The synthesis of non-symmetrical stilbene analogs of trans-resveratrol using the same Pd catalyst in a sequential double-Heck arylation of ethylene

Article abstract of DOI:10.1002/aoc.1756

We have developed a sequential and selective Pd-catalyzed double-Heck arylation of ethylene that results in non-symmetrical nitro-stilbene analogs of trans-resveratrol at excellent yields. A catalytic system consisting of Pd(OAc)₂ and P(o-tolyl)₃ permitted us to carry out the two consecutive Heck arylations without losing activity from the first to the second Heck reaction. After the first Heck arylation of ethylene, no isolation or additional catalyst loading is required for the second Heck arylation reaction. This protocol was applied to the synthesis of methylated trans-resveratrol, which was obtained at a 65% overall yield.

Full text of DOI:10.1002/aoc.1756

Full Paper
Received: 24 August 2010
Revised: 12 October 2010
Accepted: 22 October 2010
Published online in Wiley Online Library: 6 January 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1756
The synthesis of non-symmetrical stilbene
analogs of trans-resveratrol using the same Pd
catalyst in a sequential double-Heck arylation
of ethylene
Sabrina M. Nobrea†, Mauro N. Muniza, Marcus Seferinb,
Wagner M. da Silvab, and Adriano L. Monteiroa∗
We have developed a sequential and selective Pd-catalyzed double-Heck arylation of ethylene that results in non-symmetrical
nitro-stilbeneanalogsof trans-resveratrolatexcellentyields. Acatalyticsystem consistingofPd(OAc)2 andP(o-tolyl)3 permitted
us to carry out the two consecutive Heck arylations without losing activity from the first to the second Heck reaction. After the
first Heck arylation of ethylene, no isolation or additional catalyst loading is required for the second Heck arylation reaction.
This protocol was applied to the synthesis of methylated trans-resveratrol, which was obtained at a 65% overall yield. Copyright
c
ꢀ 2011 John Wiley & Sons, Ltd.
Keywords: Heck reaction; palladium; trans-resveratrol; stilbene
Introduction
the associated workup and purification procedures. In this
context, selective one-pot procedures for the construction of
symmetric and non-symmetric trans-stilbene derivatives have
been reported based on two sequential Heck-type reactions
using vinyltrimethylsilaneasanethyleneequivalent,[24] alongwith
consecutive palladium-catalyzed Hiyama–Heck reactions starting
from vinyltriethoxysilane.[34] Copper-catalyzed methylenation
reactions have been used to produce terminal alkenes that can be
directly submitted without isolation to further Heck reactions so
as to produce stilbene derivatives. The copper catalyst from the
first step is a cocatalyst for the subsequent palladium-catalyzed
cross-coupling reaction.[29] Ethylene has also been used for the
preparation of non-symmetrically substituted stilbenes using a
one-pot, two-step double Heck strategy;[35] however, in this
protocol, two different Pd catalysts were used for the two Heck
reactions. Herein, we wish to present our results on the synthesis
of non-symmetrical stilbene analogs of trans-resveratrol using
the same Pd catalyst in a sequential double-Heck arylation of
ethylene.
Hydroxylated stilbenes, such as resveratrol,[1] pterostilbene[2] and
pinosylvin[3], are natural compounds that exhibit many biological
activities. Resveratrol is a phytoalexin toxin that is produced
by plants in response to infection or stress (phytoalexin) and
has received considerable attention since Jang and colleagues
published a seminal article demonstrating its anti-carcinogenic
effects.[4] In addition, resveratrol exhibits anti-inflammatory,
antioxidant and platelet antiaggregatory activity, as well as
potential benefits to lifespan extension.[5] For these reasons,
several analogs of resveratrol have been synthesized and their
activities investigated. For example, trimethylated resveratrol
was found to be a potent and selective human cytochrome
P450 1B1 inhibitor,[6] and it has shown more activity against
several human cancer cell lines in comparison to resveratrol.[7]
Several synthetic routes based on Wittig-type reactions have
been used to prepare resveratrol and its analogs.[6–16] Most of
these approaches require relatively long synthetic routes and
have variable diastereoselectivities. Therefore, Pd-catalyzed cross-
coupling reactions are very effective alternatives due to their
synthetic versatility and efficiency.[17] Suzuki reactions between
β-halostyrenes and arylboronic acids,[18–20] decarbonylative Heck
reactions between resorcylic acid chlorides and styrenes,[21,22]
and Heck reactions between aryl halides and styrene derivatives
regioselectively furnish the trans-stilbene coupling products in
one step;[23–32] however, in all of these cases, a styrene derivative
substrate is required. Although some styrene derivatives are
commercially available, most need to be prepared by elimination
reactions, partial alkyne reductions, carbonyl olefination methods
or, more recently, via Pd-catalyzed cross-coupling reactions.[33]
In addition, styrenes can polymerize under a wide range of
conditions, and finding protocols that produce styrene derivatives
in situ not only overcomes these problems but also simplifies
∗
Correspondenceto:Adriano L. Monteiro,InstitutodeQuímica,UFRGS,Av.Bento
Gonc¸alves, 9500 Porto Alegre 91501-970, CP 15003, RS, Brazil.
E-mail: adriano.monteiro@ufrgs.br
´
†
a
Present address: Escola de Química e Alimentos- FURG, Av. Italia, km 8, Rio
Grande, 96201-900, RS, Brazil.
InstitutodeQuímica,UFRGS,Av.BentoGonc¸alves,9500PortoAlegre91501-970,
CP 15003, RS, Brazil
b
Faculdade de Química – PUCRS, Av. Ipiranga, 6681, Porto Alegre, 90619-900,
RS, Brazil
c
Appl. Organometal. Chem. 2011, 25, 289–293
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

S. M. Nobre et al.
Experimental Section
Catalytic reactions that involved ethylene were carried out in
a 100 ml stainless steel autoclave. The catalytic reactions that
involvedthesynthesisofstilbeneswerecarriedoutunderanargon
atmosphere in Schlenk tubes. Chemicals were purchased from
commercial sources and were used without further purification.
1-iodo-3,5-dinitrobenzene[36] and1-bromo-3,5-dinitrobenzene[37]
were obtained using procedures that have been described in the
literature. Elemental analyses were performed by the Analytical
Central Service of IQ-UFRGS. NMR spectra were recorded on a
Varian XL300 spectrometer. Infrared spectra were acquired on a
Varian640-IRFT-IR. MassspectrawereobtainedonaShimadzuQP-
5050 gas chromatograph/mass spectrometer (GC/MS; EI, 70 eV).
Gas chromatography (GC) analyses were performed on a Hewlett-
Packard-5890 gas chromatograph with a flame ionization detector
(FID) and a 30-m capillary column with a dimethylpolysiloxane
stationary phase. Tetradecane was used as internal standard and
the conversions were calculated based on the consumption of the
limited reagent (aryl halide).
Figure 1. S- and N-containing palladacycles tested.
General Procedure for the Heck Coupling Reaction of Ethylene
with 1-Halo-3,5-dinitrobenzene
1-Iodo-3,5-dinitrobenzene
or
1-bromo-3,5-dinitrobenzene
(1 mmol), Pd(OAc)2 (0.01 mmol, 2.24 mg), P(o-tol)3 (0.04 mmol,
12.16 mg), NaOAc (1.1 mmol, 90.2 mg) and DMF (10 ml) were
added to a 100 ml stainless steel autoclave under argon. The
reactor was pressurized with 10 atm of ethylene and the reaction
mixture was stirred at 90 ◦C for the desired time. After cooling and
releasing the excess ethylene, the reaction mixture was analyzed
by GC and GC-MS. For the isolation of 3,5-dinitrostyrene, the
reaction mixture was taken up in ether (30 ml), washed with H2O,
dried over MgSO4, filtered and the solvent removed in vacuo. The
residue was purified by column chromatography so as to produce
3,5-dinitrostyrene as a slightly yellow solid. This compound was
characterized by comparing their m.p., 1H, 13C NMR spectra with
those published in the literature.[37]
Scheme 1. The sequential double-Heck arylation of ethylene using the
same Pd catalyst (GC yields).
we used the model substrates 1-iodo-3,5-dinitrobenzene and
1-bromo-3,5-dinitrobenzene for the first arylation and 1-iodo-
4-methoxybenzene for the second arylation. The 1-halo-3,5-
dinitrobenzenes were selected because they are easily obtained
from a cheap starting material, m-dinitrobenzene. In addition,
they possess the 3,5-substitution pattern of the resveratrol
motif and facilitate the preparation of resveratrol nitrogen
analogs. We performed an extensive optimization of the reaction
conditions using S- and N-containing palladacycles[41,42] (Fig. 1),
phosphine-freePd(OAc)2 andphosphine-basedPd(OAc)2 catalysts
for each arylation reaction, and then a one-pot procedure.
S-containingpalladacycle1andphosphinefreePd(OAc)2 gavelow
conversions (<10%) for the coupling of 1-iodo-3,5-dinitrobenzene
with ethylene under the conditions used (DMF or DMA as
solvent, 90–130 ◦C, NaOAc or Et3N as base). On the other hand
both N-containing palladacycle 2 and Pd(OAc)2 associated with
P(o-tolyl)3 gave complete conversion for the arylation of the
ethylene. However, only the phosphine-containing palladium
catalyst Pd(OAc)2+P(o-tolyl)3 allowed us to carry out the two
consecutive Heck arylations without losing activity from the first
to the second Heck reaction (Scheme 1). For the N-containing
palladacycle 2 we observed formation of black palladium after the
first arylation and low conversions were obtained for the second
arylation. Therefore the presence of the phosphine ligand is crucial
to keep the catalyst active for the second arylation reaction. Thus,
General Procedure for the Synthesis of Non-symmetrical
Stilbenes
3,5-Dinitro-1-iodobenzene
or
1-bromo-3,5-dinitrobenzene
(1 mmol), Pd(OAc)2 (0.01 mmol, 2.24 mg), P(o-tol)3 (0.04 mmol,
12.16 mg), NaOAc (1.1 mmol, 90.2 mg) and DMF (10 ml) were
added to a 100 ml stainless steel autoclave under argon. The
reactor was pressurized with 10 atm of ethylene and the reaction
mixture was stirred at 90 ◦C for the desired time. After cooling
and releasing the excess ethylene, the reaction mixture was
transferred under argon to a Schlenk tube. Next, aryl halide
(1 mmol) and NaOAc (1.1 mmol, 90.2 mg) were added and the
mixture was stirred at 130 ◦C for 16 h. After cooling to room
temperature, the solution was taken up in ether (30 ml), washed
with H2O, dried over MgSO4, filtered, and the solvent removed in
vacuo. The residue was purified by column chromatography or
recrystallizationsoastoproducethecorrespondingtrans-stilbene.
These known compounds were characterized by comparing
their mp, 1H, 13C NMR spectra with those published in the
literature.[6,38–40]
Results and Discussion
To obtain a sequential double-Heck arylation of ethylene without
the isolation of the intermediate using the same Pd catalyst,
c
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Appl. Organometal. Chem. 2011, 25, 289–293

Synthesis of non-symmetrical stilbene analogs of trans-resveratrol
the coupling reaction between 1-iodo-3,5-dinitrobenzene and
ethylene (10 atm) using Pd(OAc)2 + P(o-tolyl)3 as a catalyst,
NaOAc as base, and DMF as the solvent at 90 ◦C produced
3,5-dinitrostyrene at an turnover number of 98 according to
GC, and the coupling product was isolated at an 85% yield.
As judged by GC-MS, the only by-product of the process was
the symmetric stilbene that was formed by the arylation of the
3,5-dinitrostyrene (1–2%). Our first approach to performing the
second arylation was to cool the reactor and release the excess
ethylene, followed by the addition of 4-iodoanisol (1 equiv.) and
more base (1.1 equiv.) to the autoclave (protocol 1). Using this
protocol, we obtained 83% of 4-methoxystyrene without the
formation of the stilbene product. These results indicate that
the 4-iodoanisol instead of 3,5-dinitrostyrene reacted with the
ethylene that remained in the solvent. To overcome this problem,
we decided to transfer the reaction mixture under argon to a
Schlenk tube, wherein we performed the second arylation under
an argon atmosphere at reflux (protocol 2). Using this procedure,
the 3,5-dinitro-4ꢁ-methoxystilbene was obtained at a 95% yield
with a regioselectivity of E : Z = 95 : 5 (Scheme 1). Purification of
the crude material by column chromatography resulted in pure
(E)-3,5-dinitro-4ꢁ-methoxystilbene at an 88% overall yield.
Scheme 2. Heck reaction: competitive reaction between aryl iodides.
To explain the selectivity, additional competition experiments
were carried out (Table 1 and Scheme 2). The reaction of aryl
iodides (1 equiv.) with a mixture of ethylene (5 atm) and styrene
(18.5equiv.)demonstratedthatethylenereactsfasterthanstyrene,
even when styrene is present in a large excess (Table 1, entries 1
and2).Ontheotherhand,3,5-dinitrostyrene(18.5equiv.)wasmore
reactive than 4-methoxystyrene (18.5 equiv.) in the Heck reaction
with iodobenzene (1 equiv.). Finally, we evaluated the relative
reactivitiesoftwodifferentaryliodides(1-iodo-3,5-dinitrobenzene
and 4-iodoanisol) in coupling reactions with olefins (Scheme 2). As
expected, the aryl iodide that contained electron-withdrawing
groups was more reactive than that with electron-donating
groups. Usingethylene, 93%ofthecouplingproductresultedfrom
the reaction with 1-iodo-3,5-dinitrobenzene at low conversions,
whereas only 1-iodo-3,5-dinitrobenzene coupled with styrene as
the limiting reagent (0.1 equiv.). These competition experiments
demonstrate that by choosing 1-iodo-3,5-dinitrobenzene in the
first step and 4-iodoanisol in the second step, non-symmetrical
stilbene could be obtained at an excellent yield and with a high
selectivity.
entry 1). When we tried to reverse the aryl iodide order by
adding 4-iodoanisol to the first Heck reaction and then 1-
iodo-3,5-dinitrobenzene to the second, a mixture of stilbene
(63%) and m-dinitrobenzene (27%) was obtained (Table 2, entry
2). The by-product was formed by reduction of the 1-iodo-
3,5-dinitrobenzene. We next tried some other combinations
in order to expand the scope of the reaction. When using
1-iodo-4-nitrobenzene in the first Heck reaction, the stilbene
coupling product (E)-4-methoxy-4ꢁ-nitrostilbene was obtained at
an excellent yield (Table 2, entry 3). When we tried to reverse
the aryl iodide order by adding 4-iodoanisol to the first Heck
reaction and then 1-iodo-4-nitrobenzene to the second, the yield
of the stilbene decreased to 70% and the selectivity was lower
(Table 2, entry 4). A regioselectivity of 70 : 30 for the (E)- and
(Z)-4-methoxy-4ꢁ-nitrostilbene was observed. We have also tested
a very activated aryl bromide for the second arylation but the
conversion was not complete (70%) and the stilbene product was
formed in 60% yield (Table 2, entry 5). 4-Iodoanisol gave better
results as the first arylation agent when we used a aryl iodide
with an electron donating group in para position for the second
arylation (Table 2, entry 6). These results indicate that the first
Under the optimized conditions, the second Heck reaction
proceeded without any isolation of the first Heck product using
the same Pd catalyst so as to provide pure (E)-3,5-dinitro-4ꢁ-
methoxystilbene at an 88% total yield for the two steps (Table 2,
Table 1. Heck reaction: competitive reaction between olefinsa
Entry
Ar
R1
R2
ArCH CHR1 (%)
ArCH CHR2 (%)
1
2
3
3,5-(NO2)2C6H3
4-MeOC6H4
Ph
H
Ph
Ph
85
84
74
15
16
26
H
3,5-(NO2)2C6H3
4-MeOC6H4
a ArI (1 mmol), styrene or substituted styrene (18.5 mmol), ethylene (5 atm), Pd(OAc)2 (0.01 mmol), P(o-tol)3 (0.04 mmol), NaOAc (1.1 mmol), and DMF
(10 ml).
c
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S. M. Nobre et al.
Table 2. The synthesis of non-symmetrical stilbenes via the sequential double-Heck arylation of ethylenea
Entry
1
Ar1I
Ar2I
Stilbene isolated yield (%)
88%
2
63%b
90%
70%
60%c
3
4
5
6
80%
87%
7
8d
65%
a Ar1I (1 mmol), Pd(OAc)2 (0.01 mmol), P(o-tol)3 (0.04 mmol), NaOAc (1.1 mmol), and DMF (10 ml). The reactor was pressurized with 10 atm of ethylene,
and the reaction mixture was stirred at 90 ◦C for 3–4 h. After cooling and releasing the excess ethylene, the reaction mixture was t◦ransferred under
argon to a Schlenk tube. Next, Ar2I (1 mmol) and NaOAc (1.1 mmol, 90.2 mg) were added, and the mixture was stirred at 130 C for 16 h. b GC
yield. Reduction product m-dinitrobenzene was formed in 27% GC yield. c GC yield. Only 72% conversion of 1-bromo-4-nitrobenezene. d Pd(OAc)2
(0.02 mmol), P(o-tol)3 (0.08 mmol).
c
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Synthesis of non-symmetrical stilbene analogs of trans-resveratrol
aryl iodide must preferentially have strong electron-withdrawing
groupsthatareattachedtothearylring. Finally, thearyliodidethat
contained two methoxy groups in the meta positions (moderate
electron-withdrawing groups) was evaluated (Table 2, Entry 8).
The reaction with 3,5-dimethoxy-1-iodobenzene in the first Heck
reaction resulted in a 65% yield of the methylated resveratrol,
which is known to be as biologically active as resveratrol itself.
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In summary, we have developed a sequential and selective
double-Heck arylation of ethylene that produces non-symmetrical
nitro-stilbene analogs of trans-resveratrol at excellent yields. After
the first Heck arylation of ethylene, no isolation or additional
catalyst loading is required for the second Heck arylation. This
protocol was also applied to the synthesis of methylated trans-
resveratrol, which was obtained at a 65% yield over the two Heck
reactions.
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Acknowledgments
We thank CNPq, PRONEX-FAPERGS, and INCT-Catalise for partial
financial support. We also thank CNPq (S.M.N. and M.N.M) for
scholarships.
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