Synthesis of a New Type of 1,1-Bisphosphonates Bearing S-, and N-Heterocycles, Based on the Reactions of Methylenebisphosphonate with Alkenes

Abstract

The heterocycle-substituted 1,1-bisphosphonates 3a,b, 7, 10a,b and 12a,b were synthesized from the parent alkylidene substrates 2a,b, 6, 8a,b and 11a,b and methylenebisphosphonate 1 by a Michael addition reaction in different yields. Hydrolysis of 1,1-bisphosphonate product 3a with concentrated hydrochloric acid produced the corresponding 1,1-bisphosphonic acid 13.

heterocycle-substituted 1,1-bisphosphonates - Michael addition reaction - alkylidine heterocycles - Wittig-Horner synthons

References

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Abdou, W. M.; Khidre, M. D. Eur. J. Org. Chem. 2003, submitted for publication

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Typical Procedure: 0.3 g (10 mmol) 80% suspension of NaH in 15 mL of anhyd DMF was added slowly to a stirred solution of 1 (1.4 g, 5 mmol) in anhyd DMF at 0 °C. After the addition was completed (1 h), a solution of substituted alkene 2a,b, 6, 8a,b or 11 (2.5 mmol) in anhyd DMF (10 mL) was added and the resulting mixture was allowed to warm to r.t., and stirred for an additional 20-48 h (TLC) and then cooled again to -5 °C. HCl (1 N) was added until the pH of the reaction mixture is acidic. The mixture was extracted with CHCl₃ (3 ¥ 50 mL). The combined organic phase was dried over anhyd Na₂SO₄. After removal of the solvent, under vacuum, the resulting residue was chromatographed on silica gel (hexane/EtOAc) to give compounds 3a,b, 5a,b, 7, 8a,b, 10a,b and 12a,b. Percentage yields, physical and spectral data of the products are listed in Tables [1] and [2] .

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Typical Procedure: 0.5 g (1.0 mmol) of ethylenic 1,1-bisphosphonate(3a) was dissolved in 20 mL of concentrated HCl and the mixture was heated under reflux for 22 h. After cooling, the solvent was evaporated to dryness under reduced pressure. After addition of EtOH (10 mL), the solid was filtered, washed twice with EtOH to yield 320 mg (82%) of 2[5′(4′-oxo-4′H-2-thioxo-2′H-1′,3′-thiazole)]-2-phenylethylidene-1,1-bis-phosphonic acid(13), mp >300 °C (H₂O/acetone, 1:1, v/v). ³¹P NMR (D₂O): δ = 22.0. ¹H NMR (D₂O): δ = 2.12 (dt, J = 7 Hz, 18 Hz, 1 H, H ^aC-P₂), 3.11 [dd (ABX), J = 5 Hz, 7 Hz, 1 H, HC-Ph], 4.22 (dd, J = 6 Hz, 7 Hz, 1 H, 5-CH ^c), 7.40-7.88 (m, 5 H, H-Ph). IR: 3200-2500 (P-OH), 1688 (C=O), 1435 (C=S), 1200 (P-O) cm^-1. Anal. Calcd for C₁₁H₁₃NO₇P₂S₂ (397.29): C, 33.25; H, 3.29; N, 3.52; P, 15.59; S, 16.14. Found: C, 33.32; H, 3.24; N, 3.46; P, 15.65; S, 16.06%. MS (EI): m/z (%) = 397(55) [M⁺].

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