Solid-Phase Synthesis of 2,4,5-Trisubstituted Thiazoles

Thiazoles are useful heterocycles and building blocks and a prominent stmctural element of compounds used to treat cancer, bacterial, fungal, and viral infections. Because the thiazole derivatives exhibit a wide range of important biological activities, they serve as 

The acylation with acid chloride and the urea formation with isocyanate of intermediate resin 16 afforded other substituent groups onto 4-aminothiazole. Under microwave (MW) irradiation reaction with isocyanate and acylation reaction with acid chloride, R -substituted thiazole resin 19 was obtained. Following conversion of sulfonyl resin 19 to sulfonyl resin 20 (mCPBA/CH2Cl2), substitution reactions promoted by treatment with appropriate amines (R R N diversity elements) furnished the 2,4,5-trisubstituted thiazoles 2 (29 examples 36-25% isolated yields from Merrifield resin 1, 95% purities, Table 10.1). 

2 Solid-Phase Synthesis of 2,5,6,7-Tetrasubstituted Thiazolo[4,5-6]pyridines 

The fused-thiazole heterocycles are important structural components of bioactive molecules and, as a result, serve as attractive targets for combinatorial library construction 

Finally, the sulfone group on resin 22 was displaced by a desulfonative substitution reaction with the corresponding amines (R R N diversity elements) in THF (tetrahydro-furan). This process, which is accompanied by concurrent cleavage from the resin, furnished the final thiazolo[4,5-6]pyridine derivatives 3 (50 examples 50-13% five-step overall yields from Merrifield resin 1, Table 10.2), which were purified by column chromatography ( 95% purities as judged from LC-MS traces (integration of diode array 200—400 nm traces)). 

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Scheme 10.1. Solid-phase synthesis of 2,4,5-trisubstituted thiazoles.

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