Synlett 2007(14): 2252-2256  
DOI: 10.1055/s-2007-985561
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Highly Functionalized Isoxazoles via Base-Promoted Cyclocondensation of Stable Nitrile Oxides with Active Methylene Compounds

Hiroshi Takikawa, Katsuyoshi Hikita, Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology and SORST-JST Agency, 2-12-1, O-okayama, Meguro-ku, Tokyo 152-8551, Japan
Fax: +81(3)57342788; e-Mail: ksuzuki@chem.titech.ac.jp;
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Publikationsverlauf

Received 8 June 2007
Publikationsdatum:
24. Juli 2007 (online)

Abstract

Base-promoted cyclocondensation of ortho-disubstituted benzonitrile oxides with active methylene compounds provides a concise route to highly functionalized isoxazole derivatives.

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Structure of 21 was confirmed by X-ray crystallographic analysis (CCDC 647875).

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Typical Experimental Procedure for the Synthesis of Isoxazole 14 Using 4 Å MS: To a solution of 2-bromo-6-methoxybenzonitrile oxide (12; 214 mg, 0.937 mmol) and benzoylacetonitrile (4; 161 mg, 1.11 mmol) in i-PrOH (3.1 mL) was added 4 Å MS (938 mg) at r.t. The red suspension was heated at 50 °C for 2 h. After cooling, the mixture was filtered through a Celite® pad, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc, 85:15) to give 14 (253 mg, 76%) as a yellow solid. Recrystallization of 14 from acetone-hexane gave a colorless prism; mp 177.2-177.6 °C. 1H NMR (300 MHz, CDCl3): δ = 3.85 (s, 3 H), 7.00 (dd, J = 2.0, 7.6 Hz, 1 H), 7.33 (dd, J = 2.0, 7.6 Hz, 1 H), 7.37 (dd, J = 7.6, 7.6 Hz, 1 H), 7.55-7.64 (m, 3 H), 8.12-8.19 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 56.1, 90.0, 110.2, 111.8, 116.3, 124.1, 124.9, 125.1, 126.7, 129.3, 132.5, 132.8, 158.8, 160.4, 173.8. Anal. Calcd for C17H11BrN2O2: C, 57.49; H, 3.12; N, 7.89. Found: C, 57.25; H, 3.32; N, 7.72. IR (ATR): 3014, 2941, 2836, 2239, 1590, 1573, 1456, 1395, 1268, 1032, 784 cm-1.
Typical Experimental Procedure for the Synthesis of Isoxazole 16 Using i -PrONa: To a mixture of 2-bromo-6-methoxybenzonitrile oxide (12; 199 mg, 0.872 mmol) and methanesulfonylacetone (6; 142 mg, 1.05 mmol) in i-PrOH (8.7 mL) at r.t. was added i-PrONa (0.3 M in i-PrOH, 0.43 mL, 0.13 mmol). After stirring at 40 °Cfor 1 h, the reaction was stopped at r.t. by adding H2O. After the products were extracted with EtOAc (3 ×), the combined organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc, 4:1) to give 16 (252 mg, 83%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ = 2.80 (s, 3 H), 2.96 (s, 3 H), 3.79 (s, 3 H), 6.96 (dd, J = 1.2, 8.1 Hz, 1 H), 7.28 (dd, J = 1.2, 8.1 Hz, 1 H), 7.35 (dd, J = 8.1, 8.1 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 12.8, 44.8, 56.1, 110.1, 117.5, 117.6, 124.3, 124.7, 132.5, 157.5, 159.1, 174.4. Anal. Calcd for C12H12BrNO4S: C, 41.63; H, 3.49; N, 4.05; S, 9.26. Found: C, 41.42; H, 3.60; N, 3.84; S, 9.03. IR (neat): 3009, 2929, 1571, 1431, 1378, 1313, 1259, 1134, 1026, 952, 773 cm-1.
Data of Other Isoxazole Products:
8: colorless prism; mp 159.5-160.0 °C. 1H NMR (400 MHz, CDCl3): δ = 1.34 (d, J = 13.5 Hz, 1 H), 2.09-2.17 (m, 1 H), 3.46 (s, 3 H), 3.80 (ddd, J = 2.4, 10.6, 12.3 Hz, 2 H), 4.13 (dd, J = 5.1, 10.6 Hz, 2 H), 5.20 (s, 2 H), 5.60 (s, 1 H), 7.33 (dd, J = 1.9, 7.1 Hz, 1 H), 7.48-7.52 (m, 2 H), 7.59-7.62 (m, 3 H), 8.17-8.20 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 25.5, 56.4, 67.2, 91.1, 95.1, 98.9, 112.3, 113.9, 115.0, 119.9, 125.2, 126.8, 129.4, 132.1, 132.5, 139.6, 155.5, 160.4, 173.3. Anal. Calcd for C22H20N2O5: C, 67.34; H, 5.14; N, 7.14. Found: C, 67.36; H, 5.43; N, 6.98. IR (KBr): 2960, 2856, 2238, 1604, 1569, 1475, 1382, 1261, 1159, 1108, 981, 896, 796 cm-1.
9: colorless oil. 1H NMR (300 MHz, CDCl3): δ = 0.93 (t, J = 6.9 Hz, 3 H), 1.31 (d, J = 13.4 Hz, 1 H), 2.05-2.20 (m, 1 H), 2.77 (s, 3 H), 3.35 (s, 3 H), 3.62 (br, 1 H), 3.80 (br, 1 H), 4.00 (br, 1 H), 4.02 (q, J = 6.9 Hz, 2 H), 4.16 (br, 1 H), 5.07 (s, 2 H), 5.29 (s, 1 H), 7.15-7.23 (m, 1 H), 7.40-7.43 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 13.0, 13.5, 25.5, 55.9, 60.1, 67.1, 94.7, 99.3, 111.0, 114.6, 118.0, 119.2, 130.4, 138.8, 155.2, 158.3, 162.0, 174.2. Anal. Calcd for C19H23NO7: C, 60.47; H, 6.14; N, 3.71. Found: C, 60.73; H, 6.25; N, 3.62. IR (neat): 2991, 2933, 2869, 2844, 1712, 1608, 1475, 1309, 1157, 1108, 1039, 987 cm-1.
10: colorless prism; mp 106.0-107.0 °C. 1H NMR (400 MHz, CDCl3): δ = 1.35 (d, J = 13.5 Hz, 1 H), 2.06-2.16 (m, 1 H), 2.80 (s, 3 H), 2.84 (s, 3 H), 3.42 (s, 3 H), 3.64 (ddd, J = 2.4, 11.2, 12.2 Hz, 1 H), 3.84 (ddd, J = 2.4, 11.2, 12.2 Hz, 1 H), 3.97 (dd, J = 5.0, 11.2 Hz, 1 H), 4.21 (dd, J = 5.0, 11.2 Hz, 1 H), 5.04 (d, J = 7.0 Hz, 1 H), 5.17 (d, J = 7.0 Hz, 1 H), 5.46 (s, 1 H), 7.28 (d, J = 7.97 Hz, 1 H), 7.40 (d, J = 7.97 Hz, 1 H), 7.48 (d, J = 7.97 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 12.9, 25.4, 44.4, 56.3, 66.9, 67.2, 95.6, 98.9, 114.7, 115.1, 118.5, 119.2, 131.7, 138.9, 156.4, 156.8, 173.4. Anal. Calcd for C17H21NO7S: C, 53.25; H, 5.52; N, 3.65; S, 8.36. Found: C, 53.27; H, 5.69; N, 3.64; S, 8.60. IR (KBr): 2967, 2927, 2852, 1579, 1473, 1402, 1317, 1257, 1155, 1105, 1045, 1008, 987, 954, 775 cm-1.
15: colorless oil. 1H NMR (300 MHz, CDCl3): δ = 1.03 (t, J = 7.1 Hz, 3 H), 2.77 (s, 3 H), 3.75 (s, 3 H), 4.09 (q, J = 7.1 Hz, 2 H), 6.91 (dd, J = 2.2, 6.8 Hz, 1 H), 7.22-7.30 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 13.2, 13.6, 56.0, 60.1, 109.5, 109.6, 120.0, 124.2, 124.4, 131.2, 158.7, 159.0, 161.4, 175.0. Anal. Calcd for C14H14BrNO4: C, 49.43; H, 4.15; N, 4.12. Found: C, 49.13; H, 4.36; N, 4.00. IR (neat): 2942, 1718, 1610, 1460, 1429, 1308, 1263, 1105, 1031, 776 cm-1.
17: colorless prism; mp 113.8-114.3 °C. 1H NMR (300 MHz, CDCl3): δ = 1.19 (d, J = 13.4 Hz, 1 H), 1.67-1.80 (m, 1 H), 3.75 (s, 3 H), 3.78-3.82 (m, 2 H), 3.85 (s, 3 H), 3.92-4.14 (m, 2 H), 6.01 (s, 1 H), 6.97 (d, J = 9.3 Hz, 1 H), 7.04 (d, J = 9.3 Hz, 1 H), 7.57-7.59 (m, 3 H), 8.14-8.19 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 25.6, 56.5, 56.6, 67.1, 91.7, 96.4, 112.6, 112.7, 114.5, 115.4, 125.5, 126.7, 128.0, 129.3, 132.0, 151.0, 152.3, 161.0, 172.0. Anal. Calcd for C22H20N2O5: C, 67.34; H, 5.14; N, 7.14. Found: C, 67.13; H, 5.35; N, 6.93. IR (ATR): 3065, 2957, 2915, 2837, 2233, 1607, 1595, 1519, 1479, 1446, 1394, 1259, 1082, 995, 809 cm-1.
18: colorless oil. 1H NMR (300 MHz, CDCl3): δ = 0.94 (t, J = 7.1 Hz, 3 H), 1.18 (d, J = 13.2 Hz, 1 H), 1.63-1.79 (m, 1 H), 2.73 (s, 3 H), 3.69 (s, 3 H), 3.66-3.79 (m, 2 H), 3.83 (s, 3 H), 3.87-3.98 (m, 2 H), 4.01 (q, J = 7.1 Hz, 2 H), 5.89 (s, 1 H), 6.91 (d, J = 9.0 Hz, 1 H), 6.96 (d, J = 9.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 12.6, 13.4, 25.3, 56.6, 56.7, 59.7, 66.8, 67.0, 96.7, 111.6, 112.4, 113.1, 119.3, 127.0, 150.1, 152.3, 158.8, 162.2, 172.1. Anal. Calcd for C19H23NO7: C, 60.47; H, 6.14; N, 3.71. Found: C, 60.23; H, 5.96; N, 3.50. IR (neat): 3434, 2962, 2842, 2730, 1712, 1619, 1509, 1482, 1465, 1396, 1307, 1259, 1176, 1106, 1083, 998 cm-1.
19: colorless oil. 1H NMR (300 MHz, CDCl3): δ = 1.24 (d, J = 13.4 Hz, 1 H), 1.70-1.86 (m, 1 H), 2.76 (s, 3 H), 2.90 (s, 3 H), 3.71 (s, 3 H), 3.75 (br d, J = 2.5 Hz, 1 H), 3.78 (br d, J = 2.5 Hz, 1 H), 3.83 (s, 3 H), 4.13 (br d, J = 4.7 Hz, 1 H), 4.17 (br d, J = 4.7 Hz, 1 H), 5.96 (s, 1 H), 6.93 (d, J = 9.3 Hz, 1 H), 7.01 (d, J = 9.3 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 12.6, 25.5, 44.4, 56.3, 56.6, 66.8, 67.2, 96.6, 112.3, 114.1, 116.1, 118.3, 127.2, 150.8, 152.8, 157.3, 172.2. Anal. Calcd for C17H21NO7S: C, 53.25; H, 5.52; N, 3.65; S, 8.36. Found: C, 53.49; H, 5.35; N, 3.68; S, 8.47. IR (neat): 3002, 2962, 2931, 2892, 2840, 1586, 1481, 1461, 1380, 1313, 1257, 1241, 1156, 1101, 1080, 996, 956 cm-1.
Isoxazolone 21: yellow prism; mp 120.0-120.8 °C. 1H NMR (400 MHz, CDCl3): δ = 1.38 (d, J = 13.5 Hz, 1 H), 1.79 (s, 3 H), 2.05-2.17 (m, 1 H), 2.54 (s, 3 H), 3.39 (s, 3 H), 3.76 (ddd, J = 2.4, 11.4, 12.3 Hz, 1 H), 3.92 (ddd, J = 2.4, 11.4, 12.3 Hz, 1 H), 3.99 (dd, J = 5.1, 11.4 Hz, 1 H), 4.24 (dd, J = 5.1, 11.4 Hz, 1 H), 5.13 (d, J = 6.8 Hz, 1 H), 5.16 (d, J = 6.8 Hz, 1 H), 5.56 (s, 1 H), 7.18 (d, J = 7.2 Hz, 1 H), 7.41 (d, J = 7.2 Hz, 1 H), 7.64 (t, J = 7.2 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 22.8, 24.0, 25.5, 56.3, 67.2, 67.2, 94.6, 98.8, 114.7, 117.9, 118.7, 119.6, 131.4, 139.0, 155.0, 158.7, 169.4, 172.3. Anal. Calcd for C18H21NO6: C, 62.24; H, 6.09; N, 4.03. Found: C, 62.32; H, 5.98; N, 4.00. IR (KBr): 2962, 2857, 1754, 1635, 1467, 1369, 1251, 1157, 1093, 1041, 987, 865, 800 cm-1.