Synthesis of N-substituted 5-iodouracil analogs 7a-d and 8a-b
5-Iodouracil was dissolved in DMSO (5 mL), then K2CO3 was added and the mixture stirred at 80 °C for 15 min. Alkylating agent was added dropwise (5 min) to the solution then stirred for 48 h at 80 °C. Products were collected by filtration or by solvent extractions. Purification by silica gel column using hexane-ethyl acetate (8:2) as eluting solvent gave the required compounds. The products were recrystallized from methanol or dichloromethane-methanol (1:1).
1-(1-Butyl)-5-iodopyrimidine-2,4(1H, 3H)-dione (7a) and 1,3-di(1-butyl)-5-iodopyrimidine-2,4(1H, 3H)-dione (8a): 5-Iodouracil (0.476 g, 2.0 mmol), K2CO3 (0.138 g, 1.0 mmol) and 1-butyl bromide (0.274 g, 2.0 mmol) gave 7a (0.165 g, 25.01%) and 8a (0.047 g, 6.67%). Compound 7a; mp 175-176 °C; IR (KBr): υmax 3,022, 2,949, 1,715, 1,667, 1,606 cm-1; 1H-NMR (CDCl3): δ 0.95 (t, 3H, J = 7.2 Hz, H-4′), 1.35 (sextet, 2H, J = 7.2 Hz, H-3′), 1.66 (quintet, 2H, J = 7.5 Hz, H-2′), 3.73 (t, 2H, J = 7.2 Hz, H-1′), 7.59 (s, 1H, H-6), 8.86 (br, 1H, NH-3); 13C-NMR (CDCl3): δ 13.58 (C-4′), 19.62 (C-3′), 31.19 (C-2′), 48.98 (C-1′), 67.46 (C-5), 148.87 (C-6), 150.34 (C-2), 160.31 (C-4); LRMS (EI): m/z (%) = 295 (10.97) [M + H]+, 294 (100.00) [M]+, 238 (97.07), 167 (46.60); HRMS (TOF) m/z [M + H]+ calcd for C8H12IN2O2: 294.9938 found: 294.9940. Compound 8a; mp 70-71 °C; IR (KBr): υmax 3,051, 1,698, 1,651, 594 cm-1; 1H-NMR (CDCl3): δ 0.93-1.01 (m, 6H, H-4′, H-4′′), 1.32-1.44 (m, 4H, H-3′, H-3′′), 1.57-1.74 (m, 4H, H-2′, H-2′′), 3.76 (t, 2H, J = 7.4 Hz, H-1′), 4.00 (t, 2H, J = 7.5 Hz, H-1′′), 7.60 (s, 1H, H-6); 13C-NMR (CDCl3): δ 13.57 (C-4′′), 13.69 (C-4′), 19.68 (C-3′′), 20.13 (C-3′), 29.50 (C-2′′). 31.20 (C-2′), 42.88 (C-1′′), 49.89 (C-1′), 67.57 (C-5), 146.74 (C-6), 150.97 (C-2), 160.05 (C-4); LRMS (EI): m/z (%) = 351 (20.33) [M + H]+, 350 (69.42) [M]+, 333 (100.00), 308 (32.97), 293 (58.48), 252 (72.27), 238 (30.76); HRMS (TOF): m/z [M + H]+ calcd for C12H20IN2O2: 351.2018 found: 351.0567.
1-(2-Butyl)-5-iodopyrimidine-2,4(1H, 3H)-dione (7b): 5-Iodouracil (2.38 g (10.0 mmol), K2CO3 1.382 g (10.0 mmol) and 2-butyl bromide 1.372 g (10.0 mmol) furnished compound 7b 0.18 g (6.12%). Compound 7b; mp 194-195 °C; IR (KBr): υmax3159, 3034, 2962, 1716, 1700, 1654, 1599, 612 cm-1; 1H-NMR (CDCl3): δ 0.9 (t, 3H, J = 7.2 Hz, H-4′), 1.31 (d, 3H, J = 6.9 Hz, H-1′), 1.57-1.68 (m, 2H, H-3′), 4.59 (sextet, 1H, J = 6.9 Hz H-2′), 7.53 (s, 1H, H-6), 8.73 (br, 1H, NH-3); 13C-NMR (CDCl3): δ 10.52 (C-4′), 19.64 (C-1′), 28.69 (C-3′), 53.78 (C-2′), 67.87 (C-5), 145.21 (C-6), 150.61(C-2), 159.67(C-4); LRMS (EI): m/z (%) = 295 (11.18) [M + H]+, 294(47.12) [M]+, 237 (100), 167 (37.4); HRMS (TOF) m/z [M + H]+ calcd for C8H12IN2O2: 294.9938 found: 294.9941.
1-(Cyclohexylmethyl)-5-iodopyrimidine-2,4(1H, 3H)-dione (7c) and 1,3-bis(cyclohexylmethyl)-5-iodo-pyrimidine-2,4(1H, 3H)-dione (8b): 5-Iodouracil 0.476 g (2.0 mmol), K2CO3 0.138 g (1.0 mmol) and (bromomethyl)cyclohexane 0.354 g (2.0 mmol) gave 7c 0.182 g (28.09%) and 8b 0.065 g (7.5%). Compound 7c; mp 240-241°C; IR (KBr): υmax3159, 3021, 2920, 1701, 1660, 1606, 622 cm-1; 1H-NMR (CDCl3): δ 0.92-1.75 (m, 11H, H-2′, H-3′, H-4′, H-5′), 3.54 (d, 2H, J = 7.2 Hz, H-1′), 7.54 (s, 1H, H-6), 9.04 (br, 1H, NH-3); 13C-NMR (CDCl3): δ 25.47 (C-4′), 26.07 (C-5′), 30.30 (C-3′), 37.35 (C-2′), 55.13 (C-1′), 67.14 (C-5), 149.36 (C-6), 150.58 (C-2), 160.38 (C-4); LRMS (EI) : m/z (%) = 335 (12.84) [M + H]+, 334 (76.68) [M]+, 252 (11.45), 238 (100.00), 208 (12.14); HRMS (TOF) m/z [M + H]+ calcd for C11H16IN2O2: 335.0251 found: 335.0252. Compound 8b; m.p. 138-139°C; IR (KBr): υmax 3075, 2924, 1701, 1653, 1617 cm-1; 1H-NMR (CDCl3): δ0.89-1.81 (m, 22H, H-2′, H-2′′, H-3′, H-3′′,H-4′, H-4′′, H-5′, H-5′′), 3.56 (d, 2H, J = 7.01 Hz, H-1′), 3.84 (d, 2H, J = 7.2 Hz, H-1′′), 7.53 (s, 1H, H-6); 13C-NMR (CDCl3): δ 25.51 (C-4′′), 25.77 (C-4′), 26.11 (C-5′′), 26.29 (C-5′), 30.39 (C-3′′), 30.76 (C-3′), 36.19 (C-2′′), 37.37 (C-2′), 48.80 (C-1′′), 56.17 (C-1′), 67.28 (C-5), 147.29 (C-6), 151.33 (C-2), 160.33 (C-4); LRMS (EI): m/z (%) = 431 (9.87) [M + H]+, 430 (58.49) [M]+, 333 (64.21), 238 (100), 97 (79.25); HRMS (TOF) m/z [M + H]+ calcd for C18H28IN2O2: 431.3237 found: 431.3242.
1- Benzyl-5- iodopyrimidine-2,4(1H, 3H)-dione (
7d)
: 5-Iodouracil 0.476 g (2.0 mmol), K
2CO
3 (0.138 g, 1.0 mmol) and benzyl bromide (0.342 g, 2.0 mmol) gave compound
7d (0.075 g, 11.44%); mp 209-210°C (lit. mp 210-213°C [
18]); IR (KBr): υ
max 3112, 3011, 1714, 1669, 1452, 1426, 733 cm
-1;
1H- NMR (CDCl
3): δ 5.01 (s, 2H, H-1
′), 7.30-7.42 (m, 5H, ArH), 8.17 (s, 1H, H-6), 10.46 (br, 1H, NH-3);
13C-NMR (CDCl
3): δ 50.86 (C-1
′), 67.17 (C-5), 136.63 (C-2
′),149.48 (C-6),150.79 (C-2), 160.28 (C-4), 127.88,127.97,128.73 (Ar-C); LRMS (EI): m/z (%) = 329 (5.82) [M + H]
+, 328 (48.13) [M]
+, 91 (100.00); HRMS (TOF):
m/z [M + H]
+ calcd for C
11H
10IN
2O
2: 328.9781 found: 328.9791.