5.2 General experimental procedure for the synthesis of α-aminophosphonates (4a-j)
A mixture of a 4-Amino-N-(5-methyl-4,5-dihydroisoxazol-yl) benzenesulfonamide (2 mmol), 4-methoxy benzaldehyde (2 mmol) and diethyl phosphite (2 mmol) were mixed in 50 mL conical flask and subjected to 400 W microwave irradiation. The progress of the reaction was monitored by TLC analysis by using ethyl acetate: hexane (7:3) as mobile phase. After the completion of reaction, the resulting reaction mixture was treated with dichloromethane as absorbent and filtered to separate the catalyst. After separation of the catalyst, the filtrate was washed with 20 mL of DCM and dried in the oven for reuse. The filtrate was quenched with 10 mL of water and evaporated by using rotary evaporator. The residue obtained was purified by recrystallization from ethanol to obtain the phosphate 4a. The same procedure is adopted for the synthesis of remaining compounds (4b-j).
Diethyl ((4-methoxyphenyl)((4-(N-(5-methyl-4,5-dihydroisoxazol-3-yl)sulfamoyl)phenyl) amino)methyl)phosphonate (4a)
Pale Yellow solid; Yield:93%, M.p.:138–139°C. 1H NMR (400 MHz, CDCl3, ppm): δ 7.57 (d, J = 9.2 Hz, 2H, Ar-H), 7.35 (dd, J = 9.1, 2.5 Hz, 2H, Ar-H), 6.80 (d, J = 9.1 Hz, 2H, Ar-H), 6.12 (s, 1H, NH), 6.00 (s, 1H, CH-NH), 4.74 (m, 1H, P-CH), 4.11 (2H, m, O-CH2), 3.91–3.62 (m, 2H, O-CH2), 3.77 (s, 3H, O-CH3), 2.27 (d, 5H, CH-CH3,CH2), 1.26–1.28 (m, 7H, O-CH2-CH3, CH) 13CNMR (100MHz, CDCl3, ppm): δ = 170.22, 159.58, 158.18, 150.67, 129.05, 127.19, 126.59, 114.28, 112.95, 95.58, 77.47, 77.21, 76.89, 63.91, 63.42, 53.36, 53.88, 40.06, 39.75, 25.36, 16.33, 12.69. 31P NMR (180 MHz, CDCl3, ppm): δ 22.47 ppm. HRMS (ESI) m/z calcd. for C22H30N3O7PS [M + H]+: 511.5283, found 511.5280.
Diethyl((4-ethoxyphenyl)((4-(N-(5-methyl-4,5-dihydroisoxazol-3-yl)sulfamoyl)phenyl) amino)methyl)phosphonate (4b)
Pale Yellow solid; Yield: 93%, M.p.:138–139°C. 1H NMR (400 MHz, CDCl3, ppm): δ = 9.47 (s, 1H, NH), 7.54 (d, J = 8.9 Hz, 2H, Ar-H), 7.31(dd, J = 8.2, 2.1 Hz, 2H, Ar-H), 7.13 (d, J = 8.0 Hz, 2H, Ar-H), 6.53 (d, J = 8.9 Hz, 2H, Ar-H), 6.14 (s, 1H, CH-NH), 6.04 (t, 1H, O-CH-CH3), 4.72 (m, 1H, P-CH), 4.13–3.52 (m, 4H, O-CH2), 2.62–2.29 (m, 5H, O-CH2-CH3), 1.24–1.02 (m, 11H, O-CH2-CH3, O-CH, CH3,CH-CH2).13CNMR (100MHz, CDCl3, ppm): δ = 170.43, 158.07, 150.80, 144.56, 131.89, 129.01, 128.38, 127.87, 126.92, 113.01, 95.67, 77.45, 77.14, 76.82, 64.00, 63.41, 55.87, 54.35, 28.56, 16.40, 6.18, 15.49, 12.75. 31P NMR (180 MHz, CDCl3, ppm): δ = 22.10 ppm. HRMS (ESI) m/z calcd. for C23H32N3O7PS [M + H]+: 525.5548, found 525.5544.
Diethyl(((4-(N-(5-methyl-4,5-dihydroisoxazol-3-yl)sulfamoyl)phenyl)amino)(p-tolyl)methyl)phosphonate (4c)
Pale Yellow solid; Yield: 93%, M.p.:152–154°C. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.58 (d, J = 9.2 Hz, 2H, Ar-H), 7.17 (dd, J = 9.1, 2.5 Hz, 2H, Ar-H), 6.72 (d, J = 9.1 Hz, 2H, Ar-H), 6.12 (d, J = 9.2 Hz, 2H, Ar-H), 6.07 (s, 1H, NH), 4.58 (d, J = 24.2, 8.1 Hz, 1H, P-CH), 4.04(s, 1H, CH-NH), 3.98 (m, 3H, CH3), 3.62–3.39 (m, 4H, O-CH2), 2.34 (s, 3H, CH2, CH-CH3), 1.18 (m, 9H, O-CH2-CH3, CH-CH3). 13CNMR (100MHz, CDCl3, ppm): δ = 169.43, 157.07, 152.72, 147.56, 134.82, 128.02, 128.78, 127.84, 126.62, 112.33, 94.57, 77.75, 77.34, 76.72, 64.03, 63.34, 55.82, 54.45, 28.76, 16.30, 15.32, 12.64. 31P NMR (180 MHz,CDCl3, ppm): δ = 22.53 ppm. HRMS (ESI) m/z calcd. for C22H30N3O6PS [M + H]+ :495.5289, found 495.5285.
Diethyl((2-hydroxyphenyl)((4-(N-(5-methyl-4,5-dihydroisoxazol-3-yl)sulfamoyl)phenyl) amino)methyl)phosphonate (4d)
Pale Yellow solid; Yield: 93%, M.p.:169–171°C. 1H NMR(400 MHz, CDCl3, ppm): δ = 10.67 (s, 1H, NH), 9.61 (s, 1H, CH-NH), 7.58 (m, 2H, Ar-H),7.41(m, 1H, Ar-H), 7.26 (dd, 1H, J = 7.7, 4.1 Hz, 1H, Ar-H), 7.15 (dd, J = 16.1, 9.0 Hz, 1H, Ar-H), 7.08 (dd, J = 17.3, 9.8 Hz, 1H, Ar-H), 6.91 (m, 1H, Ar-H ) 6.04 (s, 1H, OH), 5.39 (m, 1H, P-CH), 4.16 (d, 12 Hz, 2H, CH2), 3.71(s, 1H, CH), 2.38–2.28 (m, 4H, O-CH2), 1.30–1.07 (m, 9H, O-CH2-CH3, CH-CH3). 13CNMR (100MHz, CDCl3, ppm): δ = 169.52, 157.98, 155.09, 150.66, 128.32, 126.75, 125.16, 121.52, 119.65, 115.45, 112.40, 95.28, 77.94, 77.62, 77.30, 62.91, 47.20, 39.73, 21.27, 16.02, 12.39. 31P NMR (180 MHz, CDCl3, ppm): δ = 24.33 ppm. HRMS (ESI) m/z calcd. for C21H28N3O7PS [M + H]+: 497.5017, found 497.5013.
Diethyl((3-hydroxyphenyl)((4-(N-(5-methyl-4,5-dihydroisoxazol-3-yl)sulfamoyl)phenyl) amino)methyl)phosphonate (4e)
Pale Yellow solid; Yield: 93%, M.p.: 140–142°C. 1HNMR (400 MHz, CDCl3, ppm): δ = 7.58 (m, 2H, Ar-H), 7.16 (t, J = 7.7 Hz, 1H, Ar-H), 6.93 (d, J = 10.0 Hz ,2H, Ar-H),6.72 (m, 3H, Ar-H), 6.29 (t, J = 8.2Hz, 1H, -OH), 6.05 (s, 1H, NH), 5.84(s, 1H, NH ), 4.98 (m, 1H, P-CH), 3.92 (s, 1H, CH), 3.72–3.63 (m, 4H, O-CH2), 2.59 (m, 3H, CH-CH3), 1.27–1.11(m, 6H, O-CH2-CH3).13CNMR (100MHz, CDCl3, ppm): δ = 169.56, 157.65, 128.66, 127.02, 118.94, 115.40, 114.62, 112.66, 95.34, 77.93, 77.61, 77.28, 63.35, 54.87, 54.10, 40.57, 40.29, 39.55, 39.00, 16.19, 12.40. 31P NMR (180 MHz, CDCl3, ppm): δ 22.11 ppm. HRMS (ESI) m/z calcd. for C21H28N3O7PS [M + H]+: 497. 5017, found 497.5014.
Diethyl((4-isopropylphenyl)((4-(N-(5-methyl-4,5-dihydroisoxazol-3-yl)sulfamoyl) phenyl)amino)methyl)phosphonate (4f)
Yellow solid; Yield: 93%, M.p.: 156–158°C. 1H NMR (400 MHz, CDCl3, ppm): δ = 9.14 (s, 1H, NH), 7.55 (d, J = 9.2 Hz, 2H, Ar-H), 7.34 (dd, J = 8.6, 2.3 Hz, 2H, Ar-H), 7.19 (d, J = 8.6 Hz, 2H, Ar-H), 6.56 (d, J = 9.2 Hz, 2H, Ar-H), 6.17 (s, 1H, CH-NH), 4.75 (d, J = 26.0 Hz, 1H, P-CH), 4.13–3.55(m, 4H, O-CH2), 2.88 (m, 1H, CH-CH3), 2.34 (d, J = 15.3 Hz, 4H, CH-CH2, CH-CH3), 1.32–0.84 (m, 14H, O-CH2-CH3, CH-CH3, CH-CH2). 13CNMR (100MHz, CDCl3, ppm): δ = 170.53, 158.09, 150.71, 149.27, 131.92, 129.11, 129.04, 127.83, 126.94, 126.81, 112.98, 95.72, 77.43, 77.12, 76.80, 63.99, 63.39, 55.86, 54.34, 33.84, 23.96, 16.42, 16.12, 12.76. 31P NMR (180 MHz, CDCl3, ppm): δ = 23.23 ppm. HRMS (ESI) m/z calcd. for C24H34N3O6PS [M + H]+: 523.5820, found 523.5816.
Diethyl((5-bromo-2-hydroxyphenyl)((4-(N-(5-methyl-4,5-dihydroisoxazol-3-yl) sulfamoyl)phenyl)amino)methyl)phosphonate (4g)
Orange solid; Yield: 93%, M.p.:168–170°C. 1H NMR(400 MHz, CDCl3, ppm) : δ = 7.62 (m, 3H, Ar-H), 7.24 ( dd, J = 9.1, 2.5 Hz, 2H, Ar-H), 7.10 (d, J = 9.2 Hz, 2H, Ar-H), 6.72 (d, 1H, OH), 6.12 (s, 1H, NH), 4.42 (m, 1H, P-CH), 4.07 (s, 1H, CH-NH), 3.12 (m, 4H, O-CH2), 2.64 (d, J = 1.8 Hz, 1H, CH), 2.42 (m, 5H, CH-CH3,CH2), 1.26–1.18 (m, 6H, O-CH2-CH3). 13CNMR (100MHz, CDCl3, ppm): δ = 170.56, 158.67, 129.72, 128.56, 118.62, 116.38, 114.42, 112.84, 95.42, 77.75, 77.64, 77.17, 63.42, 54.67, 54.14, 41.60, 40.27, 39.72, 39.04, 16.17, 12.36. 31P NMR (180 MHz, CDCl3, ppm): δ = 23.42 ppm. HRMS (ESI) m/z calcd. for C21H27BrN3O7PS [M + H]+: 575.0491, found 575.0487.
Diethyl(((4-(N-(5-methyl-4,5-dihydroisoxazol-3-yl)sulfamoyl)phenyl)amino)(4-nitrophenyl)methyl)phosphonate (4h)
Yellow solid; Yield: 93%, M.p.:170–172°C.1H NMR (400 MHz, CDCl3, ppm): δ = 8.12 (d, J = 9.2 Hz, 2H, Ar-H), 7.64 (dd, J = 9.1, 2.5 Hz, 2H, Ar-H), 7.49 (d, J = 9.1 Hz, 2H, Ar-H), 7.12 (d, J = 9.2 Hz, 2H, Ar-H), 6.04 (s, 1H, NH), 4.52 (m, 1H, P-CH), 4.08 (s,1H, CH-NH), 3.74–3.62 (m, 4H, O-CH2), 3.91 (s, 1H, CH), 2.74 (m, 5H, CH3), 1.16 (m, ,6H, O-CH2-CH3). 13CNMR (100MHz, CDCl3, ppm): δ = 172.24, 169.62, 152.20, 147.82, 134.78, 128.02, 129.12, 127.56, 125.84, 126.87, 112.76, 97.02, 77.52, 77.14, 76.78, 64.02, 63.78, 55.82, 54.76, 33.74, 23.82, 16.42, 16.12, 12.76. 31P NMR (180 MHz, CDCl3, ppm): δ = 22.72 ppm. HRMS (ESI) m/z calcd. for C21H27N4O8PS [M + H]+: 526.4998, found 526.4996.
Diethyl((5-chloro-2-hydroxyphenyl)((4-(N-(5-methyl-4,5-dihydroisoxazol-3-yl) sulfamoyl)phenyl)amino)methyl)phosphonate (4i)
Brown solid; Yield: 93% M.p.:168–170°C. 1H NMR (400 MHz, CDCl3, ppm) : δ = 7.64 ( m, 3H, Ar-H), 7.24 (dd, J = 9.1, 2.5 Hz, 2H, Ar-H), 7.12 (d, J = 9.2 Hz, 2H, Ar-H), 6.64 (d, 1H, OH), 6.10 (s, 1H, NH), 4.64 (m, 1H, P-CH), 4.07 (s, 1H, CH-NH), 3.24 (m, 4H, O-CH2), 2.79 (d, J = 1.8 Hz, 1H, CH), 2.39 (m, 5H, CH-CH3, CH2), 1.29–1.18 (m, 6H, O-CH2-CH3). 13CNMR (100MHz, CDCl3, ppm): δ = 169.78, 157.69, 130.98, 128.72, 119.67, 116.42, 114.64, 112.72, 96.54, 77.54, 77.24, 77.16, 64.10, 56.62, 55.10, 41.72, 41.08, 39.64, 39.72, 16.12, 12.34. 31P NMR (180 MHz, CDCl3, ppm): δ = 24.11 ppm. HRMS (ESI) m/z calcd. for C21H27ClN3O7PS [M + H]+: 531.9467, found 531.9464.
Diethyl(((4-(N-(5-methyl-4,5-dihydroisoxazol-3-yl)sulfamoyl)phenyl)amino)(2-phenoxyphenyl)methyl)phosphonate (4j)
Yellow solid; Yield : 89%, M.p.:164–168°C. 1H NMR (400 MHz, CDCl3, ppm): δ = 8.12 (s, 1H, NH), 7.64 (d, J = 8.9 Hz, 2H, Ar-H), 7.42 (m,, 4H, Ar-H), 7.24 (m,4H, Ar-H), 7.12 (d, J = 8.9 Hz, 2H, Ar-H), 6.28 (s, 1H, CH-NH), 6.14 (t, 1H, O-CH-CH3), 4.72 (m, 1H, P-CH),4.18–3.64 (m, 4H, O-CH2), 2.62–2.29 (m, 5H, O-CH2-CH3), 1.28–1.02 (m, 11H, O-CH2-CH3, O-CH, CH3,CH-CH2). 13CNMR: (100MHz, CDCl3, ppm) δ = 181.02, 178.24, 174.58, 169.02, 157.56, 152.20, 147.82, 134.78, 128.02, 129.12, 127.56, 125.84, 126.87,112.76, 97.02, 77.52, 77.14, 76.78, 64.02, 63.78, 55.82, 54.76, 33.74, 23.82, 16.42, 16.12, 12.76. 31P NMR (180 MHz, CDCl3, ppm): δ = 22.18 ppm. HRMS (ESI) m/z calcd. for C21H27ClN3O7PS [M + H]+: 573.5976, found 573.5973.