5-ethyl-2-methyloxazole

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). 

Methyl 2-[(5)-l-(Benzyloxycarbonylamino)ethyl]-5-methyloxazole-4-carboxylate (33) 1 1 TEA (4.1 equiv) and a soln of 32 ( 3 mmol, 1 equiv) in dry CH2C12 (lOmL) were added sequentially to a stirred soln of Ph3P (2.0 equiv) and I2 (2 equiv) in dry CH2C12 (40 mL) at rt under N2. The mixture was stirred until TLC analysis indicated that the reaction was complete, concentrated, purified by flash chromatography (silica gel, EtOAc/petroleum ether) to yield the desired product 33 yield 66% mp 125.5-126 °C (colorless needles, EtOAc/petroleum ether) [a]D165 -34.4 (c 1.0, CHCI3). 

Benzylidene-2-methyloxazol-5-one. Warm a mixture of 29 g (0.25 mol) of acetylglycine, 39.5 g (37.5 ml, 0.37 mol) of redistilled benzaldehyde [Expt 6.133, Note (1)], 15 g (0.183 mol) of anhydrous sodium acetate and 63.5 g (59 ml, 0.62 mol) of acetic anhydride in a 500-ml flask (equipped with a reflux condenser) on a water bath with occasional stirring until solution is complete (10-20 minutes). Boil the resulting solution for 1 hour, cool and leave in a refrigerator overnight. Stir the solid mass of yellow crystals with 60 ml of cold water, transfer to a Buchner funnel and wash well with cold water. (If the odour of benzaldehyde is still apparent, wash with a little ether.) Recrystallise from carbon tetrachloride or from ethyl acetate-light petroleum. The yield of the oxazolone, m.p. 150°C, is 35 g (76%). 

Diethyloxazole 4-Methyl-5-propyloxazole 4-Methyl-5-butyloxazole 4-Methyl-5-hexy loxazole 4-Ethyl-5-propyloxazole 4-Ethyl-5-butyloxazole 4-Ethyl-5-pentyloxazole 4-Propyl-5-methylox azole 4-Propyl-5-ethyloxazole 4-Butyl-5-methyloxazole 4-Butyl-5-propyloxazole 4-Pentyl-5-methyloxazole 4-Hexy 1-5 - me thy loxazole 2,4-Diethyl-5-propyloxazole... 

Pathways C and D are less well documented, mainly because oxazoles lacking a 5-alkoxy substituent show reduced reactivity towards the usual dienophiles. An example of reaction C is the formation of 3-hydroxy-2-methylpyridine from 4-methyloxazole and acrylonitrile (equation 13). Dehydrogenation (path D) is rare but proceeds in the presence of a hydride acceptor. Thus 4-methyloxazole reacts with ethyl acrylate in the presence of hydrogen peroxide to give ethyl 3-hydroxy-2-methylpyridine-5-carboxylate in 27% yield (equation 14). 

Triphenyloxazole (5g), formamide (40g) and liquid ammonia (lOOtnl) are heated in an autoclave at 200-210°C (5h). The brownish reaction product is poured into water, and the flocculent precipitate is filtered, washed with water and recrystallized from ethanol (4.3 g, 85%), m.p. 273°C. Similarly prepared are 2,5-diethyl-4-phenyl- (25%), 2-methyl-4,5-dipropyI-(70%) [41], 4-eihyl-5-phenyl- (50%), 4-phenyl-5-propyl- (40%) and4-benzyl-5-ethyl imidazoles (5%) [40]. From 2-methyloxazole-4-carboxylic acid boiled at 150°C in a sealed tube with aqueous ammonia is obtained 2-methylimidazole (22%) boiling with aniline gives 2-methyl-l-phenylimidazole (67%) [52]. 

Acetyloxazole 2-lsopropyl-4,5-dimethyloxazole 2-lsopropyl-4-ethyl-5-methyloxazole Sweet, fruity... 

Butyl-4-ethyl-5-methyloxazole Green, herbal, weak, acidic, slight buttery... 

Closely related to the aldoxime fragmentation is the base-catalyzed ring cleavage of C(3)-substituted isoxazoles. Quite recently a novel base-catalyzed isoxazole-oxazole ring transformation was realized in the conversion of ethyl 5-hydroxy-3-(5-methylisoxazol-4-yl)isoxazole-4-carboxylate (61) into ethyl 4-cyano-5-methyloxazol-2-ylacetate (62 Scheme 5). ... 

In the case of lower alkyl amides the components are heated in a high-boiling inert solvent such as xylene or dimethylformamide.8788 Ethyl a-chloroacetoacetate reacts with benzamide at 180° to give a very poor yield of ethyl 2-phenyl-4-methyloxazole-5-carboxylate.27... 

The ammonium formate in formic acid procedure has rendered possible the first preparation of isomeric 4,5-disubstituted oxazoles.03101 Bredereck, Gompper, and Reich101 have reported the anomalous behavior of certain long-chain a-bromo ketones a single a-bromo ketone on reaction with ammonium formate in formic acid gives a mixture of two isomeric oxazoles. Refluxing of a-bromo ketones or of a-chloro-/3-keto esters with ammonium acetate in acetic acid results in the formation of substituted 2-methyl-oxazoles.40 102 Ethyl a-chloroacetoacetate on heating with ammonium carbonate or formamide in formic acid yields 4-methyloxazole-5-carboxylic ester.40 103... 

Attempts have also been made338 346 to find a theoretical explanation of the stereo or positional selectivity in the first stage of the heterodiene synthesis, especially in the interaction between 5-ethoxy-4-methyloxazole and asymmetric dienophiles, e.g., /9-acetylacrylic acid and its ethyl ester. ir-Electron density calculations for the diene and dienophile molecules by the HMO method indicate the formation of the 4-acetylpyridine derivative (187) from ethyl /3-acetylacrylate, while the opposite orientation would be expected in the reaction with the free acid, giving a substituted 5-acetylpyridine as the main product. Indeed, 5-ethoxy-4-methyloxazole on condensation with ethyl /3-acetylacrylate affords only 187, while in the condensation with /3-acetylacrylic acid, only 2-methyl-3-hydroxy-5-acetylpyridine (188) is isolated.338 348... 

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. ... 

Quinones have been shown to react with 5-aIkoxyoxazoles to yield hydroxypyr-idines. The isoquinolinequinone 60 was prepared in 60% yield from 4-ethyl-5-methoxy-2-methyloxazole 58 and the quinone 59 in benzene at 60°C for 30 h (Fig. 3.17). 3... 

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