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

Abstract

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

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

References

For the isolation of some representative compounds see:

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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.

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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.