Ferric ion sequestering agents. 19. Synthesis of N-alkyl-3-hydroxy-2(1H)-pyridinones and coordination complexes with iron(III)

Abstract

The amidation of 2,5-dimethoxytetrahydrofuran-2-carboxylic acid methyl ester by primary alkylamines followed by acid-catalyzed rearrangements yields N-alkyl-3-hydroxy-2-pyridinones. The rearrangement reaction is promoted by the presence of metal ions, such as Fe/sup 3+/, Cu/sup 2+/, and Zn/sup 2+/, which have high affinities for the bidentate hydroxypyridinone binding group. The structures of N-butyl-3-hydroxy-2-pyridinone (HL') and its 3:1 complex with iron(III) (FeL'/sub 3//center dot/3H/sub 2/O) have been determined by x-ray crystallography. Bond lengths involving the pyridine ring indicate that a catechol-like aromatic resonance form is significant, particularly in the iron complex. The visible spectra for (FeL'/sub n/)/sup (3-n)+/ (n = 1-3) are virtually identical with those of previously characterized complexes of iron(III) and 3-hydroxy-2-(1H)-pyridinone (3,2-Hopo, HL). The log K/sub a/ (protonation constant) of HL' and log K/sub 3/ for formation of FeL'/sub 3/ (from FeL'/sub 2//sup +/ and (L')/sup /minus//) are higher by 0.5 log unit than those of the unsubstituted HL and FeL/sub 3/. Differences in equilibria at pH > 7 between solutions of FeL'/sub 3/ and those of FeL/sub 3/ have been studied by spectrophotometric titrations. The N-butyl derivative FeL'/sub 3/ hydrolyzes only above pH 10.5 in the presence of 3 mM excess HL', whereas three stepwise protonations (log K/sub a/ =more » 9.2, 10.6, 12) are observed in solutions of FeL/sub 3/ containing excess (several millimolar) HL. The contrasting behaviors of FeL'/sub 3/ and FeL/sub 3/ in alkaline solution are rationalized in terms of the absence or presence of a weakly acidic proton on the ligand nitrogen. 38 refs., 8 figs., 5 tabs.« less