J.-F. Cavalier et al. / Bioorg. Med. Chem. 9 (2001) 1037±1044
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diluted with water (10 mL/mmol 4) and extracted three
times with ehtyl acetate. The combined organic layers
were washed with brine, dried over MgSO4, and con-
centrated in vacuum. The crude product 5 was puri®ed
by column-chromatography on silica gel.
3,4-dimethoxyphenylboronic acid, and 2.2 mL of 1 M
sodium carbonate. Chromatography gave 720 mg (98%)
of pure 6c as a beige solid (Rf 0.26; ethyl acetate/cyclo-
hexane, 1:1): mp 152.7 ꢀC (recrystallization from cold
ether); 1H NMR (300 MHz, CDCl3) d 8.36 (s, 1H, H-6),
7.90 (d, 2H, J=8.6 Hz), 7.41 (dd, 1H, J=1.9 and
8.2 Hz), 6.37 (d, 1H, J=1.9 Hz), 6.99 (d, 2H, J=8.6 Hz),
6.97 (d, 1H, J=8.2 Hz), 4.82 (s, 2H, NH2), 3.95 (s, 3H),
3.94 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) d
159.9, 150.6 (C-2), 149.9, 149.6, 143.0 (C-5), 139.5 (C-3),
136.8 (C-6), 130.3, 130.0, 127.2, 120.8, 114.3, 111.9,
111.3, 56.2, 55.5; EIMS m/z 337 (M+). Anal. calcd for
C19H19N3O3+0.2 H2O: C, 66.94; H, 5.69; N, 12.33.
Found: C, 66.93; H, 5.64; N, 12.09.
2-Amino-3-bromo-5-(40-methoxyphenyl)-1,4-pyrazine (5a).
5a was obtained from 1.7 g of 4a (8.45 mmol), 0.423 mL
of water, and 1.65 g of NBS. Chromatography gave
2.26 g (80%) of pure 5a as a yellow solid (Rf 0.51; ethyl
acetate/cyclohexane, 3:5): mp 167.9 ꢀC; 1H NMR
(200 MHz, CDCl3) d 8.32 (s, 1H, H-6), 7.79 (d, 2H,
J=8.8 Hz), 6.95 (d, 2H, J=8.8 Hz), 5.09 (s, 2H, NH2),
3.83 (s, 3H); 13C NMR (50 MHz, CDCl3) d 160.1, 150.7
(C-2), 143.2 (C-5), 137.0 (C-6), 129.5, 127.0, 125.7 (C-3),
114.2, 55.3; EIMS m/z 281 (M+), 279 (M+), 266, 264.
Anal. calcd for C11H10BrN3O: C, 47.16; H, 3.59; N,
15.0. Found: C, 46.84; H, 3.47; N, 14.62.
2-Amino-3-(40-methoxyphenyl)-5-(30,40 -methylenedioxy-
phenyl)-1,4-pyrazine (6d). 6d was obtained from 49 mg
of Pd (II), 65 mg of dppb, 747 mg of 5b (2.54 mmol),
425 mg of 4-methoxyphenylboronic acid, and 2.6 mL of
1 M sodium carbonate. Chromatography gave 702 mg
(86%) of pure 6d as a yellow solid (Rf 0.20; ethyl ace-
tate/cyclohexane, 3:5): mp 181.2 ꢀC; 1H NMR
(200 MHz, acetone-d6) d 8.42 (s, 1H, H-6), 7.82 (d, 2H,
J=8.9 Hz), 7.56 (dd, 1H, J=1.8 and 8.7 Hz), 7.53 (d,
1H, J=1.8 Hz), 7.07 (d, 2H, J=8.9 Hz), 6.92 (d, 1H,
J=8.7 Hz), 6.03 (s, 2H), 5.63 (s, 2H, NH2), 3.88 (s, 3H);
13C NMR (50 MHz, acetone-d6) d 161.2, 152.6 (C-2),
149.4, 148.6, 142.2 (C-5), 137.7 (C-6), 133.1 (C-3), 131.3,
130.7, 127.8, 119.9, 115.1, 109.3, 106.7, 102.3, 55.8;
EIMS m/z 321 (M+). Anal. calcd for C18H15N3O3+0.2
H2O: C, 66.54; H, 4.74; N, 12.95. Found: C, 66.56; H,
4.98; N, 13.32.
2-Amino-3-bromo-5-(30,40-methylenedioxyphenyl)-1,4-pyr-
azine (5b). 5b was obtained from 600 mg (2.78 mmol) of
4b, 0.140 mL of water, and 546 mg of NBS. Chromato-
graphy gave 784 mg (96%) of pure 5b as a pale brown
solid (Rf 0.39; ethyl acetate/cyclohexane, 3:5): mp 157 ꢀC;
1H NMR (200MHz, acetone-d6) d 8.48 (s, 1H, H-6), 7.49
(dd, 1H, J=1.7 and 8.1 Hz), 7.44 (d, 1H, J=1.7 Hz), 6.92
(d, 1H, J=8.1 Hz), 6.16 (s, 2H, NH2), 6.05 (s, 2H); 13C
NMR (50 MHz, acetone-d6) d 153.1 (C-2), 149.5, 149.0,
143.2 (C-5), 138.6 (C-6), 131.3, 125.6 (C-3), 120.1, 109.4,
106.5, 102.4; EIMS m/z 295 (M+), 293 (M+). Anal.
calcd for C11H8BrN3O: C, 45.88; H, 2.72; N, 14.28; Br,
27.17. Found: C, 45.93; H, 2.82; N, 13.88; Br, 26.97.
General procedure for the preparation of compound 6a
(symmetrical substitution). The procedure described for
compounds 4a±d was applied, using preformed palla-
dium catalyst (0.1 equiv), 2-amino-3,5-dibromo-1,4-
pyrazine 3b (1 equiv), arylboronic acid (2.1 equiv), and
1 M aqueous sodium carbonate (2 equiv), in ethanol
(0.86 mL/mmol 3b) and toluene (8 mL/mmol 3b).
General procedure for the preparation of compounds 6b±d
(unsymmetrical substitution)
The procedure described for compounds 4a±d was
applied, using preformed palladium catalyst (0.05
equiv), 2-amino-3-bromo-5 aryl-1,4-pyrazine 5a±b (1
equiv), arylboronic acid (1.1 equiv), and 1 M aqueous
sodium carbonate (1 equiv) in ethanol (0.43 mL/mmol
5) and toluene (4 mL/mmol 5).
2-Amino-3,5-bis(40-methoxyphenyl)-1,4-pyrazine (6a). 6a
was obtained from 306 mg of Pd (II), 408 mg of dppb,
2.02 g of 3b (8 mmol), 2.55 g of 4-methoxyphenylboronic
acid, and 16 mL of 1 M sodium carbonate. Chromato-
graphy gave 1.7 g (69%) of pure 6a as a yellow solid (Rf
2-Amino-3-(30,40-methylenedioxyphenyl)-5-(40-methoxy-
phenyl)-1,4-pyrazine (6b). 6b was obtained from 32 mg
of Pd (II), 42 mg of dppb, 440 mg (1.66 mmol) of 5a,
303 mg of 3,4-methylenedioxyphenylboronic acid, and
1.7 mL of 1M sodium carbonate. Chromatography gave
462 mg (92%) of pure 6b as a yellow solid (Rf 0.25;
0.21; ethyl acetate/cyclohexane, 3:5): mp 136.6 ꢀC; H
1
NMR (300 MHz, DMSO-d6) d 8.42 (s, 1H, H-6), 7.90
(d, 2H, J=8.7 Hz), 7.75 (d, 2H, J=8.7 Hz), 7.06 (d, 2H,
J=8.7 Hz), 6.98 (d, 2H, J=8.7 Hz), 6.11 (s, 2H, NH2), 3.81
(s, 3H), 3.78 (s, 3H); 13C NMR (75MHz, DMSO d-6) d
159.5, 159.0, 151.4 (C-2), 139.8 (C-5), 137.7 (C-3), 136.4
(C-6), 129.9, 129.6, 129.5, 126.2, 114.0, 55.2, 55.1; EIMS
m/z 307 (M+). Anal. calcd for C18H17N3O2: C, 70.34; H,
5.57; N, 13.67. Found: C, 70.16; H, 5.56; N, 13.53.
ethyl acetate/cyclohexane, 1:1): mp 82.2 ꢀC; H NMR
1
(300 MHz, CDCl3) d 8.34 (s, 1H, H-6), 7.88 (d, 2H,
J=8.8 Hz), 7.34 (d, 1H, J=1.7 Hz), 7.32 (m, 1H), 6.97
(d, 2H, J=8.8 Hz), 6.92 (d, 1H, J=7.7 Hz), 6.02 (s, 2H),
4.85 (s, 2H, NH2), 3.84 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 160.0, 150.4 (C-2), 148.5, 143.0 (C-5), 139.3
(C-3), 136.6 (C-6), 131.6, 129.9, 127.1, 122.2, 114.3,
109.3, 108.8, 101.6, 55.5; EIMS m/z 321 (M+). Anal.
calcd for C18H15N3O3+0.1 H2O: C, 66.91; H, 4.71; N,
13.01. Found: C, 66.86; H, 4.61; N, 12.88.
General procedure for the deprotection of 4-methoxy-
phenyl group (method A)
A stirred solution of 4 (or 6) (1 equiv), sodium ethan-
ethiolate (4 equiv or 8 equiv) in DMF (2 mL/mmol 4 or
4 mL/mmol 6) was heated, under argon atmosphere,
at 100 ꢀC for 24 h. Ethyl acetate (25 mL/mmol) and
2-Amino-3-(30,40-dimethoxyphenyl)-5-(40-methoxyphenyl)-
1,4-pyrazine (6c). 6c was obtained from 41 mg of Pd
(II), 55 mg of dppb, 600 mg (2.14 mmol) of 5a, 429 mg of