The Journal of Organic Chemistry
Article
g, 0.45 mmol, 46%) as white crystals and 15b′ (58 mg, 0.15 mmol,
15%) as a pale yellow solid. 1,4-Bis(phenylmethyl)-5,8-dichloro-
1,2,3,4-tetrahydropyrazino[2,3-d]pyridazine (15b): Mp 189.0−191.5
°C; Rf = 0.29 (AcOEt/CH2Cl2 = 1:25). 1H NMR (400 MHz, CDCl3):
δ = 7.47−7.31 (m, 10H), 4.43 (s, 4H), 2.89 (s, 4H). 13C NMR
(CDCl3, 100 MHz): δ = 148.0 (C), 136.1 (C), 136.0 (C), 128.4 (CH),
127.7 (CH), 127.7 (CH), 57.8 (CH2), 42.4 (CH2). IR: ν (cm−1) 3086,
3052, 3032, 2914, 2871, 2846, 1606, 1585, 1529, 1506, 1466, 1450,
1441, 1392, 1357, 1319, 1300, 1238, 1188, 1157, 1117, 1072, 1028,
1014, 991, 975, 939, 928, 895, 845, 791, 750, 727, 694, 669, 631, 604,
559. HR-MS (ESI Positive): Calcd for C20H18Cl2N4Na ([M + Na]+)
m/z 407.0794, found 407.0801. Anal. Calcd for C20H18Cl2N4: C,
62.35%; H, 4.71%; N, 14.54%. Found: C61.96%; H, 4.72%; N, 14.39%.
5,8-Bis(phenylmethyl)-3,4-dichloro-5,6,7,8-tetrahydropyrazino[2,3-c]-
pyridazine (15b′): Mp 193.0−194.0 °C; Rf = 0.48 (AcOEt/CH2Cl2 =
1:25). 1H NMR (CDCl3) δ = 7.44−7.20 (m, 10H), 4.93 (s, 2H), 4.50
(s, 2H), 3.21−3.14 (m, 2H), 3.12−3.05 (m, 2H). 13C NMR (CDCl3)
δ = 151.4 (C), 146.0 (C), 137.0 (C), 136.6 (C), 133.8 (C), 128.7
(CH), 128.6 (CH), 128.3 (CH), 127.8 (CH), 127.6 (CH), 127.4
(CH), 119.5 (C), 57.0 (CH2), 52.0 (CH2), 45.7 (CH2), 42.3 (CH2).
IR: ν (cm−1) 3087, 3059, 3028, 2933, 2850, 1603, 1585, 1550, 1508,
1452, 1363, 1321, 1288, 1279, 1250, 1215, 1178, 1144, 1128, 1078,
1065, 1028, 991, 930, 847, 806, 733, 700, 627, 600, 543. HR-MS (ESI
Positive): Calcd for C20H19Cl2N4 ([M + H]+) m/z 385.0981, found
385.0982.
1,4-Bis(phenylmethyl)-1,2,3,4-tetrahydropyrazino[2,3-d]-
pyridazine (11b). A solution of 1,4-bis(phenylmethyl)-5,8-dichloro-
1,2,3,4-tetrahydropyrazino[2,3-d]pyridazine (0.54 g, 1.4 mmol) in dry
THF (20 mL) was added dropwise to a suspension of LiAlH4 (0.32 g,
8.5 mmol) in dry THF (25 mL) under N2 at 0 °C. The mixture was
stirred at 0 °C for 4 h. The excess LiAlH4 was quenched with water
and 15% NaOH aq at 0 °C. The reaction mixture was filtered, and the
filtered solid was washed with 15% NaOH aq, followed by THF and
Et2O. The organic solvents were distilled off and then the residue was
extracted with Et2O. The combined organic extracts were dried over
Na2SO4 and evaporated under vacuum, and the residue was purified by
alumina column chromatography (MeOH/CH2Cl2 = 30:1) to afford
11b (0.17 g, 0.45 mmol, 46%) as a pale yellow solid. Mp 154.0−157.0
°C; Rf = 0.26 (alumina, AcOEt/CH2Cl2 = 1:30). 1H NMR (400 MHz,
CDCl3) δ = 8.33 (s, 2H), 7.39−7.23 (m, 10H), 4.53 (s, 4H), 3.47 (s,
4H). 13C NMR (100 MHz, CDCl3) δ 136.1 (CH), 134.3 (C), 131.9
(C), 129.1 (CH), 127.9 (CH), 127.2 (CH), 53.9 (CH2), 46.4 (CH2).
IR: ν (cm−1) 3028, 2926, 2858, 2349, 1560, 1495, 1452, 1408, 1352,
1279, 1244, 1228, 1201, 1136, 1082, 1070, 1028, 1003, 891, 866, 733,
700, 663. HR-MS (ESI Positive): Calcd for C20H21N4 ([M + H]+) m/z
317.1761, found 317.1765. Anal. Calcd for C20H20N4: C, 75.92%; H,
6.37%; N, 17.71%. Found: C, 75.71%; H, 6.16%; N, 17.65%.
of N1,N2-dimethylethane-1,2-diamine (0.050 mL, 0.46 mmol) and
Et3N (0.19 mL, 1.4 mmol) in CH3CN (2 mL) was added at 0 °C. The
resulting mixture was stirred at the same temperature for 1 h and then
it was allowed to warm to rt and stirred overnight. The reaction
mixture was concentrated by reduced pressure, and then it was made
alkaline with Na2CO3 aq and extracted with AcOEt. The combined
organic extracts were dried over Na2SO4 and evaporated under
vacuum. Purification by silica gel column chromatography (AcOEt/
CH2Cl2 = 1:1) afforded 15a (62.9 mg, 0.27 mmol, 58%) as a white
solid. Mp 149.0−150.5 °C (lit. 143.5−146 °C).20 Rf = 0.53 (AcOEt/
CH2Cl2 = 1:1). 1H NMR (400 MHz, CDCl3) δ = 3.07 (s, 4H), 3.05 (s,
6H). 13C NMR (100 MHz, CDCl3) δ = 147.2 (C),136.4 (C), 136.0
(C), 46.5 (CH3), 43.3 (CH2). IR: ν (cm−1) 2924, 2877, 1516, 1493,
1458, 1419, 1404, 1362, 1331, 1308, 1242, 1215, 1138, 1115, 1076,
1038, 984, 891, 852, 810, 667, 621, 590, 540. HR-MS (APCI Positive):
Calcd for C8H11Cl2N4 ([M + H]+) m/z 233.0355, found 233.0357.
1,4-Dimethyl-1,2,3,4-tetrahydropyrazino[2,3-d]pyridazine (11a).
To a solution of 5,8-dichloro-1,4-dimethyl-1,2,3,4-tetrahydropyrazino-
[2,3-d]pyridazine (50 mg, 0.21 mmol) and 10% Pd/C in EtOH under
H2, Et3N (0.090 mL, 0.63 mmol) was added at room temperature, and
the resulting mixture was stirred overnight. The reaction mixture was
then filtered through Celite and washed with hot EtOH. After
removing the solvent, NaHCO3 aq was added, and the mixture was
extracted with CH2Cl2. The organic layer was dried over Na2SO4 and
evaporated under vacuum. Purification by alumina column chromatog-
raphy (MeOH/CH2Cl2 = 1:40) afforded 11a (21.8 mg, 0.13 mmol,
61%) as a pale yellow solid. Mp 132.0−134.5 °C; Rf = 0.31 (alumina,
1
MeOH/CH2Cl2 = 1:40). H NMR (400 MHz, CDCl3) δ = 8.23 (s,
2H), 3.40 (s, 4H), 2.94 (s, 6H). 13C NMR (100 MHz, CDCl3) δ =
134.1 (CH), 132.9 (C), 40.4 (CH3), 37.8 (CH2). IR: ν (cm−1) 2962,
2927, 1655, 1577, 1462, 1400, 1350, 1315, 1284, 1257, 1203, 1107,
1061, 1038, 899, 868, 798, 748, 640, 575. HR-MS (APCI Positive):
Calcd for C8H13N4 ([M + H]+) m/z 165.1135, found 165.1132. Anal.
Calcd for C8H12N4: C, 58.51; H, 7.37; N, 34.12. Found: C, 58.72%; H,
7.50%; N, 33.75%.
1,4-Diethyl-1,2,3,4-tetrahydropyrazino[2,3-d]pyridazine (11c)
and 5,8-Diethyl-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine (11c′).
Tetrachloropyridazine (1.0 g, 4.6 mmol) was dissolved in CH3CN (30
mL) under argon. To it, a solution of N1,N2-diethylethane-1,2-diamine
(0.66 mL, 4.6 mmol) and Et3N (1.9 mL, 14 mmol) in CH3CN (20
mL) was added at 0 °C. The resulting mixture was stirred at same
temperature for 1 h, and then it was allowed to warm to rt and stirred
overnight. The reaction mixture was concentrated by reduced pressure,
and then it was made alkaline with Na2CO3 aq and extracted with
AcOEt. The combined organic extracts were dried over Na2SO4 and
evaporated under vacuum to give a crude mixture of 5,8-dichloro-1,4-
diethyl-1,2,3,4-tetrahydropyrazino[2,3-d]pyridazine (15c) and 3,4-
dichloro-5,8-diethyl-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine
(15c′). To a solution of this crude product and 10% Pd/C in EtOH
under H2, Et3N (1.6 mL, 12 mmol) was added at room temperature,
and resulting mixture was stirred at 70 °C overnight. The reaction
mixture was filtered through Celite and washed with hot EtOH. After
removing the solvent, NaHCO3 aq was added, and then the mixture
was extracted with CH2Cl2. The organic layer was dried over Na2SO4
and evaporated under vacuum. Purification by alumina column
chromatography (MeOH/AcOEt = 1:10) afforded 11c (250 mg, 1.3
mmol, 28%) as a pale yellow solid and 11c′ (210 mg, 1.1 mmol, 24%)
as a pale yellow oil. 1,4-Diethyl-1,2,3,4-tetrahydropyrazino[2,3-d]-
pyridazine (11c): Mp 97.0−98.0 °C; Rf = 0.20 (alumina, MeOH/
AcOEt = 1:10). 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 2H), 3.40 (s,
4H), 3.39 (q, J = 7.1 Hz, 4H), 1.20 (t, J = 7.1 Hz, 6H). 13C NMR (100
MHz, CDCl3) δ 133.8 (CH), 131.3 (C), 45.1 (CH2), 44.3 (CH2), 10.6
(CH3). IR: ν (cm−1) 2974, 2933, 2875, 1655, 1562, 1498, 1477, 1454,
1412, 1377, 1350, 1277, 1230, 1180, 1113, 1090, 1067, 1047, 1028,
949, 895, 870, 793, 777, 754, 723, 631, 613, 563, 503. HR-MS (APCI
Positive): Calcd for C10H17N4 ([M + H]+) m/z 193.1448, found
193.1447. 5,8-Diethyl-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine
5,8-Bis(phenylmethyl)-5,6,7,8-tetrahydropyrazino[2,3-c]-
pyridazine (11b′). To a solution of 5,8-bis(phenylmethyl)-3,4-
dichloro-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine (0.21 g, 0.54
mmol) and 10% Pd/C (24 mg) in EtOH under H2, Et3N (0.20 mL,
1.4 mmol) was added at rt and stirred overnight. The reaction mixture
was filtered through Celite and washed with hot EtOH. After removal
of the solvent, NaHCO3 aq was added, and then the mixture was
extracted with CH2Cl2. The organic layer was dried over Na2SO4 and
evaporated under vacuum to afford 11b′ (0.16 mg, 0.50 mmol, 92%)
1
as a pale yellow oil. Rf = 0.23 (alumina, MeOH/CH2Cl2 = 1:10). H
NMR (400 MHz, CDCl3) δ = 8.21 (d, J = 5.4 Hz, 1H), 7.42−7.20 (m,
8H), 7.22 (d, J = 7.0 Hz. 2H), 6.22 (d, J = 5.4 Hz, 1H), 5.01 (s, 2H),
4.48 (s, 2H), 3.46 (dd, J = 5.4, 4.3 Hz, 2H), 3.37 (dd, J = 5.4, 4.3 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ = 149.0 (C), 144.2 (CH), 137.5
(CH), 135.4 (C), 134.3 (CH), 128.7 (CH), 128.3 (CH), 127.4 (CH),
127.0 (CH), 126.6 (CH), 102.4 (CH), 53.2 (CH2), 51.0 (CH2), 46.6
(CH2), 43.2 (CH2). IR: ν (cm−1) 3062, 2920, 2870, 2364, 1639, 1601,
1570, 1529, 1496, 1454, 1358, 1300, 1257, 1180, 1161, 1119, 1084,
1030, 887, 810, 748, 702, 660, 613, 575. HR-MS (ESI Positive): Calcd
for C20H21N4 ([M + H]+) m/z 317.1761, found 317.1765.
1
(11c′): Rf = 0.48 (alumina, MeOH/AcOEt = 1:10). H NMR (400
5,8-Dichloro-1,4-dimethyl-1,2,3,4-tetrahydropyrazino[2,3-d]-
pyridazine (15a).16 Tetrachloropyridazine (0.10 g, 0.46 mmol) was
dissolved in CH3CN (4 mL) under argon with stirring. To it a solution
MHz, CDCl3) δ = 8.18 (d, J = 5.5 Hz, 1H), 6.15 (d, J = 5.5 Hz, 1H),
3.73 (q, J = 7.1 Hz, 2H), 3.51−3.32 (m, 4H), 3.32 (q, J = 7.2 Hz, 4H),
I
J. Org. Chem. XXXX, XXX, XXX−XXX