Construction of the Oxazole Ring

The oxazole ring can be dissected retrosynthetically in a variety of places to yield oxazole precursors. The synthetic routes to oxazoles can loosely be classified by the location of the Cl, C4, and C5 substituents prior to heterocycle formation. In a linear synthesis, all substituents would be contained in the same precursor. In a more convergent synthesis, one or two substituents are contained in one reagent, and the remaining substituents are contained in the other. A number of disconnections in all of these categories is known several of them will be highlighted here. 

The Davidson oxazole synthesis is the reaction of an acylated a-hydroxy carbonyl with an ammonium cation, typically ammonium acetate to yield oxazoles. The Davidson synthesis is also linear, as all three substituents are contained in the precursor. The reaction is most efficient in preparing 2,4,5-trisubstituted oxazoles, where C5 is aryl substituted. Yields suffer when preparing a 2,4-disubstituted or a mono-substituted oxazole. The COX-2 inhibitor tilmacoxib was prepared by Haruta in this manner.  

Following cyclization with DAST, in situ oxidation with DBU and BrCCU provides the 2,4-substituted oxazole in decent yield. Notably, if desired, the intermediate oxazoline can be isolated in stereochemically pure form. 

The condensation of an aromatic aldehyde with an aldehyde cyanohydrin under anhydrous acidic conditions provides oxazoles. The convergent synthesis couples the C2 substituent contained in the aromatic aldehyde and the C5 substituent in the cyanohydrin (C4 must necessarily remain unsubstituted). Through a modified procedure, Onaka prepared the alkaloid halfordinol in one step, utilizing the Fisher oxazole synthesis. 

The Japp oxazole synthesis is the coupling of 1,2-diketones with ammonia and an aromatic aldehyde. The diketone contributes the C4 and C5 substituents, and the aromatic aldehyde contributes the C2 substituent. The synthesis also proceeds when reacting an a-ketooxime with a benzylic halide 

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N—C—O + C—C. The construction of the oxazole ring by the condensation of a-halogeno ketones with primary amides (equation 122) is the Bliimlein-Lewy synthesis (1884/1888). The method succeeds best when the resulting oxazole contains one or more aryl substituents. The use of formamide leads to oxazoles with a free 2-position and in this case it is possible that the reaction proceeds as in equation (113). 2-Aminooxazoles are produced by the action of a-halogeno ketones on urea and its derivatives (equation 123) or on cyanamide (80ZOR2185). The mercury(II) sulfate-catalyzed condensation of alkynic alcohols or their esters with primary amides leads to trisubstituted oxazoles (equation 124). 

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