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L. Wu et al. / European Journal of Medicinal Chemistry 203 (2020) 112594
4.1.2.2. 7-Methoxy-2-Hydroxy-naphthalene-1,4-dione
(1c).
4.1.3.2. 1,2,3,4-Tetrahydro-4-(5-bromo-3-hydroxyphenyl)-2-
Orange solid, m.p. 225e226 ꢁC, yield 88.8%; 1H NMR (400 MHz,
thioxobenzo[h]quinazoline-5,6-dione (4b). Orange solid, m.p.
DMSO‑d6)
d
: 11.65 (s, 1H), 7.86 (d, 1H, J ¼ 8.8 Hz), 7.39 (d, 1H,
275e276 ꢁC, yield 26.1%; 1H NMR (400 MHz, DMSO‑d6)
d: 10.09 (s,
J ¼ 2.0 Hz), 7.33 (dd, 1H, J ¼ 2.4, 8.0 Hz), 6.12 (s, 1H), 3.91 (s, 3H); 13
C
1H), 10.06 (s, 1H), 9.96 (s, 1H), 8.05e7.84 (m, 4H), 6.98 (t, 1H,
J ¼ 1.2 Hz), 6.87 (t,1H, J ¼ 2.0 Hz), 6.77 (t,1H, J ¼ 2.0 Hz), 5.44 (d, 1H,
NMR (100 MHz, DMSO‑d6) d: 184.6, 181.7, 163.4, 159.7, 132.9, 128.3,
125.6, 120.5, 111.3, 110.4, 56.4; HRMS-ESI (m/z): calcd for C11H7O4
J ¼ 3.2 Hz); 13C NMR (100 MHz, DMSO‑d6)
d: 181.5, 178.5, 174.9,
159.3, 145.4, 136.4, 135.3, 134.2, 131.9, 130.9, 126.6, 126.2, 122.5,
[M ꢀ H]þ 203.0344, found: 203.0351.
120.7, 118.3, 115.6, 113.8, 52.5; HRMS-ESI (m/z): calcd for
C
18H11BrN2O3S [M ꢀ H]þ412.9601, found: 412.9607.
4.1.2.3. 6-Methoxy-2-Hydroxy-naphthalene-1,4-dione
(1d).
Yellow solid, m.p. 223e224 ꢁC, yield 92.3%; 1H NMR (400 MHz,
4.1.3.3. 1,2,3,4-Tetrahydro-4-(4-chloro-3-hydroxyphenyl)-2-
DMSO‑d6)
d
: 11.64 (s, 1H), 7.93 (d, 1H, J ¼ 8.8 Hz), 7.33 (d, 1H,
J ¼ 2.4 Hz), 7.26 (dd, 1H, J ¼ 2.4, 8.4 Hz), 6.12 (s, 1H), 3.91 (s, 3H); 13
C
thioxobenzo[h]quinazoline-5,6-dione (4c). Yellow solid, m.p.
268e270 ꢁC, yield 18.1%, 1H NMR (400 MHz, DMSO‑d6)
d: 10.31 (s,
NMR (100 MHz, DMSO‑d6) d: 184.9, 180.4, 164.6, 160.2, 134.7, 129.2,
1H), 10.06 (s, 1H), 10.00 (s, 1H), 8.05e7.83 (m, 4H), 7.32 (d, 1H,
J ¼ 8.4 Hz), 6.98 (t, 1H, J ¼ 2.0 Hz), 6.82e6.80 (m, 1H), 5.44 (d, 1H,
124.2, 119.2, 111.0, 110.2, 56.4; HRMS-ESI (m/z): calcd for C11H7O4
[M ꢀ H]þ 203.0344, found: 203.0355.
J ¼ 3.2 Hz); 13C NMR (100 MHz, DMSO‑d6)
d: 181.5, 178.6, 174.9,
153.6,142.1,136.1, 135.3,134.3,131.9, 130.7,130.6,126.6,126.2,119.9,
119.0, 116.1, 115.6, 52.5; HRMS-ESI (m/z): calcd for C18H10ClN2O3S
[M ꢀ H]þ369.0101, found: 369.0106.
4.1.2.4. 7-Fluoro-2-Hydroxy-naphthalene-1,4-dione
solid, m.p. 204e205 ꢁC, yield 81.2%; 1H NMR (400 MHz, DMSO‑d6)
: 11.84 (s, 1H), 8.01 (dd, 1H, JH-F ¼ 4.2 Hz, J ¼ 8.4 Hz), 7.74e7.66 (m,
2H), 6.17 (s, 1H); 13C NMR (100 MHz, DMSO‑d6)
: 184.1, 180.8, 166.2
(1e). Yellow
d
d
4.1.3.4. 1,2,3,4-Tetrahydro-4-(5-methyl-3-hydroxyphenyl)-2-
(JC-F ¼ 252.9 Hz), 160.2, 133.7 (JC-F ¼ 7.3 Hz), 129.3 (JC-F ¼ 8.9 Hz),
129.1 (JC-F ¼ 3.0 Hz), 121.7 (JC-F ¼ 20.3 Hz), 113.0(JC-F ¼ 23.7 Hz),
111.4; HRMS-ESI (m/z): calcd for C10H4FO3 [M ꢀ H]þ 191.0144,
found: 191.0151.
thioxobenzo[h]quinazoline-5,6-dione (4d). Yellow solid, m.p.
259e260 ꢁC, yield 15.6%; 1H NMR (400 MHz, DMSO‑d6)
d: 9.93 (s,
2H), 9.40 (s, 1H), 8.05e7.84 (m, 4H), 6.61e6.50 (m, 3H), 5.39 (d, 1H,
J ¼ 3.2 Hz), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO‑d6)
d: 181.5,
178.6, 174.8, 158.0, 143.3, 139.7, 136.0, 135.3, 134.2, 132.0, 130.8,
126.6, 126.2, 118.6, 116.5, 116.2, 111.5, 52.9, 21.6; HRMS-ESI (m/z):
calcd for C19H13N2O3S [M ꢀ H]þ349.0652, found: 349.0653.
4.1.2.5. 6,7-Dimethoxy-2-Hydroxy-naphthalene-1,4-dione
Orange solid, m.p. 206e208 ꢁC, yield 44.2%; 1H NMR (400 MHz,
DMSO‑d6) : 11.69 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 6.11 (s, 1H), 3.92
(s, 6H); 13C NMR (100 MHz, DMSO‑d6)
: 184.8, 181.0, 159.8, 154.0,
(1f).
d
d
4.1.3.5. 1,2,3,4-Tetrahydro-4-(5-chloro-3-hydroxyphenyl)-2-
152.7, 127.1, 125.0, 110.6, 108.2, 107.8, 56.5 (2C); HRMS-ESI (m/z):
thioxobenzo[h]quinazoline-5,6-dione (4e). Yellow solid, m.p.
calcd for C12H9O3 [M ꢀ H]þ 233.0450, found: 233.0454.
273e274 ꢁC, yield 14.8%,1H NMR (400 MHz, DMSO‑d6)
d: 10.09 (s,
1H), 10.07 (s, 1H), 9.97 (s, 1H), 8.05e7.84 (m, 4H), 6.85 (s, 1H), 6.74
(d, H, J ¼ 2.0 Hz), 5.45 (d, 1H, J ¼ 3.2 Hz); 13C NMR (100 MHz,
4.1.2.6. 6-Chloro-2-Hydroxy-naphthalene-1,4-dione
Yellow solid, m.p. 199e200 ꢁC, yield 73.5%; 1H NMR (400 MHz,
DMSO‑d6)
: 11.94 (s, 1H), 7.99 (d, 1H, J ¼ 8.8 Hz), 7.86e7.84 (m, 2H),
6.20 (s, 1H); 13C NMR (100 MHz, DMSO‑d6)
: 183.8, 180.8, 160.4,
(1g).
DMSO‑d6) d: 181.5, 178.5, 175.0, 159.2, 145.2, 136.4, 135.3, 134.2,
134.1, 131.9, 130.9, 126.6, 126.2, 117.9, 115.6, 115.4, 113.4, 52.6;
HRMS-ESI (m/z): calcd for C18H10ClN2O3S [M ꢀ H]þ369.0101, found:
369.0106.
d
d
140.0, 133.9, 133.4, 129.8, 128.7, 125.5, 111.4; HRMS-ESI (m/z): calcd
for C10H4ClO3 [M ꢀ H]þ 206.9849, found: 206.9855.
4.1.3.6. 1,2,3,4-Tetrahydro-4-(2-fiuoro-5-hydroxyphenyl)-2-
thioxobenzo[h]quinazoline-5,6-dione (4f). Yellow solid, m.p.
230e231 ꢁC, yield 21.8%,1H NMR (400 MHz, DMSO‑d6)
d: 10.01 (s,
4.1.3. General procedure for the preparation of compounds 4
10 mL CH3COOH was added into the mixture constituted by
1H), 9.93 (s, 1H), 9.46 (s, 1H), 8.06e7.84 (m, 4H), 7.03e6.68 (m, 3H),
5.65 (d, 1H, J ¼ 2.4 Hz); 13C NMR (100 MHz, DMSO‑d6)
d
: 181.2,
1
mmol
2-hydroxy-1,4-naphthoquinones,
1
mmol
3-
hydroxybenzaldehydes and 2 mmol thiourea. Later, the resultant
mixed product was subjected to 3.5e5.0 h of stirring under reflux
temperature. Following reaction completion, that reaction mixture
was cooled down until ambient temperature, followed by concen-
tration at reduced pressure. Thereafter, 50 mL CH2Cl2 was put into
that resultant reaction mixture, then respective 50 mL saturated
NaHCO3 and brine were used to wash that organic layer in
sequence, followed by anhydrous Na2SO4 drying, and concentration
at the reduced pressure. Then, the silica gel column chromatog-
raphy was used to purify those crude products, and the petroleum
ether: ethyl acetate (v:v ¼ 3:1) was utilized to be the eluent to give
product 4.
178.6, 174.6, 154.1, 153.5 (JC-F ¼ 247 Hz), 136.3, 135.4, 134.2, 131.9,
130.7, 129.6 (JC-F ¼ 15.0 Hz), 126.6, 126.0, 116.9, 116.7 (JC-F ¼ 13.6 Hz),
115.9 (JC-F ¼ 2.9 Hz), 115.3, 48.3; HRMS-ESI (m/z): calcd for
C
18H10FN2O3S [M ꢀ H]þ353.0396, found: 353.0405.
4.1.3.7. 1,2,3,4-Tetrahydro-4-(2-chloro-3-hydroxyphenyl)-2-
thioxobenzo[h]quinazoline-5,6-dione (4g). Orange solid, m.p.
257e258 ꢁC, yield 18.1%; 1H NMR (400 MHz, DMSO‑d6)
d: 10.26 (s,
1H), 9.93 (s, 1H), 9.86 (s, 1H), 8.06e7.83 (m, 4H), 7.10 (t, 1H,
J ¼ 8.0 Hz), 6.92e6.89 (m, 2H), 5.96 (d, 1H, J ¼ 2.0 Hz); 13C NMR
(100 MHz, DMSO‑d6) d: 181.2, 178.6, 174.4, 153.8, 140.8, 136.5, 135.3,
134.2, 132.0, 130.7, 128.2, 126.6, 126.1, 120.5, 119.8, 116.5, 115.9, 51.2;
HRMS-ESI (m/z): calcd for C18H10ClN2O3S [M ꢀ H]þ369.0101, found:
369.0106.
4.1.3.1. 1,2,3,4-Tetrahydro-4-(3-hydroxyphenyl)-2-thioxobenzo[h]
quinazoline-5,6-dione (4a). Yellow solid, m.p. 263e264 ꢁC, yield
31.0%; 1H NMR (400 MHz, DMSO‑d6)
d
: 9.98 (s, 2H), 9.53 (s, 1H),
4.1.3.8. 1,2,3,4-Tetrahydro-4-(2-bromo-5-hydroxyphenyl)-2-
8.04e7.83 (m, 4H), 7.15 (d, 1H, J ¼ 8.0 Hz), 6.80e6.68 (m, 3H), 5.44
thioxobenzo[h]quinazoline-5,6-dione (4h). Orange solid, m.p.
(d, 1H, J ¼ 2.4 Hz); 13C NMR (100 MHz, DMSO‑d6)
d: 181.5, 178.6,
190e191 ꢁC, yield 18.0%; 1H NMR (400 MHz, DMSO‑d6)
d: 9.98 (s,
147.9, 158.1, 143.5, 136.0, 135.3, 134.2, 132.0, 130.7, 130.3, 126.6,
2H), 9.76 (s, 1H), 8.06e7.83 (m, 4H), 7.39 (t, 1H, J ¼ 8.8 Hz), 6.84 (d,
126.22, 117.9, 116.5, 115.6, 114.2, 52.9; HRMS-ESI (m/z): calcd for
1H, J ¼ 3.2 Hz), 6.66 (dd, 1H, J ¼ 2.8, 8.8 Hz), 5.82 (d, 1H, J ¼ 2.0 Hz);
C
18H11N2O3S [M ꢀ H]þ335.0490, found: 335.0496.
13C NMR (100 MHz, DMSO‑d6)
d: 181.2, 178.6, 174.3, 157.9, 142.0,