One-Pot Synthesis of N-Monosubstituted Ureas from Nitriles via Tiemann Rearrangement

Abstract

Amidoximes, obtained from the reaction of nitriles with hydroxylamine, underwent Tiemann rearrangement in the presence of benzenesulfonyl chlorides (TsCl or o-NsCl) to form the N-substituted cyanamides. Subsequently, acidic hydrolysis of the cyanamides afforded the corresponding N-monosubstituted ureas. The synthesis of N-monosubstituted ureas from nitriles was accomplished by three steps in one pot, which provides a direct access to versatile N-monosubstituted urea derivatives from a wide variety of nitriles.

Key words

urea - cyanamide - amidoxime - hydrolysis - Tiemann rearrangement

• References and Notes

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• 25 General Procedure for the One-Pot Synthesis of N-Monosubstituted Urea 4 from Nitrile 1 (Scheme 3) To the solution of nitrile 1 in EtOH (0.1 M) was added 50 wt% aq hydroxylamine solution (1.2 equiv). The mixture was stirred at reflux temperature for 1.5 h. After cooling to r.t., the reaction mixture was concentrated under reduced pressure. The crude amidoxime product 2 was dissolved in CH₂Cl₂ (0.1 M), and ArSO₂Cl (TsCl or o-NsCl, 1.05 equiv) and DIPEA (1.05 equiv) were added at 0 °C. The mixture was stirred under nitrogen atmosphere at r.t. for 3 h or at reflux temperature for 1 h.²⁴ The mixture was concentrated under reduced pressure. The crude cyanamide product 3 was dissolved in the mixture of 1 N aq HCl solution and EtOH (0.1 M, 1 N HCl–EtOH = 1:4, v/v). The mixture was stirred at reflux temperature for 3 h under nitrogen. After cooling to r.t. the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography.
• 26 Analytical Data of Compounds 4e–k
  N-(4-Nitrophenyl)urea (4e) Mp 213–215 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.29 (s, 1 H, NH), 8.11 (d, 2 H, J = 9.2 Hz), 7.62 (d, 2 H, J = 9.2 Hz), 6.20 (s, 2 H, NH₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 155.4, 147.3, 140.5, 125.1 (CH), 117.0 (CH). MS (EI, 20 eV): m/z = 108 (56), 138 (100), 181 (40) [M⁺]. ESI-MS: m/z = 167 (100), 182 (73) [M + 1]. HRMS (EI): m/z calcd for C₇H₇N₃O₃: 181.0487; found: 181.0486. N-(4-Trifluoromethylphenyl)urea (4f) Mp 144–145 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.95 (s, 1 H, NH), 7.60 (d, 2 H, J = 8.7 Hz), 7.54 (d, 2 H, J = 8.7 Hz), 6.04 (s, 2 H, NH₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 155.7, 144.3, 125.9 (q, J = 3.0 Hz, CH), 124.6 (q, J = 270.0 Hz, CF₃), 121.1 (q, J = 32.0 Hz), 117.4 (CH). MS (EI, 20 eV): m/z = 161 (100), 204 (41) [M⁺]. ESI-MS: m/z = 205 (100) [M + 1]. HRMS (EI): m/z calcd for C₈H₇F₃N₂O: 204.0510; found: 204.0508. N-(3-Methoxyphenyl)urea (4g) Mp 128–130 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.51 (s, 1 H, NH), 7.08–7.12 (m, 2 H), 6.87 (d, 1 H, J = 7.9 Hz), 6.47 (d, 1 H, J = 8.0 Hz), 5.81 (s, 2 H, NH₂), 3.69 (s, 3 H, CH₃). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.7, 156.0, 141.8, 129.4 (CH), 110.2 (CH), 106.5 (CH), 103.6 (CH), 54.9 (CH). ESI-MS: m/z = 167 [M + 1]. HRMS (EI): m/z calcd for C₈H₁₀N₂O₂: 166.0742; found: 166.0741. N-(2-Methylphenyl)urea (4h) Mp 194–196 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.77 (d, 1 H, J = 8.0 Hz), 7.66 (s, 1 H, NH), 7.12–7.06 (m, 2 H), 6.87 (t, 1 H, J = 7.3), 6.00 (s, 2 H, NH₂), 2.18 (s, 3 H, CH₃). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 156.1, 138.2, 130.0 (CH), 127.0 (CH), 126.0, 123.0 (CH), 120.9 (CH), 17.9 (CH₃). MS (EI, 20 eV): m/z = 107 (100), 150 (62) [M⁺]. HRMS (EI): m/z calcd for C₈H₁₀N₂O: 150.0793; found: 150.0792. N-(2-Chlorophenyl)urea (4i) Mp 190–192 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.12 (dd, 1 H, J = 8.4, 1.3 Hz), 8.03 (s, 1 H, NH), 7.38 (dd, 1 H, J = 8.3, 0.9 Hz), 7.24–7.20 (m, 1 H), 6.96–6.92 (m, 1 H), 6.37 (s, 2 H, NH₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 155.6, 136.7, 129.0, 127.4, 122.5, 121.4, 121.1. MS (EI, 20 eV): m/z = 127 (100), 129 (30), 135 (40), 170 (18) [M⁺], 172 (8) [M + 2]. HRMS (EI): m/z calcd for C₇H₇ClN₂O: 170.0247; found: 170.0246. 1,3-Dimethyl-5-ureidouracil (4j) Mp 254–258 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.09 (s, 1 H, NH), 7.84 (s, 1 H), 6.26 (s, 2 H, NH₂), 3.29 (s, 3 H, CH₃), 3.20 (s, 3 H, CH₃). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.2, 156.5, 149.8, 128.5, 115.0, 70.2, 37.1, 28.4. MS (EI, 20 eV): m/z = 70 (42), 155 (100), 198 (10) [M⁺]. HRMS (EI): m/z calcd for C₇H₁₀N₄O₃: 198.0753; found: 198.0760. 2-Chloro-3-ureidopyridine (4k) Mp 210–212 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.50 (dd, 1 H, J = 8.2, 1.5 Hz), 8.19 (s, 1 H, NH), 7.96 (dd, 1 H, J = 4.5, 1.5 Hz), 7.32 (dd, 1 H, J = 8.2, 4.6 Hz), 6.52 (s, 2 H, NH₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 155.4, 141.5 (CH), 138.5, 133.9, 128.3 (CH), 123.3 (CH). ESI-MS: m/z = 155 (28), 172 (100) [M + 1]. HRMS (EI): m/z calcd for C₆H₆ClN₃O: 171.0199; found: 171.0201.