M. F. Proença et al.
4.87 (s, 2 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 156.61, 4-{[7-(2-Hydroxyethyl)-8-imino-7,8-dihydropyrimido[5,4-d]pyrim-
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156.07, 154.78, 148.22, 138.60, 138.23, 128.48, 125.46, 123.47,
idin-4-yl]amino}benzonitrile (4k): Yield 0.93 mmol, 97%, m.p. 265–
266 °C (dec.). 1H NMR ([D6]DMSO, 300 MHz): δ = 10.09 (s, 1 H),
8.64 (s, 1 H), 8.51 (s, 1 H), 8.22 (d, J = 9.0 Hz, 2 H), 8.07 (s, 1 H),
7.80 (d, J = 9.0 Hz, 2 H), 5.00 (brs, 1 H), 4.07 (m, 2 H), 3.71 (m,
2 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 156.07, 154.76,
154.05, 149.21, 142.97, 138.83, 132.59, 127.79, 120.70, 118.91,
121.37 ppm. IR (Nujol mull): ν = 1644, 1603, 1579, 1557 cm–1.
˜
C12H11N7 (253.27): calcd. C 56.92, H 4.35, N 38.74; found: C
57.11, H 4.43, N 38.46.
2-(8-Anilino-4-iminopyrimido[5,4-d]pyrimidin-3(4H)-yl)ethanol (4b):
Yield 1.08 mmol, 73%, m.p. 228–230 °C. 1H NMR ([D6]DMSO,
300 MHz): δ = 9.61 (brs, 1 H), 8.52 (s, 1 H), 8.40 (s, 1 H), 8.04 (s,
1 H), 7.90 (d, J = 7.8 Hz, 2 H), 7.35 (t, J = 7.8 Hz, 2 H), 7.09 (t,
J = 7.8 Hz, 1 H), 4.99 (s, 1 H), 4.07 (m, 2 H), 3.71 (m, 2 H) ppm.
13C NMR ([D6]DMSO, 75 MHz): δ = 156.50, 155.10, 154.61,
149.06, 138.65, 138.31, 128.45, 125.49, 123.31, 121.24, 56.89,
104.60, 56.83, 50.02 ppm. IR (Nujol mull): ν = 2219, 1631, 1597,
˜
1555, 1515 cm–1. C15H13N7O (307.31): calcd. C 58.63, H 4.24, N
31.92; found: C 58.86, H 4.38, N 31.55.
General Procedure for the Reactions between 6-Cyanopurines 1 and
Ammonia
50.19 ppm. IR (Nujol mull): ν = 1633, 1599, 1573, 1555, 1520,
˜
Method A: A solution of 6-cyanopurine 1 in chloroform was kept
in a round-bottomed flask fitted with a serum cap and a magnetic
bar and stirred in an ice-salt bath. Ammonia was bubbled through
the reaction mixture for 1.5 h, and stirring at 4 °C was continued
until all the starting material was no longer present (TLC evi-
dence). The solvent was partially removed in the rotary evaporator
and the solid was filtered and washed several times with diethyl
ether.
1498 cm–1. C14H13N6O·0.25H2O (285.80): calcd. C 58.84, H 4.73,
N 29.42; found: C 58.75, H 5.05, N 29.17.
8-Imino-N-(4-methoxyphenyl)-7-phenyl-7,8-dihydropyrimido[5,4-d]-
pyrimidin-4-amine (4e): Yield 0.67 mmol, 86%, m.p. 242–243 °C.
1H NMR ([D6]DMSO, 300 MHz): δ = 9.65 (s, 1 H), 8.50 (s, 1 H),
8.45 (s, 1 H), 8.06 (s, 1 H), 7.77 (d, J = 8.7 Hz, 2 H), 7.55 (m, 4
H), 7.50 (m, 1 H), 6.93 (d, J = 8.7 Hz, 2 H), 3.75 (s, 3 H) ppm. 13
C
NMR ([D6]DMSO, 75 MHz): δ = 156.52, 156.06, 155.69, 155.21,
Method B: An aqueous solution of ammonia (25%, 7 molar equiv.)
was added to a suspension of 6-cyanopurine 1 in methanol, ethanol
or dichloromethane. The round-bottomed flask was fitted with a
serum cap and a magnetic bar and stirred at room temperature.
When TLC indicated that all the purine had been consumed, the
solvent was partially removed in the rotary evaporator and the solid
suspension was filtered and washed with ethanol and diethyl ether.
142.24, 138.75, 138.66, 131.49, 129.12, 128.46, 127.56, 124.62,
123.18, 113.61, 55.18 ppm. IR (Nujol mull): ν = 1634, 1608, 1584,
˜
1576, 1558, 1534, 1507 cm–1. C19H16N6O (344.37): calcd. C 66.28,
H 4.65, N 24.42; found: C 66.18, H 4.81, N 24.45.
4-Imino-N8-(4-methoxyphenyl)pyrimido[5,4-d]pyrimidine-3,8(4H)-di-
amine (4f): Yield 0.53 mmol, 91%, m.p. 197–198 °C. 1H NMR ([D6]-
DMSO, 300 MHz): δ = 9.58 (s, 1 H), 8.46 (s, 1 H), 8.33 (s, 1 H),
8.16 (s, 1 H), 7.76 (d, J = 9.0 Hz, 2 H), 6.92 (d, J = 9.0 Hz, 2 H),
5.78 (s, 2 H), 3.74 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz):
δ = 156.78, 156.35, 156.44, 155.44, 147.14, 134.09, 130.71, 127.94,
Reaction between 6-Cyanopurine 1a and Piperidine: Piperidine
(0.14 mL, 1.44 mmol) was added to a suspension of 6-cyanopurine
1a (0.15 g, 0.72 mmol) in methanol (5 mL). The solution was
heated at reflux for 21 h, after which the TLC indicated that all the
starting material had been consumed. White crystals were formed
on cooling and were filtered and washed with methanol and diethyl
ether. The product was identified as N-phenyl-8-(piperidin-1-yl)pyr-
imido[5,4-d]pyrimidin-4-amine (6a, 0.16 g, 0.52 mmol, 72 %).
Characterization: m.p. 105–108 °C (dec.). 1H NMR ([D6]DMSO,
300 MHz): δ = 9.92 (s, 1 H), 8.56 (s, 1 H), 8.55 (s, 1 H), 7.99 (d, J
= 7.5 Hz, 2 H), 7.31 (t, J = 7.5 Hz, 2 H), 7.10 (t, J = 7.5 Hz, 1 H),
124.03, 113.71, 55.28 ppm. IR (Nujol mull): ν = 1640, 1619, 1606,
˜
1579, 1561, 1535, 1510 cm–1. C13H13N7O (283.29): calcd. C 55.12,
H 4.59, N 34.63; found: C 55.26, H 4.85, N 34.59.
4-[(8-Imino-7-phenyl-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)ami-
no]benzonitrile (4h): Yield 0.41 mmol, 60%, m.p. above 274–275 °C
1
(dec.). H NMR ([D6]DMSO, 300 MHz): δ = 10.22 (s, 1 H), 8.69
(s, 1 H), 8.59 (s, 1 H), 8.24 (d, J = 9.0 Hz, 2 H), 8.11 (s, 1 H), 7.82
(d, J = 9.0 Hz, 2 H), 7.55 (m, 5 H) ppm. 13C NMR([D6]DMSO,
75 MHz): δ = 156.23, 155.82, 154.72, 147.80, 143.06, 139.70,
138.54, 132.71, 129.14, 128.55, 127.56, 120.91, 119.03, 104.74 ppm.
1
4.35 (brs, 4 H), 1.67 (m, 6 H) ppm. H NMR (CDCl3, 300 MHz):
δ = 9.03 (s, 1 H), 8.62 (s, 1 H), 8.53 (s, 1 H), 7.88 (d, J = 7.5 Hz,
2 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.15 (t, J = 7.5 Hz, 1 H), 4.40 (brs,
4 H), 1.77 (brs, 6 H) ppm. 13C NMR([D6]DMSO, 75 MHz): δ =
157.45, 156.95, 153.65, 151.56, 138.55, 134.37, 133.07, 128.51,
IR (Nujol mull): ν = 2229, 1630, 1592, 1581, 1534, 1515 cm–1
.
˜
C19H13N7 (339.36): calcd. C 66.38, H 3.93, N 28.53; found: C
66.48, H 4.03, N 28.70.
123.55, 121.11, 48.07 (br), 26.00, 24.16 ppm. IR (Nujol mull): ν
˜
4-[(7-Amino-8-imino-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)ami-
no]benzonitrile (4i): Yield 1.06 mmol, 99 %, m.p. above 350 °C
= 1604, 1551, 1518 cm–1. HRMS: calcd. for C17H19N6 [M + H]+
307.1671; found: 307.1668.
1
(dec.). H NMR ([D6]DMSO/TFA, 300 MHz): δ = 10.78 (s, 1 H),
Reaction between 6-(Methoxyformimidoyl)purine 3 and Ethanol-
amine: Ethanolamine (0.08 mL, 1.34 mmol) was added to a suspen-
sion of 6-methoxyformimidoylpurine 3 (0.23 g, 0.89 mmol) in
methanol (2 mL). Sulfuric acid (50 µL) was added and the suspen-
sion was stirred at room temperature until the starting material was
no longer present (15 d). The suspension was filtered and washed
with methanol and diethyl ether, and the solid was identified as a
mixture of 4b and 6b in a 1:2 molar ratio (0.23 g, 8.81 mmol, 91%).
Characterization of 2-[(8-anilinopyrimido[5,4-d]pyrimidin-4-yl)-
amino]ethanol 6b: 1H NMR ([D6]DMSO, 300 MHz): δ = 9.93 (brs,
1 H), 8.60 (s, 1 H), 8.53 (s, 1 H), 8.24 (brs, 1 H), 7.90 (d, J =
8.1 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2 H), 7.11 (t, J = 7.5 Hz, 1 H),
4.86 (brs, 1 H), 3.61 (m, 4 H) ppm.
10.63 (s, 1 H), 10.08 (s, 1 H), 8.89 (s, 1 H), 8.72 (s, 1 H), 8.24 (d,
J = 8.7 Hz, 2 H), 7.87 (d, J = 8.7 Hz, 2 H), 6.80 (s, 2 H) ppm. H
NMR ([DMSO, 300 MHz): δ = 10.13 (s, 1 H), 8.65 (s, 1 H), 8.48
(s, 1 H), 8.22 (s, 1 H), 8.23 (d, J = 8.7 Hz, 2 H), 7.80 (d, J = 8.7 Hz,
2 H), 6.82 (s, 2 H) ppm. 13C NMR ([D6]DMSO/TFA, 75 MHz): δ
= 156.57, 156.44, 155.59, 147.69, 142.45, 134.81, 132.96, 128.35,
1
121.93, 119.06, 106.04 ppm. IR (Nujol mull): ν = 2221, 1642, 1601,
˜
1553, 1519 cm–1. C13H10N8 (278.28): calcd. C 56.12, H 3.60, N
40.28; found: C 56.19, H 3.77, N 40.28.
4-({8-Imino-7-[(4-methoxyphenyl)amino]-7,8-dihydropyrimido[5,4-d]-
pyrimidin-4-yl}amino)benzonitrile (4j): Yield 0.47 mmol, 38%. 1H
NMR ([D6]DMSO, 300 MHz): δ = 10.25 (brs, 1 H), 8.89 (s, 1 H),
8.66 (s, 1 H), 8.57 (s, 1 H), 8.29 (s, 1 H), 8.23 (d, J = 7.5 Hz, 2 H),
7.82 (d, J = 7.5 Hz, 2 H), 6.78 (m, 4 H), 3.66 (s, 3 H) ppm. IR Reaction between 6-Cyanopurine 1c and (4-Methoxyphenyl)hydra-
(Nujol mull): ν = 2215, 1641, 1605, 1557, 1525 cm–1.
zine: The hydrochloride salt of (4-methoxyphenyl)hydrazine (1.50 g,
˜
1330
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Eur. J. Org. Chem. 2007, 1324–1331