F.A. Calil et al. / European Journal of Medicinal Chemistry 167 (2019) 357e366
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d
d
7.95e7.85 (m, 4H), 4.17 (s, 2H); 13C NMR (75 MHz, DMSO‑d6)
190.7, 134.7, 131.4, 126.5, 55.3. The spectral data are in accordance
125.3, 121.2 (d, J ¼ 7.9 Hz), 114.2 (d, J ¼ 22.3 Hz). HRMS (-ESI) m/z:
[M e H]- calcd for C16H9FNOꢁ3 : 282.0572; Found: 282.0564.
2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-3-
with those reported in the literature [42].
General procedure for reaction of 5 with amines in water: To
a suspension of 5 (174 mg, 1 mmol, 1 equiv) in water (10 mL) was
added the amine (1.2 mmol,1.2 equiv) and ZnCl2 (136 mg, 1 mmol,1
equiv). The mixture was stirred at 80 ꢀC for 4 h. After cooling, the
precipitated compound was filtered, taken up with ethyl acetate
(100 mL), dried over MgSO4, and concentrated under reduced
pressure. The crude material was purified by column chromatog-
raphy on silica gel with hexane/ethyl acetate (9:1) to afford the
desired product.
hydroxynaphthalene-1,4-dione (6g); 192 mg (60%); dark purple
solid, mp 180e182 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d 9.98 (s, 1H),
7.95e7.91 (m, 2H), 7.82 (s,1H), 7.79e7.70 (m, 2H), 6.67 (d, J ¼ 8.5 Hz,
1H), 6.43 (dd, J ¼ 8.5, 2.6 Hz, 1H), 6.40 (d, J ¼ 2.4 Hz, 1H), 4.18 (q,
J ¼ 4.8 Hz, 4H); 13C NMR (101 MHz, DMSO‑d6)
d 182.1, 178.8, 142.4,
140.1, 138.1, 134.9,133.8, 133.3, 130.7, 126.3,125.6,125.2,115.8, 113.7,
109.2, 64.1, 63.9; HRMS (-ESI) m/z: [M e H]- calcd for C18H12NO5ꢁ:
322.0721; Found: 322.0718.
2-(benzo[d][1,3]dioxol-5-ylamino)-3-hydroxynaphthalene-1,4-
2-hydroxy-3-(phenylamino)naphthalene-1,4-dione (6a): 252 mg
dione (6h): 233 mg (76%); dark purple solid, mp 162e164 ꢀC; 1H
(95%); dark purple solid, mp 216e218 ꢀC, 1H NMR (400 MHz, CDCl3)
NMR (400 MHz, DMSO‑d6) d 10.02 (s,1H), 7.95e7.92 (m, 2H), 7.89 (s,
d
8.07 (ddd, J ¼ 6.7, 2.7, 1.4 Hz, 2H), 7.68 (dt, J ¼ 7.5, 1.7, 2H),
7.35e7.28 (m, 2H), 7.12e7.06 (m, 1H), 7.04e6.98 (m, 2H). 13C NMR
(101 MHz, CDCl3) 182.5, 179.6, 138.9, 136.4, 134.1, 133.7, 130.9,
1H), 7.79e7.71 (m, 2H), 6.75 (d, J ¼ 8.3 Hz, 1H), 6.53 (d, J ¼ 2.2 Hz,
1H), 6.41 (dd, J ¼ 8.3, 2.2 Hz, 1H), 5.94 (s, 2H); 13C NMR (101 MHz,
d
DMSO‑d6) d 182.0, 178.9, 146.6, 141.7, 140.1, 135.8, 133.7, 133.3, 130.7,
130.5, 128.4, 126.8, 126.1, 124.9, 123.4, 121.6. HRMS (þESI) m/z:
[M þ H]þ calcd for C16H12NOþ3 : 266.0812; Found: 266.0805.
2-hydroxy-3-((4-methoxyphenyl)amino)naphthalene-1,4-dione
(6b): 271 mg (92%); dark purple solid, mp 140e142 ꢀC; 1H NMR
126.4, 125.6, 125.2, 113.0, 107.2, 102.6, 100.6; HRMS (þESI) m/z:
[M þ H]þ calcd for C17H12NOþ5 : 310.0710; Found: 310.0705.
2-((3-chlorophenyl)amino)-3-hydroxynaphthalene-1,4-dione (6i):
30 mg (10%); dark purple solid, mp 209e211 ꢀC; 1H NMR (300 MHz,
(300 MHz, DMSO‑d6)
(s, 1H), 7.81e7.68 (m, 2H), 6.86 (d, J ¼ 8.9 Hz, 2H), 6.78 (d, J ¼ 8.9 Hz,
2H), 3.70 (s, 3H); 13C NMR (75 MHz, DMSO‑d6)
182.1, 178.6, 154.2,
139.4, 134.1, 133.8, 133.2, 130.7, 130.6, 126.7, 125.6, 125.2, 121.9,
113.0, 55.2. HRMS (þESI) m/z: [M þ H]þ calcd for C17H14NO4þ:
296.0917; Found: 296.0918.
d
9.93 (s, 1H), 7.93 (dd, J ¼ 6.8, 1.8 Hz, 2H), 7.90
DMSO‑d6) d 10.61 (s,1H), 8.17 (s,1H), 7.96 (s, 2H), 7.78 (s, 2H), 7.17 (t,
J ¼ 7.0 Hz, 1H), 6.84 (d, J ¼ 7.5 Hz, 3H); 13C NMR (75 MHz, DMSO‑d6)
d
d 181.9, 179.7, 143.3, 143.1, 133.7 (2), 132.4, 130.9, 130.5, 129.2, 125.7,
125.4,124.6,119.4,118.2,117.4; HRMS (þESI) m/z: [M þ H]þ calcd for
C
16H11ClNOþ3 : 300.0422; Found: 300.0416.
2-((4-chlorophenyl)amino)-3-hydroxynaphthalene-1,4-dione (6j):
2-((2-chlorophenyl)amino)-3-hydroxynaphthalene-1,4-dione (6c)
180 mg (60%); dark purple solid, mp 226e228 ꢀC; 1H NMR
151 mg (47%); dark purple solid, mp 154e155 ꢀC; 1H NMR
(300 MHz, DMSO‑d6)
d
8.13 (s, 1H), 7.95 (d, J ¼ 2.1 Hz, 2H), 7.77 (d,
(300 MHz, DMSO‑d6)
d
10.61 (s, 1H), 8.00e7.95 (m, 2H), 7.84e7.75
J ¼ 3.8 Hz, 2H), 7.20 (d, J ¼ 8.5 Hz, 2H), 6.85 (d, J ¼ 8.6 Hz, 2H); 13C
(m, 2H), 7.40 (dd, J ¼ 7.9, 1.2 Hz, 1H), 7.20 (t, J ¼ 7.7 Hz, 1H), 7.08 (s,
NMR (75 MHz, DMSO‑d6) d 181.9, 179.5, 142.4, 140.5, 133.7, 133.6,
1H), 6.95 (td, J ¼ 7.9, 1.4 Hz, 1H), 6.86 (d, J ¼ 8.1 Hz, 1H); 13C NMR
130.9, 130.5, 127.5 (2), 125.7, 125.4, 125.2, 123.8, 120.7 (2); HRMS
(þESI) m/z: [M þ H]þ calcd for C16H11ClNOþ3 : 300.0422; Found:
300.0417.
(75 MHz, DMSO‑d6)
d 219.2, 217.2, 180.1, 175.4, 171.5, 171.4, 168.3,
168.1, 166.4, 164.5, 163.4, 163.2, 162.6, 161.1, 160.0, 159.4; HRMS
(þESI) m/z: [M þ H]þ calcd for C16H11ClNaNOþ3 : 322.0241; Found:
322.0241.
2-((2,3-dichlorophenyl)amino)-3-hydroxynaphthalene-1,4-dione
(6k): 27 mg (8%); dark purple solid, mp 201e203 ꢀC; 1H NMR
2-((2,6-dimethylphenyl)amino)-3-hydroxynaphthalene-1,4-dione
(300 MHz, DMSO‑d6)
d
10.84 (s, 1H), 7.98 (dd, J ¼ 8.3, 5.2 Hz, 2H),
(6d) 161 mg (55%); dark purple solid, mp 150e152 ꢀC; 1H NMR
7.80 (dd, J ¼ 5.4, 3.1 Hz, 2H), 7.23 (s, 1H), 7.17 (t, J ¼ 7.6 Hz, 2H), 6.81
(300 MHz, DMSO‑d6)
d
8.91 (s, 1H), 7.92e7.84 (m, 2H), 7.71 (pd,
(dd, J ¼ 7.3, 1.9 Hz, 1H); 13C NMR (75 MHz, DMSO‑d6)
d 181.3, 180.0,
J ¼ 7.5, 1.7 Hz, 2H), 7.64 (s, 1H), 6.99 (s, 3H), 2.14 (s, 6H); 13C NMR
144.4, 140.4, 134.0, 133.8, 131.2, 130.8, 130.5, 127.3, 125.8, 125.6,
(75 MHz, DMSO‑d6)
d
181.6, 177.9, 138.8, 136.4, 135.2, 134.0, 132.9,
124.4, 122.1, 121.2, 119.6; HRMS (þESI) m/z: [M þ H]þ calcd for
130.7, 130.2, 129.9, 127.1, 125.4, 124.9, 18.4. HRMS (þESI) m/z:
[M þ H]þ calcd for C18H16NOþ3 : 294.1125; Found: 294.1124.
2-hydroxy-3-((3-(trifluoromethyl)phenyl)amino)naphthalene-1,4-
dione (6e); 112 mg (34%); dark purple solid, mp 219e221 ꢀC; 1H
C
16H10Cl2NOþ3 : 334.0032; Found: 334.0032.
2-hydroxy-3-(4-phenylpiperazin-1-yl)naphthalene-1,4-dione (6l):
83 mg (25%); dark purple solid, mp 78e80 ꢀC; 1H NMR (300 MHz,
CDCl3)
7.5 Hz, 2H), 6.98 (d, J ¼ 8.4 Hz, 2H), 6.91 (t, J ¼ 7.2 Hz, 1H), 3.76 (s,
4H), 3.40e3.33 (m, 4H); 13C NMR (75 MHz, CDCl3)
180.6, 180.5,
d
8.01 (d, J ¼ 6.4 Hz, 2H), 7.70e7.58 (m, 2H), 7.30 (dd, J ¼ 8.2,
NMR (300 MHz, DMSO‑d6) d 10.72 (s,1H), 8.33 (s,1H), 8.02e7.93 (m,
2H), 7.80e7.77 (m, 2H), 7.37 (t, J ¼ 7.9 Hz, 1H), 7.16 (s, 1H), 7.12 (d,
d
J ¼ 7.8 Hz, 1H), 7.07 (d, J ¼ 8.2 Hz, 1H); 13C NMR (75 MHz, DMSO‑d6)
151.2, 133.9,133.1, 132.4, 130.16, 130.10, 129.3 (2), 126.6, 126.0, 125.8,
120.5, 116.7 (2), 50.5 (2), 50.1 (2); HRMS (þESI) m/z: [M þ H]þ calcd
for C20H19N2Oþ3 : 335.1390; Found: 335.1397.
d
182.3, 180.1, 143.7, 142.8, 134.2, 134.1, 131.3, 130.9, 129.1 (d,
J ¼ 31.3 Hz), 129.1, 126.1, 125.9, 125.0, 124.8 (d, J ¼ 272.3 Hz), 122.7,
116.3 (d, J ¼ 4.2 Hz), 115.3 (d, J ¼ 3.9 Hz); HRMS (-ESI) m/z: [M e H]-
calcd for C17H9F3NOꢁ3 : 332.0540; Found: 332.0534.
2-(4-(4-chlorophenyl)piperazin-1-yl)-3-hydroxynaphthalene-1,4-
dione (6m): 202 mg (55%); dark purple solid, mp 172e174 ꢀC; 1H
General procedure for reaction of 5 with amines in isopropyl
alcohol: To a suspension of 5 (174 mg, 1 mmol, 1 equiv) in isopropyl
alcohol (10 mL) was added the amine (1,2 mmol, 1.2 equiv) and the
mixture was stirred at 80 ꢀC for 24 h. After cooling, the mixture
reaction was concentrated to dryness and the residue was purified
by column chromatography on silica gel with hexane/ethyl acetate
(8:2) to afford the desired product.
NMR (300 MHz, DMSO‑d6)
J ¼ 22.0, 6.8 Hz, 2H), 7.26 (d, J ¼ 8.8 Hz, 2H), 7.00 (d, J ¼ 8.9 Hz, 2H),
3.62 (s, 4H), 3.41 (s, 4H); 13C NMR (75 MHz, DMSO‑d6)
181.8, 177.8,
149.3, 134.1, 134.0, 132.59, 132.50, 130.4, 128.7 (2), 126.7, 125.7,
125.4, 122.8, 117.2 (2), 49.6 (2), 47.3 (2); HRMS (þESI) m/z: [M þ H]þ
calcd for C20H18ClN2Oþ3 : 369.1000; Found: 369.1001.
d
7.92 (dd, J ¼ 15.3, 7.4 Hz, 2H), 7.73 (dt,
d
2-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxynaphthalene-
2-((4-fluorophenyl)amino)-3-hydroxynaphthalene-1,4-dione (6f);
1,4-dione (6n); 244 mg (61%); dark purple solid, mp 208e209 ꢀC; 1H
169 mg (60%); dark purple solid, mp 201e203 ꢀC; 1H NMR
NMR (300 MHz, DMSO‑d6)
d
9.94 (s, 1H), 7.95 (d, J ¼ 7.3 Hz, 1H), 7.90
(400 MHz, DMSO‑d6)
7.80e7.72 (m, 2H), 7.01 (dt, J ¼ 12.3, 2.8 Hz, 2H), 6.89 (ddd, J ¼ 6.9,
5.3, 2.8 Hz, 2H). 13C NMR (101 MHz, DMSO- d6)
182.0, 179.1, 157.0
(d, J ¼ 236.9 Hz), 140.8, 137.5, 133.8, 133.4, 130.7, 130.6, 126.0, 125.6,
d
10.21 (s, 1H), 8.03 (s, 1H), 7.97e7.93 (m, 2H),
(d, J ¼ 7.2 Hz, 1H), 7.77 (t, J ¼ 7.0 Hz, 1H), 7.70 (t, J ¼ 7.3 Hz, 1H), 7.34
(d, J ¼ 4.6 Hz, 2H), 7.19 (t, J ¼ 4.7 Hz, 1H), 3.66 (s, 4H), 3.23 (s, 4H);
d
13C NMR (75 MHz, DMSO‑d6)
d 181.7, 178.2, 156.6, 150.7, 134.0, 132.7,
132.55, 132.51, 130.3, 128.6, 127.3, 126.1, 125.7, 125.4, 124.7, 119.7,