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

Hiroshi Takikawa; Katsuyoshi Hikita; Keisuke Suzuki

doi:10.1055/s-2007-985561

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Synlett 2007(14): 2252-2256
DOI: 10.1055/s-2007-985561

LETTER

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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Publication History

Received 8 June 2007
Publication Date:
24 July 2007 (online)

Abstract
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Abstract

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

Key words

benzonitrile oxide - isoxazole - active methylene compounds - cyclocondensation - molecular sieves

References and Notes

1a Caramella P. Grunanger P. In 1,3-Dipolar Cycloaddition Chemistry Vol. 1: Padwa A. Wiley; New York: 1984. p.291

Crossref Google Scholar
1b Easton CJ. Hughes CM. Savage GP. Simpson GW. In Advances in Heterocyclic Chemistry Vol. 60: Katritzky AR. Academic Press; New York: 1994. p.261

Crossref Google Scholar
1c Kotyatkina AI. Zhabinsky VN. Khripach VA. Russ. Chem. Rev. 2001, 70: 641

Crossref Google Scholar
2a Grundmann C. Dean JM. Angew. Chem. 1964, 76: 682

Crossref Google Scholar
2b Grundmann C. Dean JM. J. Org. Chem. 1965, 30: 2809

Crossref Google Scholar
2c Grundmann C. Richter R. J. Org. Chem. 1967, 32: 2308

Crossref Google Scholar
3a Bode JW. Hachisu Y. Matsuura T. Suzuki K. Tetrahedron Lett. 2003, 44: 3555

Article in Thieme Connect Google Scholar
3b Bode JW. Hachisu Y. Matsuura T. Suzuki K. Org. Lett. 2003, 5: 391

Article in Thieme Connect Google Scholar
3c Matsuura T. Bode JW. Hachisu Y. Suzuki K. Synlett 2003, 1746

Article in Thieme Connect Google Scholar
4a Wakefield BJ. In Science of Synthesis: Houben-Weyl Methods of Molecular Transformations Vol. 11: Schaumann E. Georg Thieme Verlag; Stuttgart: 2001. p.229

Article in Thieme Connect Google Scholar
4b Kashima C. Heterocycles 1979, 12: 1343

Article in Thieme Connect Google Scholar
4c Baraldi PG. Barco A. Benetti S. Pollini GP. Simoni D. Synthesis 1987, 857

Article in Thieme Connect Google Scholar
5a Purwono B. Smalley RK. Porter TC. Synlett 1992, 231

Crossref Google Scholar
5b Porter TC. Smalley RK. Teguiche M. Purwone B. Synthesis 1997, 773

Crossref Google Scholar
5c Mosher MD. Natale NR. J. Heterocycl. Chem. 1995, 32: 779

Crossref Google Scholar
5d Zamponi GW. Stotz SC. Staples RJ. Andro TM. Nelson JK. Hulubei V. Blumenfeld A. Natale NR. J. Med. Chem. 2003, 46: 87

Crossref Google Scholar
5e Xin Z. Zhao H. Serby MD. Liu B. Schaefer VG. Falls DH. Kaszubska W. Colins CA. Sham HL. Liu G. Bioorg. Med. Chem. Lett. 2005, 15: 1201

Crossref Google Scholar
Although the pKa of methanesulfonylacetone (6) has not been documented so far, we estimated it to be higher than that of ethyl acetoacetate (3) by analogy from the pKa of dimethyl sulfone (31.1 in DMSO) and EtOAc (29.5 in DMSO):
6a Bordwell FG. Acc. Chem. Res. 1988, 21: 456

Crossref Google Scholar
6b Zhang X.-M. Bordwell FG. Van Der Puy M. Fried HE. J. Org. Chem. 1993, 58: 3060

Crossref Google Scholar
For conventional synthesis of the isoxazolone via the reaction of hydroxylamine and 3-oxo ester, see reference 4a. For the access from nitrile oxides, see:
8a Scarpati R. Sorrentino P. Gazz. Chim. Ital. 1959, 8: 1525

Google Scholar
8b Singal KK. Chem. Ind. (London) 1985, 22: 761

Google Scholar

7

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

9

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.