10.1002/cmdc.202000581
ChemMedChem
FULL PAPER
3-(benzo[d]thiazol-6-yl)-7,8-dimethoxyisoquinolin-1(2H)-one
(3j).
10 mL) was heated at 100 °C for 3 hours. The resulting precipitate
was filtered off, washed subsequently with methanol and
dichloromethane and dried in vacuo to obtain pure product.
1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 9.10 (s, 1H), 8.36 (s,
1H), 8.26 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.38 (s, 2H),
6.76 (s, 1H), 3.99 (s, 3H), 3.96 (s, 3H). 13C NMR (150 MHz,
DMSO-d6) δ 161.33, 157.80, 153.56, 151.53, 148.88, 137.55,
134.56, 133.55, 131.53, 125.28, 123.41, 120.85, 119.59, 104.09,
3-(benzo[d][1,3]dioxol-5-yl)isoquinolin-1(2H)-one (3c).
1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.18 (d, 1H), 7.75
– 7.64 (m, 2H), 7.47 (ddd, J = 8.2, 6.5, 1.8 Hz, 1H), 7.38 (d, J =
1.9 Hz, 1H), 7.32 (dd, J = 8.2, 1.9 Hz, 1H), 7.04 (d, J = 8.2 Hz,
1H), 6.87 (s, 1H), 6.10 (s, 2H). 13C NMR (125 MHz, DMSO-d6) δ
163.19, 148.65, 148.17, 140.14, 138.46, 133.06, 128.32, 127.06,
125.03, 121.31, 108.95, 107.44, 103.02, 101.98. HRMS (ESI):
calcd for C16H11NNaO3 288.0631 [M+Na] +, found 288.0634.
+
61.42, 56.77. HRMS (ESI): calcd for C18H15N2O3S [M+H]
339.0798, found: 339.0801.
3-(1-(tert-butyldimethylsilyl)-1H-indol-6-yl)-7,8-dimethoxy-
isoquinolin-1(2H)-one (3k).
1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H),
7.70 (s, 1H), 7.38 – 7.31 (m, 3H), 7.28 (d, J = 3.2 Hz, 1H), 6.66
(dd, J = 0.7, 3.2 Hz, 1H), 6.56 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H),
0.96 (s, 9H), 0.66 (s, 6H). 13C NMR (150 MHz, CDCl3) δ 161.60,
151.19, 149.76, 141.20, 138.98, 134.27, 132.97, 132.35, 127.76,
122.53, 121.47, 119.41, 117.69, 111.16, 104.95, 103.14, 61.83,
56.94, 26.28, 19.50, 3.80. HRMS (ESI): calcd for C25H31N2O3Si
435.2098 [M+H] +, found: 435.2101.
3-(benzo[d][1,3]dioxol-5-yl)-6,7,8-trimethoxyisoquinolin-
1(2H)-one (3d).
1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.34 (d, J = 1.9 Hz,
1H), 7.28 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 7.7 Hz, 2H), 6.72 (s, 1H),
6.10 (d, J = 1.1 Hz, 2H), 3.90 (d, J = 1.0 Hz, 3H), 3.81 (d, J = 1.1
Hz, 3H), 3.77 (d, J = 1.1 Hz, 3H). 13C NMR (125 MHz, DMSO-d6)
δ 160.34, 156.87, 153.69, 148.14, 147.65, 140.99, 139.16, 136.98,
127.54, 120.57, 108.51, 106.76, 103.85, 102.11, 101.54, 61.74,
60.94, 55.86. HRMS (ESI): calcd for C19H18NO6 356.1129 [M+H]
+, found 356.1127.
8-(3,4-dimethoxyphenyl)-2,3-dihydro-[1,4]dioxino[2,3-h]
isoquinolin-10(9H)-one (3l).
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H),
7.20 (dd, J = 1.9, 8.1 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.08 (d, J
= 8.5 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.58 (s, 1H), 4.56 – 4.50
(m, 2H), 4.41 – 4.35 (m, 2H), 4.00 (s, 3H), 3.97 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 161.95, 150.15, 149.58, 143.91, 141.33,
137.32, 134.71, 126.85, 123.56, 119.12, 118.23, 114.76, 111.56,
108.56, 103.33, 64.89, 63.87, 56.16, 56.06. HRMS (ESI): calcd
for C19H18NO5 340.1182 [M+H] +, found: 340.1179.
4.2.3 General procedure for the preparation of 4a and 4b
3-(4-(benzyloxy)-3-methoxyphenyl)-4-chloro-7,8-dimethoxy-
isoquinolin-1(2H)-one (4a).
To
a solution of 3h (21 mg, 0.05 mmol) in anhydrous
tetrahydrofuran (4 mL) at room temperature was added N-
bromosuccinimide (8.9 mg, 0.05 mmol). The mixture was stirred
at room temperature for 2h and then poured into water and
extracted three times with ethyl acetate. The organic layer was
washed with brine, dried (Na2SO4) and evaporated. The residue
was purified by flash column chromatography to give 4a as a
white solid (15 mg, 61%). 1H NMR (600 MHz, DMSO-d6) δ 11.27
(s, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 9.1 Hz, 1H), 7.49 (d,
2H), 7.43 (t, J = 8.4, 6.8 Hz, 2H), 7.37 (t, 1H), 7.14 (d, J = 8.4 Hz,
1H), 7.12 (d, J = 2.1 Hz, 1H), 7.06 (dd, J = 8.3, 2.1 Hz, 1H), 5.16
(s, 2H), 3.91 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H). 13C NMR (125
MHz, DMSO-d6) δ 159.76, 151.96, 149.09, 148.86, 148.75,
138.56, 137.42, 131.39, 128.92, 128.40, 128.32, 127.81, 122.91,
122.80, 120.30, 119.41, 114.10, 113.01, 97.44, 70.30, 61.44,
56.73, 56.14. HRMS (ESI): calcd for C25H23BrNO5 496.0754 [M+H]
+, found 496.0764.
8-(3-methoxy-4-(methoxymethoxy)phenyl)-2,3-dihydro-
[1,4]dioxino[2,3-h] isoquinolin-10 (9H)-one (3m).
1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 7.26 (d, J = 8.6 Hz, 1H),
7.25 – 7.18 (m, 3H), 7.08 (d, J = 8.6 Hz, 1H), 6.59 (s, 1H), 5.31 (s,
2H), 4.54 – 4.47 (m, 2H), 4.40 – 4.33 (m, 2H), 4.02 (s, 3H), 3.56
(s, 3H). 13C NMR (150 MHz, CDCl3) δ 162.34, 150.09, 147.49,
143.86, 141.30, 137.52, 134.73, 128.37, 123.53, 119.12, 118.54,
116.36, 114.79, 109.28, 103.58, 95.32, 64.80, 63.86, 56.33, 56.16.
HRMS (ESI): calcd for C20H20NO6 370.1285 [M+H] +, found:
370.1282.
8-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-dihydro-
[1,4]dioxino[2,3-h]isoquinolin-10(9H)-one (3n).
1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H),
7.14 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 2.2, 8.4 Hz, 1H), 7.06 (d, J
= 8.7 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.55 (s, 1H), 4.54 – 4.49
(m, 2H), 4.40 – 4.35 (m, 2H), 4.33 (s, 4H). 13C NMR (150 MHz,
CDCl3) δ 161.84, 144.72, 144.11, 143.91, 141.30, 136.91, 134.68,
127.44, 123.46, 119.15, 118.60, 118.10, 114.83, 114.53, 103.28,
64.86, 64.50, 64.36, 63.86. HRMS (ESI): calcd for C19H16NO5
[M+H] + 338.1023, found: 338.1027.
3-(4-(benzyloxy)-3-methoxyphenyl)-4-bromo-7,8-
dimethoxyisoquinolin-1(2H)-one (4b).
To a solution of 3h (62.3 mg, 0.15 mmol) in dichloromethane (4
mL) at room temperature was added N-chlorosuccinimide (20 mg,
0.15 mmol). The mixture was stirred at room temperature for 2h
and then poured into water and extracted three times with ethyl
acetate. The organic layer was washed with brine, dried (Na2SO4)
and evaporated. The residue was purified by flash column
1
4.2.2 General procedure for the preparation of 3c and 3d
chromatography to give 4b as a white solid (15 mg, 22.3%). H
NMR (400 MHz, DMSO-d6) δ 11.28 (d, J = 14.7 Hz, 1H), 7.71 (d,
J = 9.0 Hz, 1H), 7.68 – 7.60 (m, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.42
A mixture of 7a or 7b in methanol (5 mL) and aqueous HCl (3M,
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