A Practical Radical Based Access to Functionalised Geminal Bisphosphonates

Abstract

Xanthate derivatives of tetraalkylmethylenebisphos­phonate add efficiently to various functionalised olefins to give the corresponding adducts via a radical chain reaction initiated by a small amount of lauroyl peroxide.

Key words

bisphosphonates - xanthates - radical reactions

References

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10

Procedure for the Synthesis of Xanthate 1a: To a solution of tetramethylmethylenebis-phosphonate (1.16 g, 5 mmol) in anhyd THF (50 mL) at r.t. under argon was added portionwise 60% NaH in mineral oil (0.4 g, 10 mmol). When the evolution of hydrogen ceased, the reaction mixture was cooled down to -78 °C and a solution of bis-ethoxythio-carbonyldisulfane (1.27 g, 5.25 mmol) in anhyd THF (10 mL) was added. The reaction mixture was then slowly warmed to r.t. A 1 M HCl solution was added (50 mL) and the mixture was extracted with diethyl ether (2 × 50 mL). The combined organic extracts were washed with sat. aq NaCl, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, dichloro-methane/methanol, 97:3) to give 1a (1.28 g, 73%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.45 (t, J = 7.0 Hz, 3 H), 3.84-3.87 (m, 12 H), 4.70 (q, J = 7.0 Hz, 2 H), 4.91 (t, J = 21.7 Hz, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 13.8, 41.5 (t, J _CP = 137 Hz), 54.4 (d, J _CP = 9 Hz), 72.3, 211.9. IR (CCl₄): 2955, 1459, 1264, 1239, 1184, 1112, 1042 cm^-1. MS (CI + NH₃): m/z = 353 (MH⁺), 370 (MNH₄ ⁺).

11

Typical Procedure: 352 mg (1 mmol) of xanthate 1a and 0.33 mL (2 mmol) of allyl acetate dissolved in 1,2-dichloroethane (1 mL) were refluxed a few minutes under argon before the addition of (20 mg, 0.05 mmol) of commercially available lauroyl peroxide. The reflux was maintained for another 2 h. The solvent was then removed under reduced pressure and the residue purified by flash column chromatography (silica gel, dichloromethane/methanol, 97:3) to give 2b (370 mg, 82%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.41 (t, J = 7.0 Hz, 3 H), 2.05 (s, 3 H), 2.02-2.22 (m, 1 H), 2.28-2.41 (m, 1 H), 2.66 (tdd, J = 25.0, 8.8, 3.5 Hz, 1 H), 3.78-3.82 (m, 12 H), 4.19 (dd, J = 11.1, 5.3 Hz, 1 H), 4.24-4.30 (m, 1 H), 4.34 (dd, J = 11.1, 4.1 Hz, 1 H), 4.62 (q, J = 7.0 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.8, 20.8, 26.3 (t, J _CP = 4 Hz), 33.4 (t, J _CP = 134 Hz), 48.5, 53.5 (d, J _CP = 9 Hz), 65.6, 70.5, 170.6, 212.0. IR (CCl₄): 2954, 1748, 1257, 1227, 1036 cm^-1. MS (CI + NH₃): m/z = 453 (MH⁺). Anal. Calcd for C₁₃H₂₆O₉P₂S₂: C, 34.51; H, 5.79. Found: C, 34.61; H, 5.88.