Ketones 2.4- disubstituted oxazoles

The synthesis of Bliimlein82 and Lewy,83 which affords moderate yields of 2,4-disubstituted oxazoles (29) (having at least one aryl group) by the condensation of a-halo ketones with amides (other than formamide) is even at present a method of choice because of the ready availability of the starting materials. It has been extensively applied to the preparation of many 2,4-disubstituted oxazoles20 21 40 84-86 and is equally applicable... 

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... 

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... 

The synthesis of 2,5-disubstituted oxazoles from methyl ketones and benzylamines in a metal and peroxide-free environment is achieved using l2-promoted domino oxidative cyclization involving C-H bond cleavage and the formation of C-N and C-0 bonds. Slow oxidation of A-acetyl homocysteine thiolactone by iodate to A-acetyl homocysteine thiolacone sulfoxide occurs in a reaction S1 having 1 3 stoichiometry (oxidant reductant). The stoichiometric ratio in excess of 103 (reaction S2) is 2 5 because excess 103 oxidizes the r ion, generated in reaction SI, to I2. The stoichiometry ratio for the I2 oxidation (reaction S3) is 1 1. Complex kinetics are observed because reactions SI, S2 and S3 occur simultaneously with comparable rates. 

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... 

TABLE 1.14. MICROWAVE ASSISTED SYNTHESIS OF 2-PHENYL-4-SUBSTITUTED OXAZOLES AND 4,5-DISUBSTITUTED 2-PHENYLOXAZOLES FROM ARYL KETONES, BENZONITRILE, AND MERCURY(II)TOSYLATE ... 

About 30 years ago van Leusen and co-workers pioneered the condensation of TosMIC with aldehydes and ketones to prepare 4,5-disubstituted oxazolines that eliminate toluenesulfinic acid to yield 5-substituted oxazoles. This process continues today as an important method for constructing such analogues, as evidenced by the following examples. 

TABLE 1.37. 2-SUBSTITUTED 2,5-DISUBSTITUTED AND 2,4,5-TRISUBSTITUTED OXAZOLES VIA MICROWAVE-ACCELERATED CYCLODEHYDRATION OF 2-ACYLAMINO KETONES OXAZOLES USING BURGESS REAGENT"... 

The use of Lindlar s catalyst and aqueous acidic conditions allowed the generation of /3-hydroxy ketone 62 from oxazole 61 with the disubstituted olefin remaining intact (Scheme 22).A yield of 65% was obtained even when a monosubstituted olefin was present. 

---