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Fiesselmann thiophene synthesis

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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]

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Mechanism

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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]

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Applications

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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]

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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]

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

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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]

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References

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