合成5-Substituted 3-Isoxazolol衍生物

3-Isoxazolols are most often synthesized from a β-keto ester and hydroxylamine. This cyclization typically gives rise to a major byproduct, the corresponding 5-isoxazolone. We have found that N,O-diBoc-protected β-keto hydroxamic acids can be synthesized and cyclized to 5-substituted 3-isoxazolols without formation of any byproduct. We present a novel and versatile three-step procedure in which carboxylic acid derivatives are converted into acyl Meldrum's acids which, upon aminolysis with N,O-bis(tert-butoxycarbonyl)hydroxylamine, lead to the N,O-diBoc-protected β-keto hydroxamic acids. These hydroxamic acid analogues were then, upon treatment with hydrochloric acid, cyclized to the corresponding 5-substituted 3-isoxazolols.

General Procedure for the Preparation of Acyl Meldrum's Acids. Method B:  Synthesis of 5-(1-Hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (20a). A solution of Meldrum's acid (3.00 g, 20.8 mmol) in CH₂Cl₂ (25 mL) was cooled to 0 °C, and pyridine (3.29 g, 41.6 mmol) was added. After stirring 15 min, acetyl chloride (1.63 g, 20.8 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1.5 h followed by 1.5 h at room temperature. To this solution was added 2 M aqueous HCl, and the reaction mixture was then extracted with CH₂Cl₂. The combined organic extracts were dried (MgSO₄), filtered, and concentrated in vacuo. CC (EtOAc/hexane 1:9, 1% AcOH) yielded 20a as a crystalline solid (3.20 g, 83%)

General Procedure for the Preparation of β-Keto Hydroxamic Acids. Method D:  Synthesis of N-(tert-Butoxycarbonyl)-N-(tert-butoxycarbonyloxy)acetylacetamide (21a). To 20a (1.50 g, 8.06 mmol) dissolved in toluene (75 mL) was added N,O-diBoc hydroxylamine¹⁵ (1.88 g, 8.06 mmol). The stirred solution was heated to 65 °C for 4 h and then cooled to room temperature. After concentration in vacuo, the residue was purified by CC (EtOAc/hexane 1:19) to afford compound 21a as a colorless oil (1.89 g, 74%)

General Procedure for the Preparation of 5-Substituted 3-Isoxazolols. Method A:  Synthesis of 5-Methyl-3-isoxazolol (7). Compound 21a (450 mg, 1.42 mmol) dissolved in MeOH (3 mL) was added to concentrated HCl (10 mL) at 50 °C. The mixture was stirred for 1 h, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in water (10 mL) and pH adjusted to 3−4 with 2 M aqueous NaOH followed by extraction with EtOAc. The combined organic phases were dried (MgSO₄) and concentrated in vacuo. CC (EtOAc/hexane 1:9, 1% AcOH) yielded 7 as a crystalline solid (130 mg, 92%)

J. Org. Chem. 2000, 65, 4, 1003–1007

标签： isoxazolol