Journal of Medicinal Chemistry
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= 7.53 Hz, 1H), 7.03−7.15 (m, 1H), 6.57 (s, 1H). 13C-HSQC (400
MHz, DMSO-d6) δ F1 (ppm) 39.58, 111.14, 107.15, 136.19, 112.78,
129.34, 128.11, 126.58, 124.96, 126.58, 126.58, 133.99, 126.58, 125.32,
121.82.
DMSO-d6) δ 8.59 (br s, 1H), 8.10 (t, J = 6.05 Hz, 1H), 8.02 (d, J =
7.70 Hz, 1H), 7.92 (d, J = 7.70 Hz, 1H), 7.80−7.87 (m, 2H), 7.71−
7.78 (m, 1H), 7.31−7.52 (m, 2H), 5.61 (s, 1H), 4.56 (br s, 2H). 13C-
HSQC (400 MHz, DMSO-d6) δ (ppm) 39.72, 46.52, 101.13, 122.49,
123.49, 125.86, 125.86, 132.62, 135.29, 138.79, 148.41.
2-((4-Chlorobenzyl)amino)naphthalene-1,4-dione (2q). To a
solution of 2-bromo-1,4-napthoquinone (283 mg, 1.2 mmol) in abs
EtOH (40 mL) was added an excess of 4-chlorobenzylamine (292 μL,
2.4 mmol). Progress of the reaction was monitored with TLC.
Precipitate was vacuum filtered after 20 min to give 267 mg of sparkly
orange powder (74% yield). MS m/z calcd (M+) 298.74, found 298.8.
1H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J = 6.40 Hz, 1H), 7.93 (d, J
= 7.03 Hz, 1H), 7.83 (d, J = 6.78 Hz, 1H), 7.72−7.78 (m, 1H), 7.63−
7.70 (m, 1H), 7.20−7.42 (m, 4H), 5.49 (s, 1H), 4.37 (d, J = 6.53 Hz,
2H). 13C-HSQC (400 MHz, DMSO-d6) δ (ppm)39.48, 44.11, 46.15,
100.42, 128.86, 132.53, 134.84, 125.11, 125.98.
2-(Benzylamino)naphthalene-1,4-dione (2k). To a solution of 2-
bromo-1,4-naphthoquinone (5 g, 21.1 mmol) in a minimum amount
of abs EtOH was added an excess benzylamine (4.6 mL, 42.2 mmol, 2
equiv). The reaction was stirred for 10 min at rt, then briefly
concentrated in vacuo until copious amounts of orange precipitate
were visible. The solution was then cooled to 4 °C and vacuum filtered
to yield 3.5 g of fluffy bright-orange crystals (59% yield). MS m/z calcd
(M+) 264.1, found 264.1. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (t, J
= 6.40 Hz, 1H), 8.01 (d, J = 7.03 Hz, 1H), 7.87−7.94 (m, 1H), 7.82
(dt, J = 1.13, 7.47 Hz, 1H), 7.70−7.77 (m, 1H), 7.31−7.40 (m, 4H),
7.22−7.30 (m, 1H), 5.57 (s, 1H), 4.46 (d, J = 6.53 Hz, 2H). 13C-
HSQC (400 MHz, DMSO-d6) δ (ppm) 39.62, 45.48, 100.68, 127.64,
129.05, 127.63, 132.36, 135.20, 125.67, 126.37.
2-(Benzyl(methyl)amino)naphthalene-1,4-dione (2l). To a sol-
ution of 2-bromo-1,4-napthoquinone (283 mg, 1.2 mmol) in abs
EtOH (40 mL) was added an excess of N-benzylmethylamine (310 μL,
2.4 mmol). Compound was taken up onto Celite and purified using
chromatography on silica gel eluting with ethyl acetate and hexane to
yield 230 mg of bright-orange powder (69% yield). MS m/z calcd (M
+) 278.11, found 278.1. 1H NMR (400 MHz, DMSO-d6) δ 7.87−7.97
(m, 2H), 7.81 (dt, J = 1.28, 7.43 Hz, 1H), 7.70−7.78 (m, 1H), 7.33−
7.41 (m, 2H), 7.30 (d, J = 6.97 Hz, 3H), 5.85 (s, 1H), 4.85 (s, 2H),
3.08 (s, 3H). 13C-HSQC (400 MHz, DMSO-d6) δ (ppm) 39.73, 40.38,
56.81, 106.52, 127.31, 128.99, 129.08, 127.31, 133.02, 134.48, 124.91,
126.76, 134.48.
2-((3-Chlorobenzyl)amino)naphthalene-1,4-dione (2r). To a
solution of 2-bromo-1,4-napthoquinone (283 mg, 1.2 mmol) in abs
EtOH (40 mL) was added an excess of 3-chlorobenzylamine (293 μL,
2.4 mmol). Reaction was stirred for 30 min, after which the
precipitated solid was filtered to yield 199 mg of bright-orange
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powder (56% yield). MS m/z calcd (M+) 298.06, found 298.1. H
NMR (400 MHz, DMSO-d6) δ 8.23 (t, J = 6.53 Hz, 1H), 7.95−8.05
(m, 1H), 7.87−7.94 (m, 1H), 7.79−7.87 (m, 1H), 7.70−7.79 (m, 1H),
7.45 (s, 1H), 7.25−7.42 (m, 3H), 5.60 (s, 1H), 4.47 (d, J = 6.53 Hz,
2H). 13C-HSQC (400 MHz, DMSO-d6) δ (ppm) 40.08, 44.86, 100.96,
125.82, 126.28, 126.48, 127.51, 127.51, 130.72, 132.58, 135.31.
2-((4-Methylbenzyl)amino)naphthalene-1,4-dione (2s). To a
solution of 2-bromo-1,4-napthoquinone (283 mg, 1.2 mmol) in abs
EtOH (40 mL) was added an excess of 4-methylbenzylamine (306 μL,
2.4 mmol). Reaction was stirred for 40 min, after which the
precipitated solid was filtered to yield 187 mg (56% yield) of
2-((3-Phenethylpropyl)amino)naphthalene-1,4-dione (2m). To a
solution of 2-bromo-1,4-napthoquinone (283 mg, 1.2 mmol) in abs
EtOH (40 mL) was added an excess of phenethylamine (302 μL, 2.4
mmol). The reaction was stirred for 30 min at rt and the precipitate
filtered to yield 90 mg of bright-orange powder (27% yield). MS m/z
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reddish-orange powder. MS m/z calcd (M+) 278.11, found 278.1. H
NMR (400 MHz, DMSO-d6) δ 8.25 (t, J = 6.40 Hz, 1H), 8.00−8.12
(m, 1H), 7.93−8.00 (m, 1H), 7.89 (dt, J = 1.00, 7.53 Hz, 1H), 7.75−
7.85 (m, 1H), 7.27−7.36 (m, 2H), 7.17−7.27 (m, 2H), 5.62 (s, 1H),
4.47 (d, J = 6.27 Hz, 2H), 2.34 (s, 3H). 13C-HSQC (400 MHz,
DMSO-d6) δ (ppm) 20.78, 40.11, 45.39, 100.80, 129.73, 127.84,
132.56, 135.44, 125.74, 126.52.
2-((4-Methoxybenzyl)amino)naphthalene-1,4-dione (2t). To a
solution of 2-bromo-1,4-napthoquinone (283 mg, 1.2 mmol) in abs
EtOH (40 mL) was added an excess of 4-methoxybenzylamine (314
μL, 2.4 mmol). Reaction was stirred for 10 min, after which the
precipitated solid was filtered to yield 192 mg (55% yield) of slightly
orangish-yellow powder. MS m/z calcd (M+) 294.11, found 294.0. 1H
NMR (400 MHz, DMSO-d6) δ 8.17 (t, J = 6.40 Hz, 1H), 7.95−8.05
(m, 1H), 7.87−7.94 (m, 1H), 7.82 (dt, J = 1.13, 7.47 Hz, 1H), 7.68−
7.77 (m, 1H), 7.29 (d, J = 8.53 Hz, 2H), 6.91 (d, J = 8.53 Hz, 2H),
5.59 (s, 1H), 4.37 (d, J = 6.53 Hz, 2H), 3.73 (s, 3H). 13C-HSQC (400
MHz, DMSO-d6) δ (ppm)39.99, 45.03, 55.57, 100.90, 114.25, 125.77,
126.47, 129.05, 132.58, 135.43, 146.84, 152.29.
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calcd (M+) 278.32, found 278.4. H NMR (400 MHz, DMSO-d6) δ
7.96 (dd, J = 7.78, 14.31 Hz, 1H), 7.69−7.88 (m, 2H), 7.56 (t, J = 5.77
Hz, 1H), 7.15−7.41 (m, 5H), 5.75 (s, 1H), 3.26−3.54 (m, 2H), 2.99−
3.14 (m, 1H), 2.81−2.98 (m, 2H). 13C-HSQC (400 MHz, DMSO-d6)
δ (ppm) 33.55, 33.55, 39.77, 43.57, 43.57, 100.01, 125.71, 126.27,
126.77, 129.01. 132.64, 135.24.
2-((Pyridin-4-ylmethyl)amino)naphthalene-1,4-dione (2n). To a
solution of 2-bromo-1,4-napthoquinone (283 mg, 1.2 mmol) in abs
EtOH (40 mL) was added an excess of 4-picolylamine (243 μL, 2.4
mmol). Compound was purified using chromatography on silica gel,
followed by C18 silica gel, to yield 87.8 mg of yellow powder (28%
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yield). MS m/z calcd (M+) 264.1, found 264.1. H NMR (400 MHz,
DMSO-d6) δ 8.74 (d, J = 5.27 Hz, 2H), 8.27 (t, J = 6.53 Hz, 1H), 8.04
(d, J = 6.78 Hz, 1H), 7.89−7.95 (m, 1H), 7.84 (dt, J = 1.13, 7.47 Hz,
1H), 7.73−7.80 (m, 3H), 5.56 (s, 1H), 4.69 (d, J = 6.53 Hz, 2H). 13C-
HSQC (400 MHz, DMSO-d6) δ (ppm)39.83, 43.80, 101.07, 123.72,
123.72, 125.35, 125.93, 132.32, 134.90, 145.16.
2-((Pyridin-3-ylmethyl)amino)naphthalene-1,4-dione (2o). To a
solution of 2-bromo-1,4-napthoquinone (283 mg, 1.2 mmol) in abs
EtOH (40 mL) was added an excess of 3-(aminomethyl)pyridine (244
μL, 2.4 mmol). Compound was purified using chromatography on
silica gel to yield 50 mg of orange powder (15% yield). 1H NMR (400
MHz, DMSO-d6) δ 8.61 (d, J = 1.76 Hz, 1H), 8.47 (dd, J = 1.51, 4.77
Hz, 1H), 8.23 (t, J = 6.40 Hz, 1H), 8.01 (d, J = 7.03 Hz, 1H), 7.88−
7.95 (m, 1H), 7.69−7.86 (m, 3H), 7.37 (dd, J = 4.77, 7.78 Hz, 1H),
5.65 (s, 1H), 4.50 (d, J = 6.53 Hz, 2H). 13C-HSQC (400 MHz,
DMSO-d6) δ (ppm) 39.23, 42.70, 100.63, 123.21, 132.10, 134.85,
134.84, 125.22, 125.87, 148.52, 148.52.
2-((Pyridin-2-ylmethyl)amino)naphthalene-1,4-dione (2p). To a
solution of 2-bromo-1,4-napthoquinone (283 mg, 1.2 mmol) in abs
EtOH (40 mL) was added an excess of 2-picolylamine (247 μL, 2.4
mmol). The reaction was stirred for 10 min and then concentrated in
vacuo. Compound was purified using chromatography on silica gel
eluting with ethyl acetate and hexane, followed by reverse phase
purification on C18 silica to yield 90 mg of yellowish powder (29%
yield). MS m/z calcd (M+) 265.09, found 265.1. 1H NMR (400 MHz,
Methyl 4-(((1,4-Dioxo-1,4-dihydronaphthalen-2-yl)amino)-
methyl)benzoate (2u). To a solution of 2-bromo-1,4-napthoquinone
(283 mg, 1.2 mmol) in abs EtOH (40 mL) was added an excess of
methyl 4-(aminomethyl)benzoate hydrochloride (569 mg, 2.4 mmol)
and K2CO3 dissolved in water. Reaction was stirred for 10 min, after
which the precipitated solid was filtered to yield 189 mg (49% yield) of
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yellow powder. MS m/z calcd (M+) 322.1, found 322.1. H NMR
(400 MHz, DMSO-d6) δ 8.27 (t, J = 6.40 Hz, 1H), 8.01 (d, J = 7.53
Hz, 1H), 7.87−7.98 (m, 3H), 7.82 (dt, J = 1.00, 7.53 Hz, 1H), 7.70−
7.78 (m, 1H), 7.49 (d, J = 8.03 Hz, 2H), 5.53 (s, 1H), 4.54 (d, J = 6.53
Hz, 2H), 3.84 (s, 3H). 13C-HSQC (400 MHz, DMSO-d6) δ (ppm)
40.03, 45.25, 52.64, 100.97, 125.56, 126.49, 127.84, 129.87, 132.61,
135.33, 146.82, 152.19.
2-((3-(Trifluoromethyl)benzyl)amino)naphthalene-1,4-dione
(2v). To a solution of 2-bromo-1,4-napthoquinone (283 mg, 1.2
mmol) in abs EtOH (40 mL) was added an excess of 3-
(trifluoromethyl)benzylamine (420 mg, 2.4 mmol). The reaction was
stirred for 10 min and then concentrated in vacuo. Compound was
purified using chromatography on silica gel eluting with ethyl acetate
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dx.doi.org/10.1021/jm301485d | J. Med. Chem. 2013, 56, 1007−1022