References and Notes
1a
Caramella P.
Grunanger P. In 1,3-Dipolar Cycloaddition Chemistry
Vol. 1:
Padwa A.
Wiley;
New York:
1984.
p.291
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
1c
Kotyatkina AI.
Zhabinsky VN.
Khripach VA.
Russ. Chem. Rev.
2001,
70:
641
2a
Grundmann C.
Dean JM.
Angew. Chem.
1964,
76:
682
2b
Grundmann C.
Dean JM.
J. Org. Chem.
1965,
30:
2809
2c
Grundmann C.
Richter R.
J. Org. Chem.
1967,
32:
2308
3a
Bode JW.
Hachisu Y.
Matsuura T.
Suzuki K.
Tetrahedron Lett.
2003,
44:
3555
3b
Bode JW.
Hachisu Y.
Matsuura T.
Suzuki K.
Org. Lett.
2003,
5:
391
3c
Matsuura T.
Bode JW.
Hachisu Y.
Suzuki K.
Synlett
2003,
1746
4a
Wakefield BJ. In Science of Synthesis: Houben-Weyl Methods of Molecular Transformations
Vol. 11:
Schaumann E.
Georg Thieme Verlag;
Stuttgart:
2001.
p.229
4b
Kashima C.
Heterocycles
1979,
12:
1343
4c
Baraldi PG.
Barco A.
Benetti S.
Pollini GP.
Simoni D.
Synthesis
1987,
857
5a
Purwono B.
Smalley RK.
Porter TC.
Synlett
1992,
231
5b
Porter TC.
Smalley RK.
Teguiche M.
Purwone B.
Synthesis
1997,
773
5c
Mosher MD.
Natale NR.
J. Heterocycl. Chem.
1995,
32:
779
5d
Zamponi GW.
Stotz SC.
Staples RJ.
Andro TM.
Nelson JK.
Hulubei V.
Blumenfeld A.
Natale NR.
J. Med. Chem.
2003,
46:
87
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
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
6b
Zhang X.-M.
Bordwell FG.
Van Der Puy M.
Fried HE.
J. Org. Chem.
1993,
58:
3060
7 Structure of 21 was confirmed by X-ray crystallographic analysis (CCDC 647875).
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
8b
Singal KK.
Chem. Ind. (London)
1985,
22:
761
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.