Journal of Medicinal Chemistry
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through a plug of MgSO4 and concentrated under reduced pressure to
title compound as a yellow solid (453 mg, 82%). Rf (50% EA/hex):
0.51. 1H NMR (400 MHz, CDCl3) δ 7.77−7.61 (m, 3H), 7.56 (d, J =
9.2, 1H), 7.42−7.32 (m, 2H), 7.26 (dd, J = 8.4, 1.3, 1H), 6.92 (dt, J =
6.8, 3.5, 1H), 6.50 (d, J = 8.3, 1H), 3.97 (s, 2H), 3.28−3.20 (m, 2H),
2.84 (t, J = 6.5, 2H); 13C NMR (101 MHz, CDCl3) δ 152.40, 145.46,
139.04, 133.58, 132.01, 131.37, 131.08, 127.99, 127.57, 127.55, 126.86,
125.83, 125.18, 124.46, 116.67, 116.06, 115.81, 77.32, 77.00, 76.68,
41.36, 40.64, 23.41.
yield the title compound as a yellow solid (338 mg, 80%). Rf (70%
1
EA/hex): 0.49. H NMR (400 MHz, CDCl3) δ 7.72−7.71 (m, 1H),
7.30−7.25 (m, 2H), 7.21−7.14 (m, 3H), 7.10 (dd, J = 8.4, 2.2, 1H),
6.60 (d, J = 8.3, 1H), 4.65−3.78 (bs, 1H), 3.55 (dd, J = 7.4, 6.5, 2H),
2.91−2.78 (m, 4H), 2.69 (dd, J = 7.4, 6.5, 2H); 13C NMR (101 MHz,
CDCl3) δ 193.83, 150.38, 141.62, 135.78, 131.42, 128.41, 128.30,
126.66, 125.87, 119.33, 115.89, 77.30, 76.99, 76.67, 42.45, 38.18,
37.94, 36.88.
(E/Z)-6-((2,3-Dihydro-1H-inden-2-yl)methyl)-2,3-dihydroqui-
nolin-4(1H)-one oxime (13d). 13d was synthesized according to
general procedure G starting from 12d (772 mg, 2.78 mmol) to yield
the title compound as a yellow solid (662 mg, 81%). Rf (40% EA/hex):
6-(Naphthalen-1-ylmethyl)-2,3-dihydroquinolin-4(1H)-one
(12b). 12b was synthesized according to general procedure F starting
from 11b (603 mg, 2.10 mmol) to yield the title compound as a yellow
1
1
solid (450 mg, 74%). Rf (50% EA/hex): 0.43. H NMR (400 MHz,
0.44. H NMR (400 MHz, CDCl3) 7.63 (d, J = 1.8, 1H), 7.19 −7.05
CDCl3) δ 8.00−7.95 (m, 1H), 7.84−7.79 (m, 1H), 7.77 (d, J = 1.8,
1H), 7.71 (d, J = 7.9, 1H), 7.44−7.35 (m, 3H), 7.26 (d, J = 6.5, 1H),
7.05 (dd, J = 8.4, 2.1, 1H), 6.49 (d, J = 8.4, 1H), 4.29 (s, 2H), 3.46 (t, J
= 7.04, 2H), 2.63 (t, J = 6.88, 2H); 13C NMR (101 MHz, CDCl3) δ
193.78, 150.54, 136.60, 135.66, 133.89, 131.92, 130.10, 128.62, 127.24,
127.13, 127.10, 127.07, 125.92, 125.49, 124.10, 119.16, 116.13, 77.32,
77.00, 76.68, 42.28, 38.10, 38.02.
(m, 5H), 6.60 (dd, J = 21.6, 8.3, 1H), 3.30 (t, J = 6.5, 2H), 2.93 (dt, J =
13.0, 7.6, 3H), 2.76−2.59 (m, 6H); 13C NMR (101 MHz, CDCl3) δ
152.50, 145.41, 143.38, 131.51, 131.34, 129.41, 126.08, 124.52, 124.23,
115.78, 41.57, 40.78, 40.74, 38.86, 23.45.
General Procedure H for Compounds 14a−d. 6-Phenethyl-
1,2,3,4-tetrahydroquinolin-4-amine (14a). 10% Pd/C (50 mg)
was added to a hydrogenation vessel followed by the slow addition of
MeOH (10 mL). 13a (170 mg, 0.64 mmol) was dissolved in minimal
MeOH and added to the vessel, followed by the addition of glacial
AcOH (0.4 mL). The reaction vessel was placed on the hydrogenator
under 40 psi of H2 gas and allowed to shake for 12 h. The reaction
mixture was then filtered through a pad of Celite, and solvent was
removed under reduced pressure. The crude residue was resuspended
in 1 M HCl (30 mL) and extracted with 3 × EA (30 mL). The organic
layer was washed with 3 × 2 M NaOH (30 mL), 1 × brine (30 mL),
dried under MgSO4, filtered, and concentrated to yield the title
compound as a tan oil (120 mg, 75%), which was carried to the next
6-(Naphthalen-2-ylmethyl)-2,3-dihydroquinolin-4(1H)-one
(12c). 12c was synthesized according to general procedure F starting
from 11c (2.30 g, 8.01 mmol) to yield the title compound as a yellow
1
solid (1.40 g, 61%). Rf (50% EA/hex): 0.43. H NMR (400 MHz,
CDCl3) δ 7.80−7.70 (m, 4H), 7.60 (s, 1H), 7.46−7.38 (m, 2H), 7.28
(d, J = 8.4, 1H), 7.14−7.09 (m, 1H), 6.54 (d, J = 8.4, 1H), 4.36 (s,
1H), 4.00 (s, 2H), 3.45 (t, J = 6.9, 2H), 2.64 (t, J = 6.9, 2H); 13C NMR
(101 MHz, CDCl3) δ 193.80, 150.64, 138.65, 136.04, 133.48, 131.96,
130.35, 128.01, 127.50, 127.43, 127.33, 127.13, 126.75, 125.87, 125.23,
118.99, 116.22, 77.32, 77.00, 76.68, 42.16, 41.02, 38.00.
1
6-((2,3-Dihydro-1H-inden-2-yl)methyl)-2,3-dihydroquinolin-
4(1H)-one (12d). 12d was synthesized according to general
procedure F starting from 11d (811 mg, 2.93 mmol) to yield the
title compound as a viscous yellow oil (772 mg, 95%). Rf (40% EA/
hex): 0.32. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 1.9, 1H), 7.22−
7.08 (m, 5H), 6.63 (d, J = 8.3, 1H), 4.30 (br s, 1H), 3.57 (t, J = 6.9,
2H), 2.97 (dd, J = 14.2, 5.9, 2H), 2.78−2.60 (m, 7H); 13C NMR (101
MHz, CDCl3) δ 193.84, 150.42, 143.12, 136.09, 131.00, 127.12,
126.06, 124.45, 119.30, 115.90, 42.47, 41.42, 40.42, 38.75, 38.22.
General Procedure G for Compounds 13a−d. (E/Z)-6-
Phenethyl-2,3-dihydroquinolin-4(1H)-one Oxime (13a). Com-
pound 12a (338 mg, 1.35 mmol) was suspended in 1:1 EtOH/H2O
followed by the addition of NH2OH·HCl (64.5 mg, 1.47 mmol) and
NaOAc·H2O (201 mg, 1.47 mmol). The mixture was stirred at reflux
overnight, after which time solvents were condensed and redissolved
in EA (30 mL). The organic layer was washed with brine (10 mL),
dried with MgSO4, filtered, concentrated under reduced pressure, and
chromatographed on silica gel (1:1 EA/hex) to yield the title
compound as a yellow solid (235 mg, 66%). Rf (50% EA/hex): 0.51.
1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 2.0, 1H), 7.29−7.23 (m,
2H), 7.20−7.14 (m, 3H), 6.95 (dd, J = 8.2, 2.1, 1H), 6.57−6.52 (m,
1H), 3.30 (t, J = 6.5, 2H), 2.93 (t, J = 6.5, 2H), 2.90−2.76 (m, 4H);
13C NMR (101 MHz, CDCl3) δ 152.47, 145.29, 141.92, 131.99,
130.95, 128.42, 128.27, 125.78, 123.71, 116.68, 115.85, 77.32, 77.00,
76.68, 40.71, 38.09, 37.16, 23.58.
(E/Z)-6-(Naphthalen-1-ylmethyl)-2,3-dihydroquinolin-4(1H)-
one Oxime (13b). 13b was synthesized according to general
procedure G starting from 12b (450 mg, 1.57 mmol) and
chromatographed on silica gel (4:1 EA/hex) to yield the title
compound as a yellow solid (313 mg, 66%). Rf (75% EA/hex): 0.73.
1H NMR (400 MHz, CDCl3) δ 8.02−7.97 (m, 1H), 7.83−7.77 (m,
1H), 7.70 (s, 2H), 7.41 (m, 3H), 7.26−7.21 (m, 1H), 6.85 (dt, J =
11.2, 5.6, 1H), 6.42 (d, J = 8.3, 1H), 4.28 (s, 2H), 3.17 (t, J = 6.4, 2H),
2.85 (t, J = 5.2, 2H); 13C NMR (101 MHz, CDCl3) δ 152.20, 145.35,
133.83, 130.94, 130.52, 129.49, 128.53, 127.02, 126.87, 125.85, 125.49,
125.41, 124.24, 124.20, 116.68, 115.98, 115.48, 77.32, 77.00, 76.68,
40.55, 38.18, 23.51.
reaction without further purification. H NMR (400 MHz, CDCl3) δ
8.61 (bs, 2H), 7.28−7.20 (m, 3H), 7.16 (dd, J = 13.2, 7.1, 3H), 6.82
(d, J = 8.3, 1H), 6.38 (d, J = 8.2, 1H), 4.33 (s, 1H), 3.45 (t, J = 11.2,
1H), 3.14 (dd, J = 8.2, 4.0, 1H), 2.86−2.77 (m, 2H), 2.74−2.68 (m,
2H), 2.24 (d, J = 12.2, 1H), 2.12−2.03 (m, 1H); 13C NMR (101 MHz,
CDCl3) δ 143.00, 141.99, 131.01, 130.37, 130.15, 128.49, 128.25,
125.77, 115.30, 115.03, 77.33, 77.01, 76.69, 47.35, 38.16, 36.96, 36.61,
26.38. ESI-MS 236.1 [M − NH3 + H]+. HPLC (gradient A): retention
time = 23.79 min.
6-(Naphthalen-1-ylmethyl)-1,2,3,4-tetrahydroquinolin-4-
amine (14b). 14b was synthesized according to general procedure H
starting from 13b (330 mg, 1.09 mmol) to yield the title compound as
1
a tan oil (253 mg, 84%). H NMR (400 MHz, CDCl3) δ 8.00 (d, J =
7.9, 1H), 7.81 (d, J = 7.5, 1H), 7.69 (d, J = 8.0, 1H), 7.44−7.39 (m,
2H), 7.36 (s, 1H), 7.27−7.21 (m, 1H), 7.19 (s, 1H), 6.79 (d, J = 7.9,
1H), 6.31 (d, J = 8.2, 1H), 5.06 (bs, 3H), 4.24 (s, 2H), 4.08 (s, 1H),
3.44−3.29 (m, 1H), 3.14 (m, 1H), 2.00 (s, 2H); 13C NMR (101 MHz,
CDCl3) δ 142.75, 137.30, 133.83, 132.04, 129.94, 129.58, 129.23,
128.55, 127.53, 127.04, 126.84, 125.91, 125.55, 125.44, 124.31, 115.00,
77.32, 77.00, 76.68, 46.97, 38.00, 37.00, 28.34. ESI-MS 272.1 [M −
NH3 + H]+. HPLC (gradient A): retention time = 31.71 min.
6-(Naphthalen-2-ylmethyl)-1,2,3,4-tetrahydroquinolin-4-
amine (14c). 14c was synthesized according to general procedure H
starting from 13c (618 mg, 2.04 mmol) to yield the title compound as
a tan oil (246 mg, 86%). 1H NMR (400 MHz, CD3OD) δ 7.75 (dd, J
= 15.5, 8.4, 3H), 7.62 (s, 1H), 7.41 (dt, J = 12.8, 6.3, 2H), 7.31 (d, J =
8.2, 1H), 7.14 (s, 1H), 7.07 (d, J = 8.0, 1H), 6.67 (d, J = 8.2, 1H), 4.42
(t, J = 4.5, 1H), 4.02 (s, 2H), 3.40−3.31 (m, 2H), 2.26−2.03 (m, 2H);
13C NMR (101 MHz, CD3OD) δ 143.71, 140.64, 135.10, 133.55,
132.32, 132.09, 130.74, 128.96, 128.56, 128.49, 128.47, 127.75, 126.99,
126.32, 117.45, 49.64, 49.43, 49.21, 49.00, 48.79, 48.57, 48.36, 48.01,
42.09, 37.45, 27.37. ESI-MS 272.1 [M − NH3 + H]+. HPLC (gradient
A): retention time = 34.07 min.
6-((2,3-Dihydro-1H-inden-2-yl)methyl)-1,2,3,4-tetrahydro-
quinolin-4-amine (14d). 14d was synthesized according to general
procedure H starting from 13d (662 mg, 2.26 mmol) to yield the title
compound as a brown oil (527 mg, 84%). 1H NMR (400 MHz,
CDCl3) 7.13 (ddd, J = 8.7, 7.0, 4.2, 5H), 7.05 (s, 1H), 6.87 (dd, J =
8.1, 1.8, 1H), 6.46 (t, J = 6.8, 1H), 4.00 (t, J = 4.8, 1H), 3.43−3.34 (m,
1H), 3.29 (dt, J = 11.0, 5.4, 1H), 3.02−2.94 (m, 3H), 2.77−2.59 (m,
(E/Z)-6-(Naphthalen-2-ylmethyl)-2,3-dihydroquinolin-4(1H)-
one oxime (13c). 13c was synthesized according to general
procedure G starting from 12c (522 mg, 1.81 mmol) to yield the
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dx.doi.org/10.1021/jm400050y | J. Med. Chem. 2013, 56, 2139−2149