3396 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Bookser et al.
which resulted in precipitation of the product. Filtration and
drying at 85 °C/0.1 mmHg for 1 h provided 46 mg (59%) of
compound 10b as a white solid: mp 260 °C; 1H NMR (DMSO-
d6) δ 3.27 (t, 2H, J ) 8 Hz, indolinyl C3 Hs), 3.76 (m, 2H, C5′
Hs), 4.08 (m, 1H, H4′), 4.18 (m, 1H, H3′), 4.67 (q, 1H, J ) 6
Hz, H2′), 4.76 (t, 2H, J ) 8 Hz, indolinyl C2 Hs), 5.28 (d, 1H,
J ) 4 Hz, 3′-OH), 5.42 (d, 1H, J ) 7 Hz, 2′-OH), 6.11 (br s,
1H, 5′-OH), 6.22 (d, 1H, J ) 8 Hz, H1′), 6.95 (t, 1H, J ) 8 Hz,
anilinyl H4), 7.00 (t, 1H, J ) 8 Hz, indolinyl H5), 7.20 (t, 1H,
J ) 8 Hz, indolinyl H6), 7.27 Hz, (d, 1H, indolinyl H4), 7.34
(t, 2H, J ) 8 Hz, anilinyl H3), 7.85 (d, 2H, J ) 8 Hz, anilinyl
H2), 8.33 (s, 1H, H2), 8.51 (d, 1H, J ) 8 Hz, indolinyl H7).
Anal. (C24H24N6O4) C, H, N.
5 Hz, 3′-OH), 5.42 (d, 1H, J ) 7 Hz, 2′-OH), 5.66 (dd, 1H, J )
8, 4 Hz, 5′-OH), 5.85 (d, 1H, J ) 7 Hz, H1′), 7.00 (t, 1H, J )
8 Hz, indolinyl H6), 7.23 (t, 1H, J ) 8 Hz, indolinyl H5), 8.40
(s, 1H, H2), 8.61 (d, 1H, J ) 8 Hz, indolinyl H7). Anal.
(C20H23N5O4) C, H, N.
6-Indolin-N-yl-8-(trimethylsilylacetylenyl)-9-(2,3,5-tris-
O-tert-butyldimethylsilyl-â-D-ribofuranosyl)purine (13a).
Nitrogen was bubbled for 5 min through a mixture containing
iodopurine 8a (302 mg, 0.36 mmol), trimethylsilylacetylene
(0.31 mL, 2.2 mmol), copper(I) iodide (4 mg, 0.02 mmol), and
bis(triphenylphosphine)palladium(II) chloride (6 mg, 0.01
mmol) in 7 mL of triethylamine at room temperature. Then
the mixture was heated for 2 h at 80 °C. After cooling to room
temperature, the mixture was filtered and evaporated. The
residue was triturated with ethyl ether, and again the result-
ing mixture was filtered and evaporated. The residue was
subjected to chromatography on SiO2, eluting with hexane/
EtOAc mixtures of 100:1 and 75:1 to provide 179 mg (61%) of
13a as a foam: 1H NMR (DMSO-d6) δ -0.12-0.29 (m, 27H,
TBS and TMS Me groups), 0.74 (s, 9H, t-Bu), 0.88 (s, 9H, t-Bu),
0.94 (s, 9H, t-Bu), 3.28 (m, 2H, indolinyl C3 Hs), 3.77 (m, 1H,
H5′), 4.0 (m, 1H, H5′), 4.1-4.2 (m, 1H, H4′), 4.45 (d, 1H, J )
4 Hz, H3′), 4.76 (m, 2H, indolinyl C2 Hs), 5.47 (dd, 1H, J ) 7,
4 Hz, H2′), 6.09 (d, 1H, J ) 7 Hz, H1′), 7.04 (t, 1H, J ) 8 Hz,
indolinyl H5), 7.25 (t, 1H, J ) 8 Hz, indolinyl H6), 7.33 Hz,
(d, 1H, indolinyl H4), 8.50 (s, 1H, H2), 8.64 (d, 1H, J ) 8 Hz,
indolinyl H7). Anal. (C41H69N5O4Si4) C, H, N.
8-Acetylenyl-6-indolin-N-yl-9-(â-D-ribofuranosyl)-
purine (13b). Using the general method for fluoride ion-
mediated desilylation described for the preparation of 10b,
compound 13a was converted to compound 13b (40%) as a tan
solid: mp 178-180 °C; 1H NMR (DMSO-d6) δ 3.29 (t, 2H, J )
8 Hz, indolinyl C3 Hs), 3.4-3.8 (m, 2H, C5′ Hs), 4.00 (m, 1H,
H4′), 4.2-4.3 (m, 1H, H3′), 4.76 (t, 2H, J ) 8 Hz, indolinyl C2
Hs), 5.10 (q, 1H, J ) 6 Hz, H2′), 5.28 (d, 1H, J ) 6 Hz, 3′-OH),
5.49 (t, 1H, J ) 6 Hz, 5′-OH), 5.51 (d, 1H, J ) 6 Hz, 2′-OH),
6.02 (d, 1H, J ) 6 Hz, H1′), 7.05 (t, 1H, J ) 8 Hz, indolinyl
H6), 7.26 (t, 1H, J ) 8 Hz, indolinyl H5), 7.33 (d, 1H, J ) 8
Hz, indolinyl H4), 8.51 (s, 1H, H2), 8.64 (d, 1H, J ) 8 Hz,
indolinyl H7). Anal. (C20H19N5O4‚0.25H2O) C, H, N.
8-Furan-2-yl-6-indolin-N-yl-9-(2,3,5-tris-O-tert-butyldi-
methylsilyl-â-D-ribofuranosyl)purine (14a). Nitrogen was
bubbled for 5 min through a mixture containing iodopurine
8a (200 mg, 0.25 mmol), 2-(tributylstannyl)furan (0.31 mL,
0.99 mmol), copper(II) oxide (20 mg, 0.25 mmol), and tetrakis-
(triphenylphosphine)palladium(0) (14 mg, 0.013 mmol) in 5 mL
of DMF at room temperature. Then the mixture was heated
for 2 h at 100 °C. After cooling to room temperature, the
mixture was filtered, diluted with ethyl ether, washed with
water and brine, dried (MgSO4), and evaporated. The residue
was subjected to chromatography on SiO2, eluting with hexane/
EtOAc mixtures of 50/1, 30/1 and 15/1 to provide 162 mg (83%)
of compound 11a as a foam: 1H NMR (DMSO-d6) δ -0.37-
0.16 (m, 18H, TBS Me groups), 0.71 (s, 9H, t-Bu), 0.78 (s, 9H,
t-Bu), 0.93 (s, 9H, t-Bu), 3.36 (t, 2H, J ) 8 Hz, indolinyl C3
Hs), 3.71 (dd, 1H, J ) 11, 7 Hz, H5′), 3.9-4.1 (m, 2H, H5′,
H4′), 4.69 (m, 1H, H3′), 4.85-4.95 (m, 2H, indolinyl C2 Hs),
5.64 (t, 1H, J ) 5 Hz, H2′), 6.21 (d, 1H, J ) 6 Hz, H1′), 6.60
(m, 1H, furanyl H4), 7.02 (t, 1H, J ) 8 Hz, indolinyl H5), 7.14
(d, 1H, J ) 4 Hz, furanyl H3), 7.24 (t, 1H, J ) 8 Hz, indolinyl
H6), 7.31 Hz, (d, 1H, indolinyl H4), 8.01 (s, 1H, furanyl H5),
8.46 (s, 1H, H2), 8.64 (d, 1H, J ) 8 Hz, indolinyl H7).
Compound 16 was prepared in a similar manner.
6-Indolin-N-yl-8-vinyl-9-(2,3,5-tris-O-tert-butyldimeth-
ylsilyl-â-D-ribofuranosyl)purine (11a). Nitrogen was bubbled
for 5 min through a mixture containing iodopurine 8a (350
mg, 0.42 mmol), vinyltributyltin (0.61 mL, 2.1 mmol), and
tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021 mmol)
in 8 mL of DMF at room temperature. Then the mixture was
heated for 2 h at 80 °C. After cooling to room temperature,
the mixture was diluted with ethyl ether, washed with water
and brine, dried (MgSO4), and evaporated. The residue was
subjected to chromatography on SiO2, eluting with hexane/
EtOAc mixtures of 75/1 and 50/1 to provide 260 mg (84%) of
compound 11a as a foam: 1H NMR (DMSO-d6) δ -0.44-0.14
(m, 18H, TBS Me groups), 0.67 (s, 9H, t-Bu), 0.86 (s, 9H, t-Bu),
0.94 (s, 9H, t-Bu), 3.25 (t, 2H, J ) 8 Hz, indolinyl C3 Hs), 3.7-
3.8 (m, 1H, H5′), 3.9-4.1 (m, 2H, H4′, H5′), 4.41 (m, 1H, H3′),
4.82 (t, 2H, J ) 8 Hz, indolinyl C2 Hs), 4.96 (dd, 1H, J ) 7, 4
Hz, H2′), 5.68 (d, 1H, J ) 12 Hz, vinyl H2), 6.14 (d, 1H, J ) 7
Hz, H1′), 6.47 (d, 1H, J ) 12 Hz, vinyl H2), 7.01 (t, 1H, J ) 8
Hz, indolinyl H5), 7.1-7.3 (m, 3H, indolinyl H4 and H6; vinyl
H1), 8.45 (s, 1H, H2), 8.64 (d, 1H, J ) 8 Hz, indolinyl H7).
6-Indolin-N-yl-8-vinyl-9-(â-D-ribofuranosyl)purine (11b).
Using the general method for fluoride ion-mediated desilyl-
ation described for the preparation of 10b, compound 11a was
converted to compound 11b (46%) as a tan solid: mp 193/198
1
°C; H NMR (DMSO-d6) δ 3.30 (t, 2H, J ) 8 Hz, indolinyl C3
Hs), 3.5-3.8 (m, 2H, C5′ Hs), 4.00 (m, 1H, H4′), 4.19 (br. s,
1H, H3′), 4.85 (t, 2H, J ) 8 Hz, indolinyl C2 Hs), 4.7-4.9 (m,
1H, H2′), 5.25 (d, 1H, J ) 4 Hz, 3′-OH), 5.41 (d, 1H, J ) 7 Hz,
2′-OH), 5.48 (dd, 1H, J ) 7, 5 Hz, 5′-OH), 5.73 (d, 1H, J ) 12
Hz, vinyl H), 6.05 (d, 1H, J ) 7 Hz, H1′), 6.44 (d, 1H, J ) 15
Hz, vinyl H), 7.0-7.4 (m, 3H, vinyl H and indolinyl H4, H6),
7.02 (t, 1H, J ) 8 Hz, indolinyl H5), 8.44 (s, 1H, H2), 8.64 (d,
1H, J ) 8 Hz, indolinyl H7). Anal. (C20H21N5O4‚0.25H2O) C,
H, N.
Compound 22 was prepared in a similar manner.
8-Ethyl-6-indolin-N-yl-9-(2,3,5-tris-O-tert-butyldimeth-
ylsilyl-â-D-ribofuranosyl)purine (12a). A mixture of purine
11a (145 mg, 0.20 mmol) and 10% Pd/C in 5 mL of MeOH and
5 mL of EtOAc was shaken under 45 psi H2 in a Parr
apparatus. After 2 h the mixture was filtered and evaporated.
The residue was subjected to chromatography on SiO2, eluting
with 50:1 hexane/EtOAc to provide 118 mg (80%) of compound
12a as a foam: 1H NMR (DMSO-d6) δ -0.42-0.13 (m, 18H,
TBS Me groups), 0.70 (s, 9H, t-Bu), 0.80 (s, 9H, t-Bu), 0.92 (s,
9H, t-Bu), 1.32 (t, 3H, J ) 8 Hz, Et), 2.91 (q, 2H, J ) 8 Hz,
Et), 3.24 (m, 2H, indolinyl C3 Hs), 3.7-3.8 (m, 1H, H5′), 3.9-
4.1 (m, 2H, H4′, H5′), 4.49 (m, 1H, H3′), 4.76 (m, 2H, indolinyl
C2 Hs), 5.43 (t, 1H, J ) 4 Hz, H2′), 5.86 (d, 1H, J ) 6 Hz,
H1′), 6.97 (t, 1H, J ) 8 Hz, indolinyl H5), 7.20 (t, 1H, J ) 8
Hz, indolinyl H6). 7.27 (d, 1H, J ) 8 Hz, indolinyl H4), 8.38
(s, 1H, H2), 8.58 (d, 1H, J ) 8 Hz, indolinyl H7).
8-Ethyl-6-indolin-N-yl-9-(â-D-ribofuranosyl)purine (12b).
Using the general method for fluoride ion-mediated desilyl-
ation described for the preparation of 10b, compound 12a was
converted to compound 12b (35%) as a tan solid: mp 183-
185 °C; 1H NMR (DMSO-d6) δ 1.34 (t, 3H, J ) 7 Hz, Et), 2.96
(q, 2H, J ) 7 Hz, Et), 3.27 (t, 2H, J ) 8 Hz, indolinyl C3 Hs),
3.5-3.7 (m, 1H, H5′), 3.72 (dt, 1H, J ) 12, 4 Hz, H5′), 4.01
(m, 1H, H4′), 4.19 (br. s, 1H, H3′), 4.80 (t, 2H, J ) 8 Hz,
indolinyl C2 Hs), 4.97 (q, 1H, J ) 7 Hz, H2′), 5.28 (d, 1H, J )
8-Furan-2-yl-6-indolin-N-yl-9-(â-D-ribofuranosyl)-
purine (14b). Using the general method for fluoride ion-
mediated desilylation described for the preparation of 10b,
compound 14a was converted to compound 14b (16%) as a
1
white solid: mp 170-173 °C; H NMR (DMSO-d6) δ 3.29 (t,
2H, J ) 8 Hz, indolinyl C3 Hs), 3.4-3.8 (m, 2H, C5′ Hs), 4.01
(m, 1H, H4′), 4.2-4.3 (m, 1H, H3′), 4.84 (t, 2H, J ) 8 Hz,
indolinyl C2 Hs), 5.21 (q, 1H, J ) 6 Hz, H2′), 5.24 (d, 1H, J )
4 Hz, 3′-OH), 5.48 (d, 1H, J ) 6 Hz, 2′-OH), 5.4-5.6 (m, 1H,
5′-OH), 6.18 (d, 1H, J ) 7 Hz, H1′), 6.81 (m, 1H, furanyl H4),
7.04 (t, 1H, J ) 8 Hz, indolinyl H6), 7.23 (d, 1H, J ) 4 Hz,
furanyl H3), 7.31 (t, 1H, J ) 8 Hz, indolinyl H5), 7.33 (d, 1H,