Total syntheses of three natural products, vignafuran, 2-(4-hydroxy-2-methoxyphenyl)-6-methoxybenzofuran-3-carboxylic acid methyl ester, and coumestrol from a common starting material

Article abstract of DOI:10.1039/b006623k

Vignafuran 2, 2-(4-hydroxy-2-methoxyphenyl)-6-methoxybenzofuran-3-carboxylic acid methyl ester 3, and coumestrol 4 were efficiently synthesized from the same starting material, 4-bromoresorcinol 14a, through the common intermediate, diarylacetylene 7. The key steps of these syntheses were the tetrabutylammonium fluoride (TBAF)-catalyzed benzo[b]furan ring formation for 2 and the carbonylative ring closure methodology catalyzed by a Pd complex for 3 and 4. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b006623k

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Total syntheses of three natural products, vignafuran, 2-(4-
hydroxy-2-methoxyphenyl)-6-methoxybenzofuran-3-carboxylic acid
methyl ester, and coumestrol from a common starting material
1
Kou Hiroya, Naoyuki Suzuki, Akito Yasuhara, Yuya Egawa, Atsushi Kasano and
Takao Sakamoto*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578,
Japan. E-mail: sakamoto@mail.pharm.tohoku.ac.jp; Fax: ϩ81-22-217-6864
Received (in Cambridge, UK) 14th August 2000, Accepted 29th September 2000
First published as an Advance Article on the web 20th November 2000
Vignafuran 2, 2-(4-hydroxy-2-methoxyphenyl)-6-methoxybenzofuran-3-carboxylic acid methyl ester 3, and
coumestrol 4 were efficiently synthesized from the same starting material, 4-bromoresorcinol 14a, through the
common intermediate, diarylacetylene 7. The key steps of these syntheses were the tetrabutylammonium fluoride
(TBAF)-catalyzed benzo[b]furan ring formation for 2 and the carbonylative ring closure methodology catalyzed
by a Pd complex for 3 and 4.
Introduction
Heterocyclic compounds, particularly indole1 and benzo[b]-
furan2 derivatives, are of interest because they occur widely in
Nature and have unique biological activities.3 Many synthetic
methods for indole and benzo[b]furan structures have already
been reported.4,5 Among them, the cyclization reaction of 2-
ethynylphenol or 2-ethynylaniline derivatives is a powerful
method for constructing such ring systems because of the avail-
ability of the starting materials and its efficiency.4,5 For the
last few decades, many efforts toward developing new methods
using this strategy have been published, and most studies have
been carried out using metal species, e.g., copper() species,6
Scheme 2
NaAuCl4ؒH2O,7 palladium() species,8–10 and metal alkoxides.11
Between 1966 and 1969, Castro et al.6a,b reported pioneer-
theses of substituted heterocyclic compounds, we have already
ing work involving the copper() halide-catalyzed sequential
coupling and cyclization reactions of 2-iodophenol and 2-
iodoaniline with Cu-acetylide derivatives to give benzo[b]furans
and indoles, respectively (Scheme 1). In spite of its usefulness,
published efficient synthetic procedures for 2-mono- and 2,3-di-
substituted indoles and/or benzo[b]furans, which involve (1)
the cyclization reaction of 2-ethynylphenylcarbamates to
indoles under basic conditions (sodium ethoxide in ethanol
or potassium tert-butoxide in tert-butyl alcohol),11 (2) the
Pd-catalyzed cyclization followed by alkenylation,10k (3) the
Pd-catalyzed carbonylative cyclization reaction,10a and (4) the
tetrabutylammonium fluoride (TBAF)-promoted cyclization
reaction (Scheme 3).12
However, other synthetic procedures for the methyl 2-
substituted indole-3-carboxylate derivatives have recently been
independently reported by Yang10j and Scammells.10h,i Yang
argued about the difficulty in reproducing the reaction con-
ditions reported by Scammells,10h,i which are almost the same as
those we have already reported.10a Consequently, Yang reported
an improved procedure for trapping the C-Pd species by carbon
monoxide, although their catalytic system seems to be slightly
complicated.10j
Based on the above background about the heterocyclic ring
system syntheses, we report here the synthesis of three different
natural products from the same starting materials utilizing our
own method.
Scheme 1
Castro’s method has not seen wide use, because explosive Cu-
acetylides have to be prepared and isolated. Subsequently,
Owen6c and Nilsson6d independently improved this problem by
t
using Cu2O in pyridine or BuOCu in pyridine, respectively,
although heating was necessary for the cyclization reaction.
The palladium() species-promoted cyclization reaction of
2-ethynylaniline and/or 2-ethynylphenol derivatives, which was
first reported in the middle 1980s,8a,b was found to have wide
applicability because of the milder reaction conditions than the
previously reported methods.8–10 Later on, this methodology
was extended for constructing 2,3-disubstituted benzo[b]furans
and indoles using disubstituted acetylenic compounds as the
starting materials.9 More recently, the trapping methodologies
of the resulting 3-substituted Pd species have been well investi-
gated.10 (Scheme 2).
Results and discussion
(a) Target molecules and synthetic strategy
Vignafuran 2, isolated from the leaves of cowpea seedlings
(Vigna unguiculata (L.) Walp.) grown in daylight and infected
During the course of our continuous interests in the syn-
DOI: 10.1039/b006623k
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This journal is © The Royal Society of Chemistry 2000
4339

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Scheme 3
For the synthesis of three benzo[b]furan natural products,
we planned the following strategy. Coumestrol 4 could be syn-
thesized from 3 by successive deprotection and lactonization
reactions. Compounds 2 and 3 could be synthesized from
diphenylacetylene 7 either by a cyclization reaction to benzo[b]-
furan or via our method involving the carbonylative cyclization
reaction10a to methyl benzo[b]furan-3-carboxylates. Compound
7 could be synthesized by the Sonogashira coupling reaction
between 8 and 9. Both 8 and 9 could be constructed from the
same starting material 10 (Fig. 2).
(b) Synthesis of the coumestan ring system
2-Iodophenol 11 was used as the starting material for the syn-
thesis of the coumestan ring system. Pal and Kundu reported
that the Pd-catalyzed cross-coupling reaction of aryl iodides
under an acetylene atmosphere gave the corresponding diaryl-
acetylene.20 Thus, by using their conditions, 13 was afforded in
one step using the reaction of the acetate 12 under acetylene
gas with aryl iodides in the presence of PdCl2(PPh3)2, CuI,
and Et3N (75%). Deacetylation of 13 under basic conditions,
followed by the intramolecular carbonylative cyclization
reaction of 5 as catalyzed by PdCl2 under carbon monoxide
atmosphere,10a afforded 1 in one step (35%) (Scheme 4). The
synthesized product was identified based on a comparison with
previously reported data.18,19c,d,21
Fig. 1
with Colletotrichum lindemuthianum, has been shown to have
strong antifungal activity (Fig. 1).13 The biosynthetic pathway
to vignafuran 2 has been elucidated by Martin and Dewick
utilizing feeding experiments with labelled amino acids.14
Kinoshita later showed the chemical mechanism by careful
analysis.15d The total synthesis of vignafuran 2 was first
reported at the same time as its isolation,13a after which four
different synthetic methods were reported.15
In the meantime, 2-(4-hydroxy-2-methoxyphenyl)-6-meth-
oxybenzofuran-3-carboxylic acid methyl ester 3 was isolated
from exudates released by the roots of iron-deficient alfalfa
(Medicago sativa) (Fig. 1).16 However, not only the biological
activities of 3, but also both the biosynthetic pathway and its
relationship to iron deficiency have yet to be determined.
Coumestrol 4 was isolated from alfalfa and ladino clover
by Bickoff et al. in the 1950s (Fig. 1).17 As the structure of 4
has some resemblance to the well known (E)-4,4Ј-dihydroxy-
stilbene derivatives, which has potent pharmacological activity,
coumestrol 4 shows estrogenic activity.18 Total syntheses
of 4 have been reported by several groups using different
approaches;17d,18,19 however, most of the reported methods
required multiple steps and it appears that the overall yield
could be improved.
(c) Synthesis of the substituted phenylacetylene derivatives
Commercially available 4-bromoresorcinol 14a was selectively
tosylated and the resulting monohydroxy compound was
converted into both the methyl ether 15a and the methoxy-
methyl ether 16a under standard conditions, respectively. The
Sonogashira coupling reaction22 of the bromide 15a with tri-
methylsilylacetylene catalyzed by PdCl2(PPh3)2 in the presence
of CuI and Et3N in DMF, followed by the detrimethylsilylation
reaction, gave 9 in 87% yield (2 steps). On the other hand,
the tosyl ester 16a was converted into the methyl ether 17 by
alkaline hydrolysis followed by the standard methylation
reaction. The methoxymethyl group of 17 was removed under
acidic conditions, then the resulting hydroxy group was
acetylated to afford the acetate 8a (Scheme 5).
Before the synthesis of the natural products, we planned to
apply our carbonylative cyclization strategy10a toward con-
structing the coumestan ring system 1 (Fig 1). Namely,
the intramolecular carbonylative cyclization reaction of the
diphenylacetylene 5, which would be prepared from a 2-
halogenophenol 6 and acetylene, could produce the coumestan
ring system 1 in one step.
The iodides 15b and 16b also could be synthesized in exactly
the same way as described above from the known 4-iodo-
resorcinol 14b which was synthesized from resorcinol and
iodine monochloride.23 However, as the overall yields of both
15b and 16b from 14b were quite low due to the lack of regio-
selectivity during the monotosylation reaction, we have to
improve the synthesis of these compounds.
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Fig. 2
Scheme 4 Reagents, conditions and yields: i, Ac2O, pyridine; ii, acetylene (1 atm), PdCl2(PPh3)2, CuI, Et3N, DMF, 60 ЊC, 75% from 11; iii, NaOH,
aq. MeOH, RT, 90%; iv, CO (1 atm), PdCl2, CuCl2, AcONa, K2CO3, MeCN, 35%.
Scheme 5 Reagents, conditions and yields: i, ICl, Et2O, RT, 70%; ii, TsCl, K2CO3, acetone, reflux; then MeI, reflux, 79% (14a → 15a), 56%
(14b → 15b); iii, TsCl, K2CO3, acetone, reflux; then MOMCl, reflux, 82% (14a → 16a), 56% (14b → 16b); iv, trimethylsilylacetylene,
PdCl2(PPh3)2, CuI, Et3N, DMF, 100 ЊC; v, K2CO3, MeOH, RT, 87% from 15a; vi, KOH, aq. EtOH, reflux; vii, K2CO3, MeI, acetone, reflux, 74% from
16a; viii, (COOH)2ؒ2H2O, aq. MeOH, reflux, 96%; ix, AcCl, K2CO3, acetone, reflux, 90%.
This problem has been solved by conversion of the bromides
into the iodides by employing Suzuki’s method.24 Thus,
reaction of the bromides 15a and 8a with KI and CuI in warm
HMPA gave the iodides 15b and 8b, each in 94% yield, respec-
tively. Also, the Sonogashira coupling reaction was carried out
using the iodide 15b as the starting material under milder
conditions to give 9 in a much higher overall yield (91% from
15a) (Scheme 6).
(d) Coupling and cyclization reaction
When the acetylenic compound 9 and the bromide 8a were
heated at 100 ЊC in the presence of PdCl2(PPh3)2, CuI and
Et3N in DMF, only the homocoupled product 20 was isolated
(Table 1, entry 1). However, under almost the same reaction
conditions but using the more reactive iodide 8b as the counter-
part, the desired heterocoupled product 7 was obtained in
41% yield at room temperature and 68% yield under reflux
(Table 1, entries 2 and 3).
Scheme
6
Reagents, conditions and yields: i, KI, CuI, HMPA,
150 ЊC, 94% (15a → 15b), 94% (8a → 8b); ii, trimethylsilyl-
acetylene, PdCl2(PPh3)2, CuI, Et3N, DMF, RT, 98%; iii, TBAF, THF,
RT, 99%.
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Table 1 Sonogashira coupling reaction of terminal alkyne 9 and halides 8a and 8b
Reagents and solvent: i, PdCl2(PPh3)2, CuI, base, DMF.
Yield (%)
Entry
X
Base
Temperature
Time (t/h)
7
20
1
2
3
4
5
6
Br
I
I
I
I
Et3N
Et3N
100 ЊC
RT
Reflux
RT
Reflux
60 ЊC
1
0
41
68
53
39
0
0
0
0
1.5
1.5
1.5
1.5
1.5
Et3N
iPr2NH
iPr2NH
iPr2NH
Decomposition
96
I
0
In 1997, Miller and Johnson reported the acceleration of
the Sonogashira reaction by employing iPr2NH as the base.25 In
our case, an improvement in the yield was observed using their
reaction conditions (Table 1, entry 2 vs. entry 4). However, when
the reaction mixture was refluxed, the desired product could
not be isolated at all. Presumably the instability of the coupled
compound 7 causes a decrease in the yield. Finally, the coupled
compound 7 was obtained in 96% yield when the reaction
mixture was heated at 60 ЊC for 1.5 h (Table 1, entry 6).
changed the order of the reactions based on the assumption
that the unreactivity of the second demethylation reaction will
be due to the higher electron density on the aromatic ring.
When the tosyl ester 23 was treated with BBr3 at from Ϫ78 to
Ϫ40 ЊC, as we expected, the double demethylation reaction
smoothly proceeded to afford the dihydroxy compound 24 in
72% yield. Alkaline hydrolysis of the tosyl compound 24 (3 M
KOH, THF, reflux), followed by acid-catalyzed lactonization
(cat. TsOH, THF, 60 ЊC) gave coumestrol 4 in 53% yield from
24. The spectral data of the synthesized 4 were identified with
those of the reported compound (Scheme 7).16,19d
(e) Synthesis of vignafuran, 2-(4-hydroxy-2-methoxyphenyl)-6-
methoxybenzo[b]furan-3-carboxylic acid methyl ester, and
coumestrol
Experimental
The availability of 7 described above prompted us to attempt
to use it for the syntheses of the three kinds of benzo[b]furan
natural products.
Mps were measured on a YAZAWA Micro Melting Point BY-2
apparatus. All mps and bps are uncorrected. IR spectra were
measured using a JASCO IR-810 spectrophotometer. 1H NMR
spectra were recorded on a Varian Gemini 2000 (300 MHz) and
a JEOL GX-500 (500 MHz) with samples in CDCl3 solvent,
unless otherwise stated. The chemical shifts are expressed in
δ (ppm)-values with tetramethylsilane (TMS) as the internal
reference and coupling constants (J) are given in Hz. Mass
spectra and high-resolution mass spectra were recorded on
JEOL JMS-DX303 and JMS-AX500 instruments, respectively.
Thus, the acetyl group of 7 was reductively removed by
DIBAL-H to give the phenol 21, which was cyclized by applying
the TBAF-promoted reaction12 to afford the benzo[b]furan 22
in 53% overall yield from 7. Finally, the detosylation of 22 with
sodium methoxide afforded vignafuran 2 in 78% yield (Scheme
1
7). The H NMR and mass spectral data of the synthesized
vignafuran 2 were identical with those of the reported natural
product.13
For the synthesis of 3, the methoxycarbonyl analogue of
vignafuran 2, the acetate 7 was allowed to react with carbon
monoxide in MeOH in the presence of PdCl2(PPh3)2, Cu-
Cl2ؒ2H2O, AcONa, and K2CO3 at room temperature for 2
days. Deacetylation, cyclization, and trapping reactions of the
C3-Pd species by carbon monoxide proceeded successively and
the desired methyl 2-arylbenzo[b]furan-3-carboxylate 23 was
obtained in 71% yield (Scheme 7). The structure of 23 was
confirmed by the molecular-ion peak (m/z 482) from EI mass
spectrometry, the absorption at 1720 cmϪ1 from IR spectroscopy,
and the three methoxy peaks (δ 3.71, 3.80, 3.87) and two typical
1,2,4-trisubstituted benzene ring patterns [δ 6.63 (1H, dd,
J 8.5, 2.2), 6.71 (1H, d, J 2.2), 6.98 (1H, dd, J 8.5, 2.2), 7.03
(1H, dd, J 8.5, 2.2), 7.44 (1H, d, J 8.5), 7.87 (1H, d, J 8.5)]
2,2Ј-Diacetoxydiphenylacetylene 13
Acetic anhydride (0.89 ml, 10 mmol) was added to a solution of
2-iodophenol 11 (2.2 g, 10 mmol) in pyridine (50 ml) at 0 ЊC.
After the solution had been stirred for 1 h at room temperature,
pyridine was evaporated off and 3 M HCl (50 ml) was added to
the residue. The aqueous solution was extracted by CHCl3 and
the organic solution was washed with water, dried over MgSO4
and evaporated. Crude 12 was used in the next reaction without
further purification.
A mixture of 12 (0.52 g, 2 mmol), PdCl2(PPh3)2 (50 mg, 0.07
mmol), CuI (40 mg, 0.23 mmol) and Et3N (0.59 ml, 10 mmol)
in DMF (20 ml) was stirred at 60 ЊC under dried acetylene gas.
After the mixture had been stirred for 16 h, the mixture was
filtered through a Celite pad and the filtrate was extracted with
Et2O. The combined organic solution was washed successively
with water and saturated aq. NaCl, dried over MgSO4 and
evaporated. The residue was chromatographed on silica gel
with hexane–AcOEt (7:1) as eluent to give 13 (0.45 g, 75%) as
a white powder, mp 143–145 ЊC (Found: C, 73.44; H, 4.84.
C18H14O4 requires C, 73.46; H, 4.79%); νmax (KBr)/cmϪ1 1760,
1220, 1180; δH (500 MHz) 2.36 (6H, s), 7.12 (2H, d, J 8.0), 7.22–
7.26 (2H, m), 7.38 (2H, dt, J 8.0, 1.8), 7.54 (2H, dd, J 8.0, 1.8);
1
in the H NMR spectrum. Finally, the tosyl group of 23 was
removed by treatment with sodium methoxide in MeOH to
afford quantitatively the target benzo[b]furan natural product
3 (Scheme 7).
For the coumestrol 4 synthesis, we first tried to cleave the two
methoxy group of 3. However, in our hands, it was not possible
to remove the two methyl groups at the same time (BBr3,
CH2Cl2, Ϫ78 ЊC or AlCl3, MeCN, 70 ЊC). The only isolated
product was a monodemethylated compound. Therefore, we
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Scheme 7 Reagents, conditions and yields; i, DIBAL-H, PhMe, Ϫ78 ЊC, 81%; ii, TBAF, THF, reflux, 67%; iii, NaOMe, MeOH, reflux, 78 ЊC;
iv, PdCl2(PPh3)2, CuCl2ؒ2H2O, AcONa, K2CO3, MeOH, CO, RT, 71%; v, NaOMe, MeOH, reflux, 100%; vi, BBr3, CH2Cl2, Ϫ78 to 40 ЊC, 72%;
vii, 3 M KOH, THF, reflux; then cat. TsOH, THF, 60 ЊC, 53%.
m/z 294 (Mϩ, 13.6%) and 210 (100) (Found: Mϩ, 294.0909.
C18H14O4 requires M, 294.0892).
combined organic solution was washed successively with water
and saturated aq. NaCl, dried over MgSO4 and evaporated. The
residue was successively purified with silica gel chromatography
[AcOH–CHCl3 (1:9)] and alumina chromatography [hexane–
AcOEt (2:1)] to afford 14b23 as a colorless solid (4.13 g, 70%),
δH (300 MHz) 5.21 (2H, br), 6.27 (1H, dd, J 8.6, 2.8), 6.54 (1H,
d, J 2.8), 7.46 (1H, d, J 8.6); m/z 236 (Mϩ, 100%) (Found: Mϩ,
235.9356. Calc. for C6H5IO2: M, 235.9327).
2,2Ј-Dihydroxydiphenylacetylene 5
A mixture of 13 (0.21 g, 0.78 mmol) and 3 M NaOH (0.57 ml,
1.7 mmol) in MeOH (12 ml) was stirred at room temperature.
After the mixture had been stirred for 30 min, the mixture
was concentrated under reduced pressure and the residue
was extracted with CHCl3. The combined organic solution was
washed successively with water and saturated aq. NaCl, dried
over MgSO4 and evaporated. The residue was purified by
column chromatography and elution with hexane–AcOEt (7:1)
to afford the bisphenol 5 (0.15 g, 90%) as a white powder, mp
95–97 ЊC (Found: C, 80.22; H, 5.06. C14H10O2 requires C, 79.98;
H, 4.79%); νmax (KBr)/cmϪ1 3300; δH (300 MHz) 5.87 (2H, s),
6.92–7.00 (4H, m), 7.30 (2H, ddd, J 8.8, 7.4, 1.4), 7.44 (2H, dd,
J 7.7, 1.4); m/z 210 (Mϩ, 100%) and 181 (73.3) (Found: Mϩ,
210.0725. C14H10O2 requires M, 210.0681).
1-Bromo-2-methoxy-4-(tosyloxy)benzene 15a
A mixture of 4-bromoresorcinol 14a (10.0 g, 53.0 mmol),
K2CO3 (22.0 g, 159 mmol) and TsCl (11.1 g, 58.0 mmol) in
acetone (150 ml) was refluxed for 21 h. MeI (15.0 g, 106 mmol)
was added to the mixture, which was further refluxed for 3 h.
The inorganic precipitate was filtered off and the filtrate was
concentrated under reduced pressure. The residue was diluted
with water and extracted with AcOEt. The combined organic
solution was washed successively with water and saturated aq.
NaCl, dried over MgSO4 and evaporated. The residue was
chromatographed on silica gel with hexane–AcOEt (3:1) as
eluent to give 15a (15.0 g, 79%) as a white powder. An analytical
sample was recrystallized from AcOEt–hexane to give color-
less needles, mp 69–72 ЊC (Found: C, 47.17; H, 3.76; S, 8.90.
C14H13BrO4S requires C, 47.07; H, 3.67; S, 8.97%); νmax
(CHCl3)/cmϪ1 1380, 1280, 1180, 1030; δH (300 MHz) 2.46
(3H, s), 3.79 (3H, s), 6.41 (1H, dd, J 8.5, 2.5), 6.60 (1H, d, J 2.5),
7.33 (2H, d, J 8.5), 7.41 (1H, d, J 8.5), 7.72 (2H, d, J 8.5).
6H-[1]Benzofuro[3,2-c]chromen-6-one (coumestan ring
system) 1
A mixture of 5 (0.12 g, 0.56 mmol), PdCl2 (10 mg, 0.06 mmol),
CuCl2 (0.16 g, 1.23 mmol), AcONa (0.09 g, 0.56 mmol) and
K2CO3 (0.15 g, 1.1 mmol) in MeCN (5 ml) was stirred at room
temperature for 20 h. The reaction mixture was concentrated
under reduced pressure, then the residue was extracted with
CHCl3. The combined extracts were washed successively with
water and saturated aq. NaCl. The organic solution was dried
over MgSO4 and evaporated. The residue was chromato-
graphed on silica gel with hexane–AcOEt (10:1) as eluent to
give coumestan 118,19c,d,21 (0.046 g, 35%) as a white powder, mp
178–181 ЊC (lit.,19c mp 182–183 ЊC, mp 179–180 ЊC19d) (Found:
C, 76.09; H, 3.57. Calc. for C15H8O3: C, 76.27; H, 3.41%);
δH (300 MHz) 7.40–7.53 (4H, m), 7.60–7.70 (2H, m), 8.05
(1H, d, J 7.7), 8.15 (1H, dd, J 6.3, 4.1); m/z 236 (Mϩ, 100%)
(Found: Mϩ, 236.0457. Calc. for C15H8O3: M, 236.0473).
1-Bromo-2-methoxymethoxy-4-(tosyloxy)benzene 16a
A mixture of 4-bromoresorcinol 14a (5.00 g, 26.5 mmol),
K2CO3 (11.0 g, 79.4 mmol) and TsCl (5.56 g, 29.2 mmol)
in acetone (100 ml) was refluxed for 21 h. MOMCl (4.27 g,
53.0 mmol) was added to the mixture, which was further
refluxed for 3 h. The inorganic precipitate was filtered off
and the filtrate was concentrated under reduced pressure. The
residue was diluted with water and extracted with AcOEt. The
combined organic solution was washed successively with water
and saturated aq. NaCl, dried over MgSO4 and evaporated. The
residue was chromatographed on silica gel with hexane–AcOEt
(3:1) as eluent to give 16a (8.45 g, 82%) as a white powder.
An analytical sample was recrystallized from AcOEt–hexane
to give colorless needles, mp 70–72 ЊC (Found: C, 46.54; H,
4-Iodoresorcinol 14b
A solution of resorcinol (2.75 g, 25.0 mmol) and ICl (4.0 g,
25.0 mmol) in dry Et2O (25 ml) was stirred at room temperature
for 1 h. Water (50 ml) and Na2SO3 (1.0 g) were added to the
mixture, then the aqueous phase was extracted with Et2O. The
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3.82; S, 8.25. C15H15BrO5S requires C, 46.52; H, 3.90; S, 8.28%);
νmax (CHCl3)/cmϪ1 1380, 1280, 1180, 1040; δH (300 MHz) 2.47
(3H, s), 3.43 (3H, s), 5.10 (2H, s), 6.57 (1H, dd, J 8.8, 2.7),
6.77 (1H, d, J 8.8), 7.33 (2H, d, J 8.2), 7.44 (1H, d, J 8.8), 7.72
(2H, d, J 8.2).
successively with water and saturated aq. NaCl. The organic
solution was dried over MgSO4 and evaporated. The residue
was chromatographed on silica gel with hexane–AcOEt (4:1) as
eluent to give 17 (3.56 g, 74%) as a colorless oil, bp 95 ЊC/3
mmHg (Found: C, 44.02; H, 4.62. C9H11BrO3 requires C, 43.75;
H, 4.49%); νmax (CHCl3)/cmϪ1 1310, 1280, 1060, 1030; δH (300
MHz) 3.52 (3H, s), 3.78 (3H, s), 5.20 (2H, s), 6.48 (1H, dd,
J 8.8, 2.7), 6.77 (1H, d, J 2.7), 7.41 (1H, d, J 8.8).
1-Iodo-2-methoxy-4-(tosyloxy)benzene 15b
(a) Synthesis from 4-iodoresorcinol 14b. A mixture of 4-
iodoresorcinol 14b (1.60 g, 6.78 mmol), K2CO3 (2.82 g, 20.4
mmol) and TsCl (1.40 g, 7.40 mmol) in acetone (30 ml) was
refluxed for 15 h. MeI (2.89 g, 20.4 mmol) was added to the
mixture, which was further refluxed for 3 h. The inorganic
precipitate was filtered off and the filtrate was concentrated
under reduced pressure. The residue was diluted with water
and extracted with AcOEt. The combined organic solution
was washed successively with water and saturated aq. NaCl,
dried over MgSO4 and evaporated. The residue was chromato-
graphed on silica gel with hexane–AcOEt (4:1) as eluent to give
15b (1.53 g, 56%) as a yellow viscous oil, νmax (CHCl3)/cmϪ1
1380, 1280, 1180, 1040; δH (300 MHz) 2.46 (3H, s), 3.77 (3H, s),
6.30 (1H, dd, J 8.3, 2.5), 6.52 (1H, d, J 2.5), 7.30 (2H, d, J 8.3),
7.63 (1H, d, J 8.4), 7.72 (2H, d, J 8.4); m/z 404 (Mϩ, 76.2%)
and 91(100) (Found: Mϩ, 403.9555. C14H13IO4S requires M,
403.9579).
2-Bromo-5-methoxyphenol 18
A solution of 17 (3.56 g, 14.4 mmol) and oxalic acid dihydrate
(3.66 g, 29.0 mmol) in MeOH–water (1:1; 80 ml) was refluxed
for 2.5 h. The reaction mixture was extracted with Et2O and
the combined extract was washed successively with water and
saturated aq. NaCl. The organic solution was dried over
MgSO4 and evaporated. The residue was purified by silica gel
column chromatography and elution with hexane–AcOEt
(7:1) to give 1826 (2.82 g, 96%) as a colorless oil, bp 90 ЊC/3
mmHg (Found: C, 41.39; H, 3.55. Calc. for C7H7BrO2: C, 41.41;
H, 3.47%); δH (300 MHz) 3.77 (3H, s), 5.53 (1H, br), 6.41 (1H,
dd, J 8.8, 2.9), 6.60 (1H, d, J 2.9), 7.30 (1H, d, J 8.8).
2-Acetoxy-1-bromo-4-methoxybenzene 8a
A mixture of 18 (2.30 g, 11.3 mmol), K2CO3 (3.10 g, 22.4 mmol)
and AcCl (2.21 g, 28.1 mmol) in acetone (60 ml) was refluxed
for 2 h. Water (200 ml) was added to the mixture, which was
extracted with AcOEt. The combined extract was washed
successively with water and saturated aq. NaCl, dried over
MgSO4 and evaporated. The residue was chromatographed on
silica gel with hexane–AcOEt (5:1) as eluent to give 8a (2.50 g,
90%) as a colorless oil, bp 110 ЊC/4 mmHg (Found: C, 44.30;
H, 3.79. C9H9BrO3 requires C, 44.11; H, 3.70%); νmax (CHCl3)/
cmϪ1 1780, 1290, 1200, 1020; δH (300 MHz) 2.30 (3H, s), 3.71
(3H, s), 6.66 (1H, dd, J 8.5, 2.7), 6.68 (1H, d, J 2.7), 7.43 (1H,
d, J 8.5 ).
(b) Synthesis from 15a. A mixture of 15a (0.36 g, 1.00 mmol),
KI (2.46 g, 15.0 mmol) and CuI (0.95 g, 5.00 mmol) in HMPA
(3 ml) was stirred under an Ar atmosphere at 150 ЊC for 3 h. The
reaction mixture was acidified by 3 M HCl and extracted with
Et2O. The organic solution was washed successively with aq.
Na2SO3, water, and saturated aq. NaCl, dried over MgSO4
and evaporated. The residue was purified by silica gel column
chromatography with hexane–AcOEt (2:1) as eluent to afford
15b (0.38 g, 94%) as a yellow viscous oil.
1-Iodo-2-methoxymethoxy-4-(tosyloxy)benzene 16b
A mixture of 4-iodoresorcinol 14b (3.25 g, 13.8 mmol), K2CO3
(9.54 g, 67.0 mmol) and TsCl (2.86 g, 15.0 mmol) in acetone
(50 ml) was refluxed for 5 h. MOMCl (2.20 g, 27.4 mmol)
was added to the mixture, which was further refluxed for 3 h.
The inorganic precipitate was filtered off and the filtrate was
concentrated under reduced pressure. The residue was diluted
with water and extracted with AcOEt. The combined organic
solution was washed successively with water and saturated
aq. NaCl, dried over MgSO4 and evaporated. The residue was
chromatographed on silica gel with hexane–AcOEt (2:1)
as eluent to give 16b (3.67 g, 56%) as a yellow viscous oil,
δH (300 MHz) 2.45 (3H, s), 3.43 (3H, s), 5.10 (2H, s), 6.46
(1H, dd, J 8.5, 2.6), 6.69 (1H, d, J 2.6), 7.33 (2H, d, J 8.5),
7.67 (1H, d, J 8.5), 7.72 (2H, d, J 8.5); m/z 434 (Mϩ, 13.6%)
and 45 (100) (Found: Mϩ, 433.9680. C15H15IO5S requires M,
433.9685).
2-Acetoxy-1-iodo-4-methoxybenzene 8b
A mixture of 8a (0.38 g, 1.55 mmol), KI (3.86 g, 23.3 mmol)
and CuI (1.48 g, 7.75 mmol) in HMPA (3 ml) was stirred under
an Ar atmosphere at 150 ЊC for 3 h. The reaction mixture was
acidified by 3 M HCl and extracted with Et2O. The organic
solution was washed successively with aq. Na2SO3, water, and
saturated aq. NaCl, dried over MgSO4 and evaporated. The
residue was purified by silica gel column chromatography
and elution with hexane–AcOEt (2:1) to afford 8b27 (0.43 g,
94%) as a colorless oil; νmax (film)/cmϪ1 1780, 1240, 1200, 1040;
δH (300 MHz) 2.36 (3H, s), 3.78 (3H, s), 6.60 (1H, dd, J 8.8, 3.0),
6.69 (1H, d, J 3.0), 7.66 (1H, d, J 8.8); m/z 292 (Mϩ, 76.2%)
and 250 (100) (Found: Mϩ, 291.9587. C9H9IO3 requires M,
291.9595).
2-Methoxy-4-(tosyloxy)phenylacetylene 9
1-Bromo-4-methoxy-2-(methoxymethoxy)benzene 17
(a) Synthesis from 15a. A mixture of 15a (0.20 g, 0.56 mmol),
trimethylsilylacetylene (0.33 g, 3.36 mmol), CuI (13.0 mg,
0.06 mmol) and PdCl2(PPh3)2 (23.0 mg, 0.03 mmol) in a
mixture of Et3N (1.0 ml) and DMF (0.5 ml) was heated at
100 ЊC for 24 h. The precipitate was filtered off and the filtrate
was concentrated under reduced pressure. The residue was
extracted with Et2O and the combined extracts were washed
successively with water and saturated aq. NaCl. The organic
solution was dried over MgSO4 and evaporated to afford 19 as a
colorless solid, which was used to the next reaction without
further purification.
A solution of 16a (7.51 g, 19.4 mmol) and KOH (5.88 g,
105 mmol) in a mixture of EtOH (315 ml) and water (35 ml)
was heated under reflux for 2 h. 3 M HCl was added to
the mixture at room temperature until pH 4. The aqueous
phase was extracted with Et2O and the extracts were washed
successively with water and saturated aq. NaCl. The organic
solution was dried over MgSO4 and evaporated to give the
crude phenol, which was used to the next reaction without
further purification.
A mixture of the crude phenol, K2CO3 (14.0 g, 101 mmol)
and MeI (19.0 g, 134 mmol) in acetone (1 l) was refluxed for
2.5 h. The inorganic precipitate was filtered off and the filtrate
was concentrated under reduced pressure. The residue was
extracted with Et2O and the combined extract was washed
A mixture of the crude silyl compound 19 and K2CO3
(0.35 g, 2.52 mmol) in MeOH (100 ml) was stirred at room
temperature for 1.5 h. The excess of K2CO3 was filtered off
and the residue was concentrated under reduced pressure. The
4344
J. Chem. Soc., Perkin Trans. 1, 2000, 4339–4346

View Article Online
residue was extracted with Et2O and the combined organic
solution was washed successively with water and saturated
aq. NaCl. The organic solution was dried over MgSO4 and
evaporated. The residue was purified by silica gel column
chromatography and elution with hexane–AcOEt (3:1) to give
9 (0.44 g, 87%) as a yellow viscous oil, νmax (film)/cmϪ1 3300,
1380, 1280, 1180, 1040; δH (300 MHz) 2.45 (3H, s), 3.30 (1H, s),
3.79 (3H, s), 6.48 (1H, dd, J 8.2, 2.2), 6.59 (1H, d, J 2.2),
7.32 (2H, d, J 8.3), 7.33 (1H, d, J 8.5), 7.72 (2H, d, J 8.3);
m/z 302 (Mϩ, 17.3%) and 91 (100) (Found: Mϩ, 302.0611.
C16H14O4S requires M, 302.0613).
6.55 (1H, d, J 2.2), 6.63 (1H, d, J 2.2), 6.74 (1H, s), 7.27 (1H, d,
J 8.5), 7.30 (1H, d, J 8.5), 7.33 (2H, d, J 8.0), 7.73 (2H, d, J 8.0);
m/z 424 (39.3%, Mϩ) and 269 (100) (Found: Mϩ, 424.0932.
C23H20O6S requires M, 424.0981).
6-Methoxy-2-[2-methoxy-4-(tosyloxy)phenyl]benzo[b]furan 22
A solution of 21 (120 mg, 0.28 mmol) and TBAF (1.0 M solu-
tion in THF; 0.56 ml, 0.56 mmol) in THF (7 ml) was refluxed
for 3 h. The reaction mixture was diluted with water and the
precipitate was filtered off. The filtrate was concentrated in
vacuo, then the residue was extracted with CHCl3. The com-
bined organic solution was washed successively with water
and saturated aq. NaCl, dried over MgSO4 and evaporated. The
residue was purified by silica gel column chromatography and
eluted with hexane–AcOEt (6:1) to afford 22 (80 mg, 67%) as
a colorless solid, mp 89–91 ЊC; νmax (CHCl3)/cmϪ1 3400, 1270,
1040; δH (300 MHz) 2.45 (3H, s), 3.87 (3H, s), 3.89 (3H, s), 6.58
(1H, dd, J 8.5, 2.2), 6.71 (1H, d, J 2.2), 6.86 (1H, dd, J 8.5, 2.2),
7.02 (1H, d, J 2.2), 7.25 (1H, s), 7.33 (2H, d, J 8.0), 7.44 (1H, d,
J 8.5), 7.75 (2H, d, J 8.0), 7.87 (1H, d, J 8.5); m/z 424 (33.6%,
Mϩ) and 269 (100) (Found: Mϩ, 424.1011. C23H20O6S requires
M, 424.0981).
(b) Synthesis from 15b. A mixture of 15b (1.05 g, 2.60 mmol),
trimethylsilylacetylene (1.78 g, 18.2 mmol), CuI (50 mg, 0.26
mmol) and PdCl2(PPh3)2 (92 mg, 0.13 mmol) in a mixture
of Et3N (4.0 ml) and DMF (6.0 ml) was stirred at room
temperature for 1 h. Water was added to the mixture and
extracted with Et2O. The combined extracts were washed
successively with water and saturated aq. NaCl, dried over
MgSO4 and evaporated. The residue was chromatographed on
silica gel with hexane–AcOEt (5:1) as eluent to give the TMS-
acetylene 19 (0.95 g, 98%) as a colorless solid. The analytical
sample was further purified by recrystallization from AcOEt–
hexane to afford colorless needles, mp 105–107 ЊC (Found:
C, 61.02; H, 5.96; S, 8.46. C19H22O4SSi requires C, 60.93;
H, 5.92; S, 8.56%); νmax (CHCl3)/cmϪ1 1380, 1280, 1180, 1040;
δH (300 MHz) 0.24 (9H, s), 2.44 (3H, s), 3.75 (3H, s), 6.45
(1H, dd, J 8.4, 2.2), 6.53 (1H, d, J 2.2), 7.30 (3H, d, J 8.4), 7.69
(2H, d, J 8.4).
A solution of 19 (0.56 g, 1.50 mmol) and TBAF (1.0 M
solution in THF; 1.50 ml, 1.50 mmol) in THF (30 ml) was
stirred at room temperature for 10 min. Water was added to the
mixture, which was extracted with Et2O. The organic solution
was washed successively with water and saturated aq. NaCl,
dried over MgSO4 and evaporated. The residue was chromato-
graphed on silica gel with hexane–AcOEt (3:1) as eluent to give
9 (0.45 g, 99%) as a yellow viscous oil.
Vignafuran 2
A solution of 22 (80 mg, 0.19 mmol) and NaOMe (21 mg,
0.38 mmol) in MeOH (20 ml) was refluxed for 20 h. MeOH
was evaporated off and the residue was extracted with CHCl3.
The combined organic solution was washed successively
with water and saturated aq. NaCl, dried over MgSO4 and
concentrated. The residue was chromatographed on silica
gel and eluted with hexane–AcOEt (6:1) to afford 213–15 (40 mg,
78%) as a viscous oil; νmax (CHCl3)/cmϪ1 3400, 1270, 1040;
δH (500 MHz) 3.86 (3H, s), 3.91 (3H, s), 5.36 (1H, br), 6.49–
6.51 (2H, m), 6.84 (1H, dd, J 8.5, 2.4), 7.04 (1H, d, J 2.4),
7.10 (1H, s), 7.84 (1H, d, J 8.5); m/z 270 (100%, Mϩ) and
255 (64.8) (Found: Mϩ, 270.0845. Calc. for C16H14O4: M,
270.0891).
2-Acetoxy-2Ј,4-dimethoxy-4Ј-(tosyloxy)diphenylacetylene 7.
Typical procedure (Table 1, entry 6)
Methyl 6-methoxy-2-[2-methoxy-4-(tosyloxy)phenyl]benzo[b]-
A mixture of 8b (148 mg, 0.51 mmol), 9 (200 mg, 0.66 mmol),
CuI (10.0 mg, 0.05 mmol), PdCl2(PPh3)2 (18.0 mg, 0.03 mmol)
and iPr2NH (0.11 ml, 0.77 mmol) in DMF (3.0 ml) was stirred
at 60 ЊC for 1.5 h. Water was added to the mixture, which was
extracted with CHCl3. The organic solution was washed succes-
sively with water and saturated aq. NaCl, dried over MgSO4
and evaporated. The residue was purified by silica gel column
chromatography with hexane–AcOEt (2:1) as eluent to give 7
(230 mg, 96%) as a yellow viscous oil, νmax (CHCl3)/cmϪ1 1770,
1380, 1280, 1180, 1040; δH (300 MHz) 2.35 (3H, s), 2.45 (3H,
s), 3.78 (3H, s), 3.82 (3H, s), 6.48 (1H, dd, J 8.5, 2.2), 6.59
(1H, d, J 2.2), 6.66 (1H, d, J 2.2), 6.77 (1H, dd, J 8.5, 2.2), 7.30
(1H, d, J 8.5), 7.32 (2H, d, J 8.5), 7.47 (1H, d, J 8.5), 7.72 (2H,
d, J 8.5); m/z 466 (29.9%, Mϩ) and 269 (100) (Found: Mϩ,
466.1091. C25H22O7S requires M, 466.1087).
furan-3-carboxylate 23
A mixture of 7 (440 mg, 0.94 mmol), K2CO3 (260 mg, 1.88
mmol), PdCl2(PPh3)2 (33.0 mg, 0.19 mmol), CuCl2ؒ2H2O (480
mg, 2.82 mmol) and AcONa (154 mg, 1.88 mmol) in MeOH (20
ml) was stirred under CO at room temperature. After 2 days,
the inorganic precipitate was filtered off and the filtrate was
extracted with CHCl3. The organic solution was washed succes-
sively with water and saturated aq. NaCl, dried over MgSO4
and evaporated. The residue was purified by silica gel column
chromatography with hexane–AcOEt (5:1) as eluent to afford
23 (370 mg, 71%) as a colorless solid, mp 124–126 ЊC (Found:
C, 62.31; H, 4.41; S, 6.87. C25H22O8S requires C, 62.23; H, 4.60;
S, 6.65%); νmax (CHCl3)/cmϪ1 1720, 1380, 1280, 1180, 1040;
δH (300 MHz) 2.46 (3H, s), 3.71 (3H, s), 3.80 (3H, s), 3.87 (3H,
s), 6.63 (1H, dd, J 8.5, 2.2), 6.71 (1H, d, J 2.2), 6.98 (1H, dd,
J 8.5, 2.2), 7.03 (1H, dd, J 8.5, 2.2), 7.35 (2H, d, J 8.5), 7.44 (1H,
d, J 8.5), 7.79 (2H, d, J 8.5), 7.87 (1H, d, J 8.5); m/z 482 (58.6%,
Mϩ) and 327 (100) (Found: Mϩ, 482.1021. C25H22O8S requires
M, 482.1034).
2-Hydroxy-2Ј,4-dimethoxy-4Ј-(tosyloxy)diphenylacetylene 21
DIBAL-H (1.0 M solution in PhMe; 1.56 ml, 1.56 mmol) was
added to a solution of 7 (240 mg, 0.52 mmol) in CH2Cl2 (3 ml)
at Ϫ78 ЊC. After the solution had been stirred at the same
temperature for 3 h, Et2O and saturated aq. NH4Cl were
successively added to the mixture, which was then extracted
with CHCl3. The combined organic solution was washed
successively with water and saturated aq. NaCl, dried over
MgSO4 and evaporated. The residue was chromatographed
on silica gel and eluted with hexane–AcOEt (6:1) to afford 21
(180 mg, 81%) as a viscous yellow oil, νmax (CHCl3)/cmϪ1 3400,
1380, 1280, 1180, 1040; δH (300 MHz) 2.45 (3H, s), 3.80 (3H, s),
3.85 (3H, s), 6.46 (1H, dd, J 8.5, 2.2), 6.53 (1H, dd, J 8.5, 2.2),
Methyl 2-(4-hydroxy-2-methoxyphenyl)-6-methoxybenzo[b]-
furan-3-carboxylate 3
A solution of 23 (60 mg, 0.12 mmol) and NaOMe (9.60 mg,
0.24 mmol) in MeOH (15 ml) was heated under reflux for
4 h. The mixture was acidified by 3 M HCl and extracted
with CHCl3. The organic solution was washed successively
with water and saturated aq. NaCl, dried over MgSO4 and
evaporated. The residue was chromatographed on silica gel
J. Chem. Soc., Perkin Trans. 1, 2000, 4339–4346
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J. A. Barltrop, C. M. Petty and T. C. Owen, Tetrahedron Lett., 1989,
30, 1597; (d) O. Haglund and M. Nilsson, Synlett, 1991, 723.
7 K. Iritani, S. Matsubara and K. Utimoto, Tetrahedron Lett., 1988,
29, 1799.
8 (a) E. C. Taylor, A. H. Katz, H. Salgado-zomora and A. Mckillop,
Tetrahedron Lett., 1985, 26, 5963; (b) A. Arcadi and F. Marinelli,
Synthesis, 1986, 749; (c) N. G. Kundu, M. Pal, J. S. Mahanty and
S. K. Dasgupta, J. Chem. Soc., Chem. Commun., 1992, 41;
(d) S. Torii, L. H. Xu and H. Okumoto, Synlett, 1992, 515;
(e) I. Candiani, S. DeBernardinis, W. Cabri, M. Marchi, A. Bedeschi
and S. Penco, Synlett, 1993, 269; ( f ) M. C. Fagnola, I. Candiani,
G. Visentin, W. Cabri and F. Zarini, Tetrahedron Lett., 1997, 38,
2307; (g) D. Fancelli, M. C. Fagnola, D. Severino and A. Bedeschi,
Tetrahedron Lett., 1997, 38, 2311.
and eluted with hexane–AcOEt (4:1) to give 316 (40 mg, 100%)
as a colorless solid; mp 153–155 ЊC (Found: C, 65.95; H, 4.95.
Calc. for C18H16O6: C, 65.85; H, 4.91%); νmax (CHCl3)/cmϪ1
3400, 1720, 1280, 1040; δH (500 MHz; CD3OD) 3.75 (3H, s),
3.78 (3H, s), 3.84 (3H, s), 6.48 (1H, dd, J 8.6, 1.8), 6.52 (1H, d,
J 1.8), 6.94 (1H, dd, J 8.6, 1.8), 7.08 (1H, d, J 1.8), 7.32 (1H, d,
J 8.6), 7.77 (1H, d, J 8.6); m/z 328 (100%, Mϩ) (Found: Mϩ,
328.0941. Calc. for C18H16O6: M, 328.0947).
Methyl 6-hydroxy-2-[2-hydroxy-4-(tosyloxy)phenyl]benzo[b]-
furan-3-carboxylate 24
A solution of BBr3 (1 M solution in CH2Cl2; 0.64 ml, 0.64
mmol) was added to a solution of 23 (40 mg, 0.08 mmol)
in CH2Cl2 (5 ml) at Ϫ78 ЊC. After the mixture had been stirred
at the same temperature for 30 min, the mixture was allowed to
warm at Ϫ40 ЊC and was further stirred for 30 h. The mixture
was acidified by 3 M HCl and extracted with CHCl3. The
organic solution was washed successively with water and satur-
ated aq. NaCl, dried over MgSO4 and evaporated. The residue
was chromatographed on silica gel and eluted with hexane–
AcOEt (6:1) to give 24 (26 mg, 72%) as a colorless solid; mp
95–97 ЊC; νmax (CHCl3)/cmϪ1 3350, 1700, 1380, 1260, 1180,
1040; δH (300 MHz) 2.45 (3H, s), 4.01 (3H, s), 5.88 (1H, br),
6.76 (1H, d, J 2.2), 6.81 (1H, dd, J 8.5, 2.2), 6.91 (1H, dd, J 8.5,
2.2), 6.98 (1H, d, J 2.2), 7.34 (1H, d, J 8.5), 7.56 (1H, d, J 8.5),
7.78 (2H, d, J 8.5), 7.80 (1H, d, J 8.5), 8.59 (1H, s); m/z 454
(3.6%, Mϩ) and 267 (100) (Found: Mϩ, 454.0675. C23H18O8S
requires M, 454.0721).
9 (a) R. C. Larock and E. K. Yum, J. Am. Chem. Soc., 1991, 113,
6689; (b) R. C. Larock, E. K. Yum, M. J. Doty and K. K. C. Sham,
J. Org. Chem., 1995, 60, 3270; (c) R. C. Larock, E. K. Yum and
M. D. Refvik, J. Org. Chem., 1998, 63, 7652.
10 (a) Y. Kondo, F. Shiga, N. Murata, T. Sakamoto and H. Yamanaka,
Tetrahedron, 1994, 50, 11803; (b) A. Arcadi, S. Cacchi, M. D.
Rosario, G. Fabrizi and F. Marinelli, J. Org. Chem., 1996, 61,
9280; (c) S. Cacchi, G. Fabrizi, F. Marinelli, L. Moro and P. Pace,
Synlett, 1997, 1363; (d) N. Monteiro and G. Balme, Synlett, 1998,
746; (e) S. Cacchi, G. Fabrizi and L. Moro, Synlett, 1998, 741;
( f ) N. Monteiro, A. Arnold and G. Balme, Synlett, 1998, 1111;
(g) S. Cacchi, G. Fabrizi and L. Moro, Tetrahedron Lett., 1998, 39,
5101; (h) H. Lütjens and P. J. Scammells, Tetrahedron Lett., 1998,
39, 6581; (i) H. Lütjens and P. J. Scammells, Synlett, 1999, 1079;
(j) Y. Nan, H. Miao and Z. Yang, Org. Lett., 2000, 2, 297;
(k) A. Yasuhara, M. Kaneko and T. Sakamoto, Heterocycles, 1998,
48, 1793.
11 (a) T. Sakamoto, Y. Kondo and H. Yamanaka, Heterocycles, 1986,
24, 31; (b) T. Sakamoto, Y. Kondo, S. Iwashita and H. Yamanaka,
Chem. Pharm. Bull., 1987, 35, 1823; (c) T. Sakamoto, Y. Kondo,
S. Iwashita, T. Nagano and H. Yamanaka, Chem. Pharm. Bull.,
1988, 36, 1305; (d) Y. Kondo, S. Kojima and T. Sakamoto,
Heterocycles, 1996, 43, 2741.
Coumestrol 4
A mixture of 24 (30 mg, 0.07 mmol) and 3 M KOH (0.14 ml) in
THF (20 ml) was refluxed for 2 h. The mixture was acidified by
3 M HCl and extracted with AcOEt. The organic solution was
washed successively with water and saturated aq. NaCl, dried
over MgSO4 and evaporated. The crude acid was used in the
next reaction without further purification.
A solution of the crude acid and TsOHؒH2O (10 mg,
0.06 mmol) in THF (20 ml) was stirred at 60 ЊC for 5 h.
The reaction mixture was extracted with AcOEt. The organic
solution was washed with saturated aq. NaCl, dried over
MgSO4 and evaporated. The residue was purified by silica gel
column chromatography and elution with hexane–AcOEt (5:1)
to afford 417,19 (10 mg, 53%) as a colorless solid; mp >360 ЊC
(lit.17a mp 385 ЊC); δH (500 MHz; DMSO-D6) 6.90 (1H, d,
J 1.9), 6.92 (1H, dd, J 8.8, 1.9), 6.94 (1H, dd, J 8.8, 1.9), 7.16
(1H, d, J 1.9), 7.68 (1H, d, J 8.8), 7.84 (1H, d, J 8.8); δH
(500 MHz; CD3OD) 6.84 (1H, d, J 2.4), 6.88–6.90 (2H, m), 7.04
(1H, d, J 2.4), 7.70 (1H, d, J 8.5), 7.81 (1H, d, J 8.5); m/z
268 (100%, Mϩ) (Found: Mϩ, 268.0357. Calc. for C15H8O5:
M, 268.0371).
12 A. Yasuhara, Y. Kanamori, M. Kaneko, A. Numata, Y. Kondo and
T. Sakamoto, J. Chem. Soc., Perkin Trans. 1, 1999, 529.
13 (a) N. W. Preston, K. Chamberlain and R. A. Skipp,
Phytochemistry, 1975, 14, 1843; (b) G. A. Carter, K. Chamberlain
and R. L. Wain, Ann. Appl. Biol., 1978, 88, 57; (c) K. K. Dorr and
D. I. Guest, J. Chromatogr., 1987, 387, 536.
14 M. Martin and P. M. Dewick, Phytochemistry, 1979, 18, 1309.
15 (a) R. P. Duffley and R. Stevenson, J. Chem. Soc., Perkin Trans. 1,
1977, 802; (b) M. Meyer, C. Deschamps and D. Molho, Bull.
Soc. Chim. Fr., 1991, 91; (c) M. Watanabe, K. Kawanishi and
S. Furukawa, Chem. Pharm. Bull., 1991, 39, 579; (d) T. Kinoshita,
Tetrahedron Lett., 1997, 38, 259.
16 H. Koshino, Y. Masaoka and A. Ichihara, Phytochemistry, 1993,
33, 1075.
17 (a) E. M. Bickoff, A. N. Booth, R. L. Lyman, A. L. Livingston,
C. R. Thompson and F. DeEds, Science, 1957, 126, 969; (b) E. M.
Bickoff, A. N. Booth, R. L. Lyman, A. L. Livingston, C. R.
Thompson and G. O. Kohler, J. Agric. Food Chem., 1958, 6, 536;
(c) E. M. Bickoff, R. L. Lyman, A. L. Livingston and A. N. Booth,
J. Am. Chem. Soc., 1958, 80, 3969; (d) O. H. Emerson and
E. M. Bickoff, J. Am. Chem. Soc., 1958, 80, 4381.
18 W. Stadlbauer and T. Kappe, Heterocycles, 1993, 35, 1425.
19 (a) L. Jurd, Tetrahedron Lett., 1963, 1151; (b) T. Kappe and
A. Brandner, Z. Naturforsch., Teil B, 1974, 29, 292; (c) R. Laschober
and T. Kappe, Synthesis, 1990, 387; (d) G. Kraus and N. Zhang,
J. Org. Chem., 2000, 65, 5644.
References
20 M. Pal and N. G. Kundu, J. Chem. Soc., Perkin Trans. 1, 1996,
449.
1 G. W. Gribble, Comprehensive Heterocyclic Chemistry II, ed. A. R.
Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, Oxford,
1996, vol. 2, p. 207.
2 B. A. Keay, Comprehensive Heterocyclic Chemistry II, ed. A. R.
Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, Oxford,
1996, vol. 2, p. 395.
3 P. Cagniant and D. Cagniant, Adv. Heterocycl. Chem., 1975, 18, 343.
4 (a) R. J. Sundberg, Comprehensive Heterocyclic Chemistry II,
ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon
Press, Oxford, 1996, vol. 2, p. 119; (b) G. W. Gribble, J. Chem. Soc.,
Perkin Trans. 1, 2000, 1045 and references cited therein.
5 W. Friedrichsen, Comprehensive Heterocyclic Chemistry II, ed. A. R.
Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, Oxford,
1996, vol. 2, p. 351.
21 (a) T. Kappe, G. Korbuly and W. Stadlbauer, Chem. Ber., 1978, 111,
3857; (b) R. C. Larock and L. W. Harrison, J. Am. Chem. Soc.,
1984, 106, 4218; (c) R. P. Singh and D. Singh, Heterocycles, 1985,
23, 903; (d) J. Maischein and E. Vilsmaier, Liebigs Ann. Chem.,
1988, 355; (e) S. B. Pandit and S. Y. Gadre, Synth. Commun., 1988,
18, 157; ( f ) R. S. Mali and S. G. Tilve, Synth. Commun., 1990,
20, 1781.
22 K. Sonogashira, Y. Ohda and N. Hagihara, Tetrahedron Lett., 1975,
4467.
23 I. Thomsen and K. B. G. Torssell, Acta Chem. Scand., 1991, 45,
539.
24 H. Suzuki, A. Kondo and T. Ogawa, Chem. Lett., 1985, 441.
25 M. W. Miller and C. R. Johnson, J. Org. Chem., 1997, 62, 1582.
26 M. C. Carreño, J. L. G. Ruano, G. Snaz, M. A. Toledo and
A. Urbano, Synlett, 1997, 1241.
6 (a) C. E. Castro, E. J. Gaughan and D. C. Owsley, J. Org. Chem.,
1966, 31, 4071; (b) C. E. Castro, R. Havlin, V. K. Honwad, A. Malte
and S. Mojé, J. Am. Chem. Soc., 1969, 91, 6464; (c) G. J. S. Doad,
27 H. Miao and Z. Yang, Org. Lett., 2000, 2, 1765.
4346
J. Chem. Soc., Perkin Trans. 1, 2000, 4339–4346