Synthesis of New DNA Gyrase Inhibitors: Application of the DMSO Oxidation to the Conversion of the Amine into the Imine

A novel type of pyridonecarboxylic acid with a planar thiazolopyrazine-incorporated tetracyclic skeleton, 4,9b-diaza-8,9b-dihydro-6-fluoro-5-(4-methyl-1-piperazinyl)-8-oxo-1-thia-1H-cyclopenta-[cd]phenalene-9-carboxylic acid (3), was prepared. Compound 3 was a potent inhibitor of DNA gyrase and exhibited attractive antibacterial activity against both Gram-positive and Gram-negative bacteria. In the course of the synthetic studies, we have found a new oxidation method of the amine 4 to the imine 5 with DMSO activated by trifluoroacetic anhydride or oxalyl chloride. The DMSO/trifluoroacetic anhydride method gave the byproduct 8, an unusual (methylthio)methyl adduct. The DMSO/oxalyl chloride method gave the byproducts 9 and 10, a (methylthio)methyl ester, and a halogen adduct, respectively. The mechanisms of these oxidations are also discussed.