A short-step convenient synthesis of 2-phenylbenzofuran from 3-phenylcoumarin

Article abstract of DOI:10.3987/COM-05-10424

The reaction mechanism of chemical conversion of (E)-β-[2-hydroxylphenylethylene]benzeneethanol into 2-phenylbenzofuran by DDQ, which involves loss of one carbon unit, was characterized and described. Five naturally occurring 2-phenylbenzofurans of not only the isoflavonoid but also stilbenoid origin were synthesized by use of this chemical scheme, which proved that this new scheme is a useful tool for quick synthesis of 2-phenylbenzofurans.

Full text of DOI:10.3987/COM-05-10424

HETEROCYCLES, Vol. 65, No. 7, 2005
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HETEROCYCLES, Vol. 65, No. 7, 2005, pp. 1641 - 1654
Received, 8th April, 2005, Accepted, 27th April, 2005, Published online, 28th April, 2005
A SHORT-STEP CONVENIENT SYNTHESIS OF
2-PHENYLBENZOFURAN FROM 3-PHENYLCOUMARIN
Takeshi Kinoshitaa,* and Koji Ichinoseb
aFaculty of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi,
Sagamiko-machi, Tsukui-gun, Kanagawa 199-0195, Japan
bFaculty of Pharmacy, Musashino University, 1-1-20 Shin-machi, Nishitokyo,
Tokyo 202-8585, Japan
Abstract
–
The reaction mechanism of chemical conversion of
(E)-β-[2-hydroxylphenylethylene]benzeneethanol into 2-phenylbenzofuran by
DDQ, which involves loss of one carbon unit, was characterized and described.
Five naturally occurring 2-phenylbenzofurans of not only the isoflavonoid but
also stilbenoid origin were synthesized by use of this chemical scheme, which
proved that this new scheme is a useful tool for quick synthesis of
2-phenylbenzofurans.
Naturally occurring 2-phenylbenzofurans1 have been known mainly from either legumes or mulberries.2, 3
These compounds have drawn increasing attention since many of them occur in nature as phytoalexins, a
group of secondary metabolites produced de novo as defensive substances by plants against fungal
infection.2, 3 However, those known from mulberries are distinguished from those of leguminous origin
from biogenetic viewpoints. The former are regarded as arising biogenetically from the oxidative
cyclization of the corresponding stilbenes, whereas the latter are considered to be members of the
isoflavonoid family. These two types of 2-phenylbenzofurans are also distinguished each other by the
following structural features; those of mulberry origin possess the oxygen functionality at the 3’- and
5’-positions of 2-phenyl group while those of the isoflavonoid origin possess the oxygen functionality at
the 2’- and 4’-position. Though 2-phenylbenzofurans are of interest from viewpoint of biological

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HETEROCYCLES, Vol. 65, No. 7, 2005
O
O
OH
CH2OH
DDQ
AlH3
O
1
2
3
Scheme 1.
activities other than anti-fungus activity, their biological activities have not been adequately characterized
since they occur only in small quantity naturally. In particular, those of the isoflavonoid origin are
drawing considerable attention as possible bioactive principles of herbal medicines of leguminous origin
in which a growing number of reports indicated their occurrence.4 Therefore, there is a demand from the
field of health science dealing with health food and dietary suppliments for facile and efficient chemical
tool to rapidly identify and prepare minor metabolites from natural source, such as 2-phenylbenzofurans,
in order to evaluate their safety and pharmacological efficacy. The first author reported earlier chemical
conversion of naturally occurring 3-phenylcoumarin (3-phenyl-2H-1-benzopyran-2-one) derivative
“glycyrin”, a constituent isolated from a worldwide reputed crude drug licorice, to the corresponding
2-phenylbenzofuran derivative during the course of structure elucidation of this natural product.5 The
scheme outlined in Scheme 1 will be of particular interest since it employs the starting materials common
to the synthesis of most isoflavonoids unlike the previous methods that have been accomplished by the
routes incompatible with those of other isoflavonoids.6 The advantage of this scheme for the synthesis of
naturally occurring 2-arylbenzofurans will be further substantiated by the fact that most isoflavonoidal
2-phenylbenzofurans co-occur in nature with biogenetically related isoflavonoids. However, reaction
mechanisms of the above chemical scheme has been neither characterized nor applied to the synthesis of
2-phenylbenzofurans yet. These circumstances induced us to investigate this reaction more deeply with
the aim of obtaining mechanistic information and optimizing the reaction procedure for the synthesis of
naturally occurring 2-phenylbenzofurans as an alternative to the previous methods.6 In this paper we
describe the elucidation of mechanisms of the above reaction, and its application to the synthesis of
naturally occurring 2-phenylbenzofurans of not only the isoflavonoid but also stilbenoid origin.
In order to elucidate the reaction mechanism shown in Scheme 1 that converts 3-phenylcoumarin
derivatives into 2-phenylbenzofuran derivatives, the simplest (E)-β-[2-hydroxylphenylethylene]-
benzeneethanol (referred to as the diol (2), hereafter) was prepared and treated with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) under reflux in dry benzene as described in the

HETEROCYCLES, Vol. 65, No. 7, 2005
1643
OH
CR2OH
O
O
2'
1
2a: R=H
2b: R=D
R
O
O
O
R
2
DDQH2
DDQH2
CN
Cl
CN
Cl
DDQ
O
CN
O
HO
Cl
CN
5a: R=H
5b: R=D
Cl
H
OH
O
-H2O
DDQ
H
H
O
OH
O
CHOH
CHOH
H+
2'
4
O
O
CHO
H
H+
HCHO
3
4'
Scheme 2.
literature,5 and all reaction products were subjected to structure elucidation. During the reaction, a deposit
of paraformaldehyde on the reflux condenser and precipitation of 2,3-dichloro-5,6-dicyano-1,4-
hydroquinone (DDQH2) in the reaction medium was observed. Prior to the work-up of the reaction
mixture, the formation of three products was observed on TLC. The reaction mixture obtained after the
usual workups was subjected to the chromatographic separation to furnish three products,
3-phenylcoumarin (1), 2-phenylbenzofuran (3), and 2,2’-oxybis[3-phenyl-2H-1-benzopyran] (5a)
(referred to as the dimer (5a), hereafter), at the yields of 6%, 34% and 30%, respectively (all yields based
on isolation in pure crystallized forms). It is apparent that the formation of paraformaldehyde in this
reaction resulted from loss of one carbon unit occurred during conversion of the diol (2a) to
2-phenylbenzofuran (3). It is of particular interest to note that the formation of the dimer (5a) suggested
isoflav-3-ene-2-ol (4) (3-phenyl-2H-1-benzopyran-2-ol) to be involved in the formation of
2-phenylbenzofuran (3) as an intermediate, since we have already established acid-catalyzed conversion
of isoflav-3-ene-2-ol (4) to 2-phenylbenzofuran (3).7 As the possible mechanism of the formation of
isoflav-3-ene-2-ol (4) from the diol (2a) on treatment with DDQ, the first step of the reaction would be

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HETEROCYCLES, Vol. 65, No. 7, 2005
initiated by the abstraction of a hydride at the allylic position of the diol (2a) followed by the
deprotonation of the phenol hydroxyl to form the corresponding o-quinonemethide (2’).8 The
+
+
o-quinonemethide (2’) will readily undergo
cyclization to give rise to isoflav-3-ene-2-ol
(4). Since DDQ, a strong electron accepter,
forms a charge-transfer complex with the
donor phenol, the above mechanism will be
O
D
O
H
5b
M+ 207
M+ 206
(100)
(8)
Scheme 3.
quite reasonable (Scheme 2). The mechanism depicted in an earlier paper5 for this reaction scheme was
thus found to be erroneous. When (E)-β-[2-hydroxylphenylethylene]benzeneethanol-D2 (2b) was
subjected to the same reaction condition as the diol-H2 (2a), retention of more than 93% of deuterium at
the 2- and 2’-positions of the dimer-D2 (5b) was observed according to the corresponding MS spectral
analysis (Scheme 3), supporting this mechanism as shown in Scheme 2. Conversion of isoflav-3-ene-2-ol
(4) to 2-phenylbenzofuran would be catalized by DDQH2. Though the reaction was undertaken in dry
aprotic condition while isoflav-3-ene-2-ol (4) was treated with strong acid in an earlier paper,7 it was
proved that DDQH2 acted as an acid to catalyze conversion of isoflav-3-ene-2-ol (4) to
2-phenylbenzofuran (3) involving loss of one carbon unit (Scheme 2). When isoflav-3-ene-2-ol (4)
prepared as described in the literature7 was refluxed with DDQH2 in dry benzene for 12 h, the formation
of 2-phenylbenzofuran (3) along with the dimer (5a) was confirmed at the yields of 49% and 30%,
respectively. The weak acidity and low solubility of DDQH2 in the solvent will be one of the reasons that
this reaction requires a long time heating for completion.
In order to apply the scheme described above to the practical synthesis of naturally occurring
2-phenylbenzofurans, an attempt to optimize the reaction condition was undertaken. First, the reaction
was performed in various solvents in order to select the optimum solvent to give the highest yield. The
results were summarized in Table 1. All solvents were prepared dry prior to the reaction. Benzene and
dioxane are primary solvents used for reactions in which DDQ is employed as a dehydrogenation reagent.
Table 1. Effect of Solvents on Synthesis of 2-Arylbenzofuran (3)
Solvents
Benzene
Dioxane
THF
Yields
34
Solvents
MeOH
CH2Cl2
CHCl3
Yields
9
15
25
14
39

HETEROCYCLES, Vol. 65, No. 7, 2005
1645
However, results obtained from dioxane and other solvents except for benzene and chloroform were
disappointing. In the actual application of the corresponding reaction to the synthesis of
2-phenylbenzofurans, dry benzene was employed on the ground that it is easy to dry and also the boiling
point is higher than other solvents. With the aim of shortening the reaction time, a small amount of
p-toluenesulfonic acid was added to the reaction medium. Though the starting material (2a) disappeared
in less than half time of the standard condition, the dimer (5a) was obtained as a main product (41%) and
the yield of 2-phenylbenzofuran (3) decreased dramatically (16%). However, it should be noted that the
dimer (5a) can be converted to 2-phenylbenzofuran (3) on hydrolysis with acid in moderate yield (34%).
3-Phenylcoumarins (6a-10a) were synthesized in moderate yields (36-58%) by aldol condensation of
corresponding benzaldehydes and phenylacetic acids that were readily prepared in a few steps from
commercially available materials. One of the merits utilizing 3-phenylcoumarins as starting materials for
the synthesis of the corresponding minor isoflavonoids is that they are stable, prone to crystallization, and
thus suitable for constructing a chemical library as parts of synthesizing minor isoflavonoids. Conversion
of 3-phenylcoumarins to the corresponding 2-phenylbenzofurans consists of two steps; catalytic reduction
R
OH
R6
8
5'
CHO
R1
O
O
R1
(iii)
OH
CH2OH
R5
R4
4'
3'
R'
7
6
R6
R5
5'
4'
R6
R5
(R, R' = H or OH)
R1
O
(i), (ii)
(iv)
5
COOH
4
2'
R3
2'
R2
R2
5
R6
3
R3
6a - 10a
R3
6b - 10b
(i) KOAc/Ac2O; (ii) PhCH2Br/K2CO3 or CH2N2; (iii) AlH3 ; (iv) DDQ
4
3'
R4
R2
R4
6c - 10c
R3
R5
R4
Scheme 4.
Table 2. Yields of 2-phenylbenzofurans synthesized according to Scheme 4
Substitution
naturally occurring
2-phenylbenzofurans
entry
products Yieldsa
c
R1
R2
R3
H
R4
H
R5
H
R6
1
2
3
4
5
6
H
H
H
3
6c
7c
8c
9c
10c
34
36
30b
60
65
52
-
OCH3 OCH3
H
OBz
OBz
H
H
OBz
OBz
H
moracin A
moracin M
unnamed
vignafuran
pterofuran
OBz
OBz
H
H
H
H
H
H
OBz
OCH3
OBz
OBz
OCH3
OBz
H
H
OCH3 OBz OCH3
H
a all over yields of reactions (iii) and (iv).
b including yield of the 2-phenylbenzofuran prepared from hydrolysis of the dimer.
c names of natural products after hydrogenation.

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HETEROCYCLES, Vol. 65, No. 7, 2005
of 3-phenylcoumarins by use of AlH3, and treatment of the resulting diols with DDQ (Scheme 4). This
conversion can be performed eventually in one batch by following the Micovic’s method9 during the
workup of a catalytic reduction. Though yields of this conversion are moderate as shown in Table 2, it
will be compensated by the following features: the products are prepared in short steps by use of
conventional reactions and reagents, and are easily purified. In case of an unsubstituted 3-phenylcoumarin
(1), this conversion gave rise to the dimer (5a) along with 2-phenylbenzofuran (3) as mentioned above.
The formation of the corresponding dimer was not observed except for entry 3, which ended up with the
poorest yield (11%) of the corresponding 2-phenylbenzofuran. The entry 3 gave rise to the dimer as a
by-product at the yield of 38%. Since this dimer could be converted to the corresponding
2-phenylbenzofuran derivative on hydrolysis with acid (53% yield), the substantial yield (30%) was
comparable to those of other entries. It is presumed that the occurrence of functional group at either the
2’- or 5-position of 3-phenylcoumarin skeleton will be ascribed to the restrained formation of the dimer.
As already mentioned above, 2-phenylbenzofurans of isoflavonoid origin are characterized as possessing
oxygen functionality at the 2’-position. On the other hand, those of the mulberry family origin, which are
biogenetically derived from stilbenes, do not possess oxygen functionality at the 2’-position. Therefore,
this method is less attractive for the synthesis of the latter type of 2-arylbenzofurans that have no oxygen
functionality at the 2’- and 4-position.
As mentioned above, we have succeeded in preparing 2-phenylbenzofurans of both the isoflavonoid and
stilbenoid origin starting from the corresponding 3-phenylcoumarins that are readily available from aldol
condensation between oxygenated phenylacetic acids and benzaldehydes. Synthetic routes to either
pterocarpan or isoflavan employing oxygenated phenylacetic acids and benzaldehydes as the starting
materials have also been reported by several other groups.10 Although yields of our method are moderate
as compared to those reported by other groups,6 one of the advantages of our method is that our method
can utilize starting material library commonly used for the synthesis of other minor isoflavonoids. Our
method will be more suitable for the synthesis of isotope-labeled compounds that are essential for
metabolic studies dealing with bioavailability of isoflavonoids in food and suppliments. This method will
be useful in the preparation of samples for quick identification and biological assay as mentioned in the
introduction.

HETEROCYCLES, Vol. 65, No. 7, 2005
1647
EXPERIMENTAL
General
All melting points were measured on a Yanagimoto melting point apparatus and are uncorrected. Spectral
data were obtained using the following apparatus: 1H- and 13C-NMR spectra with a JEOL JNM GSX-400
(1H, 400 MHz) spectrometer with SiMe4 as an internal standard; LRMS spectra with a JEOL SX-102A
mass spectrometer, IR spectra with a JASCO FT/IR-8000 infrared spectrophotometer and UV spectra
with a Shimadzu UV-240 spectrophotometer. Column chromatography was carried out with Wakogel
C-200 or Merck Kieselgel 60. TLC was conducted on a 0.25 mm precoated silica gel plate (60GF254,
Merck), and spots were detected by inspection under short (254 nm) or long (365 nm) wavelength UV
lights, or by the colors developed with 10% H2SO4 spraying followed by heating on a hot plate. All of the
solvents used were dried over appropriate agents and distilled prior to use.
Starting materials
Lithium aluminum deuteride (LiAlD4; 96 atom % D) was purchased from Aldrich Co. Ltd.
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; 97%) was purchased from Tokyo Kasei Organic
Chemicals, Co. Ltd. The following materials were prepared according to the procedures described in the
corresponding literatures: 3-phenyl-2H-1-benzopyran-2-one (3-phenylcoumarin) ;11 2-phenylbenzo-
furan;12 3,5-dibenzyloxyphenylacetic acid;13 3-benzyloxy-2,4-dimethoxyacetophenone;14 4-benzyloxy-2-
methoxyacetophenone.15
3-Benzyloxy-2,4-dimethoxyphenylacetic
acid
and
4-benzyloxy-2-
methoxyphenylacetic acid were prepared from 3-benzyloxy-2,4-dimethoxyacetophenone and
4-benzyloxy-2-methoxyacetophenone, respectively, according to the procedure as described bellow. Each
acetophenone (10 mmol) was dissolved in methanol (100 mL), and 4.89 g (11 mmol) of Tl(NO3)3・3H2O
added to the solution and stirred overnight at rt. The reaction mixture was poured into cold water, and the
organic materials were extracted with Et2O. The extract was successively washed with water, brine, dried
over anhydrous Na2SO4 and then evaporated to dryness. The residue was subjected to a column
chromatography over silica gel on elution with benzene-acetone to furnish the corresponding methyl
phenylacetate in pure form (oil). Each of methyl phenylacetates was dissolved in 15% NaOH, which was
then washed with Et2O. The alkaline layer was neutralized by the addition of 10% HCl, and resulting
precipitates were collected. The precipitates were recrystallized from EtOH-H2O to give amorphous
solids.

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HETEROCYCLES, Vol. 65, No. 7, 2005
3-Benzyloxy-2,4-dimethoxyphenylacetic acid Yield: 67% from 3-benzyloxy-2,4-methoxyacetophenone;
cm-1: 2935, 1724, 1606 cm-1; 1H-NMR (CDCl3): δ 3.46 (2H, s), 3.72, 3.74 (3H each,
KBr
max
amorphous; IR
ν
s), 4.98 (2H each, s), 6.59 (1H, d, J = 8.4 Hz), 6.82 (1H, d, J = 8.4 Hz), 7.20 (10H, m). Anal. Calcd for
C17H18O5: C, 67.54; H, 6.00. Found: C, 67.70; H, 6.09.
4-Benzyloxy-2-methoxyphenylacetic acid Yield: 69% from 4-benzyloxy-2-methoxyacetophenone;
1
cm-1: 2915, 1712, 1600 cm-1; H-NMR (CDCl3): δ 3.40 (2H, s), 3.77 (3H, s), 5.01
KBr
max
amorphous; IR
ν
(2H, s), 6.36 (1H, d, J = 2.5 Hz), 6.44 (1H, d, J = 8.3, 2.5 Hz), 6.88 (1H, d, J = 8.3 Hz), 7.20 (5H, m). MS
m/z 272 (M+, 60), 181 (100). Anal. Calcd for C16H16O4: C, 70.58; H, 5.92. Found: C, 70.28; H, 5.96.
3-Phenyl-2H-1-Benzopyran-2-ol (4) To a stirred solution of 3-phenylcoumarin (0.62 g, 2.79 mmol) at
-78℃ in dry toluene (50 mL) was added DIBAH (0.60 g, 4.19 mmol). After stirring for 1.5 h at this
temperature, the reaction mixture was quenched by the addition of acetic acid (5 mL) and then poured
into cold water. The organic materials were extracted with Et2O, and the extract was washed successively
by saturated NaHCO3, brine, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was
recrystallized from benzene-hexane to give colorless solids (0.42 g; 67%). mp 94-96℃; UV MeOH nm:
λmax
1
cm-1: 1483, 1452, 984 cm-1; H-NMR (CDCl3): δ 6.77 (1H, s), 6.9-7.6 (10H, m);
KBr
max
207, 289 nm; IR
ν
13C-NMR (CDCl3): δ 91.6, 116.6, 121.6, 122.1, 125.4, 127.3, 127.5, 128.2, 128.9, 130.0, 135.7, 149.4.
MS m/z 224 (M+, 94), 207 (M+-OH, 100). Anal. Calcd for C15H12O2: C, 80.34; H, 5.39. Found: C, 80.01;
H, 5.44.
General procedure for the preparation of 3-phenylcoumarins (6a-10a)
A mixture of the corresponding benzaldehyde (4 mmol), phenylacetic acid (3.5 mmol), anhydrous KOAc
(0.49 g, 5 mmol) and Ac2O (1.5 mL) was heated at 150℃ under argon atmosphere for 10 h. The reaction
mixture was acidified with 10% HCl and extracted with CHCl3. The organic layer was evaporated to
dryness and the residue was mixed with THF (12 mL) and 25% NH4OH (8 mL). After heating for 40 min,
the mixture was evaporated to dryness to afford the corresponding crude 3-phenylcoumarin derivative
(referred to as the residue, hereafter).
3-(3,5-Dibenzyloxyphenyl)-5,7-dimethoxy-2H-1-benzopyran-2-one (6a) The residue was dissolved in
THF (10 mL). To this solution an excess amount of etheral diazomethane was added at 0℃, and allowed
to stand overnight. After the mixture was quenched by the addition of formic acid, it was evaporated to
dryness, and the residue was repeatedly recrystallized from EtOH to furnish the product (6a) (yield: 39%).

HETEROCYCLES, Vol. 65, No. 7, 2005
1649
cm-1: 1707, 1597 cm-1; 1H-NMR (acetone-d6): δ 3.87, 3.91
KBr
max
Pale yellow needles, mp 114-115℃; IR
ν
(3H each, s), 5.10 (4H, br s), 6.30 (1H, d, J = 2. 4 Hz), 6.46 (1H, d, J = 2.4 Hz), 6.64 (1H, t, J = 2.0 Hz),
7.00 (2H, d, J = 2.0 Hz), 7.3-7.7 (10H, m), 8.08 (1H, s). MS m/z 494 (M+, 31), 403 (42), 312 (100). Anal.
Calcd for C31H26O6: C, 75.29; H, 5.30. Found: C, 74.97; H, 5.33.
3-(3,5-Dibenzyloxyphenyl)-7-benzyloxy-2H-1-benzopyran-2-one (7a) The residue was benzylated by
benzyl bromide-K2CO3/acetone to furnish 7a (yield: 45%). Colorless needles from acetone, mp
cm-1: 1721, 1604 cm-1; 1H-NMR (acetone-d6): δ 5.15 (4H, br s), 5.28 (2H, br s), 6.73
KBr
max
143-144℃; IR
ν
(1H, t, J = 2.0 Hz), 6.98-7.03 (2H, m), 7.05 (2H, d, J = 2.0 Hz), 7.00 (1H, d, J = 2.0 Hz), 7.3-7.5 (16H, m),
8.12 (1H, s). MS m/z 540 (M+, 74), 449 (100). Anal. Calcd for C36H28O5: C, 79.98; H, 5.22. Found: C,
79.65; H, 5.27.
3-(2,4-Dibenzyloxyphenyl)-7-benzyloxy-2H-1-benzopyran-2-one (8a) The residue was benzylated by
benzyl bromide-K2CO3/acetone to furnish 8a (yield: 58%). Colorless needles from acetone, mp
1
cm-1: 1719, 1603 cm-1; H-NMR (CDCl3): δ 5.10, 5.12, 5.15 (2H each, br s), 6.60
KBr
max
132-133℃; IR
ν
(2H, m), 6.88 (2H, m), 7.3-7.5 (7H, m), 7.69 (1H, s). MS m/z 540 (M+, 62), 449 (100). Anal. Calcd for
C36H28O5: C, 79.98; H, 5.22. Found: C, 79.84; H, 5.19.
3-(4-Benzyloxy-2-methoxyphenyl)-7-methoxy-2H-1-benzopyran-2-one (9a) The residue was
benzylated by benzyl bromide-K2CO3/acetone to furnish 9a (yield: 41%). Colorless needles from MeOH,
1
cm-1: 1722, 1605 cm-1; H-NMR (CDCl3): δ 3.79, 3.88 (3H each, s), 5.10 (2H,
KBr
max
mp 159-160℃; IR
ν
br s), 6.62 (1H, dd, J = 8.0, 2.2 Hz), 6.64 (1H, d, J = 2.2 Hz), 6.84 (1H, dd, J = 8.8, 2.4 Hz), 6.85 (1H, d, J
= 2.4 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.35-7.5 (6H, m), 7.66 (1H, s). MS m/z 388 (M+, 95), 297 (100). Anal.
Calcd for C24H20O5: C, 74.21; H, 5.19. Found: C, 74.47; H, 5.20.
3-(3-Benzyloxy-2,4-dimethoxyphenyl)-7-benzyloxy-2H-1-benzopyran-2-one (10a) The residue was
benzylated by benzyl bromide-K2CO3/acetone to furnish 10a (yield: 36%). Colorless needles from
cm-1: 1705, 1613 cm-1; 1H-NMR (acetone-d6): δ 3.83 (3H, s), 3.90 (3H,
KBr
max
acetone, mp 120-121℃; IR
ν
s), 5.04 (2H, br s), 5.23 (2H, br s), 6.8-7.7 (15H, m), 7.81 (1H, s). MS m/z 494 (M+, 13), 403 (21), 312
(100). Anal. Calcd for C31H26O6: C, 75.29; H, 5.30. Found: C, 75.50; H, 5.39.
General procedure for the preparation of (E)-β-[(2-hydroxylphenyl)ethylene]benzeneethanols (2a,
2b, 6b-10b)
To a well-stirred mixture of LAH (0.68 g, 18 mmol) and AlCl3 (0.88 g, 6.6 mmol) in dry Et2O (40 mL),

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HETEROCYCLES, Vol. 65, No. 7, 2005
3-phenylcoumarin (2 mmol) dissolved in THF (5 mL) was added dropwise and the mixture stirred for 1.5
h. After the reaction mixture was quenched by the addition of AcOEt, 1 mL of water, 1 mL of 15% aq.
NaOH and 3 mL of water were successively added to the reaction mixture, and the resulting precipitates
were filtered off. The filtrate was evaporated to dryness to give the corresponding
(E)-β-[2-hydroxylphenylethylene]benzeneethanol (the diol). The diols obtained as oil were purified by
column chromatography over silica gel on elution with benzene-acetone.
(E)-β-[2-Hydroxylphenylethylene]benzeneethanol (2a) Yield: 75%. Colorless needles from
1
cm-1: 3400, 1600, 1449 cm-1; H-NMR (CDCl3): δ 4.58 (2H, s),
KBr
max
benzene-hexane, mp 92-94℃; IR
ν
6.7-7.7 (10H, m). MS m/z 226 (M+, 9), 208 (74), 207 (100). Anal. Calcd for C15H14O2: C, 79.62; H, 6.24.
Found: C, 79.97; H, 6.15.
(E)-β-[2-Hydroxylphenylethylene]benzeneethanol-D2 (2b) The diol-D2 (2b) was prepared from
3-phenylcoumarin (1) in the same manner described above using LiAlD4 (98 atom % D). Colorless
1
cm-1: 3400, 1600, 1450 cm-1; H-NMR (CDCl3): δ
KBr
max
needles from benzene-hexane, mp 90℃; IR
ν
6.7-7.7 (10H, m). MS m/z 228 (M+, 3), 210 (M+-H2O, 64), 208 (100).
(E)-β-[2-Hydroxy-4,6-dimethoxyphenylethylene]-3,5-dibenzyloxybenzeneethanol (6b) Colorless
cm-1: 3450, 1580 cm-1; 1H-NMR (CDCl3): δ 3.73 (3H, s), 3.76 (3H, s), 4.46 (2H, br
neat
max
viscous oil; IR
ν
s), 5.02 (4H, s), 6.09 (1H, d, J = 2.0 Hz), 6.18 (1H, d, J = 2.0 Hz), 6.60 (1H, t, J = 2.0 Hz), 6.88 (2H, d, J
= 2.0 Hz), 7.3-7.5 (11H, m). MS m/z 474 (M+).
(E)-β-[2-Hydroxy-4-benzyloxyphenylethylene]-3,5-dibenzyloxybenzeneethanol
(7b)
Colorless
1
cm-1: 3470, 1596 cm-1; H-NMR (CDCl3): δ 4.51 (2H, br s), 5.04 (2H, br s), 5.05
neat
max
viscous oil; IR
ν
(4H, br s), 6.60 (3H, m), 6.93 (3H, m), 6.4-7.6 (22H, m). MS m/z 544 (M+).
(E)-β-[2-Hydroxy-4-benzyloxyphenylethylene]-2,4-dibenzyloxybenzeneethanol
(8b)
Colorless
1
cm-1: 3440, 1583 cm-1; H-NMR (CDCl3): δ 4.32 (2H, br s), 5.01, 5.02, 5.04 (2H
neat
max
viscous oil; IR
ν
each, s), 6.45-6.60 (6H, m), 6.95 (1H, d, J = 8.3 Hz), 7.3 (15H, m). MS m/z 392 (M+).
(E)-β-[2-Hydroxy-4-methoxyphenylethylene]-4-benzyloxy-2-methoxybenzeneethanol (9b) Colorless
1
cm-1: 3440, 1583 cm-1; H-NMR (CDCl3): δ 3.79, 3.81 (3H, each), 4.29 (2H, br s),
neat
max
viscous oil; IR
ν
5.04 (2H, s), 6.45-6.60 (6H, m), 6.92 (1H, d, J = 8.5 Hz), 7.2-7.3 (5H, m). MS m/z 392 (M+).
(E)-β-[2-Hydroxy-4-benzyloxyphenylethylene]-3-benzyloxy-2,4-dimethoxybenzeneethanol
(10b)
1
cm-1: 3440, 1592 cm-1; H-NMR (CDCl3): δ 3.83 (3H,s), 3.88 (3H, s),
neat
max
Colorless viscous oil; IR
ν

HETEROCYCLES, Vol. 65, No. 7, 2005
1651
4.30 (2H, br s), 5.06 (2H, br s), 6.5-7.5 (16H, m). MS m/z 474 (M+, 1).
General procedure for the preparation of 2-phenylbenzofurans (6c-10c)
A mixture of (E)-β-[2-hydroxylphenylethylene]benzeneethanol derivative (2 mmol; 2a, 2b, 6b-10b)
prepared from the corresponding 3-phenylcoumarin, DDQ (0.50 g, 2.2 mmol) and dry benzene (25 mL)
was refluxed for 7.5 h. A white solid product was deposited on a reflux condensor, and was identified
with the authentic paraformaldehyde (Wako Pure Chemical Ind. Co., Ltd.). After removing the
precipitates (DDQH2) by filtration, the filtrate was concentrated and loaded directly onto a short column
packed with 10 g of silica gel in benzene. The column was eluted with benzene and the evaporation of the
eluent gave rise to pure products (3, 5a, 5b, 6c-10c).
2-Phenylbenzofuran (3) Yield: 34%. Compound (3) was obtained from the reaction mixture along with
2,2’-oxybis[3-phenyl-2H-1-benzopyran] (5a; 30%) and 3-phenylcoumarin (1; 6%). 5a: colorless powder,
1
mp 233-235℃ (lit.,16 210℃); IR
cm-1: 1483, 1452, 1204 cm-1; H-NMR (CDCl3): δ 6.78 (2 H, s),
KBr
max
ν
7.0-7.5 (20H, m); 13C NMR (CDCl3) δ 91.9, 116.8, 121.8, 122.1, 125.6, 127.4, 127.5, 128.2, 128.9, 130.3,
136.0, 149.7. MS m/z 430 (M+, 0.2), 207 (100). Anal. Calcd for C30H22O3: C, 83.67; H, 5.39. Found: C,
83.42; H, 5.17. Reaction of (E)-β-[2-hydroxylphenylethylene]benzeneethanol-D2 (2b) with DDQ under
KBr
max
the identical condition stated above furnished 2,2’-oxybis[3-phenyl-2H-1-benzopyran]-D2 (5b). IR
ν
cm-1: 1483, 1452, 1204 cm-1; 1H-NMR (CDCl3): δ 7.0-7.5 (20H, m). MS m/z 432 (M++D2, 0.6), 207 (100),
206 (8).
cm-1:
KBr
max
2-(3,5-Dibenzyloxyphenyl)-4,6-dimethoxybenzofuran (6c) Yield: 36%. Amorphous; IR
ν
1590, 1503 cm-1; 1H-NMR (CDCl3): δ 3.78 (3H, s), 3.81 (3H, s), 5.10 (4H, br s), 6.32 (1H, d, J = 2.0 Hz),
6.58 (1H, t, J = 2.0 Hz), 6.68 (1H, br d, J = 2.0 Hz), 7.05 (1H, d, J = 2.0 Hz), 7.06 (2H, d, J = 2.0 Hz),
7.3-7.5 (11H, m). MS m/z 466 (M+, 44), 375 (100). Anal. Calcd for C30H26O5: C, 77.24; H, 5.62. Found:
C, 77.59; H, 5.51. This product (62 mg) was hydrogenated over 5% Pd-C (28 mg) in EtOH (8 mL) for 2h,
and the mixture was filtered off. The filtrate was evaporated to dryness and the residue was recrystalized
from benzene-acetone to give Morasin A (36 mg) in pure forms. Colorless needles from benzene-acetone,
mp 83-85℃.17
cm-1: 1600,
KBr
max
2-(3,5-Dibenzyloxyphenyl)-6-benzyloxybenzofuran (7c) Yield: 11%. Amorphous; IR
ν
1499 cm-1; 1H-NMR (CDCl3): δ 5.10 (4H, br s), 5.13 (2H, br s), 6.60 (1H, t, J = 2.0 Hz), 6.92 (1H, br s),
6.95 (1H, dd, J = 8.5, 2.0 Hz), 7.08 (2H, d, J = 2.0 Hz), 7.3-7.5 (16H, m). MS m/z 512 (M+, 36), 421

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HETEROCYCLES, Vol. 65, No. 7, 2005
(100). Anal. Calcd for C35H28O4: C, 82.01; H, 5.51. Found: C, 81.80; H, 5.72. The dimer
2,2’-oxybis[3-(3,5-dibenzyloxyphenyl)-6-benzyloxy-2H-1-benzopyran] was also obtained. Amorphous,
yield: 38%. 1H-NMR (CDCl3): δ 5.04 (12H, s), 6.1-7.3 (46H); 13C NMR (CDCl3) δ 70.26, 102.61, 104.72,
105.30, 105.95, 111.69, 112.04, 117.26, 127.34, 127.75, 128.33, 131.55, 136.19, 136.36, 136.54, 146.68,
149.72, 151.77, 158.81, 159.80. A mixture of the dimer (100 mg) and aq. THF (THF : H2O = 5 : 2; 70
mL) and H2SO4 (4 mL) was refluxed for 45 h. The mixture was then poured into water, and the residue
was extracted with Et2O. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness.
The residue was chromatographed over silica gel on elution with benzene to give
2-(3,5-dibenzyloxyphenyl)-6-benzyloxybenzofuran (7c). Yield: 53%. The product (7c) was hydrogenated
over 5% Pd-C in the same manner as described above to give Morasin M. Colorless needles from
benzene-MeOH, mp 258-260℃.18
cm-1: 1603,
KBr
max
2-(2,4-Dibenzyloxyphenyl)-6-benzyloxybenzofuran (8c) Yield: 60%. Amorphous; IR
ν
1506 cm-1; 1H-NMR (CDCl3): δ 5.10, 5.12, 5.15 (2H each, br s), 6.75 (1H, d, J = 2.0 Hz), 6.83 (1H, dd, J
= 8.4, 2.0 Hz), 6.95 (1H, dd, J = 8.5, 2.2 Hz), 7.10 (1H, d, J = 2.2 Hz), 7.12 (1H, s), 7.3-7.5 (17H, m). MS
m/z 512 (M+, 21), 421 (100). Anal. Calcd for C35H28O4: C, 82.01; H, 5.51. Found: C, 81.69; H, 5.66. This
product was hydrogenated over 5% Pd-C in the same manner as described above to give
2-(2,4-dihydroxyphenyl)-6-hydroxybenzofuran. Colorless needles from MeOH-H2O, mp 208-209℃.19
cm-1:
KBr
max
2-(4-benzyloxy-2-methoxyphenyl)-6-methoxybenzofuran (9c) Yield: 65%. Amorphous; IR
ν
1601, 1498 cm-1; 1H-NMR (CDCl3): δ 5.10 (2H, br s), 3.83 (3H, s), 3.92 (3H, s), 6.72 (1H, d, J = 2.1 Hz),
6.79 (1H, dd, J = 8.5, 2.1 Hz), 6.92 (1H, dd, J = 8.2, 2.0 Hz), 7.13 (1H, d, J = 2.0 Hz), 7.15 (1H, s),
7.2-7.3 (6H, m), 7.39 (1H, d, J = 8.5 Hz). MS m/z 360 (M+, 41), 269 (100). Anal. Calcd for C23H20O4: C,
76.65; H, 5.59. Found: C, 76.91; H, 5.72. This product was hydrogenated over 5% Pd-C in the same
manner as described above to give vignafuran in amorphous form.20
2-(3-Benzyloxy-2,4-dimethoxyphenyl)-6-benzyloxybenzofuran (10c) Yield: 52%. Amorphous; IR
cm-1: 1597, 1504 cm-1; 1H-NMR (CDCl3): δ 3.86 (3H, s), 3.96 (3H, s), 5.07 (2H, br s), 5.12 (2H, br
KBr
max
ν
s), 6.75 (1H, d, J = 8.5 Hz), 6.93 (1H, dd, J = 2.3, 8.6 Hz), 7.12 (1H, br d, J = 2.3 Hz), 7.17 (1H, d, J =
0.8 Hz), 7.3-7.5 (11H, m), 7.65 (1H, d, J = 8.6 Hz). MS m/z 466 (M+, 29), 375 (100). Anal. Calcd for
C30H26O5: C, 77.24; H, 5.62. Found: C, 77.69; H, 5.54. This product was hydrogenated over 5% Pd-C in
the same manner as described above to give pterofuran. Colorless needles from benzene-EtOH, mp

HETEROCYCLES, Vol. 65, No. 7, 2005
1653
210-211℃.21
ACKNOWLEDGEMENTS
This research was supported by Grant-in-aid for Scientific Research (No. 05671767) from the Ministry of
Education, Culture, Sports, Science and Technology (to T. K.).
REFERENCES AND NOTES
1. There are several biogenetic origins for naturally occurring 2-phenylbenzofurans. Some neolignans
also constitute the 2-phenylbenzofuran structure, but they are clearly distinguished from those of
mulberry and leguminous origins by the presence of the propyl unit. This article does not refer to
those of neoligan origin as 2-phenylbenzofurans.
2. P. M. Dewick, ‘The Flavonoids: Advances in Research since 1986,’ ed. by J. B. Harborne, Chapman
and Hall, London, 1992, pp. 117-238.
3. T. Nomura, Fortschr. Chem. Naturstoffe, 1988 53, 87.
4. T. Fukai, C.-B. Sheng, T. Horikoshi, and T. Nomura, Phytochemistry, 1996, 43, 1119; T.
Kinoshita, K. Kajiyama, Y. Hiraga, K. Takahashi, Y. Tamura, and K. Mizutani, Chem. Pharm. Bull.,
1996, 44, 1218 and references therein.
5. T. Kinoshita, T. Saitoh, and S. Shibata, Chem. Pharm. Bull., 1978, 26, 135.
6. O. Miyata, N. Takeda, and T. Naito, Org. Lett., 2004, 6, 1761; K. Imafuku, and R. Fujita, Chemistry
Express, 1991, 6, 323; J. M. Burke and R. Stevenson, J. Chem. Res., Synopses, 1987, 179; V. Binh, G.
Mezey-Vandor, and M. Nogradi, Liebigs Ann. Chem., 1984, 734; B. A. McKittrick, R. T. Scannell,
and R. Stevenson, J. Chem. Soc., Perkin Trans. I, 1982, 3017; A. Hercouet and M. Le Corre,
Tetrahedron Lett., 1979, 2145.
7. T. Kinoshita, Tetrahedron Lett., 1997, 38, 259.
8. G. Cardillo, R. Cricchio, and L. Merline, Tetrahedron, 1971, 27, 1875.
9. V. M. Micovic and M. J. L. Mihailovic, J. Org. Chem., 1953, 18, 1190.
10. M. Versteeg, B. C. B. Bezuidenhoudt, and D. Ferreira, Heterocycles, 1998, 48, 1373; T. G. van Aardt,
P. S. van Heerden, and D. Ferreira, Tetrahedron Lett., 1998, 39, 3881; T. G. van Aardt, H. van
Rensburg, and D. Ferreira, Tetrahedron, 2001, 57, 7113; T. G. van Aardt, H. van Rensburg, and D.
Ferreira, Tetrahedron, 1999, 55, 11773.

1654
HETEROCYCLES, Vol. 65, No. 7, 2005
11. A. K. Awasthi and R. S. Tewari, Synthesis, 1986, 1061.
12. R. E. Koenigkramer and H. Zimmer, J. Org. Chem., 1980, 45, 399.
13. H. Gerlach, Helv. Chim. Acta, 1977, 60, 3039.
14. K. Kurosawa, W. D. Ollis, I. O. Sutherland, O. R. Gottlieb, and A. B. De Oliveira, Phytochemistry,
1978, 17, 1389.
15. A. Patra, G. Ghosh, P. K. Sengupta, and S. Nath, Magn. Reson. Chem., 1987, 25, 734.
16. C. Deschamps-Vallet, J.-B. Ilotse, M. Meyer-Dayan, and D. Molho, Tetrahedron Lett., 1979, 1109.
17. M. Takasugi, S. Nagao, T. Masamune, A. Shirata, and K. Takahashi, Tetrahedron Lett., 1978, 797.
18. A. Shirata, K. Takahashi, M. Takasugi, S. Nagao, S. Ishikawa, S. Ueno, L. Munoz, and T. Masamune,
Bull. Sericul. Exp. Sta., 1983, 28, 793.
19. T. Miyase, A. Ueno, T. Noro, and S. Fukushima, Chem. Pharm. Bull., 1981, 29, 2205.
20. N. W. Preston, K. Chamberlain, and R. A. Skipp, Phytochemistry, 1975, 14, 1843.
21. R. G. Cooke and I. D. Rae, Aust. J. Chem., 1964, 17, 379.