Fiesselmann thiophene synthesis

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]

Fiesselmann thiophene synthesis
Named after Hans Fiesselmann
Reaction type Ring forming reaction

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]

References
  1. Fiesselmann, Hans; Schipprak, Peter (1954-06-01). "Über Oxythiophencarbonsäureester, I. Mitteil.: Über die Anlagerung von Thioglykolsäureester an Fumarsäure-, Maleinsäure- und Acetylendicarbonsäureester". Chemische Berichte. 87 (6): 835–841. doi:10.1002/cber.19540870608.
  2. Fiesselmann, Hans; Schipprak, Peter; Zeitler, Lorenz (1954-06-01). "Über Oxythiophen-carbonsäureester, II. Mitteil.): Synthese und Reaktionen von 3-Oxy-thiophen-carbonsäure-(2)-estern". Chemische Berichte. 87 (6): 841–848. doi:10.1002/cber.19540870609.
  3. Fiesselmann, Hans; Pfeiffer, Gerhard (1954-06-01). "Über Oxythiophencarbonsäureester, III. Mitteil.): Die Einwirkung von Thioglykolsäureester auf β-Ketosäureester (Mitbearbeitet von Ferdinand Memmel)". Chemische Berichte. 87 (6): 848–856. doi:10.1002/cber.19540870610.
  4. Fiesselmann, Hans; Schipprak, Peter (1956-08-01). "Über Hydroxythiophencarbonsäureester, IV. Mitteil.: Eine einfache Darstellungsweise von 3-Hydroxy-thiophen- dicarbonsäure-(2.5)-estern". Chemische Berichte. 89 (8): 1897–1902. doi:10.1002/cber.19560890814.
  5. Fiesselmann, Hans; Thoma, Fritz (1956-08-01). "Über Hydroxythiophencarbonsäureester, VI. Mitteil.: Darstellung von 3-Hydroxy-thiophencarbonsäure-(2)-estern aus β-Ketosäureestern". Chemische Berichte. 89 (8): 1907–1912. doi:10.1002/cber.19560890816.
  6. Gronowitz, Salo (1991-01-01). Chemistry of Heterocyclic Compounds: Thiophene and Its Derivatives, Part Four, Volume 44. Chemistry of Heterocyclic Compounds: A Series of Monographs. John Wiley & Sons, Inc. pp. 88–125. doi:10.1002/9780470187265. hdl:2027/mdp.39015078685115. ISBN 9780470187265.
  7. Li, Jie Jack (2014). Name Reactions. Springer International Publishing. pp. 250–251. doi:10.1007/978-3-319-03979-4_104. ISBN 978-3-319-03978-7.
  8. Donoso, R.; Jordán de Urríes, P.; Lissavetzky, J. (1992). "Synthesis of [b]-Condensed Alkyl 3-Hydroxythiophene-2-carboxylates". Synthesis. 1992 (6): 526–528. doi:10.1055/s-1992-26152. ISSN 0039-7881.
  9. Redman, Anikó M.; Johnson, Jeffrey S.; Dally, Robert; Swartz, Steve; Wild, Hanno; Paulsen, Holger; Caringal, Yolanda; Gunn, David; Renick, Joel; Osterhout, Martin; Kingery-Wood, Jill; Smith, Roger A.; Lee, Wendy; Dumas, Jacques; Wilhelm, Scott M.; Housley, Timothy J.; Bhargava, Ajay; Ranges, Gerald E.; Shrikhande, Alka; Young, Deborah; Bombara, Michael; Scott, William J. (2001-01-08). "p38 Kinase inhibitors for the treatment of arthritis and osteoporosis: thienyl, furyl, and pyrrolyl ureas". Bioorganic & Medicinal Chemistry Letters. 11 (1): 9–12. doi:10.1016/S0960-894X(00)00574-6. PMID 11140741.
  10. Showalter, H. D. Hollis; Bridges, Alexander J.; Zhou, Hairong; Sercel, Anthony D.; McMichael, Amy; Fry, David W. (1999-12-09). "Tyrosine Kinase Inhibitors. 16. 6,5,6-Tricyclic Benzothieno[3,2-d]pyrimidines and Pyrimido[5,4-b]- and -[4,5-b]indoles as Potent Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase". Journal of Medicinal Chemistry. 42 (26): 5464–5474. doi:10.1021/jm9903949. PMID 10639288.
  11. Nicolaou, Kyriacos Costa; Skokotas, Golfo; Furuya, S.; Suemune, H.; Nicolaou, D. Colette (September 1990). "Golfomycin A, a Novel Designed Molecule with DNA-Cleaving Properties and Antitumor Activity". Angewandte Chemie International Edition. 29 (9): 1064–1067. doi:10.1002/anie.199010641.
  12. Mullican, Michael D.; Sorenson, Roderick J.; Connor, David T.; Thueson, David O.; Kennedy, John A.; Conroy, Mary Carol (1991-07-01). "Novel thiophene-, pyrrole-, furan-, and benzene carboxamidotetrazoles as potential antiallergy agents". Journal of Medicinal Chemistry. 34 (7): 2186–2194. doi:10.1021/jm00111a039. PMID 1712394.
  13. Ram, Vishnu J.; Goel, Atul; Shukla, P. K.; Kapil, A. (1997-12-16). "Synthesis of thiophenes and thieno[3,2-c]pyran-4-ones as antileishmanial and antifungal agents". Bioorganic & Medicinal Chemistry Letters. 7 (24): 3101–3106. doi:10.1016/S0960-894X(97)10153-6.
  14. Migianu, Evelyne; Kirsch, Gilbert (2002). "Synthesis of New Thieno[b]azepinediones from α-Methylene Ketones". Synthesis. 2002 (8): 1096–1100. doi:10.1055/s-2002-31963.
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