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 15N NMR spectroscopy. The chemical shifts show significant correlations with Hammett σ values, especially for the oxime-type nitrogen with r2 > 0.99. The Hammett σ parameter reliably correlates with electron density in molecules. The presented results thus allow predictions relating to π-electron density and basicity in this functional group, and these are important parameters for the discussion of substrate enzyme interactions.