One-pot palladium-catalyzed highly chemo-, regio-, and stereoselective synthesis of trans-stilbene derivatives. A concise and convenient synthesis of resveratrol

Article abstract of DOI:10.1016/S0040-4039(02)02317-1

A convenient, efficient and highly chemo-, regio-, and stereoselective one-flask synthetic method is reported for the construction of unsymmetrical (or symmetrical) trans-stilbene derivatives based on two sequential Heck-type reactions using tetraalkylammonium salt-based catalyst systems and vinyltrimethylsilane as double bond equivalents. Resveratrol has thus been concisely synthesized.

Full text of DOI:10.1016/S0040-4039(02)02317-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 193–197
One-pot palladium-catalyzed highly chemo-, regio-, and
stereoselective synthesis of trans-stilbene derivatives. A concise
and convenient synthesis of resveratrol
Tuyet Jeffery* and Benoˆıt Ferber
Laboratoire de Synthe`se Organique Se´lective et Chimie Organome´tallique, Unite´ associe´e CNRS-UCP-ESCOM,
13, Boulevard de l’Hautil, 95092 Cergy Pontoise Ce´dex, France
Received 8 July 2002; accepted 15 October 2002
Abstract—A convenient, efficient and highly chemo-, regio-, and stereoselective one-flask synthetic method is reported for the
construction of unsymmetrical (or symmetrical) trans-stilbene derivatives based on two sequential Heck-type reactions using
tetraalkylammonium salt-based catalyst systems and vinyltrimethylsilane as double bond equivalent. Resveratrol has thus been
concisely synthesized. © 2002 Elsevier Science Ltd. All rights reserved.
Many stilbene compounds 1 which are widely encoun-
tered in nature are known to have important biological
activities.1 Additionally, the importance of p-conju-
gated oligomers with the p-phenylenevinylene (PPV)
backbone in the field of electroluminescent and non-lin-
ear optical (NLO) materials has been highlighted.2 The
double bond of the stilbene unit is usually elaborated
from substituted benzaldehydes via Wittig1b,3a,c,e,f or
Horner–Wadsworth–Emmons reactions.1c,3a,b,d,f Alter-
natively, construction of the stilbene structural unit
from a preexisting double bond via arylation of styrene
derivatives (Heck reaction) has been described.4 The
combined use of Heck and Horner–Wadsworth–
Emmons reactions5 or Heck and Wittig reactions6 has
also allowed the stepwise building of the conjugated
chain. Synthesis of stilbenes and poly(phenylene-
vinylene)s from haloarenes and ethene via two Heck
reactions has been studied.7 We wish to report herein a
one-pot synthesis of unsymmetrical (or symmetrical)
trans-stilbene derivatives based on two sequential
Heck-type reactions effected in the presence of tetra-
alkylammonium salt-based catalyst systems, using
haloarenes and vinyltrimethylsilane as double bond
equivalent.
We have recently reported that appropriate selection of
tetraalkylammonium salt-based catalyst systems [Pd/
MZ/QX] can permit, not only to accelerate Heck-type
reactions, but also to direct them in order to realise
these reactions with the desired selectivities.8–10 In par-
ticular, arylation of vinyltrimethylsilane can be
efficiently oriented towards the formation of styrene
derivatives.9 A double bond can thus be very effectively
grafted onto an aromatic structure, offering the poten-
tial of constructing trans-stilbene derivatives 1 from
haloarenes and vinyltrimethylsilane via two Heck-type
reactions (Scheme 1).
In order to use twice the palladium catalyst and tetra-
alkylammonium salt, conditions have been found to
realise the two sequential Heck-type reactions in the
same flask. As shown in Table 1 (Scheme 2), unsym-
metrical trans-stilbenes 1 can thus be obtained in high
yields. Indeed, treatment in toluene, at room tempera-
ture, of an aryl iodide with an excess of vinyltrimethyl-
silane, in the presence of potassium fluoride,
tetra-n-butylammonium chloride and catalytic amounts
Scheme 1.
Keywords: palladium and compounds; Heck reactions; ammonium
salts; vinyltrimethylsilane; resveratrol.
* Corresponding author. Tel.: (33) 01 30 75 61 96.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02317-1

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T. Jeffery, B. Ferber / Tetrahedron Letters 44 (2003) 193–197
Table 1. One-pot palladium-catalyzed synthesis of unsymmetrical stilbene derivatives (Scheme 2)a)
of bis(dibenzylideneacetone)palladium led to the forma-
tion of the corresponding styrenes.9 The excess of
vinyltrimethylsilane was then removed under reduced
pressure before effecting the second Heck reaction
which was realised in wet N,N-dimethylformamide, in
the presence of a [Pd/Base/QX] catalyst system11 consti-
tuted by the palladium catalyst and tetra-n-butylammo-
nium chloride already present in the reaction mixture,
and added potassium carbonate. This second step can
be realised in the presence or in the absence of ligand
Scheme 2.

T. Jeffery, B. Ferber / Tetrahedron Letters 44 (2003) 193–197
195
Table 2. One-pot palladium-catalyzed synthesis of symmetrical stilbene derivatives (Scheme 3)a)
The potential and efficiency of the described methodol-
ogy has been illustrated by a concise, convenient, highly
chemo-, regio-, and stereoselective synthesis of resvera-
phosphine (Table 1, entries 1–3). The reported method-
ology can be applied to heteroaromatic halides (entries
4–6) for the synthesis of heteroaromatic trans-stilbenes
whose interest has been highlighted.12 The described
one-flask, two-step reaction is highly chemo-, regio-,
and stereoselective as coupled gas chromatography with
mass spectrometry (GC–MS) analyses of the reaction
mixtures indicated a nearly exclusive formation of stil-
bene derivatives, with a very high isomeric selectivity
for the (E) configuration ranging between 96 and 99%.
trol
3 (trans-3,5,4%-trihydroxystilbene), a naturally
occurring compound found in a variety of sources—
including red wines—which has been shown to have
multiple beneficial biological effects including protec-
tion against heart diseases and tumor development,
prevention of oxidative damage and platelet aggrega-
tion.1a,14 As shown in Scheme 4, treatment of commer-
cial 4-methoxyiodobenzene with vinyltrimethylsilane
under the arylation–desilylation conditions9 followed
by (i) removal of the excess of vinyltrimethylsilane
under reduced pressure and (ii) arylation of the thus-
formed 4-methoxystyrene by 3,5-dimethoxyiodoben-
Symmetrical stilbene derivatives 2 can be synthesized by
a similar method (Table 2, Scheme 3). Treatment of 2
equiv. of an aryl iodide with 1 equiv. of vinyltrimethyl-
silane under the previously outlined arylation–desilyla-
tion conditions9 was followed by arylation in wet
DMF, of the styrene derivatives formed in situ, in the
presence of palladium catalyst and tetra-n-butylammo-
nium chloride (already present in the reaction mixture)
and potassium carbonate (added), without or with
added triarylphosphine. GC–MS analyses of the reac-
tion mixtures all show a highly selective formation of
stilbene derivatives with a very high isomeric selectivity
ranging between 95 and 99%. Although the (E)-
configuration of symmetrical stilbene derivatives can
zene,15,16
in
a
one-flask
reaction,
provides
(E)-3,5,4%-trimethoxystilbene17 in 72% yield (94% GLC
yield). Demethylation by the recently described18 boron
trichloride/tetra-n-butylammonium
iodide
reagent
cleanly affords resveratrol 319 in 85% yield.
1
not be deduced directly from H NMR spectra, it can
be expected from a Heck reaction, as resulting from a
syn-addition–syn-elimination mechanism.13
Scheme 3.

196
T. Jeffery, B. Ferber / Tetrahedron Letters 44 (2003) 193–197
Scheme 4.
In conclusion, we have developed an efficient, conve-
nient, highly chemo-, regio-, and stereoselective one-
flask, two-step synthetic methodology for the
construction of unsymmetrical (or symmetrical) trans-
stilbene derivatives based on two sequential Heck-type
reactions, using tetraalkylammonium salt-based catalyst
systems and vinyltrimethylsilane as double bond
equivalent.
C. J. Am. Chem. Soc. 1998, 120, 419–420; (d) Bazan, G.
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5. Maddux, T.; Li, W.; Yu, L. J. Am. Chem. Soc. 1997, 119,
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16). Purification by flash chromatography on silica gel
(CH2Cl2:cyclohexane 1:1 as eluent) afforded 3,5-
dimethoxyiodobenzene as a pale yellow powder (75%
yield); 1H NMR (CDCl3, 270 MHz, Me4Si): l 6.85 (d,
J=2.3 Hz, 2H), 6.40 (t, J=2.3 Hz, 1H), 3.75 (s, 6H)
ppm; 13C NMR (CDCl3, 75 MHz): l 161.0, 115.7, 100.6,
94.0, 55.4 ppm; MS (EI) m/z 264 (M+).
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2098–2101.
16. Clive, D. L. J.; Angoh, A. G.; Bennett, S. M. J. Org.
Chem. 1987, 52, 1339–1342.
17. trans-3,5,4%-Trimethoxystilbene: To a well-stirred suspen-
sion of anhydrous potassium fluoride (0.54 g, 9.29 mmol)
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197
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and tetra-n-butylammonium chloride (1.65 g, 5.93 mmol)
in dry toluene (5 mL), under a nitrogen atmosphere, were
added 4-methoxyiodobenzene (0.75 g, 3.20 mmol), bis-
(dibenzylideneacetone)palladium (69 mg, 0.12 mmol) and
vinyltrimethylsilane (2.8 mL, 18.12 mmol). Following a
24–30 h stirring at room temperature and addition of wet
(3% H2O) N,N-dimethylformamide (7 mL), the excess of
vinyltrimethylsilane was removed under reduced pressure.
Potassium carbonate (1.1 g, 7.95 mmol) and 3,5-
dimethoxyiodobenzene (0.85 g, 3.22 mmol) were then
added and the reaction mixture was heated at 70°C (oil
bath temperature) for about 24 h. After cooling, addition
of ethyl acetate and filtration through Celite, the organic
phase was washed (H2O and brine), dried (MgSO4),
concentrated and purified by flash chromatography on
silica gel (EtOAc:cyclohexane 1:4 as eluent) to provide a
white solid (0.62 g, 72% yield, 94% GLC yield determined
against n-hexadecane as internal standard); 1H NMR
(CDCl3, 270 MHz, Me4Si): l 7.43 (d, J=8.6 Hz, 2H),
7.03 (d, Jtrans=16.2 Hz, 1H), 6.88 (d, J=8.6 Hz, 2H),
6.87 (d, Jtrans=16.2 Hz, 1H), 6.64 (d, J=2.3 Hz, 2H),
6.37 (t, J=2.3 Hz, 1H), 3.81 (s, 9H) ppm; 13C NMR
(CDCl3, 75 MHz): l 161.0, 159.5, 139.8, 130.0, 128.8,
127.9, 126.6, 114.2, 104.4, 99.7, 55.4 ppm; MS (EI) m/z
270 (M+).
19. Resveratrol (trans-3,5,4%-trihydroxystilbene): Under
a
nitrogen atmosphere, boron trichloride (9 mL of a 1.0 M
solution in CH2Cl2) was added dropwise, at 0°C, to a
well-stirred mixture of trans-3,5,4%-trimethoxystilbene
(0.40 g, 1.48 mmol) and tetra-n-butylammonium iodide
(3.26 g, 8.82 mmol) in dry dichloromethane (4 mL).
Stirring was continued for 5–6 h while the reaction
mixture was allowed to warm to room temperature. After
controlling (by thin-layer chromatography) that the reac-
tion was complete, saturated aqueous sodium hydrogen
carbonate (10 mL) was added dropwise at 0°C and the
resulting suspension stirred for 1 h at room temperature.
The solid was filtered off, washed with CH2Cl2 and
dissolved in a minimal amount of MeOH. Purification by
flash chromatography on silica gel (ether:cyclohexane 4:1
as eluent) afforded trans-3,5,4%-trihydroxystilbene as a
lightly beige powder (0.29 g, 85% yield); 1H NMR
(CD3COCD3, 270 MHz, Me4Si): l 8.53 (s, 1H), 8.27 (s,
2H), 7.42 (d, J=8.6 Hz, 2H), 7.06 (d, Jtrans=16.4 Hz,
1H), 6.89 (d, Jtrans=16.4 Hz, 1H), 6.86 (d, J=8.6 Hz,
2H), 6.57 (d, J=2.2 Hz, 2H), 6.30 (t, J=2.2 Hz, 1H)
ppm; 13C NMR (CD3COCD3, 75 MHz): l 159.6, 158.2,
140.9, 130.0, 129.2, 128.8, 126.8, 116.5, 105.7, 102.7 ppm.