Preparation of the catalyst 24a

Preparation of the catalyst 24a, 29
0.37 g of BF3 (0.7 mL of BF3.Et2O) was added drop-wise to a mixture of 0.63 g of silica gel or nano-silica gel and 5 ml of chloroform. The mixture was stirred for 1 h at room temperature. The resulted suspension was filtered. The obtained solid was washed with chloroform and dried at room temperature.
2.3. Synthesis of urea/thiourea derivatives of 4-bromo-3-methylisoxazol-5-amine (3a-j)
To a stirred solution of 4-bromo-3-methylisoxazol-5-amine (1) (0.002 mol) in dry THF (20 mL), 3-isocyanatopyridine (2a) (0.002 mol) in dry THF (30 mL) was added drop wise in presence of triethylamine with stirring at 10 °C for a period of 15 minutes. The reaction mixture was stirred further at room temperature for 3 hours. The progress of the reaction was monitored by TLC and the solvent was removed in a rota-evaporator to obtain crude product. The product was purified by column chromatography on silica gel using petroleum ether-ethyl acetate (7:3) as eluent to afford 1-(4-bromo-3-methylisoxazol-5-yl)-3-(pyridin-3-yl)urea (3a). Same experimental procedure was adopted for the preparation of remaining compounds (3b-j).
2.4. Conventional procedure for the synthesis of phosphonates (5a-j)
The mixture of urea/thiourea derivatives (3a-j) (0.010 mol), triethyl phosphite (4) (3.4 mL, 0.020 mol) and 37% nano-BF3.SiO2 (0.25 g) were placed in a round bottomed flask. This mixture was heated to 70 °C and agitated for 2h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature. Dichloromethane (DCM) (15 mL) was added to the reaction content and stirred for 10 min. The catalyst, nano BF3.SiO2 was separated by filtration as residue, washed with DCM (2 ×10mL) and the residue was dried under vacuum at 100 °C to utilize in further studies. The organic layer was washed with water (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum at 50 °C to obtain crude product. The pure phosphonates (5a-j) were obtained by column chromatography using ethyl acetate: n-hexane (7:3) as eluent.
2.5. Microwave assisted synthesis of phosphonates (5a-j):
The mixture of urea/thiourea derivatives (3a-j) (0.010 mol), triethyl phosphite (4) (3.4 mL, 0.020 mol) and 37% nano BF3.SiO2 (0.25 g) were placed in a round bottomed flask. The mixture was microwave radiated at 420 W under room temperature for about 9-17 minutes. The progress of the reaction was monitored by TLC (ethylacetate: n-hexane, 7:3). After completion of the reaction as checked by TLC, the reaction mixture was cooled to room temperature. After completion of the reaction, the reaction mixture was cooled to room temperature. Dichloromethane (DCM) (15 mL) was added to the reaction content and stirred for 10 min. The catalyst, nano BF3.SiO2 was separated by filtration as residue, washed with DCM (2 ×10mL) and the residue was dried under vacuum at 100 °C to utilize in further studies. The organic layer was washed with water (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum at 50 °C to obtain crude product. The pure compound (5a-j) was obtained by column chromatography using ethyl acetate: n-hexane (7:3) as eluent.
2.6. Spectral data of title compounds (5a-j)

Diethyl 3-methyl-5-(3-pyridin-3-ylureido)isoxazol-4-ylphosphonate (5a). Yield: 90%; semi solid. 31P NMR spectrum (DMSO-d6): ? 22.5 ppm; 1H NMR spectrum (400 MHz, DMSO-d6): ? 9.25 (s, 1H, Ar-NH), 8.15 (d, 1H, Ar-H), 8.03 (d, 1H, Ar-H), 7.35 (s, 1H, NH), 7.17 (t, 1H, Ar-H), 4.09 (m, 4H, O-CH2CH3), 2.54 (s, 3H, -CH3), 1.26 (t, J = 7.2 Hz, 6H, O-CH2CH3); 13C NMR spectrum (100 MHz, DMSO-d6): ? 166.5 (C-4), 154.2 (C-8), 153.1 (C-2), 138.3 (C-22), 137.8 (C-20), 134.6 (C-18), 133.4 (C-17), 125.9 (C-21), 101.8 (C-3), 63.5 (C-12, C-15), 16.6 (C-13, C-16), 14.3 (C-6); IR (KBr) (?max cm-1): 3295, 3221 (NH), 1702 (C=O), 1222 (P=O), 1019 (P-O-Calip); LCMS (m/z, %): 360 (M+H+, 100); Anal. Calcd for C13H18N3O5PS: C, 43.45; H, 5.05; N, 11.69%; found: C, 43.52; H, 5.12; N, 11.62%.
Diethyl 3-methyl-5-(3-thiophen-2-ylureido)isoxazol-4-ylphosphonate (5b): Yield: 93%; semi solid. 31P NMR spectrum (DMSO-d6): ? 24.2 ppm; 1H NMR spectrum (400 MHz, DMSO-d6): ? 10.75 (s, 1H, Ar-NH), 7.37 (s, 1H, NH), 6.95 (d, 1H, Ar-H), 6.89 (d, 1H, Ar-H), 6.35 (s, 1H, Ar-H), 4.08 (m, 4H, O-CH2CH3), 2.54 (s, 3H, -CH3), 1.24 (t, J = 7.2 Hz, 6H, O-CH2CH3); 13C NMR spectrum (100 MHz, DMSO-d6): ? 166.7 (C-4), 154.4 (C-8), 153.1 (C-2), 139.3 (C-17), 126.4 (C-18), 119.9 (C-19), 114.8 (C-20), 101.8 (C-3), 63.3 (C-12, C-15), 16.5 (C-13, C-16), 14.3 (C-6); IR (KBr) (?max cm-1): 3298, 3224 (NH), 1716 (C=O), 1224 (P=O), 1013 (P-O-Calip); LCMS (m/z, %): 360 (M+H+, 100); Anal. Calcd for C13H18N3O5PS: C, 43.45; H, 5.05; N, 11.69%; found: C, 43.52; H, 5.15; N, 11.60%.
Diethyl 5-(3-(3,5-dimethylisoxazol-4-yl)ureido)-3-methylisoxazol-4-ylphosphonate (5c): Yield: 91%; semi solid. 31P NMR spectrum (DMSO-d6): ? 22.9 ppm; 1H NMR spectrum (400 MHz, DMSO-d6): ? 10.75 (s, 1H, Ar-NH), 7.31 (s, 1H, NH), 4.09 (m, 4H, O-CH2CH3), 2.54 (s, 3H, -CH3), 2.42 (s, 3H, -CH3), 2.38 (s, 3H, -CH3), 1.25 (t, J = 7.2 Hz, 6H, O-CH2CH3); 13C NMR spectrum (100 MHz, DMSO-d6): ? 166.4 (C-4), 154.5 (C-21), 154.5 (C-8), 153.1 (C-2), 148.4 (C-18), 118.2 (C-17), 101.8 (C-3), 63.2 (C-12, C-15), 16.4 (C-13, C-16), 14.3 (C-6), 10.2 (C-22), 9.4 (C-23); IR (KBr) (?max cm-1): 3312, 3225 (NH), 1718 (C=O), 1226 (P=O), 1014 (P-O-Calip); LCMS (m/z, %): 373 (M+H+, 100); Anal. Calcd for C14H21N4O6P: C, 45.16; H, 5.69; N, 15.05%; found: C, 45.20; H, 5.65; N, 15.09%.
Diethyl 5-(3-(furan-2-ylmethyl)ureido)-3-methylisoxazol-4-ylphosphonate (5d):
Yield: 94%; semi solid. 31P NMR spectrum (DMSO-d6): ? 25.3 ppm; 1H NMR spectrum (400 MHz, DMSO-d6): ? 7.94 (d, 1H, Ar-H), 7.35 (s, 1H, NH), 6.84 (t, 1H, Ar-H), 6.74 (s, 1H, CH2-NH), 6.35 (d, 1H, Ar-H), 5.31 (d, 2H, -CH2), 4.05 (m, 4H, O-CH2CH3), 2.54 (s, 3H, -CH3), 1.23 (t, J = 7.2 Hz, 6H, O-CH2CH3); 13C NMR spectrum (100 MHz, DMSO-d6): ? 166.6 (C-4), 154.1 (C-8), 153.1 (C-2), 144.5 (C-18), 142.2 (C-21), 112.4 (C-20), 111.6 (C-19), 101.8 (C-3), 63.5 (C-12, C-15), 36.2 (C-17), 16.5 (C-13, C-16), 14.3 (C-6); IR (KBr) (?max cm-1): 3325, 3228 (NH), 1726 (C=O), 1217 (P=O), 1014 (P-O-Calip); LCMS (m/z, %): 358 (M+H+, 100); Anal. Calcd for C14H20N3O6P: C, 47.06; H, 5.64; N, 11.76%; found: C, 47.14; H, 5.69; N, 11.79%.
diethyl 3-methyl-5-(3-tosylureido)isoxazol-4-ylphosphonate (5e):
Yield: 90%; semi solid. 31P NMR spectrum (DMSO-d6): ? 24.5 ppm; 1H NMR spectrum (400 MHz, DMSO-d6): ? 10.84 (s, 1H, SO2-NH), 7.83 (d, 2H, Ar-H), 7.42 (d, 2H, Ar-H), 7.35 (s, 1H, NH), 2.65(s, 3H, -CH3), 4.09 (m, 4H, O-CH2CH3), 2.54 (s, 3H, -CH3), 1.26 (t, J = 7.2 Hz, 6H, O-CH2CH3); 13C NMR spectrum (100 MHz, DMSO-d6): ? 166.4 (C-4), 154.2 (C-8), 153.1 (C-2), 139.5 (C-18), 139.1 (C-21), 129.4 (C-20, C-22), 128.6 (C-19, C-23), 101.8 (C-3), 63.6 (C-12, C-15), 23.2 (C-24), 16.4 (C-13, C-16), 14.3 (C-6); IR (KBr) (?max cm-1): 3299, 3265 (NH), 1743 (C=O), 1229 (P=O), 1016 (P-O-Calip); LCMS (m/z, %): 432 (M+H+, 100); Anal. Calcd for C16H22N3O7PS: C, 44.55; H, 5.14; N, 9.74%; found: C, 44.61; H, 5.19; N, 9.69%.
Diethyl 5-(3-(furan-2-ylmethyl)thioureido)-3-methylisoxazol-4-ylphosphonate (5f):
Yield: 92%; semi solid. 31P NMR spectrum (DMSO-d6): ? 26.1 ppm; 1H NMR spectrum (400 MHz, DMSO-d6): ? 7.92 (d, 1H, Ar-H), 6.35 (s, 1H, NH), 6.83 (t, 1H, Ar-H), 6.60 (s, 1H, CH2-NH), 6.32 (d, 1H, Ar-H), 5.33 (d, 2H, -CH2), 4.08 (m, 4H, O-CH2CH3), 2.54 (s, 3H, -CH3), 1.24 (t, J = 7.2 Hz, 6H, O-CH2CH3); 13C NMR spectrum (100 MHz, DMSO-d6): ? 175.5 (C-8), 166.5 (C-4), 153.1 (C-2), 147.5 (C-18), 144.3 (C-21), 112.4 (C-19), 111.8 (C-20), 101.8 (C-3), 63.4 (C-12, C-15), 46.2 (C-17), 16.6 (C-13, C-16), 14.3 (C-6); IR (KBr) (?max cm-1): 3335, 3235 (NH), 1222 (P=O), 1094 (C=S), 1019 (P-O-Calip); LCMS (m/z, %): 374 (M+H+, 100); Anal. Calcd for C14H20N3O5PS: C, 45.04; H, 5.40; N, 11.25%; found: C, 45.11; H, 5.49; N, 11.19%.
Diethyl 3-methyl-5-(3-(4-morpholinophenyl)thioureido)isoxazol-4-ylphosphonate (5g):
Yield: 95%; semi solid. 31P NMR spectrum (DMSO-d6): ? 18.7 ppm; 1H NMR spectrum (400 MHz, DMSO-d6): ? 11.43 (s, 1H, Ar-NH), 6.85 (d, 2H, Ar-H), 6.32 (s, 1H, NH), 6.46 (d, 2H, Ar-H), 3.73 (t, 4H, -CH2), 3.45 (t, 4H, -CH2), 4.09 (m, 4H, O-CH2CH3), 2.54 (s, 3H, -CH3), 1.26 (t, J = 7.2 Hz, 6H, O-CH2CH3); 13C NMR spectrum (100 MHz, DMSO-d6): ? 175.3 (C-8), 166.5 (C-4), 153.1 (C-2), 148.6 (C-20), 130.3 (C-17), 129.4 (C-18, C-22), 112.8 (C-19, C-21), 101.8 (C-3), 68.3 (C-25, C-27), 63.1 (C-12, C-15), 52.6 (C-24, C-28), 16.2 (C-13, C-16), 14.3 (C-6); IR (KBr) (?max cm-1): 3319, 3232 (NH), 1226 (P=O), 1097 (C=S), 1015 (P-O-Calip); LCMS (m/z, %): 455 (M+H+, 100); Anal. Calcd for C19H27N4O5PS: C, 50.21; H, 5.99; N, 12.33%; found: C, 50.28; H, 5.94; N, 12.39%.
Diethyl 3-methyl-5-(3-(4-(trifluoromethyl)phenyl)thioureido)isoxazol-4-ylphosphonate (5h):
Yield: 91%; semi solid. 31P NMR spectrum (DMSO-d6): ? 19.4 ppm; 1H NMR spectrum (400 MHz, DMSO-d6): ? 11.47 (s, 1H, Ar-NH), 7.45 (d, 2H, Ar-H), 6.32 (s, 1H, NH), 7.23 (d, 2H, Ar-H), 4.12 (m, 4H, O-CH2CH3), 2.54 (s, 3H, -CH3), 1.27 (t, J = 7.2 Hz, 6H, O-CH2CH3); 13C NMR spectrum (100 MHz, DMSO-d6): ? 175.8 (C-8), 166.5 (C-4), 153.1 (C-2), 142.4 (C-17), 133.5 (C-20), 127.4 (C-18, C-22), 126.8 (C-19, C-21), 123.3 (C-23), 101.8 (C-3), 63.5 (C-12, C-15), 16.6 (C-13, C-16), 14.3 (C-6); IR (KBr) (?max cm-1): 3345, 3274 (NH), 1228 (P=O), 1098 (C=S), 1021 (P-O-Calip); LCMS (m/z, %): 438 (M+H+, 100); Anal. Calcd for C16H19F3N3O4PS: C, 43.94; H, 4.38; N, 9.61%; found: C, 43.99; H, 4.44; N, 9.53%.
Diethyl 3-methyl-5-(3-(4-nitrophenyl)thioureido)isoxazol-4-ylphosphonate (5i):
Yield: 93%; semi solid. 31P NMR spectrum (DMSO-d6): ? 22.6 ppm; 1H NMR spectrum (400 MHz, DMSO-d6): ? 11.49 (s, 1H, Ar-NH), 8.13 (d, 2H, Ar-H), 6.35 (s, 1H, NH), 6.29 (d, 2H, Ar-H), 4.11 (m, 4H, O-CH2CH3), 2.54 (s, 3H, -CH3), 1.26 (t, J = 7.2 Hz, 6H, O-CH2CH3);13C NMR spectrum (100 MHz, DMSO-d6): ? 175.6 (C-8), 166.5 (C-4), 153.1 (C-2), 143.6 (C-17), 142.8 (C-20), 126.4 (C-18, C-22), 125.8 (C-19, C-21), 101.8 (C-3), 63.8 (C-12, C-15), 16.7 (C-13, C-16), 14.3 (C-6); IR (KBr) (?max cm-1): 3340, 3265 (NH), 1226 (P=O), 1097 (C=S), 1019 (P-O-Calip); LCMS (m/z, %): 415 (M+H+, 100); Anal. Calcd for C15H19N4O6PS: C, 43.48; H, 4.62; N, 13.52%; found: C, 43.49; H, 4.69; N, 13.45%.