5-substituted-4-oxazolecarboxylic acid esters

ElectophUic iodination using I2 has also been employed to effect net oxidation of oxazolines to 2-substituted 4-oxazolecarboxylic acid esters. Koskinen and co-workers" " ° prepared an intermediate oxazole fragment of calyculin using this method (Scheme 1.18). Here, the oxazoline 57 was first treated with LiHMDS and TMSCl to protect the carbamate as a sUyl amide followed by treatment with KHMDS and iodine to generate the oxazole 58. Interestingly, the authors also isolated diastereomeric spirocyclic ortho ester aminals 59 in 25 to 30% yield under these reaction conditions. 

Interestingly, only p-nitrobenzoyl chloride reacted with ethyl isocyanoacetate. Other aromatic acid chlorides, including p-chlorobenzoyl chloride, p-fluorobenzoyl chloride, and benzoyl chloride were unreactive even after 15 h at 110°C. This was attributed to marked differences in electrophilicity of the acid chlorides. The authors also considered an alternative mode of cyclization that would have produced 5-substituted 4-oxazolecarboxylic acid esters but found no evidence for these products. Selected examples are shown in Table 1.29. 

Shiori and co-workers used 5-substituted 4-oxazolecarboxylic acid esters 379 as p-hydroxy-a-amino acid synthons. They described a straightforward synthesis of 379 by acylation of an isocyanoacetic acid ester with an a-alkoxyacid 378 in the presence of diphenylphosphorylazide (DPPA) or diethylphosphoryl cyanide (DPPC) followed by base-catalyzed cyclization (Scheme 1.104). The reaction conditions do not epimerize optically active a-alkoxyacids. Dilute acid hydrolysis of 379 and reaction with (600)2 affords the protected aminotetronic acids 380. Stereoselective hydrogenation of 380 then yields the 1,4-lactones 381, key intermediates in the synthesis of amino sugars. A variety of a-alkoxyacids were studied, and some examples are shown in Table 1.30. 

TABLE 1.30. 5-SUBSTITUTED 4-OXAZOLECARBOXYLIC ACID ESTERS FROM a-ALKOXYACIDS AND ISOCYANOACETIC ACID ESTERS"... 

Wipf and co-workers developed an efficient one-pot process to prepare a variety of highly functionalized 2-substituted 4-oxazolecarboxylic acid esters 39. The starting (3-hydroxyamides 1588 were cyclodehydrated using Deoxo-fluor (bis(2-methoxyethyl)aminosulfur trifluoride) or DAST (diethylaminosulfur trifluoride) to afford intermediate oxazolines 38, which were oxidized in situ with B1CCI3/ DBU to afford 39 (Scheme 1.404). DAST was found to be preferable with serine-derived p-hydroxyamides, whereas Deoxo-fluor was more useful for threonine derived p-hydroxyamides. 

Oxidation of 25 to the 2-substituted 4-oxazolecarboxylic acid methyl ester 26 was accomplished in 41% yield. Similarly, oxidation of 27 yielded phenoxan 28. It should be noted that yields of Mn02 oxidations are variable but can be comparable to those obtained using Ni02. It is likely that both Mn02 and Ni02 oxidations are mechanistically similar. 

Shafer and Molinski reported an efficient synthesis of the parent heterocycle 1, which they required as a starting material to prepare substituted analogs as shown in Scheme 1.110. Condensation of ethyl isocyanoacetate with formic acid and l,l -carbonyldiimidazole gave 4-oxazolecarboxylic acid ethyl ester 408. Hydrolysis and decarboxylation with CuO and quinoline afforded oxazole 1 in 24-33% yield from ethyl isocyanoacetate. The authors noted this route was amenable to scale up. 

TABLE 1.42. 2-SUBSTITUTED 4-OXAZOLECARBOXYLIC ACID METHYL ESTERS FROM DIMETHYL AMINO[PHENYLTHIO)METHYL]MALONATE ... 

---