3402 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Snow et al.
mL, 0.28 mmol). After it was stirred at room temperature for
20 min, methyl iodide (20 µL, 0.30 mmol) was added, and
stirring was continued for 1 h. The solution was diluted with
water and extracted with CH2Cl2. Flash chromatography in
CH2Cl2/MeOH (99:1) gave 11 (31 mg) as the second eluted
component. Crystallization from CH2Cl2 containing a little
MeOH, by slow evaporation, yielded pure 11 (20 mg, 19%);
mp 287-290 °C. 1H NMR (DMSO-d6): δ 1.58 (6H, s), 3.28 (3H,
s), 7.24 (1H, d, J ) 8 Hz), 7.36 (1H, t, J ) 8 Hz), 7.51 (1H, d,
J ) 8 Hz), 7.58 (2H, d, J ) 8 Hz), 8.46 (1H, s), 11.44 (1H, s).
CIMS: m/z 403 (MH+). Anal. (C19H16Cl2N4O2) C, H, N.
2-(2,6-Dich lor oph en ylam in o)-3,6,6,8-tetr am eth yl-3H,6H-
im id a zo[4,5-h ]isoqu in olin e-7,9-d ion e (12) a n d 2-(N-2,6-
Dich lor op h en yl-N-m eth yla m in o)-6,6,8-tr im eth yl-1H,6H-
im id a zo[4,5-h ]isoqu in olin e-7,9-d ion e (13). Compounds 12
and 13 were acquired following the procedure described for
11 but using sodium hydride (17 mg, 0.39 mmol) and methyl
iodide (32 µL, 0.51 mmol). Flash chromatography in CH2Cl2/
MeOH (99:1) gave 12 (52 mg) as the first eluted component
and 13 (23 mg) as the second eluted component. Compound
12 was further purified by chromatography in CH2Cl2/EtOAc
(95:5) and crystallization from EtOAc/hexane; yield, 24 mg;
mp 235-237 °C. 1H NMR (CDCl3): δ 1.63 (6H, s), 3.31 (3H,
s), 3.61 (3H, s), 6.98 (1H, t, J ) 8 Hz), 7.13 (1H, d, J ) 8 Hz),
7.17 (1H, d, J ) 8 Hz), 7.37 (2H, d, J ) 8 Hz), 8.8-9.1 (1H, v.
br). CIMS: m/z 417 (MH+). Anal. (C20H18Cl2N4O2) C, H, N.
8 Hz), 7.51 (2H, d, J ) 8 Hz). This unstable intermediate was
used immediately. It was further characterized as the methyl
ether, which was prepared by dissolving 17 (20 mg, 0.05 mmol)
in MeOH/HCl and stirring for several hours. After it was
evaporated, the residue was partitioned between EtOAc/
aqueous NaHCO3. The organic phase was washed with brine,
dried, and evaporated to the methyl ether derivative (15.6 mg,
75%); mp 278-280 °C (dec). 1H NMR (CD3OD): δ 1.30 (3H,
s), 1.50 (3H, s), 3.37 (3H, s), 4.29 (1H, s), 7.08 (1H, d, J ) 8
Hz), 7.28 (1H, t, J ) 8 Hz), 7.37 (1H, d, J ) 8 Hz), 7.51 (2H,
d, J ) 8 Hz). ESMS: m/z 405, 407 (MH+). Compound 17 (100
mg, 0.26 mmol) was dissolved in TFA (2 mL), and this solution
was added to a solution of sodium tristrifluoroacetoxyborohy-
dride (generated in-situ from 160 mg, 4.2 mmol of NaBH4, and
3 mL of TFA) at 0 °C. The reaction mixture was stirred at
ambient temperature for 4 h, the solvent was evaporated, the
residue was triturated with water, and the resultant mixture
was neutralized with NaHCO3 and filtered yielding 18 (85 mg,
92%). This product was further purified by flash chromatog-
raphy using 4% MeOH/CH2Cl2 as eluant and recrystallized
1
from EtOAc; mp 287-290 °C. H NMR (CDCl3): δ 1.41 (6H,
s), 3.38 (2H, d, J ) 3 Hz), 6.22 (1H, s), 7.09 (1H, d, J ) 8 Hz),
7.17 (1H, t, J ) 8 Hz), 7.44 (2H, d, J ) 8 Hz), 7.56 (1H, d, J )
8 Hz), 10.12 (1H, br). CIMS: 375, 377 (MH+). Anal. (C18H16
-
Cl2N4O‚0.2H2O) C, H, N.
(2,6-Dich lor op h en yl)-(6,6-d im eth yl-6,7,8,9-tetr a h yd r o-
3H-im id a zo[4,5-h ]isoqu in olin -2-yl)a m in e (19). To a solu-
tion of 17 (180 mg, 0.46 mmol) in THF (15 mL) was added
NaBH4 (180 mg, 4.6 mmol) followed by a solution of TFA (1
mL) in THF (5 mL). This was repeated 5× over a 48 h period
until the absence of 17 was indicated by thin-layer chroma-
tography (TLC). Subsequently, 1 N HCl (5 mL) was added
dropwise and the reaction mixture was stirred an additional
15 min, the organic solvents were evaporated, and the aqueous
residue was neutralized with NaHCO3 and extracted with
EtOAc. The extract was washed with brine and evaporated
yielding a mixture of 18 and 19. This mixture was purified by
flash chromatography using 4% MeOH/CH2Cl2 as eluant.
Compound 19 was further purified by high-performance liquid
chromatography (HPLC) using 70% CH3CN-H2O with 1%
TFA as eluant. Compound 19 was isolated as a TFA salt (25
Compound 13 had mp 228-233 °C. 1H NMR (CDCl3): δ 1.67
(6H, s), 3.34 (3H, s), 3.61 (3H, s), 7.25 (1H, d, J ) 8 Hz), 7.41
(1H, t, J ) 8 Hz), 7.55 (2H, d, J ) 8 Hz), 7.81 (1H, d, J ) 8
Hz), 9.40 (1H, br). EIMS: m/z 416 (M+).
2-(2,6-Dich lor op h en yla m in o)-3,6,6-t r im et h yl-1H ,6H -
im id a zo[4,5-h ]isoqu in olin e-7,9-d ion e (14), 2-(2,6-Dich lo-
r op h en ylm eth yla m in o)-6,6-d im eth yl-1H,6H-im id a zo[4,5-
h ]isoqu in olin e-7,9-d ion e (15), a n d 2-(2,6-Dich lor op h en yl-
m et h yla m in o)-3,6,6-t r im et h yl-1H ,6H -im id a zo[4,5-h ]iso-
qu in olin e-7,9-d ion e (16). To a stirred solution of 1 (550 mg,
1.41 mmol) in dry dimethyl formamide (DMF, 2.5 mL) was
added CH3I (2.5 mL, 40 mmol). The reaction vessel was sealed,
and the contents were stirred at room temperature for 16 h.
The CH3I was evaporated, and the resulting solution was
diluted with 25 mL of saturated NaHCO3 and allowed to stir
for 3 h. The product was filtered, washed with H2O, and then
slurried in CHCl3. The insolubles were filtered, and the mother
liquors were evaporated to leave 480 mg of a mixture of 14-
16. Flash chromatography using a gradient (25% EtOAc in
hexane-100% EtOAc) gave 14 (130 mg, 23%), 15 (100 mg,
18%), and 16 (73 mg, 13%). Compound 14: mp 128-132 °C.
1H NMR (CDCl3): δ 1.69 (6H, s), 3.63 (3H, s), 6.99 (1H, t, J )
8 Hz), 7.15-7.22 (2H, m), 7.40 (2H, d, J ) 8 Hz), 8.08 (1H, s),
8.85 (1H, s). CIMS: m/z 403, 405 (MH+). Anal. (C19H16Cl2N4O2)
C, H, N.
1
mg, 10%); mp > 300 °C (dec). H NMR (CD3OD): δ 1.39 (3H,
s), 1.41 (3H, s), 2.77 (1H, d, J ) 12 Hz), 3.15 (1H, d, J ) 12
Hz), 3.84 (1H, d, J ) 16 Hz), 4.38 (1H, d, J ) 16 Hz), 7.35
(1H, d, J ) 8 Hz), 7.47 (1H, d, J ) 8 Hz), 7.56 (1H, t, J ) 8
Hz), 7.69 (2H, d, J ) 8 Hz). CIMS: m/z 361, 363 (M+). Anal.
(C18H18Cl2N4‚1.7TFA) C, H, N.
2-(2,6-Dich lor oph en ylam in o)-6,7-dim eth yl-1,8-dih ydr o-
im id a zo[4,5-h ]isoqu in olin e-9-on e (20). Alcohol 17 (45 mg,
0.11 mmol) was suspended in concentrated H2SO4 (1 mL), and
the resultant mixture was stirred at ambient temperature for
15 min. The solution was poured over ice, neutralized with
NaHCO3, and filtered. The filtrate was triturated with water
(10 mL) and centrifuged. The liquid was decanted, and the
residual solid was triturated with methanol and centrifuged.
The supernatant was decanted, and the residue was dried to
give 20 (35 mg, 84%); mp > 300 °C. 1H NMR (DMSO-d6): δ
2.20 (3H, s), 2.28 (3H, s), 7.29-7.36 (2H, m), 7.57-7.61 (3H,
m), 8.46 (1H, s), 11.23 (1H, s), 11.43 (1H, s). ESMS: m/z 373,
375 (M+). Anal. (C18H14Cl2N4O‚0.3H2O) C, H, N.
Further purification by flash chromatography (2% CH3OH
in CH2Cl2) yielded 15; mp 284-286 °C. 1H NMR (CDCl3): δ
1.70 (6H, s), 3.58 (3H, s), 7.24 (1H, d, J ) 8 Hz), 7.39 (1H, t,
J ) 8 Hz), 7.55 (2H, d, J ) 8 Hz), 7.83 (1H, d, J ) 8 Hz), 8.43
(1H, s), 9.30 (1H, br). CIMS: m/z 403, 405 (MH+). Anal.
(C19H16Cl2N4O2‚0.3H2O) C, H, N.
Crystallization from EtOAc containing a little MeOH, by
1
slow evaporation, yielded pure 16; mp 261-263 °C. H NMR
(CD3OD + few drops of CDCl3): δ 1.63 (6H, s), 3.01 (3H, s),
3.57 (3H, s), 7.27 (1H, d, J ) 7 Hz), 7.38 (1H, t, J ) 7 Hz),
7.46 (1H, d, J ) 7 Hz), 7.54 (2H, d, J ) 7 Hz). CIMS: m/z 417,
419 (MH+). Anal. (C20H18Cl2N4O2‚0.4H2O) C, H, N.
2-(2-Ch lor op h en yla m in o)-6,7-d im eth yl-1,8-d ih yd r o-im -
id a zo[4,5-h ]isoqu in olin e-9-on e (39). Yield, 84%; mp > 300
°C. 1H NMR (DMSO-d6): δ 2.23 (3H, s), 2.29 (3H, s), 6.99 (1H,
dd, both J ) 8 Hz), 7.40 (2H, m), 7.48 (1H, d, J ) 8 Hz), 7.83
(1H, d, J ) 8 Hz), 8.98 (1H, d, J ) 8 Hz), 9.13 (1H, s), 11.26
2-(2,6-Dich lor oph en ylam in o)-6,6-dim eth yl-7,8-dih ydr o-
1H,6H-im id a zo[4,5-h ]isoqu in olin e-9-on e (18). To a solution
of 1 (90 mg, 0.23 mmol) in THF (5 mL) was added NaBH4 (90
mg, 2.3 mmol) followed by water (4 drops). The reaction
mixture was stirred at ambient temperature for 1 h. Subse-
quently, 1 N HCl (5 mL) was added dropwise and the reaction
mixture was stirred an additional 15 min, neutralized with
NaHCO3, and extracted with EtOAc. The extract was washed
with brine and evaporated yielding alcohol 17 (90 mg, 99%).
1H NMR (CD3OD): δ 1.31 (3H, s), 1.50 (3H, s), 4.72 (1H, s),
7.13 (1H, d, J ) 8 Hz), 7.28 (1H, t, J ) 8 Hz), 7.40 (1H, d, J )
(1H, s), 12.18 (1H, br). CIMS: m/z 339, 341 (M+). Anal. (C18H15
ClN4O‚0.4H2O) C, H, N.
-
7-Acet a m id o-8-n it r o-3,4-d ih yd r o-2H -isoq u in olin e-1-
on e (22). Compound 22 was prepared from 2123 by the
1
sequence described for 7a . H NMR (DMSO-d6, 400 MHz): δ
2.04 (3H, s), 3.32 (2H, t, J ) 6 Hz), 4.39 (2H, t, J ) 6 Hz), 7.61
(1H, d, J ) 9 Hz), 7.84 (1H, d, J ) 9 Hz), 8.03 (1H, s), 9.88
(1H, s).