Radical Allylation: E-Selective Radical Conjugate Addition–Elimination Reaction from Morita–Baylis–Hillman Adducts

Abstract

Triethylborane-mediated radical allylation was performed from Morita–Baylis–Hillman alcohols with no need of protecting group. The radical conjugated addition–elimination reaction is highly selective, and trisubstituted E-alkenes were obtained. This reaction opened a new route for the preparation of functionalized α,β-unsaturated ketones.

Key words

radical - fluorine - alkenes - elimination - enols - allylation - xanthate

• References and Notes

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• 18a General Procedure for Radical Conjugated Addition–Elimination Reaction Triethylborane (1 M in hexane, 1.2 equiv) was added dropwise over 0.5 h with a syringe pump to a solution of iodoalkane (1 equiv) and Morita–Baylis–Hillman adduct (1.2 equiv) in CH₂Cl₂ under air atmosphere. After 4 h of stirring at 20 °C, the crude mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give the title compound. (E)-Diisopropyl 1,1-Difluoro-3-propionyl-3-hexenyl Phosphonate (3) General procedure was followed with iododifluorophosphonate 1a (50.0 mg, 0.15 mmol), 5-hydroxy-4-methylideneheptan-3-one (2, 25.0 mg, 0.18 mmol), and Et₃B (0.18 mL, 1 M in hexane, 0.18 mmol) in CH₂Cl₂ (2 mL). Purification by flash chromatography of the crude mixture (EtOAc/pentane, 1:1) afforded compound 3 (36.4 mg, 71%, colorless oil). ¹H NMR (400 MHz, CDCl₃): δ = 6.83 (t, ³ J _HH = 7.4 Hz, 1 H, H₄), 4.82 (dsept, ³ J _HP = ³ J _HH = 6.2 Hz, 2 H), 3.18 (td, ³ J _HF = 20.5 Hz, ³ J _HP = 3.0 Hz, 2 H), 2.70 (q, ³ J _HH = 7.4 Hz, 2 H), 2.29 (dt, ³ J _HH = ³ J _HH = 7.4 Hz, 2 H), 1.37 (d, ³ J _HH = 6.2 Hz, 12 H), 1.09, 1.06 (t, ³ J _HH = 7.4 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 201.2, 149.0, 131.3 (td, ³ J _CF = 7.9 Hz, ³ J _CP = 2.2 Hz), 119.6 (td, ¹ J _CF = 262.1 Hz, ¹ J _CP = 215.7 H), 73.9 (d, ² J _CP = 6.9 Hz), 30.5, 28.9 (td, ² J _CF = 20.3 Hz, ² J _CP = 15.9 Hz), 24.3 (d, ³ J _CP = 3.5 Hz), 23.8 (d, ³ J _CP = 4.4 Hz), 23.3, 13.1, 8.8. ¹⁹F NMR (376 MHz, CDCl₃): δ = –111.86 (dt, ² J _FP = 107.6 Hz, ³ J _FH = 20.5 Hz, 2 F). ³¹P NMR (161 MHz, CDCl₃): δ = 4.9 (t, ² J _PF = 107.6 Hz, 1 P). ESI-HRMS: m/z [M + Na]⁺ calcd for C₁₅H₂₇O₄PF₂Na; 363.1513; found: 363.1502. (E)-Ethyl 2,2-Difluoro-5-oxo-4-benzylidene-heptanoate (8b) General procedure was followed with ethyl iododifluoroacetate (1b, 100.0 mg, 0.40 mmol), 2-[hydroxy(phenyl)methyl]pent-1-en-3-one (5, 92.0 mg, 0.48 mmol), Et₃B (0.48 mL, 1 M in hexane, 0.48 mmol) in CH₂Cl₂ (3 mL). Purification by flash chromatography of the crude mixture (EtOAc/pentane, 1:9) afforded compound 8b (60 mg, 51%, colorless oil). ¹H NMR (400 MHz CDCl₃): δ = 7.56 (s, 1 H), 7.25 (m, 5 H), 4.08 (q, ³ J _HH= 7.2 Hz, 2 H), 3,21 (t, ³ J _HF= 15.6 Hz, 2 H), 2.66 (q, ³ J _HH= 7.2 Hz, 2 H), 1.16 (t, ³ J _HH= 7.2 Hz, 3 H), 0.98 (t, ³ J _HH= 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 202.1, 163.9 (t, ² J _CF= 32.5 Hz), 143.4, 134.5, 132.7 (t, ³ J _CF= 4.3 Hz), 129.2, 129.1, 128.8, 114.8 (t, ¹ J _CF= 253.8 Hz), 62.9, 32.1 (t, ² J _CF= 25.3 Hz), 30.7, 13.9, 8.6. ¹⁸F NMR (470 MHz, CDCl₃): δ = –102,12 (t, ³ J _HF= 15.6 Hz). ESI-HRMS: m/z [M + H]⁺ calcd for C₁₆H₁₉O₃F₂: 297.1302; found: 297.1305. Diisopropyl 1,1-Difluoro-3-hydroxybutyl-4-oxo-hexyl Phosphonate (14) Procedure A A solution of Bu₃SnH (0.235 mL, 0.877 mmol) in hexane (2 mL) was added dropwise over 18 h with a syringe pump to an irradiated solution, at 254 nm with 15 W lamp, of iodophosphonate 1a (300 mg, 0.877 mmol) and 5-hydroxy-4-methylideneoctan-3-one (4, 274 mg, 1.75 mmol) in hexane. The resulting mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc/pentane, 3:2) to afford compound 14 (246 mg, 75%, colorless oil). Procedure B A solution of 5-hydroxy-4-methylideneoctan-3-one (4, 55 mg, 0.35 mmol), iodophosphonate 1a (100 mg, 0.292 mmol), eosin Y (7.5 mg, 0.0117 mmol), and Et₃N (0.079 mL, 0.584 mmol) in dry CH₃CN under stirring was irradiated with a green led light (534 nm) over 18 h. The red resulting mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc/pentane, 3:2) to afford compound 14 (63 mg, 58%, colorless oil). ¹H NMR (500 MHz, CDCl₃): δ = 4.77 (m, 2 H), 3.67–3.59 (d, J _HF = 21.6 Hz, 1 H), 3.12–3.01 (d, J _HF = 33.2 Hz, 1 H), 2.65–2.44 (m, 4 H), 2.37–2.22 (m, 2 H), 1.45 (m, 2 H), 1.34 (m, 12 H), 1.01 (q, ³ J _HH= 5.6 Hz, 4 H), 0.85 (q, ³ J _HH= 5.2 Hz, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 214.8, 213.8, 120.4 (dt, ¹ J _CP= 216.5 Hz, ¹ J _CF= 258.4 Hz, dia 1),120.2 (dt, ¹ J _CP= 217.9 Hz, ¹ J _CF= 260 Hz, dia 2), 73.8 , 73.2, 70.9, 48.6 (t, ³ J _CF= 3.6 Hz), 48.3 (t, ³ J _CF= 2.5 Hz), 38.4, 37.5, 36.9, 36.4, 33.7 (td, ² J _CF = 20.4 Hz ,² J _CP = 15.1 Hz, dia 1), 31.1 (td, ² J _CF= 20.2 Hz, ² J _CP= 15.3 Hz, dia 2), 24.1 (d, ³ J _CP = 3.2 Hz, dia 1), 24.0 (d, ³ J _CP = 3.5 Hz, dia 1), 23.7 (d, ³ J _CP = 4.7 Hz, dia 2), 23.6 (d, ³ J _CP = 4.9 Hz, dia 2) 19.1, 19.0, 13.8, 7.4, 7.2. ¹⁸F NMR (470 MHz, CDCl₃): δ = –108.8 (dddd, ¹ J _FF = 293.8 Hz, ² J _PF = 109.6 Hz, ³ J _FH = 30.6 Hz,³ J _FH = 8.3 Hz, 1 F dia 1), –108.9 (dddd, ¹ J _FF = 293.6 Hz, ² J _PF = 109.6 Hz, ³ J _FH = 31.2 Hz, ³ J _FH = 8.9 Hz, 1 F dia 2), –112,6 (dddd, ¹ J _FF = 293.7 Hz, ² J _PF = 109.6 Hz, ³ J _FH = 30.4 Hz,³ J _FH = 13.4 Hz, 1 F dia 1), –113,0 (dddd, ¹ J _FF = 293.8 Hz, ² J _PF = 109.6 Hz, ³ J _FH = 30.6 Hz,³ J _FH = 12.5 Hz, 1 F dia 2). ³¹P NMR (202 MHz, CDCl₃): δ = 4.60 (t, ² J _PF = 109.6 Hz). ESI-HRMS: m/z [M + H]⁺ calcd for C₁₆H₃₂O₅F₂P: 373.1955; found: 373.1955.