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Synlett 2005(2): 259-262  
DOI: 10.1055/s-2004-837216
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Functionalized 1-Benzoxepins by Tandem Ring-Opening/Cyclocondensation of 3-Bromoisoxazoles

Martin G. Kociolek*, Nicholas G. Straub, Jolene V. Schuster
Penn State Erie, The Behrend College, School of Science, Erie, PA 16563, USA
Fax: +1(814)8986213; e-Mail: mgk5@psu.edu;
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Publikationsverlauf

Received 15 October 2004
Publikationsdatum:
17. Dezember 2004 (online)

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Abstract

A series of functionalized 1-benzoxepins were synthesized by way of a tandem ring-opening/cyclocondensation of aldehyde-containing 3-bromoisoxazoles.

Key words

benzoxepin - isoxazoles - reductive ring-opening - ferrous chloride - cyclocondensation

11

Typical Procedure:
Propargyl tosylate (2.10 g, 10 mmol) and salicylaldehyde (11, 1.05 g, 10 mmol) were dissolved in dry DMF (15 mL) at r.t. K2CO3 (2.76 g, 20 mmol) was added and the reaction stirred at r.t. for 18 h. The reaction was poured into H2O (50 mL) and extracted with Et2O (3 × 25 mL). The combined ether layers were dried (MgSO4) and evaporated giving propargyl ether 12a as a white solid (1.36 g, 85%), which gave satisfactory 1H NMR data and was used without further purification.
Compound 12b previously unreported: 1H NMR (400 MHz, CDCl3): δ = 10.51 (s, 1 H), 8.43 (d, J = 2.2 Hz, 1 H), 8.25 (dd, J = 2.2, 9.1 Hz, 1 H), 7.21 (d, J = 9.1 Hz, 1 H), 4.92 (d, J = 2.1 Hz, 2 H), 2.60 (m, 4 H).
Compound 12a (1.36 g, 8.5 mmol) was dissolved in CH2Cl2 (20 mL) and K2CO3 (42.5 mmol) was added. Dibromoformaldoxime (1.72 g, 8.5 mmol) dissolved in CH2Cl2 (30 mL) was added dropwise over 20 h via syringe pump. The reaction was poured into 1 M HCl (100 mL) and the layers separated. The aqueous layer was extracted with additional CH2Cl2 (50 mL) and the combined organic layers dried (Na2SO4) and evaporated leaving a yellow oil which was purified by column chromatography (silica gel; hexanes-EtOAc) giving 13a as a light yellow solid (2.06 g, 86% yield).
Compound 13a: light yellow solid; mp 95-96 °C. IR (KBr): 3139, 1688, 1597 cm-1. 1H NMR (400 MHz, CDCl3): δ = 10.44 (s, 1 H), 7.92-6.97 (m, 4 H), 6.53 (s, 1 H), 5.30 (s, 2 H). Anal. Calcd for C11H8BrNO3: C, 46.84; H, 2.86; N, 4.97. Found: C, 46.95; H, 2.99; N, 4.89.
Compound 13b: white solid; mp 144-145 °C. IR (KBr): 3138, 1692, 1669, 1594 cm-1. 1H NMR (400 MHz, CDCl3): δ = 10.47 (s, 1 H), 8.43 (d, J = 2.2 Hz, 1 H), 8.25 (dd, J = 2.2, 9.1 Hz, 1 H), 7.21 (d, J = 9.1 Hz, 1 H), 6.55 (s, 1 H), 5.40 (s, 2 H), 2.61 (s, 3 H). Anal. Calcd for C13H10BrNO4: C, 48.17; H, 3.11; N, 4.32. Found: C, 47.90; H, 3.20; N, 4.34.
Compound 13c: white solid; mp 147-149 °C. IR (KBr): 3153, 1665, 1619, 1592 cm-1. 1H NMR (400 MHz, CDCl3): δ = 10.80 (s, 1 H), 9.25-9.09 (m, 1 H), 8.19-7.28 (m, 5 H), 6.64 (s, 1 H), 5.41 (s, 2 H). Anal. Calcd for C15H10BrNO3: C, 54.24; H, 3.03; N, 4.22. Found: C, 53.96; H, 3.15; N, 4.19.
Compound 13d: white solid; mp 119-120 °C. IR (KBr): 3146, 1687, 1589 cm-1. 1H NMR (400 MHz, CDCl3): δ = 10.38 (s, 1 H), 7.95 (d, J = 2.3 Hz, 1 H), 7.66 (dd, J = 2.3, 9.2 Hz, 1 H), 6.92 (d, J = 2.3 Hz, 1 H), 6.48 (s, 1 H), 5.27 (s, 2 H). Anal. Calcd for C11H7Br2NO3: C, 36.60; H, 1.95; N, 3.88. Found: C, 36.72; H, 2.03; N, 3.88.
Compound 13e: colorless oil. IR (KBr): 3129, 1687, 1598 cm-1. 1H NMR (400 MHz, CDCl3): δ = 10.49 (s, 1 H), 7.93-6.90 (m, 4 H), 6.36 (s, 1 H), 5.62 (q, J = 6.7 Hz, 1 H), 1.78 (d, J = 6.7 Hz, 3 H). Anal. Calcd for C12H10BrNO3: C, 48.67; H, 3.40; N, 4.73. Found: C, 48.74; H, 3.50; N, 4.75.
Compound 13f: Colorless oil. IR (KBr): 3126, 1686, 1597 cm-1. 1H NMR (400 MHz, CDCl3): δ = 10.44 (s, 1 H), 7.92-6.98 (m, 4 H), 6.42 (s, 1 H), 1.82 (s, 6 H). Anal. Calcd for C13H12BrNO3: C, 50.34; H, 3.90; N, 4.52. Found: C, 50.16; H, 4.16; N, 4.77.

13

Typical Procedure:
Bromoisoxazole 13 (0.28 g, 1 mmol) was dissolved in MeCN (25 mL). Nitrogen was bubbled through the solution for 15 min after which FeCl2·4H2O (0.50 g, 2.5 mmol) was added and stirred at r.t. under nitrogen for 18 h. The reaction was then filtered through Celite and evaporated; the residue was purified by column chromatography (silica gel; hexanes-EtOAc) to give 14 as a yellow solid (0.14 g, 76%).
Compound 14a: yellow solid; mp 162-163 °C. IR (KBr): 2227, 1676, 1603, 1559 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.15-7.60 (m, 4 H), 4.64 (s, 2 H). Anal. Calcd for C11H7NO2: C, 71.35; H, 3.81; N, 7.56. Found: C, 71.63; H, 3.92; N, 7.49.
Compound 14b: yellow solid; mp 186-187 °C. IR (KBr): 2225, 1677, 1601, 1565 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.99-8.25 (m, 3 H), 7.31 (d, J = 9.2 Hz, 1 H), 4.71 (s, 1 H), 2.63 (s, 3 H). Anal. Calcd for C13H9NO3: C, 68.72; H, 3.99; N, 6.16. Found: C, 68.60; H, 4.18; N, 6.14.
Compound 14c: yellow solid; mp 150 °C (sub). IR (KBr): 2224, 1679, 1616, 1591, 1554 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.62 (s, 1 H), 7.26-8.13 (m, 6 H), 4.71 (s, 2 H). Anal. Calcd for C15H9NO2: C, 76.59; H, 3.86; N, 5.95. Found: C, 76.17; H, 4.07; N, 6.02.
Compound 14d: yellow solid; mp 120-122 °C. IR (KBr): 2225, 1682, 1599, 1550 cm-1. 1H NMR (400 MHz, CD3CN): δ = 7.75 (s, 1 H), 7.34-7.53 (m, 2 H), 6.89 (d, J = 9.1 Hz, 1 H), 4.41 (s, 2 H). Anal. Calcd for C11H6BrNO2: C, 50.03; H, 2.29; N, 5.30. Found: C, 49.71; H, 2.41; N, 5.23.
Compound 14e: yellow solid; mp 130-131 °C. IR (KBr): 2226, 1687, 1604, 1560 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.85 (s, 1 H), 7.15-7.60 (m, 4 H), 4.45 (q, J = 6.7 Hz, 1 H), 1.56 (d, J = 6.7 Hz, 3 H). Anal. Calcd for C12H9NO2: C, 72.35; H, 4.55; N, 7.03. Found: C, 71.98; H, 4.61; N, 6.95.
Compound 14f: yellow solid; mp 105-106 °C. IR (KBr): 2228, 1674, 1604, 1563 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.84 (s, 1 H), 7.08-7.61 (m, 4 H), 1.42 (s, 6 H). Anal. Calcd for C13H11NO2: C, 73.22; H, 5.20; N, 6.57. Found: C, 73.10; H, 5.21; N, 6.53.