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J. C. Gonzalez-Gomez et al. / Tetrahedron 61 (2005) 4805–4810
4809
125.33, 119.24 (CH), 106.36 (CH). EI-MS m/z (%) 186
(MC, 100), 185 (87), 157 (26), 129 (22). HRMS-EI Calcd
for C11H6O3: 186.0317. Found: 186.0314.
155.18, 154.69, 152.45, 143.26, 132.96, 130.06, 128.99
(CH), 121.13 (CH), 113.09, 53.49 (CH3). HRMS-EI Calcd
for C21H10N4O9: 462.0448. Found: 462.0444.
3.1.8. Pyridazino[3,4-c]psoralen-2-carboxylic acid,
methyl esther (9) and 5,9-dioxo-benzo[1,2-b;5,6-
b0]dipyran-bis[3,4-c]pyridazine-2,12-di(carboxylic acid,
methyl esther) (10). A mixture of compound 7 (128 mg,
0.81 mmol) and 3,6-dimethoxycarbonyl-1,2,4,5-tetrazine
(134 mg, 0.68 mmol) in dioxane (3 mL) was heated under
reflux for 2 h until the red colour of the tetrazine had
disappeared. The mixture was allowed to reach room
temperature. The precipitate was filtered off and washed
with fresh dioxane (2!1 mL) and diethyl ether (2!1 mL)
to give 9 as a pure yellow solid (131 mg, 65%); mp
O350 8C (dec 220 8C). IR (KBr) 1760, 1715, 1580, 1455,
1262, 1131 cmK1. 1H NMR (DMSO-d6) d 9.12 (s, 1H), 9.00
(s, 1H), 8.16 (d, 1H, JZ2.30 Hz, H9), 7.84 (s, 1H, H7), 7.10
(d, 1H, JZ2.30 Hz, H10), 4.06 (s, 3H, OMe). EI-MS m/z (%)
296 (MC, 76), 238 (100), 210 (44), 183 (32). HRMS-EI
Calcd for C15H8N2O5: 296.0433. Found: 296.0433.
3.3. 7-{[2-(Dimethylamino)ethyl]aminomethyl}-1,4-
dihydropyridazino[3,4-c]psoralen-2-carboxylic acid,
methyl esther (13) and 7-hydroxymethyl-1,4-dihydro-
pyridazino[3,4-c]psoralen-2-carboxylic acid, methyl
esther (14)
To a suspension of compound 11 (65 mg, 0.2 mmol) in
DMF (3 mL)/AcOH (0.2 mL) was added N,N-dimethyl-
ethylenediamine (0.055 mL, 0.5 mmol) followed by
NaCNBH3 (38 mg, 0.6 mmol). The mixture was stirred at
room temperature for 7 h. The reaction was quenched by
adding 1 M HCl (1.5 mL) at 0 8C and the reaction mixture
was concentrated until dryness under vacuum. Saturated
solution of NaHCO3 (5 mL) was added to the residue and
diluted with H2O (10 mL), and the resulting mixture was
extracted with CH2Cl2 (6!10 mL). The organic phases
were combined, washed with brine (10 mL) and dried over
Na2SO4. After filtration and evaporation of organic solvent,
the crude mixture was purified by flash chromatography (9:1
CH2Cl2/EtOH, then 9:1:0.1 CH2Cl2/EtOH/NH4OH) to give
13 (52 mg, 65%) and 14 (20 mg, 30%).
The filtrate was concentrated under vacuum and glacial
AcOH (5 mL) was added to the residue. The mixture was
heated under reflux for 30 min and then cooled to room
temperature. The off-white precipitate was filtered off and
washed with AcOH (1 mL) and diethyl ether (2!1 mL) to
give pure 10 (22 mg, 15%); mp O350 8C (dec 250 8C). IR
(KBr) 1774 (broad), 1628, 1583, 1282, 1162, 1121,
3.3.1. Compound 13. Mp O350 8C (dec 180 8C). IR (KBr)
3363, 1726, 1601, 1435, 1387, 1349, 1169, 1101, 1046 cmK1
.
1H NMR (CDCl3) d 8.45 (s, 1H exch., NH), 7.75 (d, 1H, JZ
2.20 Hz, H9), 7.55 (s, 1H, H11), 6.85 (d, 1H, JZ2.20 Hz,
H10), 4.35 (s, 2H, ArCH2N), 3.95 (s, 3H, OCH3), 3.80 (s,
2H, H1), 2.75 (t, 2H, JZ6.20 Hz), 2.45 (t, 2H, JZ6.20 Hz),
2.15 (s, 6H, NMe2), 2.00 (s, 1H exch., NH). 13C NMR
(CDCl3) d 164.71, 155.08, 154.30, 146.93 (CH), 146.55,
131.23, 124.85, 119.95, 119.53, 114.92, 113.15 (CH),
112.66, 106.68 (CH), 58.91 (CH2), 52.80 (CH3), 46.77
(CH2), 45.38 (CH3), 41.94 (CH2), 21.45 (CH2). EI-MS m/z
(%) 398 (MC, 6), 339 (17), 311 (77), 310 (27), 196 (21), 171
(25), 170 (19), 140 (18), 58 (100). HRMS-EI Calcd for
C20H22N4O5: 398.1590. Found: 398.1586.
1050 cmK1 1H NMR (DMSO-d6) d 9.75 (s, 1H, H14),
.
9.50 (s, 2H, H1CH13), 7.73 (s, 1H, H7), 4.11 (s, 6H, 2OMe).
13C NMR (DMSO-d6) d 163.92, 156.06, 155.22, 152.40,
143.56, 133.35, 125.01 (CH), 120.96 (CH), 113.04, 106.02
(CH), 53.52 (OCH3). HRMS-EI Calcd for C20H10N4O8:
434.0499. Found: 434.0494.
3.2. 7-Formyl-pyridazino[3,4-c]psoralen-2-carboxylic
acid, methyl esther (11) and 7-formyl-5,9-dioxo-
benzo[1,2-b;5,6-b0]dipyran-bis[3,4-c]pyridazine-2,12-
di(carboxylic acid, methyl esther) (12)
These compounds were prepared from 8 (270 mg,
1.45 mmol) in an analogous manner to 9 and 10 from 7,
but using 6:1 Dioxane/AcOH (10 mL) as solvent and
heating under reflux for 8 h.
3.3.2. Compound 14. Mp O350 8C (dec 205 8C). IR (KBr)
3482, 3337, 1705 (broad), 1595, 1444, 1349, 1184,
1
1109 cmK1. H NMR (DMSO-d6) d 10.90 (s, 1H exch.,
NH), 8.12 (d, 1H, JZ2.20 Hz, H9), 7.77 (s, 1H, H11), 7.07
(d, 1H, JZ2.20 Hz, H10), 5.31 (t, 1H exch., JZ5.40 Hz,
OH), 4.90 (d, 2H, JZ5.40 Hz, CH2O), 3.78 (s, 3H, OCH3),
3.74 (s, 2H, H1). 13C NMR (DMSO-d6) d 164.55, 154.37,
1543.12, 147.56 (CH), 145.63, 129.87, 124.46, 119.88,
119.14, 114.85, 114.18 (CH), 112.61, 106.97 (CH), 51.92
(CH2), 51.77 (CH3), 21.07 (CH2). EI-MS m/z (%) 328 (MC,
29), 310 (26), 268 (53), 240 (49), 222 (100), 196 (74), 140
(44). HRMS-EI Calcd for C16H12N2O6: 328.0695. Found:
328.0699.
3.2.1. Compound 11. Yield 273 mg (70%); mp O350 8C
(dec 225 8C). IR (KBr) 1739 (broad), 1693, 1587, 1341,
1
1267, 1170, 1141 cmK1. H NMR (DMSO-d6) d 10.74 (s,
1H, CHO), 9.37 (s, 1H, H11), 9.21 (s, 1H, H1), 8.33 (d, 1H,
JZ2.20 Hz, H9), 7.20 (d, 1H, JZ2.20 Hz, H10), 4.08 (s, 3H,
OMe). 13C NMR (DMSO-d6) d 185.55 (CHO), 163.63,
155.64, 153.95, 152.26, 151.58, 149.60 (CH), 142.72,
133.99, 125.82, 125.12 (CH), 120.64 (CH), 111.56,
109.20, 106.57 (CH), 53.37 (CH3). EI-MS m/z (%) 324
(MC, 38), 266 (84), 237 (16), 210 (100), 183 (27). HRMS-
EI Calcd for C16H8N2O6: 324.0390. Found: 324.0385.
Acknowledgements
3.2.2. Compound 12. Yield 15 mg (5%); mp O350 8C (dec
285 8C). IR (KBr) 1778, 1742, 1719, 1695, 1599, 1279,
We would like to thank to Dr. David E. Nichols for his
kindly support giving experimental details for the oxidation
of tetrahydro benzodifurans. J. C. G. G. is indebted with the
University of Santiago de Compostela for a grant.
1
1129 cmK1. H NMR (DMSO-d6) d 10.69 (s, 1H, CHO),
9.95 (s, 1H, H14), 9.57 (s, 2H, H1CH13), 4.11 (s, 6H,
2OMe). 13C NMR (DMSO-d6) d 185.71 (CHO), 163.81,