Tetrakis(trimethylsilyl) Ethenylidene-1,1-bisphosphonate: A Mild and Convenient Michael Acceptor for the Synthesis of 2-Aminoethylidene-1,1-bisphosphonic Acids and Their Potassium Salts

 

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Abstract

A straightforward synthesis of highly functionalized 2-aminoethylidene-1,1-bisphosphonic acids via the Michael addition of amines to easily available tetrakis(trimethylsilyl) ethenylidene-1,1-bisphosphonate, H₂C=C[P(O)(OTMS)₂]₂, has been described. The potassium salts of the title compounds were also easily achieved in high yield by reacting the Michael adducts with potassium fluoride.

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Tetrakis(trimethylsilyl) ethenylidenebisphosphonate (2) A hot-gun dried Schlenk-type flask stopped with rubber septum and flashed with argon was charged with tetraethyl ester 1 (5.79 g, 0.0193 mol) and dry MeCN (10 mL). Bromotrimethylsilane (12.8 g, 0.0833 mol) was added to this solution via a syringe. After a mild exothermic period the reaction mixture was allowed to stir overnight at 20 ˚C. Volatiles were removed under vacuum, and the product was distilled at 125-130 ˚C under 0.05 mm as clear viscous oil (8.27 g, 90%) which formed air-sensitive needle-like crystals when cooled below 20 ˚C. ^¹H NMR (400 MHz, C₆D₆): δ = 0.29 (s, 36 H, SiCH₃), 6.68 (dd, ^³ J _HP = 35.1 Hz, ^³ J _HP = 38.8 Hz, 2 H, CH₂=CP₂) ppm. ^¹³C{^¹H} NMR (100 MHz, C₆D₆): δ = 1.5 (s, SiCH₃), 140.3 (t, ^¹ J _CP = 173.4 Hz, CH₂=CP₂), 143.1 (s, CH₂=CP₂) ppm. ^³¹P{^¹H} NMR (162 MHz, C₆D₆): δ = -3.1 (dd, ^³ J _PH = 35.1 Hz, ^³ J _PH = 38.8 Hz) ppm. NMR spectral data were consistent with those described previously.^¹²

Calculations were performed with the Gaussian 03 programs,^¹9 using the density functional method.^²0 The hybrid exchange functional B3LYP in conjunction with the 6-31+G** basis set was used. B3LYP^²¹ is a three-parameter functional developed by Becke which combines the Becke gradient-corrected exchange functional and the Lee-Yang-Parr and Vosko-Wilk-Nusair correlation functionals with part of exact HF exchange energy. The optimized structures were confirmed as true minima on the potential energy through vibrational analysis. The frequencies were calculated with analytical second derivatives. All total energies have been zero-point energy (ZPE) and temperature corrected using unscaled density functional frequencies. Molecular orbitals have been plotted with the Molekel package.^²²

2-[4-(Ethoxycarbonyl)piperazin-1-yl]ethylidene-1,1-bisphosphonic acid (3n)
Solution of tetrasilyl ester 2 (890 mg, 1.87 mmol) and 1-carbethoxypiperazine (346 mg, 1.87 mmol) in CH₂Cl₂ was stirred at r.t. overnight. Solvent was evaporated, and the resulting oil was treated with methanol to precipitate 3n (440 mg, 68%). Colorless crystals; mp 223 ˚C. ^¹H NMR (400 MHz, D₂O): δ = 1.20 (t, ^³ J _HH = 7.3 Hz, 3H, CO₂CH₂CH ₃), 2.71 (tt, ^² J _HP = 21.5 Hz, ^³ J _HH = 8.2 Hz, 1 H, NCH₂CHP₂), 3.05-3.10 (m, 2 H, CH₂), 3.16-3.26 (m, 2 H, CH₂), 3.51 (td, ^³ J _HP = 14.2 Hz, ^³ J _HH = 8.2 Hz, 2 H, NCH ₂CHP₂), 3.60-3.68 (m, 2 H, CH₂), 4.10 (q, ^³ J _HH = 7.3 Hz, CO₂CH ₂CH₃), 4.20-4.30 (m, 2 H, CH₂) ppm. ^¹³C{^¹H} NMR (100 MHz, D₂O): δ = 13.7, 33.9 (t, ^¹ J _CP = 120.3 Hz, NCH₂ CHP₂), 41.1, 51.4, 54.3, 63.2, 156.4 (CO₂Et) ppm. ^³¹P{^¹H} NMR (162 MHz, D₂O): δ = 15.5 ppm. Anal. Calcd for C₉H₂₀N₂O₈P₂ (346.07): N, 8.09. Found: N, 8.40.

2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzeneamino]ethylidenebisphosphonic Acid Tetrapotassium Salt (4a)
Solution of tetrasilyl ester 2 (340 mg, 0.71 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzeneamine (171 mg, 0.78 mmol) in MeCN (8 mL) was stirred at 60 ˚C for 90 h and then cooled to ambient temperature. KF (174 mg, 2.99 mmol) and dibenzo-18-crown-6 (32 mg, 0.09 mmol) were added, and the mixture was stirred at 50 ˚C for another 24 h. Product was isolated via centrifugation as colourless hygroscopic air-sensitive solid in 80% yield (350 mg); mp >250 ˚C. ^¹H NMR (500 MHz, D₂O): δ = 1.22 (s, 12 H, CCH₃), 2.27 (m, 1 H, NCH₂CHP₂), 3.58 (m, 2 H, NCH ₂CHP₂), 6.87 (d, ^³ J _HH = 7.8 Hz, 0.5 H, H _Ar), 6.92 (t, ^³ J _HH = 7.8 Hz, 1.5 H, H _Ar), 7.32 (t, ^³ J _HH = 7.8 Hz, 1.5 H, H _Ar), 7.65 (d, ^³ J _HH = 7.8 Hz, 0.5 H, H _Ar) ppm. ^¹³C{^¹H} NMR (100 MHz, D₂O): δ = 23.8, 42.1, 75.7, 111.5, 119.6, 129.6 ppm. ^³¹P{^¹H} NMR (202.5 MHz, D₂O): δ = 17.0-19.0(br) ppm. Anal. Calcd for C₁₀H₁₇NO₇P₂ (325.05): P, 11.07. Found: P, 10.89.

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