Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Efficient synthesis of new 3-amino-4-cyanothiophene derivatives

  • 27 Accesses

  • 1 Citations

Abstract

An efficient and atom economic modification of a previously reported synthetic pathway to tetrasubstituted thiophenes is described. The previously published synthetic methodology involved a one pot procedure starting with ketene dithioacetal and an appropriate secondary amine, and subsequent reaction with Na2S and phenacyl bromide. However, the liberated methanethiolate by-product was competed with enethiolate intermediate for phenacyl bromide, which reduced the yield and imposed the necessity to use two molar equivalents of α-haloketone reagent to increase the yield of the target thiophene products. In the present work, the proposed modification consisted in isolation of the intermediate enethiolate derivative, thereby reducing quantity of the α-haloketone to one molar equivalent. Moreover, the reaction conditions were optimized to attain optimum base/solvent combination to improve the yield of the target derivatives. Following our modified procedure, three series of new 3-amino-4-cyanothiophene derivatives were synthesized and isolated in high yields and high purity.

This is a preview of subscription content, log in to check access.

Fig. 1
Scheme 1
Scheme 2
Scheme 3

References

  1. Ahmed GA (2008) Heterocyclic synthesis with thiophene-2-carboxamide. Phosphorus Sulfur Silic Relat Elem 183:74–81. https://doi.org/10.1080/10426500701557005

  2. Al-ghorbani MABB, Mamatha SV, Khanum SA, Al-ghorbani M (2015) Piperazine and morpholine: synthetic preview and pharmaceutical applications. Res J Pharm Technol 8(5):611–628. https://doi.org/10.5958/0974-360X.2015.00100.6

  3. Al-Nadaf A, Sheikha GA, Taha MO (2010) Elaborate ligand-based pharmacophore exploration and QSAR analysis guide the synthesis of novel pyridinium-based potent β-secretase inhibitory leads. Bioorg Med Chem 18(9):3088–3115. https://doi.org/10.1016/j.bmc.2010.03.043

  4. Alves MA, Barreiro EJ, Suzana M, Moreira A (2014) 3-Aminothiophene-2-acylhydrazones: non-toxic, analgesic and anti-inflammatory lead-candidates. Molecules 19:8456–8471. https://doi.org/10.3390/molecules19068456

  5. Cheeseright TJ, Holm M, Lehmann F, Luik S, Gottert M, Melville JL, Laufer S (2009) Novel lead structures for p38 MAP kinase via FieldScreen virtual screening. J Med Chem 52:4200–4209. https://doi.org/10.1021/jm801399r

  6. Court JJ, Poisson C, Ardzinski A, Bilimoria D, Chan L, Chandupatla K et al (2016) Discovery of novel thiophene-based, thumb pocket 2 allosteric inhibitors of the Hepatitis C NS5B polymerase with improved potency and physicochemical profiles. J Med Chem 59:6293–6302. https://doi.org/10.1021/acs.jmedchem.6b00541

  7. Farhat MF, Mezoughi A, El-saghier A (2016) Utilization of 2-ylidene-4-thiazolidinones in synthesis of heterocyclic compounds part (II): transformation of (4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene)malononitrile to 3-aminothiophene derivatives. Asian J Chem 28:1823–1827. https://doi.org/10.14233/ajchem.2016.19850

  8. Gompper R, Töpfl W (1962) Carbonsäurederivate, V Substituierte Dithiocarbonsäuren und Ketenmercaptale. Chem Ber 95(12):2861–2870. https://doi.org/10.1002/cber.19620951206

  9. Gramec D, Peterlin Mašič L, Sollner Dolenc M (2014) Bioactivation potential of thiophene-containing drugs. Chem Res Toxicol 27(8):1344–1358. https://doi.org/10.1021/tx500134g

  10. Gruner M, Böttcher G, Gewald K (2008) Heterocondensed thiophenes and thiazoles by Thorpe-Ziegler cyclization. J Heterocycl Chem 45(4):1071–1076. https://doi.org/10.1002/jhet.5570450419

  11. Kumar D, Khare G, Kidwai S, Tyagi AK, Singh R, Rawat DS (2014) Novel isoniazid–amidoether derivatives: synthesis, characterization and antimycobacterial activity evaluation. Med Chem Commun 6:131–137. https://doi.org/10.1039/C4MD00288A

  12. Li JJ (2009) Name reactions, 5th edn. https://doi.org/10.1007/s13398-014-0173-7.2

  13. Ma L, Li S, Zheng H, Chen J, Lin L, Ye X et al (2011) Synthesis and biological activity of novel barbituric and thiobarbituric acid derivatives against non-alcoholic fatty liver disease. Eur J Med Chem 46(6):2003–2010. https://doi.org/10.1016/j.ejmech.2011.02.033

  14. Monforte A-M, Ferro S, De Luca L, Lo Surdo G, Morreale F, Pannecouque C et al (2014) Design and synthesis of N1-aryl-benzimidazoles 2-substituted as novel HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg Med Chem 22(4):1459–1467. https://doi.org/10.1016/j.bmc.2013.12.045

  15. Naguib BH, El-Nassan HB (2016) Synthesis of new thieno[2,3-b]pyridine derivatives as pim-1 inhibitors. J Enzyme Inhib Med Chem. https://doi.org/10.3109/14756366.2016.1158711

  16. Papakyriakou A, Kefalos P, Sarantis P, Tsiamantas C, Xanthopoulos KP, Vourloumis D, Beis D (2014) A Zebrafish in vivo phenotypic assay to identify 3-aminothiophene-2-carboxylic acid-based angiogenesis inhibitors. Assay Drug Dev Technol 12(9):527–535. https://doi.org/10.1089/adt.2014.606

  17. Rajak H, Kumar P, Parmar P, Thakur BS, Veerasamy R, Sharma PC et al (2012) Appraisal of GABA and PABA as linker: design and synthesis of novel benzamide based histone deacetylase inhibitors. Eur J Med Chem 53:390–397. https://doi.org/10.1016/j.ejmech.2012.03.058

  18. Romagnoli R, Baraldi PG, Carrion MD, Cara CL, Cruz-lopez O, Salvador MK et al (2012) Synthesis and biological evaluation of 2-amino-3-(4-chlorobenzoyl)- 4-[(4-arylpiperazin-1-yl)methyl]-5-substituted-thiophenes. Effect of the 5-modification on allosteric enhancer activity at the A1 adenosine receptor. J Med Chem 55:7719–7735. https://doi.org/10.1021/jm3007504

  19. Sarker D, Ang JE, Baird R, Kristeleit R, Shah K, Moreno V et al (2015) First-in-human Phase I study of Pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin Cancer Res 21:77–86. https://doi.org/10.1158/1078-0432.CCR-14-0947.First-in-human

  20. Singh K, Siddiqui HH, Shakya P, Bagga P (2015) Piperazine—a biologically active scaffold. https://doi.org/10.13040/IJPSR.0975-8232.6(10).4145-58

  21. Thomae D, Perspicace E, Henryon D, Xu Z, Schneider S, Hesse S et al (2009) One-pot synthesis of new tetrasubstituted thiophenes and selenophenes. Tetrahedron 65(50):10453–10458. https://doi.org/10.1016/j.tet.2009.10.021

  22. Walayat K, Mohsin N, Aslam S, Ahmad M (2019) An insight into the therapeutic potential of piperazine-based anticancer agents. https://doi.org/10.3906/kim-1806-7

  23. Workman P, Collins I (2013) Modern cancer drug discovery: Integrating targets, technologies, and treatments for personalized medicine. In: Neidle S, Denny W, Rewcastle W (eds) Cancer drug design and discovery, 2nd edn. https://doi.org/10.1016/B978-0-12-396521-9.00001-2

  24. Yu S-Y, Cai Y-X (2003) Synthesis of polysubstituted pyrimidines from ketene dithioacetals using KF/Al2O3 catalyst. Synth Commun 33:3989–3995. https://doi.org/10.1081/SCC-120026325

  25. Zhang L, Dong J, Xu X, Liu Q (2016) Chemistry of ketene N, S-acetals: an overview. Chem Rev 116:287–322. https://doi.org/10.1021/acs.chemrev.5b00360

Download references

Author information

Correspondence to Hala B. El-Nassan.

Ethics declarations

Conflict of interest

No conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

El-Meligie, S.E.M., Khalil, N.A., El-Nassan, H.B. et al. Efficient synthesis of new 3-amino-4-cyanothiophene derivatives. Chem. Pap. (2020). https://doi.org/10.1007/s11696-020-01070-z

Download citation

Keywords

  • Thiophene
  • 3-Amino-4-cyanothiophene
  • Ketene dithioacetals
  • Thiophene-2-carboxamides