An efficient synthesis of bergapten

Article abstract of DOI:10.3987/COM-05-10451

An efficient synthesis of the linear furanocoumarin, bergapten, is reported. In order to avoid the formation of the angular furanocoumarin, we have adopted iodine as protecting group at the 8 position of the coumarin ring.

Full text of DOI:10.3987/COM-05-10451

HETEROCYCLES, Vol. 65, No. 8, 2005, pp. 1985 - 1988
Received, 19th May, 2005, Accepted, 23rd June, 2005, Published online, 28th June, 2005
AN EFFICIENT SYNTHESIS OF BERGAPTEN
Kazuaki Oda,* Naozumi Nishizono, Yukio Tamai, Yuki Yamaguchi,
Teruki Yoshimura, Keiji Wada, and Minoru Machida
Faculty of Pharmaceutical Sciences, Health Sciences University of
Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
e-mail: k-oda@hoku-iryo-u.ac.jp
Abstract - An efficient synthesis of the linear furanocoumarin, bergapten,
is reported. In order to avoid the formation of the angular furanocoumarin,
we have adopted iodine as protecting group at the 8 position of the
coumarin ring.
Furanocoumarins are natural products showing a wide range of biological properties,1 the most
prominent of which are photobiological effects that can occur upon irradiation with long-
wavelength UV light.2 Thus, many furanocoumarins are potent photosensitizers of human skin
with valuable applications in medicine for the treatment of skin deseases.3 In the field of
molecular biology, furanocoumarins have been used as photochemical reagents for the
investigation of nucleic acid structures and functions.4 Recently, it was found that components
isolated from grapefruit juice have furanocoumarin dimer structures showing extremely high
affinities for a form of cytochrome P450 (CYP3A4).5
Most approaches to the synthesis of linear furanocoumarins have involved the stepwise
elaboration of the two heterocyclic rings beginning from a central aromatic core unit.6 These are
often associated with difficulty in controlling the regiochemical problems. The biological
properties of the furanocoumarins and moderate yields in which they are obtained prompted us to
work on alternative routes for synthesis of bergapten. To insure regiochemical integrity and
convergence, we adopted iodine as an easily introducable and removable group. Herein we report
an efficient route for the synthesis of the linear furanocoumarin, bergapten.
The synthetic route used by our group to obtain bergapten is outlined in Scheme 1. The
commercially available phloroglucinol (1) was monomethylated using a previously published
procedure,7 producing the corresponding anisole derivatives (2). The reaction of 2 and ethyl
propiolate in the presence of ZnCl2 gave 7-hydroxy-5-methoxycoumarin (3) in 68% yield.8 In
order to avoid the formation of the angular furanocoumarin, the 8-position of 3 was protected by
iodine according to the reported procedure.9 The allylation of 4 afforded the O-allyl derivative (5),
which was oxidatively cleaved to the aldehyde (7) via the diol (6), using osmium tetraoxide and
sodium metaperiodate in moderate yield.10 Recently Jin et al. reported an improved procedure for
the oxidative cleavage of olefins by OsO4-NaIO4.11 The addition of 2,6-lutidine resulted in
suppression of the side reaction and improvement in the yield of the oxdation process (69%→
92%). Next, the construction of the furan ring was performed by cyclization of aldehyde (7) with
.
BF3 Et2O in the presence of tetra-n-butylammonium bromide. Ahluwalia et al. already reported

that attempts to prepare 8 via Claisen migration of 5 were unsuccessful.12 Finally, the iodine was
removed by Pd(OAc)2 to afford bergapten (9). Bergapten was isolated in 90% yield as colorless
needles, mp 180-182°C, with spectroscopic properties identical to these of an authentic sample of
the natural product.13
In summary, we have reported an efficient route for synthesis of the linear furanocoumarin,
bergapten. Bergapten is also an applicable intermediate for the synthesis of more complex natural
products. Work is currently underway to prepare various furanocoumarin dimers that have an
inhibitory effect on human CYP3A4.
EXPERIMENTAL
All melting points were determined using a Yamato melting point apparatus (model MP-21) and
are uncorrected. IR spectra were recorded using a JASCO A-102 spectrophotometer. NMR spectra
were obtained using JEOL JNM LA300 and JEOL JNM EX-400 spectrometers. The chemical
shifts are reported in ppm (d) relative to TMS (0.0 ppm) as the internal standard. MS spectra (MS,
HRMS) were obtained using a Shimadzu GC MS 9100-MK gas chromatograph-mass spectrometer.
Column chromatography was conducted using silica gel (Merck, Kieselgel 60, 70-230 mesh).
5-Methoxybenzene-1,3-diol (2)
Phloroglucinol.2H2O (3.5 g, 27.8 mmol) in dioxane (10 mL) and methanol (40 mL, saturated with
dry HCl at 0°C) were heated at 70°C in a sealed-pressure glass bottle. After evaporation, the
residue was purified by column chromatography using hexane–AcOEt (2:1, v/v) to give 2 as pale
yellow oil. Yield 3.45 g (89%). The spectral data of this product were identical to those reported in
ref. 7.
7-Hydroxy-5-methoxychromen-2-one (3)
A mixture of 2 (2.23 g, 15.9 mmol), ZnCl2 (2.18 g, 16 mmol), and ethyl propiolate (2.35 g, 24
mmol) was heated at 90 °C for 1.5 h. After cooling, the reaction mixture was treated with 1M HCl
solution. The precipitates were collected on a filter funnel. Colorless needles (from methanol),

yield 2.08 g (68%), mp 244-247 °C (lit.,14 mp 244-245 °C).
7-Hydroxy-8-iodo-5-methoxychromen-2-one (4)
Aqueous NH4OH (20%, 11 mL) was added to a solution of 3 (427 mg, 2.2 mmol) in dioxane (5
mL). A solution of iodine (620 mg, 2.44 mmol) in 36 mL of aqueous KI (5% w/v) was then added
dropwise with stirring and cooling in an iced water bath. After maintaining the agitation for 50 min,
the mixture was acidified with 2.5 M H2SO4. The precipitates were collected on a filter funnel.
Pale yellow needles (from ethanol), yield 580 mg (82%), mp 226-229 °C (lit.,9 mp 224-225 °C),
1H-NMR (300 MHz, CDCl3) d 3.87 (3H, s), 6.15(1H, d, J=9.8 Hz), 6.54 (1H, s), 7.94 (1H, d, J=9.8
Hz), 11.40 (1H, s). MS m/z 318 (M+). The spectral data of this product were identical to those
reported in ref. 9.
8-Iodo-5-methoxy-7-prop-2-enyloxychromen-2-one (5)
To a solution of 4 (540 mg, 1.7 mmol) and allyl bromide (620 mg, 5.1 mmol) in DMF (25 mL) was
added K2CO3 (700 mg 5.1 mmol), and the mixture was heated at 80 °C for 15 min. After filtration,
the solvent was removed in vacuo to give the crude 5. Pale yellow needles (from ethanol), yield
1
511 mg (86%), mp 196-200 °C (lit.,12 mp 210-212 °C), H-NMR (500 MHz, DMSO-d6) d 3.92 (3H,
s), 4.70 (2H, d, J=4.6 Hz), 5.36 (1H, d, J=9.7 Hz), 5.57 (1H, d, J=16.6 Hz), 6.05(1H, m), 6.14 (1H,
13
d, J=9.7 Hz), 6.69 (1H, s), 7.95 (1H, d, J=9.7 Hz). C-NMR (125 MHz, DMSO-d6) d 57.2, 66.1,
70.4, 93.9, 104.7, 111.8, 111.8, 133.3, 139.3, 155.3, 158.0, 160.6, 161.5. MS m/z 358 (M+). The
spectral data of this product were identical to those reported in ref. 12.
7-(2,3-Dihydroxypropoxy)-8-iodo-5-methoxychromen-2-one (6)
A mixture of N-methylmorpholine N-oxide (270 mg, 2.0 mmol) and 2 mL of 0.02 M OsO4 in tert-
BuOH (2 mL) were added to a solution of 5 (358 mg, 1 mmol) in 2:1 (v/v) of THF and H2O (30
mL). The resulting solution was stirred for 60 h at rt, treated with 1 mL of saturated Na2S2O3
solution, and stirred for 5 min. The reaction mixture diluted with AcOEt was washed with water
and brine, then dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo to
1
give the crude 6. Pale yellow needles (from methanol), yield 337 mg (86%), mp 195-199 °C, H-
NMR (300 MHz, DMSO-d6) d 3.50-3.61 (2H, m), 3.83-3.87 (1H, m), 3.96 (3H, s), 4.11-4.22 (2H,
m), 4.73 (1H, t, J=5.7 Hz), 5.03 (1H, t, J=4.8 Hz), 6.18 (1H, d, J=9.5 Hz), 6.69 (1H, s), 7.94 (1H, d,
13
J=9.5 Hz). C-NMR (75 MHz, DMSO-d6) d 56.6, 62.5, 65.5, 69.8, 71.1, 93.0, 103.9, 111.0, 138.7,
154.7, 157.5, 160.0, 161.6. MS m/z 392 (M+). Anal. Calcd for C13H13O6I: C, 39.82; H, 3.34; I,
32.36. Found: C, 39.91; H, 3.24; I, 32.26.
2-(8-Iodo-5-methoxy-2-oxochromen-7-yloxy)ethanal (7)
NaIO4 (278 mg, 1.3 mmol) was added to a solution of 6 (392 mg, 1.0 mmol) in 2:1 (v/v) of THF
and H2O (45 mL). The resulting solution was stirred for 72 h at rt and the solvent was removed in
vacuo. The residue was purified by column chromatography using hexane–AcOEt (2:1, v/v). Pale
1
yellow needles (from hexane-AcOEt), yield 287 mg (80%), mp 220-224 °C, H-NMR (300 MHz,
DMSO-d6) d 3.92 (3H, s), 4.71 (2H, s), 6.18 (1H, s), 6.21 (1H, d, J=9. 8 Hz), 7.29 (1H, d, J=9.8
Hz), 9.93 (1H, s). MS m/z 360 (M+), HRMS m/z 359.9512 (Calcd for C12H9O5I: 359.9495). Anal.
Calcd for C12H9O5I: C, 40.02; H, 2.52; I, 35.24. Found: C, 40.01; H, 2.44; I, 35.31.
One-step oxidation of 5 to 7
To a solution of 5 (358 mg, 1 mmol) in 3:1 of dioxane and water (10 mL) were added 2,6-lutidine
(214 mg, 2 mmol), OsO4 (2.5% in 2-methyl-2-propanol, 200 mg, 0.02 mmol), and NaIO4 (856 mg,
4 mmol). The reaction mixture was stirred at rt for 2 h. After the reaction was completed, water
(10 mL) and CH2Cl2 (20 mL) were added. The organic layer was separated, and the water layer

was extracted three times by CH2Cl2 (10 mL). The combined organic layer was washed with water
and brine and dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo to
give the crude 7. Pale yellow needles (from hexane-AcOEt), yield 331 mg (92%). mp 220-224 °C.
9-Iodo-5-methoxyfurano[3,2-g]chromen-2-one (8)
To a solution of 7 (180 mg, 0.5 mmol) in CHCl3 (15 mL) were added tetra-n-butylammonium
.
bromide (180 mg, 0.55 mmol) and BF3 Et2O (190mL, 1.5 mmol). The reaction mixture was refluxed
for 30 min. After cooling, a saturated NaHCO3 solution (10 mL) was added. The organic layer was
separated and then washed with water and brine then dried over anhydrous Na2SO4. The solvent
was removed in vacuo, and the residue was purified by column chromatography using
CHCl3–AcOEt (20:1, v/v). Pale yellow needles (from hexane-AcOEt), yield 122 mg (71%), mp
1
195-196 °C (lit.,15 mp 197-199 °C), H-NMR (300 MHz, CDCl3) d 4.28 (3H, s), 6.27 (1H, d, J=9.7
13
Hz), 7.17 (1H, d, J=2.4 Hz), 7.68 (1H, d, J=2.4 Hz), 8.08 (1H, d, J=9.7 Hz). C-NMR (75 MHz,
CDCl3) d 56.5, 60.3, 106.2, 107.4, 112.4, 113.0, 139.0, 144.8, 150.2, 152.2, 158.9, 160.5. MS m/z
342 (M+). The spectral data of this product were identical to those reported in ref. 15.
5-Methoxyfurano[3,2-g]chromen-2-one (9)
To a solution of 8 (35 mg, 0.1 mmol) in DMF (5 mL) were added Pd(AcO)2 (2 mg), Et3N (80 mL,
0.6 mmol), and formic acid (15 mL, 0.4 mmol). The reaction was heated at 80°C for 11 h. After
cooling, the solvent was removed in vacuo. The residue was purified by column chromatography
using hexane–AcOEt (2:1, v/v). Colorless needles (from ethanol), yield 20 mg (90%). mp 180-
1
182 °C (lit.,13 mp 188-189 °C). H-NMR (300 MHz, DMSO-d6) d 4.27 (3H, s), 6.27 (1H, d, J=9.7
13
Hz), 7.02 (1H, d, J=2.4 Hz), 7.12 (1H, s), 7.59 (1H, d, J=2.4 Hz), 8.15 (1H, d, J=9.7 Hz). C-
NMR (75 MHz, CDCl3) d 60.1, 93.8, 105.0, 106.4, 112.5, 112.6, 139.2, 144.8, 149.6, 152.7, 158.4,
161.2.
ACKNOWLEDGEMENTS
This study was partially supported by the “Academic Frontier” Project of the Ministry of
Education, Culture, Sports, Science, and Technology, Japan. We are grateful to the staff of the
Center for Instrumental Analysis, Hokkaido University, for the elemental analysis and HRMS
spectra measurements.
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