Synthesis and Characterization of para-Substituted N, N-Dihydroxybenzamidines and Their Derivatives as Model Compounds for a Class of Prodrugs

A synthetic strategy for previously unknown para-substituted N,N-dihydroxybenzamidines and their O-monosubstituted and O,O-disubstituted methyl, benzyl, and tetrahydropyranyl derivatives is described. The procedure starts with the corresponding hydroxamic acid chlorides, which after dehydrohalogenation give nitrile oxides. These intermediates in turn react with O-substituted hydroxylamines to afford the desired N,N-dihydroxybenzamidines after workup. This new class of potential prodrugs was characterized by N-15 NMR spectroscopy. The chemical shifts show significant correlations with Hammett sigma values, especially for the oxime-type nitrogen with r(2) > 0.99. The Hammett sigma parameter reliably correlates with electron density in molecules. The presented results thus allow predictions relating to -electron density and basicity in this functional group, and these are important parameters for the discussion of substrate enzyme interactions.