ATTEMPT TO APPLY LETHAL SYNTHESIS TO THE DESIGN OF CHEMOTHERAPEUTIC-AGENTS - FLUORINATED 5 BETA-(HYDROXYETHYL)-4-METHYLTHIAZOLES

2-Fluoro-5β-(hydroxyethyl)-4-methylthiazole (V) was prepared from 5β-acetoxy-2-amino-4-methylthiazole (X), which was prepared from 5β-acetoxy-3-chloropentanone (IX) and thiourea. Diazotization with NOBF4 followed by pyrolysis gave 5β-acetoxy-2-fluoro-4-methylthiazole (XII), which on hydrolysis with KHCO3 gave V. (Trifluoroacetyl)γ- butyrolactone (XIII) was chlorinated with SO2Cl2 to give 2-chloro-2-(trifluoroacetyl)-γ-butyrolactone (XIV), which on hydrolysis and decarboxylation gave 3-chloro-1, 1, 1-trifluoro-5-hydroxy-2-pentanone which exists as the hemiketal XV. Treatment with thiourea gave 2-amino-5β-(hydroxyethyl)-4-(trifluoromethyl)thiazole (XVI), but no thiazole formation was observed when XV was treated with thioformamide. Ethyl 2-(trifluoroacetyl)-γ-methoxybutyrate (XVIII), prepared from ethyl γ-methoxybutyrate and ethyl trifluoroacetate, gave after hydrolysis and decarboxylation 5-methoxy-1, 1, 1-trifluoro-2-pentanone (XIX), which on bromination followed by treatment with thioformamide gave 5β-(methoxyethyl)-4-(trifluoromethyl)thiazole (XXI). Treatment of XXI with BBr3 gave 5β-(hydroxyethyl)-4-(trifluoromethyl) thiazole (VI). Neither V nor VI showed antibacterial action against two strains of Escherichia coli. A rationalization of this lack of activity is discussed. © 1979, American Chemical Society. All rights reserved.