Thiazoles and Related Sulfur-Nitrogen-Containing Heterocycles

Thiazoles and Related Sulfur-Nitrogen-Containing Heterocycles 

The very broad structural requirements for NSAIDs that allow replacement of the benzene ring by a pyrrole or an oxazole ring have been noted earlier in this chapter. Thiazoles, too, it has been found, can substitute for the central benzene ring. 

One of the two classic schemes for constructing the thiazole ring involves the condensation of a thioamide or its equivalent with an a-haloketone. The reaction can be visualized as involving, as the first step, the displacement of halogen by sulfur from the enol form of the amide imine formation will then close the ring. Thus, reaction of bromoketone (99-2) obtained from the bromination of the corresponding keto-acid with thioamide (99-1) affords thiazole (99-3) in a single step. There is thus obtained the NSAID fentiazac [109]. 

In a similar vein, reaction of the thiobenzamide (100-1) with 4-bromoacetoacetate (100-2) in the presence of a base starts by the displacement of bromine by sulfur to afford a transitory substimtion product such as (100-3). This can then undergo internal imine formation between basic nitrogen and the adjacent carbonyl goup to afford the thiazole (100-4). Saponification then leads to the NSAID fenclosic acid (100-5) [110]. 

Thioureas serve as a convenient starting material for 2-aminothiazoles. Reaction of (3-phenethylamine (103-1) with ammonium isothiocyanate gives the thiourea (103-2). Treatment of that product with phenacyl bromide (103-3) leads to the corresponding thiazole. That compound, fanetizole (102-4) [114], shows immuno-regulating activity. 

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