Catalyst-Free, Multicomponent Reaction of Iodonium Ylides, Nitrosoarenes, and Olefins for the Synthesis of Isoxazolidine Derivatives

Abstract

A general and efficient three-component protocol for the synthesis of isoxazolidines has been developed. A range of nitrosoarenes, olefins, as well as iodonium ylides can be subjected to this reaction to generate the N-aryl isoxazolidines derivatives with moderate to excellent yields. In addition, we demonstrate that this approach employs the 1,3-dipolar cycloaddition of nitrones generated in situ from iodonium ylides and nitroso compounds, with olefins in the absence of any catalysts and additives.

Key words

iodonium ylides - nitrosoarenes - olefins - N-aryl isoxazolidine derivatives - catalyst free

Publication History

Received: 04 May 2023

Accepted after revision: 07 June 2023

Accepted Manuscript online:
07 June 2023

Article published online:
13 July 2023

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• 22 General Procedure To a sealed tube equipped with a magnetic stir bar were added 1a′ (0.20 mmol, 2.0 equiv), 2a (0.10 mmol, 10.7 mg, 1.0 equiv), 3a (0.20 mmol, 20.8 mg, 2.0 equiv), and dry DCM (1.0 mL). Then, the temperature of metal sand bath was set to 50 ℃, and the closed reaction system was stirred for 18 h. The solvent was removed by vacuum, and the crude product was purified by flash chromatography on silica gel silica: 200–300; eluant: petroleum ether/ethyl acetate (10:1) to provide pure product 4 as a yellow solid in 99% yield (33.8 mg). Dimethyl 2-(4-Hexylphenyl)-5-phenylisoxazolidine-3,3-dicarboxylate (5) ¹H NMR (400 MHz, CDCl₃, 300 K): δ = 7.54 (d, J = 6.9 Hz, 2 H), 7.42–7.33 (m, 3 H), 7.29–7.26 (m, 3 H), 7.09–7.06 (m, 2 H), 5.32 (dd, J = 9.3, 6.4 Hz, 1 H), 3.73 (s, 3 H), 3.48 (s, 3 H), 3.25–3.11 (m, 2 H), 2.55 (d, J = 7.5 Hz, 2 H), 1.27 (q, J = 5.4, 4.3 Hz, 8 H), 0.86 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 300 K): δ = 169.0, 168.3, 144.7, 139.0, 137.5, 128.6, 128.2, 127.0, 118.7, 79.0, 78.8, 78.8, 53.0, 52.7, 47.6, 35.3, 31.7, 31.5, 28.8, 22.6, 14.1 ppm. HRMS (APCI): m/z [M + H]⁺ calcd for C₂₅H₃₂NO₅: 426.2280; found: 426.2290. Dimethyl 5-Phenyl-2-(pyridin-2-yl)isoxazolidine-3,3-dicarboxylate (17) ¹H NMR (400 MHz, CDCl₃, 300 K): δ = 8.18–8.15 (m, 1 H), 7.61–7.57 (m, 1 H), 7.45–7.33 (m, 5 H), 7.15 (d, J = 8.4 Hz, 1 H), 6.83–6.80 (m, 1 H), 5.34 (dd, J = 9.1, 6.4 Hz, 1 H), 3.79 (d, J = 8.2 Hz, 6 H), 3.37 (dd, J = 12.8, 6.4 Hz, 1 H), 3.05 (dd, J = 12.8, 9.2 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 300 K): δ = 169.4, 168.8, 158.5, 146.7, 137.8, 137.0, 128.7, 128.7, 126.8, 116.9, 109.9, 80.4, 75.4, 53.3, 53.2, 47.7 ppm. HRMS (APCI): m/z [M + H]⁺ calcd for C₁₈H₁₉N₂O₅: 343.1249; found: 343.1272. Dimethyl 5-Benzyl-2-phenylisoxazolidine-3,3-dicarboxylate (27) ¹H NMR (400 MHz, CDCl₃, 300 K): δ = 7.34–7.23 (m, 9 H), 7.01 (q, J = 4.4 Hz, 1 H), 4.60–4.53 (m, 1 H), 3.62 (s, 3 H), 3.55 (s, 3 H), 3.21 (dd, J = 13.8, 6.7 Hz, 1 H), 2.96–2.90 (m, 2 H), 2.81 (dd, J = 12.7, 8.7 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 300 K): δ = 168.8, 168.6, 147.1, 137.3, 129.2, 128.5, 128.3, 126.7, 123.7, 117.8, 78.4, 77.8, 52.9, 52.8, 45.4, 38.9 ppm. HRMS (APCI): m/z [M + H]⁺ calcd for C₂₀H₂₂NO₅: 356.1498; found: 356.1497. Dimethyl 5-(2-Oxopyrrolidin-1-yl)-2-phenylisoxazolidine-3,3-dicarboxylate (30) ¹H NMR (400 MHz, CDCl₃, 300 K): δ = 7.24 (d, J = 4.1 Hz, 4 H), 7.04–6.97 (m, 1 H), 4.45–4.38 (m, 1 H), 3.69 (s, 3 H), 3.51 (s, 3 H), 2.97 (dd, J = 12.5, 5.6 Hz, 1 H), 2.68 (dd, J = 12.3, 9.6 Hz, 1 H), 1.86–1.64 (m, 6 H), 1.53 (dd, J = 13.1, 8.0 Hz, 2 H), 1.28–1.17 (m, 3 H), 1.02–0.93 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 300 K): δ = 169.2, 168.6, 147.3, 128.3, 123.4, 117.6, 78.4, 75.5, 52.9, 52.7, 46.5, 40.2, 35.3, 33.6, 33.2, 26.4, 26.2, 26.1 ppm. HRMS (APCI): m/z [M + H]⁺ calcd for C₂₀H₂₈NO₅: 362.1967; found: 362.1966. Dimethyl 5-Formyl-5-methyl-2-phenylisoxazolidine-3,3-dicarboxylate (37) ¹H NMR (400 MHz, CDCl₃, 300 K): δ = 9.68 (s, 1 H), 7.37 (d, J = 8.3 Hz, 2 H), 7.29 (d, J = 7.6 Hz, 2 H), 7.12 (t, J = 7.3 Hz, 1 H), 3.80 (s, 3 H), 3.32 (s, 3 H), 3.17 (d, J = 13.0 Hz, 1 H), 3.00 (d, J = 13.0 Hz, 1 H), 1.49 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 300 K): δ = 203.1, 168.4, 167.0, 145.7, 128.3, 125.3, 119.6, 84.0, 77.9, 53.1, 52.5, 45.8, 17.4 ppm. HRMS (APCI): m/z [M + H]⁺ calcd for C₁₅H₁₈NO₆: 308.1134; found: 308.1135. Methyl 3-Acetyl-2,5-diphenylisoxazolidine-3-carboxylate (45) ¹H NMR (400 MHz, CDCl₃, 300 K): δ = 7.48–7.43 (m, 2 H), 7.42–7.34 (m, 3 H), 7.31–7.26 (m, 2 H), 7.20 (dd, J = 8.8, 1.1 Hz, 2 H), 7.05–7.00 (m, 1 H), 5.39 (dd, J = 8.9, 6.4 Hz, 1 H), 3.72 (s, 3 H), 3.41 (dd, J = 12.9, 6.4 Hz, 1 H), 2.86 (dd, J = 12.9, 9.0 Hz, 1 H), 2.15 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 300 K): δ = 203.5, 168.8, 146.8, 137.3, 128.8, 128.7, 128.6, 126.5, 123.3, 116.7, 83.5, 79.1, 53.0, 46.5, 26.7 ppm. HRMS (APCI): m/z [M + H]⁺ calcd for C₁₉H₂₀NO₄: 326.1392; found: 326.1390. For the Synthesis of 11, 13, 39, and 40 To a sealed tube equipped with a magnetic stir bar were added 1a′ (0.20 mmol, 2.0 equiv), 2 (0.10 mmol, 1.0 equiv), 3 (0.20 mmol, 2.0 equiv), and dry DCM (1.0 mL). Then, the temperature of metal sand bath was set to 70 ℃, and the closed reaction system was stirred for 18 h. The solvent was removed by vacuum, and the crude product was purified by flash chromatography on silica gel silica: 200–300; eluant: petroleum ether/ethyl acetate (10:1) to provide pure product. Dimethyl 2-Phenyltetrahydrofuro[3,2-d]isoxazole-3,3(2H)-dicarboxylate (40) ¹H NMR (400 MHz, CDCl₃, 300 K): δ = 7.41 (s, 2 H), 7.28–7.24 (m, 3 H), 7.12 (t, J = 7.3 Hz, 1 H), 5.99 (d, J = 5.3 Hz, 1 H), 4.29–4.22 (m, 1 H), 4.03–3.99 (m, 1 H), 3.86 (dd, J = 6.4, 3.1 Hz, 1 H), 3.83 (s, 3 H), 3.32 (s, 3 H), 2.07 (s, 1 H), 1.92–1.83 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 300 K): δ = 167.1, 166.2, 146.0, 128.1, 125.8, 121.1, 104.4, 82.7, 69.1, 54.2, 52.8, 52.1, 29.1 ppm. HRMS (APCI): m/z [M + H]⁺ calcd for C₁₅H₁₈NO₆: 308.1134; found: 308.1134.