title compound (200 mg, 80%) as a yellow residue: TLC R
f
0.47 (2% MeOH/EtOAc); IR (neat) 3302, 2952, 2356, 1604, 1577, 1476, 1455,
407, 1366, 1327, 1239, 1031, 827, 488 cm ; H NMR (400 MHz, CDCl ) δ 7.93 (dd, J = 2.0 Hz, 1H), 7.80 (bdd, J = 2.2 Hz, 1H), 7.52 (dd, J =
.0, 2.1 Hz, 1H), 7.47 (dd, J = 5.1, 2.2 Hz, 1H), 7.44 (dd, J = 5.1, 2.2 Hz, 1H), 7.11 (dd, J = 8.6 Hz, 1H), 5.24 (d, J = 22.1 Hz, 1H), 4.14 (s, 3H), 3.97
–
1 1
1
6
3
13
(
3
s, 3H), 3.79 (d, J = 10.6 Hz, 3H), 3.76 (d, J = 13.5 Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 3.51 (d, J = 10.6 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ
1
62.4 (0, d, J = 257 Hz), 150.8 (0), 149.7 (0), 138.4 (0, d, J = 1.7 Hz), 136.8 (0, d, J = 3.7 Hz), 135.0 (1, d, J = 8.1 Hz), 134.6 (0, d, J = 6.9 Hz),
33.8 (0), 133.1 (1), 129.3 (1, d, J = 5.0 Hz), 129.2 (1, d, J = 2.9 Hz), 120.3 (0, d, J = 3.0 Hz), 116.4 (1, d, J = 20 Hz), 114.0 (0), 101.4 (0, d, J = 16
1
Hz), 54.7 (3), 54.5 (3), 53.9 (3, d, J = 7 Hz), 53.5 (3, d, J = 7 Hz), 51.8 (2), 50.2 (1, d, J = 16 Hz) ppm; MS (ES+) m/z 539.04 (M + H)+.
Dimethyl(((3-cyano-4-fluorobenzyl)amino)(2,3-dimethoxy-7-phenylquinoxalin-5-yl)methyl)phosphonate (18)
To a stirred solution of bromide (97 mg, 0.18 mmol, 1 eq) in anhydrous dimethoxyethane (2.5 mL) were added phenylboronic acid (35
mg, 0.29 mmol, 1.6 eq), sodium carbonate (38 mg, 0.36 mmol, 2 eq) and water (0.5 mL) and the mixture sparged with nitrogen for 5 min.
Then tetrakis(triphenylphosphine)-palladium(0) (23.4 mg, 0.02 mmol, 0.1 eq) was added and the reaction mixture heated to 85 °C for 3 h.
The reaction mixture was diluted with EtOAc (25 mL) and washed with H
were dried (MgSO ) and then concentrated under reduced pressure to leave a yellow residue. The crude product was purified by
chromatography on a silica gel (2% MeOH/EtOAc) and then crystallized from EtOAc to afford the title compound (70 mg, 0.13 mmol,
2
O (25 mL) and brine (25 mL). The combined organic phases
4
7
5
5
3%) as a white solid: TLC R
f
0.4 (2% MeOH/EtOAc); IR (neat) 3297, 2992, 2850, 1618, 1588, 1519, 1477, 1457, 1384, 1332, 1239, 1210, 828,
18 cm ; H NMR (400 MHz, CDCl ) δ 8.03-7.98 (m, 1H), 7.76-7.72 (m, 1H), 7.71-7.64 (m, 1H), 7.57-7.37 (m, 6H), 7.11 (dd, J = 8.6 Hz, 1H),
.32 (d, J = 23.4 Hz, 1H), 4.19 (s, 3H), 4.01 (s, 3H), 3.83 (d, J = 10.6 Hz, 3H), 3.79 (d, J = 13.7 Hz, 1H), 3.62 (d, J = 13.9 Hz, 1H), 3.47 (d, J = 10.5
–
1 1
3
13
Hz, 3H) ppm; C NMR (100MHz, CDCl
J = 4.0 Hz), 135.0 (1, d, J= 9.0 Hz), 133.1 (1), 132.1 (0), 129.1 (1, 2C), 128.0 (1), 127.5 (1, 2C), 125.6 (1, d, J = 6.0 Hz), 124.6 (1, d, J = 2.0 Hz),
16.5 (0, d, J = 19 Hz), 116.4 (1, d, J = 19 Hz), 114.0 (0), 101.3 (0, d, J = 15 Hz), 54.6 (3), 54.4 (3), 53.8 (3, d, J = 7 Hz), 53.5 (3, d, J = 7 Hz), 52.1
2), 50.2 (1, d, J = 17 Hz) ppm; MS (ES+) m/z 537.16 (M + H)+.
3
) δ 162.3 (0, d, J = 257 Hz), 150.6 (0), 149.5 (0), 140.1 (0), 139.8 (0, d, J = 3.0 Hz), 137.7 (0), 137.0 (0, d,
1
(
(((3-Cyano-4-fluorobenzyl)amino)(2,3-dioxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-5-yl)methyl)phosphonic acid (3)
Phosphonate (90.0 mg, 0.17 mmol, 1 eq) was suspended in 5.8 M hydrogenbromide in acetic acid (1 mL) and the mixture was allowed
to heat to 50 °C over 40 min. The reaction mixture was diluted with H
2
O and after ca 5 min a white precipitate was formed and collected
1
to yield the title compound (37.0 mg, 0.08 mmol, 46%) as white powder; H NMR (400 MHz, D
2
O + NaOD) δ 7.62-7.57 (m, 2H), 7.42-7.38
13
(
m, 2H), 7.30-7.05 (m, 5H), 6.80-6.69 (m, 1H, two conformers), 3.88 (d, J = 13.6 Hz, 1H), 3.66 (d, J = 13.6, 1H), 3.51-3.45 (m, 1H) ppm; C
NMR (100 MHz, D
2
O + NaOD) δ 159.0 (0, d, J = 227 Hz), 140.5 (0), 134.6 (1), 131.9 (0), 130.2 (0), 129.1 (1, 2C), 129.0 (1, d, J = 6 Hz), 127.1 (1),
1
26.8 (1, 2C), 126.7 (1, d, J = 12 Hz), 118.2 (1), 115.5 (1, d, J = 24 Hz), 52.0 (2) ppm; 19F NMR (376 MHz, D
2
O + NaOD) δ -119.4 (m) ppm;
Some quaternary and CH carbon peaks are missing.
Dimethyl-((benzylamino)(7-(2-chloropyridin-4-yl)-2,3-dimethoxyquinoxalin-5-yl)methyl)phosphonate (12)
Dimethyl((benzylamino)(7-bromo-2,3-dimethoxyquinoxalin-5-yl)methyl)phosphonate 5 (200 mg, 0.40 mmol, 1 eq) was dissolved in
dimethoxyethane (4.8 mL) and 2-chloropyridine-4-pyridinylboronic acid (102 mg, 0.65 mmol, 1.6 eq) was added followed by sodium
carbonate (85.6 mg, 0.81 mmol, 2 eq) and water (1.2 mL). The mixture was sparged with nitrogen for 5 min and
tetrakis(triphenylphosphine)-palladium(0) (93.6 mg, 0.08 mmol, 0.2 eq) was added. The reaction mixture was allowed to heat to 85 °C
over 22h. After this time, the reaction mixture was diluted with EtOAc (50 mL) and washed with H
combined organic extracts were dried (MgSO ) and concentrated in vacuo to give a yellow oily residue which was purified by
chromatography on a silica gel column (eluting with gradient 100% EtOAc to 2% MeOH/EtOAc) and then recrystallized from hot EtOAc
to yield the title compound as fine yellow needles (29.4 mg, 0.05 mmol, 14%): TLC R 0.18 (EtOAc); IR (neat) 3669, 3339, 2984, 2947, 2898,
586, 1514, 1484, 1449, 1407, 1385, 1373, 1335, 1285, 1236, 1175, 1126, 1058, 1035, 982, 856, 818, 784, 761, 738, 701, 651, 590, 514, 480,
2
O (50 mL) and brine (50 mL). The
4
f
1
4
–1 1
3
15. cm ; H NMR (400 MHz, CDCl ) δ 8.47 (d, J = 5.2 Hz, 1H), 8.06-8.03 (bm, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.70 (bd, J = 1.2 Hz, 1H), 7.59 (dd,
J = 5.2, 1.6 Hz, 1H), 7.30-7.16 (m, 6H), 5.43 (d, J = 21.6 Hz, 1H), 4.19 (s, 3H), 3.96 (s, 3H), 3.83 (bd, J = 14.2 Hz, 1H), 3.82 (d, J = 10.6 Hz, 3H),
.58 (d, J = 13.4 Hz, 1H), 3.52 (d, J = 10.6 Hz, 3H), 2.63 (s, 1H) ppm; MS (ES+) m/z 529.17 (M + H)+.
3
5-(Aminomethyl)-2-nitrobenzonitrile (15)
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