An efficient synthesis of cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of pipecolic acid from cyclic enaminones

First Stereoselective Synthesis of Diethyl cis- and trans-(4-Hydroxy-1,2,3,4-tetrahydroquinolin-2-yl)phosphonates and Ethyl Phenylphosphinates from Quinolin-4(1H)-one

“…1 H NMR (asterisk denotes minor rotamer detected, 600.17 MHz, CDCl3): δ = 0.97* (t, J = 7.0 Hz, 3H, CH3), 1.16 (t, J = 7.0 Hz, 3H, CH3), 3.12-3.31 (m, 4H, H-3), 3.69 (dt, J = 9.9, 6.9 Hz, 1H, H-2), 3.81-3.99 (m, 2H, CH2OP), 4.83-5.48 (m, 2H, CH2Ph), 7.08-7.92 (m, 14H, Harom). 13 C NMR (asterisk denotes minor rotamer detected, 150.91 MHz, CDCl3): δ = 15.9 (d, J = 7.8 Hz, CH3), 16.4* (d, J = 7.0 Hz, CH3), 37.1* (C-3), 37.9 (C-3), 53.4* (d, J = 110.9 Hz, C-2), 53.5 (d, J = 109.4 Hz, C-2), 61.6* (d, J = 8.0 Hz, CH2OP), 61.7 (d, J = 8.2 Hz, CH2OP), 68.6* (CH2Ph), 68.7 (CH2Ph), 123.8, 124.2, 124.6, 124.8, 125.8, 125.8, 126.9, 127.0, 127.3, 128.0, 128.1, 128.3, 128.4, 128.5, 128.6, 128.6, 128.7, 128.8, 128.9, 132.1, 132.2, 132.3, 132.9, 133.1, 134.0, 134.2, 135.1, 135.4, 140.9, 141.3, 153.4 (d, J = 30.6 General procedure for the reduction of N-Cbz diethyl (4-oxo-1,2,3,4tetrahydroquinolin-2-yl)phosphonate ( 6) and N-Cbz ethyl (4-oxo-1,2,3,4-tetrahydroquinolin-2-yl)phenylphosphinate (9) with NaBH4 (Method C) or Et3BHLi (Method D) Method C: To a stirred solution of N-Cbz diethyl (4-oxo-1,2,3,4tetrahydroquinolin-2-yl)phosphonate 6 or N-Cbz ethyl (4-oxo-1,2,3,4tetrahydroquinolin-2-yl)phenylphosphinate 9 (0.64 mmol) in a mixture of MeOH:CH2Cl2 (3:1, 6 mL) at 0 °C, was slowly added NaBH4 (72 mg, 1.92 mmol) and the reaction mixture was stirred at 0 °C for 1.0 h. The reaction mixture was then quenched by successive addition of a saturated aqueous NaHCO3 solution (5 mL), brine (5 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure.…”

“…16 (ddd,J = 7.43,7.4,7.5,1.3 Hz,1H,Harom) 7.23 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H, Harom), 7.31-7.41 (m, 5H, Harom), 7.56 (dd, J = 7.7, 1.6 Hz ppm, 7.61 (s, 1H, Harom). 13 C NMR (125.77 MHz, CDCl3): δ = 16.3 (d, J = 5.2 Hz, CH3), 16.4 (d, J = 5.5 Hz, CH3), 34.0 (d, J = 4.5 Hz, C-3), 47.2 (d, J = 158.9 Hz, C-2), 62.5 (d, J = 6.3 Hz, CH2OP), 62.6 (C-4), 63.5 (d, J = 6.7 Hz, CH2OP), 68.3 (CH2Ph),123.8,125.1,127.6,128.1,128.6,129.6,132.0,134.6,134.7,135.8,154.1 (C=O). 31 N-Cbz Ethyl cis-(4-hydroxy-1,2,3,4-tetrahydroquinolin-2-yl)phenylphosphinate (10a) (less polar) Method C: Compound 10a was obtained as a colorless oil (0.13 g, 48%).…”

“…1 H NMR (asterisk denotes minor rotamer detected, 600.17 MHz, CDCl3): δ = 1.31 (t, J = 7.0 Hz, 3H, CH3), 2.61* (dt, J = 15.1, 6.2 Hz, 1H, H-3), 2.66 (dt, J = 15.1, 6.0 Hz, 1H, H-3), 2.71 (ddd, J = 3.7, 2.4, 1.4 Hz, 1H, H-3), 2.73* (ddd, J = 3.7, 2.4, 1.4 Hz, 1H, H-3), 3.87-4.16 (m, 2H, CH2OP), 4.64-4.69 (br, 1H, H-2), 4.97 (AB system, J = 12.3, 9.5 Hz, 2H, CH2Ph), 5.20-5.35 (br, 1H, OH), 5.72-5.83 (br, 1H, H-4), 7.06-7.63 (m, 14H, Harom). 13 C NMR (150.91 MHz, CDCl3): δ = 16.6 (d, J = 5.9 Hz, CH3), 34.0 (C-3), 50.1 (d, J = 113.9 Hz, C-2), 61.7 (d, J = 6.7 Hz, CH2OP), 62.0 (C-4), 68.1, (CH2Ph), 124.1, 125.2, 127.2, 127.4, 128.0, 128.1, 128.2, 128.3, 128.4, 128.7, 130.4, 132.2, 132.3, 132.9, 134.0, 135.8, 153.6 (d N-Cbz Ethyl cis-(4-hydroxy-1,2,3,4-tetrahydroquinolin-2-yl)phenylphosphinate (10b) (more polar) Method C: Compound 10b was obtained as a colorless oil (0.14 g, 49%). Method D: (0.85 g, 30%).…”

“…1 H NMR (asterisk denotes minor rotamer detected, 600.17 MHz, CDCl3): δ = 1.12 (t, J = 7.0 Hz, 3H, CH3), 2.26* (dt, J = 6.2, 2.8 Hz, 1H, H-3), 2.28 (dt, J = 6.2, 2.8 Hz, 1H, H-3), 2.44 (ddd, J = 15.0, 7.0, 6.0 Hz, 1H, H-3), 2.50* (ddd, J = 15.0, 7.0, 6.0 Hz, 1H, H-3), 3.79-3.97 (m, 2H, CH2OP), 4.60-4.65 (br, 1H, H-2), 5.10-5.17 (br, 1H, H-4), 5.22 (AB system, J = 12.0, 11.5 Hz, 2H, CH2Ph), 5.32-5.42 (br, 1H, OH), 7.18 (t, J = 7.4, 1H, Harom), 7.24-7.29 (m, 1H, Harom), 7.34-7.42 (m, 5H, Harom), 7.47 (td, J = 7.7, 3.2 Hz, 2H, Harom), 7.56-7.62 (m, 2H, Harom), 7.74-7.83(m, 2H, Harom). 13 C NMR (asterisk denotes minor rotamer detected, 150.91 MHz, CDCl3): δ = 16.5 (d, J = 5.7 Hz, CH3), 33.0 (C-3), 33.1* (C-3), 50.7 (d, J = 105.0 Hz, C-2), 62.0 (d, J = 6.7 Hz, CH2OP), 62.8 (C-4), 68.4 (CH2Ph), 125.0, 127.7, 128.3, 128.5, 128.7, 128.9, 129.0, 129.5, 129.8, 132.2, 132.3, 133.1, 135.2, 135.9, 154.1 (C=O) ppm. 31 General procedure for the catalytic hydrogenolysis of diethyl (1,2,3,4-tetrahydroquinolin-2-yl)phosphonates or ethyl (1,2,3,4tetrahydroquinolin-2-yl)phenylphosphonates A mixture of diethyl (1,2,3,4-tetrahydroquinolin-2-yl)phosphonates or ethyl (1,2,3,4-tetrahydroquinolin-2-yl)phenylphosphonates (0.5 mmol) and 10% Pd/C (w/w) in i-PrOH (5 mL) was stirred under hydrogen atmosphere at room temperature for 4.0 h. The crude product was filtered over celite and washed with MeOH.…”

“…1 H NMR (asterisk denotes minor rotamer detected, 500.13 MHz, CDCl3): δ = 1.32 (t, J = 7.1 Hz, 3H, CH3), 1.34 (t, J = 7.1 Hz, 3H, CH3), 2.22 (dd, J = 13.7, 6.9 Hz, 1H, H-3), 2.24* (dd, J = 13.7, 6.9 Hz, 1H, H-3), 2.43 (dt, J = 13.7, 5.1 Hz, 1H, H-3), 2.48* (dt, J = 13.7, 5.1 Hz, 1H, H-3), 3.75 (ddd, J = 9.3, 7.3, 4.7 Hz, 1H, H-2), 4.11-4.23 (m, 4H, CH2OP), 4.75 (t, J = 5.9 Hz, 1H, H-4), 6.55 (d, J = 8.0 Hz, 1H, H-9), 6.74 (t, J = 7.4 Hz, 1H, H-7), 7.05 (td,J = 7.7,1.6 Hz,1H,7.37 (d,J = 7.6 Hz,1H, ppm. 13 C NMR (125.77 MHz, CDCl3): δ = 16.5 (d, J = 5.9 Hz, CH3), 16.6 (d, J = 5.9 Hz, CH3), 31.6 (C-3), 47.0 (d, J = 157.3, C-2), 62.7 (d, J = 7.4 Hz, CH2OP), 63.2 (d, J = 7.0 Hz, CH2OP), 64.6 (d,J = 11.8 Hz,114.6,118.5,123.9,128.6,128.9,142.2 (d,J = 6.7 Hz, Colorless oil (0.11 g, 70%). 1 H NMR (asterisk denotes minor rotamer detected, 600.17 MHz, CDCl3): δ = 1.35 (t, J = 7.0 Hz, 3H, CH3), 1.88* (dd, J = 13.6, 5.9 Hz, 1H, H-3), 1.90 (dd, J = 13.6, 5.9 Hz, 1H, H-3), 2.29 (dt, J = 13.9, 5.3 Hz, 1H, H-3), 2.33* (dt, J = 13.9, 5.3 Hz, 1H, H-3), 3.81 (dd, J = 5.4, This article is protected by copyright.…”