5-Ethoxy-4-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). 

Isothiazolo[5,4-c]pyridines have been prepared by a Diels-Alder reaction (Scheme 68) (90HCA69). The regioselective [4 + 2] addition of the dienophile 2-(t-butyl)isothiazol-3-one 1,1-dioxide (538) with 5-ethoxy-4-methyloxazole (537) in benzene at room temperature gave a 5 3 mixture of the exo to endo adducts (539) and (540) in an overall 85% yield. The two adducts (539) and (540) were surprisingly stable and separable by fractional crystallization from a methylene chloride/hexane mixture. Bubbling a stream of anhydrous hydrochloric acid into an ethanolic solution of these adducts (539) and (540) gave the isothiazolo[5,4-c]pyridine (541) as its hydrochloride in 63% yield. 

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 reaction of oxazoles with alkynes is entirely different, leading to furans. The adducts (157) eliminate a cyanide in a retro-Diels-Alder process (equation 15). A typical example is the formation of the ester (164) from 5-ethoxy-4-methyloxazole and dimethyl acety-lenedicarboxylate (equation 16) equation (17) illustrates the production of two regioisomers in this reaction (79MI41802) a more elaborate case is the twofold addition of benzyne to 4-methyl-2,5-diphenyloxazole to give the bridged dihydroanthracene shown in equation (18) (80TL3627). 

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... 

Refluxing a toluene solution of 5-(5-ethoxy-4-methyloxazol-2-yl)pentanal 791b gave 2-methyl-2-carbethoxycyclohexa[d]-2,7a-dihydrooxazole 792b in 78% yield. In contrast, 791a was unreactive after prolonged reflux in toluene and decomposed in refluxing xylene. 

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. ... 

The use of oxazole-alkene Diels-Alder cycloadditions to form biologically relevant molecules has recently been applied to the synthesis of isoindoles, useful intermediates for the preparation of substance P antagonists. Thus 5-ethoxy-4-methyloxazole 8 reacted with 4,4-dimethyl-2-cyclopentenone 78 in refluxing benzene in the presence of catalytic zinc bromide to give the (l//)-cyclopenta(c)-pyrrole 80 as a separable 3 1 mixture of cis and trans isomers in 53% yield (Fig. 3.22). The reaction is presumed to proceed via the intermediacy of cycloadduct 79. When cyclohexenone 81 was used as the dienophile, the product was the hydro-(l//)-isoindole 82, obtained via dehydroformylation of the cycloadduct, in 85% yield after only 30 min in refluxing benzene. 

Ethoxy-4-methyloxaole has been used to form pyridoxine (MI-286, R = H). With maleic anhydride it gives an adduct that, on treatment with ethanolic hydrogen chloride, forms the products W-287 and XII-288 (R = R - Et) and a monoester (XII-288 R = Et, R = H or R = H, R = Et). The diethyl ester MI-288 is also formed from ethyl maleate or ethyl fumarate and 5-ethoxy-4-methyloxazole. Fumaronitrile and ethoxy-4inethyloxazol ve 4,5-dicyano-2-methyl-3-pyridinol, ° also a known precursor to pyridoxine. 5-Ethoxy 4-irethyloxaolesand 2-butene-1,4-diol give pyridoxine (XII-286, R = H), which is difficult to purify when prepared in this way (assay, 23%). 

Ethoxy-4-methyloxazole reacts with cis- and rrans-2,5-dimethoxy-2,5-di-... 

Pyridoxine cyclic ether, from 5-ethoxy-4-methyloxazole and 2,5-dihydrofurar, 610 Pyridoxol, from 4-methyl-5-ethoxyoxazole, 264 Pyridoxylidene benzylamine,... 

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