2- -4-oxazolecarboxylic acid ethyl ester

Xu and co-workers prepared the previously unknown 5-ethoxy-4-(trifluoro-methyl)-2-oxazolecarboxylic acid ethyl ester 144 in 90% yield using Rh2(OAc)4-catalyzed reaction of ethyl 3,3,3-trifluoro-2-diazopropionate 143 with ethyl... 

Meguro and co-workers used this method, among others, to prepare a variety of potential antidiabetic agents. For example, cyclization of cyclohexanecarbox-amide with ethyl 4-chloroacetoacetate gave 2-cyclohexyl-4-oxazoleacetic acid 199, albeit in poor yield (Scheme 1.54). Similarly, Ohkubo and co-workersprepared 4-(nitrophenyl)-2-phenyl-5-oxazolecarboxylic acid ethyl esters 200a and 200b as precursors to potential cerebral protective agents. 

A structurally simpler analog, 338, was studied mechanistically. The rearrangement is believed to proceed via initial N-O bond cleavage to produce two radical fragments 339 that then recombine to yield the more stable C-N-bonded species 340. Intramolecular cyclization is accomplished through the enol tautotmer 341 via addition-elimination with loss of ethanol from the oxazoline 342 to afford 2-phenyl-4-oxazolecarboxylic acid ethyl ester 343 (Scheme 1.92). 

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 1.69. 2-(2-HYDROXYETHYL)-4-OXAZOLECARBOXYLIC ACID ETHYL ESTERS FROM 2-(BROMOMETHYL)-4-OXAZOLECARBOXYLIC ACID ETHYL ESTER REFORMATSKY REAGENT AND ALDEHYDES OR KETONES-... 

The requisite monooxazoles 1580 and 1584 were assembled as follows. 2-Methyl-4-oxazolecarboxylic acid ethyl ester 34 was converted to the phosphonium salt 1577 in two steps. Wittig reaction of 1577 with 1578 furnished 1579, which was converted to the allyl ester 1580 uneventfully. 

Wang and Zhu reported a general synthesis of 5-(perfluoroaIkyl)-2-substi-tuted 4-oxazolecarboxylic acid ethyl esters 1601 from decomposition of ethyl 2-diazoperfluoroalkylacetoacetates 1600 in the presence of a nitrile as solvent (Scheme 1.408). Rhodium(II) acetate was the preferred catalyst for this reaction. The yields of 1601 varied considerably. 

Searle chemists described an improved synthesis of 2-(bromomethyl)-4-oxazolecarboxylic acid ethyl ester 957. Thus slow addition of ethyl 2-diazo-3-oxo-propanoate in bromoacetonitrile to Rh2(OAc)4 in bromoacetonitrile at 70°C gave 957 in 78% yield (Scheme 1.409). Incorporation of 957 into a series of PGE2 antagonists 1604 was straightforward. Here, the 2,4-disubstituted oxazole was an isostere for a diacylhydrazine moiety. 

Hermitage and co-workers refined and improved their process of preparing 2-(chloromethyl)-4-oxazolecarboxylic acid ethyl ester 1630 (Scheme 1.418). Several improvements are noteworthy. The authors converted dichloroacetonitrile to 1630 in three steps, using DIPEA to effect oxidation of 1629. Quaternization of other tertiary amine bases (e.g., triethylamine) by 1630 was a problem. The use of serine... 

TABLE 1.20 2,5-DISUBSTITUTED-4-OXAZOLECARBOXYLIC ACID ETHYL ESTERS FROM DIETHYL a-ALKYNYLMALONATES (DAM), 58... 

Unlike ynamines, ethyl vinyl ether requires the more electron-deficient 4-nitro-2-phenyl-5-oxazolecarboxylic acid methyl ester 271b for reaction to occur. The initial [4 + 2] cycloadduct 279 undergoes further reaction with ethyl vinyl ether to give the tricyclic oxazoline 280 in 76% yield (Scheme 8.79). 

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. 

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