5-ethoxy-2-ethyl-4- oxazole

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. 

Oxazoles may be similarly prepared in good yields. Thus, 5-ethoxy-4-methyloxazole (173) was obtained by treating ethyl 2-formamide propionate (172) with phosphorus pentoxide in chloroform at 55°C (72JCS(P1)909,914). Known collectively as the Robinson-Gabriel synthesis, these cyclodehydrations can be effected by sulfuric acid or anhydrous hydrogen fluoride (cf CHEC 4.18). 

Oxazol 3-Ethyl-5-[(2-rnethoxy-ethoxy)-methyl]-4,5-dimethyl-... 

The thermal or photolytic decomposition of carbonyl azides in the presence of dipole acceptors such as acetylenes provides a valuable method for the construction of oxazoles. Thus the reaction of ethyl azidoformate with either diphenyl- or diethylacetylene produces mainly the 2-ethoxy-oxazole (77 ).166 166 The reaction involves the 1,3-dipolar cycloaddition of carbethoxy nitrene (76b) to the alkyne to give the oxazole (77). On the... 

Early work from Moody s laboratories extended the rhodium-carbene methodology to include a-diazosulfones (Scheme 1.40). Selected examples of 2-alkyl (aryl)-5-ethoxy-4-(phenylsulfonyl)oxazoles 146 prepared from ethyl phenylsul-fonyldiazoacetate 145 and nitriles are shown in Table 1.7. 

Doyle and Moody ° investigated the effect of the ligand on the formation of 5-ethoxy-2-ethyl-4-(phenylsulfonyl)oxazole 146 (R = C2Hs). They isolated comparable yields of the desired oxazole with several ligands (Table 1.8), although the reaction rate was faster using Rh2(NHCOCF3)4. The authors found Rh2(NHCO... 

TABLE 1.8. EFFECT OF RHODIUM(II) CATALYSTS ON THE SYNTHESIS OF 5-ETHOXY-2-ETHYL-4-(PHENYLSULFONYL)OXAZOLE ... 

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. 

Turchi and Cullen described the first examples of pyrazoles prepared from oxazoles (Scheme 1.231). Treatment of 5-ethoxy-p-oxo-2-phenyl-4-oxazolepropa-noic acid ethyl ester 857 with hydrazine did not afford the expected pyrazolone 858. Instead, the authors isolated ethyl-4-(benzoylamino)-5-ethoxy-l//-pyrazole-3-acet-ate 860 (R = H) in good yield. Similarly, reaction of 857 with methyUiydrazine produced 860 (R = CH3) in comparable yield. 

That these reactions proceed via the intermediacy of a Diels-Alder cycloaddition adduct has been affirmed by the isolation of a variety of the 1 1 Diels-Alder adducts.For example, the reaction of 5-ethoxy-4-methyloxazole 8 with cis-2,5-dimethoxy-2,5-dihydrofuran 9 provided the isolable endo and exo adducts 10 and 11 respectively, in a 2 1 ratio (Fig. 3.4). Similarly, 5-ethoxy-4-oxazoleacetic acid ethyl ester 12 reacted with maleic anhydride to provide the stable endo and exo adducts 13 and 14, in which the olefin has moved into conjugation with the ester moiety. In this case, compound 13 was the sole product when the reaction proceeded at 10°C, but only the exro-adduct 14 was isolated if the cycloaddition was conducted at 80°C. Heating at 50°C for 3h converted 13 into 14. The 2-carboethoxy analog of oxazole 12 behaved similarly. ... 

An oxazole-alkene Diels-Alder reaction has also been used to synthesize a tri-fluoromethylated pyridine related to pyridoxol. 5-Ethoxy-4-(trifluoromethyl)-2-oxazolecarboxylic acid 41 decarboxylated and then reacted with acrylic acid to give the expected 3-hydroxy-2-(trifluoromethyl)pyridine-4-carboxylic acid 42 in 63% yield (Fig. 3.13)." The electron-withdrawing trifluoromethyl group of 41 strongly modulates its reactivity, however, and it does not react with ethyl acrylate or A-phenyl maleimide. 

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. 

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