Copper-Catalyzed Oxydifluoroalkylation of β,γ-Unsaturated Oximes for the Construction of Isoxazolines with a Difluoroalkyl Side Chain

Abstract

A copper-catalyzed oxydifluoroalkylation of β,γ-unsaturated oximes has been developed. This reaction proceeded through a cascade of difluoroalkylation of alkene followed by a nucleophilic attack of the hydroxyl group of oximes. This protocol features mild reaction conditions, low-cost catalyst, and broad substrate scope, which provides a facile method to synthesize isoxazolines with a fluorinated side chain

Key words

copper-catalyzed - oxydifluoroalkylation - isoxazoline - oximes - radical cyclization

Publication History

Received: 28 March 2021

Accepted after revision: 30 April 2021

Accepted Manuscript online:
30 April 2021

Article published online:
19 May 2021

• References and Notes

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• 18 Copper-Catalyzed Oxydifluoroalkylation of β,γ-Unsaturated Oximes: Typical Procedure To a 25 mL of Schlenk tube was added CuI (19.0 mg, 0.1 mmol), Na₂S₂O₅ (38.0 mg, 0.2 mmol), NaHCO₃ (126.0 mg, 1.5 mmol), and 1-phenylbut-3-en-1-one oxime (161.2 mg, 1.0 mmol) under Ar atmosphere. DMSO (2.0 mL), PMDETA (42 μL, 0.2 mmol), and ethyl bromodifluoroacetate (192 μL, 1.5 mmol) were added subsequently. The reaction mixture was stirred at 110 °C (oil bath) for 12 h. After completion by TLC detection, the reaction mixture was cooled to room temperature and quenched with water and ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was purified with silica gel chromatography (petroleum ether/ethyl acetate = 10:1) to give 3aa (198 mg, 70% yield) as a light-yellow solid. Ethyl 2,2-Difluoro-3-(3-phenyl-4,5-dihydroisoxazol-5-yl)propanoate (3aa) Mp 87.4–91.7 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.68–7.62 (m, 2 H), 7.43–7.35 (m, 3 H), 5.02–4.91 (m, 1 H), 4.36 (q, J = 7.2 Hz, 2 H), 3.52 (dd, J = 16.7, 10.3 Hz, 1 H), 3.12 (dd, J = 16.7, 7.7 Hz, 1 H), 2.46–2.31 (m, 1 H), 2.77–2.60 (m, 1 H), 1.37 (t, J = 7.2 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 163.6 (t, ² J _C–F = 32.0 Hz), 156.7, 130.4, 129.2, 128.9, 126.8, 114.7 (t, ¹ J _C–F = 252.48 Hz), 75.0 (dd, ³ J _C–F = 6.2, 3.2 Hz), 63.3, 40.7, 40.0 (t, ² J _C–F = 22.9 Hz), 14.0. ¹⁹F NMR (376 MHz, CDCl₃): δ = –102.58 (ddd, J = 264.1, 16.0, 11.5 Hz, 1 F), –106.96 (ddd, J = 264.0, 19.2, 17.6 Hz, 1 F). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₆NO₃F₂ ⁺: 284.1093; found: 284.1102. N-Butyl-2,2-difluoro-3-(5-phenyl-3,4-dihydro-2H-pyrrol-3-yl)propanamide (3ab) This compound was prepared according to the typical procedure and purified with silica gel chromatography (petroleum ether/ethyl acetate = 5:1) as a light-yellow solid (158.3 mg, 51% yield); mp 104.7–105.6 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.66–7.63 (m, 2 H), 7.42–7.38 (m, 3 H), 6.50 (s, 1 H), 5.01–4.95 (m, 1 H), 3.53 (dd, J = 16.6, 10.3 Hz, 1 H), 3.34 (q, J = 6.9 Hz, 2 H), 3.13 (dd, J = 16.6, 8.1 Hz, 1 H), 2.69–2.58 (m, 1 H), 2.56–2.45 (m, 1 H), 1.59–1.53 (m, 2 H), 1.41–1.34 (m, 2 H), 0.94 (t, J = 7.4 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 163.7 (t, ² J _C–F = 27.9 Hz), 156.8, 130.4, 129.3, 128.9, 126.8, 116.7 (t, ¹ J _C–F = 253.4 Hz), 75.4 (t, ³ J _C–F = 4.0 Hz), 40.9, 39.6, 39.4 (t, ² J _C–F = 22.8 Hz), 31.3, 20.0, 13.8. ¹⁹F NMR (565 MHz, CDCl₃): δ = –103.64 (dt, J = 258.8, 17.3 Hz, 1 F), –104.64 (dt, J = 258.7, 16.4 Hz, 1 F). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₂₁N₂O₂F₂ ⁺: 311.1566; found: 311.1572.