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Synlett 2003(6): 0785-0790
DOI: 10.1055/s-2003-38729
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Wafaa M. Abdou*, Neven A. F. Ganoub, Yehia O. El-Khoshnieh
Department of Pesticide Chemistry, National Research Centre, D 12622-Dokki, Cairo, Egypt
Fax: +20(2)7601877; e-Mail: wabdou@intouch.com;
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Publication History

Received 29 February 2003
Publication Date:
17 April 2003 (online)

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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.

Key words

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

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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+].