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Efficient synthesis of 4-oxo-4,5-dihydrothieno[3,2-\(c\)]quinoline-2-carboxylic acid derivatives from aniline

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Abstract

The first reported synthesis of potential kinase inhibitors, 4-oxo-4,5-dihydrothieno[3,2-\(c\)]quinoline-2-carboxylic acid derivatives starting from aniline is described. This efficient high yielding sequence was carried out in six steps without any chromatographic purification. A tandem nucleophilic aromatic substitution/cyclization reaction was used as a key step in the sequence. The versatile intermediate 2-carboxylic acid was used as a suitable precursor to access the functionalization of the C-ring, by convergent analog synthesis of several novel derivatives.

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References

  1. Fuji N, Oguro Y, Sasaki S, Kondo S (2009) Fused heterocyclic derivative and use thereof. WO 2009107850 A2 20090903

    Google Scholar 

  2. Ohashi T, Oguro Y, Tanaka T, Shiokawa Z, Shibata S, Sato Y, Yamakawa H, Hattori H, Yamamoto Y, Kondo S, Miyamoto M, Tojo H, Baba A, Sasaki S (2012) Discovery of pyrrolo[3, 2-c]quinoline-4-one derivatives as novel hedgehog signaling inhibitors. Bioorg Med Chem 20:5496–5506. doi:10.1016/j.bmc.2012.07.039

    Google Scholar 

  3. Chua PC, Haddach M, Nagasawa J, Pierre F (2009) Protein kinase modulators. WO 2009108912 A1 20090903

  4. Pierre F, Chua PC, O’Brien SE, Siddiqui-Jain A, Bourbon P, Haddach M, Michaux J, Nagasawa J, Schwaebe MK, Stefan E, Vialettes A, Whitten JP, Chen TK, Darjania L, Stansfield R, Anderes K, Bliesath J, Drygin D, Ho C, Omori M, Proffitt C, Streiner N, Trent K, Rice WG, Ryckman DM (2011) Discovery and SAR of 5-(3-chlorophenylamino)benzo[\(c\)][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer. J Med Chem 54:635–654. doi: 10.1021/jm101251q

    Article  CAS  PubMed  Google Scholar 

  5. Pierre F, Haddach M, Regan CF, Ryckman DM (2011) Condensed quiolines as protein kinase modulators. WO 2011025859 A1 20110303

    Google Scholar 

  6. Pierre F, Regan CF, Chevrel M-C, Siddiqui-Jain A, Macalino D, Streiner N, Drygin D, Haddach M, O’Brien SE, Rice WG, Ryckman DM (2012) Novel potent dual inhibitors of CK2 and Pim kinases with antiproliferative activity against cancer cells. Bioorg Med Chem Lett 22:3327–3331. doi:10.1016/j.bmcl.2012.02.099

    Google Scholar 

  7. Gorlitzer K, Gabriel B, Jomaa H, Wiesner J (2006) Synthesis of thieno[3,2-c]quinolin-4-ylamines and antimalarial activity. Pharmazie 61:278–284

    Google Scholar 

  8. Abass M (2007) Substituted quinolinones, part 10: synthesis of ang- ular tetracyclic thieno and thiopyrano[3,2-c]benzo[h]quinolinones under PTC conditions as novel enzymatic enhancers. Phosphorus Sulfur Silicon Relat Elem 182:735–748. doi:10.1080/10426500601047503

    Google Scholar 

  9. Chemical Abstracts Service (CAS), a division of the American Chemical Society. Columbus, OH, USA. https://scifinder.cas.org

  10. Bhakuni BS, Kumar A, Balkrishna SJ, Sheikh JA, Konar S, Sangit K (2012) KOtBu mediated synthesis of phenanthridinones and dibenzoazepinones. Org Lett 14:2838–2841. doi:10.1021/ol301077y

    Article  CAS  PubMed  Google Scholar 

  11. Rajeshkumar V, Lee T-H, Chuang S-C (2013) Palladium-catalyzed oxidative insertion of carbon monoxide to \(N\)-sulfonyl-2-aminobiaryls through C–H bond activation: access to bioactive phenanthridinone derivatives in one pot. Org Lett 15:1468–1471. doi:10.1021/ol4001922

    Google Scholar 

  12. Castle LW, Elmaaty TA (2006) A new method for the synthesis of substituted indeno[1,2-\(b\)]thiophene with subsequent ring expansion to form substituted thieno[3,2-\(c\)]quinoline. J Heterocycl Chem 43:629–631. doi: 10.1002/jhet.5570430316

    Article  CAS  Google Scholar 

  13. Jayashree A, Darbarwar M (1994) Synthesis of 4,5-dihydro-4(5\(H\))-oxothieno[3,2-c]quinoline-2-carboxylicacids and their alkyl esters. Indian J Chem 33B:676–678

    Google Scholar 

  14. Majumdar KC, Ghosh M (2002) Tandem cyclization: one pot regioselective synthesis of thieno[3,2-c]quinolin-4(5\(H\))-one derivatives. Tetrahedron 58:10047–10052. doi: 10.1081/SCC-200051698

    Article  CAS  Google Scholar 

  15. Ahmed N, Brahmbhatt KG, Sabde S, Mitra D, Singh IP, Bhutani KK (2010) Synthesis and anti-HIV activity of alkylated quinoline 2,4-diols. Bioorg Med Chem 18:2872–2879. doi:10.1016/j.bmc.2010.03.015

    Article  CAS  PubMed  Google Scholar 

  16. Arya K, Agarwal M (2007) Microwave prompted multigram synthesis, structural determination, and photo-antiproliferative activity of fluorinated 4-hydroxyquinolinnes. Bioorg Med Chem Lett 17:86–93. doi:10.1016/j.bmcl.2006.09.082

    Article  CAS  PubMed  Google Scholar 

  17. Sechi M, Azzena U, Delussu MP, Dallocchio R, Dessì A, Cosseddu A, Pala N, Neamati N (2008) Design and synthesis of bis-amide and hydrazide-containing derivatives of malonic acid as potential HIV-1 integrase inhibitors. Molecules 13:2442–2461. doi:10.3390/molecules13102442

    Article  CAS  PubMed  Google Scholar 

  18. Shobana N, Yeshoda P, Shanmugam P (1989) A convenient approach to the synthesis of prenyl-, furo- and pyrano-quinoline alkaloids of the rutaceae. Tetrahedron 45:757–762. doi:10.1016/0040-4020(89)80106-1

    Article  CAS  Google Scholar 

  19. Khan KA, Shoeb A (1985) Chemistry of carbostyril: part I—oxidation reactions of 4-hydroxy- &4-hydroxy-1-methyl-2(1\(H\))-quinolinones. Indian J Chem 24B:62–66

    CAS  Google Scholar 

  20. Chilin A, Marzaro G, Marza C, Via LD, Ferlin MG, Pastorini G, Guiotto A (2009) Synthesis and antitumor activity of novel amsacrine analogs: the critical role of the acridine moiety in determining their biological activity. Bioorg Med Chem 17:523–529. doi:10.1016/j.bmc.2008.11.072

    Article  CAS  PubMed  Google Scholar 

  21. Fiala W, Stadlbauer W (1993) Nucleophilic chlorination of 3-formyl-4-hydroxy-quinolin-2(1\(H\))-ones. J Prakt Chem/Chem-Ztg 335:128–134

    Google Scholar 

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Acknowledgments

This investigation was conducted with support from the Research facilities improvement program C06RR14503-01 obtained from the National Institute of Health National Center for Research Resources. The authors would like to thank Dr. Bharati Avula for the HRMS data. We would also like to thank Dr. Ronald F. Borne for careful review of this manuscript. We would like to acknowledge Dr. Mitchell Avery, Dr. Francisco Leon and Dr. Robert J. Doerksen for their helpful discussions.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, Mississippi, MS, 38677, USA

    Arindam Chatterjee, Stephen J. Cutler & John S. Williamson

  2. National Center for Natural Product Research, University of Mississippi, Mississippi, MS, 38677, USA

    Ikhlas A. Khan

  3. Division of Extramural Research, National Center for Complementary and Alternative Medicine, National Institutes of Health, 6707 Democracy Blvd, Suite 401, Bethesda, MD, 20892-5475,  USA

    John S. Williamson

Authors
  1. Arindam Chatterjee
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  2. Stephen J. Cutler
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  3. Ikhlas A. Khan
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  4. John S. Williamson
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Corresponding authors

Correspondence to Stephen J. Cutler or John S. Williamson.

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Chatterjee, A., Cutler, S.J., Khan, I.A. et al. Efficient synthesis of 4-oxo-4,5-dihydrothieno[3,2-\(c\)]quinoline-2-carboxylic acid derivatives from aniline. Mol Divers 18, 51–59 (2014). https://doi.org/10.1007/s11030-013-9476-4

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  • DOI: https://doi.org/10.1007/s11030-013-9476-4

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