By Chance, Not Design: A New Furosemide Derivative From Zinc(II) Complex Studies

Furosemide, a sulfonamide-based diuretic, may also be of interest as a ligand capable of binding to metal ions. Our studies of zinc-(II) coordination chemistry with furosemide in organic solvents resulted in a crystalline precipitate. Initial characterization was challenging because single crystals were of insufficient quality for an unambiguous structural determination. X-ray analysis confirmed a four-coordinate zinc-(II) complex with two deprotonated furosemides (fur^-) bound in a monodentate manner and two simple monodentate ligands. Complementary techniques, i.e., infrared spectroscopy, NMR spectroscopy, and thermal analysis, revealed their identity as ammonia, generated <i>in situ</i> from acetonitrile hydrolysis. The composition of the product is thus [Zn-(fur)₂(NH₃)₂]·(CH₃CH₂)₂O (<b>1</b>). Although our attempt to prepare better-diffracting crystals was unsuccessful, it led to the serendipitous discovery of a new furosemide derivative, labeled <b>2</b>. The derivative features two structural modifications compared to the parent furosemide, namely, ester and amidine functionalities. Single-crystal analysis of <b>2</b> showed the esterification of the carboxyl group with methanol and nucleophilic addition of the sulfonamide NH₂ group to the triple bond of acetonitrile, used as a solvent. These results expand the structural chemistry of furosemide and demonstrate its capacity to undergo unprecedented transformations in zinc-(II)-mediated systems.