2.2. General procedure for the synthesis of α-aminophosphonates 4a-4i.
The diphenylphosphinic acid (10 mol%) was added to the reaction mixture of aromatic aldehyde (122.12 mg, 1 mmol), aniline (93 mg, 1 mmol) and diethylphosphite (165 mg, 1.2 mmol) in ethanol (10 mL). The reaction was stirred at 40°C for 30 min. The progress of the reaction was monitored by TLC. The solvent was removed and the resulting residue was treated with HCl (1N) then washed with water (10 mL) and extracted with dichloromethane (10 mL×2). The organic phases were combined and evaporated in vacuum. The crude product was purified by crystallization in hexane. Complete experimental data have been provided (NMR spectra and HRMS).
2.2.1. Diethyl [Phenyl(phenylamino)methyl] phosphonate (4a)
Yield: 92%, as a white crystalline solid; mp 88°C. 1H NMR (250 MHz, CDCl3, 25°C) δ 7.52–7.29 (m, 6H, ArH), 7.16–7.10 (t, 1H, J = 7.9 Hz, ArH), 6.75–6.69 (t, 1H,, J = 7.3 Hz, ArH), 6.64–6.61 (m, 2H, ArH), 4.84–4.75 (d, 1H, JHP= 24.3 Hz, CHP), 4.18–4.10 (2H, m, -OCH2- CH3), 4.01–3.76 (2H, m, -OCH2- CH3), 3.74–3.63 (1H, m, -OCH2 CH3), 1.31 (t, 3H, J = 7.1 Hz, -OCH2-CH3), 1.14 (t, 3H, J = 7.1 Hz, -OCH2-CH3). 13C NMR (63 MHz, CDCl3, 25°C) δ 146.33 (d, J = 14.5 Hz); 136.00, 129.29, 128.74, 128.71, 128.00, 127.03, 118.40, 113.87, 63.27 (d, J2CP = 6.9 Hz), 57.29, 54.90, 16.46, (d, J3CP = 15.1), 16.37 (d, J3CP = 5.6 Hz). 31P NMR (101 MHz, CDCl3, 25°C) δ 22.46 ppm. HRMS (ESI) m/z calcd for C17H23NO3P [M + H+]: 320.1408; Found 320.1410.
2.2.2. Diethyl (3-methoxyphenyl) (phenylaminomethyl) phosphonate (4b)
Yield: 98%, as a white crystalline solid; mp103°C.1H NMR (300 MHz, CDCl3, 25°C) δ 7.36–7.30 (m, 2H, HAr), 7.07–7.13 (m, 2H, HAr), 6.85 (d, J = 7.3 Hz, 2H, H Ar), 6.66 (t,
J = 16.0 Hz, 1H, HAr), 6.58 (d, 2H, J = 8.5Hz, HAr), 4.72 (d, J = 24.4 Hz, 1H, CHP), 4.15 (m, 2H, OCH2-CH3), 3.91 (m, 1H, -OCH2-CH3), 3.77 (s, 3H, -OCH3), 3.65–3.74 (m,
1H, -OCH2-CH3), 1.28 (t, 3H, J = 7.0 Hz, -OCH2-CH3), 1.14 (t, 3H, J = 7.0 Hz, -OCH2-CH3). 13C NMR (75 MHz,CDCl3, 25°C) δ 159.40, 143.54 (d, J = 15.4 Hz), 129.24, 129.08, 129.01, 127.77, 127.73, 118.43, 114.16, 114.13,63.39 (dd, J2CP = 6.9, 3.9 Hz), 56.45, 55.33, 54.43, 16.60 (d, J3C P = 14.9Hz), 16.52 (d,J3CP = 5.9 Hz).31P NMR (121 MHz, CDCl3, 25°C) δ 23.47 ppm.
2.2.3. Diethyl [4-nitrophenyl(phenylamino)methyl]phosphonate (4c)
Yield: 90%, as a yellow crystalline solid; mp 89.2°C. 1H NMR (400 MHz, CDCl3, 25°C) δ 8.22–8.19 (d, 2H, ArH), 7.68–7.64 (dd, 2H, JHP = 8.9, 2.3 Hz, ArH), 7.19–6.95 (m, 2H, ArH), 6.76–6.71 (t, 1H, J = 7.4 Hz, ArH), 6.56–6.52 (m, 2H, ArH), 4.88–4.81 (d, 1H, J HP = 25.6 Hz, CHP), 4.25–4.11 (m, 2H, OCH2-CH3), 3.99–4.02 (m, 1H, -OCH2-CH3), 3. 97 − 3. 78 (m, 1H, -OCH2-CH3), 1.32 (t, 3H, J = 7.1 Hz, -OCH2-CH3), 1.21 (t, 3H, J = 7.1Hz, -OCH2-CH3). 13C NMR (101 MHz, Chloroform-d) δ 147.59, 145.71 (d, J = 16.6 Hz), 143.92 (d, J = 2.5 Hz), 129.35, 128.64 (d, J = 4.7 Hz), 123.75, 119.12, 113.81, 63.63 (dd, J2 = 27.4, 6.8 Hz), 56.78, 55.31, 16.34 (dd, J3cp = 17.2, 5.5 Hz). 31P NMR (162 MHz, Chloroform-d) δ 20.80. HRMS (ESI) m/z calcd for C17H21N2O5P [M + H+]: 387.1094; Found 387.1080.
2.2.4. Diethyl[1-naphtyl(p-tolylamino)methyl]phosphonate (4d)
Yield: 90%, as a white crystalline solid; mp 145°C. 1H NMR (300 MHz, CDCl3, 25°C): δ 8.27 (d, 1H, JHP = 8.5 Hz, ArH), 7.91 (d, 1H, J = 7.9 Hz ArH), 7.80–7.77 (m, 2H, ArH), 7. 63 − 7. 48 (m, 2H, ArH), 7.45 (t, 1H, J = 7.7 Hz, ArH), 6.67 (d, 2H, J = 8.48 Hz, ArH), 6.48 (d, 2H, J = 8.4 Hz, ArH), 4.64 (d, 1H, JHP = 24.0 Hz, HCP), 4.23–4.15 (m, 2H, –OCH2–CH3), 3.77–3.73 (m, 1H, –OCH2–CH3), 3. 28-3.17 (m, 1H, –OCH2– CH3), 2.16 (s, 3H, CH3-Ph), 1.34 (t, 3H, J = 7.1 Hz, –OCH2–CH3), 0.75 (t, 3H, J = 7.1 Hz, –OCH2–CH3). 13C NMR (75 MHz, CDCl3) δ 143.83 (d, J = 24.8 Hz), 133.81, 131.6 (d, J = 19.7 Hz), 129.70, 129.00, 128.40, 127.50, 126.22, 125.64, 125.35 (d, J = 6.0 Hz), 123.00, 113.67, 63.63 (dd, J2CP = 27.4, 6.8 Hz), 20.33, 16.49 (dd, J3cp = 5.9, 5.9 Hz). 31P NMR (121 MHz, CDCl3, 25°C): δ 23.07 ppm. HRMS (ESI) m/z calcd for C22H26NO3P [M + H+]: 406.1532; Found 406.1542.
2.2.5. Diethyl [benzo [1, 3]dioxol-5-yl( (p-tolylamino) methyl]phosphonate (4e)
Yield: 91%, as a white crystalline solid; mp 115°C. 1H NMR (300 MHz, Chloroform-d): δ 7.51–7.33 (m, 1H, ArH), 7.00–6.89 (m, 4H, ArH), 6.78 (d, J = 8.0 Hz, 1H, ArH), 6.53 (d, J = 8.5 Hz, 2H, ArH), 5.97–5.91 (m, 2H,O-CH2-O), 4.66 (d, J HP = 24.0 Hz, 1H, HCP), 4.22–4.07 (m, 4H,-OCH2-CH3), 4.06–3.93 (m, 1H, -OCH2-CH3), 3.87–3.72 (m, 1H, -OCH2-CH3), 2.21 (s, 3H, CH3), 1.31 (t, J = 7.1 Hz, 3H, –OCH2–CH3), 1.19 (t, J = 7.1 Hz, 3H, –OCH2-CH3). 13C NMR (75 MHz, Chloroform-d) δ 147.64 (d, J = 49.1 Hz), 143.78, 129.74 (d, J = 11.6 Hz), 121.35 (d, J = 6.5 Hz), 113.99, 108.21 (d, J = 13.9 Hz), 101.10, 63.84–62.26 (m), 57.01, 54.99, 20.36, 16.37 (dd, J3cp = 12.4, 5.7 Hz). HRMS (ESI) m/z calcd for C19H24NNaO5P [M + Na+]: 400.128430; Found 400.1273. 31P NMR (121 MHz, Chloroform-d) δ 22.72.
2.2.6. Diethyl [(4-fluorophenyl)(4-tolylamino)methyl] phosphonate (4f)
Yield: 88%, as a white crystalline solid; mp 119°C. 1H NMR (300 MHz, Chloroform-d): δ 7.43 (dd, J = 12.0, 4.0 Hz, 2H, H Ar), 7.26 (m, 2H, HAr), 6.93 (d, 2H, J = 8.2 Hz, HAr), 6.48 (d, 2H, J = 8.5 Hz, HAr), 4.64–4.78 (m, 2H, CH + NH), 4.10–4.17 (m, 2H, -OCH2-CH3), 3.97–4.05 (m, 1H, -OCH2-CH3), 3.79–3.85 (m, 1H, -OCH2-CH3), 2.21 (s, 3H,
CH3–Ph), 1.31 (t, 3H, J = 7.1 Hz, -OCH2-CH3), 1.18 (t, 3H,
J = 7.1 Hz, -OCH2-CH3). 13C NMR: (75 MHz, CDCl3, 25°C): δ 143.85 (d, J = 15.0 Hz), 134.84, 133.80, 133.76, 133.71, 129.83, 129.28,128.21,127.89,127.86, 128.03, 114.06, 63.59 (dd, J2cp = 12.1,7.0 Hz),56.89,54.89,20.47,16.59(d, J3cp = 13.7 Hz), 16.52 (d, J3cp = 5.8 Hz). 31P NMR (121 MHz, Chloroform-d) δ 22.69. HRMS (ESI) m/z calcd for C18H23FNNaO3P [M+ Na+]: 374.1291; Found 374.1275. 31P NMR (121 MHz, Chloroform-d) δ 22.72.
2.2.7. Diethyl [(phenyl)(4-trifluoromethylamino)methyl] phosphonate (4g)
Yield: 88%, as white crystalline solid. mp 140°C. 1H NMR (300 MHz, CDCl3, 25°C): d = 1.12 (t, 3H, J = 7.0 Hz, –OCH2–CH3), 1.31 (t, 3H, J = 7.1 Hz, –OCH2–CH3), 3.61–3.70
(m, 1H, –OCH2–CH3), 3.90–4.08 (dd, J = 10.1,7.1Hz, 1H, -OCH2-CH3), 4.10–4.20 (m, 2H, –OCH2–CH3), 4.79 (dd, 1H, J = 24.2, 7.5 Hz, Ph–CH), 5.16–5.31 (m, 1H, NH), 6.62 (d, 2H, J = 8.5 Hz, HAr), 7.26–7.40 (m,5H,HAr),7.49 (dd, J = 7.7, 2.1 Hz, 2H, HAr). 13CNMR (75MHz, CDCl3, 25°C): δ 148.90 (d, J = 14.4 Hz), 135.13 (d, J = 3.0 Hz), 128.91, 128.87, 128.38, 128.34, 127.90, 127.83, 126.68, 126.63, 113.16, 63.75 (dd, J2cp = 22.9, 7.0 Hz), 56.77, 54.77, 16.59 (d, J3cp = 19.0 Hz), 16.51 (d, J3cp = 5.8 Hz). 31P NMR: (121 MHz, CDCl3, 25°C): δ 22.54 ppm.
2.2.8. Diethyl [3-phenoxyl(phenylamino)trifluoromethyl] phosphonate (4h)
Yield: 78%, as white crystalline solid. mp 155°C. 1H NMR (360 MHz, Chloroform-d) δ 7.43–7.25 (m, 5H, ArH), 7.20 (d, J = 7.5 Hz, 1H, ArH), 7.13–7.05 (m, 3H, ArH), 6.93 (d, J = 7.6 Hz, 2H, ArH), 6.59 (d, J = 8.6 Hz, 2H, ArH), 4.74 (d, J = 24.4 Hz, 1H, HC*), 4.20–4.06 (m, 2H), 4.05–3.93 (m, 1H, –OCH2–CH3), 3.84– 3.69 (m, 1H, –OCH2–CH3), 1.29 (t, J = 7.1 Hz, 3H, –OCH2–CH3), 1.16 (t, J = 7.1 Hz, 3H, –OCH2–CH3). 13C NMR (91 MHz, Chloroform-d) δ 157.59, 156.82, 148.74 (d, J = 14.3 Hz), 137.26, 129.92 (d, J = 30.6 Hz), 126.55, 123.45, 122.52 (d, J = 5.1 Hz), 120.35, 119.99, 118.83, 118.44, 118.14 (d, J = 5.3 Hz), 113.16, 63.49 (dd, J = 16.8, 6.9 Hz), 56.31, 54.64, 16.42 (d, J3 = 5.8 Hz), 16.24 (d, J3cp = 5.7 Hz). 31P NMR (162 MHz, Chloroform-d) δ 21.54. HRMS (ESI) m/z calcd for C24H25F3NNaO4P [M + Na+]: 502.1365; Found 400.1343.
2.2.9. Diethyl [benzo [1, 3]dioxol-5-yl( (phenylamino)trifluoro-methyl] phosphonate (4i)
Yield: 87%, as white crystalline solid. mp 148.2°C. 1H NMR (400 MHz, Chloroform-d) δ 7.36 (d, J = 8.5 Hz, 2H), 6.97 (s, 1H), 6.95–6.90 (m, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 8.5 Hz, 2H), 5.96 (d, J = 5.0 Hz, 1H), 5.18 (t, J = 8.4 Hz, 1H), 4.69 (dd, J = 23.9, 6.6 Hz, 1H), 4.15 (dq, J = 14.3, 7.1 Hz, 2H), 4.07–3.94 (m, 1H), 3.84–3.71 (m, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 148.88 (d, J = 34.5 Hz), 126.50, 121.32 (d, J = 6.2 Hz), 120.14 (d, J = 34.6 Hz), 113.08, 108.42, 107.98 (d, J = 4.2 Hz), 101.25, 63.56 (d, J = 7.0 Hz), 63.28 (d, J = 7.0 Hz), 56.14, 54.62, 16.43 (d, J3cp = 5.6 Hz), 16.27 (d, J = 5.5 Hz). 31P NMR (162 MHz, Chloroform-d) δ 21.87. HRMS (ESI) m/z calcd for C19H21F3NNaO5P [M + Na+]: 454.1001; Found 454.0991.