Fiesselmann thiophene synthesis

The Fiesselmann thiophene synthesis involves the condensation reaction of thioglycolic acid derivatives with a,P-acetylenic esters, which upon treatment with base results in the formation of 3-hydroxy-2-thiophenecarboxyIic acid derivatives. 

Soon after the 1946 report by Woodward on the condensation of thioglycolic acid and a,P-unsaturated esters in the presence of base to produce structures like 2-carbomethoxy-3-ketotetrahydrothiophene 4, Fiesselmann extended this reaction to a,p-acetylenic esters for the direct preparation of 3-hydroxy-2-thiophenecarboxyIic acid derivatives.  

Unfortunately, much of Fiesselmann s work was documented only in patents and doctoral theses, allowing for the rediscovery of this classic reaction in recent years. In fact, as late as 1997, the Fiesselmann reaction of 5 with methylthioglycolate was rediscovered as a novel, tandem Michael addition/intramolecular Knoevenagel approach to thiophenes such as 6  

The mechanism of the Fiesselmann reaction between methylthioglycolate and a,P-acetylenic esters proceeds via consecutive base-catalyzed 1,4-conjugate addition reactions to form thioacetal Enolate formation, as a result of treatment with a stronger base, causes a Dieckmann condensation to occur providing ketone 8. Elimination of methylthioglycolate and tautomerization driven by aromaticity provides the 3-hydroxy thiophene dicarboxylate 9. 

The cyclization with a,p-unsaturated nitriles has proven effective for the synthesis of 3-aminothiophene 14, a key intermediate for the synthesis of p38 kinase inhibitors.  

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 104, Springer International Publishing Switzerland 2014 

Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowilz, S., Ed. Wiley New York, 1985, 88-125. (Review). 

Mullins, R. J. Williams, D. R. Fiesselmann Thiophene Synthesis. In Name Reactions in Heterocyclic Chemistry, Li, J. J., Ed. Wiley Hoboken, NJ, 2005, pp 184-192. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 97, Springer-Verlag Berlin Heidelberg 2009 

---

The structure of sitaxsentan (2) is also somewhat modular and was divided into three building blocks—namely the phenyl ring, the central thiophene, and the aminoisoxazole. The isoxazole subunit 33 can be prepared by the reaction of hydroxylamine with butynenitrile (31) to form the heterocycle,30 followed by chlorination with NCS.22 The thiophene ring can be formed using a Fiesselmann thiophene synthesis starting from... 

Further investigation of anti-tubulin agents by Romagnoli et al. led to the development of a modified Fiesselmann thiophene synthesis to produce 3-amino-2-(3,4,5-trimethoxybenzoyl)-5-aryl-thiophenes. " The a-mercapto-ketone anion was generated in situ by treating 0-ethyI-5-[2-oxo-2-(3,4,5-trimethoxyphenyl)-ethyl]dithiocarbonate with piperidine. Reaction of the a-mercapto anion with P-chloro-arylcinnamonitriles under thermal conditions afforded the desired thiophene. Much like the 2-amino derivatives, these 3-amino-2-(3,4,5-trimethoxy-benzoyl)-5-aryl-thiophenes were shown to be potent anti-proliferation and anti-tubulin agents as well. 

---