Synthesis of 6-methoxy-4H-1-benzopyran-7-ol, a character donating component of the fragrance of Wisteria sinensis

Article abstract of DOI:10.1016/S0040-4020(02)00081-9

6-Methoxy-4H-1-benzopyran-7-ol 7, a major impact flavor compound of Wisteria sinensis has been synthesized from 2,4,5-trimethoxybenzaldehyde 1 via scopoletin 3. The synthetic sequence comprised (i) bisdemethylation of 2,4,5-trimethoxybenzaldehyde 1, (ii) Wittig reaction with ethoxycarbonylmethylenetriphenylphosphorane, (iii) hydrogenation on palladium/carbon in glacial acetic acid, (iv) DIBAL-H reduction of the intermediate lactone and (v) dehydration of the lactol with anhydrous oxalic acid.

Full text of DOI:10.1016/S0040-4020(02)00081-9

TETRAHEDRON
Pergamon
Tetrahedron 58 32002) 2163±2166
Synthesis of 6-methoxy-4H-1-benzopyran-7-ol, a character
donating component of the fragrance of Wisteria sinensis
Jan Demyttenaere,a Kris Van Syngel,a A. Peter Markusse,a Stijn Vervisch,a Silvia Debenedettib
and Norbert De Kimpea,p
aDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
bInstituto de Quimica y Metabolismo del Farmaco, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Junin 956,
1113 Buenos Aires, Argentina
This paper is dedicated to Professor Al Padwa on the occasion of his 65th birthday
Received 21 September 2001; revised 20 December 2001; accepted 22 January 2002
AbstractÐ6-Methoxy-4H-1-benzopyran-7-ol 7, a major impact ¯avor compound of Wisteria sinensis has been synthesized from 2,4,5-
trimethoxybenzaldehyde 1 via scopoletin 3. The synthetic sequence comprised 3i) bisdemethylation of 2,4,5-trimethoxybenzaldehyde 1,
3ii) Wittig reaction with ethoxycarbonylmethylenetriphenylphosphorane, 3iii) hydrogenation on palladium/carbon in glacial acetic acid,
3iv) DIBAL-H reduction of the intermediate lactone and 3v) dehydration of the lactol with anhydrous oxalic acid. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
dehyde 1 by double ether cleavage with aluminum3III)
chloride in dichloromethane via an improved procedure
3see Section 3) to give pure 2,4-dihydroxy-5-methoxy-
benzaldehyde 2 in 73% yield. Subsequent Wittig ole®nation
of the resulting 2,4-dihydroxy-5-methoxybenzaldehyde 22
with ethoxycarbonylmethylenetriphenylphosphorane in
N,N-diethylamine at 1888C afforded scopoletin 3.3 The
Wittig reagent was freshly prepared from ethyl bromo-
acetate and triphenylphosphine through the intermediate
Recently, a number of volatile compounds has been isolated
from the ¯owers of Wisteria sinensis, a popular garden plant
3Leguminosae), which blooms in May with large clusters of
violet ¯owers.1 6-Methoxy-4H-1-benzopyran-7-ol 7 was
isolated from the hexane extract of the ¯owers as a key
¯avor compound, imparting the characteristic smoked
odour to this ¯ower, along with 6,7-dimethoxy-4H-1-benzo-
pyran.1 This result was con®rmed by our groupby GC/MS
analysis of the dichloromethane extract, obtained by steam
distillation solvent extraction of blossoms of W. sinensis.
3ethoxycarbonylmethyl)triphenylphosphonium
bromide.
Scopoletin was obtained pure in a straightforward way but
the yield was rather low 327%). However, the present
synthesis offers the advantage of being simple, fast and
reliable in affording substantial amounts of the pure natural
coumarin scopoletin. It is known that major problems occur
in the synthesis of scopoletin reported in the literature.
Scopoletin has been prepared previously from several
sources, including 2,4-dihydroxy-5-methoxybenzalde-
hyde,4,5 2,4-dihydroxyanisole,5 esculin6 and isovanillin.7
Several of these syntheses suffer from harsh reaction condi-
tions, multiple protection±deprotection reactions and the
use of expensive coumarin derivatives itself. In our hands,
the reported scopoletin synthesis from isovanillin7 could not
be reproduced in the reported yields at various stages. Our
synthesis of scopoletin is based on an improved double
demethylation of 2,4,5-trimethoxybenzaldehyde 1 and the
utilization of a recent protocol for coumarin synthesis from
ortho-hydroxybenzaldehydes and a Wittig reagent.3
In this communication, a convenient synthesis of this
peculiar ¯avor compound 7 is presented.
2. Results and discussion
As a suitable precursor for the synthesis of 6-methoxy-4H-
1-benzopyran-7-ol 7 the coumarin derivative scopoletin 3,
i.e. 7-hydroxy-6-methoxycoumarin, was chosen because it
has the right substitution pattern at the 6- and 7-position. It
can be prepared in two steps from 2,4,5-trimethoxybenzal-
Keywords: 6-methoxy-4H-1-benzopyran-7-ol; scopoletin; fragrance;
Wisteria sinensis.
Corresponding author. Tel.: 132-9-264-59-51; fax: 132-9-264-62-43;
p
Two subsequent reductions of scopoletin and a ®nal
e-mail: norbert.dekimpe@rug.ac.be
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020302)00081-9

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J. Demyttenaere et al. / Tetrahedron 58 62002) 2163±2166
Scheme 1.
dehydration should lead to the title compound 7. The
reaction of scopoletin 3 with hydrogen and 10% palladium
on charcoal in ethanol led to reduction of the ole®nic double
bond and ring opening of the lactone, affording ethyl 3-32,4-
dihydroxy-5-methoxyphenyl)propionate 4 in 80% yield
3Scheme 1). Other less reactive solvents were investigated.
1,2-Dimethoxyethane is a suitable solvent for the reduction
of coumarin itself, but in the case of scopoletin no reduction
upon treatment under hydrogenation conditions was
achieved, which is probably due to the low solubility of
scopoletin in this solvent. Finally, a quantitative reduction
of scopoletin 3 was accomplished using hydrogen and
palladium on carbon in glacial acetic acid at 508C, affording
7-hydroxy-6-methoxychroman-2-one 5 in 94% yield. This
chromanone has been obtained previously by distillation of
3-32,4-dihydroxy-5-methoxyphenyl)propionic acid under
reduced pressure.8
mixture left the starting material unchanged, while stirring
in concentrated sulfuric acid at 08C proved to be too
aggressive. Attempts to dehydrate 6 with anhydrous sodium
sulfate or anhydrous copper3II) sulfate in diethyl ether5
were unsuccessful. The combined dehydrating effect of
p-toluenesulfonic acid and anhydrous calcium chloride in
dichloromethane at room temperature were not strong
enough, whereas p-toluenesulfonic acid and anhydrous
calcium chloride at 408C in acetic acid led to decomposition
products.
Dehydration of 4-chromanol10 and 2-chromanol11 by means
of heating at 1508C with anhydrous copper3II) sulfate has
been reported. Applying this method to 6 resulted in a
mixture of unchanged starting material and tar. The action
of titanium3IV) chloride in diethyl ether at room
temperature on 6 led to no reaction, but the reaction with
titanium3IV) chloride in dichloromethane at room tempera-
ture left only decomposition products. The dehydration with
anhydrous oxalic acid in boiling benzene12 proved to be
suitable for the dehydration of 6-methoxychroman-2,7-
diol 6 3see Scheme 2). The reaction mixture contained
40% of 6-methoxy-4H-1-benzopyran-7-ol 7, the remainder
being starting material. Attempts to improve the formation
of the ¯avor compound 7 by increasing the reaction time or
the added amount of oxalic acid were unsuccessful. The
desired ¯avor compound 7 was isolated from the reaction
mixture by preparative gas chromatography, as other
separation techniques 3distillation, ¯ash chromatography)
precluded its isolation due to its instability. This method
of isolation of the natural ¯avor substance proved to be
very useful for the obtention of pure material, suitable for
the study of the ¯avor characteristics.
The chromanone 5 was easily reduced with diisobutyl-
aluminum hydride in tetrahydrofuran at 2788C affording
6-methoxychroman-2,7-diol 6 as a faintly pink crystalline
substance in 88% yield. The reaction mixture was best
worked upusing sodium ¯uoride and a small amount of
water.9
The ®nal stepin the synthesis of 6-methoxy-4 H-1-benzo-
pyran-7-ol 7 proved to be dif®cult due to problems
encountered using the normal dehydration methods. Re¯ux
of lactol 6 with p-toluenesulfonic acid in benzene in a
Dean±Stark apparatus gave only tars. Treatment of the
hemiacetal 6 with trimethylsilyl tri¯ate only afforded
O-silylated products. The reaction of 6 with thionyl chloride
and trimethylamine in
a dichloromethane/chloroform
Scheme 2.

J. Demyttenaere et al. / Tetrahedron 58 62002) 2163±2166
2165
Unsubstituted 4H-1-benzopyran has been synthesized
previously.13 Dihydrocoumarin was reduced using lithium
tri-tert-butoxyaluminum hydride, which gave 2-chromanol,
which was acetylated with acetic anhydride. The
pyrolysis product of the latter ester afforded 4H-1-benzo-
pyran.13
phenyl)propionate 4 30.10 g, 80%; purity.96% based on
1
NMR). H NMR 3CDCl3, 60 MHz) d 1.2 33H, t, Jˆ8 Hz,
Me), 2.6±2.9 34H, m, Ar-CH2±CH2±CO), 3.8 33H, s, OMe),
4.2 32H, q, Jˆ8 Hz, OCH2), 6.6 and 6.7 3each 1H, each s,
H-5 and H-8).
3.2.4. 7-Hydroxy-6-methoxychroman-2-one 5. To a solu-
tion of scopoletin 3 30.96 g, 5.0 mmol) in warm acetic acid
325 ml), 10% palladium on charcoal 30.15 g) was added and
the mixture was stirred for 17 h at 508C under hydrogen
33.4 bar). The catalyst was ®ltered off and washed with
acetic acid, and the ®ltrate was evaporated and dried in
vacuo, giving pure 3.96%) 7-hydroxy-6-methoxychro-
man-2-one 5 30.92 g, 94%), mp151.5±153 8C 3recrystallized
from ether/hexane, lit.8 mp155 8C). IR 3KBr) nmax 3500±
3200 3OH), 1740 3CvO), 1515, 1438, 1147, 1119 cm21; 1H
NMR 3CDCl3, 270 MHz) d 2.72±2.77 and 2.89±2.94 3each
2H, m, Ar-CH2±CH2±CO), 3.88 33H, s, OMe), 6.64 31H, s,
H-5), 6.66 31H, s, H-8); 13C NMR 3CDCl3, 68 MHz) d 23.52
and 29.45 3C-3 and C-4), 56.42 3OMe), 104.04 3C-8),
109.76 3C-5), 113.10 3C-4a), 143.32, 143.35 and 146.04
3C-6, C-7 and C-8a), 168.80 3CvO). EIMS 370 eV) m/z
3rel. int.): 194 3M1, 100), 179 319), 152 350), 151 344),
137 317), 81 314), 69 327), 53 314).
3. Experimental
3.1. General experimental procedures
The H, 13C, DEPT, COSY and HETCOR NMR spectra
1
were obtained from CDCl3 at 270 MHz 31H) and at
68 MHz 313C) using a JEOL JNM-EX270 FT NMR spectro-
meter. Chemical shifts are reported relative to TMS. Mass
spectra were obtained with a Varian MAT-112S EI 370 eV)
mass spectrometer. IR spectra were recorded on a Thermo
Optec Nicolet Impact 410 FT-IR spectrometer. Melting
points were determined on a BuÈchi 535 apparatus.
3.2. General data and product analysis
3.2.1. 2,4-Dihydroxy-5-methoxybenzaldehyde 2 'improved
procedure of a literature method).2 To a stirred suspen-
sion of aluminum3III) chloride 367 g, 0.50 mol) in dry
dichloromethane 3350 ml), a solution of 2,4,5-trimethoxy-
benzaldehyde 1 324.53 g, 0.125 mol) in dry dichloro-
methane 3125 ml) was added dropwise. After stirring for
4 h at room temperature, another portion of aluminum3III)
chloride 367 g, 0.50 mol), suspended in dry dichloro-
methane 3150 ml), was added. The suspension was further
stirred for 19 h and the reaction mixture was poured onto
1 kg of ice to which 45 ml of concentrated hydrochloric acid
was added. The organic layer was separated and the aqueous
phase was extracted twice with dichloromethane 3200 ml).
The combined organic layers were ®ltered over silica gel,
dried over magnesium sulfate, evaporated and recrystallized
from ethyl acetate to give 2,4-dihydroxy-5-methoxybenzal-
dehyde 2 314.98 g, 73%, mp150 8C 3lit.2 mp152 8C)).
3.2.5. 6-Methoxychroman-2,7-diol 6. A solution of
7-hydroxy-6-methoxychroman-2-one 5 30.88 g, 4.5 mmol)
in THF 320 ml) was cooled to 2788C under a nitrogen
atmosphere. To this solution, a solution of 1N diisobutyl-
aluminum hydride in hexane 310 ml; 0.01 mmol) was added
dropwise and the mixture was stirred for 30 min at 2788C.
The cooling bath was removed for 10 min, and dichloro-
methane 3125 ml), sodium ¯uoride 33.78 g, 90 mmol) and
water 31.26 g, 70 mmol) were added. The mixture was stir-
red vigorously for 30 min, then ®ltered, and dried over
magnesium sulfate. After evaporation of the solvents, pure
6-methoxychroman-2,7-diol 6 30.78 g, 88%) was obtained,
mp135±136 8C 3recrystallized from ethyl acetate). IR 3KBr)
n
max 3450±3280 3OH), 2950, 2550, 2460, 1512, 1350, 1190,
1123, 1045, 1024, 898 cm21. 1H NMR 3CDCl3, 270 MHz) d
1.94±2.02 32H, m, 4-H), 2.61 31H, dt, Jdˆ16.2 Hz,
Jtˆ5.3 Hz, H-3a), 2.90 31H, ddd, J1ˆ16.2 Hz, J2ˆ
10.2 Hz, J3ˆ6.6 Hz, H-3b), 3.01 31H, broad, 2-OH), 3.83
33H, s, OMe), 5.53 31H, broad, H-2), 5.56 31H, broad,
7-OH), 6.44 31H, s, H-8), 6.54 31H, s, H-5); 13C NMR
3CDCl3, 68 MHz) d 19.93 3C-3), 27.12 3C-4), 56.50
3OMe), 91.84 3C-2), 103.54 and 112.31 3C-4a and C-8a),
103.61 3C-8), 111.23 3C-5), 144.92 and 145.96 3C-6 and
C-7). EIMS 370 eV) m/z 3rel. int.): 196 3M1, 75), 179
312), 177 313), 163 311), 153 3100), 140 340), 137 312),
125 315), 93 313), 77 312), 69 338), 67 315), 55 317).
Elem. Anal. 3C10H12O4): Calcd 61.22% C, 6.16% H;
found 61.44% C, 6.02% H.
3.2.2. Scopoletin 3. A mixture of 2,4-dihydroxy-5-methoxy-
benzaldehyde 2 312.58 g, 74.8 mmol) and 3ethoxycarbonyl-
methylene)triphenylphosphorane 331.57 g, 90.6 mmol)14
were dissolved in N,N-diethylaniline 3500 ml). Under a
nitrogen atmosphere, the mixture was heated at 1908C for
4 h, after which it was cooled and kept at room temperature
under nitrogen for 4 days. The formed crystals were ®ltered
off and washed with dry diethyl ether. The crude product
contained some N,N-diethylaniline and triphenylphosphin-
oxide. Therefore, the precipitate was recrystallized from
methanol/hexane, giving pure scopoletin 3 33.89 g, 27%),
mp205±206 8C 3lit.5 mp204 8C; lit.7 198±2008C). The H
1
NMR15 and 13C NMR data16 completely match the data
reported in the literature.
3.2.6. 6-Methoxy-4H-1-benzopyran-7-ol 7. Anhydrous
oxalic acid was prepared by keeping powdered oxalic acid
dehydrate at 1208C for 1 day. To a solution of 6-methoxy-
chroman-2,7-diol 6 30.10 g, 0.51 mmol) in benzene 320 ml),
anhydrous oxalic acid 30.23 g, 2.5 mmol) was added and the
mixture was re¯uxed for 18 h. The reaction mixture was
®ltered and the residue was washed with benzene 3®ve
times with 2 ml). The solvent was evaporated to afford a
reaction mixture 30.10 g) containing starting material 6 and
3.2.3. Ethyl 3-'2,4-dihydroxy-5-methoxyphenyl)propio-
nate 4. A solution of scopoletin 30.10 g, 0.52 mmol) in
ethanol 35 ml), to which was added 10% palladium on
charcoal 350 mg), was stirred at 508C under a hydrogen
atmosphere 350 psi, 3.4 bar) for 7 h, after which the catalyst
was ®ltered off and washed with ethanol. The ®ltrate was
evaporated to give ethyl 3-32,4-dihydroxy-5-methoxy-

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J. Demyttenaere et al. / Tetrahedron 58 62002) 2163±2166
Â
3.3.3. 6-Methoxy-4H-1-benzopyran-7-ol 7. Kovats
retention index 1597.
6-methoxy-4H-1-benzopyran-7-ol 7 in a 55:45 ratio. The
nature identical ¯avor compound 7 was isolated by prepara-
tive gas chromatography 3Delsi Intersmat IGC 120 ml glass
column, 3 m, 5% SE 30, chromosorb W-AW 60±80, TCD,
H2 carrier gas; collection in glass U-shaped vessel, used in
¯avor analysis laboratories) as a yellow oil.1 Amounts of
3.3.4. 6,7-Dimethoxy-4H-1-benzopyran. MS 370 eV) m/z
3rel. int.) 192 3M1, 90), 191 3M121, 100), 177 323), 175 37),
Â
161 35), 147 316), 134 36), 118 35), 106 35), 77 38). Kovats
retention index 1629.
1
about 15 mg per injection could be collected. H NMR
3CDCl3, 270 MHz) d 3.28±3.33 32H, m, H-4), 3.84 33H,
s, OMe), 4.88 31H, dt, Jdˆ6.5 Hz, Jtˆ3.3 Hz, H-3), 5.50
31H, s, OH), 6.41±6.47 33H, m, H-2, H-5 and H-8); 13C
NMR 3CDCl3, 68 MHz) d 22.93 3C-4), 56.35 3OMe),
99.73 3C-3), 103.22 and 110.73 3C-5 and C-8), 140.57
3C-2). The quaternary aromatic carbon atoms were not
detected at the low concentration used. EIMS 370 eV) m/z
3rel. int.): 178 3M1, 96), 177 3M121, 100), 163 331), 162
335), 147 36), 135 313), 134 312), 107 311), 93 310), 89 38),
79 37), 78 38), 77 312), 69 317), 65 311), 53 38), 51 39).
Acknowledgements
The authors are grateful to Professor Paul Goetghebeur
3Department of Biology, Faculty of Sciences, Ghent
University, Ghent, Belgium) for providing the blossoms of
Wisteria sinensis.
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Â
series 3C15±C17) was performed to calculate the Kovats
retention indexes of the compounds.