Synthesis and characterization of steroidal, anellated aminothiophenes by Gewald reaction

Synthesis and characterization of steroidal, anellated aminothiophenes by Gewald reaction

Authors

  • Oliver Kraft Martin-Luther Universität Halle-Wittenberg
  • Gregor C Mittag Martin-Luther Universität Halle-Wittenberg
  • Sophie Hoenke Martin-Luther Universität Halle-Wittenberg
  • Niels Heise Martin-Luther Universität Halle-Wittenberg
  • Ahmed Al-Harrasi University of Nizza
  • René Csuk Martin-Luther Universität Halle-Wittenberg http://orcid.org/0000-0001-7911-290X

DOI:

https://doi.org/10.13171/mjc02209261446csuk

Abstract

Gewald 3-component reactions (G-3CR), i.e., reactions of a carbonyl compound with an activated nitrile in the presence of a secondary amine and sulfur, lead straightforwardly to anellated 2-aminothiophenes. Interestingly, their application to steroidal hydrocarbons has been limited to a single example. We could show in this work that Gewald 3-component reactions can be performed successfully for molecules holding a cholesterol or sitostanol skeleton, such as 5a-cholestan3-one (8) and 5a-sitostan-3-one (11), thus leading in good yields to the corresponding anellated steroidal 2-amino-thiophenes 12-15. Gewald reaction proved to be an excellent method to access heterocyclic steroids.

Author Biography

René Csuk, Martin-Luther Universität Halle-Wittenberg

Organic Chemistry

Head of Department

References

- K.M. Elattar, A. El-Mekabaty, Heterocyclic steroids: Efficient routes and biological characteristics of steroidal fuse bicyclic pyrimidines, J. Heterocycl. Chem., 2021. 58, 389-414.

- M.A. Gouda, M.A. Berghot, G.E. El-Ghani, K.M. Elattar, A.E.G.M. Khalil, Chemistry of 2-aminothiophene-3-carboxamide and related compounds, Turk. J. Chem., 2011, 35, 815-837.

- M. Monier, A. El-Mekabaty, K.M. Elattar, Five-membered ring systems with one heteroatiom: synthetic routes, chemical reactivity, and biological properties of furan-carboxamide analogs, Synth. Commun., 2018, 48, 839-875.

- M. Monier, A. El-Mekabaty, D. Abdel-Latif, B.D. Mert, K.M. Elattar, Heterocyclic steroids: efficient routes for the annulation of pentacyclic steroidal pyrimidines, Steroids, 2020, 154, 108548.

- A. Bhalla, P. Saini, S.S. Bari, 2-aminothiophenes: a review on synthetic routes and applications (biological/synthons), Am. J. PharmTech Res., 2017, 7, 57-78.

- K. Bozorov, L.F. Nie, J. Zhao, H.A. Aisa, 2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry, Eur. J. Med. Chem., 2017, 140, 465-493.

- K. Gewald, Methods for the synthesis and reaction of 2-aminothiophenes, Khim. Geterotsikl. Soedin., 1976, 1299.

- K. Gewald, Methods for the synthesis and reaction of 2-aminothiophenes, Pyatichlen. Aromat. Geterotsikly, Riga, 1979, 85-101.

- V.P. Litvinov, Y.A. Sharanin, F.S. Babichev, Cyclization of nitriles as synthetic route to 2- and 3-aminothiophenes, Sulfur Rep., 1986, 6, 97-135.

- C. Paulmier, Synthesis and reactivity of 3-aminothiophenes and 3,4-diaminothiophenes, Sulfur Rep., 1996, 19, 215-284.

- M. Perrissin, Substituted 2-aminothiophenes. Synthesis, structure, and reactivity. Pharmacological results, Bull. Trav. Soc. Pharm. Lyon, 1982, 26, 76-79.

- R. Alivelu, B. Mohanta, Y. Jahnavi, B.U. Kiran, S.K.K. Naresh, Design, synthesis of novel ethylene bridged N-Acyl homoserine lactones as inhibitors of quorum sensing signaling in pathogenic bacteria to prevent biofilm formation, Int. J. Pharm. Biol. Sci., 2021, 11, 56-65.

- V. Duvauchelle, P. Meffre, Z. Benfodda, Recent contribution of medicinally active 2-aminothiophenes: A privileged scaffold for drug discovery, Eur. J. Med. Chem., 2022, 238, 114502.

- Y. Hu, S. Yang, F.B. Shilliday, B.R. Heyde, K.M. Mandrell, R.H. Robins, J. Xie, M.T. Reding, Y. Lai, D.C. Thompson, Novel metabolic bioactivation mechanism for a series of anti-inflammatory agents (2,5-diaminothiophene derivatives) mediated by cytochrome P450 enzymes, Drug Metab. Dispos., 2010, 38, 1522-1531.

- Y. Huang, A. Doemling, The Gewald multi-component reaction, Mol. Diversity, 2011, 15, 3-33.

- J. Hwang, X. Qiu, L. Borgelt, N. Haacke, L. Kanis, S. Petroulia, R. Gasper, D. Schiller, P. Lampe, S. Sievers, J. Imig, P. Wu, Synthesis and evaluation of RNase L-binding 2-aminothiophenes as anticancer agents, Bioorg. Med. Chem., 2022, 58, 116653.

- M.E. Khalifa, W.M. Algothami, Gewald synthesis, antitumor profile and molecular modeling of novel 5-acetyl-4-((4-acetylphenyl)amino)-2-aminothiophene-3-carbonitrile scaffolds, J. Mol. Struct., 2020, 1207.

- R.W. Sabnis, The Gewald reaction in dye chemistry, Color. Technol., 2016, 132, 49-82.

- K. Gewald, Heterocycles from CH-acidic nitriles. VI. Reaction of methylene-active nitriles with mustard oils and sulfur, J. Prakt. Chem. (Leipzig), 1966, 32, 26-30.

- K. Gewald, Heterocycles from CH-acidic nitriles. IX. Reaction of α-hydroxy ketones with malononitrile, Chem. Ber., 1966, 99, 1002-1007.

- K. Gewald, Heterocycles from CH-acidic nitriles. V. Simultaneous action of sulfur and carbon disulfide on methylene-active nitriles, J. Prakt. Chem. (Leipzig), 1966, 31, 214-220.

- K. Gewald, G. Neumann, H. Boettcher, Heterocycles from CH-acidic nitriles. XI. New synthesis of 2-aminothionaphthene, Z. Chem., 1966, 6, 261.

- K. Gewald, E. Schinke, Heterocycles from CH-acidic nitriles. X. Reaction of acetone with cyanoacetic ester and sulfur, Chem. Ber., 1966, 99, 271-275.

- K. Gewald, E. Schinke, H. Boettcher, Heterocycles from CH-acidic nitriles. VIII. 2-Aminothiophenes from methylene-active nitriles, carbonyl compounds, and sulfur, Chem. Ber., 1966, 99, 94-100.

- B. Ganem, Strategies for Innovation in Multicomponent Reaction Design, Acc. Chem. Res., 2009, 42, 463-472.

- B. Jiang, T. Rajale, W. Wever, S.-J. Tu, G. Li, Multi-component reactions for the synthesis of heterocycles, Chem. Asian J., 2010, 5,

-2335.

- C.G. Neochoritis, T. Zhao, A. Doemling, Tetrazoles via Multi-component Reactions, Chem. Rev., 2019, 119, 1970-2042.

- S. Protti, S. Garbarino, D. Ravelli, A. Basso, Photoinduced Multi-component Reactions, Angew. Chem., Int. Ed., 2016, 55, 15476-15484.

- B.H. Rotstein, S. Zaretsky, V. Rai, A.K. Yudin, Small Heterocycles in Multi-component Reactions, Chem. Rev., 2014, 114, 8323-8359.

- E. Ruijter, R. Scheffelaar, R.V.A. Orru, Multicomponent Reaction Design in the Quest for Molecular Complexity and Diversity, Angew. Chem., Int. Ed., 2011, 50, 6234-6246.

- P. Slobbe, E. Ruijter, R.V.A. Orru, Recent applications of multi-component reactions in medicinal chemistry, MedChemComm, 2012, 3, 1189-1218.

- B.B. Toure, D.G. Hall, Natural Product Synthesis Using Multicomponent Reaction Strategies, Chem. Rev., 2009, 109, 4439-4486.

- J.S.B. Forero, J. Jones, Jr., F.M. da Silva, The synthetic potential and chemical aspects of the Gewald reaction: application in the preparation of 2-aminothiophenes and related heterocycles, Curr. Org. Synth., 2013, 10, 347-365.

- Z. Puterova, A. Krutosikova, D. Veghc, Gewald reaction: Synthesis, properties and applications of substituted 2-aminothiophenes, ARKIVOC, 2011, 209-246.

- R.W. Sabnis, The Gewald synthesis, Sulfur Rep., 1994, 16, 1-17.

- R.W. Sabnis, D.W. Rangnekar, N.D. Sonawane, 2-Aminothiophenes by the Gewald reaction, J. Heterocycl. Chem., 1999, 36, 333-345.

- Y.A. Sharanin, V.K. Promonenkov, 2'-Aminoandrost-2-eno[2,3-b]thiophenes, Khim. Geterotsikl. Soedin., 1980, 1564-1565.

- N.R. Mohamed, G.A. Elmegeed, M. Younis, Studies on organophosphorus compounds VII: Transformation of steroidal ketones with Lawesson's reagent into thioxo and heterofused steroids. Results of antimicrobial and antifungal activity, Phosphorus, Sulfur Silicon Relat. Elem., 2003, 178, 2003-2017.

- S. John, A.V. Sorokin, P.D. Thompson, Phytosterols and vascular disease, Curr. Opin. Lipidol., 2007, 18, 35-40.

- F. Marangoni, A. Poli, Phytosterols and cardiovascular health, Pharmacol. Res., 2010, 61, 193-199.

- M.D. Patel, P.D. Thompson, Phytosterols and vascular disease, Atherosclerosis (Amsterdam, Neth.), 2006, 186, 12-19.

- G. Vilahur, S. Ben-Aicha, E. Diaz-Riera, L. Badimon, T. Padro, Phytosterols and Inflammation, Curr. Med. Chem., 2019, 26, 6724-6734.

- F. Blanco-Vaca, L. Cedo, J. Julve, Phytosterols in Cancer: From Molecular Mechanisms to Preventive and Therapeutic Potentials, Curr. Med. Chem., 2019, 26, 6735-6749.

- P.G. Bradford, A.B. Awad, Phytosterols as anticancer compounds, Mol. Nutr. Food Res., 2007, 51, 161-170.

- V.R. Ramprasath, A.B. Awad, Role of phytosterols in cancer prevention and treatment, J. AOAC Int., 2015, 98, 735-738.

- N. Shahzad, W. Khan, S. Md, A. Ali, S.S. Saluja, S. Sharma, F.A. Al-Allaf, Z. Abduljaleel, I.A.A. Ibrahim, A.F. Abdel-Wahab, M.A. Afify, S.S. Al-Ghamdi, Phytosterols as a natural anticancer agent: Current status and future perspective, Biomed. Pharmacother., 2017, 88, 786-794.

- H. Tapiero, D.M. Townsend, K.D. Tew, Phytosterols in the prevention of human pathologies, Biomed. Pharmacother., 2003, 57, 321-325.

- T.A. Woyengo, V.R. Ramprasath, P.J.H. Jones, Anticancer effects of phytosterols, Eur. J. Clin. Nutr., 2009, 63, 813-820.

- N.P. Peet, S. Sunder, R.J. Barbuch, A.P. Vinogradoff, Mechanistic observations in the Gewald syntheses of 2-aminothiophenes, J. Heterocycl. Chem., 1986, 23, 129-134.

- D.D. Xuan, Recent Achievement in the Synthesis of Thiophenes, Mini-Rev. Org. Chem., 2021, 18, 110-134.

- M. Carmack, M. Behforouz, G.A. Berchtold, S.M. Berkowitz, D. Wiesler, R. Barone, The Willgerodt-Kindler reactions. 6. Isomerization of the carbonyl group in alkanones and cycloalkanones, J. Heterocycl. Chem., 1989, 26, 1305.

- J.H. Cho, C. Djerassi, Sterols in marine invertebrates. Part 57. Stereostructure, synthesis and acid-catalyzed isomerization of hebesterol, a biosynthetically significant cyclopropyl-containing marine sterol, J. Chem. Soc., Perkin Trans., 1987, 1, 1307-1318.

- B.F. Cravatt, A.H. Lichtman, Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system, Curr. Opin. Chem. Biol., 2003, 7, 469-475.

- S. Gaetani, V. Cuomo, D. Piomelli, Anandamide hydrolysis: a new target for anti-anxiety drugs ?, Trends Mol. Med., 2003, 9, 474-478.

- S. Kathuria, S. Gaetani, D. Fegley, F. Valino,

A. Duranti, A. Tontini, M. Mor, G. Tarzia, G. La Rana, A. Calignano, A. Giustino, M. Tattoli, M. Palmery, V. Cuomo, D. Piomelli, Modulation of anxiety through blockade of anandamide hydrolysis, Nature Med., 2003, 9, 76-81.

- S.G. Kinsey, S.T. O'Neal, J.Z. Long, B.F. Cravatt, A.H. Lichtman, Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay, Pharmacol., Biochem. Behav., 2011, 98, 21-27.

- M. Maccarrone, A. Finazzi-Agro, Anandamide hydrolase: a guardian angel of human reproduction ?, Trends Pharmacol. Sci., 2004, 25, 353-357.

- J. Cai, F.E. Cooke, B.S. Sherborne, Antagonists of the orexin receptors, Expert Opin. Ther. Pat., 2006, 16, 631-646.

- J. Gatfield, C. Brisbare-Roch, F. Jenck, C. Boss, Orexin Receptor Antagonists: A New Concept In CNS Disorders? ChemMedChem, 2010, 5,

-1214.

- A.L. Gotter, A.J. Roecker, R. Hargreaves, P.J. Coleman, C.J. Winrow, J.J. Renger, Orexin receptors as therapeutic drug targets, Prog. Brain Res., 2012, 198, 163-188.

- T.P. Lebold, P. Bonaventure, B.T. Shireman, Selective orexin receptor antagonists, Bioorg. Med. Chem. Lett., 2013, 23, 4761-4769.

- L. Lin, J. Faraco, R. Li, H. Kadotani, W. Rogers, X. Lin, X. Qiu, P.J. De Jong, S. Nishino, E. Mignot, The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene, Cell (Cambridge, Mass.), 1999, 98, 365-376.

- T.E. Scammell, C.J. Winrow, Orexin receptors: pharmacology and therapeutic opportunities, Annu. Rev. Pharmacol. Toxicol., 2011, 51,

-266.

- C.J. Winrow, J.J. Renger, Discovery and development of orexin receptor antagonists as therapeutics for insomnia, Br. J. Pharmacol., 2014, 171, 283-293.

- M. Sridhar, R.M. Rao, N.H.K. Baba, R.M. Kumbhare, Microwave-accelerated Gewald reaction. Synthesis of 2-aminothiophenes, Tetrahedron Lett., 2007, 48, 3171-3172.

- M. Perrissin, M. Favre, C. Luu-Duc, F. Bakri-Logeais, F. Huguet, G. Narcisse, Thieno[2.3-d]-4-pyrimidones: synthesis, structure and pharmacological properties, Eur. J. Med. Chem.--Chim. Ther., 1984, 19, 420-424.

- Y.W. Dong, X. Jiang, T. Liu, Y. Ling, Q. Yang, L. Zhang, X.K. He, Structure-Based Virtual Screening, Compound Synthesis, and Bioassay for the Design of Chitinase Inhibitors, J. Agr. Food Chem., 2018, 66, 3351-3357.

- H. Mora-Rado, L. Bialy, W. Czechtizky, M. Mendez, J.P.A. Harrity, An Alkyne Diboration/6π-Electrocyclization Strategy for the Synthesis of Pyridine Boronic Acid Derivatives, Angew. Chem., Int. Ed., 2016, 55, 5834-5836.

- Y. Arai, N. Koide, F. Ohki, H. Ageta, L.L. Yang, K.Y. Yen, Fern constituents: triterpenoids isolated from leaflets of Cyathea spinulosa, Chem. Pharm. Bull., 1994, 42, 228-232.

- R.A. Abramovitch, R.G. Micetich, Extractives from Populus tremuloides heartwood--structure and synthesis of tremulone, Can. J. Chem., 1962, 40, 2017-2022.

Downloads

Additional Files

Published

26-09-2022

Issue

Vol. 12 No. 2 (2022)

Section

Organic Chemistry

License

Authors who publish with this journal agree to the following terms:

    1. Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal
    2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal
    3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).