692
X. Y. Zhu et al. / Bioorg. Med. Chem. 15 (2007) 686–695
H2O: C, 46.18; H, 2.66; N, 3.37. Found: C, 46.02; H,
2.67; N, 3.32.
polyphosphoric acid (30 g) was heated at 110 ꢁC for
3 h. After cooling to rt, the mixture was poured onto
ice/water (100 mL) and neutralized with saturated solu-
tion of NaHCO3. A solid was obtained, washed with
H2O and EtOAc to yield 180 mg, 84%. The crude prod-
uct, 4h, was used for alkylation without further purifica-
tion. Using Method B, compound 4h was converted to
5h, 53%. Mp 234–235 ꢁC. 1H NMR (300 MHz,
DMSO-d6): d 10.05 (1H, s), 9.12 (1H, d, J = 9.0 Hz),
8.96 (1H, d, J = 3.0 Hz), 8.93 (1H, s), 8.55 (1H, dd,
J = 3.0, 9.0 Hz), 8.54 (1H, s), 8.51 (1H, d, J = 3.0 Hz),
8.05 (1H, t, J = 3.0 Hz), 7.87 (2H, m), 5.12 (3H, s).
Calcd for C17H13IN2OSÆ1.25H2O: C, 46.11; H, 3.53;
N, 6.33. Found: C, 46.40; H, 3.16; N, 6.19.
5.2.4. 2-Cyano-5-methyl-benzo[b]thieno[3,2-b]quinolin-5-
ium iodide, 5e. Using Method C and 5-iodoanthranilic
acid as starting material, 2-iodo benzo[b]thieno[3,2-
b]quinolinone was obtained and subsequently converted
to 2-cyano benzo[b]thieno[3,2-b]quinoline 4e, 32%. Mp
1
244–245 ꢁC. H NMR (300 MHz, CDCl3): d 8.78 (1H,
d, J = 8.1 Hz), 8.67 (1H, s), 8.45 (1H, d, J = 10.8 Hz),
8.34 (1H,s), 7.89 (2H, dd, J = 8.1, 2.7 Hz), 7.71 (1H, t,
J = 8.1 Hz), 7.61 (1H, t, J = 8.1 Hz). Calcd for
C16H18N2S: C, 73.84; H, 3.07; N, 10.77. Found: C,
73.52; H, 3.16; N, 10.51. Compound 5e was obtained
1
from compound 4e in 74% yield. Mp 204–205 ꢁC. H
NMR (300 MHz, DMSO-d6): d 9.35 (1H, s), 9.25 (1H,
d, J = 1.8 Hz), 8.96 (1H, d, J = 8.7 Hz), 8.85 (1H, d,
J = 8.1Hz), 8.47 (1H, dd, J = 1.8, 8.1 Hz), 8.01 (1H,
dt, J = 1.8, 8.1 Hz), 7.90 (1H, d, J = 8.1 Hz), 7.57 (1H,
dt, J = 1.8, 8.1 Hz), 5.05 (3H,s). Calcd for C17H11IN2-
SÆ2.5H2O: C, 45.65; H, 3.61; N, 6.26. Found: C, 45.61;
H, 3.55; N, 6.25.
5.2.8. 5-Methyl-benzo[b]thieno[3,2-b]quinolin-5-ium tri-
flate, 6. A mixture of benzo[b]thieno[3,2-b]quinoline 4b
(80 mg, 0.34 mmol) in toluene (5 mL) and MeOTf
(0.2 mL) was stirred for 12 h at rt. A yellow solid ap-
peared and was collected by filtration. Recrystalization
from MeOH–Et2O afforded 5-methyl benzo[b]thie-
no[3,2-b]quinolin-5-ium triflate 6, 114 mg, 84%. Mp
237–238 ꢁC. 1H NMR (300 MHz, DMSO-d6): d 9.99
(1H, s), 9.10 (1H, d, J = 8.4 Hz), 8.87 (1H, d,
J = 9.0 Hz), 8.50 (1H, d, J = 3.6 Hz), 8.48 (1H,
d, J = 3.6 Hz), 8.34 (1H, t, J = 8.4 Hz), 8.09 (1H, d,
J = 7.8 Hz), 8.02 (1H, d, J = 7.8 Hz), 7.86 (1H, t,
J = 8.1 Hz), 5.10 (3H, s). Calcd for C17H12F3NO3S2Æ0.2-
H2O: C, 50.66; H, 3.00; N, 3.49. Found: C, 50.58; H,
2.89; N, 3.52.
5.2.5. 2-Methoxy-5-methyl-benzo[b]thieno[3,2-b]quinolin-
5-ium iodide, 5f. Using Method C and 5-iodoanthranilic
acid as starting material, 2-iodo benzo[b]thieno[3,2-
b]quinolinone was obtained and subsequently converted
to 2-methoxy benzo[b]thieno[3,2-b]quinoline 4f, 32%. 1H
NMR (300 MHz, CDCl3): d 8.60 (1H, d, J = 6.9 Hz),
8.44 (1H, s), 8.16 (1H, d, J = 9.3 Hz), 7.81 (1H, d, J =
7.2 Hz), 7.58 (1H, dt, J = 2.7, 7.2 Hz), 7.53 (1H, dt,
J = 2.7, 7.2 Hz), 7.41 (1H, dd, J = 2.7, 9.3 Hz), 7.11
(1H, d, J = 2.7 Hz), 3.95 (3H, s). Starting from com-
pound 4f, and using Method B, 5f was obtained in
51% yield. Mp 216–217 ꢁC. 1H NMR (300 MHz,
DMSO-d6): d 9.77 (1H, s), 9.02 (1H, d, J = 8.4 Hz),
8.78 (1H, d, J = 9.8 Hz), 8.43 (1H, d, J = 8.1 Hz), 7.96
(2H, m), 7.82 (2H, m), 5.06 (3H, s), 4.04 (3H, s). Calcd
for C17H14INOSÆ0.5H2O: C, 49.05; H, 3.63; N, 3.36.
Found: C, 49.01; H, 3.60; N, 3.30.
5.2.9. 5-(50-Cyclohexyl-pentyl)-benzo[b]thieno[3,2-b]quin-
olin-5-ium iodide, 7. Using Method B, compound 4b was
1
converted to 7 in 30% yield. Mp 182–184 ꢁC. H NMR
(300 MHz, DMSO-d6): d 10.02 (1H, s), 8.64 (1H, d,
J = 9.0 Hz), 8.65 (1H, d, J = 8.4 Hz), 8.51 (2H, d,
J = 8.2 Hz), 8.36 (1H, t, J = 7.5 Hz), 8.10 (1H, d,
J = 7.2 Hz), 8.04 (1H, d, J = 8.0 Hz), 7.92 (1H, t,
J = 7.2 Hz), 5.50 (2H, t, J = 7.8 Hz), 2.19 (2H, m),
1.66 (7H, m), 1.44 (2H, m), 1.21 (6H, m), 0.86 (2H,
m). Calcd for C26H30INSÆ2.5H2O: C, 55.71; H, 6.29;
N, 2.50. Found: C, 55.68; H, 5.88; N, 2.29.
5.2.6. 2-Carboxy-5-methyl-benzo[b]thieno[3,2-b]quinolin-
5-ium iodide, 5g. A mixture of 2-cyano benzo[b]thie-
no[3,2-b]quinoline, 4e (0.302 g, 1.16 mmol), concd
H2SO4, and H2O (1:1 mixture, 4 mL) was stirred at
55 ꢁC overnight. After cooling to rt, H2O (80 mL) was
added. A solid was collected and washed with water.
Further purification was conducted on silica gel to af-
ford a solid 4g, 200 mg, 65%; eluent:CH2Cl2:EtOAc (4/
2). The crude product was used for alkylation without
further purification. Using Method B, compound 4g
was converted to 5g, 64%. Mp decomposes at 203–
5.3. Synthesis of benzothieno[3,2-b]pyridines 10a–d
5.3.1. 3-Bromo-1-(4-nitro-phenoxy)-pyridinium tetrafluo-
roborate, 8. To a solution of 3-bromopyridine N-oxide
(4 g, 23 mmol) in anhydrous CH3CN (20 mL) was added
4-nitrobenzene diazonium tetrafluoroborate (5.5 g,
23 mmol) with vigorous stirring. The mixture was al-
lowed to stir at rt for 48 h. EtOAc (50 mL) was added,
and the solution was allowed to sit for an additional
24 h, the salt proceeded to crystallize out of solution.
The crystals were collected by filtration and washed with
MeOH to yield pure 3-bromo-1-(4-nitro-phenoxy)-pyri-
dinium tetrafluoroborate, 8, 6.1 g, 68%. Mp 149–150 ꢁC
(lit. 155–156 ꢁC). 1H NMR (DMSO-d6): d 10.27 (1H, s),
9.77 (1H, d, J = 6.4 Hz), 9.13 (1H, d, J = 8.3 Hz), 8.39
(1H, dd, J = 6.4, 8.4 Hz), 8.36 (2H, d, J = 9.27 Hz),
7.52 (2H, d, J = 8.2 Hz).
1
204 ꢁC. H NMR (300 MHz, DMSO-d6): d 13.08 (1H,
br s), 9.08 (1H, d, J = 9.0 Hz), 8.95 (1H, d,
J = 3.0 Hz), 8.84 (1H, d, J = 9.0 Hz), 8.65 (1H, dd,
J = 9.0, 3.0 Hz), 8.04 (1H, t, J = 9.0 Hz), 7.91 (1H, d,
J = 3.0 Hz), 7.86 (2H, m), 5.10 (3H, s). Calcd for
C17H12INO2S: C, 48.47; H, 2.87; N, 3.32. Found: C,
48.72; H, 2.61; N, 3.22.
5.2.7. 2-Carbamoyl-5-methyl-benzo[b]thieno[3,2-b]quino-
lin-5-ium iodide, 5h. A mixture of 2-cyano benzo[b]thie-
no[3,2-b]quinoline, 4e (0.2 g, 0.76 mmol), and
5.3.2. 3-Bromo-2-(2-hydroxy-5-nitrophenyl) pyridine, 9a.
A solution of 3-bromo-1-(4-nitrophenoxy)-pyridinium