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Synlett 2014; 25(07): 965-968
DOI: 10.1055/s-0033-1340959
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Thieno[2,3-d]imidazoles by Copper-Catalyzed Amidine Cyclization

Kostiantyn Liubchak*
a   Institute of Organic Chemistry of NAS of Ukraine, Murmanska Street 5, Kyiv 02094, Ukraine
c   Enamine Ltd., Aleksandra Matrosova Street 23, Kyiv 01103, Ukraine   Fax: +380(50)445373253   Email: kliubchak@gmail.com
,
Andrey Tolmachev
b   Kyiv National Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01601, Ukraine
,
Kostiantyn Nazarenko
a   Institute of Organic Chemistry of NAS of Ukraine, Murmanska Street 5, Kyiv 02094, Ukraine
› Author Affiliations
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Publication History

Received: 05 November 2013

Accepted after revision: 19 February 2014

Publication Date:
14 March 2014 (online)

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Abstract

A new synthetic approach to thieno[2,3-d]imidazoles is presented on the basis of the N′-(3-halothiophen-2-yl)amidine cyclization under copper-catalyzed cross-coupling. Using commercially available starting materials such as 2-aminothiophenes or their Boc-protected derivatives and copper catalysts, this method offers a convenient route to a wide range of thieno[2,3-d]imidazole derivatives, especially the 5-alkyl-subtituted thieno[2,3-d]imidazoles.

Key words

amidines - cyclization - copper - thiophenes - imidazoles

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  • References and Notes

    • 2a Toque HA. F, Priviero FB. M, Teixeira CE, Perissutti E, Fiorino F, Severino B, Frecentese F, Lorenzetti R, Baracat JS, Santagada V, Caliendo G, Antunes E, Nucci GD. J. Med. Chem. 2008; 51: 2807
      CrossrefSearch in Google Scholar
    • 2b Vernekar SK. V, Hallaq HY, Clarkson G, Lochner M, Thompson AJ, Silvestr L, Lummis SC. R. J. Med. Chem. 2010; 53: 2324
      CrossrefSearch in Google Scholar
  • 3 Shiozaki M, Maeda K, Miura T, Kotoku M, Yamasaki T, Matsuda I, Aoki K, Yasue K, Imai H, Ubukata M, Suma A, Yokota M, Hotta T, Tanaka M, Hase Y, Haas J, Fryer AM, Laird ER, Littmann NM, Andrews SW, Josey JA, Mimura T, Shinozaki Y, Yoshiuchi H, Inaba T. J. Med. Chem. 2011; 54: 2839
    CrossrefPubMedSearch in Google Scholar
    • 4a Ryo M, Shintaro H, Takahiro O, Kenta A, Satoru N, Izuru A, Toshihiro S, Yasush N. Eur. Patent EP1688420, 2006 ; Chem. Abstr. 2005, 143, 472164
    • 4b Immacolata C, Martin HJ. I, Savina M, Maria OO. J, Ia S. Int. Patent WO2006008556, 2006 ; Chem. Abstr. 2006, 144, 170989
  • 5 Weidmann K, Herling AW, Lang HJ, Scheunemann KH, Rippel R, Nimmesgern H, Scholl T, Bickel M, Metzger H. J. Med. Chem. 1992; 35: 438
    CrossrefSearch in Google Scholar
  • 7 Guerrera F, Salerno L, Sarvà MC, Siracusa MA. J. Heterocycl. Chem. 1995; 32: 591
    CrossrefSearch in Google Scholar
    • 10a Iddon B, Khan N, Lim BL. Chem. Commun. 1985; 1428
    • 10b Iddon B, Khan N, Lim BL. J. Chem. Soc., Perkin Trans. 1 1987; 1457
      Crossref
    • 10c Hartley DJ, Iddon B. Tetrahedron Lett. 1997; 38: 4647
      CrossrefSearch in Google Scholar
  • 11 Lygin AV, de Meijere A. Eur. J. Org. Chem. 2009; 5138
  • 15 Li J, Neuville L. Org. Lett. 2013; 15: 1752
    CrossrefSearch in Google Scholar
  • 16 Liubchak K, Tolmachev A, Nazarenko K. J. Org. Chem. 2012; 77: 3365
    Search in Google Scholar
  • 17 Binder D, Habison G, Noe CR. Synthesis 1977; 255
    Thieme Connect
  • 18 Bonafoux D, Abibi A, Bettencourt B, Burchat A, Ericsson A, Harris CM, Kebede T, Morytko M, Mcpherson M, Wallace G, Wu X. Bioorg. Med. Chem. Lett. 2011; 21: 1861
    CrossrefSearch in Google Scholar
  • 19 General Procedure for Amidines Cyclization: A round-bottom flask was charged with N′-halothiophenylamidine (0.84 mmol), K2CO3 (1.68 mmol), DMEDA (0.084 mmol) and anhyd DMF (3 mL). To the stirred mixture was then added powdered CuI (0.042 mmol) under Ar. The stirred mixture was heated under Ar and monitored by TLC, evaporated, diluted with CH2Cl2 (100 mL), and filtered. The organic layer was washed with H2O (2 × 50 mL), dried over Na2SO4, filtered and concentrated to give the pure product. Ethyl 1,6-Dimethyl-2-phenyl-1H-thieno[2,3-d]imidazole-5-carboxylate (4a): yield: 91%; mp 118–120 °C; Rf 0.38 (25% EtOAc–hexane). 1H NMR (500 MHz, CDCl3): δ = 1.37 (t, J = 9.0 Hz, 3 H, Et), 2.82 (s, 3 H, Me), 3.95 (s, 3 H, Me), 4.33 (q, J = 9.0 Hz, 2 H, Et), 7.45–7.55 (m, 3 H, 3 × CH), 7.55–7.75 (m, 2 H, 2 × CH). 13C NMR (125 MHz, CDCl3): δ = 163.4, 147.2, 137.8, 129.8, 129.3, 129.2, 128.8, 123.3, 60.7, 33.4, 14.3, 13.0. Anal. Calcd for C16H16N2O2S: C, 63.98; H, 5.37; N, 9.33. Found: C, 64.03; H, 5.15; N, 9.22. Ethyl 2-(3-Chlorophenyl)-1,6-dimethyl-1H-thieno[2,3-d]imidazole-5-carboxylate (4b): yield: 93%; mp 167–168 °C; Rf 0.40 (25% EtOAc–hexane). 1H NMR (500 MHz, CDCl3): δ = 1.38 (t, J = 7.1 Hz, 3 H, Et), 2.82 (s, 3 H, Me), 3.97 (s, 3 H, Me), 4.33 (q, J = 7.1 Hz, 2 H, Et), 7.40–7.49 (m, 2 H, 2 × CH), 7.49–7.60 (m, 1 H, CH), 7.63–7.71 (m, 1 H, CH). 13C NMR (125 MHz, CDCl3): δ = 12.3, 14.4, 30.5, 60.4, 123.9, 127.3, 129.0, 129.4, 129.8, 130.0, 131.5, 134.6, 137.8, 147.1, 154.3, 163.8. Anal. Calcd for C16H15ClN2O2S: C, 57.40; H, 4.52; N, 8.37. Found: C, 57.02; H, 4.75; N, 8.50. 1,5-Dimethyl-2-phenyl-1H-thieno[2,3-d]imidazole (13): yield: 92%; mp 110–115 °C; Rf 0.20 (25% EtOAc–hexane). 1H NMR (500 MHz, CDCl3): δ = 2.56 (s, 3 H, Me), 3.82 (s, 3 H, NMe), 6.62 (s, 1 H, CH), 7.34–7.45 (m, 1 H, CH), 7.48 (t, J = 7.8 Hz, 2 H, 2 × CH), 7.67 (d, J = 7.1 Hz, 2 H, 2 × CH). 13C NMR (125 MHz, CDCl3): δ = 17.0, 33.7, 106.8, 128.6, 128.7, 130.7, 137.9, 138.2, 141.8, 150.7. Anal. Calcd for C13H12N2S: C, 68.38; H, 5.30; N, 12.27. Found: C, 68.12; H, 5.50; N, 12.45.