A furan ring expansion approach to the synthesis of novel pyridazino-psoralen derivatives

Article abstract of DOI:10.1016/j.tet.2005.03.018

A convenient preparation of the parent tetrahydrobenzodifuran 2 was developed from resorcinol. The oxidation of one or both furan rings of this key intermediate was accomplished with DDQ and the resulting benzodifuran was subsequently reacted with 3,6-dimethoxycarbonyl-1,2,4,5-tetrazine to afford the expected pyridazino-psoralen derivative in good yield. This simple method allowed the efficient preparation of a pyridazino-psoralen derivative with a formyl group at C-7, which was introduced by directed ortho-lithiation in the intermediate 2. An aminoalkyl side-chain was also introduced to the tetracyclic skeleton through the aldehyde functionality in a reductive amination process, which was accompanied by an unprecedented reduction of the pyridazine ring.

Full text of DOI:10.1016/j.tet.2005.03.018

Tetrahedron 61 (2005) 4805–4810
A furan ring expansion approach to the synthesis of novel
pyridazino-psoralen derivatives
*
´
Jose C. 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 January 2005; revised 21 February 2005; accepted 4 March 2005
Available online 23 March 2005
Abstract—A convenient preparation of the parent tetrahydrobenzodifuran 2 was developed from resorcinol. The oxidation of one or both
furan rings of this key intermediate was accomplished with DDQ and the resulting benzodifuran was subsequently reacted with 3,6-
dimethoxycarbonyl-1,2,4,5-tetrazine to afford the expected pyridazino-psoralen derivative in good yield. This simple method allowed the
efficient preparation of a pyridazino-psoralen derivative with a formyl group at C-7, which was introduced by directed ortho-lithiation in the
intermediate 2. An aminoalkyl side-chain was also introduced to the tetracyclic skeleton through the aldehyde functionality in a reductive
amination process, which was accompanied by an unprecedented reduction of the pyridazine ring.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
reasoning that the inclusion of nitrogen atoms in the
polycyclic skeleton may lead to improved interaction with
DNA.5 In particular, we were encouraged by the remarkable
antiproliferative activity recently reported for pyrone side
tetracyclic psoralen derivatives.6 Prompted by this result
and the widely used Diels–Alder of 1,2,4,5-tetrazines;7 we
focused on the development of a general synthetic route to
novel pyridazino psoralens in which the pyridazine ring is
attached to the pyrone nucleus of the psoralen skeleton.8
Psoralens form a group of natural or synthetic compounds
that are of great pharmacological interest.1 One of the most
important applications of these compounds is in the field of
photochemotherapy, where psoralens are capable of under-
going photoaddition with thymine units present in DNA.2
However, the utility of the most effective compounds in this
class is limited by side-effects that are mainly related to their
ability to cross-link the two strands of the DNA helix.3 One
of the most promising strategies to obtain monofunctional
psoralens involves incorporating one of the reactive double
bonds in a benzene nucleus by forming benzopsoralens
(Fig. 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.4
In a preliminary attempt to fuse a pyridazine ring to
psoralens using 3,6-dimethoxycarbonyl-1,2,4,5-tetrazine,
we observed that the cycloaddition was accompanied by
opening of the furan ring and concomitant expansion to a
pyrone ring upon intramolecular transesterification.9 We
decided to exploit this interesting domino reaction path-
way10 to explore the use of benzodifuran derivatives to
prepare these novel pyridazino-psoralens (Scheme 1).
2. Results and discussion
An important intermediate in our synthetic proposal is the
tetrahydrobenzodifuran 2 and the synthesis of this com-
pound has been reported from 6-hydroxy-dihydrobenzo-
furan in three steps.11 Our initial goal was to develop a
more convenient preparation of this intermediate and, in
this respect, we envisaged a route based on a magnesium
mediated cyclization process, which was reported by
Nichols et al. for similar symmetrical benzodifuran
derivatives.12 The synthesis of this compound commenced
with dialkylation of resorcinol using excess 1-bromo-2-
Figure 1.
With this information in mind, we embarked on the
preparation of nitrogenated analogues of benzopsoralens
Keywords: Psoralens; Benzofurans; Tetrazines; Diels–Alder; DNA
intercalants.
*
Corresponding author. Tel.: C34 981563100; fax: C34 981594912;
e-mail: jcgg1971@yahoo.es
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.018

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J. C. Gonzalez-Gomez et al. / Tetrahedron 61 (2005) 4805–4810
4806
Scheme 1.
chloroethane and potassium carbonate in acetone reflux.
Aromatic dibromination was accomplished using bromine
in acetic acid and the product was subjected to Grignard
conditions to effect ring closure13 and afford the desired
compound 2 (Scheme 2). This three step procedure only
require one chromatographic purification and allowed the
preparation of pure compound 2 in useful scale quantities
(4.5 g). Starting from other commercially available or easily
prepared resorcinol derivatives, this procedure could also be
extended to other tetrahydrobenzodifuran derivatives.
this compound in common organic solvents is a serious
limitation in terms of reactivity. At this point, we examined
the selectivity of the Diels–Alder reaction of benzodifurans.
Oxidation of both dihydrofuran rings of compound 2 was
performed using an excess of DDQ in refluxing dioxane and
afforded compound 7 in 55% yield.15 The Diels–Alder
reaction of benzodifuran 7 with tetrazine 4 furnished the
expected compound 9 in 65% yield; this compound was
isolated pure after filtration of the cold reaction mixture.
The filtrate of this reaction was then treated with boiling
acetic acid and the symmetrical compound 10 crystallized in
15% yield (Scheme 3).
Scheme 2. (a) BrCH2CH2Cl, K2CO3, (CH3)2CO, reflux, 48 h; (b) Br2,
AcOH, rt, 3 h; (c) Mg, EtMgBr (cat) , THF, reflux, 4 h; (d) 1 equiv DDQ,
dioxane, rt, 2 h; (e) dioxane, reflux, 6 h.
With an efficient synthesis of 2 established, we attempted
the dehydrogenation of only one dihydrofuran ring in order
to achieve ring expansion in the Diels–Alder reaction with
the tetrazine 4. It was believed that this approach would
avoid competition through reaction of the other ring.
Selective oxidation of a dihydrofuran ring of 2 was
accomplished using 1 equiv of DDQ in dioxane at room
temperature to afford 3 in almost quantitative yield. This
result was very satisfactory because this simple conven-
tional oxidation method furnished the unsymmetrical
compound 3 in excellent yield; compound 3 could also
prove very useful for a variety of different synthetic
purposes.14 The Diels–Alder reaction between tetrazine 4
and compound 3 was performed in refluxing dioxane and
gave the expected compound 5. Under these conditions,
analytically pure 5 was obtained in 86% yield by simple
filtration of the cold reaction mixture (Scheme 2).
Scheme 3. (a) (i) n-BuLi, Et2O, K78 8C, then 0 8C, 4 h; (ii) DMF, 0 8C,
then rt, 16 h; (b) 3.3 equiv DDQ, dioxane, reflux, 18 h; (c) dioxane, reflux,
2 h; (d) 6:1 dioxane/AcOH, reflux, 8 h.
It was anticipated that analogues of compound 9 bearing an
aldehyde group at C-7 would allow the facile preparation of
side chain analogues at a later stage in the synthesis of these
tetracyclic compounds. With this aim in mind, we planned
to examine the reactivity of benzodifuran 8.
Regioselective ortho lithiation of compound 2 followed by
quenching the resulting anion with DMF furnished com-
pound 6 in 93% yield. The oxidation of this intermediate
with excess of DDQ to give 8 was performed under identical
conditions to the oxidation of 2, but a higher yield (73%)
was obtained. Nichols et al. have also noted that the yield of
this oxidation is strongly dependent on the nature of the
substituents attached to the benzodifuran nucleus.16 The
Although the oxidation of the residual dihydrofuran ring in
compound 5 seems reasonable, the very low solubility of

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J. C. Gonzalez-Gomez et al. / Tetrahedron 61 (2005) 4805–4810
4807
first attempt at a Diels–Alder reaction between compound 8
and tetrazine 4 in refluxing dioxane was unsuccessful. We
reasoned that the final lactonization would prove difficult
due to an intramolecular hydrogen bond with the formyl
group that stabilizes the open intermediate (Fig. 2). The
stabilizing effect was overcome by performing the reaction
in the presence of acetic acid as a protic additive. This
modification allowed compounds 11 and 12 to be obtained
in 70 and 5% yield, respectively. Once again, the major
compound 11 crystallized pure from the reaction mixture
and the minor compound was recrystallised from AcOH. As
one would anticipate,13 the introduction of the electron-
withdrawing formyl group in the benzodifuran nucleus
decreased the reactivity of the dienophile in the inverse-
electron demand Diels–Alder reaction; more importantly,
such a change increased the monoadduct 11/diadduct 12
ratio.
give a pyrone nucleus. Given the fact that benzofuro-
coumarins have been shown to possess significant photo-
chemotherapeutic activity, ready access to these new
pyridazine analogues provides avenues for investigations.
3. Experimental
3.1. General
All reactions were performed using oven-dried glassware
under an atmosphere of dry argon. Solvents were distilled
and dried before use-except DMF, which was purchased
anhydrous from Aldrich. Reagents were purchased from
Aldrich and used without further purification. Chromato-
graphic purification of products was accomplished using
forced flow chromatography on silica gel 60 (230–400
mesh). Analytical TLC was performed on plates precoated
with silica gel (Merck 60 F254, 0.25 mm). Melting points
were determined in capillary tubes using a Bu¨chi 510
apparatus and are uncorrected. IR spectra were recorded
1
using a Perkin-Elmer 1640FT spectrophotometer. H and
13C NMR spectra were recorded on a Bruker AMX
spectrometer at 300 and 75.5 MHz, respectively, using
TMS as internal standard (chemical shifts are given as d
values, J in Hz). Mass spectra were obtained using a Hewlet
Packard 5988A spectrometer.
Figure 2.
Finally, we examined the attachment of an aminoalkyl chain
to the skeleton of compound 11 through its formyl group on
the basis that this kind of side chain usually plays an
important role in the biological activity of DNA intercalant
agents and other drugs.17 The reductive amination of
compound 11 was performed with N,N-dimethylethylene-
diamine in the presence of excess of NaCNBH3.18 To our
surprise, the reduction of the pyridazine ring also occurred
under the reaction conditions and compounds 13 and 14
were obtained in 65 and 30% yield, respectively. Unfortu-
nately, assays with 0.5, 1.0 and 1.5 equiv of NaCNBH3
afforded complex mixtures of products. The reaction was
also performed with 1.1 equiv of NaBH(OAc)3,19 but no
single major product was detected and further experiments
are required to obtain the expected fully aromatised
compound. Nevertheless, it was considered appropriate to
report this preliminary result because this reduction of the
pyridazine ring is unprecedented and could be a valuable
synthetic tool in future studies (Scheme 4).20
3.1.1. 1,5-Dibromo-2,4-bis(2-chloroethoxy)benzene (1).
A mixture of resorcinol (10.00 g, 91 mmol), 1-bromo-2-
chloroethane (60 mL, 728 mmol), finely powdered K2CO3
(38.00 g, 137 mmol) and acetone (60 mL) was stirred and
heated at reflux under argon for 72 h. The reaction was
cooled to room temperature and filtered through a short pad
of Celite 535. The Celite was washed with CH2Cl2, and the
filtrate and washes were combined and evaporated to
dryness by rotatory evaporation. The residue was par-
titioned between Et2O and H2O. The organic phase was
extracted with 2 M NaOH (2!100 mL), then H2O (2!
100 mL) and brine (100 mL), dried over Na2SO4 and
evaporated under vacuum. The resulting yellow solid
(11.10 g) was suspended in glacial acetic acid (30 mL)
and a solution of Br2 (6 mL) in AcOH (15 mL) was added
dropwise at 0–5 8C. The reaction mixture was allowed to
reach room temperature and stirred for 3 h. The mixture was
poured into ice/water (50 mL) and stirred for 15 min. The
precipitate was filtered off and the solid was washed with
cold 1:1 AcOH/H2O (2!50 mL), then with cold H2O until
neutral pH (5!50 mL) and dried under vacuum with P21O5
until constant weight (17.73 g, 50%); mp 102–105 8C. H
NMR (CDCl3) d 7.60 (s, 1H, H6), 6.45 (s, 1H, H3), 3.80 (t,
4H, JZ8.95 Hz, 2CH2), 3.07 (t, 4H, JZ8.95 Hz, 2CH2).
In conclusion, we have described a general procedure for the
preparation of novel pyridazino-psoralens, that is both
convenient and operationally simple. The synthesis is based
on the Diels–Alder reaction between 3,6-dimethoxycarbo-
nyl-1,2,4,5-tetrazine and benzodifuran derivatives. This
reaction is followed by a domino furan ring expansion to
Scheme 4. (a) NH2CH2CH2NMe2, NaCNBH3, DMF–AcOH, rt, 7 h.

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4808
EI-MS m/z (%) 396 (34), 394 (92), 392 (97), 390 (37), 332
(38), 330 (52), 269 (51), 268 (100), 266 (51).
2H, JZ8.50 Hz, H9), 4.05 (s, 3H, OMe), 3.55 (t, 2H, JZ
8.50 Hz, H10). EI-MS m/z (%) 298 (MC, 100), 240 (72), 185
(38). HRMS-EI Calcd for C15H10N2O5: 298.0589. Found:
298.0587.
3.1.2. 2,3,5,6-Tetrahydrobenzo[1,2-b;5,4-b0]difuran (2).
To a suspension of magnesium turnings (3.40 g, 141 mmol)
in anhydrous THF (40 mL) was slowly added EtMgBr
(3.4 mL, 10 mmol, 3 M solution in Et2O). An anhydrous
THF solution (115 mL) of the dibrominated compound 1
(18.20 g, 46.2 mmol) was then added dropwise under argon
atmosphere such that the internal reaction temperature did
not exceed 40 8C. Upon completion of the addition, the
reaction was heated under reflux for 3 h, after which time
TLC (95:5 hexane/EtOAc) indicated completion of the
reaction. The reaction was then cooled to room temperature
and 1 M HCl (200 mL) was carefully added while cooling
with an external ice/water bath. Upon cessation of gas
evolution, the solution was extracted with Et2O (3!
300 mL). The organic layers were combined and washed
with aqueous 1 M NaOH (5!75 mL), brine (50 mL), dried
(Na2SO4), filtered, and evaporated to afford a tan solid
(6.16 g). This solid was purified by column chromatography
(95:5 hexane/EtOAc) to yield a white solid (4.45 g, 60%);
mp 60–63 8C (lit.11 75 8C). 1H NMR (CDCl3) d 6.93 (m, 1H,
H4), 6.26 (s, 1H, H8), 4.53 (t, 4H, JZ8.95 Hz, H2CH6),
3.07 (t, 4H, JZ8.95 Hz, H3CH5). 13C NMR (CDCl3) d
160.25, 120.31 (CH), 118.16, 92.57 (CH), 72.13 (CH2),
29.27 (CH2). EI-MS m/z (%) 162 (MC, 100), 133 (12), 58
(24). HRMS-EI Calcd for C10H10O2: 162.0681. Found:
162.0685.
3.1.5. 2,3,5,6-Tetrahydrobenzo[1,2-b;5,4-b0]difuran-8-
carboxaldehyde (6). To a solution of compound 2
(1.62 g, 10 mmol) in anhydrous Et2O (100 mL) was added
n-BuLi (10 mL, 1.6 M in hexane) by syringe at K78 8C
under argon. The mixture was stirred for 30 min. The
external cool bath was replaced by an ice/water bath and the
reaction mixture was stirred at 0–5 8C. Upon completion of
the reaction (4 h), DMF (2.5 mL, 30 mmol) was added and
the mixture was stirred for a further 16 h while the
temperature was allowed to increase slowly to room
temperature. Then 0.5 M HCl (50 mL) was added at 0 8C
to quench the reaction and the mixture was stirred 15 min.
The resulting mixture was extracted with Et2O (4!
100 mL), the organic phases were combined and washed
with H2O (3!50 mL) until neutral pH and finally with brine
(50 mL). The organic phase was dried over Na2SO4 and the
solvent evaporated under vacuum to afford a tan solid (TLC
7:3 hexane/EtOAc, Rf 0.15), which was used in the next step
without further purification (1.76 g, 93%). A sample was
purified by column chromatography (7:3 hexane/EtOAc) to
yield a yellow crystalline solid; mp 133–134 8C. IR (KBr)
1674, 1610, 1453, 1408, 1234, 1073 cmK1 1H NMR
.
(CDCl3) d 10.17 (s, 1H, CHO), 7.12 (s, 1H, H4), 4.69 (t,
4H, JZ8.60 Hz, H3CH5), 3.07 (t, 4H, JZ8.60 Hz, H2C
H6). 13C NMR (CDCl3) d 186.98 (CH), 160.96, 126.75
(CH), 119.34, 106.76, 73.62 (CH2), 28.29 (CH2). EI-MS m/z
(%) 190 (MC, 100), 189 (51), 161 (25), 133 (29), 91 (14), 77
(19). HRMS-EI Calcd for C11H10O3: 190.0630. Found:
190.0627.
3.1.3. 2,3-Dihydrobenzo[1,2-b;5,4-b0]difuran (3). A
solution of DDQ (113 mg, 0.5 mmol) in dioxane (8 mL)
was added slowly (over 1 h) to a solution of compound 2
(81 mg, 0.5 mmol) in dioxane (2 mL). The reaction mixture
was stirred at room temperature for a further 1 h and the
precipitate was filtered off and washed thoroughly with
CH2Cl2. The filtrate and the washes were combined and
evaporated to dryness under vacuum. The residue was
purified by column chromatography (hexane) to afford a
white solid (78 mg, 99%); mp 58–60 8C. 1H NMR (CDCl3)
d 7.47 (d, 1H, JZ2.20 Hz, H2), 7.30 (s, 1H, H4), 6.90 (s, 1H,
H8), 6.62 (d, 1H, JZ2.20 Hz, H3), 4.60 (t, 2H, JZ8.45 Hz,
H6), 3.24 (t, 2H, JZ8.45 Hz, H5). 13C NMR (CDCl3) d
158.46, 155.27, 143.80 (CH), 123.24, 120.82, 116.05 (CH),
106.35 (CH), 93.14 (CH), 72.15 (CH2), 29.42 (CH2). EI-MS
m/z (%) 160 (MC, 100), 131 (60). HRMS-EI Calcd for
C10H8O2: 160.0524. Found: 160.0520.
3.1.6. Benzo[1,2-b;5,4-b0]difuran (7). A solution of DDQ
(3.00 g, 13.2 mmol) in dioxane (70 mL) was added slowly
(over 1 h) to a solution of compound 2 (648 mg, 4 mmol) in
dioxane (70 mL). Once the addition was complete, the
reaction mixture was heated under reflux for 18 h, after
which time TLC indicated completion of the reaction. The
reaction mixture was then cooled to room temperature and
filtered through a short pad of silica gel. The silica gel was
washed well with CH2Cl2, and the filtrate and washes were
evaporated to dryness under vacuum. The residue was
purified by column chromatography (hexane) to give an
off-white solid product (347 mg, 55%); mp 57–59 8C (lit.15
1
55–58.5 8C). H NMR (CDCl3) d 7.86 (s, 1H, H4), 7.62 (s,
1H, H8), 7.60 (d, 2H, JZ2.20 Hz, H2), 6.80 (d, 2H, JZ
2.20 Hz, H3). 13C NMR (CDCl3) d 153.36, 145.26 (CH),
124.25, 111.33 (CH), 106.39 (CH), 94.44 (CH). EI-MS m/z
(%) 158 (MC, 36), 58 (100). HRMS-EI Calcd for C10H6O2:
158.0368. Found: 158.0372.
3.1.4. 9,10-Dihydro-pyridazino[3,4-c]psoralen-2-car-
boxylic acid, methyl esther (5). A mixture of compound
3 (82 mg, 0.51 mmol) and 3,6-dimethoxycarbonyl-1,2,4,5-
tetrazine21 (83 mg, 0.42 mmol) in dioxane (3 mL) was
heated under reflux for 6 h until the red colour of the
tetrazine had disappeared. The mixture was allowed to reach
room temperature and the precipitate was filtered off and
washed with fresh dioxane (1 mL) and diethyl ether (2!
1 mL). A pure yellow solid (TLC 4:1 CH2Cl2/EtOAc) was
obtained (96 mg, 77%). The filtrate was concentrated under
vacuum and purified by column chromatography (9:1
CH2Cl2/EtOAc) to afford another crop of pure 5 (12 mg,
9%); mp 279–281 8C (dec). IR (KBr) 1758, 1713, 1580,
1451, 1412, 1265, 1164, 1134 cmK1. 1H NMR (DMSO-d6)
d 8.94 (s, 1H, H1), 8.51 (s, 1H, H11), 6.95 (s, 1H, H7), 4.75 (t,
3.1.7. Benzo[1,2-b;5,4-b0]difuran-8-carboxaldehyde (8).
This compound was prepared from 6 (1.76 g, 9.2 mmol) in
an analogous manner to 7 from 2. The crude product was
purified by flash chromatography using 9:1 CH2Cl2/EtOAc
to give a white solid product (1.25 g, 73%); mp 103–104 8C.
1
IR (KBr) 1677, 1592, 1548, 1115, 1016, 743 cmK1. H
NMR (CDCl3) d 10.84 (s, 1H, CHO), 8.00 (s, 1H, H4), 7.78
C
(d, 2H, JZ2.20 Hz, H2), 6.89 (d, 2H, JZ2.20 Hz, H3). 13
NMR (CDCl3) d 185.77 (CHO), 152.61, 146.51 (CH),

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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,

´ ´
J. C. Gonzalez-Gomez et al. / Tetrahedron 61 (2005) 4805–4810
4810
11. Graffe, B.; Sacquet, M. C.; Maitte, P. J. Heterocycl. Chem.
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