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Synlett 2014; 25(07): 965-968
DOI: 10.1055/s-0033-1340959
DOI: 10.1055/s-0033-1340959
letter
Synthesis of Thieno[2,3-d]imidazoles by Copper-Catalyzed Amidine Cyclization
Further Information
Publication History
Received: 05 November 2013
Accepted after revision: 19 February 2014
Publication Date:
14 March 2014 (online)
![](https://www.thieme-connect.de/media/synlett/201407/lookinside/thumbnails/10.1055-s-0033-1340959-1.jpg)
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.
Supporting Information
- for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
- Supporting Information
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References and Notes
- 1a Luca LD. Curr. Med. Chem. 2006; 1: 1
- 1b Forte B, Malgesini B, Piutti C, Quartieri F, Scolaro A, Papeo G. Marine Drugs 2009; 7: 705
- 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
- 2b Vernekar SK. V, Hallaq HY, Clarkson G, Lochner M, Thompson AJ, Silvestr L, Lummis SC. R. J. Med. Chem. 2010; 53: 2324
- 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
- 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
- 6a Abramenko PI. Chem. Heterocycl. Compd. (Engl. Transl.) 1970; 6: 1373
- 6b Guerrera F, Siracusa MA, Tornetta B, Bousquet E, Agozzino P, Lamartina L. J. Heterocycl. Chem. 1984; 21: 587
- 7 Guerrera F, Salerno L, Sarvà MC, Siracusa MA. J. Heterocycl. Chem. 1995; 32: 591
- 8a Binder D, Noe CR, Kollmann H, Rosenwirth B. Arch. Pharm. (Weinheim, Ger.) 1985; 318: 40
- 8b Björk M, Grivas S. J. Heterocycl. Chem. 2006; 43: 101
- 9a Seley KL, Januszczyk P, Hagos A, Zhang L, Dransfield DT. J. Med. Chem. 2000; 43: 4877
- 9b Seley KL, Zhang L, Hagos A. Org. Lett. 2001; 3: 3209
- 9c Seley KL, Zhang L, Hagos A, Quirk S. J. Org. Chem. 2002; 67: 3365
- 9d Zhang Z, Wauchope OR, Seley-Radtke KL. Tetrahedron 2008; 64: 10791
- 9e Wauchope OR, Tomney MJ, Pepper JL, Korba BE, Seley-Radtke KL. Org. Lett. 2010; 12: 4466
- 9f Wauchope OR, Johnson C, Krishnamoorthy P, Andrei G, Snoeck R, Balzarini J, Seley-Radtke KL. Bioorg. Med. Chem. 2012; 20: 3009
- 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
- 10c Hartley DJ, Iddon B. Tetrahedron Lett. 1997; 38: 4647
- 11 Lygin AV, de Meijere A. Eur. J. Org. Chem. 2009; 5138
- 12a Evano G, Blanchard N, Toumi M. Chem. Rev. 2008; 108: 3054
-
12b Monnier F, Taillefer M. Angew. Chem. Int. Ed. 2009; 48: 6954
- 13a Szczepankiewicz BG, Rohde JJ, Kurukulasuriya R. Org. Lett. 2005; 7: 1833
- 13b Alen J, Robeyns K, Borggraeve WM. D, Meervelt LV, Compernolle F. Tetrahedron 2008; 64: 8128
- 13c Hirano K, Biju AT, Glorius F. J. Org. Chem. 2009; 74: 9570
- 13d Saha P, Ramana T, Purkait N, Ali MA, Paul R, Punniyamurthy T. J. Org. Chem. 2009; 74: 8719
- 13e Kumar S, Ila H, Junjappa H. J. Org. Chem. 2009; 74: 7046
-
13f Yuan Y, Thomé I, Kim SH, Chen D, Beyer A, Bonnamour J, Zuidema E, Chang S, Bolm C. Adv. Synth. Catal. 2010; 352: 2892
- 13g Peng J, Ye M, Zong C, Hu F, Feng L, Wang X, Wang Y, Chen C. J. Org. Chem. 2011; 76: 716
- 13h Liubchak K, Nazarenko K, Tolmachev A. Tetrahedron 2012; 68: 2993
- 13i Liubchak K, Tolmachev A, Grygorenko OO, Nazarenko K. Tetrahedron 2012; 68: 8564
- 13j Chen C, Chen C, Li B, Tao J, Peng J. Molecules 2012; 17: 12506
-
14a Brasche G, Buchwald SL. Angew. Chem. Int. Ed. 2008; 47: 1932
- 14b Li J, Bénard S, Neuville L, Zhu J. Org. Lett. 2012; 14: 5980
- 15 Li J, Neuville L. Org. Lett. 2013; 15: 1752
-
16 Liubchak K, Tolmachev A, Nazarenko K. J. Org. Chem. 2012; 77: 3365
- 17 Binder D, Habison G, Noe CR. Synthesis 1977; 255
- 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
- 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.