PAPER
Synthesis of 7- and 9-Alkylated Guanines
2033
13C NMR (DMSO-d6): d = 174.21, 170.8 (COCH3, NHCOCH3), n.d.
(C-6), 154.22 (C-4), 147.59 (C-2), 134.23 (C-8), 114.31 (C-5),
62.80 (C-4¢), 48.80 (CH2Ph), 48.40 (C-1¢), 24.81 (C-2¢), 25.20 (C-
3¢), 23.79 (CH3CON), 20.99 (CH3CO).
the product applied on a ‘flash’ chomatographic column and pro-
cessed [CH2Cl2 (300 mL), EtOAc (600 mL)] to obtain 16 (0.9 g,
96%) as a yellow foam.
1H NMR (DMSO-d6): d = 8.14 (s, 1 H, H-8), 7.62 (s, 1 H, AcNH),
7.27 (s, 2 H, Ar), 4.42 (t, J = 7.6 Hz, 2 H, NCH2), 4.14 (t, J = 7.0
Hz, 2 H, OCH2), 4.06–3.88 (m, 4 H, 2 CH2), 2.97–2.95 (m, 3 H, 3
CHMe2), 2.12 (s, 3 H, CH3CON), 2.07 (s, 3 H, CH3CO), 1.30 [d,
J = 6.8 Hz, 18 H, 3 CH(CH3)2].
13C NMR (DMSO-d6): d = 175.8 (NHCOCH3), 171.1 (CH3CO),
154.42 (C-6), 162.69 (C-4), 160.12 (C-2), 146.33 (C-8), 143.90,
140.50, 131.20, 130.55 (SO2Ar), 108.12 (C-5), 62.5 (C-4¢), 46.80
(C-1¢), 28.21 (C-2¢), 25.11 (C-3¢), 32.2 (CH3CON), 20.99 (CH3CO).
MS (FAB): m/z = 398 (M – Br)+.
HRMS: m/z calcd for C20H24N5O4: 398.182; found: 398.182.
Anal.Calcd. for: C,50.20; H, 5.02; N, 14.64. Found: C, 50.50; H,
5.32; N, 14.32.
7-(4-Acetoxybut-1-yl)guanine (10a)
A mixture of 9a (4.7 g, 0.01 mol), ammonium formate (1.9 g, 0.03
mol), and 10% Pd/C (0.4 g) in MeOH (80 mL) was refluxed with
stirring for 4 h, then filtered hot, and the filtrate was evaporated to
dryness under reduced pressure. The catalyst was washed with hot
aq 2 M NaOH solution (30 mL) and this solution was added to the
residue. The mixture was then heated on a steam bath for 20 min and
neutralized with concd HCl. After 1 h, crystals formed were collect-
ed and washed with H2O and thoroughly dried to yield 10a (1.88 g,
71%); mp 220–223 °C.
MS (FAB): m/z = 576 (MH+, 100%).
HRMS: m/z calcd for C28H42N5O6S: 576.286; found: 576.285.
Anal. Calcd for C28H42N5O6S: C, 58.43; H, 7.36; N, 12.17. Found:
C, 57.95; H, 7.10; N, 11.82.
7-(4-Acetoxybut-1-yl)-2-acetylamino-7H-purine (17)
To a solution of 16 (0.55 g, 1 mmol) in EtOH (25 mL) were added
10% Pd/C (0.2 g) and Et3N (0.15 mL, 1.1 mmol). Hydrogenation
was performed in a Parr apparatus at 75 °C and 3 bar of pressure.
After 6 h, the catalyst was removed by filtration and washed with
hot EtOH. A mixture of N2-acetyl-7-(4-acetoxybut-1-yl)-guanine
and 7-(4-acetoxybut-1-yl)-2-acetylamino-7H-purine (17) was ob-
tained. The products were separated by flash chromatography using
CH2Cl2–MeOH (2:1, 400 mL and 10:1, 400 mL) to obtain pure 17
(0.14 g, 50%) as a white solid; mp 131–135 °C.
1H NMR (DMSO-d6): d = 10.42 (br s, 1 H, AcNH), 9.10 (s, 1 H, H-
6), 8.62 (s, 1 H, H-8), 4.35 (t, J = 7.2 Hz, 2 H, NCH2), 4.01 (t,
J = 6.8 Hz, 2 H, OCH2), 2.18 (s, 3 H, CH3CON), 1.98 (s, 3 H,
CH3CO), 1.89–1.54 (m, 4 H, CH2, CH2).
1H NMR (DMSO-d6): d = 10.76 (br s, 1 H, NH), 7.91 (s, 1 H, H-8),
6.12 (br s, 2 H, NH2), 4.18 (t, J = 7.5 Hz, 2 H, NCH2), 3.37 (t,
J = 6.4 Hz, 2 H, OCH2), 1.99 (s, 3 H, CH3CO), 1.78–1.35 (m, 4 H,
CH2, CH2).
13C NMR (DMSO-d6): d = 172.2 (COCH3), 155.22 (C-6), 152.51
(C-2), 159.02 (C-4), 142.23 (C-8), 108.99 (C-5), 63.40 (C-4¢), 46.99
(C-1¢), 26.21 (C-2¢), 22.81 (C-3¢), 20.91 (CH3CO).
MS (FAB): m/z = 266 (MH+, 100%).
HRMS: m/z calcd for: 266.125; found: 266.126.
Anal. Calcd for C11H16N5O3: C, 47.41; H, 5.92; N, 27.65. Found: C,
47.02; H, 6.20; N, 27.23.
13C NMR (DMSO-d6): d = 172.10 (CH3CON), 170.33 (CH3CO),
143.32 (C-6), 161.31 (C-2), 162.32 (C-4), 148.03 (C-8), 120.42 (C-
5), 63.60 (C-4¢), 43.20 (C-1¢), 26.41 (C-2¢), 22.6 (C-3¢), 24.49
(CH3CON), 20.81 (CH3CO).
N2-Acetyl-7-(4-acetoxybut-1-yl)guanine (11a)
7-(4-Acetoxybut-1-yl)guanine (10a; 1 g, 4 mmol) was acetylated in
a suspension in 1-methyl-2-pyrrolidone (10 mL) after addition of
Ac2O (1.1 mL, 11 mmol) and refluxing for 10 h. The solvent was
removed at reduced pressure, the residue was triturated with EtOAc
(5 mL) and the solid separated was filtered. The solid was washed
with acetone and dried to provide 11a (1.05 g, 90%); mp 219–
223 °C.
1H NMR (DMSO-d6): d = 12.05 (br s, 1 H, AcNH), 11.58 (br s, 1 H,
NH), 8.19 (s, 1 H, H-8), 4.30 (t, J = 7.2, 2 H, NCH2), 4.00 (t, J = 6.5
Hz, 2 H, OCH2), 2.16 (s, 3 H, CH3CON), 1.98 (s, 3 H, CH3CO),
1.88–1.51 (m, 4 H, CH2, CH2).
MS (FAB): m/z = 292 (MH+, 100%).
HRMS: m/z calcd for C13H18N5O4: 292.142; found: 292.141.
Anal. Calcd for C13H18N5O4: C, 53.40; H, 6.21; N, 23.94. Found: C,
53.75; H, 6.67; N, 23.50.
5-[2-(N2-Acetyl-9-benzylguanin-7-yl)ethyl]-2,2-dimethyl-1,3-
dioxacyclohexane-4,6-dione (9c)
Compound 8 (0.9 g, 3.2 mmol) and 6,6-dimethyl-5,7-dioxa-
spiro[2.5]octane-4,8-dione (1.62 g, 9.52 mmol) were suspended in
anhyd DMF (10 mL). The reaction mixture was stirred under anhy-
drous conditions for 22 h at 60 °C. EtOAc was added and the result-
ing solid filtered to yield 1.9 g (99%) of anticipated betaine 9c; mp
234–239 °C.
1H NMR (DMSO-d6): d = 12.56 (s, 1 H, AcNH), 11.99 (s, 1 H, NH),
9.54 (s, 1 H, H-8), 7.20–7.36 (m, 5 H, Ar), 5.45 (s, 2 H, CH2Ph),
4.44 (t, J = 5.4 Hz, 2 H, NCH2), 2.65–2.60 (m, 2 H, CH2-2¢), 2.19
(s, 3 H, CH3CO), 1.34 (s, 6 H, 2 CH3).
13C NMR (DMSO-d6): d = 173.4 (CH3CON), 168.4 (CH3CO),
158.5 (C-4), 156.4 (C-6), 152.2 (C-2), 143.0 (C-8), 108.5 (C-5),
63.5 (C-4¢), 46.9 (C-1¢), 27.6 (C-3¢), 26.3 (C-2¢), 23.8 (CH3CON),
20.9 (CH3CO).
MS (EI): m/z = 307 (M+, 100%).
HRMS: m/z calcd for C13H17N5O4: 307.128; found: 307.1285.
Anal. Calcd for C13H17N5O4: C, 50.79; H, 5.58; N, 22.79. Found: C,
50.62; H, 5.79; N, 22.52.
13C NMR (DMSO-d6): d = 172.81 (C=O), 154.5 (C-4), 147.41 (C-
2), 139.2 (C-8), 128.4, 127.8, 127.3, 126.0 (Ar), 119.8 (C-5), 104.6
(OCO), 49.5 (CH2Ph), 46.0 (C-1¢), 30.0 (C-2¢), 26.7, 25.6 (CH3),
24.5 (CH3CON).
7-(4-Acetoxybut-1-yl)-2-acetylamino-6-(2¢,4¢,6¢-triisopropyl-
benzenesulfonyloxy)-7H-purine (16)
A mixture of 11a (0.5 g, 1.6 mmol), Et3N (0.9 mL, 6.4 mmol) and
DMAP (10 mg, 0.1 mmol) in anhyd CH2Cl2 (20 mL) and 2,4,6-tri-
isopropylbenzenesulfonyl chloride (1 g, 3.3 mmol) was stirred at r.t.
until the solution became clear. The solution was washed with H2O
(2 × 15 mL). The H2O phase was then washed with CHCl3 (20 mL).
The joint organic phases were washed with brine (2 × 25 mL) and
dried (Na2SO4). The solvent was removed on rotary evaporator and
MS (FAB): m/z = 454 (MH+, 50%).
HRMS: m/z calcd for C22H24N5O6: 454.1731; found: 454.1727.
Anal. Calcd for C22H24N5O6: C, 58.13; H, 5.30; N, 15.41. Found: C,
57.69; H, 4.73; N, 15.22.
Synthesis 2004, No. 12, 2026–2034 © Thieme Stuttgart · New York