The presence of the 5-functional group on 3-hydroxypyridin-4-ones (HPOs) can significantly change their chelating properties because the 5-position is adjacent to one of the chelating moieties. A 5-methoxy-substituted HPO has been successfully synthesized using a 5-bromo analogue with NaOMe in the presence of a copper(I) catalyst. The atomic charges and stability constants of the HPOs with either electron-donating or election-withdrawing groups on the 5-position were compared. The result showed that the 5-substituted HPOs possess lower stability constants, compared to those of the 5-unsubstituted analogue (deferiprone).