral, antifungal, antibacterial, and antiproliferative activities [150,151]. Classical methods for oxazole synthesis include Robinson-Gabriel synthesis by dehydration of 2-acylaminokefones, Fischer oxazole synthesis from cyanohydrins and aldehydes, Bre-dereck reaction with a-haloketones and formamide. Van Leusen reaction with aldehydes and TosMIC, Hantzsch reaction, and aza-Wittig reaction [152]. 

---