Hinsberg synthesis of thiophene derivative

The Hinsberg synthesis of thiophene derivatives describes the original condensation of diethyl thiodiglycolate and a-diketones under basic conditions which provides 3,4-disubstituted-thiophene-2,5-dicarboxylic acids upon hydrolysis of the crude ester product with aqueous acid.  

In 1910, Hinsberg described the reaction between benzil and diethylthiodiacetate, resulting in the preparation of the thiophene ring system. The reaction was run under Claisen condensation conditions, and after hydrolysis with aqueous acid at reflux, the free dicarboxylic acid 1 was produced. 

The Hinsberg thiophene synthesis has seen limited use owing to the potential for regioisomeric mixtures when unsymmetrical 1,2-dicarbonyls are condensed with unsymmetrical thiodiacetates. Thus, symmetrically substituted thiophenes are generally prepared in this manner. 

A notable utilization of the Hinsberg procedure was executed in the synthesis of a thiophene analogue of porphyrin. A previous synthesis of the tetrathioporphyrin dication of 7 found this material to be unsuitable for chemical exploration as a result of its limited accessibility and solubility. Efforts by Vogel et al. were then directed toward 

In addition to thiodiglycolic acid esters, the use of bis(cyanomethyl)sulfide in the Hinsberg reaction has facilitated the preparation of 5-cyano-thiophene-2-carboxamides. Thus, the condensation of biacetyl with bis(cyanomethyl)sulfide resulted in the efficient preparation of 10 (94% yield). 

Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., ed. Wiley-Interscience New York, 1985, 34-41. (Review). 

Mullins, R. J. Williams, D. R. Hinsberg Synthesis of Thiophene Derivatives In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 199-206. (Review). 

Name Reactions, 4th ed., DOI10.1007/978-3-642-01053-8 125, Springer-Verlag Berlin Heidelberg 2009 

Example 5, Polymer-support Hinsberg thiophene synthesis  

---

Hinsberg synthesis of thiophene derivatives. Formation of thiophene carboxylic acids from a-diketones and dialkyl thiodiacetate. 

Hinsberg Synthesis of Thiophene Derivatives Hiyama (see Nozaki-Hiyama Coupling Reaction) Hoch-Campbell Aziridine Synthesis Hoesch (see Houben-Hoesch Reaction)... 

---