Chemistry of the tricyclic form of thiamine with aldehydes in basic ethanol

Abstract

Thiamine chloride hydrochloride 1 is converted to its neutral tricyclic form 2 when suspended in a solution of ethanol containing two equivalents of NaOEt (G. D. Maier and D. E. Metzler (1957) J. Amer. Chem. Soc. 79, 4387). Upon the addition of benzaldehyde to this basic thiamine solution an intermediate accumulates which gives rise to 2-(1-hydroxyphenylmethyl)thiamine hydrochloride (HBT-HCl) 3 upon acidification of the reaction mixture with HCL after 5 min, and high yields of both 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-2-benzoyl-3a-methyl-perhydrofuro-[2,3-d]-thiazole (HBT ketone) 4 and benzoin when the reaction mixture is stirred for 5 h. Given that thiamine is unstable under these conditions such that it is converted completely to its tricyclic species, we argue that the 2-(1-hydroxylalkyl) thiamine salts, which have an increased base lability due to the addition of a C-2 N-3 torsional interaction to the base-labile thiazolium ring, would also not be expected to accumulate in appreciable concentrations under identical conditions. Based on product isolation and the synthesis of 2-benzoyl-3,4-dimethyl-5-ethoxycarbonyl-[2H]-thiazoline 12 in the reaction of 3,4-dimethyl-5-ethyoxycarbonylthiazolium iodide 11 with benzaldehyde in basic methanol, we conclude that the intermediate which accumulates during the reaction of the tricyclic form of thiamine with benzaldehyde is a 2-benzoylthiazoline 8 in equilibrium with a low concentration of its enol isomer 9, i.e., the C-2α reactive “active aldehyde.” Reasons for the increased catalytic power of thiamine under these conditions, as well as the relevance of this chemistry to the active site chemistry of thiamine pyrophosphate, are discussed.