4- Oxazolecarboxylic acid

Azolecarboxylic acids can be quite strongly acidic. Thus l,2,5-thiadiazole-3,4-dicar-boxylic acid has first and second values of 1.6 and 4.1, respectively <68AHC(9)107). The acidic strengths of the oxazolecarboxylic acids are in the order 2>5>4, in agreement with the electron distribution within the oxazole ring <74AHC( 17)99). Azolecarboxylic acids are amino acids and can exist partly in the zwitterionic, or betaine, form e.g. 394). 

METHOXYCARBONYL-2-METHYL-1.3-OXAZOLE (4-Oxazolecarboxylic acid, 2-methyl-, methyl ester)... 

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). 

A large number of 2- and 4-oxazolecarboxylic acid esters have been synthesized by this method using appropriate a-acylamino carbonyl compounds,27-30 38 40... 

The kinetics and mechanism of the decarboxylation of 5- (p-substituted phenyl )-2-oxazolecarboxylic acids in neutral, acidic, and basic media have been studied by Tanaka.392 In quinoline or in dichloroacetic acid as a nonaqueous solvent, the reaction shows first-order kinetics.392 Studies on the decarboxylation of oxazolium (and other related azolium) carboxylates indicate that both 2- and 5-acids decarboxylate through their zwitterionic tautomers.393 Heating an oxazole-2-carboxylic acid at or above its melting point may also result in decarboxylation.29 394... 

Oxazolecarboxylic acids are readily converted into acid chlorides,302 396 396... 

Activated manganese dioxide is a closely related oxidant to Ni02 but less commonly used. Meguro, Fujita, and co-workers described oxidation of oxazolines using Mn02 in their synthesis of antidiabetic agents. For example, the serine-derived P-hydroxyamide 21 was cyclized to the oxazoline 22 with polyphosphoric acid. Oxidation of 22 with activated manganese dioxide afforded 2-styryl-4-oxazolecarboxylic acid methyl ester, 23 (Scheme 1.4). 

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. 

R = CH3) was converted to 2-methyl-4-oxazolecarboxylic acid methyl ester 34 (R = CH3) in 75% yield. 

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. 

Meyers and Tavares also investigated radical bromination as a means to effect net oxidation of activated oxazolines. They found these reaction conditions were acceptable for preparing 2-alkyl-4-oxazolecarboxylic acid esters only if the 2-alkyl group was methyl or primary, i.e., 65 Rj = R2 = H or Rj = n-C4, R2 = H. However, these conditions failed completely if the 2-alkyl group was secondary, e.g., isopropyl or cyclohexyl. In these cases, the desired oxazole 65 was isolated in <1% yield. Instead, the sole product was 66, the result of oxidation with concomitant side chain bromination (Scheme 1.20, Table 1.1, entries 7 and 8). 

In a model study, Helquist and co-workers described the reaction of dimethyl diazomalonate 128 with benzonitrile to prepare 5-methoxy-2-phenyl-4-oxazolecar-boxylic acid methyl ester 129 nearly quantitatively (Scheme 1.35). Several other 2-aryl-5-methoxy-4-oxazolecarboxylic acid methyl esters were prepared analogously. In addition, 2-aIkyl(aIkenyl)-5-methoxy-4-oxazolecarboxylic acid methyl esters were also prepared, although the yields for aliphatic nitriles were not as good, unless the nitrile was used as solvent. Other metal salts—including Rh2 (NHAc)4, Cu(OTf)2, Cu(C2Hs-acac)2, Rh2(02CC3H7)4, and Rh3(CO)ie— were not as effective as Rh2(OAc)4 in this reaction. 

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... 

An iterative application of this rhodium-carbenoid NH-insertion reaction with an amide was used in their approach to the bis-oxazole core 166 of muscoride A 156 (Scheme 1.45). A -Carbobenzyloxyproline amide was converted to 162 in good yield using methyl diazoacetoactate. Cyclodehydration of 162 then gave the 2,5-disubstimted-4-oxazolecarboxylic acid methyl ester 163, which was converted to the amide 164 uneventfully. Repetition of the rhodium-carbenoid NH-insertion reaction with methyl diazoacetoactate gave 166 after cyclodehydration. This... 

TABLE 1.9. 2,5-DISUBSTITUTED-4-OXAZOLECARBOXYLIC ACID METHYL ESTERS FROM RHODIUM-CARBENOID NH INSERTION REACTIONS ... 

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. 

Treatment of 270 (R = 4-CH3-C6H4) with porcine hver esterase (PLE) did not afford the expected chiral monoacid. Instead, PLE caused sequential hydrolysis with concomitant decarboxylation to produce an aUene 271, which cyclized to a 2,5-disubstituted 4-oxazolecarboxylic acid ester. The authors isolated a series of... 

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). 

Barrett and co-workers prepared a key intermediate oxazole 350 in their synthesis of calyculin A using Comforth methodology (Scheme 1.94). The benzyl ester of (/ )-2-methyl-4-pentenoic acid 347 was converted to (/ )-2-methyl-4-pentenenitrile 348 in two steps. Pinner reaction of 348, followed by amine exchange with glycine methyl ester, gave the imidate 349 in 73% yield. Base-catalyzed formylation of 349 with in situ cyclization produced the 2-alkyl-4-oxazolecarboxylic acid methyl ester 350 in good yield. This entire sequence... 

Hermitage and co-workers at GlaxoWellcome very recently described a novel, non-oxidative method to prepare 2-(chloromethyl)-4-oxazolecarboxylic acid methyl ester 357 shown in Scheme 1.96. This oxazole was a proposed intermediate in their scale up route to GW475151 358, a potent inhibitor of human neutrophil... 

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. 

Ozaki and co-workers prepared an extensive series of 5-aryl(heteroaryl)-4-oxazolecarboxylic acid methyl esters 368 (20 compounds) from acylation of methyl isocyanoacetate, followed by in situ cyclization (Scheme 1.100). These compounds were elaborated further and evaluated as blood platelet aggregation inhibitors. 

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"... 

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