The Journal of Organic Chemistry
Article
room temperature. The solvent was evaporated, and the remaining
residue was coevaporated with MeOH (3 × 10 mL) and toluene (3 ×
10 mL). The resulting foam was applied to FC (silica gel, column 15 ×
4 cm, CH2Cl2/acetone, 4:1) to afford compound 11 (2.5 g, 88%) as a
colorless foam. TLC (silica gel, CH2Cl2/acetone, 4:1): Rf 0.35. λmax
residue was subjected to FC (silica gel, CH2Cl2/MeOH, 70:30), and
two products (14, 15) were isolated.
2,2′-Imino-1-(2-deoxy-β-D-arabinofuranosyl)uracil (14). From
the slower migrating zone compound 14 was isolated as colorless solid
(0.050 g, 54%). TLC (silica gel, CH2Cl2/MeOH, 70:30) Rf 0.27. λmax
1
(MeOH)/nm 258 (ε/dm3 mol−1 cm−1 8700). H NMR (DMSO-d6,
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(H2O)/nm 260 (ε/dm3 mol−1 cm−1 4000), 263 (4100). H NMR
300 MHz): δ 2.11 (s, 3H, CH3), 3.55−3.60 (m, 1H, H-5′), 3.68−3.71
(m, 1H, H-5′), 4.12−4.14 (m, 1H, H-4′), 5.16−5.27 (m, 2H, H-3′,
OH-5′), 5.41 (dt, J = 3.6 Hz, J = 52.5 Hz, 1H, H-2′), 5.68 (d, J = 8.1
Hz, 1H, H-5), 5.95 (dd, J = 3.0 Hz, J = 18.9 Hz, 1H, H-1′), 7.86 (d, J =
7.8 Hz, 1H, H-6), 11.46 (bs, 1H, NH). 19F NMR (DMSO-d6, 282.4
MHz): δ −202.456. ESI-TOF: m/z calcd for C11H13FN2O6 [M + Na]+
311.0650, found 311.0654.
(DMSO-d6, 300 MHz): 3.10−3.27 (m, 2H, 2 × H-5′), 3.95−4.00 (m,
1H, H-4′), 4.11 (s, 1H, H-3′), 4.19 (d, J = 6.6 Hz, 1H, H-2′), 4.92 (bs,
1H, HO-5′), 5.49 (d, J = 7.5 Hz, 1H, H-5), 5.62 (bs, 1H, HO-3′), 6.12
(d, J = 6.3 Hz, 1H, H-1′), 7.56 (d, J = 7.5 Hz, 1H, H-6), 8.47 (s, 1H,
NH). ESI-TOF: m/z calcd for C9H11N3O4 [M + Na]+ 248.0642,
found 248.0654.
Imidazo[1,2-a]pyrimidin-7-(8H)-one (15). From the faster
1-[3-O-Acetyl-2-deoxy-2-fluoro-5-O-(p-toluenesulfonyl)-β-D-
ribofuranosyl]uracil (12). Compound 11 (2.9 g, 10.06 mmol) was
dissolved in dry pyridine (15 mL), p-toluenesulfonyl chloride (6.329 g,
33.2 mmol) was added, and the resulting mixture was stirred for 12 h
at room temperature. The reaction was quenched by the addition of
ice-cold water (10 mL). Then CH2Cl2 (25 mL) was added, and the
organic layer was washed saturated NaHCO3 solution (2 × 20 mL)
and brine (2 × 20 mL). The organic phase was dried and filtrated, and
the solvent was evaporated. The remaining residue was applied to FC
(silica gel, column 15 × 4 cm, CH2Cl2/acetone, 4:1) furnishing
compound 12 (3.9 g, 88%) as a colorless foam. TLC (silica gel,
CH2Cl2/acetone, 4:1): Rf 0.70. λmax (MeOH)/nm 224 (ε/dm3 mol−1
migrating zone, compound 15 was isolated as a colorless solid
(0.006 g, 11%). TLC (silica gel, CH2Cl2/MeOH, 70:30): Rf 0.47. H
1
NMR (DMSO-d6, 300 MHz): 6.00 (d, J = 7.5 Hz, 1H, H-6), 7.00 (s,
1H, H-2), 7.33 (s, 1H, H-3), 8.28 (d, J = 7.8 Hz, 1H, H-5), 12.29 (br s,
1H, NH). Analytical data of 14 and 15 are in agreement in ref 23.
1-(2-Deoxy-2-fluoro-β-D-ribofuranosyl)-2-[[(dimethylamino)-
methylidene]amino]-pyrimidin-4(1H)-one (17). Compound 1c
(0.510 g, 2.08 mmol) was dissolved in MeOH (10 mL), and N,N-
dimethylformamide dimethyl acetal (0.900 g, 1.0 mL, 7.6 mmol) was
added. The resulting mixture was stirred for 1 h at room temperature.
The solvent was evaporated, and the remaining residue was applied to
FC (silica gel, column 10 × 4 cm, CH2Cl2/MeOH, 85:15).
Evaporation of the main zone afforded compound 17 as a colorless
solid (0.481 g, 77%). TLC (silica gel, CH2Cl2/MeOH, 4:1): Rf 0.40.
1
cm−1 14400), 260 (10400). H NMR (DMSO-d6, 300 MHz): δ 2.06
(s, 3H, CH3), 2.39 (s, 3H, CH3), 4.17−4.23 (m, 2H, 2 × H-5′), 4.37−
4.40 (m, 1H, H-4′), 5.12−5.22 (m, 1H, H-3′), 5.51 (dd, J = 5.4 Hz, J =
52.5 Hz, 1H, H-2′), 5.64 (d, J = 7.8 Hz, 1H, H-5), 5.77 (d, J = 22.2 Hz,
1H, H-1′), 7.41−7.44 (m, 2H, arom. H), 7.61 (d, J = 8.1 Hz, 1H, H-6),
7.74−7.77 (m, 2H, arom. H), 11.47 (s, 1H, NH). 19F NMR (DMSO-
d6, 282.4 MHz): δ −197.012. ESI-TOF: m/z calcd for C18H19FN2O8S
[M + Na]+ 465.0738, found 465.0740.
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λmax (MeOH)/nm 242 (ε/dm3 mol−1 cm−1 17500), 282 (25200). H
NMR (DMSO-d6, 300 MHz): δ 3.00 (s, 3H, NCH3), 3.18 (s, 3H,
NCH3), 3.58−3.65 (m, 1H, H-5′), 3.78−3.83 (m, 1H, H-5′), 3.88−
3.91 (m, 1H, H-4′), 4.04−4.14 (m, 1H, H-3′), 4.94 (dd, J = 3.6 Hz, J =
52.8 Hz, 1H, H-2′), 5.27 (t, J = 4.8 Hz, 1H, 5′−OH), 5.63 (d, J = 6.0
Hz, 1H, 3′−OH), 5.70 (d, J = 7.8 Hz, 1H, H-5), 6.32 (d, J = 16.8 Hz,
1H, H-1′), 7.96 (d, J = 7.8 Hz, 1H, H-6), 8.58 (s, 1H, NCH). 19F
NMR (DMSO-d6, 282.4 MHz): δ −202.563. ESI-TOF: m/z calcd for
C12H17FN4O4 [M + H]+ 301.1307, found 301.1310.
3′-O-Acetyl-2,5′-anhydro-2′-deoxy-2′-fluorouridine (13).
Compound 12 (1.5 g, 3.4 mmol) was dissolved in dry CH3CN (20
mL), DBU (1,8-diazabicyclo[5.4.0]undec-7-en, 540 μL, 0.550 g, 3.6
mmol) was added, and the reaction mixture was heated under reflux
for 50 min. The solvent was evaporated, and the remaining residue was
applied to FC (silica gel, column 15 × 4 cm, CH2Cl2/MeOH, 90:10).
Evaporation of the main zone afforded compound 13 as colorless solid
(0.730 g, 79%). TLC (silica gel, CH2Cl2/MeOH, 90:10): Rf 0.50. λmax
1-[2-Deoxy-2-fluoro-5-O-(4,4′-dimethoxytrityl)-β-D-ribofura-
nosyl]-2-[[(dimethylamino)methylidene]amino]pyrimidin-
4(1H)-one (18). Compound 17 (0.240 g, 0.80 mmol was dissolved in
dry pyridine (5 mL), 4,4′-dimethoxytrityl chloride (0.700 g, 2.08
mmol) was added in portions, and the reaction mixture stirred until
the starting material was completely consumed (∼5 h, TLC
monitoring). The solution was diluted with CH2Cl2 (20 mL) and
extracted with 5% NaHCO3 solution. The organic layer was dried, and
the solvent was evaporated. The remaining residue was subjected to
FC (silica gel, column 10 × 3 cm, CH2Cl2/MeOH, 90:10 containing 1
pipet triethylamine per 500 mL of solvent). Evaporation of the main
zone afforded 18 (0.365 g, 76%) as a colorless foam. TLC (silica gel,
CH2Cl2/MeOH, 9:1): Rf 0.55. λmax (MeOH)/nm 237 (ε/dm3 mol−1
1
(MeOH)/nm 237 (ε/dm3 mol−1 cm−1 11900). H NMR (DMSO-d6,
300 MHz): δ 2.11 (s, 3H, CH3), 4.20 (d, J = 12.6 Hz, 1H, H-5′), 4.57
(d, J = 12.6 Hz, 1H, H-5′), 4.84 (s, 1H, H-4′), 5.49 (d, J = 5.1 Hz, 1H,
H-3′), 5.79 (dd, J = 6.0 Hz, J = 49.5 Hz, 1H, H-2′), 5.97 (d, J = 7.5 Hz,
1H, H-5), 6.12 (d, J = 18.3 Hz, 1H, H-1′), 7.98 (d, J = 7.2 Hz, 1H, H-
6). 19F NMR (DMSO-d6, 282.4 MHz): δ −195.067. ESI-TOF: m/z
calcd for C11H11FN2O5 [M + Na]+ 293.0544, found 293.0542.
2-Amino-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)pyrimidin-
4(3H)-one (1c). Compound 8 (0.280 g, 1.23 mmol) was dissolved in
MeOH saturated with NH3 at 0 °C (50 mL), and the solution was
stirred for 12 h at room temperature. The solvent was evaporated, and
the remaining residue was adsorbed on silica gel and applied to FC
(silica gel, column 15 × 4 cm, CH2Cl2/MeOH, 80:20). Evaporation of
the main zone afforded compound 1c as colorless solid (0.173 g, 58%).
TLC (silica gel, CH2Cl2/MeOH, 80:20): Rf 0.30. λmax (MeOH)/nm
210 (ε/dm3 mol−1 cm−1 23200), 227(sh) (11700), 251(sh) (5800).
λmax (H2O)/nm 260 (ε/dm3 mol−1 cm−1 5100). 1H NMR (DMSO-d6,
300 MHz): δ 3.58−3.74 (m, 2H, H-5′), 3.90−3.92 (m, 1H, H-4′),
4.13−4.22 (m, 1H, H-3′), 5.07 (dd, J = 3.9 Hz, J = 53.1 Hz, 1H, H-2′),
5.37 (bs, 1H, HO-5′), 5.58 (d, J = 7.8 Hz, 1H, H-5), 5.74 (d, J = 5.4
Hz, 1H, HO-3′), 5.90 (dd, J = 3.3 Hz, J = 15.9 Hz, 1H, H-1′), 7.06 (bs,
2H, NH2), 7.66 (d, J = 7.8 Hz, 1H, H-6). 19F NMR (DMSO-d6, 282.4
MHz): δ −204.934. ESI-TOF: m/z calcd for C9H12FN3O4 [M + H]+
246.0885, found 246.0892.
1
cm−1 35500), 282 (33000). H NMR (DMSO-d6, 300 MHz): δ 3.00
(s, 3H, NCH3), 3.19 (s, 3H, NCH3), 3.31−3.40 (m, 2H, 2 × H-5′),
3.71 (s, 6H, 2 × OCH3), 4.02−4.06 (m, 1H, H-4′), 4.27−4.39 (m, 1H,
H-3′), 5.00 (dd, J = 3.9 Hz, J = 52.5 Hz, 1H, H-2′), 5.33 (d, J = 7.8 Hz,
1H, HO-3′), 5.72 (d, J = 6.9 Hz, 1H, H-5), 6.33 (d, J = 18.3 Hz, 1H,
H-1′), 6.88−6.91 (m, 4H, arom. H), 7.24−7.40 (m, 9H, arom. H),
7.81 (d, J = 7.8 Hz, 1H, H-6), 8.60 (s, 1H, NCH). 19F NMR
(DMSO-d6, 282.4 MHz): δ −201.243. ESI-TOF: m/z calcd for
C33H35FN4O6 [M + H]+ 603.2613, found 603.2631.
1-[2-Deoxy-2-fluoro-5-O-(4,4′-dimethoxytrityl)-β-D-ribofura-
nosyl]-2-[[(dimethylamino)methylidene]amino]pyrimidin-
4(1H)-one 3′-O-[(2-Cyanoethyl)-(N,N-diisopropyl)]-
phosphoramidite (19). Compound 18 (0.360 g, 0.60 mmol) was
dissolved in dry CH2Cl2 (10 mL), (i-Pr)2NEt (0.138 g, 180 μL, 1.07
mmol) and 2-cyanoethyl N,N-diisopropyl phosphoramidochloridite
(0.191 g, 180 μL, 0.81 mmol) were added, and the reaction mixture
was stirred for 1 h at room temperature. The solution was diluted with
CH2Cl2 (20 mL) and extracted with 5% NaHCO3 solution. The
organic layer was dried, and the solvent was evaporated. The
remaining residue was subjected to FC (silica gel, column 10 × 3
cm, CH2Cl2/MeOH/triethylamine 94.5:5:0.5). Evaporation of the
Conversion of 2-Amino-1-(2-deoxy-2-fluoro-β-D-ribofurano-
syl)-pyrimidin-4(1H)-one (1c) to Cyclic Byproducts 14 and 15.
Compound 1c (0.1 g, 0.33 mmol) was dissolved in aqueous
concentrated NH3, and the reaction mixture was heated at 55 °C in
a steel bomb for 16 h. The solvent was evaporated, the remaining
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J. Org. Chem. 2015, 80, 3124−3138