Journal of Medicinal Chemistry
ARTICLE
(br s, 2H), 4.05ꢀ4.00 (m, 2H), 2.89ꢀ2.85 (m, 2H), 2.70ꢀ2.64 (m,
8H), 2.02ꢀ1.97 (m, 2H), 1.90ꢀ1.82 (m, 4H). MS (ESI): 383.2 (M + 1).
ESI-HRMS calculated for C21H27N4SO2 (MH+), 383.1900; observed,
383.1895. HPLC purity: 98.9%.
δ 1.75 (m, 2H), 2.16 (s, 6H), 2.46 (m, 2H), 2.66 (m, 2H), 3.12 (m, 4H),
6.40 (m, 4H), 7.07 (m, 1H), 7.57 (m, 1H), 7.71 (m, 1H). ESI-MS:
347 (MH+, 33), 276 (100), 143 (12). ESI-HRMS calculated for
C18H24N4FS (MH+), 347.1700; observed, 347.1700. HPLC purity:
95.5%.
N-(1-(3-(Dimethylamino)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)
thiophene-2-carboximidamide (52). Prepared as described for com-
pound 27 using compound 48. Yield: 85%. 1H NMR (DMSO-d6) δ 7.67
(d, J = 3 Hz, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.07 (dd, J = 5.1, 3 Hz, 1H),
6.55 (m, 2H), 6.48 (m, 1H), 6.31 (br s, 2H), 3.24ꢀ3.17 (m, 4H), 2.66
(t, J = 6.3 Hz, 2H), 2.25 (t, J = 6.9 Hz, 2H), 1.88ꢀ1.82 (m, 2H),
1.67ꢀ1.60 (m, 2H). ESI-MS (m/z, %) 343 (MH+, 89), 258 (100), 135
(48), 127 (60). ESI-HRMS calculated for C19H27N4S (MH+) calcu-
lated, 343.1963; observed, 343.195. HPLC purity: 97.1%.
N-(1-(3-(Pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-
2-carboximidamide (53). Prepared as described for compound 27 using
1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine, which
was prepared by reducing compound 46. Yield: 72.8%. 1H NMR
(DMSO-d6) δ 7.67 (d, J = 3.6 Hz, 1H), 7.55 (d, J = 5 Hz, 1H), 7.06
(dd, J = 5, 3.6 Hz, 1H), 6.58 (br s, 2H), 6.48 (s, 1H), 6.27 (br s, 2H),
3.26ꢀ3.17 (m, 4H), 2.66 (t, J = 6.3 Hz, 2H), 2.45ꢀ2.40 (m, 6H),
1.89ꢀ1.81 (m, 2H), 1.70ꢀ1.62 (m, 6H). ESI-MS (m/z, %) 369 (MH+,
47), 185 (100). ESI-HRMS calculated for C21H29N4S (MH+) calcu-
lated, 369.2122; observed, 369.2107. HPLC purity: 95.4%.
N,N-Diethyl-2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanamine
(43). A solution of 1-(2-(diethylamino)ethyl)-6-nitro-3,4-dihydroqui-
nolin-2(1H)-one (1 g, 3.43 mmol) and 1 M BH3 in THF (17.16 mL,
17.16 mmol) was stirred at room temperature overnight. After this time,
the reaction was cooled to 0 °C and then treated with MeOH (25 mL)
dropwise with caution. The mixture was stirred at 0 °C for 10 min and
then concentrated on the rotovap to give a yellow solid. This compound
was dissolved in 40 mL of methanol and heated at reflux for 3 h. After
cooling, the solvent was evaporated and the resulting yellowꢀbrown
residue was subjected to flash chromatography on silica gel using 5% 2 M
NH3 in MeOH/95% CH2Cl2 to give a bright-yellow residue (0.87 g,
91%). 1H NMR (CDCl3) δ 7.96 (dd, J = 2.7, 9.0 Hz, 1H), 7.85ꢀ7.84 (m,
1H), 6.51 (d, J = 9.0 Hz, 1H), 3.47 (t, J = 5.4 Hz, 4H), 2.74 (t, J = 6.3 Hz,
2H), 2.68ꢀ2.59 (m, 6H), 1.99ꢀ1.91 (m, 2H), 1.05 (t, J = 6.9 Hz, 6H).
MS (ESI): 278.2 (M + 1).
2-(8-Fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethyl-
ethanamine (44). Prepared as described for compound 43 using
1
compound 19. Yield: 64%. H NMR (CDCl3) δ 7.77 (dd, 1H, J = 9
Hz, 2.7 Hz), 7.69 (m, 1H), 3.41 (m, 4H), 2.77 (m, 2H), 2.56 (m, 2H),
2.27 (s, 6H), 1.95 (m, 2H). ESI-MS: 268.1 (MH+, 100).
1-(1-Methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinoline (58). A solu-
tion of 1,2,3,4-tetrahydroquinoline 54 (1.0 mL, 7.94 mmol) in 20 mL
of 1,2-dichloroethane was treated with 1-methylpiperidin-4-one 55
(2.76 mL, 23.8 mmol) followed by sodium triacetoxyborohydride
(8.4 g, 39.7 mmol) and then acetic acid (2.25 mL). The suspension
was stirred at room temperature for 1 day. After this time, the mixture
was cooled to 0 °C, quenched with 5 mL of 1N NaOH, and stirred for
20 min. The suspension was extracted with 100 mL of CH2Cl2. The
organic layer was dried over MgSO4, filtered, and concentrated to give a
light residue which was subjected to flash chromatography on silica gel
using 5% MeOH/CH2Cl2 then 5% 2 M NH3 in MeOH/CH2Cl2. A
yellow oil was obtained (440 mg, 24.1%). 1H NMR (CDCl3) δ:
7.07ꢀ7.02 (m,1H), 6.95 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H),
6.55 (pseudo t, J = 7.8 Hz, 1H), 3.65ꢀ3.55 (m, 1H), 3.20 (t, J = 5.7 Hz,
2H), 2.99ꢀ2.95 (m, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.31(s, 3H),
2.11ꢀ2.05(m, 2H), 1.93ꢀ1.73 (m, 6H). MS (ESI): 231.2 (M + 1, 100%).
tert-Butyl 4-(3,4-Dihydroquinolin-1(2H)-yl)piperidine-1-carboxy-
late (59). Prepared as described for compound 58 using compound
54 and tert-butyl 4-oxopiperidine-1-carboxylate 56. The crude product
was purified by silica gel chromatography using 15% EtOAc/85%
hexanes. Yield: 37.4%. 1H NMR (CDCl3) δ 7.09ꢀ7.03 (m, 1H),
6.97ꢀ6.94 (m, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.60ꢀ6.55 (m, 1H), 4.30ꢀ
4.19 (m, 2H), 3.80ꢀ3.70 (m, 1H), 3.17 (t, J = 5.7 Hz, 2H), 2.84ꢀ2.71
(m, 2H), 2.73 (t, J = 6.3 Hz, 2H), 1.93ꢀ1.85 (m, 2H), 1.78ꢀ1.63 (m,
4H), 1.48 (s, 9H). MS (ESI): 317.2 (M + 1).
tert-Butyl 3-(3,4-Dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxy-
late (60). Prepared as described for compound 59 using compound
54 and compound 57. Yield: 78.8%. 1H NMR (CDCl3) δ 7.07 (pseudo t,
J = 7.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.62
(pseudo t, J = 7.5 Hz, 1H), 4.44ꢀ4.40 (m, 1H), 3.63ꢀ3.20 (m, 6H), 2.75
(t, J = 6.3 Hz, 2H), 2.13ꢀ2.08 (m, 2H), 1.94ꢀ1.90 (m, 2H), 1.48 (s,
9H). MS (ESI): 303.2 (M + 1).
6-Bromo-1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinoline (61).
A solution of 1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinoline 58
(500 mg, 2.17 mmol) in 7 mL of DMF was cooled to 0 °C and then
treated dropwise with NBS (386 mg, 2.17 mmol) in 7 mL of DMF. The
reaction was stirred at 0 °C for 2 h and then treated with 30 mL of H2O.
The suspension was extracted with 100 mL of EtOAc. The organic layer
was dried over MgSO4, filtered, and concentrated to give a dark residue
which was filtered through a short plug of silica gel using 5% 2 M NH3 in
N,N-Dimethyl-3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine
(45). Prepared as described for compound 43 using compound 37. 1H
NMR (DMSO-d6) δ 7.87 (dd, J = 9.3, 3 Hz, 1H), 7.77 (d, J = 3 Hz, 1H),
6.68 (d, J = 9.6 Hz, 1H), 3.43ꢀ3.38 (m, 4H), 2.74 (t, J = 6 Hz, 2H), 2.23
(t, J = 6.5 Hz, 2H), 2.13 (s, 6H), 1.85 (quint, J = 6 Hz, 2H), 1.68 (quint,
J = 7 Hz, 2H). ESI-MS (m/z, %) 264 (MH+, 100).
6-Nitro-1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinoline (46).
Prepared as described for compound 43using compound 38. Yield: 56.6%.
1H NMR (DMSO-d6) δ 7.87 (dd, J = 9.3, 2.7 Hz, 1H), 7.77 (d, J = 2.7 Hz,
1H), 6.70 (d, J = 9.3 Hz, 1H), 3.46ꢀ3.38 (m, 4H), 2.74 (t, J = 6 Hz, 2H),
2.43ꢀ2.38 (m, 6H), 1.86ꢀ1.82 (m, 2H), 1.74ꢀ1.67 (m, 6H).
1-(2-(Diethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (47).
Prepared as described for compound 24 using compound 43. Yield: 90%.
1H NMR(CDCl3) δ 6.63ꢀ6.32 (m, 3H), 3.37ꢀ3.23 (m, 4H), 2.74ꢀ2.56
(m, 8H), 1.93 (t, J = 5.7 Hz, 2H), 1.08 (t, J = 7.2 Hz, 6H). MS (ESI): 248.2
(M + 1).
1-(2-(Dimethylamino)ethyl)-8-fluoro-1,2,3,4-tetrahydroquinolin-6-
amine (48). Prepared as described for compound 24 using compound
44. Yield: 89%. ESI-MS: 238 (MH+, 100), 193 (37), 147 (31).
1-(3-(Dimethylamino)propyl)-1,2,3,4-tetrahydroquinolin-6-amine
(48a). Prepared as described for compound 20 using compound 45.
Yield: 92.2% . 1H NMR (DMSO-d6) δ 6.37ꢀ6.34 (m, 1H), 6.30ꢀ6.26
(m, 1H), 6.22ꢀ6.20 (m, 1H), 4.17 (br s, 2H), 3.12ꢀ3.03 (m, 4H), 2.55
(t, J = 6.45 Hz, 2H), 2.20 (t, J = 6.9 Hz, 2H), 2.11 (s, 6H), 1.79 (quint, J =
6 Hz, 2H), 1.56 (quint, J = 7.12 Hz, 2H). ESI-MS (m/z, %) 234 (MH+,
100), 161 (60).
1-(3-(Pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (49).
Prepared as described for compound 24 using compound 46. Yield: 98%.
MS (ESI): 360.2 (M + 1).
N-(1-(2-(Diethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thio-
phene-2-carboximidamide (50). Prepared as described for compound
27 using compound 47. Yield: 69.4%. 1H NMR (DMSO-d6) δ 7.67 (d, J =
3.0 Hz, 1H), 7.54 (d, J = 4.8 Hz, 1H), 7.07 (dd, J = 3.6, 4.5 Hz, 1H),
6.57ꢀ6.48 (m, 3H), 5.76 (br s, 2H), 3.32ꢀ3.25 (m, 4H), 2.67ꢀ2.63 (m,
2H), 2.52ꢀ2.48 (m, 6H), 1.86ꢀ1.82 (m, 2H), 0.97 (t, J = 6.9 Hz, 6H).
MS (ESI): 357.2 (M + 1). ESI-HRMS calculated for C20H29N4S
(MH+), 357.2107; observed, 357.2110. HPLC purity: 99.6%.
N-(1-(2-(Dimethylamino)ethyl)-8-fluoro-1,2,3,4-tetrahydroquinolin-
6-yl)thiophene-2-carboximidamide (51). Prepared as described for
1
compound 27 using compound 48. Yield: 15%. H NMR (DMSO)
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dx.doi.org/10.1021/jm200648s |J. Med. Chem. 2011, 54, 5562–5575