powder that was triturated in Et2O. The solid was collected and
recrystallized from water to give the hydrochloride of 4 (13 g),
mp >200 ЊC (decomp.). A mixture of this hydrochloride (13 g,
74.9 mmol) and phenylacetonitrile (11.5 g, 98.2 mmol) in
2-ethoxyethanol (100 cm3) was treated with a solution of
NaOMe (5.60 g, 104 mmol) in 2-ethoxyethanol (100 cm3). The
resultant mixture was stirred under reflux for 3 h, cooled, and
concentrated. The residue was triturated in cold water contain-
ing a few drops of dilute aq. NaOH, and the resultant solids
were collected by filtration, washed with cold water and air
dried to leave 18.4 g of crude product. Further purification by
double crystallization afforded pure diamine 5a (10.5 g, 59%),
mp 200–201 ЊC (from EtOH) (Found: C, 71.4; H, 4.9; N, 24.0.
C14H12N4 requires C, 71.2; H, 5.1; N, 23.7%); δH([2H6]DMSO)
8.43 (1 H, s, 5-H), 7.65 (1 H, s, 4-H), 7.48 (4 H, m, 2Ј,3Ј,5Ј,6Ј-
H), 7.40 (1 H, m, 4Ј-H), 6.31 (1 H, s, 8-H), 6.26 (2 H, br s,
2-NH2), 5.91 (2 H, br s, 7-NH2); δC([2H6]DMSO) 159.59, 158.30
(2 s, 2,7-C), 152.64 (s, 8a-C), 150.37 (d, 5-C), 137.59 (s, 1Ј-C),
136.01 (d, 4-C), 128.88, 128.60 (2 × 2 C, 2 d, 2Ј,3Ј,5Ј,6Ј-C),
127.51 (d, 4Ј-C), 120.96 (s, 3-C), 113.52 (s, 4a-C), 95.54 (d, 8-C).
5-C), 148.29 (s, 7-C), 136.36 (s, 1Ј-C), 135.59 (d, 4-C), 129.02,
128.54 (2 × 2 C, 2 d, 2Ј,3Ј,5Ј,6Ј-C), 128.32 (d, 4Ј-C), 126.49 (s,
3-C), 118.90 (s, 4a-C), 116.58 (d, 8-C); m/z (HREIMS)
257.0529, 255.0555 (Mϩ, C14H10ClN3 requires 257.0534,
255.0563).
Further elution with 5–10% MeOH–CH2Cl2 gave 2-amino-8-
chloro-3-phenyl-1,6-naphthyridin-7(6H)-one 16a (58 mg, 5%),
mp 318–321 ЊC (from MeOH–CH2Cl2–hexane) (Found: C,
61.8; H, 3.4; N, 15.6. C14H10ClN3O requires C, 61.9; H, 3.7;
N, 15.5%); δH([2H6]DMSO) 12.29 (1 H, br s, NH), 8.14 (1 H, s,
5-H), 7.66 (1 H, s, 4-H), 7.49 (2 H, t, J 7.3, 3Ј,5Ј-H), 7.43 (3 H,
m, 2Ј,4Ј,6Ј-H), 7.00 (2 H, br s, NH2); m/z (HREIMS) 273.0481,
271.0504 (Mϩ, C14H10ClN3O requires 273.0483, 271.0512).
Further elution with 10–12% MeOH–CH2Cl2 gave 2-amino-
3-phenyl-1,6-naphthyridin-7(6H)-one 14a (187 mg, 19%),
mp 270–276 ЊC (decomp.) (from MeOH–CH2Cl2–hexane)
(Found: C, 68.7; H, 4.9; N, 17.1. C14H11N3Oؒ0.5H2O requires
C, 68.3; H, 4.9; N, 17.1%); δH([2H6]DMSO) 11.37 (1 H, br s,
NH), 8.23 (1 H, s, 5-H), 7.64 (1 H, s, 4-H), 7.49 (2 H, t,
J 7.2, 3Ј,5Ј-H), 7.42 (3 H, m, 2Ј,4Ј,6Ј-H), 6.59 (2 H, br s, NH2),
6.13 (1 H, s, 8-H); δC([2H6]DMSO) 163.03 (s, 7-C), 159.05 (s,
2-C), 154.75 (s, 8a-C), 142.57 (br d, 5-C), 136.87 (s, 1Ј-C),
136.09 (d, 4-C), 128.89, 128.57 (2 × 2 C, 2 d, 2Ј,3Ј,5Ј,6Ј-C),
127.83 (d, 4Ј-C), 122.91 (s, 3-C), 111.69 (s, 4a-C), 100.63 (d,
8-C); m/z (HREIMS) 237.0903 (Mϩ, C14H11N3O requires
237.0902).
3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamine 5c
3,5-Dimethoxyphenylacetonitrile (5.80 g, 32.8 mmol) and 41
(3.90 g, 28.5 mmol) were added to a solution of sodium (0.69 g,
30.0 mmol) dissolved in 2-ethoxyethanol (30 cm3), then the
mixture was stirred under reflux for 30 min. The cooled solution
was treated with ice–aqueous NaHCO3 and extracted with
EtOAc (12 × 200 cm3). The extracts were evaporated to dryness
and the residue was then chromatographed on silica gel. Elu-
tion with 0–2% MeOH–CH2Cl2 gave minor impurities, then
elution with 3–7% MeOH–CH2Cl2 gave the diamine 5c (8.06 g,
96%), mp 229–232 ЊC (from MeOH–CHCl3–light petroleum)
(Found: C, 63.7; H, 5.3; N, 18.3. C16H16N4O2ؒ0.25H2O requires
C, 63.9; H, 5.5; N, 18.6%); δH([2H6]DMSO) 8.41 (1 H, s, 5-H),
7.67 (1 H, s, 4-H), 6.59 (2 H, d, J 2.2, 2Ј,6Ј-H), 6.52 (1 H, t,
J 2.2, 4Ј-H), 6.31 (2 H, br s, 2-NH2), 6.29 (1 H, s, 8-H), 5.90
(2 H, br s, 7-NH2), 3.79 (6 H, s, 2 × OCH3); δC([2H6]DMSO)
160.63 (2 C, s, 3Ј,5Ј-C), 159.58, 158.14 (2 s, 2,7-C), 152.62 (s,
8a-C), 150.36 (d, 5-C), 139.50 (s, 1Ј-C), 135.75 (d, 4-C), 120.86
(s, 3-C), 113.31 (s, 4a-C), 106.52 (2 C, d, 2Ј,6Ј-C), 99.70 (d,
4Ј-C), 95.49 (d, 8-C), 55.16 (2 C, q, 2 × OCH3).
Diazotization of 3-(2,6-dichlorophenyl)-1,6-naphthyridine-2,7-
diamine 5b
(a) In HCl. A solution of 5b1,6 (249 mg, 0.816 mmol) in 37%
HCl (10 cm3) at 0 ЊC was saturated with gaseous HCl, then
treated with solid NaNO2 (0.45 g, 6.52 mmol) and stirred at
0 ЊC for 4 h, then kept at Ϫ20 ЊC for 2 days. The resulting mixture
was neutralized with solid Na2CO3–ice, keeping the temperature
below 0 ЊC, and extracted with EtOAc (3 × 100 cm3). The sol-
vent was removed, then chromatography of the residue on silica
gel, eluting with 20% light petroleum–CH2Cl2 and CH2Cl2, gave
firstly 7,8-dichloro-3-(2,6-dichlorophenyl)-1,6-naphthyridin-2-
amine 15b (9 mg, 3%), mp 251–253.5 ЊC (from MeOH–water);
δH([2H6]DMSO) 8.72 (1 H, s, 5-H), 8.08 (1 H, s, 4-H), 7.64 (2 H,
d, J 8.2, 3Ј,5Ј-H), 7.53 (1 H, dd, J 8.9 and 7.4, 4Ј-H), 7.40 (2 H,
br s, NH2); δC([2H6]DMSO) 159.10 (s, 2-C), 149.47 (s, 8a-C),
148.43 (d, 5-C), 146.55 (s, 7-C), 137.48 (d, 4-C), 134.67 (2 C, s,
2Ј,6Ј-C), 132.98 (s, 1Ј-C), 131.41 (d, 4Ј-C), 128.71 (2 C, d, 3Ј,5Ј-
C), 122.48 (s, 3-C), 121.94 (s, 8-C), 118.87 (s, 4a-C); m/z
(HREIMS) 360.9339, 358.9368, 356.9396 (Mϩ, C14H7Cl4N3
requires 360.9335, 358.9365, 356.9394).
Further elution with 0.5% MeOH–CH2Cl2 gave 7-chloro-3-
(2,6-dichlorophenyl)-1,6-naphthyridin-2-amine 13b (129 mg,
49%), mp 216–218 ЊC (from CH2Cl2–light petroleum) (Found:
C, 51.7; H, 2.2; N, 13.0; Cl, 33.1. C14H8Cl3N3 requires C, 51.8;
H, 2.5; N, 13.0; Cl, 32.8%); δH([2H6]DMSO) 8.77 (1 H, s, 5-H),
8.00 (1 H, s, 4-H), 7.64 (2 H, d, J 8.0, 3Ј,5Ј-H), 7.52 (1 H, dd,
J 8.9 and 7.4, 4Ј-H), 7.39 (1 H, s, 8-H), 7.00 (2 H, br s, NH2);
δC([2H6]DMSO) 158.73 (s, 2-C), 153.10 (s, 8a-C), 151.06 (d,
5-C), 148.80 (s, 7-C), 136.90 (d, 4-C), 134.71 (2 C, s, 2Ј,6Ј-C),
133.36 (s, 1Ј-C), 131.22 (d, 4Ј-C), 128.64 (2 C, d, 3Ј,5Ј-C), 121.94
(s, 3-C), 118.14 (s, 4a-C), 116.70 (d, 8-C).
Diazotization of 3-phenyl-1,6-naphthyridine-2,7-diamine 5a
A solution of 5a (1.00 g, 4.24 mmol) in 37% HCl (10 cm3) at
Ϫ15 ЊC was saturated with gaseous HCl, then treated with solid
NaNO2 (2.30 g, 33.3 mmol) and stirred at Ϫ10 ЊC for 5 h, then
at 20 ЊC for 3 h, and kept at 4 ЊC for 2 days. The resulting mixture
was cooled to Ϫ15 ЊC and neutralized with solid Na2CO3–ice,
keeping the temperature below Ϫ10 ЊC. The resulting solid
(0.98 g) was collected by filtration and washed with water.
Extraction of the filtrate with EtOAc (3 × 100 cm3) and
removal of the solvent gave further material, which was com-
bined with the above solid. Chromatography on silica gel, elut-
ing with CH2Cl2, gave firstly 7,8-dichloro-3-phenyl-1,6-naph-
thyridin-2-amine 15a (10 mg, 1%), mp 271–274 ЊC (from
MeOH–CH2Cl2–hexane); δH([2H6]DMSO) 8.72 (1 H, s, 5-H),
8.04 (1 H, s, 4-H), 7.51 (5 H, m, 2Ј,3Ј,4Ј,5Ј,6Ј-H), 7.30 (2 H, br s,
NH2); δC([2H6]DMSO) 159.81 (s, 2-C), 148.86 (s, 8a-C), 148.47
(d, 5-C), 146.03 (s, 7-C), 136.08 (d, 4-C), 135.94 (s, 1Ј-C), 129.20
(2 C, d, 3Ј,5Ј-C), 128.62 (3 C, d, 2Ј,4Ј,6Ј-C), 127.05 (s, 3-C),
121.90 (s, 8-C), 119.73 (s, 4a-C); m/z (HREIMS) 291.0130,
289.0163 (Mϩ, C14H9Cl2N3 requires 291.0144, 289.0174).
Further elution with 1% MeOH–CH2Cl2 gave crude 8-chloro-
3-(2,6-dichlorophenyl)-1,6-naphthyridine-2,7-diamine 17 (8.5
mg, 3%) as an oil; δH([2H6]DMSO) 8.40 (1 H, s, 5-H), 7.73 (1 H,
s, 4-H), 7.60 (2 H, d, J 8.0, 3Ј,5Ј-H), 7.47 (1 H, dd, J 8.7 and 7.5,
4Ј-H), 6.75 (2 H, br s, NH2), 6.34 (2 H, br s, NH2); m/z
(HREIMS) 341.9847, 339.9871, 337.9894 (Mϩ, C14H9Cl3N4
requires 341.9834, 339.9863, 337.9893).
Further elution with 4% MeOH–CH2Cl2 gave recovered 5b
(2.4 mg, 1%).
Further elution with 4–5% MeOH–CH2Cl2 gave 2-amino-8-
chloro-3-(2,6-dichlorophenyl)-1,6-naphthyridin-7(6H)-one 16b
Further elution with 1–2% MeOH–CH2Cl2 gave 7-chloro-3-
phenyl-1,6-naphthyridin-2-amine 13a (660 mg, 61%), mp 206–
208 ЊC (from MeOH–CH2Cl2–hexane) (Found: C, 65.9; H, 3.8;
N, 16.7. C14H10ClN3 requires C, 65.8; H, 3.9; N, 16.4%);
δH([2H6]DMSO) 8.77 (1 H, s, 5-H), 7.98 (1 H, s, 4-H), 7.51 (5 H,
m, 2Ј,3Ј,4Ј,5Ј,6Ј-H), 7.39 (1 H, s, 8-H), 6.94 (2 H, br s, NH2);
δC([2H6]DMSO) 159.39 (s, 2-C), 152.43 (s, 8a-C), 151.00 (d,
1848
J. Chem. Soc., Perkin Trans. 1, 2000, 1843–1852