The Fiesselmann thiophene synthesis is a name reaction in organic chemistry that allows for the generation of 3-hydroxy-2-thiophenecarboxylic acid derivatives from α,β-acetylenic esters with thioglycolic acid and its derivatives under the presence of a base. The reaction was developed by Hans Fiesselmann in the 1950s.^{[1][2][3][4][5][6]}

Mechanism

After deprotonation the thioglycolic acid ester attacks the tripel bond of the alkyne. Another addition takes place on the resulting double bond. Via deprotonation of a thioglycolic acid ester moiety the cyclization is initialized. From the resulting thiolane an alcoholate is eliminated to yield a ketone. Elimination of a thioglycolic acid ester results in an α,β-unsaturated ketone. Tautomerization leads to the desired product.^[7]

Applications

A variation of the Fiesselmann synthesis by Lissavetzky starts from a cyclic β-ketoester and thioglycolic acid. In combination with an alcohol (R⁴OH) the monoadduct is the main product. Without the addition of alcohol a thioacetal is generated. In presence of potassium hydroxide it can be esterificated and cyclisized. To cyclisize the mono adduct a sodium alcoholate is used.^[8]

If the substrate contains a nitrile instead of an ester group the reaction will result in 3-aminothiophenes. Scott used this approach to synthesis a p38 kinase inhibitor.^[9]

The reaction also works with aromatic derivates. Fry used this variation for the synthesis of tyrosinkinase inhibitors, starting from a substituted pyridine.^[10]

Nicolaou used the conditions of the Fiesselmann thiophene synthesis to show potential DNA cleaving properties of golfomycin A, a cyclic alkyne with potential antitumor activity.^[11] The Fiesselmann synthesis is also used to produce potential antiallergy agents,^[12] antileishmanial and antifungal agents^[13] and thieno[b]azepinediones.^[14]