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

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]

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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