Formaldehyde → HCID 19810960, compound

Participants

Reaction Steps

As previously indicated, one method of preparing 5-carboxyaldehydehyde-1-methyl-4-(phenylmethyl)thioimidazole from 1-methyl-4-(phenylmethyl)thioimidazole comprises condensing 1-methyl-4-(phenylmethyl)thioimidazole with formaldehyde under weakly acidic conditions in a first step to form 5-hydroxymethyl-1-methyl-4-(phenylmethyl)thioimidazole and then oxidizing the formed primary alcohol in a second step to form the product. The first step is readily carried out by reacting using aqueous formaldehyde (e.g. 36.5% to 38% aqueous formaldehyde) in a buffered weakly acid medium, such as sodium formate/formic acid, preferably sodium acetate/acetic acid (pH ranging from about 5.5 to about 6.5) at 90° to 130° C., preferably at reflux over a time period ranging from about 2 to about 4 hours. The buffered weakly acid medium should be such as to protonate the formaldehyde but at most to partially protonate the imidazole moiety to enable an electrophilic attack on the imidazole ring. The second step of oxidizing the primary alcohol in the presence of a sensitive sulfide bond (i.e. without disturbing the sulfide bond) requires careful selection of oxidizing agent. Activated manganese dioxide is preferred for use as the oxidizing agent. Oxidizing agents which were functional but provided much lower yields than activated manganese dioxide included (a) 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO reagent) and CuCl, (b) RuCl2 (PPh3)3 and (c) pyridinium chlorochromate. This second step is readily carried out in a nonpolar or slightly polar solvent such as dichloromethane, acetonitrile or dioxane, preferably acetone, e.g. at a temperature ranging from room temperature to 45° C. for a time period ranging from 6 to 24 hours.

Provenance & Evidence