The Journal of Organic Chemistry
Note
with triphenylphosphine (1.85 g, 7.0 mmol), 4-nitrophenethyl alcohol
(1.18 g, 7.0 mmol), and anhydrous THF (20 mL). The mixture was
treated with diethyl azodicarboxylate (1.23 mL, 7.0 mmol) at 0 °C and
stirred at rt for 1 h. It was poured into brine (50 mL) and extracted
with ethyl acetate. The combined organic layer was dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash
chromatography (silica, CH2Cl2/hexanes = 2:1) to give a white solid
(1.04 g, 63%): mp 160−161 °C; 1H NMR (300 MHz, CDCl3) δ 8.18
(d, 2H, J = 9.0 Hz), 7.87 (s, 1H), 7.46 (d, 2H, J = 9.0 Hz), 5.30 (br s,
2H), 4.50 (t, 2H, J = 6.6 Hz), 3.18 (t, 2H, J = 6.6 Hz); 13C NMR (75
MHz, CDCl3) δ 164.5, 158.7, 151.7, 145.9, 130.3, 123.97, 115.1, 86.8,
66.9, 63.3, 35.4; HRMS (ESI) m/z calcd for C14H12IN4O3 (M + H)+
410.9949, found 410.9940, C14H11IN4O3Na (M + Na)+ 432.9738,
found 432.9768.
found 250.0834, C11H11N3NaO4 (M − 2H+Na)− 272.0653, found
272.0663.
(3-Cyano-5-(2′-deoxy-3′-O-acetyl-β-D-ribofuranosyl)-N-
[(dibutylamino)methylene]-6-[2-(4-nitrophenyl)ethoxy]-2-pyr-
idinamine (15). To a mixture of 14 (200 mg, 0.50 mmol) and
triethylamine (0.2 mL) in dichloromethane (5 mL) was added 4,4′-
dimethoxytrityl chloride (185 mg, 0.55 mmol). The mixture was
stirred at rt overnight. The mixture was poured into brine (20 mL) and
extracted with dichloromethane. The combined organic layer was
dried over Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography (silica, ethyl acetate/hexanes = 2:1)
to give a white solid: 1H NMR (300 MHz, CDCl3) δ 8.15 (d, 2H, J =
8.7 Hz), 7.45 (d, 2H, J = 8.7 Hz), 7.2−7.4 (m, 10H), 6.75−6.85 (m,
4H), 5.65 (br s, 2H), 4.99 (dd, 1H, J = 10.8, 5.4 Hz), 4.61 (m, 1H),
4.48 (t, 2H, J = 6.6 Hz), 4.00 (m, 1H), 3.78 (s, 6H), 3.39 (ddd, 2H, J =
23.1, 10.2, 3.3 Hz), 3.15 (t, 2H, J = 6.3 Hz),2.4−2.5 (m, 1H), 2.0−2.15
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 164.0, 158.8, 158.3, 147.0,
146.3, 144.3, 141.8, 135.5, 135.5, 130.3, 128.4, 128.1, 127.3, 123.8,
117.1, 113.4, 110.3, 86.9, 82.3, 78.9, 73.6, 66.4, 63.3, 55. 4, 40.2, 35.4.
This material and N,N-dibutylformamide dimethyl acetal (0.3 mL)
were dissolved in methanol (3 mL) and stirred at room temperature
overnight. The mixture was evaporated and purified by flash
chromatography (neutral silica, ethyl acetate/hexanes = 1:1). The
major fraction was collected and evaporated. This material, without
further characterization, was dissolved in dichloromethane (10 mL)
with acetic anhydride (0.3 mL), DMAP (5 mg), and pyridine (0.6
mL). The mixture was stirred at rt overnight. The mixture was poured
into brine (20 mL) and extracted with dichloromethane. The
combined organic layer was dried over Na2SO4, filtered, and
concentrated. The residue was purified by flash chromatography
(neutral silica, ethyl acetate/hexanes = 1:2). The major fraction was
collected and evaporated. This material, without further character-
ization, was dissolved in dichloromethane (5 mL), treated with
trifluoroacetic acid (0.1 mL), and stirred at rt for 10 min. The mixture
was neutralized by aqueous sodium bicarbonate and extracted with
methylene chloride. The combined organic layer was dried over
Na2SO4, filtered, and concentrated. The residue was purified by flash
chromatography (neutral silica, ethyl acetate/hexanes = 1:1) to give a
sticky syrup (90 mg, 31% for four steps): 1H NMR (300 MHz,
CDCl3) δ 8.50 (s, 1H), 8.17 (d, 2H, J = 8.7 Hz), 7.84 (d, 1H, J = 0.6
Hz), 7.48 (d, 2H, J = 8.7 Hz), 5.30 (dd, 1H, J = 10.8, 4.8 Hz), 5.17
(dd, 1H, J = 7.8, 1.8 Hz), 4.55 (t, 2H, J = 6.6 Hz), 4.03 (m, 1H), 3.84
(m, 2H), 3.45−3.55 (m, 2H), 2.51 (ddd, 1H, J = 13.8, 4.8, 0.9 Hz),
2.27 (t, 1H, J = 6.0 Hz), 2.08 (s, 3H), 1.75−1.9 (m, 1H), 3.15−3.35
(m, 4H), 0.9−1.7 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 171.1,
162.9, 162.5, 159.6, 155.5, 147.1, 146.4, 140.1, 130.3, 123.9, 122.2,
117.2, 87.4, 85.4, 76.4, 66.1, 63.5, 52.4, 47.4, 46.23, 42.1, 40.0, 35.54,
31.2, 30.9, 29.6, 29.3, 21.2, 20.5, 20.4, 19.8, 14.0, 13.8; HRMS (ESI)
m/z calcd for C30H40N5O7 (M + H)+ 582.2922, found 582.2913,
C30H39N5NaO7 (M + Na)+ 604.2742, found 604.2744.
6-Amino-5-cyano-3-(2′-deoxy-5′-O-triphosphate-β-D-ribo-
furanosyl)-2(1H)-pyridone (16). To a solution of 15 (87 mg, 0.15
mmol) in pyridine (0.8 mL) and dioxane (2.4 mL) was added a
solution of 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (48 mg,
0.24 mmol) in dioxane (1.0 mL) at room temperature. After 15 min, a
mixture of tributylammonium pyrophosphate in DMF (0.2 M, 2.4 mL,
0.48 mmol) and tributylamine (0.27 mL, 1.1 mmol) was added. After
20 min, a solution of iodine (61 mg, 0.24 mmol) and water (0.095
mL) in pyridine (4.76 mL) was added. After 30 min, the reaction was
quenched by the addition of aqueous Na2SO3 (5%, until color
disappears). The pyridine and dioxane were removed in vacuo. The
residue was dissolved in acetonitrile (3 mL) and DBU (0.2 mL). The
mixture was stirred at room temperature overnight. The volatiles were
removed in vacuo and dissolved in ammonium hydroxide (10 mL).
The mixture was stirred at room temperature overnight. Ammonia was
removed by rotary evaporation, and the residue was diluted with water
(20 mL). Purification by ion-exchange HPLC (Dionex BioLC
DNAPac PA-100, 22 × 250 mm, eluent A = water, eluent B = 1 M
aq NH4HCO3, gradient to 50% B in 30 min, flow rate =10 mL/min, tR
= 25 min) gave the triphosphate as a white solid after lyophilization
2-Amino-3-cyano-5-(2′-deoxy-β-D-ribofuranosyl)-6-[2-(4-
nitrophenyl)ethoxy]-2-pyridine (14). Palladium acetate (110 mg,
0.49 mmol) and triphenylarsine (299 mg, 0.98 mmol) were dissolved
in chloroform (15 mL), and the mixture was stirred at rt for 30 min.
The mixture was then added to a solution of 13 (1.00 g, 2.44 mmol),
glycal 3 (0.95 g, 2.68 mmol), and silver carbonate (1.35 g, 4.88 mmol)
in chloroform (15 mL). The resulting mixture was refluxed overnight.
After being cooled to rt, the mixture was filtered through Celite and
washed with ethyl acetate. The combined filtrate was concentrated in
vacuo. The residue was purified by flash chromatography (silica, ethyl
1
acetate/hexanes = 1:1) to give a white solid (∼1.0 g): H NMR (300
MHz, CDCl3) δ 8.14 (d, 2H, J = 8.7 Hz), 7.7−7.8 (m, 4H), 7.4−7.6
(m, 8H), 6.80 (s, 1H), 5.41 (dd, 1H, J = 4.2, 1.5 Hz), 5.37 (br s, 2H),
4.71 (m, 1H), 4.45 (t, 2H, J = 6.6 Hz), 4.29 (s, 1H), 3.8−3.9 (m, 2H),
3.13 (t, 2H, J = 6.6 Hz). This material, without further character-
ization, was dissolved in THF (40 mL), and acetic acid (0.2 mL) and
TBAF (1 M in THF, 2 mL) were added. The mixture was stirred at rt
for 30 min, poured into brine (120 mL), and extracted with ethyl
acetate. The combined organic layer was dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash chromatography
(silica, ethyl acetate/hexanes = 2:1) to give a white solid (443 mg): 1H
NMR (300 MHz, CDCl3) δ 8.16 (d, 2H, J = 8.7 Hz), 7.46 (d, 2H, J =
8.7 Hz), 7.44 (s, 1H), 6.03 (br s, 2H), 5.10 (dd, 1H, J = 11.4, 6.3 Hz),
4.45−4.55 (m, 2H), 3.9−4.1 (m, 3H), 3.17 (t, 2H, J = 6.3 Hz), 2.88
(dd, 1H, J = 18.3, 11.4 Hz), 2.59 (dd, 1H, J = 18.0, 6.0 Hz); 13C NMR
(75 MHz, CDCl3) δ 213.0, 164.3, 158.3, 147.1, 146.2, 142.9, 130.3,
123.9, 116.6, 109.0, 82.9, 82.2, 66.6, 61.2, 40.7, 35. 4. This material was
dissolved in acetic acid (12 mL) and acetonitrile (12 mL), treated with
sodium triacetoxyborohydride (600 mg, 2.83 mmol), and stirred at rt
for 2 h. The mixture was poured into brine (100 mL) and extracted
with ethyl acetate. The combined organic layer was dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash
chromatography (silica, ethyl acetate) to give a white solid (257 mg,
26% for three steps): mp 55−57 °C; 1H NMR (300 MHz, CD3OD) δ
8.14 (d, 2H, J = 9.0 Hz), 7.55 (d, 2H, J = 9.0 Hz), 7.54 (d, 1H, J = 0.3
Hz), 4.97 (dd, 1H, J = 10.8, 5.4 Hz), 4.56 (t, 2H, J = 6.5 Hz), 4.36 (m,
1H), 3.90 (dd, 1H, J = 6.0, 3.3 Hz), 3.71 (d, 2H, J = 3.3 Hz), 3.17 (t,
2H, J = 6.3 Hz), 2.18 (ddd, 1H, J = 13.2, 12.1, 6.3 Hz), 1.97 (ddd, 1H,
J = 13.2, 5.4, 1.5 Hz); 13C NMR (75 MHz, CD3OD) δ 164.0, 159.0,
147.0, 146.8, 141.2, 130.2, 123.2, 117.1, 111.1, 88.1, 80.2, 78.2, 72.9,
66.1, 61.9, 39.6, 35.0; HRMS (ESI) m/z calcd for C19H21N4O6 (M +
H)+ 401.1456, found 401.1461, C19H20N4O6Na (M + Na)+ 423.1275,
found 423.1287, C19H19N4O6Na2 (M-H + 2Na)+ 445.1095, found
445.1109, C38H40N8O12Na (2M + 2Na)+ 823.2658, found 823.2654.
6-Amino-5-cyano-3-(2′-deoxy-β-D-ribofuranosyl)-2(1H)-pyri-
done (4). A mixture of 14 (30 mg, 0.075 mmol) and DBU (57 mg,
0.375 mmol) in acetonitrile (3 mL) was stirred at rt for 2 days. The
mixture was concentrated, and the residue was purified by flash
chromatography (silica, CH2Cl2/MeOH = 4:1) to give a white solid
1
(15 mg, 80%): mp 130−131 °C; H NMR (300 MHz, CD3OD) δ
7.66 (s, 1H), 4.97 (dd, 1H, J = 11.1, 5.1 Hz), 4.37 (d, 1H, J = 6.0 Hz),
3.90 (d, 1H, J = 2.4 Hz), 3.72 (m, 2H), 2.20 (ddd, 1H, J = 13.2, 12.1,
5.7 Hz), 1.95 (dd, 1H, J = 12.6, 5.1 Hz); 13C NMR (75 MHz,
CD3OD) δ 162.4, 154.2, 147.2, 117.7, 102.1, 88.1, 83.1, 78.5, 73.3,
61.8, 39.8; UV λmax (triethylammonium acetate, pH 7.0) 338 nm (ε
15800); HRMS (ESI) m/z calcd for C11H12N3O4 (M − H)− 250.0833,
3668
dx.doi.org/10.1021/jo300230z | J. Org. Chem. 2012, 77, 3664−3669