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M. Madre et al.
PAPER
8-Bromo-6-(N,N-diphenylcarbamoyloxy)-2-formylamino-
move the traces of pyridine, an oily residue was obtained. The
residue was purified by flash chromatography on silica gel
(CH2Cl2–EtOH, 100:1.5) to afford chromatographically and spec-
trally pure 8 (0.37 g, 77.1%).
1H NMR (200 MHz, DMSO-d6): d = 1.87–2.07 (m, 1 H, H-4¢),
2.31–2.51 (m, 1 H, H-3¢), 2.53–2.71 (m, 1 H, H-4¢), 2.72–2.90 (m,
1 H, H-3¢), 3.84–3.98 (m, 1 H, H-5¢), 4.20–4.34 (m, 1 H, H-5¢),
6.20–6.29 (m, 1 H, H-2¢), 7.25–7.65 (m, 13 H, ArH), 7.89–8.00 (m,
2 H, ArH), 11.17 (s, 1 H, NH).
9(7)H-purine (12)
Compound 11 (0.24 g, 0.53 mol) was dissolved in EtOH (10 mL)
and heated at reflux temperature for 20 min. The solution was
cooled in a refrigerator and the precipitated solid was collected by
filtration, recrystallized from EtOH and dried in air to afford 12.
Yield: 0.21 g (87.5%); mp 264–265 °C.
1H NMR (200 MHz, DMSO-d6): d = 7.23–7.64 (m, 10 H, ArH),
9.27 (d, J = 9.4 Hz, 1 H, CH), 11.08 (d, J = 9.4 Hz, 1 H, NH), 14.37
(br s, 1 H, NH).
2-Benzoylamino-8-bromo-6-(N,N-diphenylcarbamoyloxy)-
9(7)H-purine (9)
Compound 8 (0.28 g, 0.47 mmol) was dissolved in a minimal
amount of boiling EtOH. The solution was cooled in a refrigerator
and the precipitated solid was collected by filtration, recrystallized
from EtOH and dried in air to afford 9.
Anal. Calcd for C19H13BrN6O3·0.5H2O: C, 49.37; H, 3.05; N, 18.18.
Found: C, 49.39; H, 3.03; N, 17.95.
1-Benzoyl-8-bromo-2-(N,N-dimethyliminoformamido)-6-oxo-
9(7)H-purine (13)
To a suspension of 10 (1.24 g, 3.5 mmol) in MeCN (30 mL) were
added pyridine (3.0 mL, 3.9 mmol), DMAP (0.043 g, 0.035 mmol)
and BzCl (1.23 g, 1.0 mL, 8.75 mmol) in a dropwise manner. The
reaction mixture was stirred at r.t. until a clear solution was obtained
and TLC indicated the disappearance of the starting material (~72
h). The reaction mixture was diluted with EtOH (20 mL) and stir-
ring was continued for another 30 min. All volatiles were removed
under reduced pressure and, after several co-evaporations with tol-
uene, a thick yellow oil was obtained. The oil was dissolved in
CHCl3 (100 mL) and any precipitate was removed by filtration. The
filtrate was concentrated and the residue was purified by flash chro-
matography on silica gel (CHCl3–EtOH, 40:1) to afford chromato-
graphically and spectrally pure 9 (0.98 g, 72.1%). An analytical
sample was recrystallized from EtOH and a crystal was submitted
for X-ray crystallographic analysis (Figure 1 and Table 1).
Yield: 0.19 g (79.2%); mp 215–217 °C.
1H NMR (200 MHz, DMSO-d6): d = 7.26–7.64 (m, 13 H, ArH),
7.91–7.99 (m, 2 H, ArH), 11.09 (s, 1 H, NH), 14.46 (br s, 1 H, NH).
Anal. Calcd for C25H17BrN6O3: C, 56.73; H, 3.24; N, 15.88. Found:
C, 56.45; H, 3.06; N, 15.51.
8-Bromo-2-(N,N-dimethyliminoformamido)-6-oxo-9-(tetrahy-
drofuran-2-yl)purine (10)
Compound 5 (1.20 g, 4.0 mmol) was dissolved in DMF (20 mL)
with slight heating, then the solution was allowed to cool to r.t. and
N,N-dimethylformamide dimethylacetal (2.38 g, 20.0 mmol) was
added in one portion. The reaction mixture was stirred at r.t. and,
within 10 min, a white solid began to separate. Stirring was contin-
ued for 4 h then the separated solid was collected by filtration,
washed with EtOH and dried in air to afford 10 (1.16 g, 81.7%). The
product was used for the next step without further purification. An
analytical sample was recrystallized (EtOH–H2O, 3:1) for analysis.
Mp >165 °C (decomp.).
1H NMR (200 MHz, DMSO-d6): d = 2.59 (s, 3 H, CH3), 3.05 (s,
3 H, CH3), 7.51–7.83 (m, 5 H, ArH), 8.49 (s, 1 H, CH), 13.57 (s,
1 H, NH), 14.04 (s, 1 H, NH).
Mp 220–223 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.92–2.13 (m, 1 H, H-4¢),
2.27–2.48 (m, 2 H, H-3¢ and H-4¢), 2.36 (s, 3 H, CH3), 2.63–2.84
(m, 1 H, H-3¢), 3.04 (s, 3 H, CH3), 3.15 (s, 3 H, CH3), 3.84–3.97 (m,
1 H, H-5¢), 4.09–4.24 (m, 1 H, H-5¢), 6.09–6.20 (m, 1 H, H-2¢), 8.51
(s, 1 H, CH), 11.49 (s, 1 H, NH).
Anal. Calcd for C15H13BrN6O2·0.5C2H5OH: C, 45.73; H, 3.84; N,
20.00. Found: C, 46.00; H, 3.67; N, 19.92.
2-Acetylamino-8-bromo-6-[(4-methylphenyl)sulfonyloxy]-9-
(tetrahydrofuran-2-yl)purine (14)
To a suspension of 2 (0.34 g, 1.0 mmol) in CH2Cl2 (20 mL) were
added Et3N (0.52 mL, 3.7 mmol), DMAP (0.031 g, 0.26 mmol) and
TsCl (0.50 g, 2.6 mmol). The reaction mixture was stirred at r.t. un-
til a clear solution was obtained and TLC indicated the disappear-
ance of starting material (24–48 h). The reaction mixture was
diluted with CH2Cl2 (80 mL) and washed with 5% aq NaHCO3 (20
mL), H2O (20 mL) and brine (20 mL), dried (MgSO4) and filtered.
The solvent was removed under reduced pressure to give a thick oil
that was purified by flash chromatography on silica gel (CH2Cl2–
EtOH, 100:2.5) to afford chromatographically and spectrally pure
10 (0.37 g, 74.0%).
1H NMR (200 MHz, DMSO-d6): d = 1.87–2.08 (m, 1 H, H-4¢), 2.16
(s, 3 H, CH3), 2.44 (s, 3 H, CH3), 2.31–2.67 (m, 2 H, H-3¢ and H-4¢),
2.69–2.87 (m, 1 H, H-3¢), 3.84–3.97 (m, 1 H, H-5¢), 4.17–4.32 (m,
1 H, H-5¢), 6.17–6.25 (m, 1 H, H-2¢), 7.46–7.55 (m, 2 H, ArH),
8.10–8.18 (m, 2 H, ArH), 10.72 (s, 1 H, NH).
Anal. Calcd for C12H15BrN6O2: C, 40.58; H, 4.26; N, 23.66. Found:
C, 40.39; H, 4.12; N, 23.61.
8-Bromo-6-(N,N-diphenylcarbamoyloxy)-2-formylamino-9-
(tetrahydrofuran-2-yl)purine (11)
To a suspension of 10 (0.36 g, 1.0 mmol) in pyridine (6 mL) were
added DIPEA (0.40 mL, 2.3 mmol) and DPC-Cl (0.25 g, 1.1 mmol).
The reaction mixture was stirred for 6 h at r.t. to obtain a dark red
mixture. All volatiles were removed under reduced pressure and the
oily residue was co-evaporated several times with toluene to re-
move the traces of pyridine and taken up in CH2Cl2 (50 mL). The
CH2Cl2 solution was washed with 5% aq. NaHCO3 (15 mL), H2O
(2 × 15 mL) and brine (15 mL), dried (MgSO4) and filtered. The
solvent was removed under reduced pressure and the residue was
purified by flash chromatography on silica gel (CH2Cl2–EtOH,
50:1) to afford chromatographically and spectrally pure 11 (0.28 g,
78.9%).
2-Acetylamino-8-bromo-6-[(4-methylphenyl)sulfonyloxy]-
9(7)H-purine (15)
1H NMR (200 MHz, DMSO-d6): d = 1.90–2.12 (m, 1 H, CH-4¢),
2.31–2.48 (m, 2 H, CH-4¢ and CH-3¢), 2.69–2.88 (m, 1 H, CH-3¢),
3.85–3.99 (m, 1 H, CH-5¢), 4.08–4.23 (m, 1 H, CH-5¢), 6.19–6.28
(m, 1 H, NCH-2¢), 7.03–7.53 (m, 10 H, ArH), 9.29 (d, J = 9.7 Hz,
1 H, CH), 11.20 (d, J = 9.7 Hz, 1 H, NH).
Compound 14 (0.15 g, 0.30 mmol) was dissolved in EtOH (10 mL)
and heated at reflux temperature for 20 min. The solution was
cooled in a refrigerator and the precipitated solid, consisting mostly
of 1, was removed by filtration. The filtrate was evaporated under
reduced pressure and the residue was purified by flash chromatog-
raphy on silica gel (CHCl3–EtOH, 40:0.5) to afford 15.
Synthesis 2007, No. 9, 1325–1332 © Thieme Stuttgart · New York