Regioselective synthesis of linear and angular pyridazine furocoumarins

Article abstract of DOI:10.1055/s-2002-19292

With a view to develop a general regioselective route to pyridazine analogues of benzofurocoumarins, the angular compound 3 and the linear compound 9 were synthesized. In both cases the key step in the construction of the fused pyridazine ring was a Diels-Alder reaction of the intermediate dihydrofura-3-ones with 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine. The furocoumarinone precursor 2 of compound 3 was synthesized in 60% yield by regioselective Fries rearrangement of 7-(chloroacetyloxy)coumarin (1). The benzofuranone 7, the precursor of compound 9, was obtained in a preparatively useful scale and 34% overall yield from ethyl 2,4-dimethoxycinnamate (4) in 3 steps by regioselective Friedel-Crafts chloroacetylation and further cyclization. The coumarin skeleton of compound 9 was completed in the final step by lactonization with BBr₃.

Full text of DOI:10.1055/s-2002-19292

PAPER
43
Regioselective Synthesis of Linear and Angular Pyridazine Furocoumarins
L
inear and
o
A
ngular Py
s
ridazine
F
é
urocoumarins Carlos González-Gómez, Lourdes Santana, Eugenio Uriarte*
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Fax +34(981)594912; E-mail: qofuri@usc.es
Received 3 August 2001; revised 3 October 2001
Dedicated to the memory of Prof. Yolanda Rodríguez-Esteva of the Chemistry Faculty of Habana University
We had initially attempted the synthesis of pyridazinefu-
Abstract: With a view to develop a general regioselective route to
rocoumarins by inverse electron demand Diels–Alder re-
actions between furocoumarins and 1,2,4,5-tetrazines, but
pyridazine analogues of benzofurocoumarins, the angular com-
pound 3 and the linear compound 9 were synthesized. In both cases
the key step in the construction of the fused pyridazine ring was a
the reaction was accompanied by the release of diatomic
Diels–Alder reaction of the intermediate dihydrofura-3-ones with nitrogen and the opening of the furan ring.9 Although the
3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine. The furocoumarinone
precursor 2 of compound 3 was synthesized in 60% yield by regi-
Diels–Alder reactions of 1,2,4,5-tetrazines with many
electron-rich dienophiles have been extensively stud-
oselective Fries rearrangement of 7-(chloroacetyloxy)coumarin (1).
ied,10–13 very few reactions with carbonyl compounds as
The benzofuranone 7, the precursor of compound 9, was obtained
dienophiles had been reported.14 Since some reactions of
in a preparatively useful scale and 34% overall yield from ethyl 2,4-
dihydrofurocoumarinones are accompanied with the enol
form,15 we decided to examine dihydrofuro[2,3-h]cou-
marin-9-one (2) as dienophile in the Diels–Alder reaction
for the fusing of the pyridazine ring. Gratifyingly, reaction
of this substrate with 3,6-bis(trifluoromethyl)-1,2,4,5-tet-
razine did indeed bring about cycloaddition of the diene to
the enolic double bond of the furan ring, with concomitant
loss of N2 and water, giving the angular pyridazineangeli-
cin 3 in good yield (Scheme 1).
dimethoxycinnamate (4) in 3 steps by regioselective Friedel–Crafts
chloroacetylation and further cyclization. The coumarin skeleton of
compound 9 was completed in the final step by lactonization with
BBr3.
Key words: Diels–Alder reactions, electrophilic aromatic substitu-
tions, polycycles, heterocycles, regioselectivity
Furocoumarins are of pharmacological interest due to
their capacity to link covalently to DNA1 and other bio-
logical macromolecules2 upon irradiation with long-
wavelength UV light (UVA, 320–400 nm). This photore-
activity is generally greatest for linear furocoumarins
(psoralens), among which 8-methoxypsoralen (8-MOP),
5-methoxypsoralen (5-MOP) and 4,8,5’-trimethylpsor-
alen are currently in clinical use for PUVA (Psoralen +
UVA) therapy of various skin diseases.1–4
a
60%
O
O
O
O
O
O
Cl
O
O
1
2
b
54%
Certain adverse side-effects of PUVA therapy have been
attributed to the cross-linking of DNA molecules by pso-
ralens through di-adduct formation.3 To avoid this, mono-
functional PUVA agents are sought that retain the high
photoreactivity and intercalation capacity of psoralens.
An interesting class of such agents is constituted by the
benzoangelicins and benzopsoralens,5 in which the reac-
tive double bond of the furocoumarin furan ring is deacti-
vated by fusing it to an aromatic ring. Evaluation of this
class of compounds has shown that they are not only much
less phototoxic than psoralens, but also have increased ca-
pacity to intercalate and photoreact with DNA.6,7
O
O
O
F3C
CF3
N
N
3
Scheme 1 Reagents and conditions: a) AlCl3, 120 °C; b) 3,6-
bis(trifluoromethyl)-1,2,4,5-tetrazine, dioxane, reflux
The Fries rearrangement of 7-(chloroacetoxy)coumarins
afford the angular dihydrofuro[2,3-h]coumarin-9-ones in
good yield but the linear isomers are only obtained in trac-
es.16 The regioselective electrophilic substitution at C-6
has been accompanied by disruption of the aromaticity of
the pyrone ring.17 In this work we use the Friedel–Crafts
chloroacetylation of ethyl 2,4-dimethoxycinnamate (4)
and further lactonization for the regioselective synthesis
of the desired linear isomer.
In this work we studied the regioselective synthesis of lin-
ear and angular pyridazine analogues of benzofurocou-
marins, reasoning that the inclusion of nitrogen atoms in
the polycyclic skeleton may improve interaction with
DNA.8
Synthesis 2002, No. 1, 28 12 2001. Article Identifier:
1437-210X,E;2002,0,01,0043,0046,ftx,en;E15201SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
We therefore attempted simultaneous formation of the
furanone and pyranone ring by demethylation and lacton-

44
J. C. González-Gómez
PAPER
ization of compound 5a, which was prepared as a 7:1 mix- previously elusive lactonization could be accomplished
ture with its monodemethylated derivative 5b by a by reacting 8 with BBr3 to furnish the desired compound
Friedel–Crafts reaction between ethyl 2,4-dimethoxycin- 9 in 68% yield.
namate (4)18 and excess chloroacetyl chloride at 0 °C in
In conclusion, dihydrofuro[2,3-h]coumarin-9-one (2), re-
gioselectively obtained by Fries rearrangement of 7-
(chloroacetoxy)coumarin (1), afforded the angular py-
ridazinefurocoumarin 3 in good yield by Diels–Alder re-
action with 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine.
Compound 7, synthesized from ethyl 2,4-dimethoxycin-
namate (4) in 34% overall yield, was transformed into the
the presence of AlCl3 (Scheme 2, reaction a; combined
yield 40%).19 Unfortunately, when compound 5a was
treated with BBr3 under the conditions reported for the
preparation of hydroxycoumarins by demethylation and
concomitant lactonization,18 the starting material decom-
posed.
linear pyridazinefurocoumarin 9 in two steps and 48%
O
overall yield. The synthesis of an extensive series of py-
EtO2C
EtO2C
Cl
ridazinefurocoumarins with different substituents is in
progress with a view to evaluate them as DNA-intercalat-
ing drugs and photochemotherapeutic agents.
a
H3CO
OCH3
40%
H3CO
5a R = Me
5b R = H
OR
4
Melting points were determined in capillary tubes in a Büchi 510
apparatus, and are uncorrected. IR spectra were recorded in a Per-
kin-Elmer 1640FT spectrometer. 1H and 13C NMR spectra (the mul-
tiplicity of carbons were determined by DEPT experiments) were
recorded in a Bruker AMX spectrometer at 300 MHz and 75.47
MHz, respectively, using TMS as internal standard (chemical shifts
are given as values, J in Hz). Mass spectra were obtained using a
Hewlett Packard 5988A spectrometer. Elemental analyses were
performed by a Perkin-Elmer 240B microanalyzer and were within
0.4% of calculated values in all cases. 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).
b
93%
O
O
O
EtO2C
EtO2C
Br
c
92%
H3CO
H3CO
OH
7
6
d
71%
F3C
N
N
EtO2C
8,11-Bis(trifluoromethyl)pyridazine[4,5-j]angelicin (3)
2,3-Dichloro-5,6-dicyanobenzoquinone (228 mg, 1 mmol) was
added to a solution of 1,2-dihydro-3,6-bis(trifluoromethyl)-1,2,4,5-
tetrazine23 (220 mg, 1 mmol) in dioxane (5 mL) and the mixture was
stirred for 15 min at r.t. The precipitate was filtered and the solid di-
hydrofuro[2,3-h]coumarin-9-one (2)16 (131 mg, 0.5 mmol) was
added to the red filtrate and refluxed for 5 h. The precipitate was fil-
tered out and washed with fresh dioxane and Et2O, yielding 101 mg
(54%) of pure 3 as a brown solid; mp 281–283 °C (dec.).
CF3
O
H3CO
F3C
e
8
N
68%
N
CF3
O
O
O
9
IR (KBr): 3061, 1746, 1612, 1396, 1202, 1172, 1151, 1123, 1110,
1084, 1044, 852 cm–1.
1H NMR (DMSO-d6): = 8.37 (d, 1 H, J = 8.7 Hz, H-5), 8.35 (d, 1
H, J = 9.7 Hz, H-4), 8.17 (d, 1 H, J = 8.7 Hz, H-6), 6.70 (d, 1 H,
J = 9.7 Hz, H-3).
Scheme 2 Reagents and conditions: a) ClCH2COCl, AlCl3, 0 °C;
b) 1 M BBr3, CH2Cl2, –30 °C; c) K2CO3, acetone, r.t.; d) 3,6-
bis(trifluoromethyl)-1,2,4,5-tetrazine, dioxane, reflux; e) 1 M BBr3,
CH2Cl2, reflux
13C NMR (DMSO-d6): = 158.64, 158.60, 153.00, 149.89, 145.07,
134.81, 123.13, 121.75, 116.64, 115.84, 109.99, 106.36.
MS: m/z (%) = 374 (M+), 346 (100), 221, 193, 173, 99, 69.
Eventually we found that treatment of 5a with 1 equiva-
lent of BBr3 at –30 °C simultaneously deprotected the ox-
ygen ortho to the haloacetyl group22 and replaced the
chlorine of 5a with bromine, affording 6 in 93% yield.
This allowed the furanone ring to be constructed by stir-
ring 6 with K2CO3 in acetone at room temperature, which
gave 7 in 92% (a similar yield was obtained from the mi-
nor product of reaction a, 5b). However, attempts to com-
plete the desired furocoumarinone by BBr3 treatment of 7
were unsuccessful.
Ethyl 5-Chloroacetyl-2,4-dimethoxycinnamate (5a) and Ethyl
5-Chloroacetyl-4-hydroxy-2-methoxycinnamate (5b)
Ethyl 2,4-dimethoxycinnamate (4;18 0.944 g, 4 mmol) was added to
a cold solution of AlCl3 (1.2 g, 8.8 mmol) in chloroacetyl chloride
(10 mL) and stirred for 3 h at 0 °C under Ar. The reaction was
quenched by adding H2O cautiously and the product was extracted
with CH2Cl2. The organic phase was washed with aq sat. solution of
NaHCO3 and dried (Na2SO4). Filtration and solvent evaporation af-
forded a residue which was chromatographed on silica gel using
CH2Cl2 as eluent, giving 5a as a white solid; yield: 440 mg (35%).
Further elution with CH2Cl2–MeOH, 98:2 afforded 5b; yield 60 mg
(5%).
In view of the above results, we decided to subject the
furanone ring to the Diels–Alder reaction before comple-
tion of the coumarin moiety. This approach proved suc-
cessful. Treatment of 7 with 3,6-bis(trifluoromethyl)-
1,2,4,5-tetrazine afforded compound 8 in 71% yield. The
Synthesis 2002, No. 1, 43–46 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Linear and Angular Pyridazine Furocoumarins
45
5a
IR (KBr): 3075, 2984, 2946, 1718, 1699, 1616, 1478, 1264, 1245,
1198, 1174, 1152 cm–1.
Mp 150–152 °C.
IR (KBr): 2988, 1733, 1669, 1604, 1475, 1337, 1285, 1217, 1193,
1170 cm–1.
1H NMR (CDCl3): = 8.16 (s, 1 H, H-6), 7.86 (d, 1 H, J = 16.1 Hz,
=CH–Ar), 6.52 (d, 1 H, J = 16.1 Hz, =CHCO2Et), 6.45 (s, 1 H, H-
3), 4.72 (s, 2 H, CH2Cl), 4.25 (q, 2 H, J = 7.1 Hz, CH2CH3), 4.01 (s,
3 H, CH3O), 3.98 (s, 3 H, CH3O), 1.33 (t, 3 H, J = 7.1 Hz, CH3CH2).
13C NMR (CDCl3): = 189.81, 167.44, 163.58, 162.11, 138.35
(CH), 134.52 (CH), 126.67 (CH), 118.31, 117.57, 94.47 (CH3),
60.39 (CH2), 55.99 (CH3), 55.85 (CH3), 51.25 (CH2), 14.35 (CH3).
1H NMR (CDCl3): = 7.89 (d, 1 H, J = 16.1 Hz, =CH–Ar), 7.82 (s,
1 H, H-4), 6.58 (s, 1 H, H-7), 6.45 (d, 1 H, J = 16.1 Hz, =CHCO2Et),
4.65 (s, 2 H, CH2CO), 4.25 (q, 2 H, J = 7.1 Hz, CH2CH3), 3.96 (s, 3
H, CH3O), 1.32 (t, 3 H, J = 7.1 Hz, CH3CH2).
13C NMR (CDCl3): = 197.4 (C), 177.2 (C), 167.6 (C), 166.7 (C),
138.9 (CH), 124.5 (CH), 120.4 (C), 119.2 (CH), 114.6 (C), 95.6
(CH), 76.1 (CH2), 60.9 (CH2), 56.7 (CH3), 14.7 (CH3).
MS: m/z (%) = 262 (M+), 217 (100), 203.
(E)-8-[2-(Ethoxycarbonyl)ethenyl]-7-methoxy-1,4-bis(trifluo-
romethyl)benzofuro[2,3-d]pyridazine (8)
MS: m/z (%) = 314 ([M + 2]+, 3), 312 (M+, 11), 263 (100), 203, 175,
131, 89, 77.
This compound was prepared from 7 (131 mg, 0.5 mmol) in an anal-
ogous manner to 3. When the reaction was complete the solvent and
excess tetrazine were removed under vacuum and the crude reaction
mixture was purified by FC using CH2Cl2 as eluent, giving 8 as a
white solid; yield: 154 mg (71%); mp 168–170 °C.
5b
Mp (EtOH) 164.5–166.5 °C.
IR (KBr): 3077, 3052, 2983, 2948, 1694, 1642, 1383, 1285, 1273,
1214 cm–1.
IR (KBr): 3085, 2987, 1702, 1630, 1421, 1398, 1303, 1275, 1183,
1156, 1130, 1035, 996, 966 cm–1.
1H NMR (CDCl3): = 8.33 (s, 1 H, H-9), 8.05 (d, 1 H, J = 16.1 Hz,
=CH–Ar), 7.36 (s, 1 H, H-6), 6.64 (d, 1 H, J = 16.1 Hz,
=CHCO2Et), 4.31 (q, 2 H, J = 7.0 Hz, CH2CH3), 4.10 (s, 3 H,
CH3O), 1.38 (t, 3 H, J = 7.0 Hz, CH3CH2).
13C NMR (CDCl3): = 167.1 (C), 163.2 (C), 160.0 (C), 152.6 (C),
138.6 (CH), 124.8 (CH), 124.5 (C), 123.6 (C) 121.6 (CH), 109.7
(C), 95.8 (CH), 61.2 (CH2), 57.0 (CH3), 14.7 (CH3).
1H NMR (CDCl3): = 12.24 (s, 1 H exchange, OH), 7.81 (s, 1 H,
H-6), 7.78 (d, 1 H, J = 15.8 Hz, =CH–Ar), 6.47 (s, 1 H, H-3), 6.46
(d, 1 H, J = 15.8 Hz, =CHCO2Et), 4.63 (s, 2 H, CH2Cl), 4.26 (q, 2
H, J = 7.0 Hz, CH2CH3), 3.94 (s, 3 H, CH3O), 1.33 (t, 3 H, J = 7.0
Hz, CH3CH2).
13C NMR (CDCl3): = 195.40, 167.68, 167.30, 165.60, 139.05
(CH), 131.90 (CH), 118.80 (CH), 117.13, 111.62, 100.61 (CH),
60.89 (CH2), 56.56 (CH3), 44.98 (CH2), 14.76 (CH3).
MS: m/z (%) = 300 ([M + 2]+, 10), 298 (M+, 30), 249 (100), 221,
189, 161, 133, 105, 77.
MS: m/z (%) = 435 ([M + 1]+, 10), 434 (M+), 403, 389 (100), 375,
346.
Ethyl 5-Bromoacetyl-4-hydroxy-2-methoxycinnamate (6)
A solution of BBr3 in CH2Cl2 (1.5 mL, 1 M) was added at –50 °C to
a solution of 5a (460 mg, 1.5 mmol) under Ar. The mixture was
stirred for 4 h while allowing the temperature of the external bath to
reach –30 °C, and was then poured into ice-water and extracted with
CH2Cl2. The organic phase was washed with H2O and dried
(Na2SO4). Filtration and solvent evaporation afforded a yellow solid
that was purified by FC using CH2Cl2 as eluent to give 6; yield: 477
mg (93%); mp 152–155 °C.
6,9-Bis(trifluoromethyl)pyridazine[4,5-h]psoralen (9)
A 1 M solution of BBr3 in CH2Cl2 (1 mL) was added at 0 °C by sy-
ringe to a solution of 8 (122 mg, 0.28 mmoL) in anhyd CH2Cl2 (8
mL) under Ar. The cooling bath was removed and the reaction mix-
ture was refluxed for 3 h. The reaction was quenched by addition of
MeOH (ca. 0.5 mL) until total dissolution of solid. The crude mix-
ture was diluted with CH2Cl2 and washed with H2O, the separated
organic layer was dried (Na2SO4) and the solvent was evaporated
under vacuum. The residue was purified by FC using hexane–
EtOAc, 3:1 as eluent to afford 2; yield: 71 mg (68%); mp (white
needles, EtOH) 205–206 °C (EtOH).
IR (KBr): 3076, 3051, 2982, 2948, 1693, 1640, 1588, 1381, 1368,
1299, 1282, 1261, 1214 cm–1.
1H NMR (CDCl3): = 12.35 (s, 1 H exchange, OH), 7.87 (s, 1 H,
H-6), 7.80 (d, 1 H, J = 16.0 Hz, =CH–Ar), 6.49 (d, 1 H, J = 16.0 Hz,
=CHCO2Et), 6.48 (s, 1 H, H-3), 4.38 (s, 2 H, CH2Cl), 4.27 (q, 2 H,
J = 6.9 Hz, CH2CH3), 3.95 (s, 3 H, CH3O), 1.35 (t, 3 H, J = 6.9 Hz,
CH3CH2).
13C NMR (CDCl3): = 195.4 (C), 167.7 (C), 167.3 (C), 165.6 (C),
133.9 (CH), 127.3 (CH), 117.1 (C), 113.5 (CH), 111.6 (C), 95.4
(CH), 55.7 (CH2), 24.5 (CH2), 51.3 (CH3), 14.7 (CH3).
1H NMR (CDCl3): = 8.40 (s, 1 H, H-5), 7.96 (d, 1 H, J = 9.7 Hz,
H-4), 7.82 (s, 1 H, H-11), 6.59 (d, 1 H, J = 9.7 Hz, H-3).
13C NMR (CDCl3): = 159.1 (C), 158.6 (C), 157.6 (C), 153.2 (C),
143.2 (CH), 125.0 (CH), 124.9 (C), 122.9 (C), 118.7 (C), 117.7
(CH), 114.0 (C), 102,2 (CH).
MS: m/z (%) = 374 (M+), 346 (100), 318, 221, 193.
MS: m/z (%) = 344 ([M + 2]+, 22), 342 (M+, 22), 249 (100), 221,
189.
Acknowledgement
We thank the Spanish Ministry of Education Culture and Sport and
The Xunta de Galicia for financial support under contracts PM99-
0125 and PGIDT00PXI20317PR respectively, and the University
of Santiago de Compostela for the award of a fellowship to J.C.G.G.
(E)-6-Methoxy-5-[2-(ethoxycarbonyl)ethenyl]dihydrobenzo-
furan-3-one (7)
Solid K2CO3 (400 mg) was added to a solution of 6 (477 mg, 1.39
mmol) in anhyd acetone (30 mL) and the reaction mixture was
stirred for 4 h at r.t. After replacing the solvent with CH2Cl2, the
mixture was acidified with 0.1 M HCl and the organic phase was
washed with H2O to neutral pH and dried (Na2SO4). Filtration and
solvent evaporation afforded a residue that was purified by FC us-
ing CH2Cl2–MeOH, 99:1 as eluent to obtain 7 as a white solid;
yield: 334 mg (92%); mp 190–193 °C.
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Synthesis 2002, No. 1, 43–46 ISSN 0039-7881 © Thieme Stuttgart · New York