Assembled catalyst of palladium and non-cross-linked amphiphilic polymer ligand for the efficient heterogeneous Heck reaction

Article abstract of DOI:10.1016/j.tet.2004.02.068

The efficient heterogeneous Heck reaction was achieved by a new networked and supramolecular catalyst PdAS-V (1b). Employing of PdAS-V in 5.0×10^-5molequiv. efficiently progressed the heterogeneous Heck reaction of a series of aryl iodides with acrylates, styrenes and acrylic acid. PdAS-V was successfully recycled five times without any decrease in its activity, and showed good stability in toluene and water, and hence the Heck reaction was efficiently performed in both reaction media. The use of 8.0×10^-7molequiv. of PdAS-V resulted in the coupling product in 92% yield with the turnover number (TON) and the turnover frequency (TOF) of PdAS-V reached up to 1,150,000 and 12,000, respectively. The efficient synthesis of resveratrol was achieved via the PdAS-V-promoted Heck reaction.

Full text of DOI:10.1016/j.tet.2004.02.068

Tetrahedron 60 (2004) 4097–4105
Assembled catalyst of palladium and non-cross-linked
amphiphilic polymer ligand for the efficient heterogeneous
Heck reaction
*
Yoichi M. A. Yamada, Koji Takeda, Hideyo Takahashi and Shiro Ikegami
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan
Received 26 January 2004; accepted 19 February 2004
Abstract—The efficient heterogeneous Heck reaction was achieved by a new networked and supramolecular catalyst PdAS-V (1b).
Employing of PdAS-V in 5.0£1025 mol equiv. efficiently progressed the heterogeneous Heck reaction of a series of aryl iodides with
acrylates, styrenes and acrylic acid. PdAS-V was successfully recycled five times without any decrease in its activity, and showed good
stability in toluene and water, and hence the Heck reaction was efficiently performed in both reaction media. The use of 8.0£1027 mol equiv.
of PdAS-V resulted in the coupling product in 92% yield with the turnover number (TON) and the turnover frequency (TOF) of PdAS-V
reached up to 1,150,000 and 12,000, respectively. The efficient synthesis of resveratrol was achieved via the PdAS-V-promoted Heck
reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
We conceived that new structural design and methodology
to develop highly active, reusable and solid-phase palladium
catalysts should be needed. The traditional resin or silica
gel-supported palladium catalysts are prepared by the
linking of palladium species onto insoluble supports
(Scheme 1, above). On the other hand, we focused on a
different strategy: self-assembled process between non-
cross-linked amphiphilic polymer ligands and palladium to
prepare the solid-phase catalysts (Scheme 1, below).3 This
process was expected to produce networked and supra-
molecular complexes where the polymers were cross-linked
by palladium. Based on our strategy, PdAS (1a), a supra-
molecular complex of (NH4)2PdCl4 (2) and poly[(N-iso-
propylacrylamide)10-co-(4-diphenylstyrylphosphine)] (3a)),
was developed as a solid-phase catalyst for the hetero-
geneous Suzuki–Miyaura reaction.3c PdAS, used in
8£1027 –5£1024 mol equiv., catalyzed efficiently the
coupling, and was recycled 10 times without declining the
catalytic activity.
Development of reusable and solid-phase palladium cata-
lysts is a very important theme in recent organic chemistry
and industrial process.1,2 Although homogeneous palladium
catalysts are widely used and essential in organic synthesis,
they have several drawbacks to be resolved. For example,
palladium is an expensive and precious metal so that
disposable palladium catalysts are wasteful, and perfect
removal of palladium from a reaction mixture is bothersome
and difficult, resulting in contamination of the products and
the waste fluid by palladium. By contrast, reusable and
solid-phase palladium catalysts, in an ideal system, will
resolve these problems: such palladium catalysts are reused
infinitely; a work-up of the reaction is simple and easy; they
are recovered from the reaction mixture by simple filtration.
Therefore, many immobilized and insoluble palladium
catalysts have been reported, which were supported mainly
onto insoluble resins, silica gels and metal oxides. Their
catalytic system, however, has not been established in
reality. Their catalytic activity is generally lower than that
of homogeneous counterparts. Besides, they have a
tendency to decrease the catalytic activity of themselves
in repeated use owing to leaching of metal species from
their supports.2
Since PdAS was a highly active and reusable catalyst, we
focused on its application to the efficiently recycled system
of the Heck reaction. The Heck reaction, the coupling of
sp2-halides with alkenes promoted by palladium catalysts, is
an important reaction for the synthesis of natural products
and bioactive compounds as well as for the industrial
process chemistry.4 Although many efforts to prepare solid-
phase catalysts for the Heck reaction have been made,
homogeneous catalytic systems have advantages on cata-
lytic activity.5 In fact, it was known that designing
recyclable system for the Heck reaction was more
Keywords: N-Isopropylacrylamide; Heck reaction; Palladium and
compounds; Polymer support; Self-assembly.
*
Corresponding author. Tel.: þ81-426-85-3728; fax: þ81-426-85-1870;
e-mail address: shi-ike@pharm.teikyo-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.068

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Y. M. A. Yamada et al. / Tetrahedron 60 (2004) 4097–4105
Scheme 1. Concept for the preparation of an assembled catalyst of palladium and non-cross-linked amphiphilic polymer.
challenging than that for the Suzuki–Miyaura reaction.
These catalysts were less stable under the Heck reaction
condition, and thus often decompose physically or chemi-
cally.4a,b For example, resulting salts accumulated in the
reaction lead to degradation of the catalytic system and
choke of catalysts under the Heck conditions. Besides, the
reductive elimination of phosphonium cation causes
depletion of phosphine-containing palladium catalysts.
While a preliminary investigation by using PdAS was
carried out, it was concluded that PdAS was not so effective
owing to its pulverization under the recycled condition of
the Heck reaction. We supposed that cross-linking in PdAS
was not sufficient to preserve physical strength for the Heck
reaction. This hypothesis struck us that a more cross-linked
palladium catalyst should enhance the physical strength and
the stability. Based on our working hypothesis, we have
reported a reformed palladium solid-phase catalyst PdAS-V
(1b) and partial results on the Heck reaction in toluene.3e In
this article, we report here the full detail of the development
of PdAS-V and a highly efficient and recyclable system for
the heterogeneous Heck reaction.6,7 This time, it is found
that PdAS-V showed good stability not only in toluene but
Scheme 2. Working model of PdAS and PdAS-V.
Scheme 3. Preparation of assembled palladium catalyst PdAS-V. (a) AIBN (2.2 mol %), t-BuOH, 75 8C, 41 h, 82%; (b) (1) (NH4)2PdCl4 (1 mol equiv.), 3b
(3 mol equiv. as PPh2 unit), THF–H2O, rt, 62 h, (2) added H2O, (3) distilled with Dean–Stark equipment at 80 8C, (4) washed with H2O, THF, and H2O
successively at 100 8C, 95%.

Y. M. A. Yamada et al. / Tetrahedron 60 (2004) 4097–4105
Table 1. Recycling of PdAS-V for the Heck reaction
4099
Entry
Cycle
Yield (%)
TON
TOF (h21
)
1
2
3
4
5
1st cycle
2nd cycle
3rd cycle
4th cycle
5th cycle
92
93
95
94
95
18,400
18,600
19,000
18,800
19,000
1230
1240
1270
1250
1270
A total TON
94,000
Av. TOF
1250
also in water, and thus both solvents were suitable for this
reaction of versatile substrates such as alkylacrylates,
styrenes, and acrylic acid with aryl iodides. It is noteworthy
that employment of 8.0£1027–5.0£1025 mol equiv. of
PdAS-V facilitated the recycled system of the Heck reaction
with the turnover number (TON (¼mol of product/mol of
catalyst)) up to 1,150,000 and the turnover frequency (TOF
trace amount of unreacted palladium species and polymers,
PdAS-V was obtained in 95% yield. It was a dark reddish
solid that was insoluble in water, methanol, DMF, ethyl
acetate, dichloromethane, THF and toluene as well as was
PdAS, whereas polymer 3b was soluble in organic solvents
such as CHCl3, CH2Cl2 and THF. Gel-phase 31P NMR of
PdAS-V showed the similar broad signals at 26.1 and
32.5 ppm as that of PdAS, which must be assigned as the
peak of PdCl2(PPh2Ar)2 and ArPh2PvO, respectively.
These results indicated that the structure of PdAS-V was
analogous to that of PdAS, and thus the self-assembly
process of 3b and 2 to form the cross-linked and
supramolecular complex was successful.
(h21)¼the turnover number per an hour) up to 12,000 h21
.
PdAS-V was reused five times without any decrease in its
activity. Furthermore, the efficient synthesis of resveratrol, a
promising COX-II inhibitor, was achieved via the PdAS-V-
promoted Heck reaction.
2.2. The catalytic activity of PdAS-V
2. Results and discussions
2.1. Preparation of PdAS-V
To check the potency of PdAS-V for the Heck reaction,
PdAS-V was treated with the reaction of 6a with
1.5 mol equiv. of 7a in the presence of Et3N in toluene at
100 8C (Table 1). The results agreed with our working
hypothesis that PdAS-V was a highly active and reusable
catalyst; the employment of 5.0£1025 mol equiv. of PdAS-
V in the 5th cycled run afforded 8a in 95% yield with TON
being 19,000 (entry 5).8 PdAS-V was recycled five times
without any loss of its activity. The average yield of five
runs was 94%. A total turnover number of PdAS-V in the 1st
to the 5th cycled runs was 94,000, and the average of TOF
was 1250.
The difference of PdAS-V and PdAS was that the ratio of
the N-isopropylacrylamide unit to the phosphine unit was
5/1 in PdAS-V while that in PdAS was 10/1.7 Theoretically,
the polymers in PdAS-V were cross-linked eight-fold more
than those in PdAS per unit volume, and thus the amount of
palladium in PdAS-V increased eight-fold over PdAS per
unit content (Scheme 2). This implied that physical strength
of PdAS-V was superior to that of PdAS, so that PdAS-V
was expected to be prevented from pulverization under the
Heck reaction conditions.
Since the recycled ability and high TON of PdAS-V was
achieved in the Heck reaction, we further investigate the
The reformed catalyst PdAS-V was prepared from 2 and 3b
using the method for the preparation of PdAS as shown
in Scheme 3.3c Random copolymerization of 4-diphenyl-
styrylphosphine (4) with 6 mol equiv. of N-isopropylacryl-
amide (5) in the presence of 2.2 mol% of AIBN gave 3b in
82% yield. The gel permeation chromatography showed that
the molecular weight of 3b was wide-ranging (approxi-
mately 5000–70,000). The ratio of the phosphine to the
1
amide units in 3b was determined by H NMR measure-
ments in CDCl3 to be 1/5, and the phosphine unit was hardly
oxidized in this polymerization as shown by 31P NMR. This
ratio of the phosphine to the amine unit as 1/5 was found to
be reproducible in several lots. Thus, PdAS-V (1b) was
prepared by self-assembly of 2 and 3b (3 mol equiv. in
phosphine) in THF and H2O, resulting in the formation of
precipitates. After the suspension was washed to remove a
Scheme 4. The heterogeneous Heck reaction catalyzed by 8£1027
mol equiv. of PdAS-V. (a) The product 8b was purified by crystallization.

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Y. M. A. Yamada et al. / Tetrahedron 60 (2004) 4097–4105
Table 2. The Heck reaction of aryl iodides 6 with acrylates 7 and 9
Entry
R1I
Time (h)
Product
Yield
1
2
3
6a
6a
6a
7b
7c
7d
12
20
20
8b:93%
8c:98%
8d:97%
4
5
6a
7e
5
8e:95%
8f:95%
6b
7b
20
6
7
8
9
6c
6d
6e
6f
7b
7b
20
20
20
20
8g:92%
8h:95%
8i:93%
8j:92%
7f
7b
7b
10
11
6g
6h
40
8k:90%
7b
60
5
8l:82%
12
13
6a
6f
9
10a:93%a
6i
9
9
4
8
10b:90%a
10c:87%a
14
a
The product was purified by recrystallization without column chromatography.
limitation of its catalytic activity. It was found that less than
1 ppm mol equiv. of PdAS-V catalyzed the coupling
efficiently as shown in Scheme 4. The employment of
8£1027 mol equiv. of PdAS-V in the coupling of 6a
(1.37 mol; 153 mL) with 7b (2.06 mol; 186 mL) for 96 h
provided 8b (1.27 mol; 205 g) in 92% yield, isolated by
crystallization. It is notable that PdAS-V promoted the
reaction on a scale of more than 1 mol with TON and TOF
in its reaction reaching 1,150,000 and 12,000 h21, respec-
tively. That is, PdAS-V was the most active solid-phase
catalyst for the Heck reaction. As far as we know, this is the
highest TON value by the reusable catalysts for the Heck
reaction.
2.3. The Heck reaction of aryl iodides with acrylates in
toluene
In order to establish the scope of the sequence as depicted in
Table 2, the coupling of various aryl halides with acrylates
was investigated. All the reactions in Table 2 were
performed under identical conditions as in Table 1: aryl
iodide 6 (1 mol equiv.), alkene 7 (1.5 mol equiv.), PdAS-V

Y. M. A. Yamada et al. / Tetrahedron 60 (2004) 4097–4105
Table 3. The Heck reaction of aryl iodides 6 with styrenes 11
4101
Entry
R1I
Time (h)
Product
Yield
1
2
6a
11a
12
20
12a:90%
6j
6c
6d
6f
11a
11a
11a
11a
12b:86%a
3
4
5
20
20
20
12c:75%a
12d:87%a
12e:92%a
6
7
6a
6a
6a
11b
11c
11d
20
20
20
12c:95%a
12d:88%a
12e:93%a
8
a
These products were purified by recrystallization without column chromatography.
(5.0£1025 mol equiv.), Et3N (1.5 mol equiv.) in toluene at
100 8C. Full conversions were achieved for these couplings
in the presence of PdAS-V to afford cinnamic esters in high
yields with TON and TOF of PdAS-V reached approxi-
mately 20,000 and 1000 h21, respectively. The reaction of
6a with alkylacrylates 7b–e proceeded in 5–20 h to give
the corresponding couplings in 93–98% yields (entries
1–4). It is notable that the coupling of hexafluoroisopropyl
acrylate (7e), an electron-deficient olefin, proceeded much
faster and completed in 5 h to furnish 8e in 95% yield (entry
4). Electron-deficient aryl iodides such as ethoxycarbonyl-,
acetoxy-, chloro-, and fluoro-substituted iodobenzenes were
also converted to 8f–i in more than 90% yields (entries
5–8). The reaction system was applicable to the reaction of
an electron-rich iodoarene (entry 9). Moreover, the coupling
of ortho-substituted aryl iodides, sterically hindered sub-
strate, proceeded to afford the corresponding products in
high yields while it was slower (entries 10–11). Interest-
ingly, the reactions of acrylic acid (9) in toluene were faster
than that of alkyl acrylates to afford cinnamic acids 10a and
10b in 93 and 90% yields (Table 2).
styrene (11a) was carried out, stilbene (12a) was obtained
in 90% yield. Both electron-deficient (entries 2–4) and
-donating (entry 5) aryl iodides were efficiently coupled
with 11a to provided the corresponding coupling products
12b–12e in high yields. Besides, the electron-deficient and
-donating styrenes 11b–d were also useful reactants to give
12c–e in approximately 90% yields (entries 6–8) (Table 3).
2.5. The Heck reaction in water
All the reactions above mentioned were performed in
toluene. Since PdAS-V was composed of an amphiphilic
polymer, it was expected that PdAS-V was also stable and
works in water. Water is inexpensive, nontoxic, nonflam-
mable, and easily available solvent. It nowadays receives
much attention as a reaction solvent, although it has not
been commonly used because palladium catalysts were
generally unstable in water and hydrophobic substrates were
insoluble in water.8 Thus, the heterogeneous Heck reaction
in water was investigated as shown in Table 4.9 We were
fueled by finding that PdAS-V has a good stability and
activity even in water. The coupling of 6a with acrylic acid
(9) proceeded smoothly in 6 h to result in the formation of
cinnamic acid (10a) in 94% yield (entry 1). Substituted aryl
iodides including an ortho-substituted aryl iodide were also
appropriate substrates in these couplings (entries 2–7). It
was notable that styrene (11a) was also a useful reactant in
water while both aryl iodides and styrene was not dissolved
in water (entries 8 and 9). This result suggested that
dispersion of reagents in water might be effective for
promoting the reaction. Furthermore, it should be noted that
2.4. The Heck reaction of aryl iodides with styrenes in
toluene
PdAS-V was applicable to the coupling of styrene
derivatives 11. The reaction conditions were identical with
that in the reaction of acrylates. Aryl iodides with styrenes
were also converted smoothly to the corresponding stilbenes
in high yields with TON and TON being approximately
20,000 and 1000 h21. The reaction of iodobenzene (6a) with

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Y. M. A. Yamada et al. / Tetrahedron 60 (2004) 4097–4105
Table 4. The Heck reaction in water
Entry
R1I
Time (h)
Product
Yielda
1
2
3
4
5
6a
6d
6i
9
6
10a:94%
10d:91%
10b:91%
10e:94%
10c:88%
9
9
9
9
6
4
6k
6f
6
24
6
6g
6h
9
9
24
8
10f:95%
10g:92%
7
8
6a
11a
36
30
12a:76%
12f:97%
9
6i
11a
a
These products were purified by recrystallization without column chromatography.
any catalytic activity in the reaction filtrate could not be
observed, indicating obviously non-leaching of the metal
catalyst from PdAS-V even in the reactions in water.
resveratrol from commercially available 6j was 75% in 3
steps (Scheme 5).
In conclusion, we have developed a new insoluble and
reusable catalyst PdAS-V prepared from self-assembly of
2.6. Efficient synthesis of resveratrol via the Heck
reaction by PdAS-V
To demonstrate the utility of PdAS-V for the synthesis of
bioactive compounds, resveratrol (12h) was synthesized via
the heterogeneous Heck reaction. Resveratrol is a new type
antitumor agent that can inhibit all three stages of cancer by
inducing quinone reductase activity, inhibiting cyclooxy-
genase-2 (COX-2), and inducing the expression of nitroblue
tetazolium reduction activity. Furthermore, it can inhibit the
development of cardiovasacular disease through its ability
as an antioxidant to inhibit platelet aggregation and
eicosanoid synthesis and its ability to modulate lipoprotein
metabolism.10 However, it is isolated from natural sources
in trace amounts,10d so that efficient chemical syntheses of
12h are required.11,12 The starting materials 4-iodophenol
(6j) and 3,5-dihydroxystyrene (11e)13 were protected by
benzoyl group to afford 6k and 11f in 82 and 87% yield,
respectively. The heterogeneous Heck reaction12 of aryl
iodide 6k and alkene 11f proceeded smoothly in the
presence of PdAS-V to furnish the coupling 12g in 93%
yield. Deprotection of 12g over NaOMe in THF and MeOH
Scheme 5. Efficient synthesis of resveratrol via the Heck reaction by PdAS-
V. Reagents and conditions: (a) BzCl, pyridine, CH2Cl2, 0 8C; (b) 6k
(1 mol equiv.), 11f (1.5 mol equiv.), PdAS-V (5£1024 mol equiv.), Et3N
(1.5 mol equiv.), toluene, 100 8C, 12 h; (c) NaOMe, THF–MeOH, 50 8C,
5 h.
provided resveratrol (12h) in 98% yield. The total yield of

Y. M. A. Yamada et al. / Tetrahedron 60 (2004) 4097–4105
4103
(NH4)2PdCl4 (2) and non-cross-linked amphiphilic phos-
phine polymer 3b. The heterogeneous Heck reaction using
PdAS-V afforded the corresponding couplings in high yields
with TON up to 1,150,000. Using only 5£1025 mol equiv.,
PdAS-V was reused up to five times while still retaining
its activity. PdAS-V was stable in toluene and water, so
that it efficiently catalyzed the Heck reaction in these
media. Resveratrol was synthesized via the Heck reaction
by PdAS-V.
stirred for 62 h at room temperature, a yellow precipitate
was formed. Water (30 mL) was added to the suspension,
and THF was removed at 80 8C for 4 h with Dean–Stark
equipment to give a reddish precipitate. This precipitate was
stirred at 100 8C successively in H2O (100 mL) for 12 h, in
THF (100 mL) for 3 h and in H2O (100 mL) for 12 h to wash
the unreacted palladium species and polymers. After drying
in vacuo (ca. 0.08 mm Hg), a dark red solid 3 was obtained
in almost quantitative yield: IR (KBr, cm21): n 2971, 2934,
1651, 1537, 1460, 694; gel-phase 1H NMR (600 MHz,
CDCl3): d 1.06 (br, 60H), 1.54–2.10 (br, 30H), 3.68 (10H),
6.56–7.47 (br, 24H); gel-phase 13C NMR (150 MHz,
CDCl3): d 22.6, 41.3, 128.0, 174.1; gel-phase 31P NMR
(243 MHz, CDCl3) 26.1 (br), 32.1 (br). Anal. Calcd
for C150nH234nO24nN15nP3Pd1nCl2n as PdAS·9nH2O: C
62.090%; H 8.123%, N 7.240%, found: C 60.956%; H
8.445%, N 8.304%.
3. Experimental
3.1. General
All the products were isolated, and hence all the yields
presented meant isolated yields. Melting points were
1
uncorrected. H and 13C NMR spectra were recorded with
400 and 600 MHz (1H NMR) pulse Fourier transform NMR
spectrometers in CDCl3 solution with tetramethylsilane as
an internal standard. Gel-phase 31P NMR spectra were
recorded with a 600 MHz (1H NMR) pulse Fourier trans-
form NMR spectrometers in CDCl3 suspension with 85%
H3PO4 aqueous solution as an external standard. All the
reactions were performed under an argon atmosphere unless
cited.
3.2.3. Recycle of PdAS-V for the Heck reaction (general
procedure for the Heck reaction catalyzed by PdAS-V in
toluene) (Table 1). The mixture of 6a (4.1 mL; 36.5 mmol),
7a (8.0 mL; 54.7 mmol), Et3N (7.6 mL; 54.7 mmol) in
toluene (18 mL) was degassed by untrasonication for
30 min. The solution was added to PdAS-V (5 mg;
1.82 mmol), and the resulting suspension was stirred at
100 8C for 15 h. After the reaction mixture was cooled to
room temperature, methanol was added to the mixture, and
the resulting solution with insoluble PdAS-V was filtered.
At that time, PdAS-V was recovered on the filter. The
filtrate was evaporated and it was diluted with EtOAc and
water. The two-phase solution was extracted with EtOAc,
washed with water and brine, dried over MgSO4. The
residue was purified by column chromatography or
recrystallization (toluene–EtOH) to give 8a in 82–95%
yields. The recovered PdAS-V was dried in vacuo and
reused.
3.2. Materials
Toluene was distilled from CaH2 prior to use. Purchased
aryl iodides, acrylates, styrenes, and triethyl amine were
purified by distillation. N-isopropylacrylamide (purchased
from Aldrich), AIBN, t-BuOH, and (NH4)2PdCl4, were used
without purification.
3.2.1. Poly[(N-isopropylacrylamide)5-co-(4-diphenyl-
phosphinostyrene)] (3b). To a solution of 4 (4.65 mmol)
in t-BuOH (50 mL), after treatment of ultrasonication for
20 min at 60 8C to degass and dissolve 4 in t-BuOH, was
added 5 (27.8 mmol) at rt, and the mixture was degassed by
ultrasonication for 20 min. To the solution was added AIBN
(0.10 mmol), and the resulting solution was again degassed
by ultrasonication for 2£25 min, stirred at 75 8C for 41 h,
and evaporated at 80 8C to give a crude polymer. It was
purified by precipitation (£3) from CH2Cl2 (10 mL) and
Et2O (150 mL), dried in vacuo (ca. 0.08 mm Hg) to afford
3b in 82% yield: IR (KBr, cm21): n 3306, 2971, 2934, 1653,
3.2.4. Hexafluoropropyl cinnamate (8e). IR (KBr, cm21):
n 3088, 3034, 2971, 1748, 1636, 766, 691; 1H NMR
(400 MHz, CDCl3): d 5.83 (hept, J¼2.9 Hz, 1H)), 6.38 (d,
J¼15.8 Hz, 1H), 7.25–7.34 (m, 3H), 7.42–7.45 (m, 2H),
7.75 (d, J¼15.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
66.6, 114.1–124.8 (m), 114.8, 128.5, 128.9, 131.3,
133.4, 149.1, 163.2; MS(EI): m/z 298 (Mþ), 131, 103, 77;
HR-MS (EI): calcd for C12H8F6O2 298.0428, found
298.0423.
1
3.3. Synthesis of resveratrol
1539, 1460, 747, 698; H NMR (400 MHz, CDCl3 with a
trace of D2O): d 1.12 (br, 60H), 1.64–1.78 (br, 20H), 2.10
(br, 10H), 3.98 (br, 10H), 7.00–7.64 (br, 28H); 13C NMR
(100 MHz, CDCl3): d 22.6, 41.3, 42.4, 128.3, 128.5, 133.4,
133.6, 174.2; 31P NMR (243 MHz, CDCl3): d 23.0 (br,
Ar2PhP). Anal. Calcd for C50nH74nO6nN5nPn as 2·1nH2O: C
68.861%, H 8.550%, N 8.030%, found: C 68.207%, H
8.975%, N 8.395%.
3.3.1. 3,5-Dibenzoyloxystyrene (11f). To a solution of
3,5-dihydroxystyrene (11e) (408 mg; 3.0 mmol) was added
pyridine (1.21 mL; 15.0 mmol) and benzoyl chloride
(1.04 mL; 9.0 mmol) at 0 8C. After the resulting solution
was stirred for 1.5 h, water was added. The two-phase
solution was extracted with CH2Cl2, washed with water and
brine, dried over MgSO4, and purified by column chroma-
tography to give 11f in 87% yield (898 mg; 2.61 mmol).
IR (KBr, cm21): n 3071, 2988, 1732, 1590; 1H NMR
(400 MHz, CDCl3): d 5.36 (d, J¼11.0 Hz, 1H)), 5.80 (d,
J¼17.6 Hz, 1H), 6.72 (dd, J¼11.0, 17.6 Hz, 1H), 7.10–7.11
(m, 1H), 7.21–7.22 (m, 2H), 7.54–7.55 (m, 4H), 7.63–7.67
(m, 2H), 8.20–8.22 (m, 4H); 13C NMR (100 MHz, CDCl3):
d 114.9, 115.9, 116.9, 128.5, 129.1, 130.1, 133.6, 135.2,
3.2.2. Poly{dichlorobis[(N-isopropylacrylamide)5-co-(4-
diphenylstyrylphosphine)]palladium} (PdAS-V) (1b).
All solvents were degassed by ultrasonication and argon
substitution prior to use. To a well-stirred solution of 3b
(307 mg; 0.36 mmol in phosphine) in THF (72 mL) was
added a solution of 2 (34.1 mg; 0.12 mmol) in H2O (30 mL),
and the mixture was again degassed. After the mixture

4104
Y. M. A. Yamada et al. / Tetrahedron 60 (2004) 4097–4105
139.9, 151.4, 164.5; MS(EI): m/z 344 (Mþ), 105, 77;
HR-MS (EI): Calcd for C22H16O4 344.1049, found
344.1055.
99–115. (e) Bergbreiter, D. E. Curr. Opin. Drug Discov. Dev.
2001, 4, 736–744. (f) Leadbeater, N. E.; Marco, M. Chem.
Rev. 2002, 102, 3217–3274. (g) McNamara, C. A.; Dixon,
M. J.; Bradley, M. Chem. Rev. 2002, 102, 3275–3300.
(h) Cameron, J. H. In Solid state organometallic chemistry;
Gielen, M., Willem, R., Eds.; Wiley: Chichester, 1999.
(i) Beletskaya, I. P.; Cheprakov, A. V. Aqueous palladium
catalysts. In Handbook of organopalladium chemistry for
organic synthesis; Negishi, E., de Meijere, A., Eds.; Wiley-
VCH, 2002.
3.3.2. (E)-3,5,40-Tribenzoyloxystyrene (12g) (the Heck
reaction by PdAS-V). The mixture of 6k (251 mg;
0.774 mmol), 11f (400 mg; 1.16 mmol), Et3N (0.162 mL;
1.16 mmol) in toluene (0.39 mL) was degassed by untra-
sonication for 30 min. The solution was added to PdAS-V
(1.1 mg; 0.387 mmol), and the resulting suspension was
stirred at 100 8C for 12 h. After the reaction mixture was
cooled to room temperature and was filtered with EtOAc
and water, the filtrate was washed with water and brine,
dried over MgSO4, and purified by column chromatography
(eluent: hexane) to afford (E)-3,5,40-tribenzoyloxystyrene
(12g) in 93% yield (390 mg; 0.72 mmol). IR (KBr, cm21): n
3. (a) Yamada, Y. M. A.; Ichinohe, M.; Takahashi, H.; Ikegami,
S. Org. Lett. 2001, 3, 1837–1840. (b) Yamada, Y. M. A.;
Ichinohe, M.; Takahashi, H.; Ikegami, S. Tetrahedron Lett.
2002, 43, 3431–3434. (c) Yamada, Y. M. A.; Takeda, K.;
Takahashi, H.; Ikegami, S. Org. Lett. 2002, 4, 3371–3374.
Yamada, Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami, S.
J. Org. Chem. 2003, 68, 7733–7774. In this manuscript, it was
ensured that the catalytic runs by PdAS were based on a
heterogeneous pathway. (d) Yamada, Y. M. A.; Tabata, H.;
Takahashi, H.; Ikegami, S. Synlett 2002, 2031–2034.
(e) Yamada, Y. M. A.; Tabata, H.; Takahashi, H.; Ikegami,
S. Tetrahedron Lett. 2003, 44, 2379–2382. (f) Yamada, Y. M.
A.; Tabata, H.; Ichinohe, M.; Takahashi, H.; Ikegami, S.
Tetrahedron 2004, 60, preceding article. See doi: 10.1016/
j.tet.2004.02.072.
1
3061, 3034, 1738, 1599; H NMR (400 MHz, CDCl3): d
7.06 (d, J¼16.1 Hz, 1H)), 7.10–7.11 (m, 1H), 7.15 (d, J¼
16.1 Hz, 1H), 7.21–7.24 (m, 2H), 7.32–7.32 (m, 2H),
7.48–7.56 (m, 8H), 7.61–7.66 (m, 3H), 8.19–8.23 (m, 6H);
13C NMR (100 MHz, CDCl3): d 114.7, 117.1, 121.9, 127.1,
127.6, 128.4, 128.5, 129.1, 129.3, 129.6, 130.0, 130.1,
133.5, 133.6, 134.4, 139.6, 150.5, 151.5, 164.6, 164.8;
MS(EI): m/z 540 (Mþ), 105, 77; HR-MS (EI): Calcd for
C35H24O6 540.1573, found 540.1570.
4. For reviews of homogeneous and heterogeneous catalysis of
the Heck reaction, see: (a) Beletskaya, I. P.; Cheprakov, A. V.
Chem. Rev. 2000, 100, 3009–3066. (b) Whitcombe, N. J.; Hii,
K. K.(M.); Gibson, S. E. Tetrahedron 2001, 57, 7449–7476.
(c) Biffis, A.; Zecca, M.; Basato, M. J. Mol. Catal. A: Chem.
2001, 173, 249–274. (d) Uozumi, Y.; Hayashi, T. Solid-phase
palladium catalysis for high-throughput organic synthesis. In
Handbook of combinatorial chemistry; Nicolaou, K. C.,
Hanko, R., Hartwig, W., Eds.; Wiley: Weinheim, 2002.
5. For recent developments and improvements for heterogeneous
catalysis of the Heck reaction, see: (a) Mehnert, C. P.; Weaver,
D. W.; Ying, J. Y. J. Am. Chem. Soc. 1998, 120,
12289–12296. (b) Leese, M. P.; Williams, J. M. J. Synlett
1999, 1645–1647. (c) Buchmeiser, M. R.; Wurst, K. J. Am.
Chem. Soc. 1999, 121, 11101–11107. (d) Uozumi, Y.;
Watanabe, T. J. Org. Chem. 1999, 64, 6921–6923. (e) Alper,
H. A.; Arya, P.; Bourque, C.; Jefferson, G. R.; Manzer, L. E.
3.3.3. Resveratrol (12h). The solution of 12g THF–MeOH
was stirred at 50 8C for 5 h. After the mixture was cooled to
rt, EtOAc and water was added. The two-phase solution was
extracted with EtOAc, washed with water and brine, dried
over MgSO4, purified by column chromatography to afford
resveratrol (12h) in 98% yield (22.4 mg; 0.098 mmol).
Acknowledgements
We thank Ms. Junko Shimode, and Ms. Maroka Kitsukawa
for spectroscopic measurement. This work was partially
supported by a Grant-in-Aid for Scientific Research from
the ministry of Education, Science and Technology. Y. M.
A. Y. thanks the Inoue Foundation for Science (IFS) for
Inoue Research Award for Young Scientists, and Dainippon
Ink and Chemicals, Inc. Award in Synthetic Organic
Chemistry, Japan.
¨
Can. J. Chem. 2000, 78, 920–924. (f) Schwarz, J.; Bohm, V. P.
W.; Gardiner, M. G.; Grosche, M.; Herrmann, W. A.;
Hieringer, W.; Raudaschl-Sieber, G. Chem. Eur. J. 2000, 6,
1773–1780. (g) Pathak, S.; Greci, M. T.; Kwong, R. C.;
Mercado, K.; Prakash, G. K. S.; Olah, G. A.; Thompson, M. E.
Chem. Mater. 2000, 12, 1985–1989. (h) Mubofu, E. B.; Clark,
J. H.; Macquarrie, D. J. Stud. Surf. Sci. Catal. 2000, 130,
2333–2338. (i) Bergbreiter, D. E.; Osburn, P. L.; Frels, J. D.
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