3-Hydroxythiophene-2-carboxylates, tautomers

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity. The synthesis of this compound starts by a multi-step conversion of hydroxythiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycine ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 ( shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22],... 

The presence of alkyl, or other groups, both stabilise the oxy compounds and the double bond to which they are attached. In these more stable compounds alternative tautomers are found, thus 5-methyl-2-hydroxythiophene exists as a mixture (actually separable by fractional distillation ) of the two enone tautomers and ethyl 5-hydroxythiophene-2-carboxylate is in the hydroxy-form to the extent of 85%. ... 

Compounds such as (246) having a carbonyl substituent at position 3 and a hydroxyl at 2 exist exclusively in the enol form. On the other hand, if the ester is located at position 5, then about 15% of the keto form is seen at equilibrium along with 85% of the enol. 3-Hydroxythiophene-4-carboxylic acid esters seem to exist as a mixture of both tautomers <86HC(44/3)l>. 

The prior to imiversal synthesis to this kind of product was reported in 1910 by Senary [27] as the multi step reaction of ethyl 4-chloro-2-( ano-3-oxobutanoate (1). After the treatment of 1 with potassium hydrosulfide the reactive sufanyl-substituted intermediate 2 was created, which in the subsequent intramolecular addition of sulfanyl group to cyano group proceeded ethyl 2-amino-4-hydroxythiophene-3-carboxylate (4) in equilibrium with its cyclic tautomer - the appropriate imine 3 (Scheme 1). 

---