Efficient Access to Isoxazoles from Alkenes

Abstract

The direct regioselective synthesis of 3,5-disubstituted isoxazoles was achieved in one reaction vessel through a sequence of reactions involving the net bromination of an electron-deficient alkene, in situ generation of a nitrile oxide, 1,3-dipolar cycloaddition, and loss of HBr from an intermediate 5,5-disubstituted bromoisoxazoline. This one-pot process enables the synthesis of 3,5-disubstituted isoxazoles directly from electron-deficient alkenes thereby negating the isolation of the 1,1-disubstituted bromoalkene alkyne surrogate.

Key words

cycloadditions - heterocycles - tandem reactions - alkyne surrogate - dehydrohalogenation

References and Notes

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15

General Experimental Procedure
After the alkene (0.5 mmol) was dissolved in CH₂Cl₂ (15 mL), bromine (0.55 mmol) was added dropwise. After all of the alkene was completely consumed, as confirmed by TLC on silica gel (hexanes-EtOAc, 4:1), the hydroximoyl chloride (0.5 mmol) was added, and Et₃N (1.2 mmol) was added shortly thereafter. The reaction mixture was stirred at r.t. until the disappearance of the bromoalkene, as verified by TLC on silica gel (hexanes-EtOAc, 4:1). The reaction mixture was washed with H₂O (3 × 10 mL), and the organic layer was dried over anhyd Na₂SO₄. The crude products were purified by flash column chromatography over silica gel using hexanes-EtOAc (4:1) as the eluent system. This procedure provides pure isoxazole products for entries 1-15 in 58-97% yield.
Spectroscopic data for Entry 9, Table 1
Colorless solid (74 mg, 73%), mp 84-87 °C. IR (CaF₂, CCl₄): ν = 1696 cm^-1. ¹H NMR: δ = 3.89 (s, 3 H), 7.00 (d, J = 8.9 Hz, 2 H), 7.25 (s, 1 H), 7.79 (d, J = 8.9 Hz, 2 H), 10.02 (s, 1 H). ¹³C NMR: δ = 55.4, 106.4, 114.2 (2 C), 119.9, 128.3 (2 C), 161.5, 162.7, 165.9, 178.5. HRMS (EI): m/z calcd for C₁₁H₉NO₃ [M⁺ + 1]: 203.0582; found: 203.0628. All spectroscopic and HRMS data were obtained for previously unreported compounds.