Synthesis of 4-Pyridone-3-sulfate and an improved synthesis of 3-Hydroxy-4-Pyridone

3-Hydroxy-4-pyridone is a constituent of mimosine (also called leucenol) where it occurs as a derivative of L-alanine (Fig. 1) [1]. It is also an intermediate in the bacterial metabolism of 4-pyridone [2] and affects thyroid function [3]. 3-Hydroxy-4-pyridone was first synthesized by Ost in 1873 [4] from pyrone precursors and since then by other related transformations of the pyrone ring system [5-8], by degradation of mimosine [2,9,10], and by the Elbs peroxydisulfate oxidation of both 3-hydroxypyridine and 4-pyridone [2,11,12]. None of these routes is entirely satisfactory: the required pyrones are easily synthesized from meconic (poppy) acid but this is no longer commercially available [13] (the closest available structures are maltol and kojic acid); mimosine currently sells at about $200/g; and the yields in the Elbs oxidation have been, at best, less than 10% and have involved difficult purifications. There is a promising route via lithiation of 4-methoxypyridine which has been carried as far as 3-hydroxy-4-methoxypyridine in connection with the synthesis of orelline, a mushroom toxin [14].I report improvements to the Elbs procedure although the yield has been increased only modestly. The oxidation of 4-pyridone by peroxydisulfate is an example of an Elbs oxidation in which the substitution occurs ortho to the existing phenolic group (Fig. 2). In a phenol with both ortho and para positions free, the ortho-para ratio is typically about 0.1. Yields of the ortho-substitution product when the para-position is blocked (as in 4-pyridone) are usually low [15]. However, considerable quantities of starting material are recoverable and increasing the peroxydisulfate-phenol ratio increases the yield of the ortho-product in these cases [16]. A speculation about the reason for this situation involves destruction of peroxydisulfate by reaction with a phenolic free-radical and regeneration of the phenol by decomposition of an aromatic hydroperoxide according to Scheme 1[17].