N. Effendi et al.
Bioorganic&MedicinalChemistry27(2019)383–393
CDCl3): δ 2.48 (3H, s), 2.65–2.95 (4H, m), 3.39–3.51 (7H, m),
2.83–3.85 (2H, m), 4.21–4.25 (2H, m), 7.15–7.17 (1H, m), 7.28–7.29
(1H, m), 7.37 (1H, s), 7.47–7.53 (2H, m), 7.71 (1H, dd, J = 1.6,
8.8 Hz), 8.33 (1H, dd, J = 1.6, 8.4 Hz), 8.49 (1H, d, J = 8.8 Hz), 8.66
(1H, s). LRMS (DART+) calcd for C24H28N5O2 [M+H+]: m/z = 418.2,
found 418.2.
TFA by nitrogen gassing, the residue was dissolved in dichloromethane
and washed with 0.1 M HCl. After adjusting pH to 9.0 using 0.1 M
NaOH aqueous solution, the water layer was extracted using di-
chloromethane (3 × 25 mL). The organic layer was dried over sodium
sulfate, filtered, and concentrated under reduced pressure to obtain the
titled compound (7a). The same procedure was carried out to obtain
compound 7b.
2.2.3.3. N-{2-[5-(2-Methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-
8-yl}-N′,N′-dimethylethane-1,2-diamine (5f). The title compound 5f was
afforded (145 mg, 85%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ
2.38 (6H, s), 2.73–2.76 (2H, m), 3.38–3.39 (2H, m), 3.50 (3H, s),
3.82–3.84 (2H, m), 4.23–4.25 (2H, m), 6.48 (1H, br s), 6.76 (1H, d,
J = 8.0 Hz), 7.10–7.14 (2H, m), 7.37 (1H, d, J = 2.4 Hz), 7.40–7.44
(1H, m), 7.64 (1H, dd, J = 1.6, 8.8 Hz), 8.24–8.26 (1H, m), 8.31 (1H, d,
J = 9.2 Hz), 8.60 (1H, d, J = 1.6 Hz). LRMS (DART+) calcd for
2.2.5.1. 2-[5-(2-Methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperidin-
4-yloxy)quinoline (7a). The title compound 7a was afforded (80 mg,
40%) as a pale white solid. 1H NMR (400 MHz, CDCl3): δ 3.44–3.49
(4H, m), 3.50 (3H, s), 3.62–3.63 (1H, m), 3.82–3.85 (2H, m), 4.05–4.06
(4H, m), 4.23–4.26 (2H, m), 6.80 (1H, br s), 7.15–7.18 (1H, m),
7.24–7.26 (1H, m), 7.37–7.38 (1H, m), 7.40–7.54 (2H, m), 7.71 (1H,
dd, J = 2.0, 8.8 Hz), 8.34 (1H, dd, J = 1.6, 8.4 Hz), 8.50 (1H, d,
J = 2.4, 9.2 Hz), 8.64 (1H, d, J = 1.6 Hz). LRMS (DART+) calcd for
C
23H28N5O2 [M+H+]: m/z = 406.2, found 406.2.
C
24H27N4O3 [M+H+]: m/z = 419.2, found 419.2.
2.2.3.4. N,N-Diethyl-N′-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-
1-yl]quinolin-8-yl}ethane-1,2-diamine (5g). The title compound 5g was
afforded (105 mg, 52%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ
1.06–1.10 (6H, m), 2.65–2.70 (4H, m), 2.87–2.89 (2H, m), 3.38–3.39
(2H, m), 3.50 (3H, s), 3.82–3.84 (2H, m), 4.22–4.25 (2H, m), 6.48 (1H,
br s), 6.77 (1H, d, J = 7.6 Hz), 7.10–7.12 (2H, m), 7.37 (1H, d,
J = 2.4 Hz), 7.40–7.44 (1H, m), 7.65 (1H, dd, J = 1.6, 8.8 Hz),
8.19–8.24 (1H, m), 8.26 (1H, dd, J = 1.2, 8.4 Hz), 8.63 (1H, s). LRMS
(DART+) calcd for C25H32N5O2 [M+H+]: m/z = 434.2, found 434.3.
2.2.5.2. cis-4-({2-[5-(2-Methoxyethoxy)-1H-benzo[d]imidazol-1-yl]
quinolin-8-yl}oxy)cyclohexan-1-amine (7b). The title compound 7b was
afforded (97 mg, 45%) as a pale white solid. 1H NMR (400 MHz,
CDCl3): δ 1.62 (2H, br s), 1.72–1.74 (2H, m), 1.78–1.86 (4H, m),
2.28–2.31 (2H, m), 2.81–2.85 (1H, m), 3.50 (3H, s), 3.82–3.84 (2H, m),
4.22–4.24 (2H, m), 4.84 (1H, br s), 7.16–7.21 (2H, m), 7.35 (1H, d,
J = 2.4 Hz), 7.42–7.48 (2H, m), 7.70 (1H, d, J = 8.8 Hz), 8.29 (1H, d,
J = 8.8 Hz), 8.64 (1H, s), 8.86 (1H, d, J = 8.8 Hz). LRMS (DART+)
calcd for C25H29N4O3 [M+H+]: m/z = 433.2, found 433.2.
2.2.4. General procedure for the preparation of compounds (6a, 6b)
A mixture of piperidin-4-ol (610 mg, 6.0 mmol, 1.0 eq.), N,N-diiso-
propylethylamine (DIPEA) (1.6 mL, 9.0 mmol, 1.5 eq.), and di-tert-butyl
dicarbonate (Boc2O) (520 mg, 2.4 mmol, 0.4 eq.) in dry di-
chloromethane (15 mL) was stirred at room temperature for 19 h under
nitrogen atmosphere. The reaction mixture was diluted with di-
chloromethane and washed with saturated aqueous NaHCO3 and brine.
The organic layer was dried over anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (chloroform/methanol = 50/1) to
afford Boc-aminoalcohol (tert-butyl 4-hydroxypiperidine-1-carboxylate)
as a colorless solid (350 mg, 29%). The purified material (350 mg,
1.7 mmol, 1.0 eq.) was dissolved in dichloromethane (DCM) (5 mL).
Triethylamine (TEA) (480 µL, 3.7 mmol, 2.2 eq.) was added to the so-
lution and the solution was cooled to 0 °C using an ice bath. To the
mixture, methane sulfonyl chloride (MsCl) (160 µL, 2.0 mmol, 1.2 eq.)
was added dropwise at 0 °C. The mixture was gradually warmed to
room temperature and stirred overnight. The reaction mixture was
quenched by addition of water (10 mL) dropwise and extracted with
DCM (3 × 20 mL). The organic layer was dried over anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure to obtain 6a
(280 mg) as a colorless solid. The product was used for the next step
without further purification. The same procedure was performed to
obtain compound 6b.
2.2.6. 5-Iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-
(piperazin-1-yl)quinoline (8)
A mixture of N-chlorosuccinimide (NCS) (53 mg, 0.4 mmol, 1.2 eq.)
and sodium iodide (NaI) (60 mg, 0.4 mmol, 1.2 eq.) in acetic acid
(5 mL) was added to 5a (119 mg, 0.3 mmol, 1.0 eq.) in acetic acid
(5 mL) and the mixture was stirred at 50 °C overnight under nitrogen
atmosphere. After adjusting pH to 9.0 using saturated aqueous sodium
bicarbonate (NaHCO3), the reaction mixture was extracted with di-
chloromethane (3 × 30 mL). The organic layer was dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel
(chloroform/methanol = 50/1) to afford 8 (103 mg, 65%) as a pale
yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.90–2.94 (1H, br s),
3.21–3.24 (3H, m), 3.38–3.45 (4H, m), 3.50 (3H, s), 3.82–3.84 (2H, m),
4.23–4.25 (2H, m), 6.98–7.02 (1H, m, 7.16 (1H, d, J = 8.8 Hz), 7.37
(1H, s), 7.74 (1H, d, J = 8.8 Hz), 8.00 (1H, d, J = 8.4 Hz), 8.46 (1H, d,
J = 8.0 Hz), 8.56 (1H, d, J = 8.0 Hz), 8.65 (1H, s). 13C NMR (100 MHz,
CDCl3): δ 156.15, 150.39, 147.16, 145.53, 144.76, 141.23, 137.52,
129.21, 126.73, 119.41, 114.86, 114.68, 113.64, 103.67, 89.03, 71.11,
67.87, 59.29, 53.25 (2C), 51.94, 46.47 (2C). LRMS (ESI+) calcd for
C
23H24IN5O2 [M+H+]: m/z = 530.1, found 530.1.
2.2.7. tert-Butyl 4-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-
1-yl]quinolin-8-yl}piperazine-1-carboxylate (9)
2.2.5. General procedure for the preparation of compounds (7a and 7b)
To a mixture of 2 (168 mg, 0.5 mmol, 1.0 eq.) and tert-butyl 4-
[(methylsulfonyl)oxy]piperidine-1-carboxylate (223 mg, 0.8 mmol,
1.6 eq.) (6a) in dry toluene (5 mL) was added cesium carbonate
(495 mg, 1.5 mmol, 3.0 eq.). The mixture was stirred at 100 °C for
overnight under nitrogen atmosphere. After reaction completion, water
was added to the mixture and the mixture was extracted using ethyl
acetate (3 × 30 mL). The organic layers were collected and washed
with saturated aqueous NaHCO3. The organic layer was dried over
sodium sulfate, filtered, and concentrated under reduced pressure. The
intermediate product was obtained after purification by column chro-
matography on silica gel (chloroform/methanol = 100/1). TFA (1 mL)
was added to the intermediate product (0.5 mmol, 1.0 eq.), and the
mixture was stirred at room temperature for 15 min. After removing
A mixture of 8 (103 mg, 0.2 mmol, 1.0 eq.), N,N-diisopropylethyla-
mine (DIPEA) (54 µL, 0.3 mmol, 1.5 eq.) and di-tert-butyl dicarbonate
(Boc2O) (43 mg, 0.2 mmol, 1.0 eq.) in dry dichloromethane (3 mL) was
stirred at room temperature for 3 days under nitrogen atmosphere. The
reaction mixture was diluted with dichloromethane and washed suc-
cessively with saturated aqueous NaHCO3 and brine. The organic layer
was dried over sodium sulfate, filtered, and concentrated under reduced
pressure to afford 9 (76 mg) as a pale yellow solid. The product was
used in the following reaction without further purification.
2.2.8. tert-Butyl 4-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-
5-(tributylstannyl)quinolin-8-yl}piperazine-1-carboxylate (10)
A mixture of 9 (45 mg, 71.5 µmol, 1.0 eq.), hexabutyldistannane
(144 µL, 286 µmol, 4.0 eq.), and tetrakis(triphenylphosphine)palladium
386