6082
C. Gasse et al. / Bioorg. Med. Chem. 16 (2008) 6075–6085
(ESI-TOF) m/z calcd for C16H18N2O4+Na 325.1164;
found 325.1162.
4.2.9. 1-(4-Hydroxy-butyn-1-yl-benzyl)-1H-pyrimidine-
2,4-dione (18). As for 14, reaction of 17 (0.52 g,
1.87 mmol) and 3-butyn-1-ol (0.17 g, 2.40 mmol) in dry
CH2Cl2 (28 mL) with Et3N (32 mL), at 80 ꢁC for 48 h
afforded after column chromatography 18 (0.33 g,
64%). 1H NMR (DMSO-d6) d 2.54 (t, 2H, CH2,
J = 6.8), 3.57 (q, 2H, CH2), 4.87 (s, 2H, PhCH2), 4.89
(t, 1H, OH), 5.60 (dd, 1H, H5, J = 7.8, J = 2.1), 7.25
(d, 2H, H arom., J = 8.3), 7.38 (dd, 2H, H arom.,
J = 6.5, J = 2.7), 7.76 (d, 1H, H6), 11.33 (br s, 1H,
NH). 13C NMR (DMSO-d6) d 24.12 (CH2), 50.88
(PhCH2), 60.56 (CH2), 81.52 (C), 89.72 (C), 102.26
(C5), 123.36 (CH ortho), 128.41 (CH meta), 132.38 (C
arom.), 137.50 (C arom.), 146.38 (C6), 151.85 (C2),
164.50 (C4). MS (ESI-TOF) m/z 293.1 (100%,
M+Na)+, 333.2 (5%, M+Na+K)+.
4.2.6. 4-[4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H -pyrimi-
din-1-yl-methyl)-phenyl]-butanoic acid methyl ester (12).
Hydrogenation of 10 afforded 12 (95%) after silica gel
1
column chromatography. H NMR (DMSO-d6) d 1.80
(d, 3H, CH3), 1.86 (m, 2H, CH2), 2.36 (t, 2H, CH2,
J = 7.4), 2.62 (t, 2H, CH2, J = 7.5), 3.63 (m, 3H,
OCH3), 4.85 (s, 1H, PhCH2), 7.23 (d, 2H, H meta),
7.27 (d, 2H, H ortho), 7.67 (d, 1H, H6, J = 1.1),
11.32 (br s, 1H, NH). 13C NMR (DMSO-d6) d 12.77
(CH3), 27.01 (CH2), 33.55 (CH2), 34.78 (CH2), 50.61
(PhCH2), 52.07 (OCH3), 109.83 (C5), 128.39 (CH
ortho), 129.46 (CH meta), 135.43 (C arom.), 141.71
(C arom.), 142.11 (C6), 151.85 (C2), 165.07 (C4),
173.95 (COOCH3). MS (ESI-TOF) m/z 339.1 (100%,
M+Na)+.
4.2.10. 1-[4-(4-Hydroxy-butyl)-benzyl]-1H-pyrimidine-
2,4-dione (19). Hydrogenation of 18 (0.19 g, 0.71 mmol)
1
4.2.7. 4-[4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H -pyrimi-
din-1-yl-methyl)-phenyl]-butanamide (13). Compound 12
(40 mg, 0.13 mmol) was treated with a saturated solu-
tion of ammonia in MeOH (4 mL) at 65 ꢁC overnight
to give after purification on silica gel (5% MeOH in
CH2Cl2) unreacted ester 12 (8 mg, 20%) and amide 13
(20 mg, 47%). 1H NMR (DMSO-d6) d 1.76 (m, 5H,
CH2 and CH3), 2.05 (t, 2H, CH2, J = 7.5), 2.54 (t, 2H,
CH2), 4.80 (s, 1H, PhCH2), 6.73 (br s, 1H, CONH2),
7.17 (d, 2H, H ortho), 7.21 (d, 2H, H meta), 7.62 (d,
1H, H6, J = 1.2), 7.25 (br s, 1H, CONH2), 11.31 (br s,
1H, NH). 13C NMR (DMSO-d6) d 12.78 (CH3), 27.64
(CH2), 35.17 and 35.36 (2·CH2), 50.63 (PhCH2),
109.83 (C5), 128.35 (CH ortho), 129.44 (CH meta),
135.28 (C arom.), 142.13 (C6), 142.17 (C arom.),
151.86 (C2), 165.09 (C4), 174.82 (CONH2). HRMS
(ESI-TOF) m/z calcd for C16H19N3O4+Na 324.1324;
found 324.1342.
gave 19 (0.17 g, 88%). H NMR (DMSO-d6) d 1.41 (m,
2H, CH2), 1.57 (m, 2H, CH2), 2.55 (t, 2H, CH2, J = 7.6),
3.39 (m, 2H, CH2), 4.35 (t, 1H, OH), 4.83 (s, 2H,
PhCH2), 5.58 (dd, 1H, H5, J = 7.8, J = 2.3), 7.19 (m,
4H, H arom.), 7.74 (d, 1H, H6, J = 7.8), 11.30 (br s,
1H, NH). 13C NMR (DMSO-d6) d 28.26 (CH2), 32.93
(CH2), 35.46 (CH2), 50.84 (PhCH2), 61.34 (CH2),
102.14 (C5), 128.40 (CH ortho), 129.42 (CH meta),
134.95 (C arom.), 142.74 (C arom.), 146.45 (C6),
151.86 (C2), 164.50 (C4). MS (ESI-TOF) m/z 297.1
(100%, M+Na)+, 431.4 (40%).
4.2.11. 4-[4-(2,4-Dioxo-3,4-dihydro-2H -pyrimidin-1-yl-
methyl)-phenyl]-butanoic acid (20). Chromic oxidation
of 19 (135 mg, 0.5 mmol) as for 11 gave the correspond-
ing tert-butyl ester (125 mg, 70%). Saponification of the
ester (105 mg, 0.29 mmol) afforded 20 as a white powder
1
(68 mg as sodium salt, 80%). H NMR (DMSO-d6) d
1.77 (m, 2H, CH2), 2.21 (t, 2H, CH2, J = 7.4), 2.57 (t,
2H, CH2, J = 7.7), 4.83 (s, 2H, PhCH2), 5.58 (dd, 1H,
H5, J = 2.2, J = 7.8), 7.20 (m, 4H, H arom.), 7.74 (d,
1H, H6, J = 8.8), 11.30 (br s, 1H, NH), 12.05 (br s,
1H, COOH). 13C NMR (DMSO-d6) d 27.08 (CH2),
33.91 (CH2), 34.89 (CH2), 50.83 (PhCH2), 102.15 (C5),
128.40 (CH ortho), 129.46 (CH meta), 135.19 (C arom.),
141.97 (C arom.), 146.44 (C6), 151.86 (C2), 164.50 (C4),
175.04 (COOH). HRMS (ESI-TOF) m/z calcd for
C15H16N2O4+Na 311.1008; found 311.1022.
4.2.8. 1-[4-(4-Hydroxy-butyn-1-yl)-benzyl]-5-methyl-1H -
pyrimidine-2,4-dione (14). To a solution of 3 (0.51 g,
1.50 mmol) in dry CH2Cl2 (15 mL) were added under ar-
gon freshly distilled Et3N (0.31 mL), 3-butyn-1-ol
(0.13 g, 1.95 mmol), tetrakis(triphenylphosphine)palla-
dium (0.06 g, 0.05 mmol) and cuprous iodide (26 mg,
0.02 mmol). After heating at 90 ꢁC under argon over-
night, the reaction mixture was concentrated to dryness.
To the residue was added CH2Cl2 (100 mL) and the
resulting solution was washed with 10% HCl, and water.
The organic layer was dried over Na2SO4, then evapo-
rated in vacuo. Purification by silica gel column chroma-
tography (0–3% MeOH in CH2Cl2) afforded recovered
iodide 3 (0.52 g, 27%) and 14 as a white powder
(0.18 g, 43%). 1H NMR (DMSO-d6) d 1.75 (d, 3H,
CH3, J = 1.2), 2.54 (m, 2H, CH2), 3.58 (m, 2H, CH2),
4.83 (s, 2H, PhCH2), 4.92 (t, 1H, OH), 7.25 (d, 2H, H
ortho, J = 8.0), 7.37 (d, 2H, H meta, J = 8.0), 7.61 (d,
1H, H6, J = 1.2), 11.33 (br s, 1H, NH). 13C NMR
(DMSO-d6) d 12.77 (CH3), 24.09 (CH2), 50.72 (PhCH2),
60.57 (CH2), 81.54 (C), 89.68 (C), 109.98 (C5), 123.32 (C
arom.), 128.40 (CH ortho), 132.38 (CH meta), 137.63 (C
arom.), 142.14 (C6), 151.84 (C2), 165.13 (C4). HRMS
(ESI-TOF) m/z calcd for C16H17N2O3+Na 307.1059;
found 307.1048.
4.2.12. 4-(5-Bromo-2,4-dioxo-3,4-dihydro-2H -pyrimidin-
1-ylmethyl)-butanoic acid (21). A 1 M solution of bro-
mine in CCl4 (1.3 equiv) was added to uracil derivative
20 (50 mg, 0.17 mmol) in pyridine (20 mL/mmol). After
stirring for 90 min at room temperature, the reaction
was complete (TLC) and the solution was concentrated
under vacuum. The residue was purified by silica gel col-
umn chromatography (0–20% MeOH in CH2Cl2) to af-
ford compound 21 as a pale yellow powder (45 mg,
1
70%). H NMR (DMSO-d6) d 1.77 (m, 2H, CH2), 2.21
(t, 2H, CH2, J = 7.3), 2.57 (t, 2H, CH2, J = 7.6), 4.84
(s, 2H, PhCH2), 7.18 (d, 2H, H meta, J = 8.1), 7.25 (d,
2H, H ortho), 8.35 (d, 1H, H6), 11.83 (br s, 1H, NH),
12.05 (br s, 1H, COOH). 13C NMR (DMSO-d6) d
27.08 (CH2), 33.92 (CH2), 34.90 (CH2), 51.32 (PhCH2),