A novel strategy for the synthesis of benzofuran skeleton neolignans: Application to ailanthoidol, XH-14, and obovaten

Article abstract of DOI:10.1021/jo0258960

A convenient and general approach to the synthesis of the benzofuran skeleton compounds ailanthoidol, XH-14, and obovaten was developed. Starting from vanillin, a series of reactions afforded 7 in 71% yield. Treatment of 7 with n-BuLi followed by addition of substituted benzaldehydes resulted in the formation of carbinols 11 and 31. The substituted benzophenones obtained from oxidation of 11 and 31 were treated with trimethylsilyldiazomethane lithium salt to give diphenylacetylenes 15 and 33, respectively. 15 and 33 were then cyclized in the presence of either mercury acetate in acetic acid or bromine in chloroform to give 3-chloromercurio- or 3-bromobenzofuran, respectively. The 3-chloromercurio intermediates could be reduced to proton or derivatized to ester or bromide, leading to the synthesis of ailanthoidol, XH-14, and obovaten, respectively. In addition, necleophilic substitution was used to introduce a formyl or methyl group into the 3-bromobenzofuran derivatives, providing an alternative pathway to XH-14 and obovaten. The final elongation and deprotection reaction furnished the desired ailanthoidol, XH-14, and obovaten in yields of 30, 15, and 11%, respectively.

Full text of DOI:10.1021/jo0258960

A Novel Str a tegy for th e Syn th esis of Ben zofu r a n Sk eleton
Neolign a n s: Ap p lica tion to Aila n th oid ol, XH-14, a n d Obova ten
Chai-Lin Kao and J i-Wang Chern*
School of Pharmacy, College of Medicine, National Taiwan University, No. 1, Section 1, J en-Ai Road,
Taipei (100), Taiwan
chern@jwc.mc.ntu.edu.tw
Received May 2, 2002
A convenient and general approach to the synthesis of the benzofuran skeleton compounds
ailanthoidol, XH-14, and obovaten was developed. Starting from vanillin, a series of reactions
afforded 7 in 71% yield. Treatment of 7 with n-BuLi followed by addition of substituted
benzaldehydes resulted in the formation of carbinols 11 and 31. The substituted benzophenones
obtained from oxidation of 11 and 31 were treated with trimethylsilyldiazomethane lithium salt to
give diphenylacetylenes 15 and 33, respectively. 15 and 33 were then cyclized in the presence of
either mercury acetate in acetic acid or bromine in chloroform to give 3-chloromercurio- or
3-bromobenzofuran, respectively. The 3-chloromercurio intermediates could be reduced to proton
or derivatized to ester or bromide, leading to the synthesis of ailanthoidol, XH-14, and obovaten,
respectively. In addition, necleophilic substitution was used to introduce a formyl or methyl group
into the 3-bromobenzofuran derivatives, providing an alternative pathway to XH-14 and obovaten.
The final elongation and deprotection reaction furnished the desired ailanthoidol, XH-14, and
obovaten in yields of 30, 15, and 11%, respectively.
In tr od u ction
platelet,9 antioxidantive,10 insecticidal,11 anti-inflamana-
tory,12 antifungal,13 antifeedant,14 and cancer preventa-
tive.15 These compounds are also important sources of
phytoestrogens.16
The structures of benzofuran lignans have one common
characteristic: they all contain a 2-phenyl-7-methoxy-
Ailanthoidol (1),1 XH-14 (2),2 and obovaten (3)3 are
natural products and characteristic members of the
neolignan family. The lignanoids are dimers of propyl-
benzene units that connect at the side chain carbon.
Those whose linkage of two phenylpropanoid units is
other than the above type are known as neolignans.4
Lignans and neolignans are widespread in nature. They
have a wide variety of chemical structures and exhibit a
broad range of biological activities such as anticancer,5
antiproliferative,6 antiviral,7 immunosuppressive,8 anti-
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10.1021/jo0258960 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/27/2002
6772
J . Org. Chem. 2002, 67, 6772-6787

Synthesis of Benzofuran Skeleton Neolignans
CHART 1
benzofuran skeleton. The different lignans and neo-
lignans are formed by different substitutions at the 3-
and 5-positions and the 2-phenyl ring. XH-14 was the
first reported nonnucleoside-type potent adenosine A1
agonist17 and obovaten is known as an active antitumor
agent.18 No biological activity has been reported for
ailanthoidol. However, the limited supply of XH-14 and
obovaten from natural sources has prevented the full
characterization of their biological activities. As a result
of our interest in developing an adenosine A1 agonist,19
and in view of the pharmacological interest of XH-14, we
wished to develop a novel and general approach for the
construction of the benzofuran skeleton. To achieve this
goal, two fundamental criteria needed to be considered:
(1) Since most benzofuran lignans contain a substituted
phenyl ring at the 2-position and various functional
groups at the 3-position, the synthetic approach must
allow for the assemblage of the individual components
of the molecules. (2) To investigate the relationship
between lignan and macromolecule and develop potential
candidate drugs, an efficient approach toward allowing
the preparation of a variety of analogues from available
building blocks is required. To meet these requirements,
we set out to develop a general and convenient method
for the synthesis of the benzofuran skeleton.Several
approaches can be used to prepare ailanthoidol and XH-
14; however, they do not all meet our proposed criteria.
The prime method involves base-promoted cyclization of
diphenylacetylene, which is obtained through cuprous
coupling of o-halophenol derivatives with phenylacetylene
derivatives.20 However, this method is frequently limited
in versatility by the availability of the requisite starting
materials. A further drawback of this approach is that it
generally uses an electrophilic reaction such as Gatter-
man-Adams formylation to install a functional group at
the 3-position, but the reaction of benzofuran with
electrophiles is complicated by competitive substitution
at either C3 or C4. An alternative to the base-promoted
reaction is to use palladium-catalyzed cyclization to
construct the benzofuran skeleton.21 Although organo-
palladium chemistry can induce the cyclization of di-
phenylacetylene and install an ester group onto the
3-position simultaneously22 and overcome the problems
of poor regioselectivity of electrophilic substitution en-
countered in base-promoted cyclization, this key reaction
is not always efficient due to the low yields when this
method is applied in reactions similar to the ones
considered here.23 The limited available starting material
and inconvenient process also limit their application of
both approaches as well. Moreover, both of the above
methods require the presence of an o-hydroxy group to
provide a nucleophilic center, necessitating additional
synthetic steps to achieve this requirement. In addition,
synthesis of ailanthoidol starting from a preparation of
furan with subsequent benzo-annulation reaction to
construct the benzene ring has also been reported.24 This
method gave ailanthoidol in 12% total yield. Neverthe-
less, application of this approach to the synthesis of
3-substituted benzofurans such as XH-14 and obovaten
faces the problem of introducing a substituent at the
3-position. Another recently reported approach to con-
structing the benzofuran structure is the use of a bio-
mimetic oxidative coupling reaction, which involves a
homocoupling reaction of two cinnamic acid derivatives.25
This approach has been found to give benzofurans in low
to moderate yield. However, this strategy does not allow
the heterocoupling reaction and is therefore not appro-
priate for our goal. Since the known strategies are of no
advantage over analogous preparation, a novel diversity-
oriented method is still needed.
Retr osyn th etic An a lysis
We began our work with the conjecture that 2-substi-
tuted phenyl-3-chloromercuriobenzofuran could be a key
intermediate that, by reaction with various electrophiles
and subsequent functionalization at the C-5 position,
could lead to the three compounds of interest and a
variety of their analogues. For the preparation of 2-sub-
stituted phenyl-3-chloromercuriobenzofuran, we selected
substituted diphenylacetylenes as the appropriate pre-
cursor because of their ability to deliver a variety of
2-phenyl-ring substituents. The substituted diphenyl-
acetylenes themselves can be prepared from substituted
benzophenone, themselves obtained by a series of reac-
tions starting from different benzaldehydes and using the
(17) Yang, Z.; Hon, P. M.; Chui, K. Y.; Xu, Z. L.; Chang, H. M.; Lee,
C. M.; Cui, Y. X.; Wong, H. N. C.; Poon, C. D.; Fung, B. M. Tetrahedron
Lett. 1991, 32, 2061-2064.
(21) (a) Cachi, S.; Fabrizi, G.; Moro, L. Synlett 1998, 741-745. (b)
Monteiro, N.; Balme, G. Synlett 1998, 746-747. (c) Kunda, N. G.; Pal,
M.; Mahanty, J . S.; De, M. J . Chem. Soc., Perkin. Trans. 1 1987, 2815-
2820. (d) Konda, Y.; Sakamoto, T.; Yamanaka, H. Heterocycles 1989,
29, 1013-1012.
(18) Tsai, I.-L.; Hsieh, C.-F.; Duh, C. Y. Phytochemistry 1998, 48,
1371-1375.
(19) (a) Lee, Y.-M.; Chern, J .-W.; Yen, M.-S. Br. J . Pharmacol. 1994,
112, 1031-1036. (b) Tao, P.-L.; Yen, M.-S.; Shyu, W.-S.; Chern, J .-W.
Eur. J . Pharmacol. 1993, 243, 135-139. (c) Chern, J .-W.; Lin, G.-W.;
Chen, C. S.; Townsend, L. B. J . Org. Chem. 1991, 56, 4213-4218.
(20) (a) Sakai, A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1999,
40, 4211-4214. (b) Lutjens, H.; Scammells, P. J . Synlett 1999, 1079-
2082. (c) Sogawa, A.; Tsukayama, M.; Nozaki, H.; Nakayama, M.
Heterocycles 1996, 43, 101-111. (d) Buckle, D. R.; Rockell, C. J . M. J .
Chem. Soc., Perkin. Trans. 1 1985, 2443-2446.
(22) Scammels, P. J .; Lutjens, H. Tetrahedron Lett. 1998, 39, 6581-
6584.
(23) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297-299.
(24) Serra, S.; Fuganti, C. Tetrahedron Lett. 1998, 39, 5609-5610.
(25) (a) Kuo, Y.-H.; Wu, C.-H. J . Nat. Prod. 1996, 59, 625-627. (b)
Pieters, L.; Dyck, S. V.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.;
Lemie’re, G. J . Med. Chem. 1999, 42, 5475-5481. (c) Nascimento, I.
R.; Lopes, L. M. X.; Davin, L. B.; Lewis, N. G. Tetrahedron 2000, 56,
9181-9193.
J . Org. Chem, Vol. 67, No. 19, 2002 6773

Kao and Chern
F IGURE 1. Retrosynthetic analysis.
lithium salt of trimethylsilyldiazomethane in Colvin
rearrangement.26 Treatment of the resulting substituted
diphenylacetylene with electrophiles will then induce
cyclization with simultaneous removal of the o-methoxy
group and afford the 2-substituted phenyl-3-chloromer-
curiobenzofuran derivatives.27 Consequently, the choice
of methyl group for protection of the o-hydroxy group
allows the application of a wider range of reaction
conditions in the subsequent steps because it provides
greater stability than other ether-type protective groups.
The chloromercurio group at the 3-position can be
explored to introduce versatile substituents by adding a
suitable electrophile to afford the desired functional
group. In addition, the aldehyde group at the 5-position
obtained after deprotection of the acetal group can be
further derivativized.28 Thus, the designed intermediate
depicted in Figure 1 by a variation of functional group
at the 3- and 5-position is able to enroll diverse reactions
to give the desired target compounds. In a preliminary
study,29 we reported that mercury acetate could be
utilized for the cyclization of the substituted diphenyl-
acetylene and the resulting chloromercurio group could
be further reduced to a proton. In addition, the aldehyde
group could be transformed to a 3-hydroxypropenyl group
through the Wittig reaction. This successful result
prompted us to investigate the general application of this
methodology for the preparation of other neolignans.
Here we report an efficient and convenient general
strategy for the synthesis of compounds of this type. To
the best of our knowledge, this is the first report of the
total synthesis of obovaten (3).
Resu lts a n d Discu ssion
Syn t h esis of Key In t er m ed ia t e 2-Su b st it u t ed
P h en yl-3-ch lor om er cu r iob en zofu r a n Der iva t ives.
We began with the preparation of the benzophenone
derivatives. 1-Bromo-2,3-dimethoxy-5-(5,5-dimethyl-1,3-
dioxan-2-yl)benzene (7) was prepared starting from van-
illin (4) following the procedure in the literature.30
A
treatment of the dimethylpropandiol and methylated
product 6, which was obtained from the methylation of
3-bromo-4-hydroxy-5-methylbenzaldehyde (5) with meth-
(26) Colvin, E. W.; Hamill, B. J . J . Chem. Soc., Perkin Trans. 1 1977,
1379-1382.
(27) Larock, R. C.; Harrison, L. W. J . Am. Chem. Soc. 1984, 106,
4218-4227.
(28) Nicolaou, K. C.; Pfefferkorn, J . A.; Mitchell, H. J .; Roecker, A.
J .; Barluenga, S.; Cao, G.-Q.; Affleck, R. L.; Lillig, J . E. J . Am. Chem.
Soc. 2000, 122, 9954-9967.
(29) Kao, C.-L.; Chern, J .-W. Tetrahedron Lett. 2001, 42, 1111-1113.
(30) Shriner, R. L.; McCutcham, P. J . Am. Chem. Soc. 1929, 51,
2193-2195.
6774 J . Org. Chem., Vol. 67, No. 19, 2002

Synthesis of Benzofuran Skeleton Neolignans
SCHEME 1
SCHEME 2
benzaldehyde, the reaction temperature, and the con-
centration of the two starting materials. Preliminary
investigation showed that the use of low concentrations
of starting materials and slow addition rates reduce the
amount of side products.
Oxidation of 11 with manganese oxide furnished
4-benzyloxy-3-methoxyphenyl 5-(5,5-dimethyl-1,3-dioxan-
2-yl)-2,3-dimethoxyphenyl ketone (14) in 96% yield.
Compound 14 was then treated with trimethylsilyl-
diazomethane lithium salt at -78 °C to give the key
intermediate, 1-(4-benzyloxy-3-methoxyphenyl)-1-(2,3-
dimethoxy-5-(5,5-dimethyl-1,3-dioxan-2-yl)phenyl)acety-
lene (15) in 98% yield via a Covlin rearrangement.
Compound 15 was treated with mercury acetate in acetic
acid and then quenched with saturated sodium chloride
solution to afford a quantitive yield of 2-(4-benzyloxy-3-
methoxyphenyl)-3-chloromercurio-5-(5,5-dimethyl-1,3-di-
oxan-2-yl)-7-methoxybenzofuran (16).
Syn th esis of Aila n th oid ol. Since we had the key
intermediate 16 in hand, we used it to synthesize
ailanthoidol (1) as a model study. The chloromercurial
intermediate 16 was isolated without further purification
and then treated with NaBH4 in THF to afford 17 in 85%
yield. The catalytic hydrogenation of 17 afforded a
debenzylated product in 88% yield, which was subse-
quently deacetylated in a mixture of acetone and 6 N
hydrochloric acid to provide 18 in 72% yield. When these
two reactions were carried out in the reverse order, the
resulting product was 2-(4-hydroxy-3-methoxyphenyl)-5-
hydroxymethyl-7-methoxybenzofuran, an unexpected over-
reductive product accomplished with reduction of the
aldehyde group, instead of the desired product 18.
Finally, elongation of the side chain at the 5-position of
18 via the Wittig reaction gave 2-(4-benzyloxy-3-meth-
oxyphenyl)-7-methoxy-5-(carbethoxy-1-propen-1-yl)benzo-
furan (19), which was then treated with DIBAL-H to
afford the target compound 1 in 97% yield (Scheme 4).
To facilitate the Pd-promoted cyclization in this strat-
egy, it is necessary to replace the methoxy group at the
ortho-position of 15 with a free hydroxyl group. Therefore,
compound 4 was directly treated with dimethylpropan-
diol to give 2-bromo-6-methoxy-4-(5,5-dimethyl-1,3-di-
oxan-2-yl)phenol (20), which was then reacted with 10
in the presence of 2 equiv of n-BuLi to furnish (4-
benzyloxy-3-methoxyphenyl)-(5-(5,5-dimethyl-1,3-dioxan-
2-yl)-2-hydroxy-3-methoxyphenyl)carbinol (21) in 72%
yield. However, the subsequent attempt to oxidize 21
with MnO2 was unsuccessful. This reaction gave several
inseparable products, of which the only identified product
was 4-benzyloxy-3-methoxybenzaldehyde (10). Compound
10 is possibly formed through the reverse aldol reaction.
Further unsuccessful attempts were made for oxidation
of 21, utilizing different kinds of deprotonative oxidative
reagents including PCC, DDQ, Dess-Martin reagent,
Mofft oxidation, and Swern oxidation, as well as a
different reaction involving active palladium in air. All
yl iodide in the presence of tetrabutylammonium iodide
(TBNI)31 as catalyst, with a catalytic amount of p-toluene-
sulfonic acid in benzene to afford compound 7 in 71%
yield in one pot. However, an investigation on direct
methylation of 5 with methyl iodide under other condi-
tions was unsuccessful.32 The failure of this approach
may be due to the lower nucleophilicity of 5 in the polar
solvent33 (Scheme 1). It should be noted that when
compound 8, which was obtained from methylation of 4
with methyl iodide in the presence of potassium carbon-
ate in ethanol, was treated with bromine in acetic acid,
the result was a 65% yield of 2-bromo-4,5-dimethoxy-
benzaldehyde (9) instead of the expected 6 (Scheme 2).34
Compound 7 was treated with n-BuLi and then coupled
with 4-benzyloxy-3-methoxybenzaldehyde (10) to give
1-(4-benzyloxy-3-methoxyphenyl)-1-(2,3-dimethoxy-5-(5,5-
dimethyl-1,3-dioxan-2-yl)phenyl)carbinol (11) in 77% yield.
Two minor products have been isolated from this reaction
and fully characterized as 1,2-dimethoxy-4-(5,5-dimethyl-
1,3-dioxan-2-yl)benzene (12) and 1-n-butyl-2,3-dimethoxy-
5-(5,5-dimethyl-1,3-dioxan-2-yl)benzene (13). Compound
12 is the debrominated product of 7, while compound 13
may be the result of the SN2 reaction of 7 with n-BuLi
via lithium-halogen exchange. The yield of these side
products is related to the reactivity of the substituted
(31) McKillop, A.; Fiand, J .-C.; Hug, R. P. Tetrahedron 1974, 30,
1379-1382.
(32) Account of the preliminary study: see reference 28 and refer-
ences therein.
(33) Dehmlow, E. V.; Dehmlow, S. S. Phase transfer catalysis;
VCH: New York, 1993; p 5.
(34) Hazlet, S. E.; Brotherton, R. J . J . Org. Chem. 1962, 27, 3253-
3256.
J . Org. Chem, Vol. 67, No. 19, 2002 6775

Kao and Chern
SCHEME 3
SCHEME 4
of these reactions gave 10 as the only identified product
along with some other inseparable products. Given that
the deprotonation process is the key step in oxidative
reactions, the more acidic proton should be a better
reactive center than the other one. This result ruled out
the possibility of applying organopalladium chemistry in
this strategy.
Syn th esis of XH-14. We aimed to synthesize XH-14
(2) by conferring a formyl group at the 3-position of 16.
The strategy proposed for achieving this was the initial
introduction of an ester group followed by reduction and
then oxidation. To introduce the ester group at the
3-position, 16 was treated with a stoichiometric amount
of PdCl2, 2 equiv of MgO, and LiCl under a carbon
monoxide balloon in methanol at room temperature to
give 2-(4-benzyloxy-3-methoxyphenyl)-3-methoxycarbo-
nyl-5-(5,5-dimethyl-1,3-dioxan-2-yl)-7-methoxybenzofu-
ran (22) in 69% yield for the two steps accompanied by a
small amount of 2-(4-benzyloxy-3-methoxyphenyl)-5-(5,5-
dimethyl-1,3-dioxan-2-yl)-7-methoxybenzofuran (17) as
side product. Acidic hydrolysis of 22 with hydrochloric
acid furnished 2-(4-benzyloxy-3-methoxyphenyl)-7-meth-
oxybenzofuran-5-carboxaldehyde (23) in 97% yield. Sub-
sequent condensation of 23 with (carbethoxymethyl)-
triphenylphosphonium bromide lithium salt afforded
2-(4-benzyloxy-3-methoxyphenyl)-3-methoxycarbonyl-7-
methoxy-5-(carbethoxy-1-propen-1-yl)benzofuran (24) in
78% yield, which was then treated with DIBAL-H to give
2-(4-benzyloxy-3-methoxyphenyl)-3-hydroxymethyl-7-meth-
oxy-5-(3-hydroxy-1-propen-1-yl)benzofuran (25) in 49%
yield. The following catalytic hydrogenation and then
selective oxidation with manganese oxide of the hydroxy
group at the 3-position successfully furnished XH-14 (2)
in 24% yield (Scheme 6).
Syn th esis of Obova ten . The successful synthesis of
ailanthoidol and XH-14 encouraged us to apply the same
6776 J . Org. Chem., Vol. 67, No. 19, 2002

Synthesis of Benzofuran Skeleton Neolignans
SCHEME 5
SCHEME 6
approach to the preparation of obovaten (3). To introduce
a methyl group at the 3-position, 2-(4-benzyloxy-3-meth-
oxyphenyl)-3-hydroxymethyl-5-(5,5-dimethyl-1,3-dioxan-
2-yl)-7-methoxybenzofuran (27), obtained from the re-
duction of 23 in the presence of DIBAL-H, was treated
with palladium oxide in CHCl3 under 50 psi of hydrogen
gas at 80 °C to afford 2-(4-benzyloxy-3-methoxyphenyl)-
5-(5,5-dimethyl-1,3-dioxan-2-yl)-7-methoxy-3-methylben-
zofuran (29) in 13% yield and 2-(4-benzyloxy-3-methoxy-
phenyl)-3-methyl-7-methoxybenzofuran-5-carbaldehyde
(28) as the major product (52%), which was formed from
the further deprotection of 29 (Scheme 7).
The synthetic approach for the preparation of 2-(3,4-
dibenzyloxy-5-methoxyphenyl)-1-(5-(5,5-dimethyl-1,3-di-
oxan-2-yl)-2,3-dimethoxyphenyl)acetylene (33) is similar
to the procedure used to obtain 15. 3,4-Dibenzyloxy-5-
J . Org. Chem, Vol. 67, No. 19, 2002 6777

Kao and Chern
SCHEME 7
methoxybenzaldehyde (30), which was obtained in 98%
yield from benzylation of 3,4-dihydroxy-5-methoxybenz-
aldehyde with benzyl bromide and potassium carbonate
in dimethylacetamide, were coupled with 7 in the pres-
ence of 1 equiv of n-BuLi to furnish 2-(3,4-dibenzyloxy-
5-methoxyphenyl)-1-(5-(5,5-dimethyl-1,3-dioxan-2-yl)-2,3-
dimethoxyphenyl)carbinol (31) in 77% yield. The key
intermediate, 1-(3,4-dibenzyloxy-5-methoxyphenyl)-1-
(2,3-dimethoxy-5-(5,5-dimethyl-1,3-dioxan-2-yl)phenyl)-
acetylene (33) was obtained in 99% yield via Colvin
rearrangement of the corresponding ketone (32), which
was prepared in 96% yield by oxidation of 31 in the
presence of MnO2. Remarkably, no side product was
observed in the coupling reaction between 7 and 30, in
contrast to the coupling reaction between 7 and 10, which
formed the side products 12 and 13. Exposure of 33 to
mercury acetate in acetic acid provided 2-(3,4-dibenzyl-
oxy-5-methoxyphenyl)-3-chloromercurio-5-(5,5-dimethyl-
1,3-dioxan-2-yl)-7-methoxybenzofuran (34), which was
then subjected to Pd-catalyzed carboxylation. However,
The carboxylation reaction in the mixture of PdCl2, MgO,
and LiCl was unsuccessful in this case. The demercurated
product (35) was isolated as a single product in 89% yield
and none of the desired product, 2-(3,4-dibenzyloxy-5-
methoxyphenyl)-3-methylcarbmethyl-5-(5,5-dimethyl-1,3-
dioxan-2-yl)-7-methoxybenzofuran (36), was isolated
(Scheme 8).
Alternatively, the chloromercurio 34 was treated with
a stoichiometric amount of bromine in CHCl3 to provide
2-(3,4-dibenzyloxy-5-methoxyphenyl)-3-bromo-5-(5,5-di-
methyl-1,3-dioxan-2-yl)-7-methoxybenzofuran (37) in 64%
yield. We found that the reaction conditions were crucial
to the successful preparation of 37. For example, higher
reaction temperature and longer reaction times dramati-
cally decreased the yield of product and give complicated
results. Methylation of 37 with methyl iodide was
performed in the presence of n-BuLi to give 2-(3,4-
dibenzyloxy-5-methoxyphenyl)-3-methyl-5-(5,5-dimethyl-
1,3-dioxan-2-yl)-7-methoxybenzofuran (38) in 90% yield.
The acetal group in 38 was then deprotected by hydro-
chloric acid in acetone to afford 2-(3,4-dibenzyloxy-5-
methoxyphenyl)-3-methyl-7-methoxybenzofuran-5-car-
baldehyde (39). The olefination of 39 with ethyltriphenyl-
phosphine iodide gave 40, which was then treated with
borontribromide to cleave the benzyloxy ether linkage at
low temperature to give compound 3 in 31% yield from
the last two steps (Scheme 9).
P r ep a r a tion of 3-Br om oben zofu r a n by Br om ocy-
cliza tion of Dip h en yla cetylen e. In this mercury ac-
etate induced cyclization, we overcome the regioselectiv-
ity at the 3-position and improve the reproducibility of
cyclization. The advantage of the organomercury com-
pound is its stability, which makes the chloromercurio
intermediate easy to handle and means that the disad-
vantages of this synthetic route should be considered.
This approach requires a stoichiometric amount of pal-
ladium chloride, which is an expensive material in
comparison to other reagents. In addition, the toxicity of
organomercury reagents may restrict future applications
of this method. For these reasons, it would be worthwhile
to develop an alternative reagent that can be used
instead of mercury acetate. In this cyclization process,
intramolecular alkoxymercuration of acetylene is as-
sumed to proceed through a two-electron, three-center
mercurinium ion. Due to the stability of the mercury-
stabilized cation,35 the oxymercuration reaction gave an
oxonium ion instead of any rearrangment and the fol-
lowing demethylation procedure afforded the desired
benzofuran skeleton. On the basis of this proposed
mechanism, we conjectured that other electrophilic re-
agents might undergo this kind of reaction. Despite the
lower reactivity of bromonium ion in comparison to
mercurinium ion,36 we believed that the bromine would
be an alternative reagent for the cyclization, and directly
provided 3-bromobenzofuran derivatives. The bromide
planted on the 3-position could be used for various
reactions via facile transformation into a variety of
products (Scheme 10).
To test the synthesis with bromine, compound 15 was
treated with bromine in chloroform at -15 °C giving a
mixture of 41 and 42. However, when the mixture was
treated with hydrochloric acid it afforded 42 in 95% yield
from 15. Elongation of compound 42 with ethoxycarb-
(35) Thies, R. W.; Boop, J . L.; Schiedler, M.; Zimmerman, D. C.;
LaPage, T. H. J . Org. Chem. 1983, 48, 2021-2024.
(36) Carey, F. A.; Sundberg, R. J . Acvanced Organic Chemistry. Part
A: Structure and mechanisms, 3rd ed.; Plenum Press: New York, 1990;
p 361.
6778 J . Org. Chem., Vol. 67, No. 19, 2002

Synthesis of Benzofuran Skeleton Neolignans
SCHEME 8
SCHEME 9
methyltriphenylphosphine bromide in THF afforded 43
in 88% yield. Reduction of 43 with DIBAL-H gave 44 in
73% yield, which was treated with 5 equiv of t-BuLi and
then coupled with 5 equiv of N-formylpiperidine to
furnish 45. The formylated compound 45, without puri-
fication, was reduced with activated palladium under
hydrogen to afford the desired XH-14 (2) in 62% yield. It
is noteworthy that the halogen-lithium exchange will
only occur in the presence of five or more equivalents of
t-BuLi. In addition, when n-BuLi was used instead of
J . Org. Chem, Vol. 67, No. 19, 2002 6779

Kao and Chern
SCHEME 10
SCHEME 11
t-BuLi, the debrominated compound was isolated as
major product and a trace amount of 3-butylbenzofuran
was obtained as minor product. Besides, an attempt to
apply N,N-dimethylformamide instead of N-formylpip-
eridine was unsuccessful.
In conclusion, a novel strategy for constructing 2-phen-
ylbenzofuran skeletons has been established. TMSC(Li)-
N2-induced Colvin rearrangement of benzofuran deriva-
tives provided substituted diphenylacetylenes as key
intermediates. Mercury acetate-induced or bromine-
induced cyclization of these intermediates affords the
corresponding 3-chloromercurio- or 3-bromobenzofurans,
respectively. Reduction of 3-chloromercuriobenzofuran
with sodium borohydride gave compound 17, a precursor
of ailanthoidol. Subsequently, the 3-chloromercurio group
could be utilized to introduce a variety of functional
groups at the 3-position of the benzofuran skeleton, for
example the ester group or methyl group. Transformation
of the functional group from 3-bromide to the formyl
group or methyl group was achieved. However, the total
yield of the reactions proceeding via bromine-induced
cyclization was higher than that with mercury acetate.
The syntheses of ailanthoidol (1), XH-14 (2), and obovaten
After the successful synthesis of XH-14 (2) through the
bromine-promoted cyclization of 15, we applied this
method to the preparation of the key intermediate 37
which led to the synthesis of obovaten. To develop an
efficient process for the preparation of obovaten, com-
pound 33 was subjected to the same conditions, which
previously afforded compound 41. As expected, 37 was
obtained as the sole product without removing the acetal
group at the 5-position. This result suggests that the
5-acetal group is stable in this skeleton and further
implies that the substituted phenyl ring at the 2-position
may have certain influence on the electronic properties
of the 5-position (Scheme 12).
6780 J . Org. Chem., Vol. 67, No. 19, 2002

Synthesis of Benzofuran Skeleton Neolignans
SCHEME 12
propan-1,3-diol (63.81 g, 613.6 mmol), p-toluenesulfonic acid
(11.80 g, 62.1 mmol), and benzene (250 mL), respectively. The
resulting solution was heated at reflux with Dean-Stark
apparatus for 26 h and then partitioned between CH2Cl2 (500
mL) and water (300 mL). The aqueous layer was extracted
with CH2Cl2 (200 mL × 3). The combined organic layer was
washed with brine (500 mL) and dried over MgSO4. The
MgSO4 was removed by filtration and the filtrate was concen-
trated in vacuo to give a yellow liquid. The liquid was purified
by column chromatography (silica gel: φ 5 × 13.5 cm; eluent:
Hex/EA ) 7/3). The desired fraction (Rf ) 0.53, Hex/EA ) 3/1)
was collected and the solvent was evaporated. The solid was
recrystallized from 2-propanol to yield 7 (40.93 g, 71%). Mp
76-78 °C; 1H NMR (400 MHz, CDCl3) δ 0.78 (s, 3 H), 1.26 (s,
3 H), 3.61 (d, J ) 11 Hz, 2 H), 3.74 (d, J ) 11 Hz, 2 H), 3.81
(s, 3 H), 3.87 (s, 3 H), 5.29 (s, 1 H), 7.00 (d, J ) 2 Hz, 1 H),
7.27 (d, J ) 2 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 22.3,
23.5, 30.7, 56.5, 61.0, 78.1, 101.0, 110.0, 117.9, 123.1, 136.0,
147.2, 154.1; MS (EI, 70 eV) m/z 251 (100%), 330 (M+, 39%),
332 (M+ + 2, 39%). Anal. Calcd for C14H19BrO4: C, 50.77; H,
5.78. Found: C, 50.63; H, 5.83.
3,4-Dim eth oxyben za ld eh yd e (8). To a solution of vanillin
(6.73 g, 44.2 mmol) in EtOH (150 mL) was added K2CO3 (13.24
g, 96.0 mmol) with stirring until the solid disappear. To the
resulting solution was added the methyl iodide (3.5 mL) in
several portions. After being stirred at room temperature for
10 h, the solution was concentrated in vacuo to remove EtOH.
The resulting mixture was partitioned between CH2Cl2 (150
mL) and water (100 mL). The aqueous layer was extracted
with CHCl3 (50 mL × 3). The combined organic layer was
washed with brine (100 mL) and dried over MgSO4. The
MgSO4 was removed by filtration and the filtrate was concen-
trated in vacuo to give a yellowish mixture. The mixture was
purified by column chromatography (silica gel: φ 3.5 × 12 cm;
eluent: Hex/EA ) 3/1). The desired fraction (Rf ) 0.72, Hex/
EA ) 3/1) was collected and the solvent was evaporated to
give a solid that was recrystallized from EtOH to obtain 8 (5.71
g, 78%). Mp 53-55 °C [lit.38 mp 54-56 °C]; 1H NMR (400 MHz,
CDCl3) δ 3.81 (s, 3 H), 3.90 (s, 3 H), 6.92 (d, J ) 8 Hz, 1 H),
7.34 (d, J ) 2 Hz, 1 H), 7.40 (dd, J ) 8 Hz, 2 Hz, 1 H), 9.79 (s,
1 H); 13C NMR (100 MHz, CDCl3) δ 56.4, 56.5, 109.4, 110.8,
127.2, 130.5, 150.0, 154.9, 191.2, 191.3; HRMS calcd for
C9H10O3 166.0630, found 166.0630.
(3) starting from vanillin gave the excellent total yields
of 30, 15, and 11%, respectively. As hoped, the strategy
developed here can be generalized to other benzofuran
systems. In addition to the development of new synthetic
strategies, the successful synthesis of XH-14, obovaten,
and ailanthoidol opens the way for the construction of
designed 2-phenylbenzofurans for biological investigation
of these natural products. By this approach, analogue
preparation and screening should be accelerated to
facilitate further detailed biological study of this family
of compounds.
Exp er im en ta l Section
Gen er a l Meth od s. Analytical samples were homogeneous
by thin-layer chromatography (TLC) and afforded spectroscopic
data which were consistent with the assigned structures. The
dried solvents were either heated to reflux in situ or stored in
a
freezer. The n-BuLi and t-BuLi were titrated by R,R-
diphenylacetic acid prior to use. Moisture-sensitive reactions
were performed in predried glassware (in an oven at 100 °C
over 24 h) under an inert atmosphere of argon.
1-Br om o-2,3-d im et h oxy-5-(5,5-d im et h yl-1,3-d ioxa n -2-
yl)ben zen e (7). To a solution of vanillin (26.71 g, 175.6 mmol)
in glacial acetic acid (300 mL) was added a solution of Br2 (20
mL, 388.8 mmol) in acetic acid (30 mL) dropwise over 1 h at
0 °C. After the addition, the resulting solution was stirred at
0 °C for 1 h and at room temperature for 25 h. After removal
of acetic acid with the assistance of toluene, the resulting red
mixture was washed with EtOH. A green solid was recrystal-
lized from EtOH to give 5 (36.43 g). Mp 156-158 °C [lit.37 mp
158 °C]; 1H NMR (400 MHz, CDCl3) δ 3.96 (s, 3 H), 6.57 (br s,
1 H), 7.34 (d, J ) 2 Hz, 1 H), 7.61 (d, J ) 2 Hz, 1 H), 9.76 (s,
1 H); 13C NMR (100 MHz, CDCl3) δ 56.9, 108.0, 108.2, 130.0,
130.1, 147.7, 148.9, 189.6; MS (EI, 70 eV) m/z 230 (M+, 100%),
232 (M + 2+, 100%). Compound 5 (36.43 g, 24.0 mmol) was
dissolved in CH2Cl2 (600 mL) and NaOH(aq) (12.84 g in 200
mL of water) was added. To the resulting solution was added
tetrabutylammonium iodide (12.92 g) with stirring at room
temperature until the solid disappear. To the reaction mixture
was added methyl iodide (18 mL, 291.0 mmol) with stirring
at room temperature for 30 h. The reaction mixture was
neutralized by 6 N HCl solution and the resulting solution was
extracted with CH2Cl2 (200 mL × 5). The combined organic
layer was washed with brine (300 mL) and dried over MgSO4.
The MgSO4 was removed by filtration and the filtrate was
concentrated in vacuo to give a yellowish mixture. The mixture
was washed with 2-propanol and the solid was recrystallized
2-Br om o-4,5-d im eth oxyben za ld eh yd e (9). To a solution
of 8 (5.71 g, 34.2 mmol) in glacial acetic acid (50 mL) was added
a solution of Br2 (2.5 mL, 48.6 mmol) in acetic acid (50 mL)
dropwise over 5 h at 0 °C. After the addition was finished, the
resulting solution was stirred at 0 °C for 1 h and at room
temperature for 16 h. After azeotropic removal of acetic acid
with toluene, the resulting green mixture was purified by
column chromatography (silica gel: φ 4.5 × 12.5 cm; eluent:
Hex/EA ) 7/3). The desired fraction (Rf ) 0.51, Hex/EA ) 3/1)
was collected and the solvent was evaporated to give a
yellowish solid that was recrystallized from EtOH to obtain 9
(5.41 g, 65%). Mp 148-150 °C [lit.39 mp 148-150 °C]; 1H NMR
1
from 2-propanol to give 6. Mp 65-66 °C; H NMR (400 MHz,
CDCl3) δ 3.90 (s, 3 H), 3.92 (s, 3 H), 3.76 (d, J ) 2 Hz, 1 H),
7.62 (d, J ) 2 Hz, 1 H), 9.81 (s, 1 H); 13C NMR (100 MHz,
CDCl3) δ 56.7, 61.3, 110.7, 118.4, 129.2, 133.5, 152.3, 157.7,
190.4; MS (EI, 70 eV) m/z 246 (M+ + 2, 100%), 244 (M+, 100%).
Anal. Calcd for C9H9BrO3: C, 44.11; H, 3.70. Found: C, 43.98;
H, 3.76. To the bottle containing 6 was added 2,2-dimethyl-
(38) Fleet, G. W. J .; Harding, P. J . C. Tetrahedron Lett. 1979, 11,
975-978.
(39) Coltart, D. M.; Charlton, J . L. Can. J . Chem. 1996, 74, 88-94.
(37) Lam, T. B. T.; Iiyama, K.; Stone, B. A. Phytochemistry 1996,
41, 1507-1510.
J . Org. Chem, Vol. 67, No. 19, 2002 6781

Kao and Chern
(400 MHz, CDCl3) δ 3.90 (s, 3 H), 3.94 (s, 3 H), 7.03 (s, 1 H),
7.40 (s, 1 H), 10.17(s, 1 H); 13C NMR (100 MHz, CDCl3) δ 56.1,
56.4, 110.4, 115.4, 120.3, 126.5, 148.7, 154.5, 190.7; MS (ESI)
m/z 244 (M + H+, 100%), 246 (M + 2 + H+, 98%). Anal. Calcd
for C9H9BrO3: C, 44.11; H, 3.70. Found C, 43.98; H, 3.76.
J ) 4 Hz, 1 H), 7.32-7.34 (m, 2 H), 7.38 (d, J ) 8 Hz, 2 H),
7.55 (d, J ) 2 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 22.1,
22.2, 23.4, 30.5, 56.2, 56.4, 71.1, 78.0, 101.3, 101.3, 111.7, 111.9,
112.3, 118.7, 126.4, 127.6, 128.4, 129.0, 131.0, 134.3, 134.8,
136.6, 147.3, 149.8, 152.9, 153.0, 194.8; MS (ESI) m/z 493 (M
+ H+). Anal. Calcd for C29H32O7: C, 70.71; H, 6.55. Found: C,
70.31; H, 6.67.
(4-Ben zyloxy-3-m et h oxyp h en yl)-(5-(5,5-d im et h yl-1,3-
d ioxa n -2-yl)-2,3-d im eth oxyp h en yl)ca r bin ol (11), 4-(5,5-
Dim eth yl-1,3-dioxan -2-yl)-1,2-dim eth oxyben zen e (12), an d
1-Bu t yl-5-(5,5-d im et h yl-1,3-d ioxa n -2-yl)-2,3-d im et h oxy-
ben zen e (13). To a solution of 7 (4.48 g, 13.6 mmol) in THF
(250 mL) was added n-BuLi (1.5 M, 10 mL) at -78 °C under
argon. After the mixture was stirred at the same conditions
for 1 h, to the resulting solution was added a solution of 10
(3.69 g, 15.2 mmol) in THF (150 mL) via cannula at -78 °C
under argon. Without removal of the ice trap, the resulting
solution was stirred under argon for 6 h. After being quenched
with saturated NH4Cl(aq) (50 mL), the resulting solution was
partitioned between ether (300 mL) and water (10 mL). The
organic layer was washed with saturated NaHCO3(aq) (30 mL),
water (30 mL), brine (50 mL) and dried over MgSO4. The
MgSO4 was removed by filtration and the filtrate was concen-
trated in vacuo to give a yellowish mixture. The mixture was
purified by column chromatography (silica gel: φ 5 × 11 cm;,
eluent: Hex/EA ) 7/3). The slow moving fraction (Rf ) 0.20,
Hex/EA ) 3/1) was collected and the solvent was evaporated
to give yellowish solid that was recrystallized from the mixture
of hexane and ethyl acetate (3/1) to yield compound 11 (4.71
1-(4-Ben zyloxy-3-m et h oxyp h en yl)-2-(5-(5,5-d im et h yl-
1,3-d ioxa n -2-yl)-2,3-d im eth oxyp h en yl)a cetylen e (15). To
a solution of trimethylsilyldiazomethane (2.0 M, 2 mL) in THF
(30 mL) was added n-BuLi (1.5 M, 2.5 mL) at -78 °C under
argon. After the mixture was stirred for 30 min at the same
conditions, the resulting lithium salt solution was added to
the solution of 14 (0.98 g, 2.0 mmol) in THF at -78 °C under
argon via cannula. After being stirred at -78 °C under argon
for 5 h, the reaction mixture was quenched with saturated
NH4Cl(aq) (30 mL). The resulting solution was partitioned
between ether (150 mL) and water (10 mL). The organic layer
was washed with saturated NaHCO3(aq) (20 mL), water (20
mL), and brine (30 mL) and dried over MgSO4. The MgSO4
was removed by filtration and the filtrate was concentrated
in vacuo to give a yellowish mixture. The mixture was purified
by column chromatography (silica gel: φ 4 × 9 cm; eluent:
Hex/EA ) 3/1). The desired fraction (Rf ) 0.34, Hex/EA ) 3/1)
was collected and the solvent was evaporated to give the white
solid that was recrystallized from EtOH to yield 15 (958 mg,
1
98%). Mp 106-109 °C; H NMR (400 MHz, CDCl3) δ 0.74 (s,
1
g, 77%). Mp 69-71 °C; H NMR (400 MHz, CDCl3) δ 0.75 (s,
3 H), 1.26 (s, 3 H), 3.59 (d, J ) 11 Hz, 2 H), 3.73 (d, J ) 11 Hz,
2 H), 3.84 (s, 6 H), 3.96 (s, 3 H), 5.10 (s, 2 H), 5.29 (s, 1 H),
6.81 (d, J ) 8 Hz, 1 H), 7.05-7.07 (m, 3 H), 7.25-7.28 (m, 2
H), 7.32 (t, J ) 7 Hz, 2 H), 7.39 (d, J ) 7 Hz, 2 H); 13C NMR
(100 MHz, CDCl3) δ 21.9, 22.0, 23.3, 30.3, 56.1, 61.1, 71.0, 77.8,
84.5, 93.8, 101.1, 110.7, 113.9, 115.0, 116.3, 118.0, 123.0, 125.1,
127.5, 128.1, 128.8, 134.6, 137.0, 148.9, 149.5, 150.6, 152.8;
MS (ESI) m/z 489 (M + H+). Anal. Calcd for C30H32O6: C,
73.75; H, 6.60. Found: C, 73.76; H, 6.71.
3 H), 1.26 (s, 3 H), 3.12 (s, 1 H, exchangeable proton), 3.53 (s,
3 H), 3.58 (d, J ) 11.0 Hz, 2 H), 3.70 (d, J ) 11.0 Hz, 2 H),
3.80 (s, 3 H), 3.83 (s, 3 H), 5.06 (s, 2 H), 5.29 (s, 1 H), 5.91 (s,
1 H), 6.74 (s, 2 H), 7.00 (s, 1 H), 7.05 (d, J ) 2 Hz, 1 H), 7.12
(d, J ) 2 Hz, 1 H, exchangeable proton), 7.23 (d, J ) 8 Hz, 1
H), 7.30 (t, J ) 8 Hz, 2 H), 7.38 (d, J ) 7 Hz, 2 H); 13C NMR
(100 MHz, CDCl3) δ 21.8, 23.1, 30.2, 55.6, 56.0, 60.4, 71.1, 71.6,
101.5, 109.4, 110.9, 114.1, 117.6, 119.0, 127.4, 127.7, 128.5,
134.4, 137.3, 137.4, 146.6, 147.3, 149.6, 152.5; MS (ESI) m/z
494 (M+). HRMS calcd for C29H34O7 494.2305, found 494.2304.
The fast moving fraction (Rf ) 0.65, Hex/EA ) 3/1) was
collected and the solvent was evaporated to give 12 as colorless
2-(4-Ben zyloxy-3-m eth oxyp h en yl)-5-(5,5-d im eth yl-1,3-
d ioxa n -2-yl)-7-m eth oxyben zofu r a n (17). To a solution of
15 (7.84 g, 16.1 mmol) in glacial acetic acid (300 mL) was added
Hg(OAc)2 (6.51 g, 20.4 mmol) at 0 °C. The resulting solution
was stirred at 0 °C for 1 h and room temperature for an
additional 1 h. The resulting mixture was poured into an iced
saturated NaCl solution (300 mL) with vigorous stirring. After
the mixture was stirred until it warmed to room temperature,
the resulting mixture was filtered and the residue was washed
with water (100 mL) and hexane (20 mL). The residue was
dried with the aid of air flow overnight. The residue was
dissolved in boiling CHCl3. The chloroform mixture was
filtered through Celite 545. The filtrate was concentrated in
vacuo to give 16, which was used for the next step without
further purification as a white solid in quantitative yield. To
the solution of 16 (7.10 g, 10.0 mmol) in dry THF (200 mL)
was added NaBH4 (1.25 g, 32.8 mmol). After 12.5 h of being
stirred at room temperature, the resulting solution was
saturated by adding NaCl and stirred for another 30 min. The
resulting reaction mixture was filtered through Celite 545 to
give a solution with a green solid. The mixture was purified
by column chromatography (silica gel: φ 4 × 10.5 cm; eluent:
Hex/EA ) 7/3). The desired fraction (Rf ) 0.42, Hex/EA ) 3/1)
was collected and the solvent was evaporated to give a solid
that was recrystallized from MeCN to obtain 17 (4.07 g, 85%
1
oil. H NMR (400 MHz, CDCl3) δ 0.75 (s, 3 H), 1.26 (s, 3 H),
3.60 (d, J ) 11 Hz, 2 H), 3.72 (d, J ) 11 Hz, 2 H), 3.82 (s, 3 H),
3.86 (s, 3 H), 5.30 (s, 1 H), 6.81 (d, J ) 8 Hz, 1 H), 6.99-7.03
(m, 2 H); 13C NMR (100 MHz, CDCl3) δ 22.2, 23.4, 30.5, 56.1,
56.2, 77.9, 102.0, 109.4, 111.1, 119.0, 131.7, 149.2, 149.7; MS
(EI, 70 eV) m/z 252 (M+, 100%), 221 (10%); HRMS calcd for
C
14H20O4 252.1362, found 252.1360. The fastest moving frac-
tion (Rf ) 0.65, Hex/EA ) 3/1) was collected and the solvent
was evaporated to give 13 as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 0.77 (s, 3 H), 0.90 (t, J ) 7 Hz, 3 H), 1.28 (s, 3 H),
1.32-1.38 (m, 2 H), 1.51-1.57 (m, 2 H), 2.60 (t, J ) 8 Hz, 2
H), 3.61 (d, J ) 11 Hz, 2 H), 3.74 (d, J ) 12 Hz, 2 H), 3.77 (s,
3 H), 3.86 (s, 3 H), 5.30 (s, 1 H), 6.89 (d, J ) 2 Hz, 1 H), 6.92
(d, J ) 2 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 13.9, 21.8,
22.6, 23.1, 29.6, 30.1, 32.9, 55.6, 60.4, 77.6, 101.7, 107.6, 119.7,
133.9, 136.3, 147.4, 152.5; MS (EI, 30 eV) m/z 115 (28%), 308
(M+, 67%), 309 (M + H, 100%); HRMS calcd for C18H28O4
308.1988, found 308.1982.
4-Ben zyloxy-3-m eth oxyp h en yl 5-(5,5-Dim eth yl-1,3-d i-
oxa n -2-yl)-2,3-d im eth oxyp h en yl Keton e (14). To a solution
of 10 (1.52 g, 3.1 mmol) in CH2Cl2 (70 mL) was added active
MnO2 (90%, 6.03 g). After the mixture was stirred at the same
conditions for 15 h, the resulting solution was filtered through
Celite 545 to give a yellowish liquid. The mixture was purified
by column chromatography (silica gel: φ 4.5 × 10 cm; eluent:
Hex/EA ) 7/3). The desired fraction (Rf ) 0.26, Hex/EA ) 3/1)
was collected and the solvent was evaporated to give colorless
oil. The white foam was generated in vacuo to give 14 (1.43 g,
96%). 1H NMR (400 MHz, CDCl3) δ 0.75 (s, 3 H), 1.24 (s, 3 H),
3.59 (d, J ) 11 Hz, 2 H), 3.69 (s, 3 H), 3.71 (d, J ) 11 Hz, 2 H),
3.89 (s, 6 H), 5.15 (s, 2 H), 5.32 (s, 1 H), 6.79 (d, J ) 9 Hz, 1
H), 7.00 (s, 1 H), 7.19 (s, 1 H), 7.21 (d, J ) 2 Hz, 1 H), 7.26 (d,
1
from 15). Mp 160-162 °C; H NMR (400 MHz, CDCl3) δ 0.80
(s, 3 H), 1.33 (s, 3 H), 3.67 (d, J ) 11 Hz, 2 H), 3.79 (d, J ) 11
Hz, 2 H), 3.97 (s, 3 H), 4.05 (s, 3 H), 5.17 (s, 2 H), 5.44 (s, 1 H),
6.85 (s, 1 H), 6.91 (d, J ) 8 Hz, 1 H), 6.98 (s, 1 H), 7.30 (s, 2
H), 7.34-7.39 (m, 4 H), 7.44 (d, J ) 8 Hz, 2 H); 13C NMR (100
MHz, CDCl3) δ 22.4, 23.6, 30.7, 56.5, 56.7, 71.5, 78.2, 101.2,
102.6, 104.9, 109.2, 111.6, 114.5, 118.5, 124.3, 127.8, 128.4,
129.0, 131.3, 134.9, 137.3, 144.6, 145.5, 149.2, 150.3, 157.0;
HRMS calcd for C29H30O6 474.2042, found 474.2042. Anal.
Calcd for C29H30O6: C, 73.40; H, 6.37. Found: C, 72.37; H,
6.37.
6782 J . Org. Chem., Vol. 67, No. 19, 2002

Synthesis of Benzofuran Skeleton Neolignans
2-(4-Hydr oxy-3-m eth oxyph en yl)-7-m eth oxyben zofu r an -
5-ca r ba ld eh yd e (18). To a solution of 17 (1.75 g, 3.7 mmol)
in CH2Cl2 (100 mL) was added active palladium (10%, 387.5
mg) with shaking in Parr-Shaker equipment under 60 psi of
H2 for 30 h. The reaction mixture was filtered through Celite
545 and the filtrate was concentrated to give a yellow oil. The
mixture was purified by column chromatography (silica gel:
φ 3.5 × 9.5 cm; eluted by Hex/EA ) 6/4). The desired fraction
(Rf ) 0.15, Hex/EA ) 1/1) was collected and the solvent was
evaporated to give a solid that was recrystallized from EtOH
to obtain 2-(4-hydroxy-3-methoxyphenyl)-5-(5,5-dimethyl-1,3-
dioxan-2-yl)-7-methoxybenzofuran (1.25 g, 88%). Mp 183-185
Na2SO4‚10H2O(aq) (30 mL). The resulting solution was parti-
tioned between ether (200 mL) and water (20 mL). The organic
layer was washed with water (50 mL) and brine (50 mL), dried
over MgSO4, and concentrated in vacuo to give yellow oil. The
mixture was purified by column chromatography (silica gel:
φ 3.5 × 13 cm; eluted by Hex/EA ) 1/1). The desired fraction
(Rf ) 0.60, Hex/EA ) 1/3) was collected and the solvent was
evaporated to give a solid that was recrystallized from EtOH
to yield 1 (325.6 mg, 97%). Mp 195-197 °C [lit.3 mp 199-201
1
°C]; H NMR (400 MHz, CDCl3) δ 3.86 (s, 3 H), 3.98 (s, 3 H),
4.13 (t, J ) 5 Hz, 2 H), 4.83 (t, J ) 5 Hz, 1 H), 6.37 (td, J ) 5,
16 Hz, 1 H), 6.60 (d, J ) 16 Hz, 1 H), 6.87 (dd, J ) 1, 8 Hz, 1
H), 6.99 (s, 1 H), 7.16 (s, 1 H), 7.17 (d, J ) 1 Hz, 1 H), 7.32
(dd, J ) 2, 8 Hz, 1 H), 7.37 (s, 1 H), 9.41 (s, 1 H); 13C NMR
(100 MHz, CDCl3) δ 55.7, 61.6, 100.2, 104.4, 108.7, 110.9,
115.9, 117.9, 121.1, 129.1, 129.6, 130.8, 133.3, 142.5, 144.6,
147.7, 1148.0, 156.3; HRMS calcd for C19H18O5 326.1154, found
326.1154.
1
°C; H NMR (400 MHz, CDCl3) δ 0.80 (s, 3H), 1.32 (s, 3 H),
3.67 (d, J ) 11 Hz, 2 H), 3.79 (d, J ) 11 Hz, 2 H), 3.96 (s, 3H),
4.05 (s, 3H), 5.44 (s, 1 H), 5.75 (s, 1 H, exchangeable), 6.83 (s,
1 H), 6.95 (d, J ) 8 Hz, 1 H), 6.97 (s, 1 H), 7.29 (d, J ) 2 Hz,
1 H), 7.38 (dd, J ) 8, 2 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ 22.4, 23.6, 30.7, 56.5, 56.7, 78.3, 100.9, 102.6, 104.9, 108.1,
111.6, 115.1, 115.2, 119.4, 123.4, 131.3, 134.9, 144.5, 145.4,
146.9, 147.2, 157.2. Anal. Calcd for C22H24O6: C, 68.74; H, 6.29.
Found: C, 68.77; H, 6.23. A solution of 2-(4-hydroxy-3-
methoxyphenyl)-5-(5,5-dimethyl-1,3-dioxan-2-yl)-7-methoxy-
benzofuran in acetone (100 mL) was added to HCl(aq) (6 N, 10
mL) and the mixture was stirred at room temperature for 5
h. The resulting solution was neutralized with NaOH(aq) (1 N,
60 mL) and the aqueous solution was extracted with CHCl3
(200 mL × 2). The organic layer was washed with water (50
mL) and brine (30 mL) and dried over MgSO4. The MgSO4 was
removed by filtration and the filtrate was concentrated in
vacuo to give black oil. The mixture was subjected to column
chromatography (silica gel: φ 3.5 × 8 cm; eluted by Hex/EA
) 1/1) to give the product that was recrystallized from EtOH
to yield 18 (792 mg, 72%). Mp 178-180 °C; 1H NMR (400 MHz,
acetone-d6) δ 3.99 (s, 3 H), 4.07 (s, 3 H), 5.55 (s, 1 H,
exchangeable proton), 6.81 (s, 1 H), 6.97 (s, 1 H), 7.15 (d, J )
8 Hz, 1 H), 7.22 (s, 1 H), 7.29 (d, J ) 2 Hz, 1 H), 7.39 (dd, J )
8, 2 Hz, 1 H), 10.02 (s, 1 H); 13C NMR (100 MHz, acetone-d6)
δ 56.7, 56.9, 105.0, 108.5, 111.6, 115.1, 115.2, 119.3, 123.3,
131.3, 134.9, 144.5, 145.4, 146.9, 147.3, 157.2, 191.1. HRMS
calcd for C17H14O5 298.0841, found 298.0840.
2-Br om o-6-m et h oxy-4-(5,5-d im et h yl-1,3-d ioxa n -2-yl)-
p h en ol (20). To the bottle with 4 (1.09 g, 4.8 mmol) was added
2,2-dimethylpropan-1,3-diol (2.37 g, 22.8 mmol), p-toluene-
sulfonic acid (165.2 mg, 0.9 mmol), and benzene (150 mL),
respectively. The resulting solution was heated to reflux with
Dean-Stark apparatus for 20 h. The resulting solution was
partitioned between CH2Cl2 (100 mL) and water (20 mL). The
organic layer was washed with water (20 mL × 5) and brine
(30 mL) and dried over MgSO4. The MgSO4 was removed by
filtration and the filtrate was concentrated in vacuo to give a
yellow liquid. The liquid was purified by column chromatog-
raphy (silica gel: φ 3.5 × 15.5 cm; eluent: Hex/EA ) 7/3). The
desired fraction (Rf ) 0.36, Hex/EA ) 7/3) was collected and
1
the solvent was evaporated to give 20 (1.10 g, 73%) as oil. H
NMR (400 MHz, CDCl3) δ 0.77 (s, 3 H), 1.25 (s, 3 H), 3.60 (d,
J ) 11 Hz, 2 H), 3.73 (d, J ) 11 Hz, 2 H), 3.88 (s, 3 H), 5.26
(s, 1 H), 6.02 (br s, 1 H), 6.96 (s, 1 H), 7.22 (s, 1 H); 13C NMR
(100 MHz, CDCl3) δ 22.3, 23.5, 30.6, 56.8, 78.1, 101.2, 108.4,
123.2, 131.9, 143.9, 147.5; MS (ESI) m/z 317 (M+ + H), 319
(M+ + 2 + H); HRMS calcd for C13H17BrO4 316.0310, found
316.0311.
(4-Ben zyloxy-3-m eth oxyp h en yl)(5-(5,5-d im eth yl-1,3-d i-
oxa n -2-yl)-2-h yd r oxy-3-m eth oxyp h en yl)ca r bin ol (21). To
a solution of 20 (1.57 g, 5.0 mmol) in THF (20 mL) was added
n-BuLi (1.20 M, 4.5 mL) at -78 °C under argon. After the
mixture was stirred at the same conditions for 70 min, the
resulting solution was added to a solution of 10 (1.35 g, 5.6
mmol) in THF (20 mL) via cannula at -78 °C under argon.
Without removal of the ice trap, the resulting solution was
stirred under argon for 6 h. After the mixture was quenched
with saturated NH4Cl(aq) (30 mL), the resulting solution was
partitioned between ether (200 mL) and water (10 mL). The
organic layer was washed with saturated NaHCO3(aq) (20 mL),
water (30 mL), and brine (30 mL) and dried over MgSO4. The
MgSO4 was removed by filtration and the filtrate was concen-
trated in vacuo to give a yellowish mixture. The mixture was
purified by column chromatography (silica gel: φ 4 × 12 cm;
eluent: Hex/EA ) 1/1). The desired fraction (Rf ) 0.31, Hex/
EA ) 1/1) was collected and the solvent was evaporated to
give 21 (1.72 g, 72%) as a yellow oil. 1H NMR (400 MHz, CDCl3)
δ 0.75 (s, 3 H), 1.25 (s, 3 H), 3.31 (d, J ) 3 Hz, 1 H), 3.56 (d,
J ) 11 Hz, 2 H), 3.69 (d, J ) 11 Hz, 2 H), 3.80 (s, 3 H), 3.83
(s, 3 H), 5.07 (s, 2 H), 5.23 (s, 1 H), 5.89 (d, J ) 3 Hz, 1 H),
6.75 (br s, 3 H), 6.87 (d, J ) 2 Hz, 1 H), 6.98 (d, J ) 2 Hz, 1
H), 7.00 (br s, 1H), 7.25-7.27 (m, 1 H), 7.32 (t, J ) 8 Hz, 2 H),
7.39 (d, J ) 7 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 30.5,
56.3, 71.4, 73.1, 78.0, 102.1, 102.2, 108.1, 111.1, 114.0, 118.3,
119.3, 127.6, 127.6, 128.1, 128.7, 128.8, 128.9, 130.4, 136.5,
137.6, 144.1, 147.3, 147.8, 149.8; HRMS calcd for C28H32O7
480.2149, found 480.2148. Anal. Calcd for C28H32O7: C, 69.98;
H, 6.71. Found: C, 69.81; H, 6.63.
2-(4-H yd r oxy-3-m et h oxyp h en yl)-5-(ca r b et h oxyet h yl-
en e)-7-m eth oxyben zofu r a n (19). To a solution of 18 (4.44
g, 14.9 mmol) in THF (250 mL) was added a solution of the
lithium salt of carbethylmethyltriphenylphosphine bromide
(6.76 g, 15.8 mmol) at -78 °C under argon. The resulting
solution was stirred at -78 °C under argon for 1 h and room
temperature for 5 h. After being quenched with saturated NH4-
Cl(aq) (30 mL), the reaction mixture was partitioned between
ether (150 mL) and water (20 mL). The organic layer was
washed with water (50 mL) and brine (30 mL) and dried over
MgSO4. The MgSO4 was removed by filtration and the filtrate
was concentrated in vacuo to give a yellowish mixture. The
mixture was purified by column chromatography (silica gel:
φ 3.5 × 13 cm; eluted by Hex/EA ) 1/1). The desired fraction
(Rf ) 0.41, Hex/EA ) 1/1) was collected and the solvent was
evaporated to give a solid that was recrystallized from EtOH
1
to yield 19 (325.6 mg, 97%). Mp 149-151 °C; H NMR (400
MHz, CDCl3) δ 1.33 (t, J ) 7 Hz, 3 H), 3.95 (s, 3H), 4.03 (s,
3H), 4.26 (q, J ) 7 Hz, 2H), 5.90 (s, 1 H, exchangeable proton),
6.38 (d, J ) 16 Hz, 1 H), 6.81 (s, 1H), 6.92 (s, 1H), 6.96 (d, J
) 8 Hz, 1 H), 7.27 (s, 1H), 7.32 (d, J ) 2 Hz, 1H), 7.37 (dd, J
) 2, 8 Hz, 1 H), 7.72 (d, J ) 16 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 14.8, 56.5, 56.6, 60.9, 100.6, 105.6, 108.1, 114.9, 115.3,
117.3, 117.4, 119.5, 122.9, 131.0, 131.9, 145.6, 145.9, 147.1,
147.3, 157.8, 167.7. Anal. Calcd for C21H20O6: C, 68.47; H, 5.47.
Found: C, 68.63; H, 5.52.
2-(4-Hydr oxy-3-m eth oxyph en yl)-5-(3-h ydr oxypr open yl)-
7-m eth oxyben zofu r a n (1). To a solution of 19 (1.25 g, 3.0
mmol) in THF (120 mL) was added DIBAL-H (1.0 M in hexane,
6 mL) at -78 °C under argon. After being stirred at the same
conditions for 2 h, the reaction was quenched with saturated
(4-Ben zyloxy-3-m et h oxyp h en yl)-3-m et h ylca r b on yl-5-
(5,5-d im eth yl-1,3-d ioxa n -2-yl)-7-m eth oxyben zofu r a n (22)
a n d 2-(4-Ben zyloxy-3-m eth oxyp h en yl)-5-(5,5-d im eth yl-
J . Org. Chem, Vol. 67, No. 19, 2002 6783

Kao and Chern
1,3-d ioxa n -2-yl)-7-m eth oxyben zofu r a n (17). Compound 16
prepared by the same approach as described in the preparation
of 17 starting from 15 (7.84 g, 16.1 mmol) was used directly
without further purification. To the bottle with MgO (240 mg,
6.0 mmol), LiCl2 (216.4 mg, 2.8 mmol), and PdCl2 (562.5 mg,
3.2 mmol) was added dry MeOH (80 mL) at -78 °C under CO.
After the mixture was stirred at the same conditions for 30
min, to the resulting mixture was added 16 (2.18 g, 2.8 mmol)
at the same conditions. The resulting solution was stirred at
the same conditions for an additional 5 h. The reaction was
quenched with active palladium (85 mg). The resulting mixture
was filtered and the filtrate was concentrated in vacuo to
remove MeOH. The residue was dissolved in ether (300 mL)
and the mixture was washed with water (30 mL) and brine
(50 mL) and dried over MgSO4. The MgSO4 was removed by
filtration and the filtrate was concentrated in vacuo to give a
yellowish mixture. The mixture was purified by column
chromatography (silica gel: φ 4 × 11 cm; eluent: Hex/EA )
3/1). The slow moving band (Rf ) 0.2, Hex/EA ) 3/1) was
collected and the solvent was evaporated. The solid was
recrystallized from EtOH to yield 22 (1.04 g, 69%). Mp 170-
eluted by Hex/EA ) 2/1). The desired fraction (Rf ) 0.45, Hex/
EA ) 3/1) was collected and the solvent was evaporated. The
solid was recrystallized from EtOH to yield 24 (284.7 mg, 78%).
1
Mp 165-166 °C; H NMR (400 MHz, CDCl3) δ 1.34 (t, J ) 7
Hz, 3 H), 3.94 (s, 3 H), 3.96 (s, 3 H), 4.02 (s, 3 H), 4.27 (q, J )
7 Hz, 2 H), 5.22 (s, 2 H), 6.44 (d, J ) 16 Hz, 1 H), 6.78 (dd, J
) 2, 9 Hz, 1 H), 6.95 (d, J ) 9 Hz, 1 H), 7.00 (s, 1 H), 7.30 (d,
J ) 7 Hz, 1 H), 7.36 (t, J ) 8 Hz, 1 H), 7.44 (d, J ) 7 Hz, 2 H),
7.73 (d, J ) 2 Hz, 1 H), 7.76 (d, J ) 4 Hz, 1 H), 7.80 (s, 1 H);
13C NMR (100 MHz, CDCl3) δ 12.9, 50.3, 54.6, 54.7, 59.0, 69.4,
75.7, 104.4, 106.6, 111.5, 111.6, 114.6, 116.1, 120.5, 121.5,
125.7, 126.5, 127.1, 127.8, 130.0, 135.1, 142.6, 143.7, 147.5,
148.8, 160.2, 162.8, 165.5; MS (FAB) m/z 516. Anal. Calcd for
C30H28O8: C, 69.76; H, 5.46. Found: C, 69.70; H, 5.54.
2-(4-Ben zyloxy-3-m eth oxyp h en yl)-3-h yd r oxym eth yl-5-
(3-h yd r oxyp r op -1-en -1-yl)-7-m eth oxyben zofu r a n (25). To
a solution of 24 (420.0 mg, 0.8 mmol) in THF (50 mL) was
added a solution of DIBAL-H (1.0 M in CH2Cl2, 4 mL) at room
temperature under argon. After the mixture was stirred at
room temperature for 1.5 h, the reaction was quenched with
saturated Na2CO3‚10H2O(aq) (20 mL). The resulting mixture
was partitioned between CH2Cl2 (150 mL) and water (30 mL).
The organic layer was washed with water (30 mL) and brine
(30 mL) and dried over MgSO4. The MgSO4 was removed by
filtration and the filtrate was concentrated in vacuo to give a
yellow oil. The oil was purified by column chromatography
(silica gel: 4 × 9 cm; eluted by Hex/EA ) 1/1). The desired
fraction (Rf ) 0.22, Hex/EA ) 1/1) was collected and the solvent
was evaporated. The solid was recrystallized from EtOH with
drops of CHCl3 to yield 25 (174 mg, 49%). Mp 136-137 °C; 1H
NMR (400 MHz, CDCl3) δ 3.94 (s, 3 H), 4.00 (s, 3 H), 4.23 (s,
2 H), 4.70 (s, 2 H), 5.17 (s, 2 H), 6.30 (dt, J ) 21, 6 Hz, 1 H),
6.62 (d, J ) 16 Hz, 1 H), 6.83 (s, 1 H), 6.93 (d, J ) 8 Hz, 1 H),
7.20 (s, 1 H), 7.30 (d, J ) 21 Hz, 1 H), 7.31 (s, 1 H), 7.33 (d, J
) 2 Hz, 2 H), 7.43 (d, J ) 7 Hz, 3 H); 1H NMR (400 MHz,
CDCl3 + MeOH-d4) δ 3.78 (s, 3 H), 3.85 (s, 3 H), 4.65 (s, 2 H),
5.01 (s, 2 H), 6.15 (dt, J ) 16, 6 Hz, 1 H), 6.49 (d, J ) 16 Hz,
1 H), 6.71 (s, 1 H), 6.81 (d, J ) 8 Hz, 1 H), 7.08 (s, 1 H), 7.15
(d, J ) 12 Hz, 1 H), 7.19 (d, J ) 6 Hz, 3 H), 7.25 (d, J ) 6 Hz,
1 H), 7.28 (d, J ) 6 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ
54.1, 54.6, 54.7, 62.3, 69.5, 103.6, 108.7, 109.5, 112.3, 112.5,
118.9, 121.7, 125.8, 126.1, 126.5, 127.1, 129.7, 130.2, 131.4,
135.3, 141.3, 143.6, 147.5, 148.3, 153.0; MS (FAB) m/z 446
(M+). Anal. Calcd for C27H26O6: C, 72.63; H, 5.87. Found: C,
71.60; H, 5.90.
2-(4-Hyd r oxy-3-m eth oxyp h en yl)-5-(3-h yd r oxyp r op yl)-
7-m eth oxyben zofu r a n -3-ca r ba ld eh yd e (2). To a solution
of 25 (785 mg, 1.8 mmol) in EtOH (50 mL) was added active
palladium (10%, 105 mg) and the mixture was stirred at room
temperature for 15 h. After being filtered through Celite 545,
the filtrate was concentrated in vacuo to give a brown oil. The
oil was dissolved in CH2Cl2 (100 mL) and the solution was
added to active MnO2 (1.02 g, 90%) and stirred at room
temperature for 5 h. The resulting solution was filtered
through Celite 545. The filtrate was concentrated in vacuo to
give a yellowish oil. The oil was purified by column chroma-
tography (silica gel: φ 3.5 × 13 cm; eluted by Hex/EA ) 1/3).
The desired fraction (Rf ) 0.18, Hex/EA ) 1/9) was collected
and evaporated to give a solid that was recrystallized from
EtOH to yield 2 (154 mg, 24%). Mp 77-79 °C [lit.2 mp 78-80
°C]; 1H NMR (400 MHz, CDCl3) δ 1.94 (m, 2 H), 2.80 (t, J ) 8
Hz, 2 H), 3.70 (t, J ) 8 Hz, 2 H), 3.98 (s, 3 H), 4.00 (s, 3 H),
6.05 (br s, 1 H), 6.73 (d, J ) 1 Hz, 1 H), 7.05 (d, J ) 8 Hz, 1
H), 7.30 (d, J ) 1 Hz, 1 H), 7.35 (d, J ) 8 Hz, 1 H), 7.64 (s, 1
H), 10.26 (s, 1 H).
1
172 °C; H NMR (400 MHz, CDCl3) δ 0.82 (s, 3 H), 1.34 (s, 3
H), 3.73 (d, J ) 11 Hz, 2 H), 3.86 (s, 3 H), 3.86 (d, J ) 11 Hz,
2 H), 3.92 (s, 3 H), 4.02 (s, 3 H), 5.21 (s, 2 H), 5.48 (s, 1 H),
6.93 (d, J ) 8 Hz, 1 H), 7.07 (s, 1 H), 7.24 (s, 1 H), 7.29 (d, J
) 2 Hz, 1 H), 7.32 (dd, J ) 2, 5 Hz, 2 H), 7.36 (t, J ) 8 Hz, 2
H), 7.43 (d, J ) 7 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 21.8,
23.7, 30.0, 51.9, 56.0, 56.1, 70.8, 78.0, 102.9, 107.0, 109.0, 112.8,
113.0, 122.5, 122.9, 127.1, 127.9, 128.5, 131.2, 133.5, 136.4,
140.7, 143.0, 145.1, 148.8, 149.9, 162.0, 165.0; MS (FAB) m/z
532 (M+). Anal. Calcd for C31H32O8 HgCl2: C, 46.31; H, 4.01.
Found: C, 46.25; H, 4.37. The fast moving band (Rf ) 0.42,
Hex/EA ) 3/1) was collected and the solvent was evaporated.
The solid was recrystallized from MeCN to yield 17 (12 mg,
9%).
2-(4-Ben zyloxy-3-m et h oxyp h en yl)-3-m et h ylca r b on yl-
7-m eth oxyben zofu r a n -5-ca r boxa ld eh yd e (23). To a solu-
tion of 22 (705 mg, 1.3 mmol) in acetone (50 mL) was added
HCl(aq) (6 N, 50 mL) and the mixture was stirred at room
temperature for 4 h. The resulting black mixture was concen-
trated to remove acetone. The resulting solution was extracted
with CH2Cl2 (150 mL × 2). The combined organic layer was
washed with saturated NaHCO3(aq) (30 mL), water (30 mL),
and brine (30 mL) and dried over MgSO4. The MgSO4 was
removed by filtration and the filtrate was concentrated in
vacuo to give a yellowish mixture. The mixture was purified
by column chromatography (silica gel: φ 4 × 10 cm; eluent:
Hex/EA ) 3/1). The desired fraction (Rf ) 0.37, Hex/EA ) 3/1)
was collected and the solvent was evaporated. The solid was
recrystallized from EtOH to yield 23 (571 mg, 97%). Mp 165-
1
166 °C; H NMR (400 MHz, CDCl3) δ 3.96 (s, 3 H), 3.97 (s, 3
H), 4.04 (s, 3 H), 5.22 (s, 2 H), 6.96 (d, J ) 9 Hz, 1 H), 7.31 (d,
J ) 8 Hz, 1 H), 7.35 (d, J ) 8 Hz, 2 H), 7.38 (s, 2 H), 7.44 (d,
J ) 7 Hz, 2 H), 7.65 (dd, J ) 2, 8 Hz, 1 H), 7.76 (d, J ) 2 Hz,
1 H), 8.10 (s, 1 H), 10.03 (s, 1 H); 13C NMR (100 MHz, CDCl3)
δ 52.3, 56.6, 56.7, 71.3, 105.2, 108.8, 113.4, 113.5, 121.5, 122.0,
123.5, 127.7, 128.5, 129.1, 129.6, 134.6, 137.0, 146.3, 146.7,
149.5, 150.9, 162.7, 164.4, 192.3; HRMS calcd for C26H22O7
446.1366, found 446.1365.
2-(4-Ben zyloxy-3-m et h oxyp h en yl)-3-m et h ylca r bon yl-
5-(eth ylca r beth en yl)-7-m eth oxyben zofu r a n (24). To a
solution of 23 (316.7 mg, 0.7 mmol) in THF (100 mL) was
added a solution of the lithium salt of carbethylmethyltri-
phenylphosphine bromide (330 mg 0.8 mmol) at -78 °C under
argon. The resulting solution was stirred at -78 °C under
argon for 3 h. After being quenched with saturated NH4Cl (30
mL), the resulting solution was partitioned between ether (150
mL) and water (30 mL). The organic layer was washed with
water (30 mL) and brine (30 mL) and dried over MgSO4. The
MgSO4 was removed by filtration and the filtrate was concen-
trated in vacuo to give a yellowish mixture. The mixture was
purified by column chromatography (silica gel: φ 3.5 × 8 cm;
2-(4-Ben zyloxy-3-m eth oxyp h en yl)-3-h yd r oxym eth yl-5-
(5,5-dim eth yl-1,3-dioxa n -2-yl)-7-m eth oxyben zofu r a n (27).
To thae solution of 23 (346.3 mg, 0.7 mmol) in THF (30 mL)
was added DIBAL-H (1.0 M in CH2Cl2) at room temperature.
After the mixture was stirred at room temperature for 5 h,
the reaction was quenched with saturated Na2SO4‚10H2O (10
mL). The resulting mixture was partitioned between CH2Cl2
6784 J . Org. Chem., Vol. 67, No. 19, 2002

Synthesis of Benzofuran Skeleton Neolignans
(150 mL) and water (20 mL). The organic layer was washed
with water (30 mL × 2) and saturated NaCl solution (30 mL)
and dried over MgSO4. The MgSO4 was removed by filtration
and the filtrate was concentrated in vacuo to give a yellow
oil. The oil was purified by column chromatography (silica
gel: φ 3 × 8 cm; eluted by Hex/EA ) 3/1) to give a solid that
was recrystallized form EtOH to yield 27 (138.5 mg, 43%). Mp
in vacuo to give a brown mixture. The mixture was purified
by column chromatography (silica gel: φ 4.5 × 11 cm; eluted
by Hex/EA ) 1/1) to give a solid that was recrystallized from
2-propanol to yield 30 (1.15 g, 94%). Mp 156-158 °C [lit.36 mp
1
158 °C]; H NMR (400 MHz, CDCl3) δ 3.86 (s, 3 H), 5.11 (s, 2
H), 5.15 (s, 2 H), 7.12 (s, 1 H), 7.17 (s, 1 H), 7.29-7.39 (m, 6
H), 7.41-7.46 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 56.4,
71.4, 75.3, 106.9, 109.0, 127.8, 128.3, 128.3, 128.5, 128.7, 128.8,
132.1, 136.7, 137.6, 143.3, 153.2, 154.4, 191.2; MS (FAB) m/z
349 (M + H+); HRMS calcd for C22H21O4 349.1440, found
349.1439.
1
221-222 °C; H NMR (400 MHz, CDCl3) δ 0.81 (s, 3 H), 1.32
(s, 3 H), 1.73 (t, J ) 6 Hz, 1 H), 3.67 (d, J ) 11 Hz, 2 H), 3.79
(d, J ) 11 Hz, 2 H), 3.96 (s, 3 H), 4.03 (s, 3 H), 4.88 (d, J ) 6
Hz, 2 H), 5.19 (s, 2 H), 5.45 (s, 1 H), 6.94 (d, J ) 8 Hz, 1 H),
6.99 (d, J ) 1 Hz, 1 H), 7.30 (d, J ) 7 Hz, 1 H), 7.35 (d, J ) 2
Hz, 2 H), 7.37 (d, J ) 2 Hz, 1 H), 7.40 (d, J ) 1 Hz, 7 H), 7.43
(d, J ) 7 Hz, 2 H), 7.46 (d, J ) 2 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ 54.6, 54.7, 62.3, 64.4, 69.5, 99.0, 99.1, 103.1,
104.3, 107.3, 110.0, 110.2, 112.5, 116.6, 125.8, 125.9, 126.4,
127.1, 129.6, 129.8, 130.4, 135.2, 135.3, 143.3, 143.6, 143.7,
147.3, 148.3, 155.1; MS (FAB) m/z 504 (M+); HRMS calcd for
2-(3,4-Diben zyloxy-5-m eth oxyph en yl)-1-(5-(5,5-dim eth yl-
1,3-d ioxa n -2-yl)-2,3-d im eth oxyp h en yl)ca r bin ol (31). To a
solution of 7 (4.47 g, 13.5 mmol) in THF (300 mL) was added
n-BuLi (1.4 M, 11 mL) at -78 °C under argon. After the
mixture was stirred at the same conditions for 30 min, to the
resulting solution was added thae solution of 30 (3.43 g, 9.9
mmol) in THF (100 mL) via cannula at -78 °C under argon.
Without removal of the ice trap, the resulting solution was
stirred under argon for 4 h. After the solution was quenched
with saturated NH4Cl(aq) (50 mL), the resulting mixture was
partitioned between ether (300 mL) and water (20 mL). The
organic layer was washed with water (30 mL) and brine (50
mL) and dried over MgSO4. The MgSO4 was removed by
filtration and the filtrate was concentrated in vacuo to give a
yellowish mixture. The mixture was purified by column
chromatography (silica gel: φ 5 × 11 cm; eluent: Hex/EA )
7/3). The desired fraction (Rf ) 0.23, Hex/EA ) 3/1) was
collected and evaporated to give a product that was recrystal-
lized from 2-propanol to yield 31 (4.34 g, 77%). Mp 69-71 °C;
1H NMR (400 MHz, CDCl3) δ 0.79 (s, 3 H), 1.29 (s, 3 H), 3.00
(br s, 1 H), 3.43 (s, 3 H), 3.63 (d, J ) 11 Hz, 2 H), 3.75 (d, J )
11 Hz, 2 H), 3.78 (s, 3 H), 3.88 (s, 3 H), 5.01 (s, 2 H), 5.03 (s,
2 H), 5.33 (s, 1 H), 5.87 (d, J ) 5 Hz, 1 H), 6.64 (d, J ) 14 Hz,
2 H), 7.06 (d, J ) 12 Hz, 2 H), 7.24-7.33 (m, 8 H), 7.41-7.44
(m, 2 H); 13C NMR (400 MHz, CDCl3) δ 21.8, 23.1, 30.1, 55.7,
56.1, 60.3, 70.9, 72.0, 74.9, 77.6, 101.4, 104.2, 105.8, 109.4,
117.7, 127.5, 127.7, 127.8, 128.0, 128.4, 128.5, 134.4, 136.5,
137.2, 137.9, 139.7, 146.5, 152.2, 152.5, 153.5; MS (FAB) m/z
601 (M + H+); HRMS calcd for C36H41O8 601.2802, found
601.2803.
C
30H32O7 504.2148, found 504.2148.
2-(4-Ben zyloxy-3-m eth oxyp h en yl)-5-(5,5-d im eth yl-1,3-
dioxan -2-yl)-7-m eth oxy-3-m eth ylben zofu r an (29) an d 2-(4-
Ben zyloxy-3-m et h oxyp h en yl)-3-m et h yl-7-m et h oxyb en -
zofu r a n -5-ca r ba ld eh yd e (28). To a solution of 27 (420.7 mg,
0.8 mmol) in a mixture of CHCl3 (30 mL) and THF (30 mL)
was added PdO (24 mg) and the mixture was stirred at 85 °C
under 50 psi of H2. After being stirred at the same conditions
for 3 d, the reaction mixture was filtered through Celite 545
and the residue was washed with CHCl3 (150 mL) and water
(20 mL). The filtered was partitioned between CHCl3 (30 mL)
and water (30 mL). The water layer was extracted with CHCl3
(30 mL × 2). The combined organic layer was washed with
water (30 mL) and brine (30 mL) and dried over MgSO4. The
MgSO4 was removed by filtration and the filtrate was concen-
trated in vacuo to give a yellow oil. The oil was purified by
column chromatography (silica gel: φ 2.5 × 8 cm; eluted by
Hex/EA ) 3/1) to give two products. The slower moving band
(Rf ) 0.21, Hex/EA ) 3/1) was collected and the solvent was
evaporated to afford solid that was recrystallized from 2-pro-
1
panol to yield 28 (179.9 mg, 52%). Mp 180-181 °C. H NMR
(400 MHz, CDCl3) δ 3.95 (s, 3 H), 3.97 (s, 3 H), 4.04 (s, 3 H),
5.22 (s, 2 H), 6.96 (d, J ) 9 Hz, 1 H), 7.30 (d, J ) 7 Hz, 1 H),
7.35 (d, J ) 6 Hz, 1 H), 7.37 (d, J ) 5 Hz, 1 H), 7.38 (s, 1 H),
7.44 (d, J ) 7 Hz, 2 H), 7.65 (dd, J ) 2, 8 Hz, 1 H), 7.76 (d, J
) 2 Hz, 1 H), 8.09 (d, J ) 1 Hz, 1 H), 10.03 (s, 1 H); 13C NMR
(100 MHz, CDCl3) δ 51.9, 56.2, 56.2, 70.8, 104.8, 108.3, 112.9,
113.1, 121.0, 121.6, 123.1, 127.2, 128.0, 128.6, 129.1, 134.1,
136.5, 145.8, 146.2, 149.0, 150.5, 162.2, 164.0, 191.8; HRMS
calcd for C24H20O4 372.1362, found 372.1361. The faster moving
band (Rf ) 0.25, Hex/EA ) 3/1) was collected and the solvent
was evaporated to afford a solid that was recrystallized from
EtOH to yield 29 (55 mg, 13%). Mp 165-167 °C; 1H NMR (400
MHz, CDCl3) δ 0.83 (s, 3 H), 1.34 (s, 3 H), 3.73 (d, J ) 11 Hz,
2 H), 3.84 (s, 3 H), 3.83 (d, J ) 11 Hz, 2 H), 3.92 (s, 3 H), 4.02
(s, 3 H), 5.21 (s, 2 H), 5.48 (s, 1 H), 6.93 (d, J ) 8 Hz, 1 H),
7.07 (s, 1 H), 7.30 (s, 1 H), 7.32-7.38 (m, 5 H), 7.43 (d, J ) 7
Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 21.9, 23.8, 30.1, 52.0,
56.0, 56.2, 70.9, 78.1, 103.0, 107.1, 109.0, 112.9, 113.2, 122.6,
123.0, 127.3, 128.0, 128.6, 131.3, 133.6, 136.6, 140.8, 143.1,
145.2, 148.9, 150.1, 162.1, 165.1; HRMS calcd for C30H32O6
372.2199, found 372.2198.
3,4-Diben zyloxy-5-m eth oxyp h en yl 5-(5,5-Dim eth yl-1,3-
d ioxa n -2-yl)-2,3-d im eth oxyp h en yl Keton e (32). To a solu-
tion of 31 (4.34 g, 7.2 mmol) in CH2Cl2 (270 mL) was added
active MnO2 (90%, 12.13 g). After the mixture was stirred at
the same conditions for 24 h, the resulting solution was filtered
through Celite 545 to give a yellow liquid. The mixture was
purified by column chromatography (silica gel: φ 4 × 10 cm;
eluent: Hex/EA ) 6/4) to give a colorless oil. The desired
fraction (Rf ) 0.28, Hex/EA ) 3/1) was collected and evapo-
rated. The white foam was generated in vacuo to afford 32
1
(4.14 g, 96%). H NMR (400 MHz, CDCl3) δ 0.78 (s, 3 H), 1.27
(s, 3 H), 3.75 (d, J ) 11 Hz, 2 H), 3.80 (s, 3 H), 3.77 (d, J ) 11
Hz, 2 H), 3.92 (s, 3 H), 5.02 (s, 2 H), 5.11 (s, 2 H), 5.36 (s, 1H),
7.05 (d, J ) 2 Hz, 1 H), 7.13 (d, J ) 2 Hz, 2 H), 7.24-7.34 (m,
9 H), 7.40-7.42 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 21.7,
23.0, 30.1, 55.8, 56.1, 61.5, 71.8, 74.9, 77.5, 100.7, 107.3, 109.6,
111.7, 118.3, 127.5, 127.8, 128.0, 128.3, 128.3, 132.6, 133.4,
136.5, 137.3, 142.1, 147.0, 152.1, 152.5, 153.3, 194.5; MS (FAB)
(m/z) 599 (M + H+); HRMS calcd for C36H39O8 599.2645, found
599.2645. Anal. Calcd for C36H38O8: C, 72.22; H, 6.40. Found:
C, 72.22; H, 6.38.
4,5-Diben zyloxy-3-m et h oxyben za ld eh yd e (30). To a
solution of 4,5-dihydroxy-3-methoxybenzaldehyde (2.27 g, 3.5
mmol) in N,N-dimethylacetamide (100 mL) was added K2CO3
(6.2 g) and the mixture was stirred at room temperature for
30 min. To the resulting solution was added benzyl bromide
(1 mL, 8.4 mmol) at room temperature. After the solution was
stirred at room temperature for 21 h, the resulting mixture
was concentrated in vacuo to give a deep brown liquid. The
reaction mixture was partitioned between CH2Cl2 (100 mL)
and water (50 mL). The organic layer was washed with water
(30 mL) and brine (30 mL) and dried over MgSO4. The MgSO4
was removed by filtration and the filtrate was concentrated
2-(3,4-Ben zyloxy-5-m eth oxyp h en yl)-1-(5-(5,5-d im eth yl-
1,3-d ioxa n -2-yl)-2,3-d im eth oxyp h en yl)a cetylen e (33). To
a solution of trimethylsilyldiazomethane (2 M, 2.6 mL) in THF
(30 mL) was added n-BuLi (1.5 M, 3.6 mL) at -78 °C under
argon. After the mixture was stirred for 30 min at the same
conditions, the resulting lithium salt solution was added to a
solution of 32 (2.11 g, 3.5 mmol) in THF (100 mL) at -78 °C
under argon via cannula. After the mixture was stirred at -78
°C under argon for 3 h, the resulting solution was quenched
with saturated NH4Cl(aq) (30 mL). The resulting solution was
J . Org. Chem, Vol. 67, No. 19, 2002 6785

Kao and Chern
partitioned between ether (150 mL) and water (10 mL). The
organic layer was washed with saturated NaHCO3(aq) (20 mL),
water (20 mL), and brine (50 mL), dried over MgSO4, and
concentrated in vacuo to give a yellowish mixture. The mixture
was purified by column chromatography (silica gel: φ 5 × 8
cm; eluent: Hex/EA ) 3/1). The desired fraction (Rf ) 0.30,
Hex/EA ) 3/1) was collected and the solvent was evaporated
to give the 33 (2.07 g, 99%) as an oil. 1H NMR (400 MHz,
CDCl3) δ 0.78 (s, 3 H), 1.29 (s, 3 H), 3.62 (d, J ) 11 Hz, 2 H),
3.76 (d, J ) 11 Hz, 2 H), 3.83 (s, 3 H), 3.87 (s, 3 H), 3.97 (s, 3
H), 5.06 (s, 2 H), 5.08 (s, 2H), 5.33 (s, 1 H), 6.80 (d, J ) 2 Hz,
1 H), 6.85 (d, J ) 2 Hz, 1 H), 7.08 (d, J ) 1 Hz, 1 H), 7.27-
7.41 (m, 7 H), 7.42-7.46 (m, 4 H); 13C NMR (100 MHz, CDCl3)
δ 22.0, 23.3, 30.4, 56.2, 56.4, 60.6, 61.2, 71.4, 75.4, 78.0, 84.9,
93.7, 101.1, 109.6, 110.9, 111.1, 117.8, 118.7, 123.1, 127.7,
128.1, 128.2, 128.4, 128.7, 134.7, 137.1, 137.9, 138.7, 150.7,
152.8, 152.8, 153.8; MS (FAB) m/z 595 (M + H+); HRMS calcd
for C37H39O7 595.2696, found 595.2696.
61.2, 71.4, 75.6, 77.8, 100.6, 106.7, 110.1, 112.4, 127.4, 127.5,
128.2, 128.2, 128.3, 128.4, 128.5, 128.6, 128.7, 132.6, 135.9,
136.8, 143.5, 144.0, 145.2, 1521, 152.4, 158.7. Anal. Calcd for
C36H35BrO7HgBr2: C, 42.39; H, 3.46. Found: C, 42.74; H, 3.37.
Meth od 2: To a solution of 33 (2.71 g, 4.6 mmol) in CHCl3
(200 mL) was added a solution of Br2 (0.23 mL, 4.5 mmol) in
CHCl3 (20 mL) at -15 °C dropwise over a period of 30 min.
After the mixture was stirred at the same conditions for
another 3 h, the reaction was quenched with saturated
NaHCO3(aq) (50 mL). The resulting solution was partitioned
between CHCl3 (200 mL) and water (20 mL). The organic layer
was washed with water (50 mL) and brine (50 mL), dried over
MgSO4, and concentrated in vacuo to give a yellow oil. The
resulting residue was purified by column chromatography
(silica gel: φ 5 × 7 cm; eluted by Hex/EA ) 3/1) to give a yellow
solid that was recrystallized from EtOH to yield 37 (2.52 g,
84%).
(3,4-Dib en zyloxy-5-m et h oxyp h en yl)-3-m et h yl-5-(5,5-
d im eth yl-1,3-d ioxa n -2-yl)-7-m eth oxyben zofu r a n (38). To
a solution of 37 (1.33 g, 2.0 mmol) in THF (40 mL) was added
n-BuLi (1.48 M, 1.4 mL) at -78 °C under argon. After the
mixture was stirred at the same conditions for 30 min, to the
resulting solution was added methyl iodide and the mixture
was stirred for an additional 3 h. The reaction was quenched
with saturated NH4Cl(aq) (30 mL). The resulting mixture was
partitioned between ether (300 mL) and water (20 mL). The
organic layer was washed with water (20 mL × 2) and brine
(30 mL) and dried over MgSO4. The MgSO4 was removed by
filtration and the filtrate was concentrated in vacuo to give a
yellowish mixture. The mixture was purified by column
chromatography (silica gel: φ 4 × 12 cm; eluted by Hex/EA )
8/2). The desired fraction (Rf ) 0.45, Hex/EA ) 3/1) was
collected and the solvent was evaporated to give 38 (1.08 mg,
2-(3,4-Diben zyloxy-5-m eth oxyp h en yl)-5-(5,5-d im eth yl-
1,3-d ioxa n -2-yl)-7-m eth oxyben zofu r a n (35). Compound 34
prepared by the same approach as described in the preparation
of 17 starting from 33 (2.07 g, 3.5 mmol) was used directly
without purification. The resulting mixture of chloromercurio
intermediate, MgO (295 mg, 7.3 mmol), PdCl2 (631 mg, 3.6
mol), and LiCl (310 mg, 7.3 mmol) was dissolved in dry MeOH
(80 mL) and stirred at 0 °C for 1 h and at room temperature
for another 1.5 h. After the reaction was quenched by water
(20 mL), the resulting solution was filtered through Celite 545.
The filtrate was partitioned between CHCl3 (150 mL) and
water (30 mL). The organic layer was washed with water (20
mL) and brine (50 mL), dried over MgSO4, and concentrated
in vacuo to give a yellowish mixture. The mixture was purified
by column chromatography (silica gel: φ 4.5 × 11 cm; eluent:
Hex/EA ) 3/1). The desired fraction (Rf ) 0.32, Hex/EA ) 3/1)
was collected and the solvent was evaporated to give a solid
that was recrystallized from 2-propanol to yield 35 (1.43 g,
1
90%) as a yellow oil. H NMR (400 MHz, CDCl3) δ 0.82 (s, 3
H), 1.36 (s, 3 H), 2.56 (s, 3 H), 3.74 (d, J ) 11 Hz, 2 H), 3.81
(d, J ) 11 Hz, 2 H), 3.90 (s, 3 H), 4.04 (s, 3 H), 5.11 (s, 2 H),
5.16 (s, 2 H), 5.85 (s, 1 H), 6.95 (d, J ) 4 Hz, 2 H), 7.25 (s, 1
H), 7.29-7.32 (m, 3 H), 7.34 (d, J ) 7 Hz, 2 H), 7.38 (d, J ) 7
Hz, 2 H), 7.43 (d, J ) 8 Hz, 2 H), 7.48 (d, J ) 7 Hz, 2 H); 13C
NMR (100 MHz, CDCl3) δ 20.3, 21.8, 28.7, 54.8, 54.8, 69.8,
73.7, 81.4, 99.7, 107.9, 108.6, 1098.6, 110.9, 115.0, 116.5, 125.8,
126.1, 126.4, 126.5, 126.7, 127.0, 127.1, 127.3, 128.1, 135.3,
136.1, 137.3, 144.5, 146.8, 151.0, 152.1; MS (FAB) m/z 594
(M+); HRMS calcd for C37H38O7 595.2618, found 595.2617.
1
89%). Mp 128-130 °C; H NMR (400 MHz, CDCl3) δ 0.81 (s,
3 H), 1.34 (s, 3 H), 3.68 (d, J ) 11 Hz, 2 H), 3.80 (d, J ) 11 Hz,
2 H), 3.91 (s, 3 H), 4.06 (s, 3 H), 5.07 (s, 2 H), 5.16 (s, 2 H),
5.46 (s, 1H), 6.89 (s, 1 H), 7.00 (d, J ) 1 Hz, 1 H), 7.10 (d, J )
2 Hz, 1 H), 7.15 (d, J ) 2 Hz, 1 H), 7.27-7.30 (m, 3 H), 7.32-
7.40 (m, 4 H), 7.43-7.46 (m, 4 H); 13C NMR (100 MHz, CDCl3)
δ 22.1, 23.4, 56.3, 56.6, 71.7, 75.4, 78.0, 101.8, 102.3, 103.2,
104.8, 104.9, 111.5, 126.1, 127.8, 128.1, 128.2, 128.3, 128.7,
128.8, 130.8, 134.7, 137.1, 137.9, 138.6, 144.4, 145.2, 153.2,
154.3, 156.6. Anal. Calcd for C36H36O7: C, 74.46; H, 6.25.
Found: C, 74.15; H, 6.32.
2-(3,4-Diben zyloxy-5-m eth oxyph en yl)-3-m eth yl-7-m eth -
oxyben zofu r a n -5-ca r ba ld eh yd e (39). A solution of 38 (649.9
mg, 1.1 mmol) in acetone (50 mL) was added to 6 N HCl(aq)
(10 mL) at room temperature and the resulting mixture was
stirred at room temperature for 2 h. The reaction mixture was
concentrated in vacuo to give a yellow oil. The oil was dissolved
in CHCl3 (200 mL), washed with water (30 mL) and brine (30
mL), and dried over MgSO4. The MgSO4 was removed by
filtration and the filtrate was concentrated in vacuo to give a
yellow oil. The oil was purified by column chromatography
(silica gel: φ 2.5 × 7 cm; eluted by Hex/EA ) 4/1), the desired
fraction (Rf ) 0.3, Hex/EA ) 3/1) was collected, and the solvent
3-Br om o-2-(3,4-d iben zyloxy-5-m eth oxyp h en yl)-5-(5,5-
dim eth yl-1,3-dioxan -2-yl)-7-m eth oxyben zofu r an (37). Com-
pound 34 prepared by the same approach as described in the
preparation of 17 starting from 33 (7.34 g, 12.4 mmol) was
used directly without further purification. Two methods were
applied for the preparation of 37. Meth od 1: To a solution of
34 (8.98 g, 11.0 mmol) in CHCl3 (200 mL) was added Br2 (0.58
mL, 11.3 mmol) in CHCl3 (20 mL) dropwise at -15 °C. The
resulting solution was stirred at -15 °C for 30 min and then
filtered through Celite 545. The filtrate was partitioned
between CH2Cl2 (150 mL) and saturated NaHCO3(aq) (30 mL).
The organic layer was washed with water (30 mL) and
saturated NaCl (30 mL) and dried over MgSO4. The MgSO4
was removed by filtration and the filtrate was concentrated
in vacuo to give a yellow oil. The oil was purified by column
chromatography (silica gel: φ 5 × 10 cm; eluted by Hex/EA )
3/1). The desired fraction (Rf ) 0.48, Hex/EA ) 3/1) was
collected and the solvent was evaporated to give a solid that
was recrystallized form EtOH and ethyl acetate to yield 37
1
was evaporated to give 39 (423.2 mg, 77%) as a yellow oil. H
NMR (400 MHz, CDCl3) δ 2.56 (s, 3 H), 3.91 (s, 3 H), 4.01 (s,
3 H), 5.09 (s, 2 H), 5.17 (s, 2 H), 6.92 (d, J ) 4 Hz, 2 H), 7.25
(s, 1 H), 7.22-7.34 (m, 5 H), 7.35 (d, J ) 7 Hz, 2 H), 7.41 (d,
J ) 8 Hz, 2 H), 7.51 (d, J ) 7 Hz, 2 H), 10.45 (s, 1 H); 13C
NMR (100 MHz, CDCl3) δ 50.4, 54.7, 69.4, 103.3, 111.5, 119.6,
121.6, 125.8, 125.8, 126.5, 126.5, 127.2, 127.6, 132.6, 135.1,
144.4, 147.5, 149.0, 162.5, 190.4; HRMS calcd for C32H28O6
595.1886, found 595.1880.
2-(3,4-Dih yd r oxy-5-m eth oxyp h en yl)-3-m eth yl-5-(p r op -
1-en -1-yl)-7-m et h oxyb en zofu r a n (3). To a solution of 39
(422 mg, 1.0 mmol) in THF (20 mL) was added the lithium
salt of ethyltriphenylphosphine iodide (655 mg, 1.6 mmol) in
THF (20 mL) at -78 °C under argon. After the mixture was
stirred at the same conditions for 5 h, the saturated NH4Cl(aq)
(30 mL) was added to quench the reaction. The resulting
1
(4.52 g, 64%). Mp 222-224 °C; H NMR (400 MHz, CDCl3) δ
0.80 (s, 3 H), 1.32 (s, 3 H), 3.65 (d, J ) 11 Hz, 2 H), 3.75 (d, J
) 11 Hz, 2 H), 3.93 (s, 3 H), 4.05 (s, 3 H), 5.10 (s, 4 H), 5.72 (s,
1 H), 7.10 (s, 1 H), 7.30 (s, 1 H), 7.31 (d, J ) 2 H, 1 H), 7.32 (d,
J ) 2 Hz, 1 H), 7.34-7.36 (m, 3 H), 7.37 (br s, 1 H), 7.39-7.44
(m, 6 H); 13C NMR (100 MHz, CDCl3) δ 21.7, 23.1, 30.1, 56.4,
6786 J . Org. Chem., Vol. 67, No. 19, 2002

Synthesis of Benzofuran Skeleton Neolignans
solution was partitioned between CHCl3 (100 mL) and water
(30 mL). The organic layer was washed sequentially with
water (20 mL) and brine (20 mL) and dried over MgSO4. The
MgSO4 was removed by filtration and the filtrate was concen-
trated in vacuo to give a yellow solid. To a solution of the yellow
solid in THF (100 mL) was added BBr3 (0.1 mL, 1 M in THF)
dropwise at -78 °C under argon. After the mixture was stirred
for another 5 min, the resulting solution was neutrilized with
saturated NaHCO3(aq). The resulting solution was partitioned
between CHCl3 (150 mL) and water (10 mL). The organic layer
was washed with water (30 mL) and brine (30 mL), dried over
MgSO4, and concentrated in vacuo to give a yellow oil. The
residue was subjected to column chromatography (silica gel:
φ 4 cm × 8 cm; eluent: Hex/EA ) 1/1). The desired fraction
(Rf )0.21, Hex/EA ) 1/3) was collected and the solvent was
mide (956.3 mg, 2.3 mmol) at -78 °C under argon. The
resulting solution was stirred at -78 °C under argon for 2 h.
After the mixture was quenched with saturated NH4Cl(aq) (30
mL), the resulting solution was partitioned between ether (200
mL) and water (30 mL). The organic layer was washed with
water (30 mL) and brine (30 mL) and dried over MgSO4. The
MgSO4 was removed by filtration and the filtrate was concen-
trated in vacuo to give a yellowish mixture. The mixture was
purified by column chromatography (silica gel: φ 4 × 8 cm;
eluted by Hex/EA ) 3/1). The desired fraction (Rf ) 0.22, Hex/
EA ) 3/1) was collected and the solvent was evaporated to
give a solid that was recrystallized from MeCN to yield 43 (897
mg, 88%). Mp 183-185 °C; 1H NMR (400 MHz, CDCl3) δ 1.35
(t, J ) 7 Hz, 3 H), 3.96 (s, 3 H), 4.01 (s, 3 H), 4.28 (q, J ) 7 Hz,
2 H), 5.21 (s, 2 H), 6.33 (d, J ) 16 Hz, 1 H), 6.96 (d, J ) 8 Hz,
1 H), 7.01 (s, 1 H), 7.24 (s, 1 H), 7.31 (d, J ) 7 Hz, 1 H), 7.36
(t, J ) 7 Hz, 2 H), 7.44 (d, J ) 7 Hz, 2 H), 7.65 (br s, 2 H), 8.24
(d, J ) 16 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 12.8, 54.7,
54.8, 59.2, 60.4, 104.5, 109.7, 111.9, 119.0, 119.5, 120.3, 125.8,
126.5, 127.1, 141.9, 143.1, 147.9, 148.0, 165.0; HRMS calcd
for C28H25BrO6 536.0835, found 536.0835.
1
evaporated to give 39 (108 mg, 31%) as a yellow oil. H NMR
(400 MHz, CDCl3) δ 1.96 (dd, J ) 6, 2 Hz 3 H), 2.50 (s, 3 H),
3.97 (s, 3 H), 4.06 (s, 3 H), 6.19-6.32 (m, 1 H), 6.49 (dd, J )
16, 2 Hz, 1 H), 6.83 (s, 1 H), 6.97 (s, 1 H), 7.03 (s, 1 H), 7.07 (s,
1 H); MS (EI) m/z 340 (M+); HRMS calcd for C20H20O5
340.1311, found 340.1310.
2-(4-Ben zyloxy-3-m eth oxyp h en yl)-3-br om o-7-m eth oxy-
ben zofu r a n -5-ca r ba ld eh yd e (42). To a solution of 15 (4.12
g, 8.4 mmol) in CHCl3 (300 mL) was added a solution of Br2
(450 µL, 8.8 mmol) in CHCl3 (20 mL) at -15 °C. The resulting
solution was stirred at -15 °C under argon for 2 h. The
resulting solution was concentrated in vacuo to give a yellow
oil. The oil was dissolved in acetone. To the resulting solution
was added HCl (6 N, 30 mL) and the mixture was stirred at
room temperature for an additional 3 h. After being quenched
with NaOH(aq) (3 N), the resulting solution was partitioned
between CHCl3 (200 mL) and saturated NaHCO3(aq) (50 mL).
The organic layer was washed with water (30 mL × 2) and
brine (30 mL) and dried over MgSO4. The MgSO4 was removed
by filtration and the filtrate was concentrated in vacuo to give
a yellowish mixture. The mixture was purified by column
chromatography (silica gel: φ 4 × 12 cm; eluted by Hex/EA )
4/1). The desired fraction (Rf ) 0.42, Hex/EA ) 3/1) was
collected and the solvent was evaporated to give a yellowish
solid that was recrystallized from EtOH to yield 40 (3.41 g,
2-(4-Benzyloxy-3-methoxyphenyl)-3-bromo-5-(3-hydroxy-
p r op -1-en -1-yl)-7-m eth oxyben zofu r a n (44). To a solution
of 43 (1.38 g, 2.6 mmol) in THF (50 mL) was added a solution
of DIBAL-H in CH2Cl2 (1.0 M, 10 mL) at room temperature
under argon. After the mixture was stirred at room temper-
ature for 21 h, the reaction was quenched with saturated Na2-
CO3‚10H2O(aq). The resulting solution was partitioned between
CHCl3 (200 mL) and water (20 mL). The organic layer was
washed with water (30 mL × 3) and brine (30 mL) and dried
over MgSO4. The MgSO4 was removed by filtration and the
filtrate was concentrated in vacuo to give a yellowish oil. The
residue was purified by column chromatography (silica gel: φ
4.5 × 9 cm; eluted by Hex/EA ) 2/3). The desired fraction (Rf
) 0.35, Hex/EA ) 1/1) was collected and the solvent was
evaporated to give a solid that was recrystallized from EtOH
1
to yield 44 (918.2 mg, 73%). Mp 185-187 °C; H NMR (400
MHz, CDCl3) δ 3.97 (s, 3 H), 4.02 (s, 3 H), 4.33 (dd, J ) 6, 1
Hz, 2 H), 5.20 (s, 2 H), 6.36 (dt, J ) 6, 16 Hz, 1 H), 6.67 (d, J
) 16 Hz, 1 H), 6.88 (d, J ) 1 Hz, 1 H), 6.95 (d, J ) 8 Hz, 1 H),
7.09 (d, J ) 1 Hz, 1 H), 7.31 (d, J ) 7 Hz, 1 H), 7.36 (t, J ) 7
Hz, 2 H), 7.44 (d, J ) 8 Hz, 2 H), 7.67 (dd, J ) 6, 8 Hz, 1 H),
7.70 (d, J ) 2 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 56.1,
56.2, 63.7, 70.9, 92.6, 105.8, 110.1, 110.3, 113.5, 120.0, 122.5,
127.2, 127.9, 128.1, 128.6, 131.2, 131.4, 133.4, 136.7, 142.0,
144.9, 148.9, 149.4, 151.0. Anal. Calcd for C26H23BrO5: C,
63.04; H, 4.68. Found: C, 62.80; H, 4.41.
1
86%). Mp 104-106 °C; H NMR (400 MHz, CDCl3) δ 3.98 (s,
3 H), 4.06 (s, 3 H), 5.21 (s, 2 H), 6.97 (d, J ) 9 Hz, 1 H), 7.31
(d, J ) 7 Hz, 1 H), 7.35 (d, J ) 6 Hz, 1 H), 7.37 (d, J ) 7 Hz,
1 H), 7.38 (s, 1 H), 7.45 (d. J ) 7 Hz, 1 H), 7.64 (d, J ) 1 Hz,
1 H), 7.68 (d, J ) 2 Hz, 1 H), 7.70 (br s, 1 H); 13C NMR (100
MHz, CDCl3) δ 56.2 56.3, 70.9, 92.7, 105.3, 110.3, 113.5, 117.5,
120.2, 121.8, 127.3, 128.0, 128.6, 131.5, 133.7, 136.6, 145.8,
149.4, 149.5, 152.2, 191.3; MS (FAB) m/z 467 (M + H+), 469
(M + 2 + H+); HRMS calcd for C24H19BrO5 466.0416, found
466.0415.
Ack n ow led gm en t . This investigation was sup-
ported by research grants (NSC 89-2314-002-135, NSC89-
2320-B-002-268, and NSC90-2320-B-002-203) from the
National Science Council of the Republic of China.
2-(4-Ben zyloxy-3-m eth oxyp h en yl)-3-br om o-7-m eth oxy-
5-(eth ylca r beth en yl)ben zofu r a n (43). To a solution of 42
(924.8 mg, 1.9 mmol) in THF (20 mL) was added a solution of
the lithium salt of carbethylmethyltriphenylphosphine bro-
J O0258960
J . Org. Chem, Vol. 67, No. 19, 2002 6787