Synthesis and convenient functionalisation of pyridazinofurocoumarins: Nitrogenated isosters of potent DNA inhibitors

Article abstract of DOI:10.1016/j.tet.2003.08.051

Pyridazino[3,4-h]psoralens and pyridazino[3,4-j]angelicins are prepared in good yield from resorcinols through a direct, easy and generally applicable synthetic route. The key step in this route is the inverse electron-demand Diels-Alder reaction between linear or angular furocoumarins and 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine to give the dicarboxymethylated tetracycles. The ester group in the peri position with respect to the oxygen in the furan ring can be regioselectively transformed to give primary or secondary amides. Similarly, the two ester groups in the tetracycle can be transformed in a high-efficiency process to give bis-amides that can be either symmetrical (from the same amine) or unsymmetrical (from two different amines).

Full text of DOI:10.1016/j.tet.2003.08.051

Tetrahedron 59 (2003) 8171–8176
Synthesis and convenient functionalisation of
pyridazinofurocoumarins: nitrogenated isosters of
potent DNA inhibitors
*
´ ´ ´
Jose Carlos Gonzalez-Gomez, Lourdes Santana and Eugenio Uriarte
´ ´
Departamento de Quımica Organica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Received 3 June 2003; revised 11 August 2003; accepted 20 August 2003
Abstract—Pyridazino[3,4-h]psoralens and pyridazino[3,4-j]angelicins are prepared in good yield from resorcinols through a direct, easy and
generally applicable synthetic route. The key step in this route is the inverse electron-demand Diels–Alder reaction between linear or angular
furocoumarins and 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine to give the dicarboxymethylated tetracycles. The ester group in the peri
position with respect to the oxygen in the furan ring can be regioselectively transformed to give primary or secondary amides. Similarly, the
two ester groups in the tetracycle can be transformed in a high-efficiency process to give bis-amides that can be either symmetrical (from the
same amine) or unsymmetrical (from two different amines).
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Furocoumarins form a group of natural or synthetic
compounds that are of great pharmacological interest. One
of the most important applications of these compounds is in
the field of photochemotherapy, where furocoumarins are
capable of undergoing photoaddition with thymine units
present in DNA. However, the most effective compounds in
this class are associated with side-effects, mainly related to
their ability to stabilize bridging bonds between the strands
of the DNA helix.1 One of the most promising strategies
to obtain monofunctional furocoumarins efficiently
involves incorporating one of the reactive double bonds in
a benzene nucleus by forming benzofurocoumarins
(Chart 1). This approach results in molecules that have a
high propensity for intercalation and photoreaction with
DNA and also helps to overcome some of the negative
phototoxic effects.2,3
Chart 1. Tetracyclic skeleton of a benzo[j]angelicin I and a benzo[h]-
psoralen II.
demand Diels–Alder reactions between a furocoumarin and
the particularly reactive compound 3,6-bis(trifluoromethyl)-
1,2,4,5-tetrazine.5 However, for the current target it is
necessary to easily and conveniently functionalise one or
both positions adjacent to the nitrogen atoms of the
pyridazine ring. This aspect is important because equivalent
positions are substituted with different chains in a range of
tricyclic and tetracyclic compounds that are known to
intercalate with DNA.6
With this information in mind, it was decided to investigate
the effect of introducing nitrogen atoms into the polycyclic
skeleton on the basis that this could increase the stability of
the complex formed by the interaction of the molecule with
DNA.4 This aim could be achieved by replacing the fourth
benzene ring in the benzofurocoumarin system with a
pyridazine, which would be attached to the furan ring
through its 4,5-bond. We have previously obtained
tetracyclic skeletons of this type through inverse electron-
Chains bearing an amide function are amongst the most
widely used in this type of intercalating anticancer
compound. For this reason, the diene chosen for the
Diels–Alder reaction with linear and angular furocoumarins
was the 3,6-dicarboxymethyl-substituted tetrazine. It was
then planned to investigate the possible amidation of one or
both ester groups in the resulting tetracycles. Pyrrolidine
Keywords: furocoumarins; DNA inhibitors; Diels–Alder reaction.
*
Corresponding author. Tel.: þ34-981563100; fax: þ34-981594912;
e-mail: qofuri@usc.es
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.051

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J. C. Gonzalez-Gomez et al. / Tetrahedron 59 (2003) 8171–8176
8172
was used as an example of a secondary amine and
dimethylaminoethylamine was used as a primary amine on
the basis that the resulting side-chains are themselves
interesting objectives.7,8
described for the preparation of compound 2 from resorcinol
(Scheme 2).12
The inverse electron-demand Diels–Alder reactions of
furocoumarins 2 and 10 with 3,6-bis(methoxycarbonyl)-
1,2,4,5-tetrazine15 were performed in dichloromethane
heated to 1008C in a sealed tube in the presence of
p-toluenesulfonic acid. This method proved satisfactory for
the preparation of the tetracycles 4 and 11 (69 and 74%
yield, respectively). This route also allowed the introduction
of the two carboxymethyl groups in the positions contiguous
to the nitrogen atoms in the ring (i.e. positions 1 and 4 of the
tetracycle), a situation that offers the possibility of further
substitution. Given that side-chains bearing a carboxamide
group are among the most interesting in terms of the
pharmacological properties of these compounds, it was
decided to investigate amidation of the pyridazinofuro-
coumarins 4 and 11, both of which are key intermediates.
Transformation of one of the ester groups gives rise to
monoamides through reaction with primary or secondary
amines. On the other hand, diamides can be obtained that
are either symmetrical, by reacting the intermediate twice
with the same amine, or unsymmetrical, by sequential
reaction with two different amines.
2. Results and discussion
Attachment of a pyridazine to a furan through a Diels–
Alder reaction with a tetrazine9 requires the dienophile to be
a furan with a good leaving group in position 3—otherwise
ring opening occurs rather than aromatization of the
resulting pyridazine.10,11 For this reason, we chose to
synthesise the desired pyridazinofurocoumarins from the
appropriate precursor furocoumarin-6-ones.12,13 These
compounds were obtained in good yields from resorcinols
in three steps: (a) Pechmann reaction with ethyl acetate in
sulfuric acid, (b) acylation of the resulting 7-hydroxy-
coumarins with acetyl chloride and (c) a tandem Fries
rearrangement/cyclization of the chloroacetate. This pro-
cedure gave a good overall yield (60%) of the angular
furocoumarin 2 from resorcinol. However, the isomeric
product 3 was obtained in only 5% yield because the
rearrangement of chloroacetate 1 occurred mainly at
position 8 of the furocoumarins (Scheme 1).13
In the most simple tricyclic pyridazino[4,5-b]benzo[b]furan
systems there is a regioselectivity that favours formation
of the carboxamide on the carboxymethyl group in the
peri position with respect to the oxygen of the furan
ring. This reaction is performed using magnesium
chloride as a catalyst and works best with secondary
amines.16 The regioselectivity is particularly marked in
the case of 8-methyl-1,4-bis(methoxycarbonyl)pyrida-
zino[4,5-j]angelicin (4), where the use of 1.5 equiv. of the
pyrrolidine with 1 equiv. of 4 gives monocarboxamide 5 in
92% yield.
We recently reported a regioselective synthesis of dihydro-
furo[3,2-g]coumarin-6-one.14 However, given that the final
outcome of the subsequent reaction is independent of the
presence or absence of a methyl group in position 8 of the
coumarin nucleus, it was decided to synthesise the linear
dimethylated furocoumarin 10. This compound can be
prepared in a straightforward manner that provides
reasonable quantities of material from 2-methylresorcinol
(48% overall yield) through the same reaction scheme as
Scheme 1. Reagents and conditions: (i) (a) CH3COCH2CO2Et, H2SO4, rt, (b) ClCOCH2Cl, DMAP, dioxane, reflux; (ii) AlCl3, 1208C; (iii) 3,6-bis-
(methoxycarbonyl)-1,2,4,5-tetrazine, p-TsOH, CH2Cl2, 1008C; (iv) amine, MgCl2, CH2Cl2, rt; (v) N,N-dimethyletilenediamine, MgCl2, CH2Cl2, rt.

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8173
3. Conclusions
A convenient procedure has been developed for the
synthesis of angular and linear pyridazinofurocoumarins
with carboxamide chains at C4 or C1 and C4. The route
involves only a small number of steps starting from
resorcinols. The Diels–Alder reaction of 3,6-dimethoxy-
carbonyl-1,2,4,5-tetrazine with dihydrofurocoumarinones is
the key step in this approach to attach the pyridazine ring to
the furan nucleus. The mild amidation conditions allow the
regioselective substitution of C4 methoxycarbonyl, the
synthesis of C1 and C4 dicarboxamides using an excess of
amine, and the synthesis of unsymetrical dicarboxamides
through sequential treatment with two different amines.
These advantages make this route an easy and general
method to prepare a wide range analogues for pharmaco-
logical evaluation.
4. Experimental
4.1. General
Melting points were determined in capillary tubes using a
Bu¨chi 510 apparatus and are uncorrected. IR spectra were
recorded using a Perkin–Elmer 1640FT spectrophotometer.
1H and 13C NMR spectra were recorded on a Bruker AMX
spectrometer at 300 and 75.47 MHz, respectively, using
TMS as internal standard (chemical shifts are given as d
values, J in Hz). Mass spectra were obtained using a Hewlett
Packard 5988A spectrometer. Elemental analyses were
performed using a Perkin–Elmer 240B microanalyser.
Silica gel (Merck 60, 230–400 mesh) was used for
flash chromatography (FC). Analytical TLC was performed
on plates precoated with silica gel (Merck 60 F254,
0.25 mm).
Scheme 2. Reagents and conditions: (i) (a) CH3COCH2CO2Et, H2SO4, rt,
(b) ClCOCH2Cl, DMAP, dioxane, reflux, (c) AlCl3, 1208C; (ii) 3,6-bis-
(methoxycarbonyl)-1,2,4,5-tetrazine, p-TsOH, CH2Cl2, 1008C; (iii) amine,
MgCl2, CH2Cl2, rt; (iv) N,N-dimethyletilenediamine, MgCl2, CH2Cl2, rt.
4.2. 8-Methyl-1,4-bis(methoxycarbonyl)pyridazino[4,5-
j]angelicin (4)
A mixture of 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine
(1.98 g, 10 mmol),15 furocoumarinone
The synthesis of the dicarboxamides was also a target in
this study and amidation reactions with large excesses
of amine (5 equiv.) were performed on 4 and 11. The
use of this method always gave acceptable yields of
the 4-monocarboxamides, i.e. substituted in the peri
position with respect to the oxygen of the furan ring,
and the dicarboxamides, although the proportions of
these products ranged considerably. The same
reaction conditions were used in each case: The reaction
mixture contained magnesium chloride in dichloro-
methane and was stirred for three hours at room
temperature. The overall yields (monoamide and
diamide) were in the range 74–90% and it appeared
that the diamide was formed more easily with linear
substrates.
2 (2.376 g,
11 mmol) and p-TsOH (172 mg, 1 mmol) in CH2Cl2
(50 mL) was heated at 1008C in a sealed tube for 8 h until
the red colour of the tetrazine had disappeared. The solvent
was removed under vacuum and the residue was purified by
flash chromatography using CH2Cl2/AcOEt (9:1) as eluent;
yield: 2.54 g (69%); mp 240–2428C (from dioxane). IR
(KBr) 1737, 1654, 1616, 1389, 1200, 1161, 1045 cm21. 1H
NMR (DMSO-d6) d 8.28 (d, 1H, J¼8.7 Hz, H-7), 8.07 (d,
1H, J¼8.7 Hz, H-6), 6.58 (s, 1H, H-9), 4.23 (s, 3H, OCH3),
4.11 (s, 3H, OCH3), 2.57 (s, 3H, CH3). 13C NMR (DMSO-
d6) d 165.1, 162.0, 158.8, 158.3, 154.5, 154.3, 151.1, 149.2,
139.5, 130.6, 119.6, 117.0, 113.7, 109.7, 106.8, 54.3, 53.7,
19.2. EI-MS m/z (%) 369 (10), 368 (Mþ, 22), 337, 310, 252
(33), 251 (100), 222, 221 (63), 58 (12). Anal. calcd for
C18H12N2O7: C, 58.70; H, 3.28; N, 7.61. Found: C, 58.74;
H, 3.25; N, 7.55.
The possibility of obtaining unsymmetrical dicarboxamides
was also explored and compounds 9 and 16 were obtained
in yields of around 70%. The method used in the
preparation of these compounds was similar to that used
for the amidation of the monocarboxamide precursors 5
and 12, respectively.
4.3. 6,10-Dimethyl-1,4-bis(methoxycarbonyl)pyridazino-
[4,5-h]psoralen (11)
This compound was prepared from 10 (2.3 g) in an

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8174
analogous manner to 4 from 2. The crude product was
purified by flash chromatography using CH2Cl2/AcOEt
(95:5) as eluent; yield 2.83 g (74%); mp 280–2828C
(from dioxane). IR (KBr) 1756, 1723, 1439, 1380, 1370,
4.4.2. 6,10-Dimethyl-1-methoxycarbonyl-4-pyrrolidin-
carbonylpyridazino[4,5-h]psoralen (12) and 6,10-
dimethyl-1,4-bis(pyrrolidincarbonyl)pyridazino[4,5-
h]psoralen (13). These compounds were prepared from 11
(114 mg) with pyrrolidine (125 mL).
1288, 1244, 1214, 1176, 1094, 1064 cm21 1H NMR
.
(DMSO-d6) d 8.30 (s, 1H, H-11), 6.58 (s, 1H, H-9), 4.23
(s, 3H, OCH3), 4.11 (s, 3H, OCH3), 2.55 (s, 6H, 2CH3).
EI-MS m/z (%) 382 (Mþ, 23), 325, 324 (75), 323, 266,
265 (100), 264 (65). Anal. calcd for C19H14N2O7: C,
59.69; H, 3.69; N, 7.33. Found: C, 59.74; H, 3.62; N,
7.41.
Compound 12. Yield 49 mg (39%); mp 272–2758C. 1H
NMR (CDCl3) d 9.16 (s, 1H, H-11), 6.40 (s, 1H, H-9), 4.25
(s, 3H, OCH3), 3.88 (t, 2H, J¼6.6 Hz, CH2–N), 3.75 (t,
J¼6.6 Hz, 2H, CH2–N), 2.75 (s, 3H, CH3), 2.67 (s, 3H,
CH3), 2.05 (m, 4H, 2CH2). 13C NMR (CDCl3) d 165.20,
161.22, 160.30, 158.08, 154.58, 153.32, 146.66, 145.44,
131.81, 125.64, 121.90, 118.76, 114.82, 111.63, 54.11,
49.16, 47.14, 26.71, 24.57, 19.75, 9.48. EI-MS m/z (%) 421
(Mþ, 5), 265, 235, 168, 98, 70 (100), 55. HRMS-EI calcd for
C22H19N3O6: 421.1273. Found: 421.1279.
4.4. General procedure for amidation of dimethoxy-
carbonylpyridazinofurocoumarins 4 and 11 with
pyrrolidine
To the corresponding dimethoxycarbonylpyridazinofuro-
coumarin (1 mmol) in dry CH2Cl2 (10 mL) was added
anhydrous MgCl2 (3 mmol) and the mixture was stirred
for 5 min at room temperature. Pyrrolidine (5 mmol) was
added and the mixture was stirred for 3 h at room
temperature. The mixture was acidified with 0.5 M HCl
(15 mL) and extracted with CH2Cl2. The organic phase
was washed, dried over NaSO4, the solvent evaporated
under reduced pressure, and the residue purified by flash
chromatography (SiO2) using CH2Cl2/i-PrOH (97:3) as
eluent.
Compound 13. Yield 48 mg (35%); mp 288–2918C. 1H
NMR (CDCl3) d 8.63 (s, 1H, H-11), 6.29 (d, 1H, J¼1.1 Hz,
H-9), 3.82 (m, 6H), 3.62 (m, 2H), 2.66 (s, 3H, CH3), 2.54 (d,
3H, J¼1.1 Hz, CH3), 1.95 (m, 8H). 13C NMR (CDCl3) d
163.52, 161.67, 160.42, 157.76, 153.93, 153.35, 151.80,
145.10, 124.05, 120.54, 118.59, 115.30, 114.66, 111.10,
49.73, 48.97, 47.63, 46.99, 26.94, 26.64, 24.64, 24.48,
19.73, 9.48. EI-MS m/z (%) 460 (Mþ, 3), 265, 235, 168, 98,
70 (100), 55. HRMS-EI calcd for C25H24N4O5: 460.1746.
Found: 460.1755.
4.4.1. 8-Methyl-1-methoxycarbonyl-4-pyrrolidin-
carbonylpyridazino[4,5-j]angelicin (5) and 8-methyl-
1,4-bis(pyrrolidincarbonyl)pyridazino[4,5-j]angelicin
(6). These compounds were prepared from 4 (108 mg) with
pyrrolidine (125 mL).
4.5. General procedure for the amidation with
N,N-dimethylethylenediamine of dimethoxycarbonyl-
pyridazinofurocoumarins 4 and 11
To the corresponding dimethoxycarbonylpyridazinofuro-
coumarin (1 mmol) in dry CH2Cl2 (10 mL) was added
anhydrous MgCl2 (3 mmol) and the mixture was stirred for
5 min at room temperature. N,N-Dimethylethylenediamine
(5 mmol) was added and the mixture was stirred for 3 h at
room temperature. The mixture was acidified with 0.5 M
HCl (15 mL) and washed with CH2Cl2. The aqueous phase
was then basified with NaHCO3 and extracted with CH2Cl2.
The organic phase was washed, dried over NaSO4,
evaporated under reduced pressure, and purified by flash
chromatography (SiO2) using CH2Cl2/EtOH/NH3 (68:30:2)
as eluent.
Compound 5. Yield 91 mg (75%); mp 265–2668C. IR
(KBr) 1731, 1651, 1631, 1452, 1384, 1234, 1062 cm21
.
1H NMR (CDCl3) d 7.98 (d, 1H, J¼8.8 Hz, H-7), 7.74
(d, 1H, J¼8.8 Hz, H-6), 6.40 (d, 1H, J¼1.1 Hz, H-9),
4.36 (s, 3H, OCH3), 3.85 (m, 4H, CH2NCH2), 2.55
(d, J¼1.1 Hz, 3H, CH3), 2.02 (m, 4H, 2CH2). 13C
NMR (CDCl3) d 165.06, 160.83, 158.41, 158.18,
152.50, 152.30, 149.72, 144.54, 128.38, 119.16,
116.79, 114.43, 109.19, 107.81, 54.42, 48.88, 46.82,
26.33, 24.11, 19.41. EI-MS m/z (%) 407 (Mþ, 4), 376,
320, 252, 251, 221, 195, 185, 140, 71, 70 (100), 56.
HRMS-EI calcd for C21H17N3O6: 407.1117. Found:
407.1122.
4.5.1. 8-Methyl-4-(dimethylaminoethylcarbamoyl)-1-
methoxycarbonyl-pyridazino[4,5-j]angelicin (7) and 8-
methyl-1,4-bis(dimethylaminoethylcarbamoyl)pyrida-
zino[4,5-j]angelicin (8). These compounds were prepared
This compound was also obtained in 92% yield using the
same procedure but with 1.5 mmol of pyrrolidine.
from 4 (108 mg) with N,N-dimethylethylenediamine
(166 mL).
Compound 6. Yield 20 mg (15%); mp 256–2598C. IR
(KBr) 1729, 1645, 1614, 1451, 1362, 1068 cm21
.
1H
Compound 7. Yield 70 mg (57%); mp 225–2268C. IR (KBr)
3432, 1747, 1685, 1619, 1519, 1443, 1382, 1058,
NMR (CDCl3) d 7.96 (d, 1H, J¼8.8 Hz, H-7), 7.72 (d,
1H, J¼8.8 Hz, H-6), 6.37 (d, 1H, J¼1.2 Hz, H-9), 4.15
(m, 2H), 3.85 (m, 4H), 3.44 (m, 2H), 2.54 (d, 3H,
J¼1.2 Hz, CH3), 2.02 (m, 8H). 13C NMR (CDCl3) d
163.92, 161.64, 158.79, 158.56, 154.51, 152.90, 152.56,
149.87, 144.54, 128.48, 119.12, 117.17, 114.87, 109.47,
108.17, 49.25, 48.62, 47.15, 46.39, 26.72, 26.35, 24.89,
24.54, 19.41. EI-MS m/z (%) 448 (3), 446 (Mþ, 12), 348,
321, 251, 98, 70 (100), 58 (37). HRMS-EI calcd for
C24H22N4O5: 446.1590. Found: 446.1579.
1
1030 cm21. H NMR (CDCl3) d 8.63 (bs, 1H, NH), 8.00
(d, 1H, J¼8.9 Hz, H-7), 7.81 (d, 1H, J¼8.9 Hz, H-6), 6.39
(d, 1H, J¼1.2 Hz, H-9), 4.37 (s, 3H, OCH3), 3.71 (m, 2H,
CH2NHCO), 2.62 (t, 2H, J¼6.1 Hz, CH2NMe2), 2.56
(d, J¼1.2 Hz, CH3-4), 2.32 (s, 6H, N(CH3)2). 13C NMR
(CDCl3) d 165.32, 161.27, 159.18, 158.78, 153.10, 152.77,
152.06, 150.14, 140.73, 129.04, 120.53, 117.22, 114.78,
109.81, 107.85, 58.11, 54.86, 37.56, 19.80. HRMS-EI calcd
for C21H20N4O6: 424.1382. Found: 424.1373.

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8175
Compound 8. Yield 40 mg (29%); mp 242–2448C. IR
(KBr) 3421, 3306, 1736, 1671, 1522, 1459, 1381,
.
1060 cm21 1H NMR (CDCl3) d 8.63 (bs, 1H, NH),
108.96, 108.38, 57.17, 48.87, 46.80, 45.09, 37.56, 26.36,
24.13, 19.41. HRMS-EI calcd for C24H25N5O5: 463.1855.
Found: 463.1867.
7.97 (d, 1H, J¼8.7 Hz, H-7), 7.78 (d, 1H, J¼8.7 Hz,
H-6), 7.44 (bs, 1H, NH), 6.36 (s, 1H, H-9), 3.93 (m, 2H,
CH2NCO), 3.69 (m, 2H, CH2NCO), 2.72 (t, 2H,
J¼6.0 Hz, CH2NMe2), 2.62 (t, 2H, J¼6.2 Hz,
CH2NMe2), 2.54 (s, 3H, CH3 –C8), 2.32 (s, 12H,
2N(CH3)2). 13C NMR (CDCl3) d 164.87, 161.40,
159.32, 158.90, 154.88, 153.67, 152.48, 150.30, 140.59,
128.74, 121.10, 117.21, 114.82, 109.53, 108.37, 58.08,
57.55, 45.66, 45.41, 37.91, 37.50, 19.76. HRMS-EI calcd
for C24H28N6O5: 480.2121. Found: 480.2129.
4.7. 6,10-Dimethyl-1-(dimethylaminoethylcarbamoyl)-4-
pyrrolidincarbonyl-pyridazino[4,5-h]psoralen (16)
This compound was prepared from 12 (42 mg) in an
analogous manner to 9 from 5. The crude product was
purified by flash chromatography using CH2Cl2/EtOH/NH3
(90:10:0.5) as eluent; yield 33 mg (69%); mp 275–2788C.
IR (KBr) 3330, 1750, 1734, 1671, 1639, 1522, 1448, 1364,
1098 cm21. 1H NMR (CDCl3) d 9.50 (s, 1H, H-11), 8.81 (t,
1H, J¼5.3 Hz, NH), 6.37 (s, 1H, H-9), 3.89 (t, 2H,
J¼6.6 Hz), 3.63 (m, 4H), 2.73 (s, 3H, CH3), 2.68 (s, 3H,
CH3), 2.35 (s, 6H, 2CH3), 2.06 (m, 4H), 1.91 (m, 2H). 13C
NMR (CDCl3) d 163.46, 161.48, 160.53, 158.09, 154.53,
154.35, 153.81, 148.78, 145.41, 124.61, 123.57, 118.65,
115.47, 114.48, 111.13, 58.21, 48.99, 47.00, 45.71, 37.74,
26.65, 24.63, 19.90, 9.45. MS-CI m/z (%) 478.2 ([Mþ1]þ,
13), 177.0, 78.9, 40.9 (53), 30.3 (53), 27.0 (52), 17.0 (57),
19.1 (100). HRMS-CI calcd for C25H28N5O5: 478.2090.
Found: 478.2082.
4.5.2. 6,10-Dimethyl-1-methoxycarbonyl-4-(dimethyl-
aminoethylcarbamoyl)-pyridazino[4,5-h]psoralen (14)
and 6,10-dimethyl-1,4-bis(dimethylaminoethylcar-
bamoyl)pyridazino[4,5-h]psoralen (15). These compounds
were prepared from 11 (114 mg) with N,N-dimethylethylene-
diamine (166 mL).
Compound 14. Yield 14 mg (11%). IR (KBr) 3432, 1747,
1725, 1650, 1449, 1365, 1230, 1180, 1101 cm21. 1H NMR
(CDCl3) d 9.16 (s, 1H, H-11), 8.79 (bs, 1H, NH), 6.40 (s,
1H, H-9), 4.26 (s, 3H, OCH3), 3.73 (m, 2H, CH2NCO), 2.80
(s, 3H, CH3), 2.65 (m, 5H, CH3þCH2NMe2), 2.38 (s, 6H,
N(CH3)2). HRMS-EI calcd for C22H22N4O6: 438.1539.
Found: 438.1547.
Acknowledgements
We thank the Spanish Ministry of Education, Culture and
Sport (PM99-0125) for financial support and the University
of Santiago de Compostela for the award of a fellowship to
J. C. G. G.
Compound 15. Yield 110 mg (74%); mp 265–2688C. IR
(KBr) 3333, 1729, 1673, 1637, 1597, 1518, 1462, 1366,
1333, 1218, 1180, 1101 cm21. 1H NMR (CDCl3) d 9.45 (s,
1H, H-11), 8.82 (s, 1H, NH), 8.57 (s, 1H, NH), 6.36 (s, 1H,
H-9), 3.73 (m, 4H, 2CH2NCO), 2.77 (s, 3H, CH3), 2.64 (m,
7H, CH3 þ 2CH2NMe2), 2.35 (s, 6H, N(CH3)2), 2.34 (s, 6H,
N(CH3)2). 13C NMR (CDCl3) d 162.65, 160.98, 160.00,
158.19, 155.38, 154.04, 153.30, 149.14, 140.25, 125.19,
123.13, 118.22, 114.50, 114.07, 110.86, 57.75, 57.71, 45.29,
45.26, 37.31, 37.05, 19.45, 8.96. HRMS-EI calcd for
C25H30N6O5: 494.2277. Found: 494.2267.
References
1. Rodighiero, G.; Dall’Acqua, F.; Averbeck, D. In Psoralen
DNA Photobiology; Gasparro, F. P., Ed.; CRC: Boca Raton,
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2. Dalla Via, L.; Gia, O.; Marciani-Magno, S.; Santana, L.;
Teijeira, M.; Uriarte, E. J. Med. Chem. 1999, 42, 4405–4413.
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4.6. 8-Methyl-1-(dimethylaminoethylcarbamoyl)-4-
pyrrolidincarbonyl-pyridazino[4,5-j]angelicin (9)
To compound 5 (28 mg, 0.07 mmol) in dry CH2Cl2 (2 mL)
was added anhydrous MgCl2 (18 mg, 0.19 mmol) and
the mixture was stirred for 5 min at room temperature.
N,N-Dimethylethylenediamine (40 mL, 0.37 mmol) was
added and the mixture stirred for 48 h at room temperature.
0.5 M HCl (10 mL) was added and the mixture washed with
CH2Cl2. The aqueous layer was basified using Na2CO3 and
extracted with CH2Cl2. The organic phase was washed,
dried over NaSO4, evaporated under reduced pressure, and
the residue purified by flash chromatography using CH2Cl2/
EtOH/NH3 (90:10:1) as eluent; yield 23 mg (72%); mp
264–2678C (dec.). IR (KBr) 3300, 1733, 1674, 1652, 1614,
1456, 1376, 1062, 857, 817 cm21. 1H NMR (CDCl3) d 7.95
(d, 1H, J¼8.9 Hz, H-7), 7.71 (d, 1H, J¼8.9 Hz, H-6), 7.38
(bs, 1H, NH), 6.36 (d, 1H, J¼1.1 Hz, H-9), 3.80 (m, 6H),
2.71 (t, 2H, J¼6.1 Hz, CH2NMe2), 2.53 (d, J¼1.1 Hz, CH3),
2.29 (s, 6H, N(CH3)2), 2.00 (m, 4H, 2CH2). 13C NMR
(CDCl3) d 164.65, 161.06, 158.59, 158.36, 153.51, 152.95,
152.07, 149.92, 144.52, 128.12, 119.75, 116.82, 114.51,
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