Synthesis of a Library of Imidazolin-4-ones Using Poly(ethylene glycol) as Soluble Support

Abstract

A library of imidazolin-4-ones has been synthesized ­using poly(ethylene glycol) (PEG) as soluble polymer support. The imidazolin-4-ones 6 or 7 were synthesized effectively by reaction of primary amine with PEG-supported carbodiimides 4, which were obtained from aza-Wittig reaction of PEG-supported iminophosphoranes 3 with isocyanates.

poly(ethylene glycol) - polymer-supported - aza-Wittig reaction - imidazolin-4-one - ylides

References and Notes

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<A NAME="RW03807ST-8">8</A>

PEG-Supported Azide 2. A mixture of PEG-supported chloride 1 (10 mmol) and sodium azide (0.78 g, 12 mmol) in anhyd MeCN (100 mL) was stirred for 20 h at reflux under a nitrogen atmosphere. The mixture was filtered, the filtrate was condensed and Et₂O was added to precipitate the PEG-supported azides 2. ¹H NMR (400 MHz, CDCl₃): δ = 3.47-3.82 (s, PEG-OCH₂CH₂O), 3.92 (s, 2 H, CH₂N), 4.34 (t, J = 6.4 Hz, 2 H, PEG-OCH₂CH ₂OCO). IR (KBr): 2108 (N₃), 1744 (C=O), 1242 cm^-1.

<A NAME="RW03807ST-9">9</A>

PEG-Supported Carbodiimide 4a. A solution of triphenylphosphine (2.62 g, 10 mmol) in anhyd CH₂Cl₂ (10 mL) was added dropwise under nitrogen at r.t. to a well-stirred solution of the PEG-supported azide 2 (10 mmol) in anhyd CH₂Cl₂ (100 mL). The reaction mixture was stirred at r.t. for 1 h, then phenyl isocyanate (1.19 g, 10 mmol) was added at 0 °C. After the reaction mixture was stirred at r.t. for 2 h, the solvent was removed under reduced pressure. The PEG-supported carbodiimide 4a (Ar = Ph) was precipitated by addition of Et₂O and was separated by simple filtration. ¹H NMR (400 MHz, CDCl₃): δ = 3.48-3.64 (m, PEG-OCH₂CH₂O), 3.82 (s, 2 H, NCH₂COO), 4.30 (t, J = 6.4 Hz, 2 H, PEG-CH₂OCO). IR (KBr): 2144 (N=C=N), 1753 (C=O), 1242 cm^-1.

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<A NAME="RW03807ST-11">11</A>

Imidazolin-4-ones 6 and 7: A solution of primary amine (2 mmol) in CH₂Cl₂ (5 mL) was added to PEG-supported carbodiimide 4 (2 mmol) in CH₂Cl₂ (10 mL), and the mixture was stirred for the time shown in Table [1] at r.t. The PEG was precipitated by addition of Et₂O and was separated by simple filtration. The imidazolin-4-ones were obtained by recrystallization from a solvent mixture of hexane and CH₂Cl₂ (1:1-1:3) or by column chromatography on silica gel (EtOAc-PE, 1:3-1:1). Spectral data for imidazolin-4-ones 6 and 7: 6a: white crystals; mp 130-131 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.52 (d, J = 7.2 Hz, 6 H, 2 × Me), 3.84 (s, 2 H, CH₂), 4.57-4.61 (m, 2 H, NH, CH), 6.97-7.34 (m, 5 H, ArH). MS: m/z (%) = 217 (32) [M⁺], 174 (100), 118 (77), 146 (30), 106 (48). Anal. Calcd for C₁₂H₁₅N₃O: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.03; H, 7.12; N, 19.38. 7a: white crystals; mp 101-102 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.17-1.22 (m, 6 H, 2 × Me), 3.79-4.02 (m, 2 H, NH, CH), 4.20-4.25 (m, 2 H, CH₂), 7.24-7.57 (m, 5 H, ArH). MS: m/z (%) = 217 (11) [M⁺], 174 (66), 118 (100). Anal. Calcd for C₁₂H₁₅N₃O: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.41; H, 7.05; N, 19.11. 6b: white crystals; mp 132-134 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.22-2.38 (m, 10 H, 5 × CH₂), 3.81 (s, 2 H, CH₂), 4.14-4.21 (m, 1 H, CH), 4.53 (s, 1 H, NH), 6.94-7.33 (m, 5 H, ArH). MS: m/z (%) = 257 (6) [M⁺], 176 (88), 131 (10), 118 (100). Anal. Calcd for C₁₅H₁₉N₃O: C, 70.01; H, 7.44; N, 16.33. Found: C, 70.25; H, 7.41; N, 16.24. 7b: white crystals; mp 92-93 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.07-2.04 (m, 10 H, 5 × CH₂), 3.73 (s, 1 H, NH), 3.80-3.90 (m, 1 H, CH), 4.22 (s, 2 H, CH₂), 7.25-7.55 (m, 5 H, ArH). MS: m/z (%) = 257 (5) [M⁺], 202 (3), 174 (100), 146 (15), 119 (70). Anal. Calcd for C₁₅H₁₉N₃O: C, 70.01; H, 7.44; N, 16.33. Found: C, 70.17; H, 7.57; N, 16.18. 6c: white crystals; mp 76-77 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.98 (t, J = 7.2 Hz, 3 H, Me), 1.73-1.82 (m, 2 H, CH₂), 3.66 (t, J = 7.2 Hz, 2 H, NCH₂), 3.91 (s, 2 H, CH₂), 4.58 (s, 1 H, NH), 6.98-7.34 (m, 5 H, ArH). MS: m/z (%) = 217 (54) [M⁺], 174 (100), 118 (85). Anal. Calcd for C₁₂H₁₅N₃O: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.45; H, 6.78; N, 19.38. 6d: white crystals; mp 46-47 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.97 (t, J = 7.2 Hz, 3 H, Me), 1.37-1.73 (m, 4 H, CH₂CH₂), 3.69 (t, J = 7.2 Hz, 2 H, NCH₂), 3.89 (s, 2 H, CH₂), 4.60 (s, 1 H, NH), 6.96-7.33 (m, 5 H, ArH). MS: m/z (%) = 231 (58) [M⁺], 202 (18), 188 (58), 176 (64), 146 (33), 100 (100). Anal. Calcd for C₁₃H₁₇N₃O: C, 67.51; H, 7.41; N, 18.17. Found: C, 67.42; H, 7.36; N, 18.22. 6e: white crystals; mp 82-84 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.97 (d, J = 6.8 Hz, 6 H, 2 × Me), 2.20-2.30 (m, 1 H, CH), 3.51 (d, J = 7.6 Hz, 2 H, NCH₂), 3.90 (s, 2 H, CH₂), 4.60 (s, 1 H, NH), 6.95-7.33 (m, 5 H, ArH). MS: m/z (%) = 231 (7) [M⁺], 176 (100), 119 (32), 106 (28). Anal. Calcd for C₁₃H₁₇N₃O: C, 67.51; H, 7.41; N, 18.17. Found: C, 67.47; H, 7.53; N, 18.36. 6f: white crystals; mp 87-88 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.91 (s, 2 H, CH₂), 4.65 (s, 1 H, NH), 4.87 (s, 2 H, NCH₂), 6.96-7.54 (m, 10 H, ArH). MS: m/z (%) = 265 (7) [M⁺], 236 (9), 207 (21), 160 (38), 91 (100). Anal. Calcd for C₁₆H₁₅N₃O: C, 72.43; H, 5.70; N, 15.84. Found: C, 72.28; H, 5.61; N, 15.98. 6g: white crystals; mp 264-266 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.74 (s, 2 H, CH₂), 7.05-7.49 (m, 5 H, ArH), 7.55 (s, 1 H, NH), 9.92 (s, 1 H, NH). MS: m/z (%) = 175 (83) [M⁺], 146 (112), 118 (100). Anal. Calcd for C₉H₉N₃O: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.95; H, 5.17; N, 23.93. 6h: white crystals; mp 97-98 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.98 (s, 3 H, NMe), 3.84 (s, 2 H, CH₂), 7.02 (s, 1 H, NH), 6.95-7.29 (m, 5 H, ArH). MS: m/z (%) = 189 (92) [M⁺], 160 (62), 132 (100). Anal. Calcd for C₁₀H₁₁N₃O: C, 63.48; H, 5.86; N, 22.21. Found: C, 63.41; H, 5.71; N, 22.36. 6i: white crystals; mp 113-114 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.31 (t, J = 7.2 Hz, 3 H, Me), 3.77 (q, J = 7.2 Hz, 2 H, NCH₂), 3.91 (s, 2 H, CH₂), 4.60 (s, 1 H, NH), 7.01-7.34 (m, 5 H, ArH). MS: m/z (%) = 203 (51) [M⁺], 174 (36), 160 (63), 146 (21), 104 (100). Anal. Calcd for C₁₁H₁₃N₃O: C, 65.01; H, 6.45; N, 20.67. Found: C, 65.25; H, 6.57; N, 20.60. 6j: white crystals; mp 253-255 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.29 (s, 3 H, Me), 3.86 (s, 2 H, CH₂), 6.75-7.24 (m, 4 H, ArH), 7.53 (s, 1 H, NH), 9.86 (s, 1 H, NH). MS: m/z (%) = 203 (46) [M⁺], 174 (45), 160 (9), 146 (100), 91 (60). Anal. Calcd for C₁₀H₁₁N₃O: C, 63.48; H, 5.86; N, 22.21. Found: C, 63.31; H, 5.94; N, 22.02. 6k: white crystals; mp 108-109 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.33 (s, 3 H, Me), 3.17 (s, 3 H, Me), 3.91 (s, 2 H, CH₂), 4.60 (s, 1 H, NH), 6.78-7.22 (m, 4 H, ArH). MS: m/z (%) = 203 (45) [M⁺], 174 (45), 146 (100), 118 (41). Anal. Calcd for C₁₁H₁₃N₃O: C, 65.01; H, 6.45; N, 20.67. Found: C, 65.13; H, 6.59; N, 20.53. 6l: white crystals; mp 101-102 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.30 (t, J = 7.2 Hz, 3 H, Me), 2.33 (s, 3 H, Me), 3.75 (q, J = 7.2 Hz, 2 H, NCH₂), 3.90 (s, 2 H, CH₂), 4.64 (s, 1 H, NH), 6.79-7.20 (m, 4 H, ArH). MS: m/z (%) = 217 (100) [M⁺], 188 (48), 174 (94), 160 (21), 118 (82). Anal. Calcd for C₁₂H₁₅N₃O: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.31; H, 6.82; N, 19.46.