Oxazoles, 2,5-disubstituted

In 1949, Comforth showed that preparation of 2,5-disubstituted oxazoles was not limited to diaryloxazoles through condensation of aldehydes (benzaldehyde, n-hept-aldehyde) with a-hydroxy-amides (lactamide). The intermediate oxazolidone 13 were converted into oxazoles 14 on warming with phosphoryl chloride. ... 

A new approach to the synthesis of 2,4,5-trisubstituted and 2,5-disubstituted oxazoles, 97 and 98, used l-(methylthio)acetone 95 with nitriles in the presence of trifluoromethanesulfonic anhydride. The proposed mechanism involves an unstable 1-(methylthio)-2-oxopropyl triflate 96 which was detected using NMR spectroscopy <06JOC3026>. 

Natural product o-methylhalfordinol 117 is a basic principle of the oxa-zole alkaloids of Halfordia scleroxyla and Aegle marmelos. Annuloline 119, a blue fluorescent pigment, has been isolated from the roots of rye stalk Lolium multifiorum. The total synthesis of 2,5-disubstituted oxazole alkaloids o-methylhalfordinol and annuloline is based on the aza-Wittig reaction (Scheme 48). Thus 4-methoxyphenacylazide 115, triphenylphos-... 

N Diaye, I., Guella, G., Mancini, I., and Pietra, F., Almazole D, a new type of antibacterial 2,5 disubstituted oxazolic dipeptide from a red alga of the coast of Senigal, Tetrahedron Lett., 37, 3049, 1996. 

Thus, an oxygen nucleophile reacted intramolecularly with the alkynyl triple bond, and another example of this is provided by the synthesis of 2,5-disubstituted oxazoles from 7V-propargylcarboxamides under mild conditions using 5 mol% AUCI3 in acetonitrile 22... 

Oxazole IV-oxides cannot be made by oxygenation of oxazoles. The only method of synthesis remains the condensation of monooximes of 1,2-dicarbonyl compounds with aldehydes in the presence of hydrogen chloride (equation 132) (15CB897). The aldehyde may be aromatic or aliphatic (including formaldehyde) and the oxime may be derived from an aromatic diketone or it may be an a-keto aldoxime, leading to a 2,5-disubstituted oxazole IV-oxide. It may also contain an additional carbonyl group as in equation (133). 

Propargylamine amides without electron-withdrawing groups can also cyclize to oxazoles using a Lewis acid such as AuCls <20040L4391>, or under basic conditions. Treatment of amide 178 with NaHMDS gave 2,5-disubstituted oxazole 179 (Scheme 49) <1998JOC7132>. 

Several new syntheses of 2,5-disubstituted oxazoles have been reported. The reaction of allyl zinc bromides with )V-cyanomethylimidates (136) leads to 2-alkyl- or aryl-5-allyloxazoles in 50-65% yields after hydrolysis of intermediate imine salts (137) <91SC1501>. The allyl zinc reagents add to the nitrile, in contrast to organolithium and magnesium reagents, which are too basic (Scheme 62). 

Disubstituted oxazoles are obtained from A -propargylamides by acid, base, and metal catalysis <89JHC269>. The reaction proceeds through an allene intermediate (138) (Scheme 63). The base-... 

Perhaps the simplest method of oxazole synthesis would involve bromina-tion of a ketone in the presence of an amide as shown in Eq. (6), that is, generating the required a-bromo ketone in situ. Marquez88 thus prepared several 4-phenyl 2,5-disubstituted oxazoles by adding calculated amounts of bromine to a heated mixture of ketone and amide. With unsymmetrical... 

In the case of 4-methyl-2,5-disubstituted oxazoles, bromination with either bromine or A-bromosuccinimide affords the 4-bromomethyl compound.307 2-Bromomethyl-4,5-diphenyloxazole is obtained by bromination of the corresponding oxazole with NBS in the presence of dibenzoyl peroxide.121 Reaction with phosphorus pentachloride similarly gives the side-chain-chlorinated products.80... 

In a similar way, irradiation converts many simpler pyrazoles into imidazoles, phenylisothiazoles and methylisothiazoles partially into the corresponding thiazoles, and 3,5-diarylisoxazoles converted into 2,5-disubstituted oxazoles. " 3-Alkoxyisoxazoles undergo an extraordinary ring contraction with iron(II) chloride, producing azirine esters... 

Balaban and co-workers " prepared 2,5-disubstituted oxazoles via side-chain bromination with NBS, followed by dehydrobromination with pyridine. Kashima and Arao described a synthesis of oxazoles using NBS/AIBN to effect oxidation of an oxazoline. In this case, the product was a 5-bromooxazole, e.g., 63 (Scheme 1.19). This study was limited to only three examples of 2-aryloxazoles. 

In some cases, mixtures of 2,4-disubstituted and 2,5-disubstituted oxazoles were isolated. For example, pyrolysis of 2-benzoyl-3-phenyl-isoxazol-5-one 106 gave the expected 2,4-diphenyloxazole 110 in 60% yield together with 10% of 2,5-diphen-yloxazole 111 and 15% of benzanilide (Scheme 1.30). The authors explained these products by initial formation of a singlet iminocarbene 107. This then... 

Hajjem and Baccar used cyanomethylimidates as substrates for addition of organozinc reagents to prepare (3-ketoimidates that cyclized to 2,5-disubstituted-oxazoles as shown in Scheme 1.95. For example, addition of an alkenylzinc... 

TABLE 1.28. 2,5-DISUBSTITUTED OXAZOLES FROM CYANOMETHYLIMIDATES AND ORGANOZINC REAGENTS"... 

Kaufmann and co-workersexplored several complementary methods to prepare 2,5-disubstituted oxazoles and 2,4,5-trisubstituted oxazoles as flash-lamp pumped laser dyes (Scheme 1.122). Prolonged reflux of 440 with POCI3 effected cyclodehydration to 5-(4-methoxyphenyl)-2-(4-pyridyl)oxazole 441 in modest... 

TABLE 1.63. 2-SUBSTlTUTED AND 2,5-DISUBSTITUTED OXAZOLES FROM 2-LITHIOOXAZOLE-BORANE COMPLEXES AND ELECTROPHILES"" ... 

TABLE 1.78. 2-ACYL-1-METHYI 5-SUBSTITUTED PYRROLE-3.4-DICARBOXYLIC ACID DIMETHYL ESTERS FROM 2,5-DISUBSTITUTED OXAZOLES, METHYLTRIFLATE,... 

Radspieler and Liebscher prepared several 4-chloro-2,5-disubstituted oxazoles 1520 from aromatic acyl cyanides 1519. These oxazoles are the first examples in which the 2-substitutent was not derived from an aromatic aldehyde. They extended this methodology to prepare suitably functionalized dichloro indole bis-oxazole C-D-E fragments. Their approach is noteworthy as the first synthesis of such fragments that does not involve chlorination of an intact oxazole ring. 

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