Synlett 2021; 32(10): 1029-1033
DOI: 10.1055/a-1495-7966
letter

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

Lianxin Wang
,
,
Wentao Zhao
,
The authors are grateful to the financial support of Major National Science and Technology Projects of China (2017ZX07402003). We also thank the Natural Science Foundation of Tianjin City (19JCYBJC20200) and Tianjin University for support of this research.


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

Supporting Information



Publication History

Received: 28 March 2021

Accepted after revision: 30 April 2021

Publication Date:
30 April 2021 (online)

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
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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.