CORNFORTH Oxazole Rearrangement

Without additional reagents Cornforth oxazole rearrangement... 

The Cornforth rearrangement involves the thermal interconversion of 4-carbonyl substituted oxazoles, with exchange between the C-C-O side-chain and the C-C-O fragment of the oxazole ring. These reactions generally involve compounds where a heteroatom (-OR, -SR, -Cl) is attached to the 5-position (R2) of the starting oxazole. 

The thermally induced Cornforth rearrangement can be rationalized by postulating the dicarbonylnitrile ylid 103 as intermediate. It is especially the natures of the substituents R and R" that determine the direction of the rearrangement. For example, heating of 5-alkoxy-4-(aminocarbonyl)oxazole (102, R = OAlkyl, R" = NR2) readily gives in a good yield rearrangement into the isomeric 5-(substituted amino)-4-(alkoxycarbonyl) oxazole (104, R = OAlkyl, R" = NR2) (Scheme IV.40). 

The formation of oxazoles by the Cornforth rearrangement, which is a useful synthetic procedure, is described in Section 4.18.3.1.2(i). Oxazoles are also satisfactorily prepared by reduction of their IV-oxides (see next section) with zinc and acetic acid. Treatment of oxazoles and benzoxazoles with alkylating agents gives quaternary salts. 

Keywords Oxazoles Tandem alkylation/cyclisation Cornforth rearrangement Anti-proliferative agent Antibacterial activity... 

The 2-aryloxazoles have also been synthesized under microwave activation by the direct Stille and Suzuki cross-coupling reactions of 1,3-oxazoline (OXT) [17]. Nolt et al. [18] utilized the microwave-assisted Cornforth rearrangements for the preparation of substituted 5-amino-oxazole-4-carboxylate (v). 

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. 

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

Although oxazole and its alkyl and aryl derivatives are thermally stable to high temperatures, the introduction of functionalized substituents can lead to reaction at lower temperature. The Cornforth rearrangement, discussed in <84CHEC-I(6)177>, is one example. An application of the Cornforth reaction is the conversion of 4-aminothiocarbonyl-5-ethoxyoxazoles (33) to 5-aminothiazoles (34)... 

Carbonyl-substituted oxazoles 20 (aldehydes, ketones, carboxylic acids, and their derivatives) undergo a thermally induced rearrangement to the isomeric oxazoles 22, in which the residue located at the 4-carbonyl moiety and the 5-substitutent have changed places (CoRNFORTH rearrangement) [261] ... 

Analogously, oxazole-4-thioamides 23 can be thermally isomerized by Cornforth rearrangement to afford 5-amino-(4-alkoxycarbonyl)thiazoles 24 ... 

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