Y. Yoshida et al. / Bioorg. Med. Chem. 7 (1999) 2647±2666
2659
pressure. The obtained solid was recrystallized from a
mixtureofAcOEtandhexanetogive363 mgof10b0 (56%):
2.05 (s, 3H), 2.21 (s, 3H), 2.36 (s, 3H), 5.30 (s, 2H), 7.10 (d,
1H, J=8.1Hz), 7.26 (d, 1H, J=8.1 Hz), 7.50 (dd, 1H,
J=0.9, 6.9 Hz), 7.62±7.79 (m, 3H), 8.43 (d, 1H,
J=5.8Hz), 9.28 (s, 1H), 9.39 (s, 1H); MS m/z 321 (MH+).
mp 155±157ꢀC; IR (KBr) 1718, 1627, 1585 cm
;
1H
1
NMR (CDCl3) d 2.34 (s, 6H), 5.42 (s, 2H), 7.18 (d, 1H,
J=7.4 Hz), 7.28 (d, 1H, J=8.6 Hz), 7.45±7.70 (m, 3H),
7.78 (d, 1H, J=7.0 Hz), 8.19 (d, 1H, J=5.8 Hz), 8.56 (d,
1H, J=5.8 Hz), 9.29 (s, 1H); MS m/z 369 (MH+).
5-(2-Acetamido-3,6-dichlorobenzyloxy)isoquinoline (15).
Yield 36%; mp 104±106ꢀC; IR (KBr) 1684, 1630,
1585 cm 1; 1H NMR (DMSO-d6) d 1.97 (s, 3H), 5.28 (s,
2H), 7.42 (d, 1H, J=7.3 Hz), 7.56±7.73 (m, 4H), 7.82 (d,
1H, J=5.8 Hz), 8.45 (d, 1H, J=5.8 Hz), 9.27 (s, 1H),
9.98 (s, 1H); MS m/z 361 (MH+).
5-(3-Acetamido-2,6-dichlorobenzyloxy)isoquinoline (10c),
5-{3-(N,N-Diacetylamino)-2,6-dichlorobenzyloxy}isoqui-
noline (10c0). A solution of 9c (1.05 g, 3.29mmol) in a
1:1:1 mixture of pyridine:CH2Cl2:acetic anhydride
(15 mL) was treated with 4-dimethylaminopyridine (5mg)
and stirred for 18h at room temperature. Ice-cooled satu-
rated sodium hydrogen carbonate solution was then added
and the mixture stirred 30min then evaporated under
reduced pressure. The residue was taken up in AcOEt then
washed with saturated sodium hydrogen carbonate solu-
tion (2Â), water (3Â), brine, dried over magnesium sulfate
and evaporated under reduced pressure. AcOEt (100mL)
was added to the residue and the solid removed by ®ltra-
tion to give 75mg of 10c (6%) as a white solid. The ®ltrate
was evaporated under reduced pressure and column chro-
matographed on silica-gel (eluent AcOEt:hexane) to give
an additional 600 mg of 10c (51%) and 200 mg of 10c0
(15%). 10c: mp 219±220ꢀC (from CH2Cl2:hexane); IR
(KBr) 1697cm 1; 1H NMR (CDCl3) d 2.27 (s, 3H), 5.48 (s,
2H), 7.20±7.26 (m, 1H), 7.43 (d, 1H, J=9.0Hz), 7.51±7.63
(m, 2H), 7.72 (brs, 1H), 7.94 (d, 1H, J=5.8 Hz), 8.42±8.50
(m, 2H), 9.22 (s, 1H); MS m/z 361 (MH+). 10c0: 1H NMR
(CDCl3) d 2.33 (s, 6H), 5.51 (s, 2H), 7.21±7.31 (m, 2H),
7.52±7.64 (m, 3H), 7.92 (d, 1H, J=6.0 Hz), 8.49 (d, 1H,
J=6.0Hz), 9.22 (s, 1H); MS m/z 403 (MH+).
5-(3-Acetamido-2,6-bis-methylthiobenzyloxy)isoquinoline
(26a). Yield 80%; mp 210±212ꢀC (from CHCl3:IPE:
1
hexane); IR (KBr) 1655 cm 1; H NMR (DMSO-d6) d
2.15 (s, 3H), 2.24 (s, 3H), 2.46 (s, 3H), 5.66 (s, 2H),
7.48±7.54 (m, 2H), 7.62±7.79 (m, 3H), 7.92 (d, 1H,
J=8.7 Hz), 8.43 (d, 1H, J=5.8 Hz), 9.28 (s, 1H), 9.46 (s,
1H); MS m/z 385 (MH+).
5-(5-Acetamido-2-chloro-6-methylthio)benzyloxyisoquin-
oline (26b). Yield 69%; mp 196±198ꢀC (from CHCl3:
IPE); IR (KBr) 1664cm 1; 1H NMR (DMSO-d6) d 2.18 (s,
3H), 2.26 (s, 3H), 5.63 (s, 2H), 7.52±7.72 (m, 4H), 7.77 (d,
1H, J=6.0 Hz), 7.99 (d, 1H, J=8.8 Hz), 8.44 (d, 1H,
J=5.8 Hz), 9.29 (s, 1H), 9.53 (s, 1H); MS m/z 373 (MH+).
5-(3-Acetamido-2-chloro-6-methylthio)benzyloxyisoquin-
oline (26c). Yield 89%; mp 211±214ꢀC (from CHCl3:IPE:
hexane); IR (KBr) 1676 cm 1; 1H NMR (DMSO-d6) d 2.11
(s, 3H), 2.49 (s, 3H), 5.49 (s, 2H), 7.49 (d, 1H, J=8.7 Hz),
7.50±7.53(m, 1H), 7.61±7.80(m, 4H), 8.44(d, 1H,J=5.8 Hz),
9.28 (s, 1H), 9.61 (s, 1H); MS m/z 373 (MH+).
5-(3-Acetamido-2,5-dichlorobenzyloxy)isoquinoline (10d).
To a solution of 9d (256 mg, 0.80 mmol) in 1,2-dichloro-
ethane (6 mL) was added acetic anhydride (1.1 g,
10.6 mmol), then stirred at 75ꢀC for 2.5 h, and cooled to
room temperature. The mixture was poured into saturated
sodium hydrogen carbonate, stirred at room temperature
for 30 min, and extracted with AcOEt (3Â). The combined
extracts were washed with brine, dried over magnesium sul-
fate and evaporated under reduced pressure. The residual
solid was recrystallized from a mixture of CH2Cl2 and hex-
ane to give 140 mg of 10d (48%): mp 217±220ꢀC; IR (KBr)
1668, 1585 cm 1; 1H NMR (CDCl3) d 2.29 (s, 3H), 5.31 (s,
2H), 7.11 (d, 1H, J=7.4 Hz), 7.39 (d, 1H, J=2.3 Hz), 7.52±
7.73 (m, 2H), 8.14 (d, 1H, J=5.8 Hz), 8.51 (s, 1H), 8.57 (d,
1H, J=5.8 Hz), 9.28 (s, 1H); MS m/z 361 (MH+).
5-(3-Acetamido-2-chlorobenzyloxy)isoquinoline (10b). To
a solution of 10b0 (187 mg, 0.51 mmol) in ethanol (2mL)
was added pyrrolidine (36 mg, 0.51 mmol) at room tem-
perature. After stirring at room temperature for 5 min, the
solution was poured into water, extracted with CH2Cl2,
dried over magnesium sulfate and evaporated under
reducedpressure. The residualsolid wasrecrystallized from
a mixture of CH2Cl2, hexane and IPE to give 118 mg of 10b
(71%):mp196±198ꢀC;IR(KBr) 1662,1583, 1537cm 1;1H
NMR (DMSO-d6) d 2.11 (s, 3H), 5.41 (s, 2H), 7.37±7.75 (m,
6H), 7.98 (d, 1H, J=5.8 Hz), 8.51 (d, 1H, J=5.8 Hz), 9.29
(s, 1H), 9.62 (s, 1H); MS m/z 327 (MH+).
5-(2-Amino-3,6-dichlorobenzyloxy)isoquinoline (14). To
a solution of 13 (200 mg, 0.70 mmol) in CHCl3 (2 mL)
was added N-chlorosuccinimide (95 mg, 0.71 mmol) and
then stirred under re¯ux for 3.5 h. The obtained sus-
pension was ®ltered and evaporated under reduced
pressure. The residue was puri®ed by silica-gel chroma-
tography (eluent AcOEt:IPE) to give 146 mg of 14
Preparation of 10c,e, 15, 26a±c was carried out by a
similar method to that described for 10d.
5-(3-Acetamido-2,6-dichlorobenzyloxy)isoquinoline (10c).
Yield 95%; mp 219±220ꢀC (from CH2Cl2:hexane); IR
1
(65%) as a solid: H NMR (DMSO-d6) d 5.41 (s, 2H),
1
(KBr) 1697cm 1; H NMR (CDCl3) d 2.27 (s, 3H), 5.48
5.83 (s, 2H), 6.74 (d, 1H, J=8.5 Hz), 7.33 (d, 1H,
J=8.5 Hz), 7.44 (d, 1H, J=4.5 Hz), 7.60±7.73 (m, 2H),
7.84 (d, 1H, J=5.8 Hz), 8.45 (d, 1H, J=5.8 Hz), 9.27
(s, 1H); MS m/z 319 (MH+).
(s, 2H), 7.20±7.26 (m, 1H), 7.43 (d, 1H, J=9.0Hz), 7.51±
7.63 (m, 2H), 7.72 (brs, 1H), 7.94 (d, 1H, J=5.8 Hz), 8.42±
8.50 (m, 2H), 9.22 (s, 1H); MS m/z 361 (MH+).
5-(3-Acetamido-2,6-dimethylbenzyloxy)isoquinoline (10e).
Yield 91%; mp 214±215ꢀC (from CH2Cl2:hexane); IR
2,6-Di¯uoro-3-nitrobenzoic acid (17). Fuming nitric acid
(39 g, 620 mmol) was cooled to 50ꢀC and treated
with 2,6-di¯uorobenzoic acid (5.0 g, 31.6 mmol), added
1
(KBr) 1658, 1585, 1529cm 1; H NMR (DMSO-d6) d