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Typical Procedure for the Synthesis of α-Ketophosphonate Dimethyl Esters 2.
The adequate acid chloride 1 (50 mmol) was added dropwise at -10 °C under argon to trimethylphosphite (5.9 mL, 50 mmol). The reaction mixture was then stirred at r.t. for 2 h (the end of the reaction was ascertained by 31P {1H} NMR or IR spectroscopy). The crude product was purified as indicated in Table
[1]
to furnish the corresponding α-keto-phosphonate dimethyl ester 2.
Compound 2a: 1H NMR (200 MHz, CDCl3): δ = 2.45 (d, 3 H, 3
J
P-H = 5.0 Hz, CH
3C=O), 3.83 (d, 6 H, 3
J
P-H = 10.6 Hz, OCH
3). 31P NMR {1H} (80.9 MHz, CDCl3): δ = -0.6 (s). 13C NMR {1H} (50.3 MHz, CDCl3): δ = 29.9 (CH3C=O), 52.6 (OCH3), 202.1 (C=O). IR (H2O): 1040, 1060 (P-O), 1270 (P=O), 1703 (C=O) cm-1. Anal. Calcd for C4H9O4P: C, 31.59; H, 5.96; P, 20.37. Found: C, 31.70; H, 5.92; P, 20.33.
Compound 2d: 1H NMR (200 MHz, CDCl3): δ = 3.58 (d, 6 H, 3
J
P-H = 10.8 Hz, OCH
3), 7.17 (dd, 2 H, 3
J
H-H = 7.4 Hz and 3
J
H-H = 7.4 Hz, H m-C6H5), 7.33 (d, 1 H, 3
J
H-H = 7.4 Hz, H p-C6H5), 7.92 (d, 2 H, 3
J
H-H = 7.4 Hz, H o-C6H5). 31P NMR {1H} (80.9 MHz, CDCl3): δ = -0.9 (s). 13C NMR {1H} (50.3 MHz, CDCl3): δ = 53.0 (OCH3), 127.8 (p-C
6H5), 128.3 (o-C
6H5), 129.0 (m-C
6H5), 133.7 (C
6H5-C=O), 202.1 (C=O). IR (H2O): 1040, 1067 (P-O), 1270 (P=O), 1667 (C=O) cm-1. Anal. Calcd for C9H11O4P: C, 50.48; H, 5.18; P, 14.46. Found: C, 50.39; H, 5.20; P, 14.51.
24
Typical Procedure for the Synthesis of 1-Hydroxy-methylene-1,1-bisphosphonate Monomethyl Esters 4.Method A: To α-ketophosphonate dimethyl ester 2 (5 mmol) in 4 mL of distilled THF or CH2Cl2 at 0 °C under argon was added dropwise trimethylsilyl bromide (1.65 mL, 12.5 mmol). The reaction was exothermic and the temperature had to be maintained below 10 °C during the addition. The reaction mixture was stirred at r.t. for 5-6 h (the end of the reaction was controlled by 31P {1H} NMR) and evaporation of volatile fractions (0.01 Torr) at 50 °C gave bis(silylated) α-ketophosphonate 3. Methyl bis(trimethylsilyl) phosphite (1.2 g, 5 mmol) was then added dropwise to 3 at 0 °C under argon. The reaction mixture was stirred overnight at r.t. and methanolysis for 2 h led to 1-hydroxymethylene-1,1-bisphosphonate monomethyl esters 4. After reduced pressure evaporation of volatile fractions, the crude compound 4 was purified as indicated in Table
[2]
.
Method B [(preparation of 1-hydroxymethylene-1,1-bisphosphonate monomethyl ester (4g)]: To phenyl acetyl chloride 1g (0.66 mL, 5 mmol) in 25 mL of distilled CH2Cl2 at -70 °C under argon was added dropwise tris(trimethylsilyl) phosphite (1.76 mL, 5 mmol). The reaction mixture was stirred at -70 °C for 30 min and methyl bis(trimethylsilyl) phosphite (1.2 g, 5 mmol) was then added dropwise at the same temperature. After stirring at -70 °C for 45 min, methanolysis for 2 h led to 1-hydroxymethylene-1,1-bisphosphonate monomethyl ester (4g). After vacuum evaporation of volatile fractions, the crude compound 4g was purified by reverse phase column chromatography using C-18 resin (Polygoprep 60-130, Macherey-Nagel) and obtained with 47% yield.
Compound 4a: 1H NMR (200 MHz, D2O): δ = 1.44 (dd, 3 H, 3
J
P-H = 16.0 Hz and 3
J
P-H = 16.0 Hz, CH
3C-OH), 3.58 (d, 3 H, 3
J
P-H = 9.8 Hz, OCH
3). 31P NMR {1H} (80.9 MHz, D2O): δ = 20.6 [d, 1 P, 2
J
P-P = 36.2 Hz, P(O)(OH)(OMe)], 21.8 [d, 1 P, 2
J
P-P = 36.2 Hz, P(O)(OH)2]. 13C NMR {1H} (50.3 MHz, D2O): δ = 21.5 (CH3C-OH), 55.8 (OCH3), 72.6 (dd, 1
J
C-P = 152.4 Hz and 1
J
C-P = 152.4 Hz, COH). IR (H2O): 1008, 1053, 1125 (P-O), 945, 1049 (P-O-CH3), 1190 (P=O) cm-1. Anal. Calcd for C3H10O7P2: C, 16.37; H, 4.58; P, 28.15. Found: C, 16.47; H, 4.53; P, 28.19.
Compound 4d: 1H NMR (200 MHz, D2O): δ = 3.53 (d, 3 H, 3
J
P-H = 4.0 Hz, OCH
3), 7.33 (d, 1 H, 3
J
H-H = 7.6 Hz, H p-C6H5), 7.38 (dd, 2 H, 3
J
H-H = 7.6 Hz and 3
J
H-H = 7.6 Hz, H m-C6H5), 7.71 (d, 2 H, 3
J
H-H = 7.6 Hz, H o-C6H5). 31P NMR {1H} (80.9 MHz, D2O): δ = 17.0 [d, 1 P, 2
J
P-P = 26.6 Hz, P(O)(OH)(OMe)], 17.9 [d, 1 P, 2
J
P-P = 26.6 Hz, P(O)(OH)2]. 13C NMR {1H} (50.3 MHz, D2O): δ = 56.8 (OCH3), 79.6 (dd, 1
J
C-P = 144.6 Hz and 1
J
C-P = 144.6 Hz, COH), 129.2 (o-C
6H5), 131.0 (p-C
6H5), 131.4 (m-C
6H5), 139.3 (C
6H5-C=O). IR (H2O): 1035, 1077, 1094 (P-O), 960, 1054 (P-O-CH3), 1200 (P=O) cm-1. Anal. Calcd for C8H12O7P2: C, 34.06; H, 4.29; P, 21.96. Found: C, 34.21; H, 4.32; P, 21.91.
