5-ethoxy-4-substituted oxazoles

The primary adducts (156) and (157) of oxazoles with alkenes and alkynes, respectively, are usually too unstable to be isolated. An exception is compound (158), obtained from 5-ethoxy-4-methyloxazole and 4,7-dihydro-l,3-dioxepin, which has been separated into its endo and exo components. If the dienophile is unsymmetrical the cycloaddition can take place in two senses. This is usually the case in the reactions of oxazoles with monosubstituted alkynes with alkenes on the other hand, regioselectivity is observed. Attempts to rationalize the orientation of the major adducts by the use of various MO indices, such as 7r-electron densities or localization energies and by Frontier MO theory (80KGS1255) have not been uniformly successful. A general rule for the reactions of alkyl- and alkoxy-substituted oxazoles is that in the adducts the more electronegative substituent R4 of the dienophile occupies the position shown in formula (156). The primary adducts undergo a spontaneous decomposition, whose outcome depends on the nature of the groups R and on whether alkenes or alkynes have been employed. 

The synthetic utility of oxazoles as azadienes was further advanced when Grigg and co-workers reported that the Diels-Alder reactions of oxazoles with alkynes provided furans via a tandem Diels-Alder retro-Diels-Alder sequence. Thus 5-ethoxy-4-substituted oxazoles 119 reacted with dimethyl acetylenedicar-boxylate in cold ether to yield 2-ethoxy-3,4-furandicarboxylic acid dimethyl ester 121 in >50% yield (Fig. 3.33). In this case, the intermediate cycloaddition adduct 120 extrudes a molecule of hydrogen cyanide or a nitrile derived from the C-4 substituent of the oxazole, via a retro-Diels-Alder reaction to provide a substituted... 

The use of the CFs-substituted oxazole as an aza-diene for a Diels-Alder reaction was briefly examined. Thus, prolonged heating of the mixture of 5-ethoxy-4-trifluoromethyloxazole and an excess of acrylic acid afforded the CFs-substituted pyridine derivative in reasonable yield [61], However, cycloaddition with other olefins, such as ethyl acrylate, N-phenylmaleimide, 2,5-dihydrofuran, maleic anhydride, and 2-buten-4-olide did not take place to any appreciable extent presumably because of the deactivation of the oxazole ring by a strongly electron-withdrawing CF3 group. 

Huisgen et al. also studied the thermal decomposition of ethyl diazoacetate in the presence of benzonitrile and phenylacetonitrile to give the corresponding 2-substituted-5-ethoxy oxazoles 3 in variable yields (Scheme 3).<64CB2864> The authors found that the solvent had an effect on the rate of decomposition of ethyl diazoacetate in the polar solvent, niuobenzene, the rate was found to be twice that in the hydrocarbon solvent, decalin. 

Ducept and Marsden described a general synthesis of 5-ethoxy-2-substituted 4-(triethylsilyl)oxazoles 176 from the rhodium(II)octanoate-catalyzed diazo-transfer reaction of ethyl (triethylsilyl)diazoacetate 175 and nitriles (Scheme 1.48). The reaction conditions tolerate a wide variety of functional groups on the nitrile, including alkyl, aryl, heteroaryl, vinyl, carbonyl, sUyloxy, and dialkylamino. Desilylation of 176 with TBAF afforded the corresponding 2-alkyl(aryl)-5-ethoxy-oxazoles 177, which are normally inaccessible from diazoesters using conventional rhodium-carbene methodology. The authors noted that carbonyl groups in the 2 position of 176 are not compatible with TBAF deprotection. 

Alkoxyoxazoles have also proven to be valuable heterodienes in the synthesis of highly substituted furans and biologically active natural products via oxazole-aUtyne Diels-Alder reactions. Thus the synthesis of a synthon for the DEF ring system of fredericamycin began with the cycloaddition of 5-ethoxy-4-methyl-oxazole 8 with enyne ester 149 (Fig. 3.45). This reaction proceeded in 24 h in refluxing toluene to afford a 65% yield of the 2-ethoxyfuran 150. Furan 150 was then converted to the isoquinoline 151 in six steps. ... 

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