Synthesis of 3,4-Disubsituted Isoxazoles via Enamine [3+2] Cycloaddition

Abstract

Enamine-triggered [3+2]-cycloaddition reactions of ­aldehydes and N-hydroximidoyl chlorides in the presence of tri­ethylamine give rise to 3,4-disubstituted isoxazoles upon oxidation of the cycloadduct 3,4,5-trisubstituted 5-(pyrrolidinyl)-4,5-dihydroisoxazoles. This offers a high yielding, regiospecific and metal-free synthetic route for the synthesis of 3,4-disubstituted isoxazoles.

Key words

isoxazole - enamines - 1,3-dipoles - [3+2] cycloaddition

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• 12 Synthesis of 4aa–ia; General Procedure: Pyrrolidine 3a (74.5 μL, 0.88 mmol) and Et₃N (53.9 μL, 0.4 mmol) was dissolved in CH₂Cl₂ (4 mL), the mixture was cooled to 0 °C and isovaleraldehyde 2a–i (173.9 μL, 1.6 mmol) was added. Immediately afterwards, N-hydroxybenzimidoyl chloride 1a (62.2 mg, 0.4 mmol) in CH₂Cl₂ (0.2 mL) was added in five portions in five-minute intervals. After complete addition of N-hydroxybenzimidoyl chloride, the reaction mixture was stirred for a further 10 min at 0 °C, after which, it was allowed to warm to r.t. slowly and stirred for another 1.5 h. The reaction was then stopped and the product was purified by flash column chromatography with silica gel (EtOAc–hexane, 10%) to afford 4aa–ia.
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