Horner-Wadsworth-Emmons Modification for Ramirez gem-Dibromoolefination of Aldehydes and Ketones Using P(Oi-Pr)₃

Abstract

A simple procedure for the use of triisopropylphosphite in the Ramirez olefination is described. This reagent is equally or more reactive than PPh₃ toward aldehydes and ketones in the gem-dibromoolefination of aldehydes and ketones. Under the reaction conditions, an α-bromoketone gave a novel tribromomethyl-substituted oxirane product in good yield. The substrate-dependent nature of this reaction suggests that this Horner-Wadsworth-Emmons equivalent of the Ramirez gem-dibromoolefination reaction proceeds through an ionic mechanism.

Key words

olefination - phosphite - Horner-Wadsworth-Emmons reaction - aldehydes - ketones

References and Notes

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9

General Procedure for Ramirez OlefinationTo a solution of 1a (0.151 g, 1 mmol) and CBr₄ (0.49 g, 1.5 mmol) in CH₂Cl₂ (4 mL) was added dropwise a solution of the corresponding phosphine or phosphite (3.0 mmol) in CH₂Cl₂ (1 mL) at 0 °C. After 30 min, the reaction was warmed to r.t., quenched with NaHCO₃, extracted with Et₂O, and dried over MgSO₄. The product was isolated using column chromatography, and yields are shown in Table [2] .Preparation of 2a Using CBr ₄ /P(O i -Pr) ₃ without Chromatographic PurificationTo a solution of 1a (2.0 g, 13.2 mmol) and CBr₄ (6.6 g, 19.9 mmol) in CH₂Cl₂ (50 mL) was added dropwise a solution of P(Oi-Pr)₃ (7.2 mL, 29 mmol) in CH₂Cl₂ (10 mL) at 0 °C. After 30 min, the reaction was warmed to r.t., quenched with NaHCO₃, and extracted with Et₂O. After removal of solvent, the mixture was taken into concd HCl (12 M, 15 mL) and AcOH (15 mL) and heated to reflux overnight. The mixture was cooled to r.t., diluted with H₂O (50 mL), neutralized with Na₂CO₃, and extracted with Et₂O. After drying over MgSO₄, solvent was removed under vacuum to give an off-white solid (3.51 g, 87%). The ¹H NMR spectrum of the product was identical to the authentic sample.Compound 2f: The general procedure was followed using 1f (0.135 g, 0.5 mmol), CBr₄ (0.250 g, 0.75 mmol), and P(Oi-Pr)₃ (0.37 mL, 1.5 mol). The product was obtained as a slightly yellow solid (0.207 g, 98%). R _f = 0.41 (10% EtOAc in hexane); mp 63-65 °C. IR (neat): 3079, 2921, 1624, 1528, 1347, 1254, 1099 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.28-8.36 (2 H, m), 7.47-7.49 (2 H, m), 7.28-7.38 (4 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 162.4 (J _C-F = 262 Hz), 144.4, 131.8, 129.7, 128.7, 126.8 (J _C-F = 4.6 Hz), 126.3 (J _C-F = 10.7 Hz), 123.5, 122.1, 117.6 (J _C-F = 24.5 Hz), 104.1, 98.9, 87.2. HRMS (EI): m/z calcd for C₁₆H₈Br₂FNO₂ [M]⁺: 422.8906; found: 422.8907.

10

Product 4: The general procedure for Ramirez olefination was followed using α-bromoacetophenone (1.08 g, 5.4 mmol), CBr₄ (3.54 g, 10.8 mmol), and P(Oi-Pr)₃ (5.3 mL, 21.6 mol). The product was obtained as a white crystalline solid (1.5 g, 80%). The single crystal suitable for X-ray determination was obtained by slow diffusion of hexanes in a solution of 4 in CH₂Cl₂. R _f = 0.70 (10% EtOAc in hexane); mp 98-100 °C. IR (neat): 3017, 1582, 1447 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.80-7.82 (2 H, m), 7.36-7.42 (3 H, m), 3.84 (1 H, d, J = 5.0 Hz), 3.12 (1 H, d, J = 5.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 133.3, 131.2, 129.4, 127.7, 67.8, 55.4, 45.8. HRMS (EI): m/z calcd for C₉H₇Br₃O [M]⁺: 367.8047; found: 367.8041.

11

The general procedure for Ramirez olefination was followed using phenylpropynal (0.130 g, 1 mmol), CBr₄ (0.498 g, 1.5 mmol), and P(Oi-Pr)₃ (0.74 mL, 3 mol) in CH₂Cl₂ at -20 °C. The crude material was separated by chromatography to give 6 (0.136 g, 47%) and 7 (0.232 g, 50%).Compound 6: ¹H NMR (400 MHz, CDCl₃): δ = 7.33-7.52 (5 H, m), 6.77 (1 H, s).Compound 7: R _f = 0.22 (25% EtOAc in hexane). IR (neat): 2980, 2934, 2211, 1572, 1488, 1375, 1280, 1158 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.50-7.57 (2 H, m), 7.33-7.42 (3 H, m), 4.84 (2 H, septet, J = 6.2 Hz), 1.39 (12 H, t, J = 6.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 131.8, 129.8, 128.6, 121.4, 99.7, 91.4 (d, J _C-P = 11.8 Hz), 81.3 (d, J _C-P = 2.4 Hz), 79.1 (d, J _C-P = 4.3 Hz), 74.2 (d, J _C-P = 6.3 Hz), 23.8 (d, J _C-P = 4.6 Hz), 23.7 (d, J _C-P = 5.4 Hz). ³¹P NMR (300 MHz, CDCl₃): δ = -9.44. ESI-HRMS: m/z calcd for C₁₆H₂₀O₄PBr₂ [M + H]⁺: 464.9460; found: 464.9458.