Oxazoles, Isoxazoles, and their Derivatives

An oxazole substituted with a complex aminohydantoin side chain is described as a muscle relaxant. Imine formation between glyoxylic acid and aminohydantoin (38-1) results in the imino acid (38-2). Use of that intermediate to acylate the amine on 4-chloro-2 -aminoacetophenone (38-3) leads to the amide (38-4), which now includes a 1,4-dicarbonyl array. Treatment of the keto-amide with phosphorus 

The dimethylaminooxazolidone derivative thozalinone (40-3) is described as an antidepressant. The synthesis of this agent again uses a cyanamide, provided in this case as a preformed reagent. Thus, reaction of alkoxide from ethyl mandelate (40-1) with A,A-dimethylcyanamide leads to the amidine (40-2) by addition to the nitrile. Internal displacement of the ester ethoxide group closes the ring to an oxazo-lidinone, forming the product (40-3) [42]. 

The classical method for preparing isoxazole involves the condensation of 1,3-dicarbonyl compounds with hydroxylamine, a reagent that contains the preformed N—O bond. The regiochemistry of the reactions can usually be rationalized by assuming that the first step involves imine bond formation at the more reactive carbonyl group. Thus, reaction of formyl ketone (44-1) with hydroxylamine gives 

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

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