Alkyl substituted oxazoles

In 1909, Robinson demonstrated the utility of acylamidoketones as intermediates to aryl-and benzyl-substituted 1,3-oxazoles through cyclization with sulfuric acid. Extension of sulfuric acid cyclization conditions to alkyl-substituted oxazoles can give low yields, for example 10-15% for 2,5-dimethyl-l,3-oxazole. Wiegand and Rathbum found that polyphosphoric acid can provide alkyl-substituted oxazoles 4 in yields equal to or greater than those obtained with sulfuric acid. Significantly better yields are seen in the preparation of aryl- and heteroaryl-substituted oxazoles. For example, reaction of ketoamides 5 with 98% phosphoric acid in acetic anhydride gives oxazoles 6 in 90-95% yield. ... 

Alkyl-substituted oxazoles have been found to react with maleic acid or its anhydride in a diene synthesis to yield substituted pyridine readily converted to pyridoxine (39). In this route, ethyl d, 1-alaninate hydrochloride is treated with formic-acetic anhydride to yield ethyl N-formyl d,1-alaninate (78%). This compound is refluxed in chloroform with phosphorous pentoxide (40), quenched with aqueous potassium hydroxide, and the organic layer distilled to give 4-methyl-5-ethoxyoxazole (I) (60%). The resulting oxazole (I) is condensed readily with a number of appropriate dienophiles to form 2-methyl-3-hydroxy-4,5-disubstituted-pyridines containing substituents (III, a, b, c) which could be converted to pyridoxine as follows ... 

Oxazoles with 5-alkyl substituents can undergo benzylic cleavage (Equation 1) and for 2-alkyl-substituted oxazoles, McLafferty rearrangement often takes place (Equation 2). 

The dipole moments of the oxazole molecule determined by dielectric218 and Stark-effect measurements in the microwave spectrum233 are 1.4 and 1.5 0.1 D, respectively. On the basis of small inertial defects in oxazole, Mackrodt et al.m have concluded that the molecule is planar. There is a complete lack of data on the dipole moment of simple alkyl-substituted oxazoles. On the other hand, the values of the dipole moments of a number of aryl-substituted oxazoles have been reported (see Table V). As might be expected, a nitro substituent into the para position of a phenyl ring attached to oxazole increases the value of dipole moment by 2.0-3.5 D. 

Alkyl-substituted oxazoles can also give benzylic cleavage products from the initial radical cation (Fig. 2.17). With substituents at C2, cleavage with McLafferty rearrangement is often noted (Fig. 2.18). 

The first use of an oxazole as an azadiene in a Diels-Alder cycloaddition was reported by Kondrat eva in 1957. In these seminal studies a variety of alkyl-substituted oxazoles 1 (Ri, R2, R3 = H, alkyl) reacted with maleic anhydride in either benzene or ether to provide the cinchomeronic anhydrides 2, rather than the expected bicyclic ethers analogous to the Diels-Alder adducts of furans (Fig. 3.1). 

The first iodine-catalyzed synthesis of 2-alkyl substituted oxazoles 130 by a decarboxylative domino reaction was reported. Aryl methyl ketones 128 were transformed in situ into a-iodo ketones and then, by the Kornblum oxidation, into 1,2-diketones. After the addition of the a-amino acid 129, an l2-mediated cyclization/decarboxylation gave oxazoles 130. The reaction proceeds better if the Ar has electron-donating substituents and if the R group is a branched alkyl chain or phenyl residue. The reaction used oxone to regenerate iodine (13JOC6065). 

Van Leusen and Possel described the use of mono-substituted tosylmethyl isocyanides (TosCHRN=C R = alkyl, benzyl, allyl) in the synthesis of 4,5-substituted oxazoles. For example, 4-ethyl-5-phenyloxazole (8) was prepared in 82% yield by refluxing a-tosylpropyl isocyanide (7) and benzaldehyde for 1 hr with 1.5 equivalent of K2CO3 in MeOH. 

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

Williams, D. R. McClymont, E. L. Carbanion methodology for alkylations and acylations in the synthesis of substituted oxazoles. The formation of Comforth rearrangement products. Tetrahedron Lett. 1993, 34, 7705—7708. 

Heterocyclic compounds are primarily formed through non-enzymatic browning reactions. Recent studies of deep-fat fried food flavors led to the identification of pyrazines, pyridines, thiazole, oxazoles and cyclic polysulfides which had long-chain alkyl substitutions on the heterocyclic ring. The involvement of lipid or lipid decomposition products in the formation of these compounds could account for the long-chain alkyl substitutions. Model systems were used to study the participation of lipids in the formation of pyrazines, pyridines, thiophenes and cyclic polysulfides. 

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. 

Photolytic (68CB302) or rhodium-catalyzed decomposition of alkyl 3,3,3-trifluoro-2-diazopropionates gives carbenes and carbene complexes, respectively, which exhibit an enormous synthetic potential. [3 + 2] cycloaddition reactions have been performed, e.g., with nitriles to give 4-trifluoromethyl-substituted oxazoles [90JOC3383 9IJFC(52)149]... 

Zhu and coworkers implemented a family of Ugi-type MCRs, based on intramolecular trapping of the intermediate nitrilium ion by a carboxamido group, to prepare diversely substituted oxazoles as versatile synthetic intermediates [192-194], They later reported an interesting example of the Ugi-Reissert process using this feature (237, Scheme 34a) [195], This strategy enabled the direct addition of isocyanides to the Ai-alkyl nicotinamide salts 239. However, the different substitution pattern of the carboxamido group, led to a different outcome isomerization of the putative bis-iminofurane intermediate to the cyano-carbamoyl derivative 240. Remarkably, the process is also efficient in a Reissert-type reaction (Scheme 34b, c) [196]. 

In the laboratory of D.R. Williams, a carbanion methodology for the alkylations and acylations of substituted oxazoles was investigated. The study showed that the monoalkylation of the dianion generated from 2-(5-oxazolyl)-1,3-dithiane exclusively led to the substitution of the carbon adjacent to sulfur. However, acylation reactions of the dianion afforded 4,5-disubstituted oxazoles. These new products presumably arose from carbonyinitrile ylide intermediates, which were generated by the selective C-acylation of a ring-opened dianion tautomer. This is the first example of a base-induced, low-temperature Cornforth rearrangement. 

Infrared absorption spectral data for several oxazole derivatives,86 90 including alkyl-98 186 and aryl-263 264 substituted oxazoles, 2-amino- and substituted-amino derivatives109 112 136, 5-amino179 198-201 and 5-alkoxy-oxazoles,66 carboxylic acids,112 147 esters,126 179 184 carboxamides,199 200 4-acetyloxazoles,147 halogenoalkyl oxazoles,91 oxazolines,262 and benzoxazoles262 have been reported. 

The interaction of oxazoles with unsymmetrical dienophiles yields, as a rule, only one of the two possible isomers, in contrast to the usual Diels-Alder reactions where both possible products are generally obtained.337-337a Thus, the reaction of 5-alkyl- or 5-alkoxy-substituted oxazoles with acrylic acid leads almost exclusively to the substituted isonicotinic acids (179)... 

Derivatives of 1,2,4-triazine have been obtained by quatemization of the substituted oxazoles with alkyl p-toluenesulfonate above 100°, followed by treatment of the product with hydrazine hydrate in a solvent.384... 

Efforts to isolate the initial alkyne oxazole [4 + 2] cycloadducts have been unsuccessful, and only the furan cycloaddition products have been detected in the reaction mixtures. The Diels-Alder reaction of alkyl- or aryl-substituted oxazoles with neutral, conjugated, or electron-deficient al-kynes displays little regioselectivity whereas polarized, electron-rich oxazoles (e.g., 1, = OEt) do participate in regioselective, intermolecu-... 

Peanut flavor. The aroma of roasted peanuts is mainly due to thermally formed flavor compounds. Major constituents include pyrazines, e.g., methyl-, 2,5-dimethyl-, trimethyl-, and 2-ethyl-3,5(6)-dimethyl-pyrazine, as well as pyrroles, thiophenes, oxazoles, and thiazoles, e.g., 2-isopropyl-4,5-dimethylthiazole (CgHijNS, Mr 155.26), also contributing to the typical P. f. Also important are alkyl-substituted dihydro-4//-... 

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