PAPER
Exocyclic Nitrogen Benzylation in 2-Amino-6-oxopurines
3059
1H NMR (DMSO-d6): d = 1.12 (t, J = 7.1 Hz, 3 H, CH3), 2.17 (s, 3
H, CH3), 4.05 (q, J = 7.1 Hz, 2 H, CH2), 5.06 (s, 2 H, CH2), 7.25–
7.52 (m, 10 H, ArH), 10.69 (s, 1 H, NH).
4.04–4.13 (m, 1 H, H5¢), 4.23–4.38 (m, 2 H, H4¢, H5¢), 5.19 (s, 2 H,
CH2), 5.44 (t, J = 5.8 Hz, 1 H, H3¢), 5.91–5.97 (m, 1 H, H2¢), 6.26
(d, J = 4.8 Hz, 1 H, H1¢), 7.11–7.41 (m, 13 H, ArH), 7.60 (d, J = 8.0
Hz, 1 H, ArH), 8.69 (s, 1 H, H8).
Anal. Calcd for C24H21BrN6O5: C, 52.09; H, 3.83; N, 15.19. Found:
C, 52.06; H, 3.65; N, 14.99.
9-[(2-Acetoxyethoxy)methyl]-2-[acetyl(2-bromobenzyl)amino]-
6-(diphenylcarbamoyloxy)-9H-purine (10b)
Light-yellow oil; yield: 0.140 g (70%).
1H NMR (DMSO-d6): d = 1.84 (s, 3 H, CH3), 2.54 (s, 3 H, CH3),
3.61–3.65 (m, 2 H, CH2), 3.95–4.00 (m, 2 H, CH2), 5.21 (s, 2 H,
CH2), 5.60 (s, 2 H, CH2), 7.12–7.40 (m, 13 H, ArH), 7.61 (d, J = 7.8
Hz, 1 H, ArH), 8.64 (s, 1 H, CH).
2-(Acetylamino)-6-(diphenylcarbamoyloxy)-9H-purine Deriva-
tives 9a–c; General Procedure
To a suspension of 8a–c (0.5 mmol) in pyridine (7.0 mL) were add-
ed DIPEA (0.280 g, 0.38 mL, 2.2 mmol) and DPC-Cl (0.232 g, 1.0
mmol). The mixture was stirred at r.t. for 4 h. H2O (0.5 mL) was
added and the mixture was stirred for another 20 min. Volatiles
were removed under reduce pressure and the oily residue obtained
was co-evaporated several times with EtOH to remove traces of py-
ridine and then taken up in CH2Cl2 (50 mL). The soln was washed
with 5% aq NaHCO3 (10 mL), H2O (2 × 10 mL), and brine (10 mL),
dried (MgSO4), and filtered. The solvent was removed under re-
duced pressure. The residue was purified by chromatography (silica
gel, CH2Cl2–EtOH, 100:1.5) and recrystallized (EtOH).
9-[(2-Acetoxyethoxy)methyl]-2-[acetyl(2-bromobenzyl)amino]-
8-(benzylsulfanyl)-6-(diphenylcarbamoyloxy)-9H-purine (10c)
Colorless crystals; yield: 0.187 g (78%); mp 54 °C.
1H NMR (DMSO-d6): d = 1.83 (s, 3 H, CH3), 2.50 (s, 3 H, CH3,
overlapped with DMSO), 3.53–3.63 (m, 2 H, CH2), 3.92–4.01 (m,
2 H, CH2), 4.65 (s, 2 H, CH2), 5.19 (s, 2 H, CH2), 5.46 (s, 2 H, CH2),
7.08–7.65 (m, 19 H, ArH).
13C NMR (DMSO-d6): d = 20.88, 25.80, 35.43, 50.26, 63.03, 67.68,
72.54, 120.50, 122.20, 127.87, 127.98, 128.13, 128.88, 129.11,
129.58, 129.85, 132.83, 137.07, 137.23, 141.99, 150.33, 152.80,
153.76, 156.15, 157.38, 170.53, 171.76.
2-(Acetylamino)-6-(diphenylcarbamoyloxy)-9-(b-D-tri-O-
acetylribofuranosyl)-9H-purine (9a)
Light-yellow crystals; yield: 0.214 g (66%); mp 41 °C
1H NMR (DMSO-d6): d = 1.96 (s, 3 H, CH3), 2.03 (s, 3 H, CH3),
2.10 (s, 3 H, CH3), 2.15 (s, 3 H, CH3), 4.28–4.44 (m, 3 H, H4¢, H5¢),
5.74–5.80 (m, 1 H, H3¢), 5.89–5.94 (m, 1 H, H2¢), 6.24 (d, J = 4.6
Hz, 1 H, H1¢), 7.30–7.50 (m, 10 H, ArH), 8.60 (s, 1 H, H8), 10.83
(s, 1 H, NH).
Anal. Calcd for C39H35BrN6O6S: C, 58.87; H, 4.43; N, 10.56.
Found: C, 58.82; H, 4.33, N, 10.44.
2-[2-Acetyl(2-bromobenzyl)amino]-8-bromo-6-(diphenylcar-
bamoyloxy)-9-[(ethoxycarbonyl)methyl]-9H-purine (10d)
Colorless crystals; yield: 0.157 g (72%); mp 123–124 °C.
Anal. Calcd for C31H30N6O10: C, 57.58; H, 4.68; N, 13.00. Found:
C, 57.32; H, 4.56; N, 4.79.
1H NMR (DMSO-d6): d = 1.17 (t, J = 7.0 Hz, 3 H, CH3), 2.52 (s, 3
H, CH3), 4.15 (q, J = 7.0 Hz, 2 H, CH2), 5.09 (s, 2 H, CH2), 5.19 (s,
2 H, CH2), 7.08–7.46 (m, 13 H, ArH), 7.58–7.62 (m, 1 H, ArH).
9-[(2-Acetoxyethoxy)methyl]-2-(acetylamino)-6-(diphenylcar-
bamoyloxy)-9H-purine (9b)
Light-yellow crystals; yield: 0.194 g (77%); mp 130–132 °C.
13C NMR (DMSO-d6): d = 14.38, 26.03, 45.67, 50.07, 62.42,
120.26, 122.29, 127.87, 128.17, 129.16, 129.87, 132.85, 134.30,
137.04, 141.78, 149.87, 154.09, 154.70, 155.8, 166.97, 171.96.
1H NMR (DMSO-d6): d = 1.89 (s, 3 H, CH3), 2.20 (s, 3 H, CH3),
3.74–3.79 (m, 2 H, CH2), 4.05–4.09 (m, 2 H, CH2), 5.60 (s, 2 H,
CH2), 7.25–7.50 (m, 10 H, ArH), 8.59 (s, 1 H, H8), 10.75 (s, 1 H,
NH).
Anal. Calcd for C31H26Br2N6O5·0.5 H2O: C, 50.91; H, 3.72; N,
11.49. Found: C, 50.83; H, 3.60; N, 11.28.
Anal. Calcd for C25H24N6O6: C, 59.52; H, 4.80; N, 16.66. Found: C,
59.52; H, 4.67; N, 16.70.
9-[(2-Acetoxyethoxy)methyl]-2-[acetyl(2-bromobenzyl)amino]-
8-bromo-1,9-dihydro-6H-purin-6-one (12)
9-[(2-Acetoxyethoxy)methyl]-2-(acetylamino)-8-(benzylsulfa-
nyl)-6-(diphenylcarbamoyloxy)-9H-purine (9c)
Colorless crystals; yield: 0.263 g (84%); mp 137–138 °C
1H NMR (DMSO-d6): d = 1.87 (s, 3 H, CH3), 2.18 (s, 3 H, CH3),
3.63–3.73 (m, 2 H, CH2), 3.98–4.06 (m, 2 H, CH2), 4.66 (s, 2 H,
CH2), 5.45 (s, 2 H, CH2), 7.18–7.36 (m, 5 H, ArH), 7.37–7.57 (m,
10 H, ArH), 10.69 (s, 1 H, NH).
To a soln of 11 (0.200 g, 0.37 mmol) in DMF (8.0 mL) were added
K2CO3 (0.057 g, 0.41 mmol) and bromide 2e (0.102 g, 0.41 mmol).
The mixture was stirred at r.t. for 24 h. The solvent was removed un-
der reduced pressure. The residue was purified by chromatography
(silica gel, CHCl3–EtOH, 50:1) and recrystallized (EtOH) to afford
12 as colorless crystals; yield: 0.072 g (37%); mp 168–170 °C.
1H NMR (DMSO-d6): d = 1.92 (s, 3 H, CH3), 2.24 (s, 3 H, CH3),
3.45–3.49 (m, 2 H, CH2), 3.90–3.94 (m, 2 H, CH2), 5.10 (s, 2 H,
CH2), 5.39 (s, 2 H, CH2), 7.13–7.47 (m, 3 H, ArH), 7.58 (d, J = 8.4
Hz, 1 H, ArH).
Anal. Calcd for C32H30N6O6S: C, 61.33; H, 4.83; N, 13.41. Found:
C, 61.11; H, 4.73; N, 13.33.
N2-Benzylation of 2-(Acetylamino)-6-(diphenylcarbamoyloxy)-
9H-purine Derivatives 7a, 9a–c; General Procedure
The reactions were carried out according to the general procedure
applied for the synthesis of 3, 4a–h, 5 using 7a, 9a–c (0.3 mmol),
K2CO3 (0.083 g, 0.6 mmol), and bromide 2e (0.112 g, 0.45 mmol)
in DMF (8.0 mL).
Anal. Calcd for C19H19Br2N5O5: C, 40.96; H, 3.44; N, 12.57. Found:
C, 41.22, H, 3.13, N, 12.36.
Deprotection of 2-(Acetylamino)- and 2-[Acetyl(benzyl)amino]-
6-(diphenylcarbamoyloxy)-9H-purine derivatives 4f, 5, 10b–d;
General Procedure
A soln of 4f, 5, 10b–d (0.2 mmol) in EtOH saturated with NH3 (7.0
mL) was stirred overnight at r.t. and then refluxed for 1 h. Volatiles
were removed under reduced pressure. The residue was purified ei-
ther by crystallization (EtOH–H2O, 13a–c) or by chromatography
[silica gel, CHCl3–EtOH, 50:3 (13d) or CHCl3–EtOH, 20:1 (13e)].
2-[Acetyl(2-bromobenzyl)amino]-6-(diphenylcarbamoyloxy)-9-
(b-D-tri-O-acetylribofuranosyl)-9H-purine (10a)
Colorless oil; yield: 0.167 g (68%).
1H NMR (DMSO-d6): d = 1.86 (s, 3 H, CH3), 2.00 (s, 3 H, CH3),
2.08 (s, 3 H, CH3), 2.52 (s, 3 H, CH3, overlapped with DMSO),
Synthesis 2008, No. 19, 3053–3060 © Thieme Stuttgart · New York