G. Xu, Y. Gao, B. Sun, L. Peng, L. Mao, Y. Jiang, and Q. Ding
Vol 000
(s, 1H), 4.37 (s, 2H), 3.70 (s, 2H), 3.67 (t, J1 = 4.0 Hz,
J2 = 8.0 Hz, 2H), 2.77 (t, J1 = 4.0 Hz, J2 = 8.0 Hz, 2H),
1.49 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 164.13,
156.15, 151.56, 148.97, 144.29, 117.71, 112.16, 82.03,
68.15, 28.59, 27.32. HRMS ((+)-ESI): m/z = 307.0782
(calcd. 307.0820 for C13H17ClN2O3, [M + Na]+).
6.52–6.48 (m, 2H), 6.42 (dd, J1 = 12.0 Hz, J2 = 6.0 Hz,
1H), 5.04 (s, 1H), 2.12 (s, 3H), 2.02–1.98 (m, 2H),
1.72–1.70 (m, 4H); 13C NMR (100 MHz, CDCl3):
δ 161.89, 153.00, 145.89, 145.02, 143.39, 141.68,
138.68, 132.04, 128.38, 125.69, 122.22, 120.30, 117.87,
106.05, 41.40, 40.00, 30.29, 24.09; HRMS ((+)-ESI):
m/z = 348.0869 (calcd. 348.0874 for C18H16ClN3O,
[M + Na]+).
Synthesis of tert-butyl 4-chloro-1-methyl-2-oxo-1,2,7,8-
tetrahydro-1,6-naphthyridine-6(5H)-carboxylate
(9).
Compound 8 (28 g, 0.1 mol) was added to DMF
(300 mL), followed by the addition of Cs2CO3 (48 g,
0.15 mol) and of iodo methane (22 g, 0.13 mol). The
mixture was stirred at room temperature overnight and
quenched by cold water. After that, the mixture was
extracted with ethyl acetate (300 mL × 3). The
combined organic phase was washed with brine, dried
over Na2SO4, and evaporated to give the crude of 8.
Pulp refining with ether (100 mL) was used to purify
8. After filtration and vacuum drying, compound 8 was
obtained as a white solid in a yield of 83.2%. 1H
NMR (400 MHz, CDCl3): δ 6.63 (s, 1H), 4.37 (s, 2H),
3.70 (t, J1 = 4.0 Hz, J2 = 8.0 Hz, 2H), 3.49 (s, 3H),
2.73 (t, J1 = 8.0 Hz, J2 = 4.0 Hz, 2H), 1.50 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 161.66, 154.21,
145.21, 134.39, 117.15, 111.02, 103.39, 80.76, 42.63,
30.45, 28.37, 27.31. HRMS ((+)-ESI): m/z = 321.0972
4-(2-Methoxypyridin-3-yl)-1-methyl-5,6,7,8-tetrahydro-
1,6-naphthyridin-2(1H)-one hydrochloride (10c).
1
Brown solid; yield 59%; H NMR (600 MHz, CDCl3):
δ 8.21 (dd, J1 = 6.0 Hz, J2 = 6.0 Hz, 1H), 7.39 (dd,
J1
= 12.0 Hz, J2 = 6.0 Hz, 1H), 6.96 (dd,
J1 = 12.0 Hz, J2 = 6.0 Hz, 1H), 6.37 (s, 1H), 4.75
(s, 2H), 3.93 (s, 3H), 3.54 (s, 3H), 3.18 (s, 2H), 2.72
(t, J1 = 6.0 Hz, J2 = 12.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3): δ 162.64, 160.25, 147.75, 147.34,
141.64, 138.40, 120.95, 118.04, 116.83, 114.24, 53.62,
44.77, 43.00, 30.03, 28.02; HRMS ((+)-ESI):
m/z = 272.1372 (calcd. 272.1394 for C15H17N3O2,
[M + H]+).
4-(1,5-Dimethyl-1H-pyrazol-4-yl)-1-methyl-5,6,7,8-
tetrahydro-1,6-naphthyridin-2(1H)-one
(10d).
hydrochloride
White solid; yield 64%; 1H NMR
(calcd. 321.1009 for C9H20N2O6, [M + Na]+).
(600 MHz, CDCl3): δ 6.59 (s, 1H), 5.29 (s, 1H), 2.76 (s,
2H), 2.59 (s, 3H), 2.35 (s, 3H), 2.24 (t, J1 = 12.0 Hz,
J2 = 6.0 Hz, 2H), 1.92–1.90 (m, 3H), 0.99 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 161.69, 152.38, 144.48,
143.24, 141.29, 125.00, 116.21, 115.09, 111.62, 99.99,
42.14, 40.04, 35.38, 31.26; HRMS ((+)-ESI): m/
z = 259.1540 (calcd. 259.1553 for C14H18N4O, [M + H]+).
Synthesis of 10a–i. (General procedure) Compound 9
(10 mmol) was added to THF (60 mL), followed by the
addition of 1 mol/L potassium phosphate solution
(30 mL), and substituted boronic acid (12 mmol). The
mixture was refluxed overnignt and extracted with ethyl
acetate (30 mL × 3). The combined organic phase was
concentrated, followed by the addition of methanol
(30 mL) and HCl/1,4-dioxane (30 mL V/V = 1:5). The
mixture was stirred at room temperature for 5 h. The
reaction mixture was concentrated, followed by pulp
refining with ether (30 mL) to purify 10a–i.
Methyl-4-(pyridin-4-yl)-5,6,7,8-tetrahydro-1,6-
naphthyridin-2(1H)-one hydrochloride (10e).
Yellow
1
solid; yield 77%; H NMR (600 MHz, CDCl3): δ 8.17 (s,
1H), 7.92–7.91 (m, 1H), 7.37 (dd, J1 = 12.0 Hz,
J2 = 6.0 Hz, 2H), 6.79 (s, 1H), 3.16 (s, 3H), 2.42 (t,
J1 = 12.0 Hz, J2 = 6.0 Hz, 2H), 1.99–1.97 (m, 4H); 13C
NMR (100 MHz, CDCl3): δ 162.77, 158.72, 147.51,
129.17, 114.35, 112.69, 108.72, 93.83, 41.17, 39.54,
31.46, 25.67; HRMS ((+)-ESI): m/z = 242.1879 (calcd.
242.1895 for C14H16N3O, [M + H]+).
4-(1H-indol-3-yl)-1-methyl-5,6,7,8-tetrahydro-1,6-
naphthyridin-2(1H)-one hydrochloride (10a).
White
solid; yield 72%; 1H NMR (600 MHz, DMSO-d6): δ
11.76 (s, 1H), 9.57 (s, 2H), 7.61 (d, J = 6.0 Hz, 1H), 7.54–
7.49 (m, 1H), 7.21–7.18 (m, 1H), 7.13–7.09 (m, 1H), 6.47
(s, 1H), 4.00 (s, 2H), 3.50 (s, 3H), 3.10 (t, J1 = 6.0 Hz,
J2 = 12.0 Hz, 2H), 2.51 (t, J1 = 6.0 Hz, J2 = 6.0 Hz, 2H);
13C NMR (100 MHz, CDCl3): δ 161.53, 152.36, 145.50,
142.01, 136.76, 126.32, 125.84, 122.46, 120.60, 119.26,
116.41, 112.70, 110.78, 106.98, 42.24, 30.22, 24.47;
HRMS ((+)-ESI): m/z = 280.1429 (calcd. 280.1444 for
C17H17N3O, [M + H]+).
Methyl-4-(2-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydro-
1,6-naphthyridin-2(1H)-one hydrochloride (10f).
1
White solid; yield 69%; H NMR (600 MHz, MeOD): δ
7.15–7.14 (m, 1H), 6.68 (t, J1 = 12.0 Hz, J2 = 6.0 Hz,
2H), 6.42–6.41 (m, 2H), 5.51 (s, 1H), 3.17–3.15 (m,
2H), 2.92 (s, 3H), 2.45 (t, J1 = 12.0 Hz, J2 = 12.0 Hz,
2H), 1.99 (d, J = 12.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ 161.92, 153.17, 141.59, 136.81, 131.52,
131.19, 130.56, 128.79, 125.94, 124.44, 116.35,
109.11, 45.17, 40.12, 30.83, 24.05; HRMS ((+)-ESI):
4-(7-Chloroquinolin-4-yl)-1-methyl-5,6,7,8-tetrahydro-
1,6-naphthyridin-2(1H)-one hydrochloride (10b).
1
White solid; yield 83%; H NMR (600 MHz, MeOD):
δ 7.80 (d, J = 6.0 Hz, 1H), 6.83 (d, J = 6.0 Hz, 1H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet