Acid-Promoted Phosphonyl Migration in N-Phosphonyl-α-Aminoalcohols. from N-(2-Hydroxyethyl)Phosphonamides to O-(2-Aminoethyl)Phosphonates

References

• This research has been partially funded by CDTI, Centro para el Desarrollo Tecnológico e Industrial, Spain
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• Compound 1 has been prepared as follows: 118 mg (1.93 mmols) of 2-aminoethanol, 117 mg (0.96 mmols) of DMAP and 195 mg (1.93 mmols) of TEA were dissolved in 10 mL of DMF in inert atmosphere. 400 mg (0.96 mmols) of O-methyl n-hexadecylphosphonyl chloride dissolved in 10 mL of dried CH2Cl2 were added dropwise. The mixture was kept stirring at room temperature during 30 minutes. The solvent was evaporated in vucuo giving 568 mg of crude product that was purified by column chromatography, using Florisil as stationary phase and CH2Cl2/CH3OH (95:5) as eluent. 72 mg (16% yield) of pure 1 were obtained. 1H NMR δ (ppm) 3.62 (m, 1H, NCH2CH2O), 3.62 (d J = 6, 3H, CH 3OP), 3.31 (m, 1H, NCH2CH2O), 3.01 (m, 2H, NCH2CH2O), 1.79 (m, 2H, alkylCH2CH2P), 1.65 (m, 2H, alkylCH2CH2P), 1.10–1.35 (m, 26H, alkyl chain), 0.85 (dd J = 3 and 3, 3H, CH 3alkyl), 13C NMR δ (ppm) 63.28 (dt, NCH2C H2O), 50.52 (dq, C H3OP), 43.88 (dt, NC H2CH2O), 32.13 (t), 31.09 (t), 30.86 (t), 29.40–29.90 (t), 26.54 (dt, alkylC H2P), 22.86 (t), 22.40 (dt, alkylC H2CH2P), 14.26 (q, alkylC H3)
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• Compound 2 has been prepared as indicated for phosphonamide 1, starting with 1.04 g (11.67 mmols) of 2-aminobutanol and 1.0 g (7.78 mmols) of O-methyl methylphosphonyl chloride. After Silica-gel purification, 314 mg (20.1% yield) of pure 2 were obtained. 1H NMR δ (ppm) 3.50 (d J = 6, 3H, CH 3OP), 3.35–3.50 (m, 3H, OH and NHCHCH OH), 2.85 (m, 1H, NHCH CH2OH), 1.25–1.50 (m, 2H, CH3CH 2), 1.40 (d J = 9, 3H, CH 3P), 0.80 (dd J = 3 and 3, 3H, CH3CH2). 13C NMR δ (ppm) 65.85 (dt, NCHC H2O), 55.09 (dd, NHC HCH2O), 50.67 (dq, C H3OP), 26.45 (dt, C H2CH3), 13.24 (dq, C H3P), 10.74 (q, CH2C H3)
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• Compound 3 has been prepared as indicated for phosphonamide 1, starting with 0.95 g (15.6 mmols) of 2-aminoetanol and 1.0 g (7.78 mmols) of O-methyl methylphosphonyl ∗∗∗. After Florisil purification, 117 mg (10.1% yield) of pure 3 were obtained. 1H NMR δ (ppm) 3.60 (d J = 6, 3H, CH OP), 3.60 (m, 2H, NHCH2CH 2OH), 2.95 (m, 2H, NHCH 2CH2OH), 2.40–2.60 (bs, 1H, NH), 1.42 (d J = 9, 3H, CH 3P). 13C NMR δ (ppm) 63.15 (t, NC H2CH2O), 50.70 (dq, C H3OP), 43.60 (t, NHCH2C H2O), 12.35 (dq, C H3P)
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• Compound 7 has been prepared as indicated for phosphonamide 1, starting with 2.36 g (15.6 mmols) of 2-aminociclohexanol and 1.0 g (7.78 mmols) of O-methyl methylphosphonyl chloride. After Silica-gel purification, 1.03g (63.9% yield) of pure 7 were obtained. 1H NMR δ (ppm) 4.70 (d, 0.5H, NH), 4.55 (d, 0.5H, NH), 3.61 (dd J = 3 and 6, 1H, CH 3OH), 3.37 (d J = 6, 1.5H, CH 3OP), 3.35 (d J = 6, 1.5H, CH 3OP), 2.95 (bs, 1H, NHCH), 2.49 (d, 0.5H, OH), 2.37 (d, 0.5H, OH), 1.70 (m, 2H, HOCHCH 2), 1.40 (m, 2H, HNCHCH 2), 1.22 (d J = 9, 3H, CH 3P), 0.97 (m, 4H, Cy). 13C NMR δ (ppm) 74.56 (dd, NCHC HO), 57.63 (dd, NHC HCHO), 51.00 (ddq, C H3OP), 34.33 and 34.10 (t, HNCHC H2 and HOCHC H2), 25.15 and 24.42 (t, Cy), 13.06 (ddq, C H3P)
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• Conversion of 1 into 4 was achieved (Cf. text) by shaking a solution in 0.1N HCl during 10 minutes. Compound 4: 1H NMR δ (ppm) 4.08 (m, 2H, NCH2CH2O), 3.70 (d J = 6, 3H, CH 3OP), 1.78 (m, 2H, alkylCH2CH 2P), 1.54 (m, 2H, alkylCH 2CH2P), 1.10–1.40 (m, 28H, alkyl + NCH2CH2O), 0.85 (dd J = 3 and 3, 3H, CH 3alkyl). 13C NMR δ (ppm) 61.98 (dt, NCH2CH2O), 52.34 (dq, CH3OP), 32.14 (t), 30.93 (t), 30.71 (t), 29.40–29.90 (t), 25.37 (dt, alkylCH2P), 22.88 (t), 22.50 (dt, alkylC H2CH2P), 16.65 (dt, NC H2CH2O), 14.28 (q, alkylCH3)
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• The rearrangement of 2 into 5 was observed in a sealed NMR tube, dissolved in 0.01N acetic acid-d in chloroform-d, under inert atmosphere and during 20 hours. Compound 5: 1H NMR δ (ppm) 3.70 (d J = 6, 3H, CH 3OP), 1.30 (d J = 9, 3H, CH 3P), 0.80 (dd J = 3 and 3, 3H, CH3CH2). 13C NMR δ (ppm) 61.38 (dt, NCHCH2O), 52.90 (dq, C H3OP), 22.60 (dt, C H2CH3), 20.70 (dd, NHC HCH2O), 12.00 (dq, C H3P), 9.92 (q, CH2C H3)
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• The rearrangement of 3 into 6 was observed in a sealed NMR tube, dissolved in 0.01N acetic acid-d in chloroform-d, under inert atmosphere and during 20 hours. Compound 6: 1H NMR δ (ppm) 3.77–3.78 (m, 2H, NHCH2CH 2O), 3.70 (d J = 6, 3H, CH OP), 3.25 (m, 2H, NHCH 2CH2O), 1.52 (d J = 9, 3H, CH 3P). 13C NMR δ (ppm) 58.20 (t, NCH2C H2O), 52.38 (t, NHC H2CH2O), 42.24 (dq, C H3OP), 10.88 (dq, C H3P)
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• The rearrangement of 7 into 8 was observed in a sealed NMR tube, dissolved in 0.01N acetic acid-d in chloroform-d, under inert atmosphere and during 5 days. Compound 8: 1H NMR δ (ppm) 3.40–3.58 (m, 2H, NHCHCH O), 3.65 (d J = 6, 3H, CH 3OP), 3.00–3.25 (m, 2H, NHCHCHO), 1.30–1.60 (m, 4H, NHCHCH 2 and OCHCH 2), 1.35 (d J = 9, 3H, CH 3P), 1.10–1.30 (m, 4H, Cy). 13C NMR δ (ppm) 71.32 (t, NHCHC HO), 57.58 (dq, NHC HCHO), 52.22 (t, C H3OP), 34.50 and 34.23 (t, HNCHC H2 and HOCHC H2), 24.88 and 24.52 (t, Cy), 11.44 (dq, C H3P)
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• Hydrolysis of 2 to give acid 9 was achieved by treatment with aqueous 1.5N LiOH during 2 hours at room temperature. Compound 9: 1H NMR δ (ppm) 3.28 (dd J = 3 and 7, 1H, NHCHCH 2OH), 3.17 (dd J = 5 and 7, 1H, NHCHCH 2OH), 2.75 (m, 1H, NHCHCH2OH), 1.26 (m, 1H, CH3CH 2), 1.11 (m, 1H, CH3CH 2), 1.05 (d J = 11, 3H, CH 3P), 0.72 (dd J = 5 and 5, 3H, CH 3CH2). 13C NMR δ (ppm) 68.28 (t, NHCHC H2OH), 56.00 (d, NHC HCH2OH), 27.70 (dt, CH3C H2), 16.44 (dq, C H3P), 11.24 (q, C H3CH2)
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• Hydrolysis of 3 to give acid 10 was achieved by treatment with aqueous 1.5N LiOH during 2 hours at room temperature. Compound 10: 1H NMR δ (ppm) 3.28 (dd J = 3 and 7, 1H, NHCHCH 2OH), 3.32 (m, 2H, NHCH2CH 2OH), 2.72 (m, 1H, NHCH 2CH2OH), 2.45 (bs, 1H, NH), 1.00 (d J = 11, 3H, CH 3P). 13C NMR δ (ppm) 64.96 (t, NHCH2C H2OH), 45.15 (t, NHC H2CH2OH), 15.86 (dq, C H3P)
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• Hydrolysis of 7 to give acid 11 was achieved by treatment with aqueous 1.5N LiOH during 24 hours at room temperature. Compound 11: 1H NMR δ (ppm) 8.29 (bs, 1H, P(O)OH), 3.08 (bs, 1H, NH), 2.92 (m, 1H, NHCHCH OH), 2.45 (m, 1H, NHCH CHOH), 1.60 (m, 2H, CH 2CHOH), 1.43 (m, 2H, CH 2CHNH), 1.05 (d J = 6, 3H, CH 3P), 1.00 (bs, 4H, Cy). 13C NMR δ (ppm) 77.72 (d, NHCHC HOH), 58.33 (d, NHC HCHOH), 35.71 (t, C H2CHOH), 35.26 (t, C H2CHNH), 26.92 (t, Cy), 26.85 (t, Cy), 16.31 (dq, C H3P)
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