Synthesis of angular pyrrolocoumarins

Article abstract of DOI:10.1055/s-2002-20952

The new pyrrolocoumarin 3 was synthesized in two steps from 7-amino-4-methylcoumarin by selective o-chloroacetylation at position 8 and subsequent cyclization (the Sugasawa route to indoles). Regioselective inverse electron demand Diels-Alder reaction of

Full text of DOI:10.1055/s-2002-20952

PAPER
475
Synthesis of Angular Pyrrolocoumarins
Synthesis
o
of
A
ngular
P
s
yrrolocou
é
m
arins Carlos González,a Joana Lobo-Antunes,a Paulo Pérez-Lourido,b Lourdes Santana,a Eugenio Uriarte*a
a
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
b
Departamento de Química Inorgánica, Facultade de Ciencias, Universidade de Vigo, 36200 Vigo, Pontevedra, Spain
Received 3 December 2001
pyridazinepyrrolocoumarins by inverse electron demand
Diels–Alder reactions12 with tetrazines.
Abstract: The new pyrrolocoumarin 3 was synthesized in two steps
from 7-amino-4-methylcoumarin by selective o-chloroacetylation
at position 8 and subsequent cyclization (the Sugasawa route to in-
doles). Regioselective inverse electron demand Diels–Alder reac-
tion of 3 with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate or 3,6-
bis(trifluoromethyl)-1,2,4,5-tetrazine then gave the angular py-
ridazinepyrrolocoumarins 4 and 5, respectively, in good yield.
Pyrrolocoumarin 3 was synthesized in two steps and 54%
overall yield from 7-aminocoumarin 113 using the general
methodology introduced by Sugasawa for synthesis of in-
doles.14,15 Chloroacetylation of 1 with chloroacetonitrile,
2 M boron trichloride–dimethyl sulfide and aluminum
trichloride in dichloromethane afforded compound 2 as
the only product in 90% yield (whereas the Fisher method
produces a mixture of C-6 and C-8 isomers).11 The use of
gallium trichloride instead of aluminium trichloride,
though previously reported to improve the chloroacetyla-
tion of indoles,16 gave similar yields. The occurrence of
electrophilic substitution at C-8 but not at C-6 is presum-
ably due to valence-bond stabilization brought about by
the aromatic nature of the pyrone ring of the coumarin.17
Key words: antitumour agents, Diels–Alder reaction, electrophilic
aromatic substitution, indoles, polycycles
Natural coumarins and their synthetic analogues consti-
tute an important class of compounds with properties of
pharmacological or industrial relevance.1,2 In particular,
both linear and angular furocoumarins are important as
photochemotherapeutic agents that are used to treat a va-
riety of skin diseases, thanks to their ability to intercalate
in double-stranded DNA and undergo photoaddition to
thymine, thereby blocking cell growth and replication.3,4
Compound 2 was converted directly into 3 in 60% yield
by reduction with sodium borohydride in refluxing diox-
ane. When the reaction was performed at room tempera-
In the course of our continuing research on polycondensed
coumarin derivatives including furocoumarins fused to
pyridazines,5–7 we have recently synthesized a benzoan-
gelicin which we found to have significant antitumoral ac-
tivity.8 In view of this, and of the known tendency of
nitrogenated polycyclic compounds to have greater anti-
tumoral activity than their oxygenated analogues because
of their greater capacity to bind to DNA and to replica-
tion-related enzymes,9 we wished to synthesize nitroge-
nated isosteres of benzoangelicins. As precursors, and as
potential antitumour agents in their own right, we needed
to prepare angular pyrrolocoumarins without any substi-
tuents on the pyrrole ring. Pyrrolocoumarins are nitroge-
nated isosteres of furocoumarins that in spite of the
tendency noted above have been studied much less exten-
sively than the latter. Known linear pyrrolocoumarins
without pyrrole-ring substituents have absorption peaks in
the near UV-A region (320–400 nm),10 and some linear
and angular benzopyrrolocoumarins have also been ob-
tained, using Fisher methodology.11
ture, the product was the intermediate
-
chloromethylbenzyl alcohol 6 in nearly quantitative yield
which was transformed into compound 3 by treatment
with sodium hydride at room temperature under basic
conditions; however, the yield of this latter step was only
25%, giving an overall yield of less than 25% from 2
(Scheme).
The enamine nature of pyrrolocoumarin 3 dominates its
reactivity and facilitates its inverse electron demand
Diels–Alder reactions with dimethyl 1,2,4,5-tetrazine-
3,6-dicarboxylate18 and 3,6-bis(trifluoromethyl)-1,2,4,5-
tetrazine,19 which afforded the desired pyridazinepyrrolo-
coumarins 4 and 5 in 69 and 45% yield, respectively
(Scheme). These cycloadditions were carried out with an
additional equivalent of tetrazine in order to promote de-
hydrogenation and prevent the rearrangement of the inter-
mediate following the release of diatomic nitrogen.20
Under these conditions aromatization was favoured rather
than the opening of the pyrrole ring, whereas reaction of
furocoumarins with tetrazines opens their furan ring.21
In this communication we report the direct, selective first
synthesis of a 4 ,5 -unsubstituted angular pyrrolocou-
marin and its easy conversion to the desired angular
The crystal structure of 4, determined by X-ray diffracto-
metry, confirms the expected structure (Figure). The pyr-
rolocoumarin skeleton is completely flat and form a
dihedral angle of only 2.6(1)o with the pyridazine ring.
N(1)H and O(6) form an intramolecular hydrogen bond.
Synthesis 2002, No. 4, 15 03 2002. Article Identifier:
1437-210X,E;2002,0,04,0475,0478,ftx,en;E08201SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
The cycloaddition of other heteroaromatic dienes to pyr-
rolocoumarin 3, and the derivatization of their pyridazine

476
J. C. González et al.
PAPER
O
O
NH2
1
2
3
a
O
O
NH2
COCH2Cl
e
b
O
O
NH2
Figure ORTEP plot of the molecular structure of 4 in the crystal
(crystallographic numbering does not correspond to the systematic
numbering)
CHOHCH2Cl
6
f
O
O
NH
hydrogen atoms were refined with anisotropic displacement para-
meters. Hydrogen atoms were included in ideal positions and re-
fined with isotropic displacement parameters. Atomic scattering
factors and anomalous dispersion corrections for all atoms were tak-
en from International Tables for X-ray Crystallography.23
c or d
7-Amino-8-chloroacetyl-4-methylcoumarin (2)
A 2 M solution of BCl3–Me2S in CH2Cl2 (1 mL) was added under
Ar at 0 °C to a solution of 7-amino-4-methylcoumarin (1; 175 mg,
1 mmol) in the same solvent (25 mL). ClCH2CN (0.127 mL, 2
mmol) and AlCl3 (267 mg, 2 mmol) were added, and the mixture
was stirred for 30 min at 0 °C and then refluxed for 24 h. 1 M HCl
(20 mL) was added, and refluxing was continued until complete dis-
solution of the precipitate (ca. 1 h). The phases were separated and
the organic phase was washed with brine (2 10 mL), dried
(Na2SO4) and concentrated under vacuum. The residue was purified
by FC using CH2Cl2–EtOAc (9:1) as eluent; yield: 227 mg (90%);
mp 236–237 °C.
O
O
NH
R
4
5
R = CO2Me
R = CF3
R
N
N
Scheme Reaction conditions: a) ClCH2CN/BCl3–SMe2/AlCl3/
CH2Cl2, 0 °C to reflux, then 1 M HCl, reflux (90%); b) NaBH4/dioxa-
ne–H2O, reflux (60%); c) dimethyl 1,2,4,5-tetrazine-3,6-dicarboxyla-
te/dioxane, reflux (69%); d) 1,2-dihydro-3,6-bis(trifluoromethyl)-
1,2,4,5-tetrazine/DDQ/dioxane, r.t., then reflux (45%); e) NaBH4/
dioxane–MeOH–H2O, r.t. (99%); f) NaH/DMF, r.t. (30%)
IR (KBr): 3423, 3313, 1705 cm–1.
1H NMR (DMSO-d6): = 7.80 (s, 2 H, NH2), 7.60 (d, 1 H, H-5,
J = 9.0 Hz), 6.80 (d, 1 H, H-6, J = 9.0 Hz), 6.10 (s, 1 H, H-3), 5.10
(s, 2 H, CH2), 2.30 (s, 3 H, CH3).
13C NMR (DMSO-d6): = 192.2, 159.3, 155.9, 154.7, 154.5, 130.3,
114.1, 108.0, 107.7, 104.6, 52.2, 14.8.
MS: m/z (%) = 252 ([M + 1]+, 100), 218 (33), 176 (12).
rings, are now in progress with a view to biological eval-
uation of a series of these compounds.
Anal. Calcd for C12H10ClNO3 (251.7): C, 57.27; H, 4.00; N, 5.57.
Found: C, 57.01; H, 4.32; N, 5.27.
Melting points were determined in a Reichert Kofler thermopan or
in capillary tubes in a Büchi 510 apparatus, and are uncorrected. IR
spectra were recorded in a Perkin-Elmer 1640FT spectrometer. H
1
7-Amino-8-(2-chloro-1-hydroxyethyl)-4-methylcoumarin (6)
A mixture of compound 2 (252 mg, 1 mmol), NaBH4 (46 mg, 1.2
mmol) and dioxane–MeOH–H2O (7:2:1, 10 mL) was stirred for 15
min at r.t. A 5% aq solution of NH4Cl (3 mL) was added, and the
precipitate was filtered, washed with EtOH and dried over P2O5 un-
der vacuum; yield: 251 mg (99%); mp 169–171 °C (dec.).
and 13C NMR spectra were recorded in a Bruker AMX spectrometer
at 300 and 75.47 MHz, respectively, using TMS as internal standard
(chemical shifts in values, J in Hz). Mass spectra were obtained
using a Hewlett Packard 5988A spectrometer. Elemental analyses
were performed on 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). Single crystal X-ray crystallograph-
ic structure determination was performed at r.t. on a Siemens Smart
CCD area-detector diffractometer using graphite monochromated
MoK radiation ( = 0.71073 Å). The structure was resolved by di-
rect methods and refined by full-matrix least-squares on F2.22 Non-
IR (KBr): 3440, 3351, 3081, 1772 cm–1.
1H NMR (DMSO-d6): = 7.4 (d, 1 H, H-5, J = 8.5 Hz), 6.70 (d, 1
H, H-6, J = 8.5 Hz), 6.4 (s, 1 H, OH), 6.2 (s, 2 H, NH2), 5.95 (s, 1
H, H-3), 5.4 (m, 1 H, CHOH), 3.8 (m, 2 H, CH2), 2.30 (s, 3 H, CH3).
Synthesis 2002, No. 4, 475–478 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Angular Pyrrolocoumarins
477
13C NMR (DMSO-d6): = 161.9, 153.9, 149.2, 147.9, 125.7, 119.3,
114.6, 113.1, 107.9, 67.0, 46.7, 18.1.
MS: m/z (%) = 254 ([M + 1]+, 10), 228 (14), 200 (100).
the mixture was stirred for 15 min at r.t. The precipitate was filtered
and the filtrate was placed in a sealed ampoule with pyrrolocou-
marin 3 (50 mg, 0.25 mmol). This mixture was refluxed for 24 h.
After cooling, the precipitate was recovered by filtration and
washed with Et2O; yield: 43.7 mg (45%); mp > 350 °C.
Anal. Calcd for C12H12ClNO3 (253.7): C, 56.82; H, 4.77; N, 5.52.
Found: C, 57.09; H, 4.80; N, 5.34.
IR (KBr): 3250, 2906, 2851, 2746, 1772 cm–1.
4-Methylpyrrolo[2,3-h]coumarin (3)
1H NMR (DMSO-d6): = 13.65 (s, 1 H, NH), 8.2 (d, 1 H, H-5,
J = 8.7 Hz), 7.8 (d, 1 H, H-6, J = 8.7 Hz), 6.5 (s, 1 H, H-3), 2.55 (s,
3 H, CH3).
Method A: A mixture of compound 2 (252 mg, 1 mmol), NaBH4 (46
mg, 1.2 mmol) and dioxane–H2O (9:1, 5 mL) was refluxed for 35 h.
The solvent was evaporated under vacuum and the residue was par-
titioned between H2O and EtOAc. The organic phase was dried
(Na2SO4) and concentrated under vacuum, and the resulting residue
was purified by flash chromatography using CH2Cl2–EtOAc (9:1)
as eluent; yield: 120 mg (60%).
13C NMR (DMSO-d6):
= 161.0, 155.6, 152.1, 149.3, 143.1,
139.28, 132.6, 125.8, 124.7, 117.8, 116.4, 115.0, 110.9, 109.8,
109.2, 19.5.
MS: m/z (%) = 388 ([M + 1]+, 100), 389 (29), 387 (13), 370 (12),
368 (18).
Method B: NaH (60% in mineral oil, 40.8 mg, 1 mmol) was added
to a solution of 6 (215.5 mg, 0.85 mmol) in anhyd DMF (4 mL) and
the mixture was stirred for 1 h at r.t., poured into ice-water, and ex-
tracted with EtOAc. The organic phase was dried (Na2SO4) and the
solvent was evaporated under vacuum. The crude product was puri-
fied by flash chromatography using CH2Cl2–EtOAc (9:1) as eluent;
yield: 24 mg (30%); mp 256–58 °C.
Anal. Calcd for C16H7F6N3O2 (387.24): C, 49.63; H, 1.82; N, 10.85.
Found: C, 49.97; H, 1.80; N, 10.59.
Acknowledgements
We thank the Spanish Ministry of Education and Culture (PM99-
0125) and the Xunta de Galicia (PGIDT00PXI20317PR) for finan-
cial support. J.C.G. and J.L.A. thank the University of Santiago de
Compostela and the European Commission, respectively, for finan-
cial support.
IR (KBr): 3260, 1690, 1622, 1600, 1391, 1368, 1354, 897, 748
cm–1.
1H NMR (DMSO-d6): = 11.70 (s, 1 H, NH), 7.40 (m, 3 H, H-
5,6,5 ), 6.70 (s, 1 H, H-4 ), 6.20 (s, 1 H, H-3), 2.50 (s, 3 H, CH3).
13C NMR (DMSO-d6): = 161.4, 156.2, 148.8, 139.0, 127.3, 118.1,
116.5, 111.5, 110.2, 109.7, 99.3, 19.7.
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9,10-Diaza-4-methyl-8,11-bis(methoxycarbonyl)benzopyrro-
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A mixture of pyrrolocoumarin 3 (100 mg, 0.5 mmol) and dimethyl
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Synthesis 2002, No. 4, 475–478 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis 2002, No. 4, 475–478 ISSN 0039-7881 © Thieme Stuttgart · New York