Convenient syntheses of 2-acylamino-4-halothiazoles and acylated derivatives using a versatile Boc-intermediate

The 2-aminothiazole grouping is a significant feature of many series of biologically active molecules, including antibiotics, anticancer agents and NSAIDs. We have a longstanding interest in the synthesis and biological evaluation of thiazolides, viz. [2-hydroxyaroyl- N -(thiazol-2-yl)-amides] which have broad spectrum antiinfective, especially antiviral, properties. However, 2-amino-4-substituted thiazoles, especially 4-halo examples, are not easily available. We now report practical, efficient syntheses of this class from readily available pseudothiohydantoin, or 2-aminothiazol-4(5 H )-one: the key intermediate was its Boc derivative, from which, under Appel-related conditions, Br, Cl and I could all be introduced at C(4). Whereas 2-amino-4-Br/4-Cl thiazoles gave low yields of mixed products on acylation, including a bis-acyl product, further acylation of the Boc intermediates, with a final mild deprotection step, afforded the desired thiazolides cleanly and in good yields. In contrast, even mild hydrolysis of 2-acetamido-4-chlorothiazole led to decomposition with fast reversion to 2-aminothiazol-4(5 H )-one. We also present a correction of a claimed synthesis of 2-acetamido-4-chlorothiazole, which in fact produces its 5-chloro isomer. Pseudothiohydantoin was readily converted into 2-amino-4-halothiazoles in Boc-protected form. The products were readily converted into potential antiviral thiazolides.