E. Ofori, E.K. Onyameh, U.M. Gonela et al.
European Journal of Medicinal Chemistry 214 (2021) 113243
144e145 ꢀC. 1H NMR (300 MHz, DMSO‑d6)
d
9.98 (1H, s), 8.07 (1H,
2.67e2.58 (2H, m), 2.31e2.17 (2H, m). 13C NMR (75 MHz, CDCl3)
d, J ¼ 4.8 Hz), 7.49 (1H, dd, J ¼ 1.8, 6.8 Hz), 7.00e6.88 (2H, m),
6.81e6.70 (2H, m), 6.65e6.54 (1H, m), 3.45e3.38 (4H, m),
3.37e3.32 (3H, m), 2.84e2.75 (2H, m), 2.48 (2H, t, J ¼ 7.2 Hz),
2.44e2.33 (3H, m), 2.28 (2H, t, J ¼ 7.0 Hz), 1.59e1.47 (2H, m),
d 205.17, 164.29, 158.13, 130.51, 125.29, 115.58, 110.29, 64.62, 41.25,
36.39, 31.97, 25.84.
4.1.12. 5-(3-(4-(pyridin-2-yl)piperazin-1-yl)propoxy)-2,3-dihydro-
1H-inden-1-one (11)
Following the general alkylation reaction 4.1.4, intermediate 4b
was reacted with 1-(pyridin-2-yl)piperazine to produce compound
11 as a white solid crystal. Yield: 68% Mp: 103e104 ꢀC. 1H NMR
1.47e1.32 (2H, m). 13C NMR (75 MHz, DMSO‑d6)
d 170.51, 159.51,
147.96, 137.87, 136.50, 136.18, 128.01, 127.22, 123.79, 115.30, 113.34,
107.43, 58.19, 53.06 (2C), 45.10, 34.85, 30.95, 29.44, 26.31, 25.31,
25.22. Anal. C22H28N4O$ 0.8H20 (C, H, N).
(300 MHz, DMSO‑d6)
d 8.08 (1H, s), 7.59e7.42 (2H, m), 7.04 (1H, s),
4.1.9. 6-(3-chloropropoxy)-3,4-dihydroquinolin-2(1H)-one (3b)
A modified O-alkylation method reported by Rampa and col-
leagues [41] was followed to access intermediate 3b. Succinctly, 6-
hydroxy-3,4-dihydroquinolin-2(1H)-one 3a (0.82 g, 5 mmol), 1-
bromo-3-chloropropane (1 mL, 10 mmol), K2CO3, and KI (cata-
lytic) were suspended in DME (15 mL) placed in a 20-mL Biotage
microwave vial equipped with a vial. The vial was sealed and
subjected to microwave heating (Biotage, 130 ꢀC, 200 W, 5 bar) for
1 h. After this period, the vial was removed from the microwave,
allowed to cool, internal pressure released and opened. The excess
alkylating agent was removed in-vacuo and the residue purified
directly on silica using a Combiflash ® (gradient elution: up to 40%
EtOAc in hexanes) to afford 6-(3-chloropropoxy)-3,4-
dihydroquinolin-2(1H)-one, 3b (0.98 g, 82%) as white crystals. 1H
6.92 (1H, d, J ¼ 8.0 Hz), 6.76 (1H, d, J ¼ 8.6 Hz), 6.66e6.55 (1H, m),
4.10 (2H, t, J ¼ 6.3 Hz), 3.52e3.38 (4H, m), 3.05e2.95 (2H, m),
2.59e2.50 (4H, m), 2.00e1.80 (2H, m), 1.63e1.22 (4H, m). 13C NMR
(75 MHz, DMSO‑d6)
d 204.58, 164.60, 159.49, 158.66, 147.98, 137.85,
130.21, 124.97, 116.02, 113.36, 110.99, 107.42, 66.86, 54.79, 53.05
(2C), 45.10 (2C), 36.44, 26.48, 25.90. Anal. C21H25N3O2.0.1H2O (C, H,
N).
4.1.13. 1-(2,3-Dihydro-1H-inden-5-yl)-4-(4-(pyridin-2-yl)
piperazin-1-yl)butan-1-one (12)
The commercially available indane, 5a was acylated under
Friedel-Crafts acylation conditions and the intermediate 5b ob-
tained was subsequently reacted with 1-(pyridin-2-yl)piperazine
under general N-alkylation conditions to afford the final compound
12 as white solid crystals. Yield: 59%, Mp: 74e75 ꢀC. 1H NMR
NMR (300 MHz, DMSO‑d6)
d 9.88 (1H, s), 6.82e6.71 (3H, m), 4.00
(2H t, J ¼ 6.2 Hz), 3.75 (2H, t, J ¼ 6.8 Hz), 2.81 (2H, t, J ¼ 7.7 Hz), 2.38
(300 MHz, DMSO‑d6)
d 8.07 (1H, s), 7.78 (1H, s), 7.72 (1H, d,
(2H, t, J ¼ 7.7 Hz), 2.16e2.06 (2H, m). 13C NMR (75 MHz, DMSO‑d6)
J ¼ 8.0 Hz), 7.52e7.42 (1H, m), 7.29 (1H, d, J ¼ 7.8 Hz), 6.73 (1H, d,
J ¼ 8.6 Hz), 6.63e6.52 (1H, m), 3.44e3.30 (4H, m), 2.96 (2H, t,
J ¼ 7.0 Hz), 2.91e2.79 (4H, m), 2.44e2.26 (6H, m), 2.06e1.92 (2H,
d
170.18, 153.94, 132.37, 125.32, 116.21, 114.53, 113.47, 64.92, 42.46,
32.20, 30.78, 25.52.
m), 1.87e1.69 (2H, m). 13C NMR (75 MHz, DMSO‑d6)
d 199.95,
4.1.10. Synthesis of compounds 9 and 10 used the same alkylation
conditions described in section 3.1.4
159.49, 149.82, 147.95, 144.70, 137.80, 135.89, 126.78, 124.69, 124.14,
113.29, 107.37, 57.63, 52.93 (2C), 45.03 (2C), 36.15, 32.85, 32.47,
25.42, 21.83. Anal. C22H27N3O (C, H, N).
4.1.10.1. 6-(3-(4-(pyridin-2-yl)piperazin-1-yl)propoxy)-3,4-
dihydroquinolin-2(1H)-one (9). Using alkylating agent 3b and 1-
(pyridin-2-yl)piperazine, compound 9 was obtained as its free base
as white solid. Yield: 54%. Mp: 154e155 ꢀC. 1H NMR (300 MHz,
4.1.14. 5-Fluoro-2-(2-(4-(pyridin-2-yl)piperazin-1-yl)ethyl)-2,3-
dihydro-1H-inden-1-one (13)
DMSO‑d6)
d
9.88 (1H, s), 8.08 (1H, d, J ¼ 5.0 Hz), 7.49 (1H, ddd,
A mixture of 2-(2-chloroethyl)-5-fluoro-2,3-dihydro-1H-inden-
1-one, 6a (1.1 g, 5.2 mmol), 1-(pyridin-2-yl)piperazine (0.90 g,
5.5 mmol), KI (100 mg), NaHCO3 (1.0 g, 11.9 mmol) in toluene
(10 mL) was heated to reflux under N2 for 12 h. After cooling to rt,
the mixture was diluted with EtOAc (500 mL) and followed by
washing with water (2 ꢁ 300 mL). The organic layer was dried over
Na2SO4, and filtered. The filtrate was concentrated in vacuo to
dryness and followed by column chromatography on silica gel
afforded 5-fluoro-2-(2-(4-(pyridin-2-yl)piperazin-1-yl)ethyl)-2,3-
dihydro-1H-inden-1-one, 13. The crystals were obtained by crys-
tallization from EtOAc/Hexane in a yield of 26%. 1H NMR (300 MHz
CDCl3): 8.16 (1H, m), 7.73 (1H, dd, J ¼ 5.1, 8.1 Hz), 7.46 (1H, ddd,
J ¼ 1.8, 6.9, 8.7 Hz), 7.02e7.13 (2H, m), 6.58e6.63 (2H, m), 3.38e2.90
(4H, m), 3.32 (1H, dd, J ¼ 7.5, 16.8 Hz), 2.86 (1H, dd, J ¼ 4.2, 16.8 Hz),
2.75e2.81 (1H, m), 2.45e2.60 (6H, m), 2.12e2.21 (1H, m), 1.78e1.88
(1H, m). 13C NMR (300 MHz, CDCl3): 206.4, 167.0 (d, J ¼ 254.2 Hz),
159.5, 156.2 (d, J ¼ 10.4 Hz), 147.9, 137.4, 133.4, 126.0 (d, J ¼ 10.4 Hz),
115.6 (d, J ¼ 24.0 Hz), 113.2 (d, J ¼ 3.4 Hz), 112.9, 107.0, 55.7, 53.0
(2C), 45.6, 45.0 (2C), 32.2, 28.3. Anal. C20H22FN3O (C, H, N).
J ¼ 8.9, 7.1, 2.0 Hz), 6.80e6.66 (4H, m), 6.60 (1H, dd, J ¼ 7.0, 4.9 Hz),
3.93 (2H, t, J ¼ 6.3 Hz), 3.44 (4H, t, J ¼ 5.0 Hz), 2.80 (2H, t, J ¼ 7.3 Hz),
2.47e2.41 (6H, m), 2.40e2.39 (1H, m), 2.38e2.35 (1H, m),1.93e1.77
(2H, m).13C NMR (75 MHz, DMSO‑d6)
d 170.17, 159.51, 154.25, 147.97,
137.87, 132.12, 125.26, 116.20, 114.46, 113.43, 113.36, 107.45, 66.51,
54.99, 53.07, 45.11, 30.81, 26.73, 25.55. Anal. C21H26N4O2 (C, H, N).
4.1.10.2. 6-(3-(4-(pyridin-2-yl)-1,4-diazepan-1-yl)propoxy)-3,4-
dihydroquinolin-2(1H)-one oxalate (10). Using alkylating agent 3b
and 1-(pyridin-2-yl)-1,4-diazepane as the amine, compound 10
was obtained as an oxalate salt. Yield: 30%. Mp: 190e192 ꢀC. 1H
NMR (300 MHz, DMSO‑d6)
d
9.90 (1H, s), 8.08 (1H, d, J ¼ 4.8 Hz),
7.62e7.46 (1H, m), 6.86e6.51 (5H, m), 4.11e3.78 (4H, m), 3.64e3.47
(2H, m), 3.41e3.06 (6H, m), 2.80 (2H, t, J ¼ 7.4 Hz), 2.37 (2H, t,
J ¼ 7.4 Hz), 2.26e1.96 (4H, m). 13C NMR (75 MHz, DMSO‑d6)
d 170.17,
163.94, 157.89, 153.79, 147.94, 138.13, 132.44, 125.30, 116.20, 114.55,
113.52,112.66,106.29, 65.67, 54.96, 54.05, 53.93, 45.61, 30.78, 25.52,
24.49, 24.19. Anal. C22H28N4O2$1.7(COOH)2 (C, H, N).
4.1.11. 5-(3-chloropropoxy)-2,3-dihydro-1H-inden-1-one (4b)
Using similar O-alkylation reaction method described for 3b
above, intermediate 4b was obtained as white solid crystal by
reacting commercially available 5-hydroxy-2,3-dihydro-1H-inden-
1-one, 4a with 1-bromo-3-chloropropane. Yield: 73%.1H NMR
4.1.15. 2-(2-Chloro-ethyl)-5-fluoro-indan-1-ol (7a)
To a solution of 2-(2-chloro-ethyl)-5-fluoro-indan-1-one (2 g,
9.4 mmol) and CeCl3 (160 mg, 0.65 mmol) in MeOH (10 mL) was
added with stirring NaBH4 (0.7 g, 18.5 mmol) at rt. After stirring at
rt for 1 h, the mixture was diluted with EtOAc (200 mL) and washed
with sat NaHCO3 (50 mL). The organic layer was dried over Na2SO4,
and filtered. The filtrate was concentrated in vacuo and followed by
(300 MHz, CDCl3)
d
7.64 (1H, d, J ¼ 8.3 Hz), 6.92e6.82 (2H, m), 4.16
(2H, t, J ¼ 5.8 Hz), 3.72 (2H, t, J ¼ 6.3 Hz), 3.04 (2H, t, J ¼ 5.7 Hz),
10