Anionic Domino C-O-Heterocyclization Approach for the Synthesis of 5-Vinyl Isoxazolines

Abstract

5-Vinyl isoxazolines were isolated in high yields through domino nucleophilic addition-anionic C-O-heterocyclization, when allyl organometallics derived from trans-1,4-dihalobutene were reacted with nitrile oxides.

Key words

1 - 4-dihalobutene - nitrile oxide - 5-vinyl isoxazoline - organometallic addition

References and Notes

• 1a Caramella P. Gurnager P. In 1,3-Dipolar Cycloaddition Chemistry   Vol. 1:  Padwa A. Wiley; New York: 1984.  p.291 
• 1b Huisgen R. Angew. Chem.  1963,  75:  604 
• 1c Padwa A. Angew. Chem.  1976,  88:  123 
• 1d Torssel KBG. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis: Novel Strategies in Synthesis   VCH; New York: 1988. 
• 2a Caramella P. Bianchessi P. Tetrahedron  1970,  26:  5773 
• 2b Torsell KBG. Hazell AC. Hazel RG. Tetrahedron  1985,  41:  5569 
• 2c Das NB. Torsell KBG. Tetrahedron  1983,  39:  2247 
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4

Typical Procedure for the Grignard Addition: 3-(4-Fluorophenyl)-5-vinyl-4,5-dihydroisoxazole (Table 1, entry d): To a suspension of Mg turnings (0.015 g, 5 mmol, 5 equiv) in anhyd THF was added trans-1,4-dibromobutene (0.214 g, 1 mmol, 1 equiv) in small portions while stirring the reaction mixture at r.t. (a small grain of iodine is generally required to promote formation of the Grignard reagent). The mixture was stirred at r.t. for 1-2 h and was then cooled to 0-5 °C. It was then added dropwise to a solution of p-fluorobenzonitrile oxide (equivalent to 0.137 g, 1 mmol, generated in situ by treatment of Et₃N with the corresponding chlorooxime 0.173g, 1 mmol) in THF (15 mL), over a period of 10 min while maintaining the temperature between 0-5 °C. The reaction was allowed to reach r.t. and stirring was continued for a further 2-3 h. The reaction was then quenched using aq NH₄Cl soln (10 mL) and diluted with CH₂Cl₂ (50 mL). The organic layer was separated and the aq layer extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were dried (anhydrous Na₂SO₄) and evaporated under reduced pressure to afford the crude product, which was subjected to column chromatography (silica gel, 60-120 mesh, n-hexane-EtOAc, gradient) to afford pure 3-(4-fluorophenyl)-5-vinyl 4,5-dihydroisoxazole (0.16g, 83%) as a colorless amorphous solid. IR (KBr): 1383, 1430, 1602, 2851, 2919, 2959, 3444 cm^-1; ¹H NMR (200 MHz, CDCl₃): δ = 2.85-2.95 (q, J = 8.0 Hz, 1 H), 3.33-3.46 (dd, J = 10.1, 6.3 Hz, 1 H), 5.1 (m, 1 H), 5.12-5.55 (m, 2 H), 5.85-5.95 (m, J = 7.36 Hz, 1 H), 7.2 (d, J = 9.0 Hz, 2 H), 7.59 (d, J = 9.0 Hz, 2 H); ¹³C NMR (50 MHz, CDCl₃): δ = 40.4, 82.5, 115.2, 115.7, 118.2, 128.4, 128.5, 137.3, 157.5, 161.1, 163.5; MS (EI): m/z = 191.20; Anal. Calcd for C₁₁H₁₀FNO: C, 69.10; H, 5.27; N, 7.33. Found: C, 69.19; H, 5.18; N, 7.48.

5

Typical Procedure for the Indium-Mediated Synthesis: 3-(4-Fluorophenyl)-5-vinyl-4,5-dihydroisoxazole (Table 1, entry d): A suspension of In powder (1.15 g, 10 mmol) and trans-1,4-dibromobutene (1.2 g, 10 mmol) were stirred at ambient temperature for 5 h in THF-H₂O (15 mL, 1:1) until the metal dissolved completely forming the allylindium reagent. The reagent was then cooled to 0-5 °C and added dropwise to a solution of p-fluorobenzonitrile oxide, generated in situ by treatment of Et₃N with the corresponding chlorooxime (equivalent to 1.53 g, 10 mmol) in THF (15 mL), over a period of 5 min while maintaining the temperature between 0-5 °C. The reaction was allowed to reach r.t. and stirring was continued for a further 45 h. The reaction was then quenched using aq NH₄Cl soln (10 mL) and diluted with CH₂Cl₂ (50 mL). The organic layer was separated and the aq layer extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were dried (anhydrous Na₂SO₄) and evaporated under reduced pressure to afford the crude product, which was subjected to column chromatography (silica gel, finer than 200 mesh, n-hexane-EtOAc, gradient) to afford pure 3-(4-fluorophenyl)-5-vinyl-4,5-dihydroisoxazole (1.53 g, 80%) as a colorless amorphous solid.