Regioselective synthesis of dihydrofuro[3,2-g]coumarin-6-one

Article abstract of DOI:10.1055/s-2003-36262

New regioselective routes for the preparation of dihydrofuro[3,2-g]coumarin-6-one (5) have been studied. An efficient three-step synthesis of methyl 3-(5′-chloroacetyl-2′,4′-dihydroxyphenyl)propanoate (7) from resorcinol was the key for the success of our preparation of the target compound 5.

Full text of DOI:10.1055/s-2003-36262

SHORT PAPER
27
Regioselective Synthesis of Dihydrofuro[3,2-g]coumarin-6-one
Synthesis
o
of
D
ihydrofu
s
ro[3,2-
g
]c
é
oumarin-6-one C. 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(98)1594912; E-mail: jcgg1971@yahoo.es
Received 22 July 2002; revised 21 October 2002
to examine new routes for the regioselective preparation
Abstract: New regioselective routes for the preparation of dihydro-
of compound 5.
furo[3,2-g]coumarin-6-one (5) have been studied. An efficient
three-step synthesis of methyl 3-(5 -chloroacetyl-2 ,4 -dihydroxy-
phenyl)propanoate (7) from resorcinol was the key for the success
of our preparation of the target compound 5.
The preference of 7-hydroxycoumarins to react at C-8 in
electrophilic reactions is generally attributed to the aro-
maticity of the pyrone ring.11 We therefore examined the
preparation of linear dihydrofurocoumarinones using the
Fries rearrangement of 7-chloroacetoxy-3,4-dihydrocou-
marin (Scheme 1). Compound 3 was synthesized in good
yield by chloroacetylation of 7-hydroxy-3,4-dihydrocou-
marin (2), which is readily available from resorcinol.12
The only compound isolated from the Fries rearrangement
of compound 3 was the linear compound 4, but only in
20% yield. The final dehydrogenation of 4 was performed
by refluxing in Ph2O in the presence of 10% Pd/C to af-
ford 5 in a modest 40% yield.13 In order to improve the
yield of this oxidation step we attempted the dehydroge-
nation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(2–4 equiv) in toluene under reflux (48 h), but in this case
the yields were even lower.14 Unfortunately, this regiose-
lective route afforded just 6% overall yield of linear com-
pound 5 from compound 2.
Key words: acylations, dehydrogenations, rearrangements, regio-
selectivity, ring closure
Certain linear furocoumarins (psoralens) are currently
used clinically for PUVA (psoralen + ultraviolet-A radia-
tion) treatment of psoriasis, vitiligo and some other skin
disorders, but the several adverse side effects arising from
this treatment have been attributed to the formation of
crosslinking diadducts. Therefore, there have been many
attempts to obtain psoralens that are capable of forming
monoadducts with DNA, however, the blocking of one of
the reactive double bonds – usually that of the furan ring –
prevents diadduct formation.1,2 In our laboratory, for ex-
ample, promising results have been achieved with psor-
alens in which the furan ring is fused to an aromatic ring.3
In particular, we have embarked on the preparation of py-
ridazine analogues of benzofurocoumarins, reasoning that
the inclusion of nitrogen atoms in the polycyclic skeleton
may improve interaction with DNA.4 However, attempts
to perform inverse-electron-demand Diels–Alder reac-
tions between psoralens and tetrazines have failed, caus-
ing the opening of the furan ring.5 For the successful
construction of the desired tetracyclic framework we pre-
viously used the corresponding dihydrofurocoumari-
nones.6 These compounds may themselves have
properties similar to those of psoralens. In any case, they
constitute potential substrates not only for inverse-elec-
tron-demand Diels–Alder reactions with tetrazines, but
also for the synthesis of new furocoumarins by bromina-
tion, condensation with aldehydes or ketones,7 oxime for-
mation,8 aza coupling with benzenediazonium salts,9 and
other processes that modify the furan ring.
The tandem Fries rearrangement-cyclization reaction of
7-chloroacetoxycoumarin provided a convenient route to
the angular dihydrofuro[2,3-h]coumarin-9-one, but the
linear dihydrofuro[3,2-g]coumarin-6-one (5) was ob-
tained only in traces.10 The versatility of dihydrofurocou-
marinones in the furocoumarin field, as well as the lack of
an efficient way to obtain the linear isomers, prompted us
Scheme 1 Reagents and conditions: a) CH2=CHCO2H, Amberlyst
15, toluene, reflux; b) (ClCH2CO)2O, DMAP, THF, reflux; c) AlCl3,
120 °C; d) Amberlyst 15, MeOH, r.t.; e) ClCH2COCl, AlCl3,
CH3NO2, r.t.; f) Amberlyst 15, toluene, reflux; g) i-(Pr)2NEt, MeCN
r.t.; h) Ph2O, reflux; i) 10% Pd/C, Ph2O, reflux
Synthesis 2003, No. 1, Print: 30 12 2002.
Art Id.1437-210X,E;2003,0,01,0027,0029,ftx,en;T08302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

28
J. C. González-Gómez et al.
SHORT PAPER
1H NMR (250.13 MHz, CDCl3): = 7.23 (d, J = 8.1 Hz, 1 H, H-5),
6.87–6.92 (m, 2 H, H-6,8), 4.31 (s, 2 H, CH2Cl), 3.02 (m, 2 H, H-
4), 2.81 (m, 2 H, H-3).
13C NMR (62.83 MHz, CDCl3): = 168.14 (C=O), 166.15 (C=O),
152.84 (C), 150.15 (C), 129.16 (C-5), 121.23 (C), 117.62 (C-6),
110.84 (C-8), 41.11 (CH2Cl ), 29.32 (CH2), 23.73 (CH2).
The low yield in the Fries rearrangement was attributed to
the poor electron-donating capacity of the oxygen of the
lactone ring and so we decided to make the benzene ring
more electron-rich by opening the lactone ring prior to
performing the electrophilic aromatic substitution. Ac-
cordingly, we opened the lactone ring of compound 2 in
excellent yield by treatment with MeOH in the presence
of Amberlyst 15 at room temperature.15 The crude com-
pound 6 was acylated with high regioselectivity, under
very mild conditions, by treatment with chloroacetyl
chloride/AlCl3 in nitromethane at room temperature, af-
fording compound 7 in 65% yield. When the intermediate
compound 7 was refluxed with 10% Pd/C in Ph2O, the de-
sired compound 5 was obtained in a one-pot lactone/fura-
MS (70 eV): m/z (%) = 242 (8), 240 (M+, 23), 164 (100), 136 (34).
Anal. Calcd for C11H9ClO4: C, 54.90; H, 3.77; Cl, 14.73. Found: C,
54.50; H, 3.97; Cl, 15.03.
3,4,6,7-Tetrahydrofuro[3,2-g]coumarin-6-one (4)
Method A: A mixture of 3 (1.20 g, 5 mmol) and AlCl3 (3.34 g, 25
mmol) was heated at 120 °C for 5 h. The cooled mixture was poured
into cold dil. HCl. The crude solid, thus obtained, were washed with
H2O, dried with P2O5 under vacuum, and purified by FC (CH2Cl2–
MeOH, 98:2); yield: 196 mg (20%).
none
formation
process
with
concomitant
dehydrogenation. Although the yield of this last step was
just 30%, the route provided a convenient three-step syn-
thesis of 5 from 2 in an overall yield of 18.5%.
Method B: A solution of 7 (136 mg, 0.5 mmol) in Ph2O (5 mL) was
refluxed under argon for 1 h. After cooling, the residue was purified
by FC (initially hexanes–EtOAc, 3:1 to remove Ph2O, followed by
2:1 and then 1:1); yield: 84 mg (82%).
The key to the success of our synthesis of compound 5
was the preparation of intermediate 7 in 62% yield from
compound 2.16 In order to improve the overall yield of tar-
get compound 5 we attempted new routes from 7 to 5
through the intermediate 4.
Method C: To a solution of 8 (240 mg, 1 mmol) in MeCN (10 mL)
was added diisopropylethylamine (0.3 mL, 1.7 mmol) and the mix-
ture was stirred 12 h at r.t. The mixture was then quenched with aq
0.2 M HCl (30 mL), extracted with CH2Cl2 (3 20 mL), and the
combined organic extracts were washed with brine (2 10 mL) un-
til neutral and dried (Na2SO4). The solvent was removed under vac-
uum and the residue was purified by FC (hexanes–EtOAc, 3:2);
yield: 98 mg (92%); mp 222–224 °C (toluene).
IR (KBr): 1770, 1709, 1634, 1256, 1136 cm–1.
1H NMR (250.13 MHz, CDCl3): = 7.52 (s, 1 H, H-5), 6.80 (s, 1 H,
H-9), 4.65 (s, 2 H, CH2O), 3.03 (m, 2 H, H-4), 2.81 (m, 2 H, H-3).
On refluxing compound 7 in Ph2O we obtained 82% yield
of compound 4 in a one-pot lactone/furanone ring forma-
tion. A better overall yield (91%) was achieved on em-
ploying sequential formation of the lactone and furanone
rings on 4, the former by refluxing compound 7 in toluene
with Amberlyst 15 as catalyst and the latter by stirring
crude compound 8 in the presence of i-Pr2EtN. Although 13C NMR (62.83 MHz, CDCl3): = 197.21 (C=O ester), 174,33
we could not achieve more than 40% yield in the dehydro-
genation of 4, this improvement in the conversion of 7 to
4 allowed us to reach an overall yield of 22.5% of the tar-
(C=O ketone), 167.19 (C), 159.87 (C), 123.61 (CH), 118.20 (C),
118.14 (C), 102.38 (CH), 75.87 (CH2), 29.33 (CH2), 23.72 (CH2).
MS (70 eV): m/z (%) = 204 (M+, 100), 176 (21), 147 (74), 134 (14),
106 (21).
get compound 5 from 2.
Anal. Calcd for C11H8O4: C, 64.71; H, 3.95. Found: C, 65.00; H,
3.56.
Melting points were determined on a Reichert Kofler thermopan or
in capillary tubes in a Büchi 510 apparatus, and are uncorrected. IR
Dihydrofuro[3,2-g]coumarin-6-one (5)
spectra were recorded on a Perkin-Elmer 1640FT spectrometer. 1H
Method A: To a solution of 4 (102 mg, 0.5 mmol) in Ph2O (10 mL)
and 13C NMR spectra were recorded on a Bruker AMX spectrome-
was added 10% Pd/C (100 mg) and the mixture was refluxed under
ter at 300 and 75.47 MHz, respectively, using TMS as internal stan-
argon for 10 h. After cooling, the residue was purified by FC (ini-
dard (chemical shifts in values, J in Hz). Mass spectra were
tially 3:1 hexanes–EtOAc to remove Ph2O, followed by 2:1, and
obtained using a Hewlett Packard 5988A spectrometer. Elemental
then 1:1 hexanes–EtOAc); yield: 40 mg (40%). The spectral and
analyses were performed on a Perkin-Elmer 240B microanalyser.
physical data are in agreement with the values reported previous-
Silica gel (Merck 60, 230–400 mesh) was used for flash chromatog-
ly.10
raphy (FC). Analytical TLC was performed on plates precoated
Method B: To a solution of 7 (136 mg, 0.5 mmol) in Ph2O (10 mL)
was added 10% Pd/C (100 mg) and the mixture was refluxed under
argon for 10h. After cooling, the residue was purified by FC (initial-
ly hexanes–EtOAc, 3:1 to remove Ph2O, followed by 2:1 and then
1:1); yield: 33 mg (30%).
with silica gel (Merck 60 F254, 0.25 mm).
7-Chloroacetoxy-3,4-dihydrocoumarin (3)
To a solution of chloroacetic anhydride (8.45 g, 49.4 mmol) in an-
hyd THF (100 mL) was added solid 7-hydroxy-3,4-dihydrocou-
marin (2; 5.27 g, 32.9 mmol) and 4-dimethylaminopyridine
(DMAP, 420 mg, 3.4 mmol). The mixture was refluxed under argon
for 1.5 h and the solvent was removed under vacuum. The residue
was dissolved in CH2Cl2 (250 mL) and the solution was consecu-
tively washed with H2O (50 mL), NaHCO3 (50 mL), and brine (50
mL). The solution was dried (Na2SO4), concentrated under vacuum
and the product was purified by FC using CH2Cl2 as eluent; white
solid; yield: 5.8 g (75%); mp 104.5–107 °C.
Methyl 3-(2 ,4 -Dihydroxyphenyl)propanoate (6)
A solution of 7-hydroxy-3,4-dihydrocoumarin (2; 480 mg, 3 mmol)
in absolute MeOH (7 mL) was added to Amberlyst-15 (6 g) under
argon. The mixture was occasionally stirred during the first hour
and left at r.t. under argon for 24 h; then diluted with MeOH (20
mL) and filtered under vacuum, washing the resin with MeOH
(5 20 mL). The solvent was removed and the residue was dried
under vacuum; red oil; yield: 526 mg (95%).
IR (KBr): 1765, 1153, 1103 cm–1.
IR (KBr): 3210, 1715, 1590, 1245, 802 cm–1.
Synthesis 2003, No. 1, 27–29 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Dihydrofuro[3,2-g]coumarin-6-one
29
1H NMR (250.13 MHz, DMSO-d6): = 8.20 (br s, 2 H, 2 OH, ex-
changeable with D2O), 6.77 (d, J = 8.1 Hz, 1 H, H-5), 6.24 (d,
J = 1.0 Hz, 1 H, H-2), 6.09 (d, J = 8.0 Hz, 1 H, H-6), 3.55 (s, 3 H,
CH3O), 2.61 (m, 2 H, CH2Ph), 2.46 (m, 2 H, CH2CO2).
HRMS: m/z calcd for C11H9ClO4: 240.0189; found: 240.0192.
Acknowledgement
13C NMR (62.83 MHz, DMSO-d6): = 173.42 (C=O), 157.00 (C),
156.14 (C), 130.30 (CH), 117.28 (C), 106.25 (CH), 102.73 (CH),
51.48 (OCH3), 34.21 (CH2), 25.30 (CH2).
We thank the Spanish Ministry of Education, Culture and Sport for
financial support under contract PM99-0125, and the University of
Santiago de Compostela for the award of a fellowship to J.C.G.G.
MS (70 eV): m/z (%) = 196 (M + 1, 48), 164 (100), 136 (39), 123
(51).
References
HRMS: m/z calcd for C10H12O4: 196.0736; found: 196.0731.
(1) Dall’Acqua, F.; Vedaldi, D. In CRC Handbook of Organic
Photochemistry and Photobiology; Horspool, W. M.; Song,
P.-S., Eds.; CRC Press: Boca Raton, 1995, 1357–1366.
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Methyl 3-(5 -Chloroacetyl-2 ,4 -dihydroxyphenyl)propanoate
(7)
To a solution of AlCl3 (1.73 g, 13 mmol) in nitromethane (4 mL)
was added chloroacetyl chloride (0.25 mL, 3.1 mmol) and a solution
of 6 (510 mg, 2.6 mmol) in nitromethane (4 mL) at 0 °C. The ice-
water bath was removed 5 min later and the mixture was allowed to
warm up to r.t. The stirring was continued for an additional 2 h. The
mixture was then quenched with ice-cold aq 1 M HCl (50 mL), ex-
tracted with CH2Cl2 (5 20 mL), and the combined organic extracts
were washed with brine (2
15 mL) until neutral and dried
(Na2SO4). Complete removal of the solvent in vacuo below 40 °C
(CAUTION! nitromethane may explode if heated) followed by FC
(hexane–EtOAc, 2:1) afforded pure 7 as a white solid; yield: 455 mg
(64%); mp 129–131 °C (toluene).
(6) González-Gómez, J. C.; Santana, L.; Uriarte, E. Synthesis
2002, 43.
(7) Traven, V. F.; Kravtchenko, D. V.; Chivisova, T. A.
Heterocycl. Commun. 1997, 3, 331.
IR (KBr): 3198, 1696, 1641, 1251, 1160, 1136, 790 cm–1.
1H NMR (250.13 MHz, CDCl3): = 11.92 (s, 1 H, OH-1, exchange-
able with D2O), 8.28 (s, 1 H, OH-3, exchangeable with D2O), 7.43
(s, 1 H, H-5), 6.43 (s, 1 H, H-2), 4.60 (s, 2 H, CH2Cl), 3.73 (s, 3 H,
CH3O), 2.86 (m, 2 H, CH2Ph), 2.73 (m, 2 H, CH2CO2).
13C NMR (62.83 MHz, CDCl3): = 194.89 (CO), 176.41 (CO2),
164.84 (C), 163.21 (C), 132.69 (C), 120.27 (C), 111.95 (C), 105.32
(CH), 52.91 (OCH3), 45.10 (CH2Cl), 35.14 (CH2), 24.95 (CH2).
(8) Traven, V. F.; Roshkov, R. V.; Tolmachev, A. Y.;
Kuznecova, N. F.; Podhaluzina, N. Y.; Carberry, E. A.
Heterocycl. Commun. 1997, 3, 4.
(9) Traven, V. F.; Sahharuk, I. I.; Kravtchenko, D. V.
Heterocycl. Commun. 1998, 4, 429.
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Org. Chem. 1983, 48, 2709. (b) Zubia, E.; Rodríguez, F. L.;
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J. Chem. Soc., Perkin Trans. 1 1994, 3095.
MS (70 eV): m/z (%) = 274 (8), 272 (M+, 26), 223 (40), 199 (23),
191 (100), 164 (94), 136 (33), 77 (36).
Anal. Calcd for C12H13ClO5: C, 52.86; H, 4.81; Cl, 13.00. Found: C,
53.26; H, 4.32; Cl, 13.40.
(12) (a) Hoefnagel, A. J.; Gunnewegh, E. A.; Downing, R. S.; van
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(16) (a) Cairns, N.; Harwood, L. M.; Astles, D. P. Tetrahedron
1992, 48, 7581. (b) Our approach to 7 is reminiscent of that
used in this reference but the method described by us provide
a more efficient 3-step synthetic route from resorcinol.
6-Chloroacetyl-7-hydroxy-3,4-dihydrocoumarin (8)
A suspension of 7 (272 mg, 1 mmol) in anhyd toluene (15 mL) was
refluxed with Amberlyst-15 (100 mg) for 1 h. The mixture was fil-
tered under vacuum and the resin was washed with CH2Cl2 (3 10
mL). The solvent was removed in vacuo affording pure 8; yield: 238
mg (99%).
IR (KBr): 1771, 1654, 1252, 1133 cm–1.
1H NMR (250.13 MHz, CDCl3): = 11.80 (s, 1 H, OH, exchange-
able with D2O), 7.65 (s, 1 H, H-5), 6.70 (s, 1 H, H-8), 4.62 (s, 2 H,
CH2Cl), 2.84 (m, 2 H, H-4), 2.73 (m, 2 H, H-3).
MS (70eV): m/z (%) = 242 (8), 240 (M+, 23), 191 (100), 163 (33).
Synthesis 2003, No. 1, 27–29 ISSN 0039-7881 © Thieme Stuttgart · New York