Cyclization of Activated Methylene Isocyanides with Methyl N(N),N′-Di(tri)substituted Carbamimidothioate: A Novel Entry for the Synthesis of N,1-Aryl-4-tosyl/ethoxycarbonyl-1H-imidazol-5-amines

Abstract

Base-induced cyclization of active methylene isocyanides with carbamimidothioates for the synthesis of N,1-aryl-4-tosyl/ethylcarboxy-1H-imidazol-5-amines is reported. The diversity of the reactions is exemplified by using various carbamimidothioates obtained from symmetrical N,N-disubstituted, unsymmetrical N,N,N-trisubstituted, and unsymmetrical N,N-disubstituted thioureas. This diversity is further enriched by different isocyanides. A mechanism for the formation of the title compounds is proposed.

Key words

imidazoles - isocyanides - cyclization - carbamimidothioate - oxazole

• References and Notes

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• 54 Synthesis of Substituted Thioureas 3; General Procedure: A mixture of arylisothiocyanate 1 (10 mmol), amine 2 (10 mmol) and triethylamine (0.1 mmol) in dichloromethane (10 mL) was stirred for 1–2 h. The progress of the reaction was monitored by TLC and, after completion, the dichloromethane was removed under reduced pressure. The residue was treated with conc. HCl (1 mL) in water (50 mL) and filtered. The precipitate was washed with water, drained, and dried at room temperature.1,3-Diphenylthiourea (3a): Yield: 89%; white solid; mp 150–153 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 8.19 (s, 2 H, NH), 7.35–7.41 (m, 8 H, Ar-H), 7.24–7.28 (m, 2 H, Ar-H). ¹³C NMR (DMSO-d ₆, 100 MHz): δ = 179.6, 137.1, 129.6, 127.1, 125.3. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₃N₂S: 229.0799; found: 229.0790.
• 55 Synthesis of Carbamimidothioates 4; General Procedure: To a solution of substituted thiourea 3 (8 mmol) in benzene (20 mL) and 20% NaOH (20 mL), tetra-n-butylammonium bromide (0.8 mmol) and MeI (8 mmol) were added. The progress of the reaction was monitored by TLC and, after the completion of the reaction, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography over silica gel, eluting with hexane/ethyl acetate (8:2).Methyl N,N′-Diphenylcarbamimidothioate (4a): Yield: 95%; white solid; mp 95–100 °C. ¹H NMR (CDCl₃, 400 MHz): δ = 7.08–7.33 (m, 10 H, Ar-H), 6.34 (s, 1 H, NH), 2.30 (s, 3 H, SCH₃). ¹³C NMR (CDCl₃, 100 MHz): δ = 150.0, 131.6, 129.0, 123.1, 134.0, 131.4, 123.5, 121.6, 121.1, 14.5. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₅N₂S: 243.0955; found: 243.0950.
• 56 Synthesis of Imidazole 6; General Procedure: To a solution of sodium hydride (6 mmol) in DMF (3 mL), substituted carbamimidothioate 4 (3 mmol) and tosylmethyl isocyanide/ethyl isocyanoacetate 5 (3 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by TLC. After completion of the reaction, water (25 mL) was added and the mixture was extracted with ethyl acetate (3 × 25 mL), the combined organic phases were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography over silica gel, eluting with hexane/ethyl acetate (8:2). N,1-Diphenyl-4-tosyl-1H-imidazol-5-amine (6a): Yield: 77%; brown solid; mp 204–209 °C. ¹H NMR (CDCl₃, 400 MHz): δ = 7.79 (d, J = 8.0 Hz, 2 H, Ar-H), 7.49 (s, 1 H, Ar-H), 7.25–7.28 (m, 2 H, Ar-H), 7.20–7.25 (m, 4 H, Ar-H), 6.97–7.00 (m, 2 H, Ar-H), 6.89 (s, 1 H, Ar-H), 6.78–6.80 (m, 2 H, Ar-H), 6.60 (d, J = 8.0 Hz, 2 H, Ar-H), 2.36 (s, 3 H, CH₃). ¹³C NMR (CDCl₃, 100 MHz): δ = 143.9, 142.1, 138.6, 136.2, 134.7, 129.6, 129.4, 128.9, 128.7, 128.1, 127.5, 126.1, 124.2, 122.1, 117.7, 29.6. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₂H₂₀N₃O₂S: 390.1276; found: 390.1274.