Notes
((3,4-Dih yd r o-2H-p yr a n -2-ylm eth yl)oxy)-Lin k ed Mer r i-
J . Org. Chem., Vol. 62, No. 1, 1997 203
2 H), 4.6 (bs, 2 H), 3.7 (s, 3 H); ESIMS m/ z 290 (M + H+, 100).
Anal. Calcd for C13H12N5OCl: C, 53.89; H, 4.17; N, 24.17.
Found: C, 53.52; H, 3.88; N, 23.81.
2-Ch lor o-6-[(p h en ylsu lfon yl)a m in o]p u r in e (11): amor-
phous solid; NMR (DMSO-d6) δ 13.2 (bs, 1 H), 8.4 (bs, 1 H), 8.1
(s, 1 H), 8.0 (d, J ) 8 Hz, 2 H), 7.6 (m, 3 H); ESIMS m/ z 310 (M
+ H+, 100); HRMS calcd for C11H9N5O2SCl (M + H+) 310.0165,
found 310.0144.
field Resin (3). A solution of 3,4-dihydro-2H-pyran-2-methanol
(2) (0.75 g, 6.6 mmol) in DMF (15 mL) at rt was treated with
NaH (0.28 g, 6.8 mmol, 60% suspension in oil) in one portion.
After 30 min, Merrifield resin (3 g, 2.28 mmol, 0.76 mmol Cl/g)
was added in one portion and the mixture stirred for 16 h. The
reaction was quenched by the addition of water (1 mL), and the
resin was collected on a Buchner funnel, washed with DMF (3
× 10 mL), methanol (3 × 10 mL), and CH2Cl2 (3 × 10 mL), and
dried in a vacuum oven at 60 °C overnight to give the desired
product 3 (3.0 g, 92%). Elemental analysis did not detect the
presence of chlorine at a sensitivity level of 100 ppm.
Su p p or t Bou n d 2,6-Dich lor op u r in e (4). A solution of 2,6-
dichloropurine (0.29 g, 1.52 mmol), resin 3 (1.0 g, 0.76 mmol),
and camphorsulfonic acid (0.08 g, 0.34 mmol) in 1,2-dichloro-
ethane (10 mL) was stirred at 60 °C for 16 h. The mixture was
filtered, and the resin was collected on a Buchner funnel, washed
with CH2Cl2 (2 × 10 mL), DMF (3 × 10 mL), and CH2Cl2 (3 ×
10 mL), and dried in a vacuum oven at 60 °C overnight to give
the desired product 4 (1.13 g). The loading level of 2,6-
dichloropurine was determined to be 0.47 mmol/g by gravimetric
methods.
Su p p or t Bou n d 2-Ch lor o-6-(ben zyla m in o)p u r in e (5). A
suspension of resin 4 (0.5 g, 0.235 mmol), benzylamine (0.13 mL,
1.18 mmol), and triethylamine (0.17 mL, 1.18 mmol) in 1-butanol
(5 mL) was heated to 80 °C for 3 h. The mixture was cooled to
rt and filtered, and the resin was washed with MeOH (3 × 10
mL) and CH2Cl2 (3 × 10 mL) and dried in a vacuum oven at 60
°C to give the desired product 5 (0.55 g).
2-Ch lor o-6-(ben zyla m in o)p u r in e (8). Resin 5 (0.1 g, 0.47
mmol) was suspended in CH2Cl2:TFA (8:1) (2 mL) and stirred
for 10 min at rt. The solution was filtered and the resin washed
with methanol (2 × 10 mL). The filtrate was concentrated at
reduced pressure to give the crude product 8 as a foam (11.5
mg, 95%). An analytical sample was purified by chromatography
(silica, 5% MeOH/CH2Cl2). 8: mp 254-255 °C; NMR (DMSO-
d6) δ 13.1 (bs, 1 H), 8.75 (bs, 1 H), 8.1 (s, 1 H), 7.3 (m, 5 H), 4.6
(d, J ) 6.8 Hz, 2 H); ESIMS m/ z 260 (M + H+, 100). Anal.
Calcd for C12H10N5Cl: C, 55.50; H, 3.88; N, 26.97. Found: C,
55.22; H, 3.78; N, 27.00.
2-Ch lor o-6-[(3-n itr oben zyl)a m in o]p u r in e (12): mp >300
°C; NMR (DMSO-d6) δ 13.1 (bs, 1 H), 8.9 (bs, 1 H), 8.2 (s, 1 H),
8.1 (m, 2 H), 7.8 (d, J ) 8 Hz, 1 H), 7.6 (t, J ) 6.5 Hz, 1 H), 4.8
(bs, 2 H); ESIMS m/ z 305 (M + H+, 100). Anal. Calcd for
C
12H9N6O2Cl: C, 47.30; H, 2.98; N, 27.58. Found: C, 47.06; H,
3.20; N, 27.55.
2-Ch lor o-6-[3-(h yd r oxym eth yl)-1-p ip er id yl]p u r in e (13):
mp 206-207 °C; NMR (DMSO-d6) δ 13.1 (bs, 1 H), 8.1 (s, 1 H),
4.55 (t, J ) 5.5 Hz, 2 H), 3.3 (m, 4 H), 1.8-1.2 (m, 5 H); ESIMS
m/ z 268 (M + H+, 100). Anal. Calcd for C11H14N5OCl: C, 49.35;
H, 5.27; N, 26.16. Found: C, 49.31; H, 5.10; N, 26.49.
2-Ch lor o-6-(p h en yla m in o)p u r in e (14): mp 320 °C dec;
NMR (DMSO-d6) δ 10.15 (bs, 1 H), 8.3 (s, 1 H), 7.8 (d, J ) 8 Hz,
1 H), 7.35-7.3 (m, 2 H), 7.1-7.0 (m, 2 H); ESIMS m/ z 246 (M
+ H+, 100); HRMS calcd for C11H9N5Cl (M + H+) 246.0546, found
246.0543. Anal. Calcd for C11H8N5Cl: C, 53.78; H, 3.28; N,
28.51. Found: C, 53.88; H, 3.44; N, 28.36.
2-Ch lor o-6-[[3-(ben zyloxy)ben zyl]oxy]p u r in e (15): mp
161-162 °C; NMR (CDCl3) δ 11.5 (bs, 1 H), 8.1 (s, 1 H), 7.5-7.1
(m, 8 H), 6.95 (d, J ) 8 Hz, 1 H), 5.6 (s, 2 H), 5.1 (s, 2 H); ESIMS
m/ z 367 (M + H+, 100). Anal. Calcd for C19H15N4O2Cl: C,
62.21; H, 4.12; N, 15.27. Found: C, 62.02; H, 3.80; N, 15.05.
2-Ch lor o-6-(p h en ylh yd r a zin o)p u r in e (16): mp 249-250 °C
dec; NMR (DMSO-d6) δ 13.2 (bs, 1 H), 8.3 (s, 1 H), 7.6 (d, J ) 7
Hz, 1 H), 7.4 (t, J ) 6 Hz, 1 H), 7.2 (m, 3 H), 6.9 (d, J ) 7 Hz,
1 H), 6.8 (d, J ) 7 Hz, 1 H); ESIMS m/ z 261 (M + H+, 100).
C11H9N6Cl: C, 50.68; H, 3.48; N, 32.24.
Found: C, 50.31; H, 3.10; N, 32.59.
2-[[3-(1,4-oxa zin -4-yl)p r op yl]a m in o]-6-(ben zyla m in o)p u -
r in e (17): amorphous solid; NMR (CD3OD) δ 8.0 (bs, 1 H), 7.3
(m, 5 H), 3.8 (bs, 2 H), 3.5 (m, 4 H), 3.3-3.1 (m, 8 H), 2.0 (m, 2
H); ESIMS m/ z 368 (M + H+, 100); HRMS calcd for C19H26N7O
(M + H+) 368.2199, found 368.2190.
2-[[2-(1H -4-Im id a zolyl)et h yl]a m in o]-6-[(3,4-d ih yd r oxy-
ben zyl)a m in o]p u r in e (18): amorphous solid; NMR (CD3OD)
δ 8.85 (s, 1 H), 8.8 (s, 1 H), 8.2 (bs , 1 H), 7.5 (m, 1 H), 7.3 (s, 1
H), 6.85 (s, 1 H), 6.75 (s, 2 H), 4.7 (s, 2 H), 3.8 (m, 2 H), 3.1 (m,
2 H); ESIMS m/ z 367 (M + H+, 23), 184 (M + 2H+, 100); HRMS
calcd for C17H18N8O2 (M + H+) 367.1631, found 367.1620.
Anal. Calcd for
Su p p or t Bou n d 2-[(2-H yd r oxyet h yl)a m in o]-6-(b en zyl-
a m in o)p u r in e (6). A suspension of resin 5 (0.1 g, 0.047 mmol)
in ethanolamine (0.5 mL) was heated to 150 °C for 2.5 h. The
mixture was then cooled and filtered, and the resin was washed
with MeOH (3 × 10 mL), DMF (3 × 10 mL), MeOH (3 × 10
mL), and CH2Cl2 (3 × 10 mL) and dried at 60 °C in a vacuum
oven overnight to give the desired product 6 (0.1 g).
2-[(2-Hyd r oxyeth yl)a m in o]-6-(ben zyla m in o)p u r in e (7).
Resin 6 (0.1 g, 0.47 mmol) was subjected to the same acid
cleavage protocol described for compound 8 to give the crude
product 7 as a foam (8 mg, 90%). An analytical sample was
purified by chromatography (silica, 10% MeOH/CH2Cl2). 7: mp
184-186 °C; NMR (DMSO-d6) δ 12.15 (bs, 1 H), 7.6 (s, 1 H), 7.3
(m, 5 H), 6.0 (bs, 1 H), 4.6 (m, 2 H), 3.4 (m, 2 H), 3.2 (m, 2 H);
ESIMS m/ z 285 (M + H+, 100). Anal. Calcd for C14H16N6O:
C, 59.14; H, 5.67; N, 29.56. Found: C, 59.01; H, 5.78; N, 29.32.
2-[(2-Hydr oxyeth yl)am in o]-6-(ben zylam in o)-9-m eth ylpu -
r in e (Olom ou cin e) (1). A solution of purine 7 (20 mg, 0.07
mmol) in dimethylacetamide (1 mL) at rt was treated with
sodium hydride (4 mg, 0.08 mmol, 60% oil dispersion) in one
portion. After the solution was stirred for 30 min, methyl iodide
(8 µL, 0.08 mmol) was added. After the reaction mixture was
stirred an additional 30 min, the reaction was quenched with
MeOH (40 µL) and the solvent removed at reduced pressure.
Chromatography (silica, 2.5-5% MeOH/CH2Cl2) gave the desired
product as a white solid (14.5 mg, 70%). 1: mp 125-126 °C
(lit.11 mp 125-126 °C); λmax 232 (ꢀ 23 260), 290 (ꢀ 12 878); NMR
(DMSO-d6) δ 7.6 (s, 1 H), 7.3 (m, 5 H), 6.1 (bs, 1 H), 4.6 (m, 2
H), 3.5 (s, 3 H), 3.45 (m, 2 H), 3.25 (m, 2 H); ESIMS m/ z 299 (M
+ H+, 100). Anal. Calcd for C15H18N6O: C, 60.39; H, 6.08; N,
28.17. Found: C, 60.32; H, 6.01; N, 27.92.
2-[(2-Hydr oxyeth yl)am in o]-6-[(3-m eth oxyben zyl)am in o]-
p u r in e (19): mp 161-162 °C; NMR (DMSO-d6) δ 12.15 (bs, 1
H), 7.6 (s, 1 H), 7.2 (t, J ) 8 Hz, 1 H), 6.8 (m, 2 H), 6.75 (m, 1
H), 6.0 (m, 1 H), 4.6 (m, 3 H), 3.7 (s, 3 H), 3.45 (m, 2 H), 3.2 (m,
2 H); ESIMS m/ z 315 (M + H+, 100). Anal. Calcd for
C
15H18N6O2: C, 57.31; H, 5.77; N, 26.74. Found: C, 57.22; H,
5.78; N, 27.01.
2-[(2-Hyd r oxyeth yl)a m in o]-6-[(p h en ylsu lfon yl)a m in o]-
p u r in e (20): amorphous solid; NMR (CD3OD) δ 8.6 (bs, 1 H),
8.1 (s, 1 H), 8.0 (s, 1 H), 7.5 (m, 5 H), 3.7 (m, 2 H), 3.5 (m, 2 H);
ESIMS m/ z 335 (M + H+, 100); HRMS calcd for C13H15N6O3S
(M + H+) 335.0926, found 335.0901.
2-[(5-H yd r oxyp en t yl)a m in o]-6-[(3-n it r ob en zyl)a m in o]-
p u r in e (21): amorphous solid; NMR (DMSO-d6) δ 12.15 (bs, 1
H), 8.2 (s, 1 H), 8.05 (d, J ) 8 Hz, 1 H), 7.9 (m, 1 H), 7.75 (d, J
) 8 Hz, 1 H), 7.6 (s, 1 H), 6.2 (bs, 1 H), 4.3 (s, 2 H), 3.2 (m, 4 H),
1.6-1.2 (m, 6 H); ESIMS m/ z 372 (M + H+, 100); HRMS calcd
for C17H22N7O3 (M + H+) 372.1784, found 372.1759.
2-[[3-(2-Oxop yr r olid in yl)p r op yl]a m in o]-6-[3-(h yd r oxy-
m eth yl)-1-p ip er id yl]p u r in e (22): amorphous solid; NMR (CD3-
OD) δ 7.6 (s, 1 H), 3.5-3.3 (m, 10 H), 2.4 (t, J ) 6 Hz, 2 H), 2.0
(m, 2 H), 1.9-1.4 (m, 9 H); ESIMS m/ z 374 (M + H+, 100);
HRMS calcd for C18H28N7O2 (M + H+) 374.2304, found 374.2300.
2-[(2-H y d r o x y e t h y l)a m in o ]-6-(p h e n y la m in o )p u r in e
(23): mp 230-231 °C; NMR (DMSO-d6) δ 12.35 (bs, 1 H), 9.3
(s, 1 H), 8.0 (m, 2 H), 7.8 (s, 1 H), 7.25 (m, 2 H), 7.0-6.9 (m, 1
H), 6.4 (bs, 1 H), 3.5 (m, 2 H), 3.2-3.05 (m, 2 H); ESIMS m/ z
270 (M + H+, 100); HRMS Calcd for C13H14N6O (M + H+)
270.1307, found 270.1306.
2-Ch lor o-6-[(3,4-d ih yd r oxyben zyl)a m in o]p u r in e (9): mp
205-208 °C; NMR (CD3OD) δ 8.0 (s, 1 H), 6.8 (s, 1 H), 6.75 (s,
2 H), 4.6 (bs, 2 H); ESIMS m/ z 292 (M + H+, 100). Anal. Calcd
for C12H10N5O2Cl: C, 49.41; H, 3.46; N, 24.01. Found: C, 49.49;
H, 3.55; N, 23.80.
2-Ch lor o-6-[(3-m eth oxyben zyl)a m in o]p u r in e (10): mp
238-239 °C; NMR (DMSO-d6) δ 13.1 (bs, 1 H), 8.7 (bs, 1 H), 8.0
(s, 1 H), 7.2 (t, J ) 8 Hz, 1 H), 6.9 (m, 1 H), 6.75 (d, J ) 8 Hz,
J O961909W