The Journal of Organic Chemistry
Note
extracted one more time with CH2Cl2. The organic layers were
gathered, washed with brine, dried over magnesium sulfate, and
evaporated over reduced pressure. AcOEt was added to the brown
solid, which was filtrated, washed with a few quantities of AcOEt, and
dried in a desiccator to afford 2 as a white solid (22.07g, 94%). Mp =
190−191 °C. 1H NMR (CDCl3, 250 MHz): δ 3.81 (s, 3H), 7.17−7.46
(m, 5H), 7.76 (s, 1H), 8.31 (s, 1H). 13C NMR (CDCl3, 100 MHz):
42.7 (CH3), 48.8, 126.3, 127.7, 129.3, 144.4, 148.6, 150.1, 150.7, 154.0.
IR (KBr): ν 750, 952, 1550, 1589 cm−1. HRMS (ESI+) m/z: calcd for
C12H11IN5 352.0053 [M + H+], found 352.0056.
Ge): ν 1353, 1590, 2360, 3393 cm−1. HRMS (ESI+) m/z: calcd for
C17H20N5O3 342.1560 [M + H+], found 342.1565.
8-(2′-Deoxy-3′,5′-bis(tert-butyldimethylsilyl)-β-D-ribofura-
nosyl)-4-aminopyrazolo[1,5-a]-1,3,5-triazine (6). To a solution of
nucleoside 5 (1.21g, 3.54 mmol, 1 equiv) and imidazole (2.89 g, 42.53
mmol, 12 equiv) in N,N-dimethylformamide (25 mL) was added tert-
butyldimethylsilyl chloride (3.20 g, 21.27 mmol, 6 equiv). The solution
was stirred at rt for 60 h. Then the solvent was evaporated. The crude
material was purified by chromatography (eluent PE/AcOEt 98/2
then 95/5). The product was obtained as yellow oil which crystallized
after addition/evaporation of MeOH to afford a white solid (1.43g,
1,4-Anhydro-2-deoxy-D-erythro-pent-1-enitol (3). A solution
of thymidine (4.48 g, 18.5 mmol, 1 equiv), hexamethyldisilazane (25
mL), and ammonium sulfate (489 mg, 307 mmol, 0.2 equiv) was
heated at reflux for 2 h. The volatile compounds were evaporated, and
a mixture of ice and water was added to the residue until precipitation
of a gummy solid. Cold CH2Cl2 (40 mL) was added, and the solid
observed (thymine) was filtrated and washed with cold CH2Cl2. The
organic layer was recovered after a rapid and cold extraction. The
extraction was realized two more times with cold CH2Cl2. The organic
layers were gathered, washed with cold brine (40 mL), dried over
magnesium sulfate, and concentrated under reduced pressure. The
brown oily residue was used without further purification. The silylated
compound (1.74 g, 5.57 mmol, 1 equiv) was dissolved in THF (10
mL) before the addition of TBAF 1 M in THF (12.25 mL, 12.25
mmol, 2.2 equiv). The solution was stirred at rt for 3 h. The solvent
was evaporated and the crude was purified by chromatography (eluent
1
71%). Mp = 94−95 °C. [α]20 = −18.0 (c = 1, CHCl3) H NMR
D
(CDCl3, 250 MHz): δ 0.07 (s, 3H), 0.08 (s, 3H), 0.14 (s, 6H), 0.91 (s,
9H), 0.94 (s, 9H), 2.09 (ddd, 1H, J = 1.4 Hz, J = 5.6 Hz, J = 12.7 Hz),
2.30 (ddd, 1H, J = 5.3 Hz, J = 10.6 Hz, J = 12.7 Hz), 3.63 (dd, 1H, J =
6.5 Hz, J = 10.6 Hz), 3.71 (dd, 1H, J = 4.4 Hz, J = 10.6 Hz), 3.79 (s,
3H), 3.86 (ddd, 1H, J = 1.7 Hz, J = 4.4 Hz, J = 6.5 Hz), 4.51−4.55 (m,
1H, J = 5.2 Hz), 5.38 (dd, 1H, J = 5.6 Hz, J = 10.5 Hz), 7.29−7.40 (m,
5H), 7.81 (s, 1H), 8.12 (s, 1H). 13C NMR (acetone-d6, 100 MHz): δ
−5.2, −5.2, −4.4, −4.4, 26.2, 26.3, 42.1, 42.5, 64.8, 71.8, 75.5, 88.4,
110.1, 127.3, 127.7, 129.6, 144.2, 146.0, 148.9, 150.8, 152.8. IR (ATR-
Ge): ν 695, 772, 832, 1088, 1252, 1536, 1613, 2856, 2952 cm−1.
HRMS (ESI+) m/z: calcd for C29H48N5O3Si2 570.3290, found
570.3290. To a solution of this product (1.43 g, 2.5 mmol, 1 equiv)
in MeOH (50 mL) in a sealed tube was added a solution of ammonia
(7 N) in MeOH (4 mL, 28 mmol, 11.2 equiv). The sealed tube was
closed, and the mixture was heated at 100 °C for 19 h. After the
mixture was cooled at rt, the ammonia and solvent were removed by
evaporation. The crude product was purified by chromatography
1
Et2O/acetone 2/1) to afford colorless oil (363 mg, 56%). H NMR
(CDCl3, 250 MHz): δ 1.67 (sl, 2H), 3.65 (dd, 1H, J = 11.9 Hz, J = 6.7
Hz), 3.70 (dd, 1H, J = 11.9 Hz, J = 4.4 Hz), 4.38−4.44 (m, 1H), 4.72−
4.73 (m, 1H), 5.20 (t, 1H, J = 2.7 Hz, J = 2.7 Hz), 6.56 (dd, 1H, J = 2.7
Hz, J = 1.0 Hz). 13C NMR (CDCl3, 62.5 MHz): δ 63.2, 75.5, 89.5,
103.9, 149.9. MS characterization has been unsuccessful.
(eluent PE/AcOEt 95/5 to 70/30) to afford 6 as a white solid (0.92 g,
1
77%). Mp = 126−128 °C. [α]20 = −1.5 (c = 1, CHCl3). H NMR
D
(CDCl3, 250 MHz): δ −0.04 (s, 3H), −0.04 (s, 3H), 0.00 (s, 6H),
0.80 (s, 9H), 0.81 (s, 9H), 2.07 (dd, 1H, J = 4.5 Hz, J = 11.9 Hz),
2.20−2.27 (m, 1H), 3.52 (dd, 1H, J = 10.6 Hz, J = 6.3 Hz), 3.62 (dd,
1H, J = 10.6 Hz, J = 3.9 Hz), 3.85−3.86 (m, 1H), 4.39−4.40 (m, 1H),
5.37 (dd, 1H, J = 5.2 Hz, J = 10.4 Hz), 6.95 (sl, 2H), 7.96 (s, 1H), 8.05
(s, 1H). 13C NMR (CDCl3, 100 MHz): δ −5.3, −5.2, −4.5, −4.5, 18.2,
18.5, 26.0, 26.1, 41.5, 64.0, 71.3, 74.5, 87.9, 111.1, 145.0, 146.1, 150.9,
152.9. IR (ATR-Ge): ν 773, 832, 1092, 1251, 1548, 2929 cm−1. HRMS
(ESI+) m/z: calcd for C22H42N5O3Si2 480.2820 [M + H+], found
480.2823.
8-(2′-Deoxy-β-D-glycero-pentofuran-3′-ulos-1′-yl)-4-(N-
methyl-N-phenylamino)pyrazolo[1,5-a]-1,3,5-triazine (4). A
solution of bis(dibenzylideneacetone)palladium(0) (1.12 g, 1.94
mmol, 0.06 equiv) and triphenylarsine (1.19 g, 3.88 mmol, 0.12
equiv) in CH3CN (200 mL) was stirred at rt for 1 h. This palladium
complex was then added to a solution of iodopyrazolotriazine 2 (10.87
g, 30.96 mmol, 1 equiv), glycal 3 (7.19g, 61.92 mmol, 2 equiv), and
triethylamine (5.18 mL, 35.15 mmol, 1.2 equiv) in CH3CN (300 mL).
The solution was stirred at 100 °C for 16 h. After cooling at rt, the
palladium was filtrated over Celite and washed with CH3CN until the
filtrate became colorless. The filtrate was evaporated and purified by
chromatography (eluent PE/AcOEt 95/5 to 2/8 then AcOEt) to
afford 4 as a brown solid (1.70 g, 34%). The product was washed with
AcOEt to obtain a beige solid. Mp = 157−158 °C. [α]20D = +1.46 (c =
1, CHCl3). 1H NMR (CDCl3, 250 MHz): δ 2.78 (dd, 1H, J = 6.5 Hz, J
= 17.8 Hz), 2.95 (dd, 1H J = 10.7 Hz, J = 17.8 Hz), 3.82 (s, 3H), 3.89
(dd, 1H, J = 1.8 Hz, J = 12.1 Hz), 3.96 (dd, 1H, J = 12.1 Hz, J = 2.3
Hz), 4.07−4.08 (m, 1H), 4.74 (sl, 1H), 5.42 (dd, 1H, J = 6.5 Hz, J =
10.7 Hz), 7.18−7.22 (m, 2H), 7.39−7.43 (m, 3H), 7.76 (s, 1H), 8.21
(s, 1H). 13C NMR (CDCl3, 62.5 MHz): δ 42.6, 44.6, 62.7, 70.7, 82.3,
108.5, 126.3, 127.7, 129.2, 143.5, 144.3, 148.1, 150.0, 152.7, 214.3. IR
(KBr): ν 1020, 1405, 1494, 1602 cm−1. HRMS(ESI+) m/z: calcd for
C17H17N5O3Na [M + Na+] 362.1229, found 362.1227.
8-(2′-Deoxy-β-D-ribofuranosyl)-4-(N-benzoylamino)-
pyrazolo[1,5-a]-1,3,5-triazine (7). Compound 6 (0.99g, 2.06 mmol,
1 equiv) was solubilized in pyridine (11 mL) and cooled at 0 °C, and
benzoyl chloride (1.2 mL, 10.32 mmol, 5 equiv) was added dropwise.
The solution was stirred at rt for 2 h 30 and the solution cooled again
at 0 °C. After dropwise addition of water (10 mL) and then NH4OH
(15 mL), the solution was stirred at rt for 50 min. After evaporation of
the solvent and then coevaporation with toluene, water (50 mL) was
added, and the product was extracted with CH2Cl2 (2 × 50 mL). The
organic layers were gathered, washed with brine (40 mL), dried over
magnesium sulfate, and evaporated under reduced pressure. After
purification by chromatography (eluent PE/AcOEt 90/10 to 70/30) a
white solid was obtained (0.92 g, 80%). Mp = 70−72 °C. [α]20
=
D
1
−10.8 (c = 1, CHCl3). H NMR (CDCl3, 400 MHz): δ 0.06 (s, 3H,
SiCH3), 0.07 (s, 3H, SiCH3), 0.11 (s, 6H, Si(CH3)2), 0.91 (s, 9H, Si−
C(CH3)3), 0.93 (s, 9H, SiC(CH3)3), 2.22 (ddd, 1H, H-2′, J2′a‑3′ = 1.5
Hz, J2′a‑1′ = 5.4 Hz, J2′a‑2′b = 12.6 Hz), 2.34 (ddd, 1H, H-2′b, J2′b‑3′ = 5.2
Hz, J2′b‑1′ = 10.6 Hz, J2′b‑2′a = 12.6 Hz), 3.64 (dd, 1H, H-5′a, J5′a‑4′ = 5.9
8-(2′-Deoxy-β-D-ribofuranosyl)-4-(N-methyl-N-phenyl-
amino)pyrazolo[1,5-a]-1,3,5-triazine (5). To a solution of the keto
compound 4 (1.69 g, 4.98 mmol, 1 equiv) in CH3CN (60 mL) was
added sodium tri(acetoxy)borohydride (4.22 g, 19.92 mmol, 4 equiv)
portionwise. After 5 h of stirring at rt, the solvent was evaporated. The
product was purified by chromatography (eluent CH2Cl2/MeOH 95/
Hz, J5′a‑5′b = 10.7 Hz), 3.73 (dd, 1H, H-5′b, JH5′b‑4′ = 3.8 Hz, J5′b‑5′a
10.7 Hz), 3.98 (ddd, 1H, H-4′, J4′‑3′ = 1.8 Hz, J4′‑5′b = 3.8 Hz, J4′‑5′a
=
=
5.8 Hz), 4.50−5.51 (m, 1H, H-3′), 5.50 (dd, 1H, H-1′, J1′‑2′a = 5.4 Hz,
J1′‑2′b = 10.6 Hz), 7.57 (t, 2H, Hm Bz, 3J = 1.9 Hz), 7.67 (t, 1H, Hp Bz,
3J = 1.9 Hz), 8.09 (d, 2H, Ho Bz, 3J = 1.9 Hz), 8.18 (s, 1H, H-7), 8.47
(sl, 1H, H-2), 9.95 (sl, 1H, NH). 13C NMR (CDCl3, 100 MHz): δ
−5.3 (SiCH3), −5.2 (SiCH3), −4.6 (SiCH3), −4.5 (SiCH3), 18.2 (Cq
tBu), 18.5 (Cq tBu), 25.9 (3 CH3 tBu), 26.0 (3 CH3 tBu), 41.7 (C-2′),
63.9 (C-5′), 71.2 (C-1′), 74.4 (C-3′), 88.1 (C-4′), 112.9 (Cq), 128.3
(2 CH Bz), 129.3 (2 CH Bz), 132.6 (Cq), 133.8 (CH Bz), 145.2
(CH), 145.6 (Cq), 145.7 (Cq), 152.6 (CH), 163.4 (CO). IR(ATR-
5 to 9/1) to afford 5 as a white solid (1.16 g, 68%). Mp = 196−198 °C
1
(degradation). [α]20 = +4.2 (c = 1, DMF). H NMR (CDCl3, 250
D
MHz): δ 1.61 (sl, 1H), 2.11 (dd, 1H, J = 13.1 Hz, J = 5.4 Hz), 2.59
(ddd, 1H, J = 13.1 Hz, J = 11.2 Hz, J = 4.9 Hz), 3.73 (dd, 1H, J = 12.6
Hz, J = 1.9 Hz), 3.80 (s, 3H), 3.94 (dd, 1H, J = 12.6 Hz, J = 2.04), 4.11
(sl, 1H), 4.66 (d, 1H, J = 4.9 Hz), 5.37 (dd, 1H, J = 11.2 Hz, J = 5.4
Hz), 5.77 (sl, 1H), 7.17 (m, 2H), 7.40 (m, 3H), 7.71 (s, 1H), 8.18 (s,
1H). 13C NMR (CDCl3, 100 MHz): δ 41.0, 43.7, 64.2, 73.9, 75.8, 88.8,
109.1, 126.3, 127.7, 129.3, 144.1, 144.6, 147.9, 150.2, 152.2. IR (ATR-
E
dx.doi.org/10.1021/jo5000253 | J. Org. Chem. XXXX, XXX, XXX−XXX