Pappo et al.
(s, 1H), 7.03 (s, 1H), 6.95 (d, J ) 8 Hz, 1H), 6.91 (d, J ) 8 Hz,
1H), 5.32 (br t, 1H), 4.99 (s, 2H), 4.81 (d, J ) 7 Hz, 2H), 3.73
(s, 6H), 1.73 (s, 3H), 1.64 (s, 3H); 13C NMR (100 MHz) δ 150.3,
148.8, 148.7, 143.3, 140.6, 140.2, 136.7, 130.9, 120.9, 120.4,
112.5, 111.7, 109.5, 75.2, 55.8, 55.7, 44.7, 25.5, 18.2; MS (FAB)
m/z (rel intens) 370 (100, MH+); HRMS (FAB) m/z calcd for
C19H24N5O3 (MH+) 370.1887, found 370.1879.
N6-(Benzyloxy)-7-(3-bromo-3-methylbutyl)adenine (16d).
Compound 14d (150 mg, 0.32 mmol) in a solution of 15% HBr
in AcOH (2 mL) was stirred for 12 h at room temperature,
the solvent was then evaporated, and the residue was parti-
tioned between ethyl acetate (20 mL) and 0.5 N aq NaHCO3
(20 mL). The organic layer was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified
by VLC (methanol/EtOAc, 1:20), affording compound 16d (90
mg, 72%) as an amorphous solid: 1H NMR (200 MHz) δ 11.28
(br s, 1H), 7.94 (s, 1H), 7.54 (s, 1H), 7.37-7.19 (m, 5H), 5.02
(s, 2H), 4.33 (br t, 2H), 2.17 (br t, 2H) 1.67 (s, 6H); 13C NMR
(50 MHz) δ 150.5, 143.6, 141.4, 140.1, 139.0, 128.5, 127.9,
109.8, 75.1, 66.6, 55.3, 47.9, 34.3; MS (CI) m/z (rel intens) 390
(7, MH+), 310 (80), 204 (100); HRMS (EI) m/z calcd for C17H20-
BrN5O (M+) 389.0851, found 389.0850.
N6-(Benzyloxy)-7-(3-bromo-3-methylhexyl)adenine(16e).
Compound 16e was prepared from compound 14e (350 mg,
0.69 mmol) via the same procedure described for the prepara-
tion of 16d. The residue was purified by VLC (methanol/
EtOAc, 1:20), affording compound 16e (190 mg, 68%) as an
amorphous solid: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H),
7.35-7.27 (m, 5H), 7.15 (s, 1H), 5.08 (s, 2H), 4.34 (t, J ) 8 Hz,
2H), 2.15 (t, J ) 8 Hz, 2H), 1.79 (t, 2H), 1.70 (s, 3H), 1.53 (m,
2H), 0.95 (t, J ) 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 147.3,
144.5, 139.6, 138.6, 137.6, 128.7, 128.6, 128.4, 128.1, 127.9,
110.4, 76.0, 69.4, 48.2, 46.1, 46.0, 31.1, 18.8, 14.0; MS (CI) m/z
(rel intens) 418 (10, MH+), 338 (30), 107 (100); HRMS (EI) m/z
calcd for C19H24BrN5O (M+) 417.1164, found 417.1167.
7,8,9,10-Tetrahydro-10-(benzyloxy)-8-iodo-9,9-dimethyl-
[1,4]diazepino[1,2,3-g,h]purine (17a). To a stirred solution
of compound 15a (60 mg, 0.19 mmol) and NaHCO3 (16 mg,
0.19 mmol) in 95% EtOH (4 mL) was added dropwise a solution
of I2 (144 mg, 0.57 mmol) in 95% EtOH (2 mL), and the mixture
was stirred in the dark at room temperature for 48 h. The
solvent was then evaporated and the residue purified by VLC
(methanol/EtOAc, 1:9), affording compound 17a (62 mg, 75%)
as a yellow amorphous solid: 1H NMR (400 MHz) δ 8.64 (s,
1H), 8.54 (s, 1H), 7.61 (m, 2H), 7.43 (m, 3H), 5.40 (d, J ) 10
Hz, 1H), 5.25 (br t, 1H), 4.90 (d, J ) 10 Hz, 1H), 4.63 (br m,
2H), 1.72 (s, 3H), 1.41 (s, 3H); 13C NMR (100 MHz) δ 159.2,
151.6, 150.9, 144.0, 135.4, 128.5, 128.4, 127.8, 109.9, 77.4, 66.6,
51.1, 48.6, 29.1, 18.0; MS (CI) m/z (rel intens) 436 (15, MH+),
310 (49), 202 (100). HRMS (CI) m/z calcd for C17H19N5O1I
(MH+) 436.0635, found 436.0634.
From Compound 17a. A solution of compound 17a (14 mg,
0.032 mmol) and Bu3SnH (32 mg, 0.11 mmol) in dry THF (1
mL) under an argon atmosphere was refluxed for 3 h under
light radiation. After cooling, the solvent was evaporated and
the residue purified by VLC (EtOAc/methanol, 6:1), affording
compound 18a (8 mg, 81%) as an amorphous solid.
7,8,9,10-Tetrahydro-10-(3,4-dimethoxybenzyloxy)-9,9-
dimethyl[1,4]diazepino[1,2,3-g,h]purine (18b). Compound
18b was prepared from compound 15b (140 mg, 0.38 mmol)
and mercury(II) acetate (241 mg, 0.76 mmol) in dry THF (5
mL) followed by NaBH4 (29 mg, 0.76 mmol) in 2.5 N aq NaOH
(1 mL) via the same procedure described for the preparation
of 18a. The residue was purified by VLC (methanol/EtOAc,
1:5), affording compound 18b (80 mg, 57%) as an amorphous
solid: 1H NMR (400 MHz, 96 °C), compound 18b exhibited a
complex spectum suggesting the existence of several conform-
ers, δ 8.55 and 8.51 (2s, 1H), 8.38 (s, 1H), 6.82-7.25 (m, 3H),
5.13 and 5.09 (2s, 2H), 4.31 (br t, 2H), 3.66-3.82 (several s,
6H), 2.34 (br t, 2H), 1.44 and 1.42 (2s, 6H); 13C NMR (100 MHz)
δ 159.7, 151.7, 151.6, 149.6, 149.3, 147.6, 145.4, 145.3, 134.6,
133.7, 122.0, 120.8, 116.3, 115.2, 114.4, 114.0, 113.4, 112.9,
110.4, 108.5, 77.8, 75.4, 63.2, 56.2, 56.1, 42.1, 38.6, 24.6; MS
(FAB) m/z (rel intens) 369 (90, MH+), 204 (75), 175 (100);
HRMS (ES) m/z calcd for C19H24N5O3 370.1873, found 370.1851.
7,8,9,10-Tetrahydro-10-hydroxy-9,9-dimethyl[1,4]-
diazepino[1,2,3-g,h]purine (6). From Compound 18a.
Compound 18a (73 mg, 0.24 mmol) was dissolved in cold 30%
HBr in glacial acetic acid (3 mL) and heated to 100 °C for 3.5
h. The solvent was then evaporated and the residue triturated
with ether (2 × 2 mL). The obtained residual hydrobromide
salt was dissolved in methanol basified with K2CO3. The
remaining gum after evaporation was purified by VLC (metha-
nol/EtOAc, 1:6), affording compound 6 (50 mg, 96%) as an
amorphous solid: 1H NMR (400 MHz, 60 °C) δ 8.34 (s, 1H),
8.28 (s, 1H), 4.30 (br t, 2H), 2.28 (br t, 2H), 1.37 (s, 6H); 13C
NMR (125 MHz) δ 158.6, 151.5, 151.0, 144.6, 109.4, 62.0, 42.0,
38.1, 24.7; MS (EI) m/z (rel intens) 219 (28, M+), 188 (100);
HRMS (EI) m/z calcd for C10H13N5O (M+) 219.1120, found
219.1121.
From Compound 18b. To a solution of compound 17c (23
mg, 0.06 mmol) in a mixture of CH2Cl2-H2O (18:1, 3.8 mL)
was added DDQ (28 mg, 0. 12 mmol) in one portion. The
reaction was stirred vigorously at room temperature for 4 h
and the solvent then evaporated to dryness. The residue was
dissolved in methanol basified with K2CO3 and then concen-
trated under vacuum. The remaining gum was purified by VLC
(methanol/EtOAc, 1:6), affording compound 6 (10 mg, 76%) as
an amorphous solid.
From Compound 16d. Compound 16d (13 mg, 0.03 mmol)
was dissolved in cold 30% HBr in AcOH (1 mL) and the
solution stirred at 100 °C for 3 h. The solvent was then
evaporated and the residue triturated with ether (2 × 2 mL).
The hydrobromide salt was dissolved in methanol basified with
K2CO3 and the solvent evaporated to dryness. The remaining
gum was purified by VLC (methanol/EtOAc, 1:6), affording
compound 6 (7 mg, 95%) as an amorphous solid.
7,8,9,10-Tetrahydro-10-(benzyloxy)-9,9-dimethyl[1,4]-
diazepino[1,2,3-g,h]purine (18a). From Compound 15a.
To a stirred solution of 15a (130 mg, 0.42 mmol) in dry THF
(5 mL) at 0 °C under an argon atmosphere was added mercury-
(II) acetate (400 mg, 1.25 mmol) in one portion. The solution
was kept at 40 °C for 24 h. After the solution was cooled to
room temperature, NaBH4 (32 mg, 0.84 mmol) in 2.5 N aq
NaOH (1 mL) was added and the solution stirred further for
20 min. The black precipitate was filtered off through Celite,
the filtrate extracted with ethyl acetate (2 × 10 mL), and the
combined organic layer washed with brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by VLC
(methanol/EtOAc, 1:6), affording 18a (90 mg, 69%) as a
colorless oil: 1H NMR (400 MHz, 50 °C) δ 8.54 (s, 1H), 8.38
(s, 1H), 7.56 (m, 2H), 7.39 (m, 3H), 5.15 (br s, 2H), 4.31 (br t,
2H), 2.34 (br t, 2H), 1.42 (br s, 6H); 13C NMR (100 MHz) δ
159.5, 151.8 (2C), 145.7, 135.8, 129.0, 128.4, 110.1, 77.7, 63.1,
42.1, 38.0, 22.9; MS (CI) m/z (rel intens) 310 (23, MH+), 204
(100); HRMS (CI) m/z calcd for C17H20N5O1 (MH+) 310.1667,
found 310.1662.
Form Compound 20a. Compound 6 was prepared from
compound 20a (10 mg, 0.02 mmol) via the same procedure
described for the acid-catalyzed cyclization of 16d. The residue
was purified by VLC (methanol/EtOAc, 1:6), affording com-
pound 6 (5.2 mg, 93%) as an amorphous solid.
7,8,9,10-Tetrahydro-10-hydroxy-9-methyl-9-propyl[1,4]-
diazepino[1,2,3-g,h]purine Hydrobromide (7). Compound
7 was prepared from compound 16e (20 mg, 0.05 mmol) via
the same procedure described for the acid-catalyzed cyclization
of 16d. The obtained solid from the reaction mixture was
filtered and washed with ether to afford compound 7‚HBr (8
mg, 48%) as a white solid: 1H NMR (500 MHz) δ 8.69 (s, 1H),
8.50 (s, 1H), 4.43 (br t, 2H), 2.54 (m, 1H), 2.42 (m, 1H), 1.97
(m, 1H), 1.76 (m, 1H), 1.49 (s, 3H), 1.36 (m, 2H), 0.89 (t, J )
7.5 Hz, 3H); 13C NMR (100 MHz) δ 155.2, 147.3, 146.2, 144.4,
108.3, 68.9, 42.5, 39.1, 35.0, 23.7, 16.9, 14.4; MS (EI) m/z (rel
204 J. Org. Chem., Vol. 70, No. 1, 2005