4-chloro-2,5-disubstituted oxazoles

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. 

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... 

In the presence of moisture, the chloro-oxazoline 4 is converted to oxazolidone of structure 7, which can form the 2,5-disubstituted oxazole end product if warmed up with phosphoryl chloride (POCI3), where it is believed to reform intermediate 4, and then to proceed to the oxazole end-product formation. ... 

Whereas a-amino ketones readily form imidazoles with formamide, they are often not easy to prepare. Accordingly, they can be replaced by precursors, a-oximino ketones, which can be reduced either by dithionite or using catalytic mehods in formamide at 70-100 °C. Ring closure can then be achieved by raising the temperature (Scheme 80). When a-ketol esters are used it appears that the imidazole formation may in this instance proceed by way of the oxazole. A further special case is the formation of 4,5-disubstituted imidazoles from 1-chloro-l,2-epoxides and formamide. One recent example of an application of Bredereck s method is the synthesis of the imidazolepropanol (144) from 3-bromo-2-methoxytetra-hydropyran (Scheme 81) (80AHC(27)241). 

This method has afforded some 2-phenyl-4-(/3-aminoethyl)-, and 2-pheny 1-4- (/3-disubstituted-aminoethyl) oxazoles from benzamide and the appropriate substituted bromobutanones.90 A 5-oxazolylethanol derivative is obtained from the corresponding substituted a-chloro ketone and amide in the presence of calcium carbonate (to neutralize the generated hydrogen chloride.)91 Condensation of a-bromophenylacetaldehyde and p-bromo-benzamide at 110°-120° gives 50% yield of 2-p-bromophenyl-5-phenyl-oxazole.18... 

---