The Preparation of 2-Isoxazolines from O-Propargylic Hydroxylamines via a Tandem Rearrangement-Cyclisation Reaction

Abstract

A method for the conversion of O-propargylic hydroxyl­amines into 2-isoxazolines in 60-84% yield is described. For 3-alkylpropargyl or 3-arylpropargyl hydroxylamines this was achieved by heating a methanolic solution of the hydrochloride salt in the presence of K₂CO₃. In the case of the 3-unsubstituted compounds, the hydrochloride salts were first converted to the free bases, which rearranged upon heating in methanol. In one case, the methodology was extended to enable the direct transformation of a O-propargyl phthalimide into a 2-isoxazoline in 65% yield by treatment with methyl hydrazine at room temperature over 19 hours.

isoxazoline synthesis - O-propargylic hydroxylamine - sigmatropic rearrangement

References and Notes

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11

Preparation of 3-(2-Chlorophenyl)-2-isoxazoline ( 11).
A mixture of the O-propargylic hydroxylamine hydrochloride salt 1 (275 mg, 1.26 mmol), K₂CO₃ (175 mg, 1.27 mmol) and dry MeOH (5 mL) was heated at reflux under a nitrogen atmosphere for 7.5 h. The solution was then concentrated in vacuo at 40 °C, H₂O (5 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were dried with MgSO₄ and concentrated in vacuo at 40 °C. The crude product was purified by flash chromatography (gradient elution; EtOAc-heptane) to give the isoxazoline 11 as an oil (169 mg, 0.93 mmol, 74%). IR: ν_max = 3066 (w), 2954 (m), 2887 (m), 1584 (m), 1476 (m), 1434 (s), 1342 (s), 1037 (m), 934 (m), 880 (s), 643 (m) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.48 (2 H, t, J = 8.7 Hz, C4-H₂), 4.51 (2 H, t, J = 8.7 Hz, C5-H₂), 7.26-7.38 (2 H, m, Ph), 7.43 (1 H, dd, J = 0.7, 6.3 Hz, Ph), 7.64 (1 H, dd, J = 0.8, 7.9 Hz, Ph). MS (EI): m/z (%) 183 (33) [M⁺], 181 (100) [M⁺], 155 (20), 153 (79), 151 (87), 137 (65), 113 (20), 111 (53), 75 (74). Anal. Calcd for C₉H₈ClNO: C, 59.52; H, 4.44; N, 7.71. Found: C, 59.60; H, 4.46; N, 7.79%. Compounds 12, 13, [13] 14, 15, [14] 16, 17 [13] and 18 [15] were prepared using an analogous procedure.
Preparation of 5-Phenyl-2-isoxazoline ( 19).
The O-propargylic hydroxylamine hydrochloride salt 9 (1.84 g, 10.0 mmol) was dissolved in CH₂Cl₂ (20 mL) and washed with sat. NaHCO₃ solution (20 mL). The aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL) and the combined extracts were dried over MgSO₄ and concentrated in vacuo at 40 °C to give the free hydroxylamine (1.44 g, 9.8 mmol). A portion of this material (300 mg, 2.04 mmol) was dissolved in dry MeOH (5 mL) and heated at reflux under a nitrogen atmosphere for 8 h. The solution was then concentrated in vacuo at 40 °C and the crude product purified by flash chromatography (gradient elution; EtOAc-heptane) to give the isoxazoline 19 as an oil (188 mg, 1.28 mmol, 63%). IR and ¹H NMR spectra as previously reported. [16] Compound 20 was prepared using an analogous procedure.
Preparation of 3-(4-Chlorophenyl)-2-isoxazoline ( 13).
Methyl hydrazine (0.15 g, 3.3 mmol) was instilled into a cooled solution (0 °C) of the phthalimide (25) (1.00 g, 3.2 mmol) in CH₂Cl₂ (10 mL) under a nitrogen atmosphere. The mixture was stirred at r.t. for 19 h, after which time the precipitated 2-methyl-2,3-dihydrophthalazine-1,4-dione was removed by filtration and discarded. The filtrate was diluted with Et₂O (50 mL), cooled to 0 °C and anhyd HCl_(g) was bubbled through for approximately 5 min to give a small amount of brown precipitate which was filtered off and discarded. The filtrate was then concentrated in vacuo at 40 °C and the crude product purified by flash chromatography (gradient elution; EtOAc-heptane) to give the isoxazole 13 as a crystalline solid (380 mg, 2.1 mmol, 65%); mp 114-116 °C (lit. [13] 116-117 °C). IR and ¹H NMR spectra as previously reported. [13]
Compounds 17-20 were isolated as racemic mixtures.

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