3.3. General Procedure for the Synthesis of 1-Benzylquinazoline-2,4-Diones 26a–d
Urea (1.50 mmol) was added to a solution of the respective 1-benzylbenzo[d][1,3]oxazine-2,4-dione 26a–d (1.00 mmol) in anhydrous DMF (10 mL) and the mixture was heated under reflux for 5 h. The solvent was removed in vacuo and the residue was crystallized from ethanol to produce the corresponding 27a–d.
1-Benzylquinazoline-2,4-dione (27a). According to the general procedure from 1-benzylbenzo[d][1,3]oxazine-2,4-dione 26a (0.500 g, 1.97 mmol) and urea (0.178 g, 2.96 mmol), 1-benzylquinazoline-2,4-dione 27a (0.238 g, 48%) was obtained as a white amorphous solid, m.p. 218–220 °C. IR (KBr, cm–1) νmax: 3170, 2923, 1704, 1605, 1480, 1311, 1151, 1020, 856, 722. 1H NMR (600 MHz, CDCl3): δ = 8.70 (s, 1H, NH), 8.25 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H), 7.60–7.58 (m, 1H), 7.38–7.36 (m, 2H), 7.32–7.29 (m, 3H), 7.26 (t, J = 7.9 Hz, 1H), 7.16 (t, J = 8.5 Hz, 1H), 5.39 (s, 2H, CH2). 13C NMR (150 MHz, CDCl3): δ = 161.84 (C(O)), 150.72 (C(O)), 141.11, 135.56, 135.39, 129.04, 128.81, 127.78, 126.50, 123.32, 116.13, 114.95, 46.58. Anal. calcd. for C15H11FN2O2: C, 71.42; H, 4.79; N, 11.10. Found: C, 71.12; H, 4.54; N, 10.87.
1-(2-Fluorobenzyl)quinazoline-2,4-dione (27b). According to the general procedure from 1-(2-fluorobenzyl)benzo[d][1,3]oxazine-2,4-dione 26b (0.500 g, 1.84 mmol) and urea (0.166 g, 2.76 mmol), 1-(2-fluorobenzyl)quinazoline-2,4-dione 27b (0.253 g, 49%) was obtained as a white amorphous solid, m.p. = 228–230 °C. IR (KBr, cm–1) νmax: 3177, 2922, 1701, 1606, 1457, 1371, 1230, 1020, 852, 749. 1H NMR (600 MHz, CDCl3): δ = 8.42 (s, 1H, NH), 8.25 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H), 7.64–7.61 (m, 1H), 7.32–7.27 (m, 2H), 7.19–7.13 (m, 3H), 7.11–7.09 (m, 1H), 5.44 (s, 2H, CH2). 13C NMR (150 MHz, CDCl3): δ = 161.49 (C(O)), 160.31 (d, 1J(CF) = 245.7 Hz, C2’), 150.58 (C(O)), 140.79, 135.72, 129.53 (d, 3J(CCCF) = 8.0 Hz, C6’), 128.87, 128.18 (d, 3J(CCCF) = 3.9 Hz, C4’), 124.76 (d, 4J(CCCCF) = 3.9 Hz, C5’), 123.47, 122.46 (d, 2J(CCF) = 14.2 Hz, C3’), 116.11, 115.65 (d, 2J(CCF) = 21.7 Hz, C1’), 114.47 (d, 5J(CNCCCF) =1.7 Hz), 40.18 (d, 3J(CCCF) = 5.4 Hz). Anal. calcd. for C15H11FN2O2: C, 66.66; H, 4.10; N, 10.37. Found: C, 66.55; H, 3.90; N, 10.60.
1-(3-Fluorobenzyl)quinazoline-2,4-dione (27c). According to the general procedure from 1-(3-fluorobenzyl)benzo[d][1,3]oxazine-2,4-dione 26c (0.500 g, 1.84 mmol) and urea (0.166 g, 2.76 mmol), 1-(3-fluorobenzyl)quinazoline-2,4-dione 27c (0.225 g, 45%) was obtained as a white amorphous solid, m.p. = 227–229 °C. IR (KBr, cm–1) νmax: 3176, 2964, 1691, 1607, 1439, 1317, 1244, 1020, 939, 738. 1H NMR (600 MHz, CDCl3): δ = 8.65 (s, 1H, NH), 8.25 (dd, J = 7.9Hz, J = 1.5 Hz, 1H), 7.63–7.60 (m, 1H), 7.36–7.34 (m, 1H), 7.33–7.27 (m, 1H), 7.12 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.02–6.99 (m, 2H), 5.37 (s, 2H, CH2). 13C NMR (150 MHz, CDCl3): δ = 163.25 (d, 1J(CF) = 247.7 Hz, C3), 161.46 (C(O)), 150.47 (C(O)), 140.91, 138.03 (d, 3J(CCCF) = 6.8 Hz, C5), 135.61, 130.68 (d, 3J(CCCF) = 7.9 Hz, C1), 128.96, 123.50, 122.07 (d, 4J(CCCCF) = 2.6 Hz, C6), 116.17, 114.85 (d, 2J(CCF) = 21.0 Hz, C2), 114.66, 113.61 (d, 2J(CCF) = 22.1 Hz, C4), 45.05 (d, 4J(CCCCF) = 1.6 Hz). Anal. calcd. for C15H11FN2O2 × 0.5 H2O: C, 64.51; H, 4.33; N, 10.03. Found: C, 64.41; H, 4.03; N, 10.31.
1-(4-Fluorobenzyl)quinazoline-2,4-dione (27d). According to the general procedure from 1-(4-fluorobenzyl)benzo[d][1,3]oxazine-2,4-dione 26d (0.500 g, 1.84 mmol) and urea (0.166 g, 2.76 mmol), 1-(4-fluorobenzyl)quinazoline-2,4-dione 27d (0.250 g, 50%) was obtained as a white amorphous solid, m.p. = 214–215 °C. IR (KBr, cm–1) νmax: 3153, 3020, 2922, 1679, 1606, 1437, 1321, 1224, 1018, 920, 759. 1H NMR (600 MHz, CDCl3): δ = 9.08 (s, 1H, NH), 8.26 (dd, J = 7.9Hz, J = 1.5 Hz, 1H), 7.62–7.60 (m, 1H), 7.31–7.26 (m, 3H), 7.15 (d, J = 8.5 Hz, 1H), 7.07–7.04 (m, 2H), 5.35 (s, 2H, CH2). 13C NMR (150 MHz, CDCl3): δ = 162.29 (d, 1J(CF) = 246.8 Hz, C4), 161.71 (C(O)), 150.68 (C(O)), 140.96, 135.53, 131.18 (d, 4J(CCCCF) = 3.2 Hz, C1), 128.94, 128.36 (d, 3J(CCCF) = 7.9 Hz, C2, C6), 123.41, 116.21, 115.98 (d, 2J(CCF) = 21.9 Hz, C3, C5), 114.68, 45.93. Anal. calcd. for C15H11FN2O2: C, 66.66; H, 4.10; N, 10.37. Found: C, 66.83; H, 4.34; N, 10.57.
3.4. General Procedure for Allylation of 1-Benzylquinazolin-2,4-Dione 27a–d
Allyl bromide (2.20 mmol) was added to a suspension of the respective 1-benzylquinazoline-2,4-dione 27a–d (1.00 mmol) and potassium hydroxide (3.00 mmol) in anhydrous acetonitrile (15 mL). The reaction mixture was stirred at 105 °C for 4 h. The solvent was removed in vacuo and the residue was dissolved in methylene chloride (10 mL) and extracted with water (3 × 10 mL). The organic layer was dried (MgSO4), concentrated, and purified by column chromatography with a chloroform–hexane mixture (7:3, v/v), then crystallized from a chloroform–petroleum ether mixture to produce compounds 24a–d.
3-Allyl-1-benzylquinazoline-2,4-dione (24a). According to the general procedure from 1-benzylquinazoline-2,4-dione 27a (0.150 g, 0.594 mmol), potassium hydroxide (0.100 g, 1.78 mmol), and allyl bromide (0.113 mL, 1.31 mmol), 3-allyl-1-benzylquinazoline-2,4-dione 24a (0.174g, 89%) was obtained as a white amorphous solid, m.p. = 101–103 °C. IR (KBr, cm–1) νmax: 3063, 2963, 1701, 1606, 1454, 1341, 1272, 1025, 941, 762. 1H NMR (600 MHz, CDCl3): δ = 8.27 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H), 7.58–7.55 (m, 1H), 7.37–7.35 (m, 2H), 7.31–7.28 (m, 3H), 7.25–7.23 (m, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.03 (ddt, 3J = 17.1 Hz, 3J = 10.2 Hz, 3J = 5.8 Hz, 1H, CH2–CH=CH2), 5.42 (s, 2H, CH2Ph), 5.37 (dd, 3J = 17.1 Hz, 2J = 1.3 Hz, 1H, CH2–CH=CHH), 5.26 (dd, 3J = 10.2 Hz, 2J = 1.3 Hz, 1H, CH2–CH=CHH), 4.80 (d, 3J = 5.8 Hz, 2H, CH2–CH=CH2). 13C NMR (150 MHz, CDCl3): δ = 161.46 (C(O)), 151.17 (C(O)), 140.02, 135.74, 135.04, 131.93, 129.10, 128.98, 127.62, 126,48, 123.07, 117.64, 115.93, 115.80, 47.34, 44.01. Anal. calcd. for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C, 73.87; H, 5.23; N; 9.77.
3-Allyl-1-(2-fluorobenzyl)quinazoline-2,4-dione (24b). According to the general procedure from 1-(2-fluorobenzyl)quinazoline-2,4-dione 27b (0.250 g, 0.925 mmol), potassium hydroxide (0.156 g, 2.78 mmol), and allyl bromide (0.176 mL, 2.04 mmol), 3-allyl-1-(2-fluorobenzyl)quinazoline-2,4-dione 24b (0.269 g, 94%) was obtained as a white amorphous solid, m.p. = 93–94 °C. IR (KBr, cm–1) νmax: 3086, 2988, 1703, 1660, 1606, 1454, 1339, 1225, 1025, 935, 756. 1H NMR (600 MHz, CDCl3): δ = 8.28 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H), 7.61–7.58 (m, 1H), 7.31–7.25 (m, 2H), 7.15–7.11 (m, 3H), 7.10–7.07 (m, 1H), 5.95 (ddt, 3J = 17.1 Hz, 3J = 10.2 Hz, 3J = 5.8 Hz, 1H, CH2–CH=CH2), 5.47 (s, 2H, CH2Ph), 5.36 (dd, 3J = 17.1 Hz, 2J = 1.3 Hz 1H, CH2–CH=CHH), 5.27 (d, 3J = 10.2 Hz, 2J = 1.3 Hz, 1H, CH2–CH=CHH), 4.80 (d, 3J = 5.8 Hz, 2H, CH2–CH=CH2). 13C NMR (150 MHz, CDCl3): δ = 161.39 (C(O)), 160.33 (d, 1J(CF) = 246.2 Hz, C2), 151.23 (C(O)), 139.69, 135.22, 131.85, 129.39 (d, 3J(CCCF) = 8.0 Hz, C6), 129.16, 128.10 (d, 3J(CCCF) = 4.0 Hz, C4), 124.70 (d, 4J(CCCCF) = 3.6 Hz, C5), 123.23, 122.78 (d, 2J(CCF) = 13.8 Hz, C3), 117.96, 115.78, 115.61 (d, 2J(CCF) = 21.7 Hz, C1), 113.97 (d, 5J = 1.7 Hz), 44.03, 40.97 (d, 3J(CCCF) = 5.4 Hz). Anal. calcd. for C18H15FN2O2: C, 69.67; H, 4.87; N, 9.03. Found: C, 69.77; H, 4.60; N, 9.26.
3-Allyl-1-(3-fluorobenzyl)quinazoline-2,4-dione (24c). According to the general procedure from 1-(3-fluorobenzyl)quinazoline-2,4-dione 27c (0.260 g, 0.962 mmol), potassium hydroxide (0.162 g, 2.89 mmol), and allyl bromide (0.183 mL, 2.12 mmol), 3-allyl-1-(3-fluorobenzyl)quinazoline-2,4-dione 24c (0.249 g, 83%) was obtained as a white amorphous solid, m.p. = 115–116 °C. IR (KBr, cm–1) νmax: 3091, 2963, 1700, 1655, 1604, 1485, 1342, 1252, 1001, 940, 929, 765. 1H NMR (600 MHz, CDCl3): δ = 8.28 (dd, J = 7.9 Hz, J = 1.4 Hz 1H), 7.60–7.57 (m, 1H), 7.35–7.32 (m, 1H), 7.29–7.26 (m, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 7.01–6.97 (m, 2H), 5.95 (ddt, 3J = 17.1 Hz, 3J = 10.2 Hz, 3J = 5.8 Hz, 1H, CH2–CH=CH2), 5.40 (s, 2H, CH2Ph), 5.36 (dd, 3J = 17.1 Hz, 2J = 1.3 Hz, 1H, CH2–CH=CHH), 5.24 (d, 3J = 10.2 Hz, 2J = 1.3 Hz, 1H, CH2–CH=CHH), 4.80 (d, 3J = 5.8 Hz, 2H, CH2–CH=CH2). 13C NMR (150 MHz, CDCl3): δ = 163.23 (d, 1J(CF) = 247.6 Hz, C3), 161.33 (C(O)), 151.11 (C(O)), 139.81, 138.38 (d, 3J(CCCF) = 7.0 Hz, C5), 135.12, 131.83, 130.62 (d, 3J(CCCF) = 8.5 Hz, C1), 129.25, 123.26, 122.05 (d, 4J(CCCCF) = 3.1 Hz, C6), 118.05, 115.83, 114.72 (d, 2J(CCF) = 21.3 Hz, C2), 114.14, 113.57 (d, 2J(CCF) = 22.1 Hz, C4), 46.91, 44.05. Anal. calcd. for C18H15FN2O2: C, 69.67; H, 4.87; N, 9.03. Found: C, 69.59; H, 4.58; N, 9.31.
3-Allyl-1-(4-fluorobenzyl)quinazoline-2,4-dione (24d). According to the general procedure from 1-(4-fluorobenzyl)quinazoline-2,4-dione 27d (0.215 g, 0.796 mmol), potassium hydroxide (0.134 g, 2.39 mmol), and allyl bromide (0.150 mL, 1.75 mmol), 3-allyl-1-(4-fluorobenzyl)quinazoline-2,4-dione 24d (0.159 g, 64%) was obtained as a white amorphous solid, m.p. = 120–122 °C. IR (KBr, cm–1) νmax: 3155, 2924, 1702, 1660, 1607, 1485, 1324, 1221, 1051, 967, 743. 1H NMR (600 MHz, CDCl3): δ = 8.28 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H), 7.60–7.57 (m, 1H), 7.29–7.25 (m, 3H), 7.13 (d, J = 8.5 Hz, 1H), 7.07–7.04 (m, 2H), 6.02 (ddt, 3J = 16.1 Hz, 3J = 10.2 Hz, 3J = 5.8 Hz, 1H, CH2–CH=CH2), 5.37 (s, 2H, CH2Ph), 5.36 (dd, 3J = 16.1 Hz, 2J = 1.4 Hz, 1H, CH2–CH=CHH), 5.26 (d, 3J = 10.2 Hz, 2J = 1.4 Hz, 1H, CH2–CH=CHH), 4.79 (d, 3J = 5.8 Hz, 2H, CH2–CH=CH2). 13C NMR (150 MHz, CDCl3): δ = 162.24 (d, 1J(CF) = 246.3 Hz, C4), 161.35 (C(O)), 151.13 (C(O)), 139.85, 135.07, 131.87, 131.49 (d, 4J(CCCCF) = 3.1 Hz, C1), 129.21, 128.31 (d, 3J(CCCF) = 7.86 Hz, C2, C6), 123.18, 117.99, 115.93 (d, 2J(CCF) = 21.8 Hz, C3, C5), 115.83, 114.17, 46.69, 44.01. Anal. calcd. for C18H15FN2O2: C, 69.67; H, 4.87; N, 9.03. Found: C, 69.76; H, 4.60; N, 9.27.
3.5. General Procedure for the Synthesis of Isoxazolidines cis-20 and trans-20 As Well As cis-21 and trans-21
Solutions of nitrones 14 or 15 (1.00 mmol) and the respective N3-allylated quinazoline-2,4-dione 24a–d (1.00 mmol) in toluene were stirred at 60 °C until the starting nitrone disappeared. Solvents were evaporated in vacuo and the crude products were obtained as the mixtures of the respective diastereoisomeric isoxazolidines cis-20/trans-20 or cis-21/trans-21, which were then purified on a silica gel purified on silica gel column chromatography with chloroform–hexane mixtures as eluents.
Diethyl trans-5-((1-benzyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)methyl)-2-methylisoxazolidin-3-yl)phosphonate (trans-20a). Colorless oil. IR (film, cm–1) νmax: 2981, 1706, 1660, 1607, 1484, 1350, 1238, 1052, 1025, 968, 759. NMR signals of trans-20a were extracted from the spectra of 10:90 mixtures of cis-20a and trans-20a, 1H NMR (600 MHz, CDCl3): δ = 8.24 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H), 7.56–7.54 (m, 1H), 7.35–7.32 (m, 2H), 7.29–7.26 (m, 3H), 7.23–7.21 (m, 1H), 7.13 (d, J = 8.5 Hz, 1H), 5.41 (AB, JAB = 16.4 Hz, 1H, HCHN), 5.36 (AB, JAB = 16.4 Hz, 1H, HCHN), 4.53–4.48 (m, 2H, HC5, HCHN), 4.26 (dd, 2J = 16.7 Hz, 3J(HC–H5) = 8.4 Hz, 1H, HCHN), 4.23–4.16 (m, 4H, 2 × CH2OP), 3.10 (ddd, 3J(H3–H4β) = 9.7 Hz, 3J(H3–H4α) = 7.0 Hz, 2J(H3–P) = 2.3 Hz, 1H, HC3), 2.91 (s, 3H, CH3N), 2.67 (dddd, 3J(H4α–P) = 19.4 Hz, 2J(H4α–H4β) = 12.4 Hz, 3J(H4α–H3) = 7.0 Hz, 3J(H4β–H5) = 7.0 Hz, 1H, HαC4), 2.42 (dddd, 2J(H4β–H4α) = 12.4 Hz, 3J(H4β–P) = 12.4 Hz, 3J(H4β–H3) = 9.7 Hz, 3J(H4β–H5) = 6.4 Hz, 1H, HβC4), 1.35 (t, 3J = 7.0 Hz, 3H, CH3CH2OP), 1.34 (t, 3J = 7.1 Hz, 3H, CH3CH2OP). 13C NMR (150 MHz, CDCl3): δ = 161.683 (C(O)), 151.38 (C(O)), 139.97, 135.66, 135.12, 129.15, 128.95, 127.66, 126.49, 123.09, 115.68, 114.38, 74.49 (d, 3J(CCCP) = 7.7 Hz, C5), 63.89 (d, 1J(CP) = 168.7 Hz, C3), 63.11 (d, 2J(COP) = 6.4 Hz, CH2OP), 62.36 (d, 2J(COP) = 6.3 Hz, CH2OP), 47.41 (CH2N), 46.51 (d, 3J(CNCP) = 4.3 Hz, CH3N), 44.32 (CH2Ph), 36.27 (d, 2J(CCP) = 1.7 Hz, C4), 16.50 (d, 3J(CCOP) = 6.2 Hz, CH3CH2OP), 16.46 (d, 3J(CCOP) = 6.3 Hz, CH3CH2OP). 31P NMR (243 MHz, CDCl3): δ = 22.14. Anal.calcd. for. C24H30N3O6P: C, 59.13; H, 6.20; N, 8.62. Found: C, 59.38; H, 5.97; N, 8.91 (obtained on 10:90 mixtures of cis-20a and trans-20a).
Diethyl trans-(5-((1-(2-fluorobenzyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)methyl)-2-methylisoxazolidin-3-yl)phosphonate (trans-20b). Colorless oil. IR (film, cm–1) νmax: 2981, 1707, 1661, 1608, 1483, 1351, 1231, 1052, 1023, 967, 756. NMR signals of trans-20b were extracted from the spectra of 8:92 mixtures of cis-20b and trans-20b, 1H NMR (600 MHz, CDCl3): δ = 8.24 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H), 7.60–7.57 (m, 1H), 7.28–7.23 (m, 2H), 7.14–7.10 (m, 3H), 7.07–7.05 (m, 1H), 5.46 (AB, JAB = 16.8 Hz, 1H, HCHN), 5.42 (AB, JAB = 16.8 Hz, 1H, HCHN), 4.54–4.48 (m, 2H, HC5, HCHN), 4.29–4.25 (m, 1H, HCHN), 4.24–4.1 (m, 4H, 2 × CH2OP), 3.12–3.09 (m, 1H, HC3), 2.91 (s, 3H, CH3N), 2.68 (dddd, 3J(H4α–P) = 19.8 Hz, 2J(H4α–H4β) = 12.7 Hz, 3J(H4α–H3) = 7.3 Hz, 3J(H4β–H5) = 7.3 Hz, 1H, HαC4), 2.43 (dddd, 2J(H4β–H4α) = 12.7 Hz, 3J(H4β–P) = 12.7 Hz, 3J(H4β–H3) = 11.2 Hz, 3J(H4β–H5) = 6.7 Hz, 1H, HβC4), 1.35 (t, 3J = 7.1 Hz, 3H, CH3CH2OP), 1.34 (t, 3J = 7.1 Hz, 3H, CH3CH2OP). 13C NMR (150 MHz, CDCl3): δ = 161.62 (C(O)), 160.30 (d, 1J(CF) = 245.6 Hz, C2’), 151.44 (C(O)), 139.65, 135.23, 129.40 (d, 3J(CCCF) = 8.0 Hz, C6’), 129.21, 128.13 (d, 3J(CCCF) = 3.7 Hz, C4’), 124.69 (d, 4J(CCCCF) = 3.3 Hz, C5’), 123.26, 122.69 (d, 2J(CCF) = 14.0 Hz, C3’), 115.66, 115.57 (d, 2J(CCF) = 21.9 Hz, C1’), 113.97 (d, 5J = 1.4 Hz), 74.46 (d, 3J(CCCP) = 7.7 Hz, C5), 63.86 (d, 1J(CP) = 168.6 Hz, C3), 63.15 (d, 2J(COP) = 6.5 Hz, CH2OP), 62.38 (d, 2J(COP) = 7.1 Hz, CH2OP), 46.44 (d, 3J(CNCP) = 3.6 Hz, CH3N), 44.33 (CH2N), 41.01 (d, 3J(CCCF) = 5.2 Hz, CH2Ph), 35.22 (d, 2J(CCP) = 1.6 Hz, C4), 16.50 (d, 3J(CCOP) = 6.3 Hz, CH3CH2OP), 16.46 (d, 3J(CCOP) = 5.9 Hz, CH3CH2OP). 31P NMR (243 MHz, CDCl3): δ = 21.95. Anal.calcd. for C24H29FN3O6P × 1.5 H2O: C, 54.13; H, 6.06; N, 7.89. Found: C, 54.16; H, 5.77; N, 7.61 (obtained on 8:92 mixtures of cis-20b and trans-20b).
Diethyl trans-(5-((1-(3-fluorobenzyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)methyl)-2-methylisoxazolidin-3-yl)phosphonate (trans-20c). Colorless oil. IR (film, cm–1) νmax: 2983, 1706, 1653, 1609, 1484, 1401, 1346, 1251, 1097, 1024, 967, 762. NMR signals of trans-20c were extracted from the spectra of 8:92 mixtures of cis-20c and trans-20c, 1H NMR (600 MHz, CDCl3): δ = 8.23 (dd, J = 7.9 Hz, J = 1.2 Hz, 1H), 7.57–7.55 (m, 1H), 7.32–7.28 (m, 1H), 7.24–7.22 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.97–6.94 (m, 2H), 5.40 (AB, JAB = 16.6 Hz, 1H, HCHN), 5.31 (AB, JAB = 16.6 Hz, 1H, HCHN), 4.51–4.46 (m, 2H, HC5, HCHN), 4.25 (dd, 2J = 16.4 Hz, 3J(HC–H5) = 8.1 Hz, 1H, HCHN), 4.21–4.14 (m, 4H, 2 × CH2OP), 3.10–3.07 (m, 1H, HC3), 2.89 (s, 3H, CH3N), 2.66 (dddd, 3J(H4α–P) = 19.3 Hz, 2J(H4α–H4β) = 12.8 Hz, 3J(H4α–H3) = 7.0 Hz, 3J(H4β–H5) = 7.0 Hz, 1H, HαC4), 2.40 (dddd, 2J(H4β–H4α) = 12.8 Hz, 3J(H4β–P) = 12.8 Hz, 3J(H4β–H3) = 10.2 Hz, 3J(H4β–H5) = 6.8 Hz, 1H, HβC4), 1.34 (t, 3J = 7.0 Hz, 3H, CH3CH2OP), 1.34 (t, 3J = 7.1 Hz, 3H, CH3CH2OP). 13C NMR (150 MHz, CDCl3): δ = 163.19 (d, 1J(CF) = 246.9 Hz, C3’), 161.55 (C(O)), 151.32 (C(O)), 139.75, 138.32 (d, 3J(CCCF) = 7.2 Hz, C5’), 135.22, 130.58 (d, 3J(CCCF) = 8.0 Hz, C1’), 129.26, 123.27, 122.10 (d, 4J(CCCCF) = 2.4 Hz, C6’), 115.69, 114.71 (d, 2J(CCF) = 21.1 Hz, C2’), 114.11, 113.60 (d, 2J(CCF) = 22.1 Hz, C4’), 75.43 (d, 3J(CCCP) = 7.7 Hz, C5), 63.88 (d, 1J(CP) = 168.8 Hz, C3), 63.11 (d, 2J(COP) = 6.3 Hz, CH2OP), 62.36 (d, 2J(COP) = 7.2 Hz, CH2OP), 46.95 (CH2N), 46.46 (d, 3J(CNCP) = 4.1 Hz, CH3N), 44.32 (CH2Ph), 35.06 (d, 2J(CCP) = 1.4 Hz, C4), 16.49 (d, 3J(CCOP) = 6.3 Hz, CH3CH2OP), 16.44 (d, 3J(CCOP) = 6.6 Hz, CH3CH2OP). 31P NMR (243 MHz, CDCl3): δ = 22.09. Anal.calcd. for C24H29FN3O6P × 2.5 H2O: C, 52.36; H, 6.23; N, 7.63. Found: C, 52.35; H, 5.95; N, 7.42 (obtained on 8:92 mixtures of cis-20c and trans-20c).
Diethyl trans-(5-((1-(4-fluorobenzyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)methyl)-2-methylisoxazolidin-3-yl)phosphonate (trans-20d). Colorless oil. IR (film, cm–1) νmax: 2983, 1706, 1661, 1608, 1483, 1329, 1232, 1052, 967, 1024, 756. NMR signals of trans-20d were extracted from the spectra of 8:92 mixtures of cis-20d and trans-20d, 1H NMR (600 MHz, CDCl3): δ = 8.13 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H), 7.60–7.57 (m, 1H), 7.28–7.24 (m, 3H), 7.12–7.28 (d, J = 8.4 Hz, 1H), 7.06–7.03 (m, 2H), 5.31 (AB, JAB = 16.3 Hz, 1H, HCHN), 5.32 (AB, JAB = 16.3 Hz, 1H, HCHN), 4.61–4.52 (m, 1H, HC5), 4.50 (dd, 2J = 12.4 Hz, 3J(HC–H5) = 7.6 Hz, 1H, HCHN), 4.26 (dd, 2J = 12.4 Hz, 3J(HC–H5) = 3.8 Hz, 1H, HCHN), 4.24–4.17 (m, 4H, 2 × CH2OP), 3.14–3.12 (m, 1H, HC3), 2.70 (dddd, 3J(H4α–P) = 19.8 Hz, 2J(H4α–H4β) = 12.6 Hz, 3J(H4α–H3) = 7.3 Hz, 3J(H4β–H5) = 7.3 Hz, 1H, HαC4), 2.43 (dddd, 2J(H4β–H4α) = 12.6 Hz, 3J(H4β–P) = 12.6 Hz, 3J(H4β–H3) = 9.9 Hz, 3J(H4β–H5) = 6.7 Hz, 1H, HβC4), 1.37 (t, 3J = 7.1 Hz, 3H, CH3CH2OP), 1.36 (t, 3J = 7.1 Hz, 3H, CH3CH2OP). 13C NMR (150 MHz, CDCl3): δ = 162.25 (d, 1J(CF) = 246.3 Hz, C4’), 161.44 (C(O)), 151.35 (C(O)), 139.82, 135.19, 130.89 (d, 4J(CCCCF) = 3.0 Hz, C1’), 129.30, 128.32 (d, 3J(CCCF) = 8.4 Hz, C2’, C6’), 123.24, 115.17 (d, 2J(CCF) = 21.8 Hz, C3’, C6’), 115.71, 114.16, 74.67 (d, 3J(CCCP) = 7.8 Hz, C5), 63.81 (d, 1J(CP) = 163.9 Hz, C3), 63.25 (d, 2J(COP) = 6.4 Hz, CH2OP), 62.49 (d, 2J(COP) = 6.7 Hz, CH2OP), 46.80 (CH2N), 46.30 (d, 3J(CNCP) = 2.0 Hz, CH3N), 44.32 (CH2Ph), 36.16 (C4), 16.51 (d, 3J(CCOP) = 5.5 Hz, CH3CH2OP), 16.4 (d, 3J(CCOP) = 5.6 Hz, CH3CH2OP). 31P NMR (243 MHz, CDCl3): δ = 21.70. Anal.calcd. for C24H29FN3O6P × 1.5 H2O: C, 54.13; H, 6.06; N, 7.89. Found: C, 54.32; H, 5.90; N, 7.73 (obtained on 10:90 mixtures of cis-20d and trans-20d).
Diethyl trans-(2-benzyl-5-((1-benzyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)methyl)isoxazolidin-3-yl)phosphonate (trans-21a). Colorless oil. IR (film, cm–1) νmax: 2979, 1710, 1657, 1607, 1483, 1404, 1231, 1054, 1020, 967, 764. NMR signals of trans-21a were extracted from the spectra of 10:90 mixtures of cis-21a and trans-21a. 1H NMR (600 MHz, CDCl3): δ = 8.25 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H), 7.56–7.53 (m, 1H), 7.43–7.39 (m, 2H), 7.33–7.31 (m, 2H), 7.29–7.21 (m, 7H), 7.11 (d, J = 8.5 Hz, 1H), 5.40 (AB, JAB = 16.3 Hz, 1H, HCHN), 5.34 (AB, JAB = 16.3 Hz, 1H, HCHN), 4.57–4.53 (m, 1H, HC5), 4.49 (dd, 2J = 12.9 Hz, 3J(HC–H5) = 5.5 Hz, 1H, HCHN), 4.46 (d, 2J = 13.9 Hz, 1H, HCHPh), 4.26–4.18 (m, 5H, 2 × CH2OP, HCHN), 4.09 (d, 2J = 13.9 Hz, 1H, HCHPh), 3.42 (ddd, 3J(H3–H4β) = 9.2 Hz, 3J(H3–H4α) = 7.3 Hz, 2J(H3–P) = 3.0 Hz, 1H, HC3), 2.69 (dddd, 3J(H4α–P) = 17.3 Hz, 2J(H4α–H4β) = 12.6 Hz, 3J(H4α–H3) = 7.3 Hz, 3J(H4β–H5) = 7.3 Hz, 1H, HαC4), 2.42 (dddd, 2J(H4β–H4α) = 12.6 Hz, 3J(H4β–P) = 12.6 Hz, 3J(H4β–H3) = 9.2 Hz, 3J(H4α–H5) = 7.3 Hz, 1H, HβC4), 1.35 (t, 3J = 7.0 Hz, 3H, CH3CH2OP), 1.34 (t, 3J = 7.0 Hz, 3H, CH3CH2OP). 13C NMR (150 MHz, CDCl3): δ = 161.73 (C(O)), 151.35 (C(O)), 139.98, 137.17, 135.65, 135.11, 129.56, 128.98, 128.07, 127.63, 127.63, 127.18, 126.43, 123.10, 115.71, 114.42, 74.47 (d, 3J(CCCP) = 7.4 Hz, C5), 63.25 (d, 2J(COP) = 6.5 Hz, CH2OP), 62.96 (d, 3J(CNCP) = 5.5 Hz, CH2Ph), 62.44 (d, 2J(COP) = 6.8 Hz, CH2OP), 60.90 (d, 1J(CP) = 170.3 Hz, C3), 47.43 (CH2N), 44.69 (CH2Ph), 35.49 (C4), 16.53 (d, 3J(CCOP) = 5.6 Hz, CH3CH2OP), 16.50 (d, 3J(CCOP) = 5.7 Hz, CH3CH2OP). 31P NMR (243 MHz, CDCl3): δ = 22.13. Anal.calcd. for C30H34N3O6P: C, 63.93; H, 6.08; N, 7.46. Found: C, 63.66; H, 6.38; N, 7.20 (obtained on 10:90 mixtures of cis-21a and trans-21a).
Diethyl trans-(2-benzyl-5-((1-(2-fluorobenzyl)-2,4-dioxo-1,2-dihydroquinazolin-3(2H)-yl)methyl)isoxazolidin-3-yl)phosphonate (trans-21b). Colorless oil. IR (film, cm–1) νmax: 2981, 1710, 1657, 1607, 1482, 1354, 1246, 1054, 1020, 967, 764. NMR signals of trans-21b were extracted from the spectra of 15:85 mixtures of cis-21b and trans-21b. 1H NMR (600 MHz, CDCl3): δ = 8.26 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H), 7.60–7.57 (m, 1H), 7.42–7.38 (m, 2H), 7.29–7.21 (m, 5H), 7.14–7.10 (m, 2H), 7.07–7.05 (m, 1H), 7.03–7.00 (m, 1H), 5.45 (AB, JAB = 16.9 Hz, 1H, HCHN), 5.41 (AB, JAB = 16.9 Hz, 1H, HCHN), 4.56 (d, 2J = 13.9 Hz, 1H, HCHPh), 4.50 (dd, 2J = 12.8 Hz, 3J(HC–H5) = 7.5 Hz, 1H, HCHN), 4.40–4.39 (m, 1H, HC5), 4.26–4.18 (m, 5H, 2 × CH2OP, HCHN), 4.08 (d, 2J = 13.9 Hz, 1H, HCHPh), 3.42 (ddd, 3J(H3–H4β) = 9.1 Hz, 3J(H3–H4α) = 7.2 Hz, 2J(H3–P) = 3.0 Hz, 1H, HC3), 2.69 (dddd, 3J(H4α–P) = 19.7 Hz, 2J(H4α–H4β) = 12.8 Hz, 3J(H4α–H3) = 7.2 Hz, 3J(H4β–H5) = 7.2 Hz, 1H, HαC4), 2.42 (dddd, 3J(H4β–P) = 12.8 Hz, 2J(H4β–H4α) = 12.8 Hz, 3J(H4β–H3) = 9.1 Hz, 3J(H4β–H5) = 6.5 Hz, 1H, HβC4), 1.35 (t, 3J = 7.1 Hz, 3H, CH3CH2OP), 1.34 (t, 3J = 7.1 Hz, 3H, CH3CH2OP). 13C NMR (150 MHz, CDCl3): δ = 161.66 (C(O)), 160.29 (d, 1J(CF) = 245.6 Hz, C2’), 151.40 (C(O)), 139.66, 136.87, 135.30, 129.63, 129.35 (d, 3J(CCCF) = 8.3 Hz, C6’), 129.18, 128.08, 128.05 (d, 3J(CCCF) = 3.5 Hz, C4’), 127.26, 124.75 (d, 4J(CCCCF) = 3.3 Hz, C5’), 123.27 122.67 (d, 2J(CCF) = 14.0 Hz, C3’), 115.70, 115.57 (d, 2J(CCF) = 21.5 Hz, C1’), 113.98, 74.48 (d, 3J(CCCP) = 7.3 Hz, C5), 63.32 (d, 2J(COP) = 6.5 Hz, CH2OP), 62.80 (d, 3J(CNCP) = 5.4 Hz, CH2Ph), 62.47 (d, 2J(COP) = 6.9 Hz, CH2OP), 60.79 (d, 1J(CP) = 169.6 Hz, C3), 44.68 (CH2N), 41.08 (d, 3J(CCCF) = 5.3 Hz, CH2Ph), 35.43 (d, 2J(CCP) = 1.6 Hz, C4), 16.53 (d, 3J(CCOP) = 5.6 Hz, CH3CH2OP), 16.49 (d, 3J(CCOP) = 5.8 Hz, CH3CH2OP). 31P NMR (243 MHz, CDCl3): δ = 22.12. Anal.calcd. for C30H33FN3O6P: C, 61.96; H, 5.72; N, 7.23. Found: C, 61.86; H, 5.57; N, 7.35 (obtained on 15:85 mixtures of cis-21b and trans-21b).
Diethyl trans-(2-benzyl-5-((1-(3-fluorobenzyl)-2,4-dioxo-1,2-dihydroquinazolin-3(2H)-yl)methyl)isoxazolidin-3-yl)phosphonate (trans-21c). Colorless oil. IR (film, cm–1) νmax: 2978, 1704, 1656, 1607, 1483, 1351 1246, 1053, 1022, 968, 765. NMR signals of trans-21c were extracted from the spectra of 15:85 mixtures of cis-21c and trans-21c. 1H NMR (600 MHz, CDCl3): δ = 8.13 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H), 7.58 (ddd, J = 8.6 Hz, J = 7.3 Hz, J = 1.6 Hz, 1H), 7.42–7.38 (m, 2H), 7.31–7.21 (m, 5H), 7.07 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 7.00–6.94 (m, 2H), 5.39 (AB, JAB = 16.7 Hz, 1H, HCHN), 5.33 (AB, JAB = 16.7 Hz, 1H, HCHN), 4.56–4.47 (m, 1H, HC5), 4.50 (dd, 2J = 13.8 Hz, 3J(HC–H5) = 5.3 Hz, 1H, HCHN), 4.45 (d, 2J = 13.8 Hz, 1H, HCHPh), 4.26–4.17 (m, 5H, 2 × CH2OP, HCHN), 4.08 (d, 2J = 13.8 Hz, 1H, HCHPh), 3.41 (ddd, 3J(H3–H4β) = 9.2 Hz, 3J(H3–H4α) = 7.1 Hz, 2J(H3–P) = 3.1 Hz, 1H, HC3), 2.69 (dddd, 3J(H4α–P) = 17.3 Hz, 2J(H4α–H4β) = 12.9 Hz, 3J(H4α–H3) = 7.1 Hz, 3J(H4β–H5) = 7.1 Hz, 1H, HαC4), 2.42 (dddd, 2J(H4β–H4α) = 12.9 Hz, 3J(H4β–P) = 12.9 Hz, 3J(H4β–H3) = 9.2 Hz, 3J(H4β–H5) = 6.6 Hz, 1H, HβC4), 1.36 (t, 3J = 7.1 Hz, 3H, CH3CH2OP), 1.35 (t, 3J = 7.1 Hz, 3H, CH3CH2OP). 13C NMR (150 MHz, CDCl3): δ = 163.20 (d, 1J(CF) = 247.6 Hz, C3’), 161.61 (C(O)), 151.30 (C(O)), 139.78, 138.30 (d, 3J(CCCF) = 6.8 Hz, C5’), 137.11, 135.20, 130.65 (d, 3J(CCCF) = 8.0 Hz, C1’), 129.56, 129.25, 128.06, 127.19, 123.29, 122.01 (d, 4J(CCCCF) = 2.8 Hz, C6’), 115.75, 115.70 (d, 2J(CCF) = 21.0 Hz, C2’), 114.14, 113.57 (d, 2J(CCF) = 22.4 Hz, C4’), 75.45 (d, 3J(CCCP) = 7.1 Hz, C5), 63.25 (d, 2J(COP) = 6.5 Hz, CH2OP), 62.94 (d, 3J(CNCP) = 5.7 Hz, CH2Ph), 62.45 (d, 2J(COP) = 6.8 Hz, CH2OP), 60.87 (d, 1J(CP) = 169.8 Hz, C3), 47.01 (CH2N), 44.73 (CH2Ph), 35.17 (d, 2J(CCP) = 1.7 Hz, C4), 16.51 (d, 3J(CCOP) = 5.7 Hz, CH3CH2OP), 16.48 (d, 3J(CCOP) = 5.6 Hz, CH3CH2OP). 31P NMR (243 MHz, CDCl3): δ = 22.09. Anal.calcd. for C30H33FN3O6P: C, 61.69; H, 5.72; N, 7.23. Found: C, 61.97; H, 5.89; N, 7.11 (obtained on 10:90 mixtures of cis-21c and trans-21c).
Diethyl trans-(2-benzyl-5-((1-(4-fluorobenzyl)-2,4-dioxo-1,2-dihydroquinazolin-3(2H)-yl)methyl)isoxazolidin-3-yl)phosphonate (trans-21d). Colorless oil. IR (film, cm–1) νmax: 2978, 1710, 1657, 1607, 1482, 1353, 1243, 1054, 1020, 967, 764. NMR signals of trans-21d were extracted from the spectra of 15:85 mixtures of cis-21d and trans-21d. 1H NMR (600 MHz, CDCl3): δ = 8.24 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H), 7.59–7.57 (m, 1H), 7.42–7.38 (m, 2H), 7.27–7.22 (m, 6H), 7.10 (d, J = 8.5 Hz, 1H), 7.03–6.99 (m, 2H), 5.38 (AB, JAB = 15.1 Hz, 1H, HCHN), 5.30 (AB, JAB = 15.1 Hz, 1H, HCHN), 4.56–4.48 (m, 2H, HC5, HCHN), 4.46 (d, 2J = 13.8 Hz, 1H, HCHPh), 4.26–4.18 (m, 5H, 2 × CH2OP, HCHN), 4.08 (d, 2J = 13.8 Hz, 1H, HCHPh), 3.41 (ddd, 3J(H3–H4β) = 9.2 Hz, 3J(H3–H4α) = 7.1 Hz, 2J(H3–P) = 3.1 Hz, 1H, HC3), 2.70 (dddd, 3J(H4α–P) = 19.6 Hz, 2J(H4α–H4β) = 12.07 Hz, 3J(H4α–H3) = 7.1 Hz, 3J(H4β–H5) = 7.1 Hz, 1H, HαC4), 2.42 (dddd, 2J(H4β–H4α) = 12.7 Hz, 3J(H4β–P) = 12.7 Hz, 3J(H4β–H3) = 9.2 Hz, 3J(H4β–H5) = 6.3 Hz, 1H, HβC4), 1.37 (t, 3J = 7.0 Hz, 3H, CH3CH2OP), 1.36 (t, 3J = 7.0 Hz, 3H, CH3CH2OP). 13C NMR (150 MHz, CDCl3): δ = 162.21 (d, 1J(CF) = 246.5 Hz, C4’), 161.63 (C(O)), 151.31 (C(O)), 139.82, 137.18, 135.13, 131.37 (d, 4J(CCCCF) = 3.0 Hz, C1’), 129.52, 129.23, 128.85, 128.25 (d, 3J(CCCF) = 7.9 Hz, C2’, C6’), 128.06, 127.99, 127.18, 123.21, 115.93 (d, 2J(CCF) = 21.3 Hz, C3’, C5’), 115.77, 114.17, 74.42 (d, 3J(CCCP) = 7.0 Hz, C5), 63.23 (d, 2J(COP) = 6.5 Hz, CH2OP), 62.95 (d, 3J(CNCP) = 5.5 Hz, CH2Ph), 62.45 (d, 2J(COP) = 6.8 Hz, CH2OP), 60.92 (d, 1J(CP) = 169.8 Hz, C3), 46.79 (CH2N), 44.75 (CH2Ph), 35.50 (d, 2J(CCP) = 1.8 Hz, C4), 16.52 (d, 3J(CCOP) = 5.4 Hz, CH3CH2OP), 16.48 (d, 3J(CCOP) = 5.4 Hz, CH3CH2OP). 31P NMR (243 MHz, CDCl3): δ = 22.09. Anal.calcd. for C30H33FN3O6P: C, 61.96; H, 5.72; N, 7.23. Found: C, 62.26; H, 5.80; N, 7.00 (obtained on 10:90 mixtures of cis-21d and trans-21d).