5- -4-oxazolecarboxylic acid methyl ester

Meyers and co-workers" also investigated lateral lithiation of a 2-methyloxazole derivative during their synthesis of the oxazole dienyl amine moiety 1203, common to 1183 and 1184. The authors proposed a retrosynthetic path, wherein selective functionalization of a 2-methyl-4-oxazolecarboxylic acid ester would be the starting point for 1203 (Scheme 1.305). 

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). 

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). 

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. 

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 ... 

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... 

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. 

Further work firom Shiori s group described the total synthesis of 1191a, but not via their original strategy. Originally, the authors focused on an oxazole-containing linear precursor to the pyran fragment, which was to be prepared fi om 2-styryl-4-oxazolecarboxylic acid methyl ester 1426 (Scheme 1.366). Preparation of... 

The valine-derived-4-oxazolecarboxylic acid 1491 was coupled with tryptophan methyl ester to generate an intermediate that underwent oxidation and cyclodehydration with DDQ to afford the C-D-E-F indole bis-oxazole fragment... 

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. 

Duarte and co-workers correctly identified the product from the Michael addition of benzohydroxamic acid to a propiolate ester to be a 1,4,2-dioxazole 1626, not an oxaziridine 1627 (Scheme 1.417). The authors converted 1626 to a mixture of (E/Z) lactoxime (9-vinylether sodium salts 1628, from which 2-phenyl-4-oxazolecarboxylic acid methyl ester was isolated upon thermolysis. 

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