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

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

• References and Notes

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• 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; R_f 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; R_f 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; R_f 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.