Syntheses of polyfunctionalized resveratrol derivatives using Wittig and Heck protocols

Article abstract of DOI:10.1016/j.tet.2012.03.025

Improved protocols for Wittig reaction and palladium-catalyzed Heck coupling give expedient access to a series of unprecedented polyfunctionalized artificial-resveratrol derivatives. In the modified Wittig protocol, trimethylsilyl was used as a highly valuable protective group of the phenolic functions of starting aromatic materials. A clean O-alkylation of hydroxylated stilbenes with ethylene carbonate was also conducted. Thus, Wittig reaction followed by hydroxyethylation take place one-pot with only carbon dioxide as waste. Additionally, a palladium-catalyzed Heck coupling strategy was developed by using ferrocenyl phosphane ligands, and multi-functionalized hydroxylated stilbenes were obtained without the need of any protection/deprotection sequence. Up to six functional groups are introduced by these procedures, which limit the number of reactions steps, the waste toxicity, and the use of costly reagents.

Full text of DOI:10.1016/j.tet.2012.03.025

Tetrahedron 68 (2012) 3899e3907
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Syntheses of polyfunctionalized resveratrol derivatives using Wittig and Heck
protocols
*
*
ꢀ ꢁ
Malik Chalal, Dominique Vervandier-Fasseur , Philippe Meunier, Helene Cattey, Jean-Cyrille Hierso
ꢀ
ꢀ
ꢀ
Universite de Bourgogne, Institut de Chimie Moleculaire de l’Universite de Bourgogne, (ICMUB) UMR-CNRS 6302, 9 avenue Alain Savary, 21078 Dijon, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Improved protocols for Wittig reaction and palladium-catalyzed Heck coupling give expedient access to
a series of unprecedented polyfunctionalized artificial-resveratrol derivatives. In the modified Wittig
protocol, trimethylsilyl was used as a highly valuable protective group of the phenolic functions of
starting aromatic materials. A clean O-alkylation of hydroxylated stilbenes with ethylene carbonate was
also conducted. Thus, Wittig reaction followed by hydroxyethylation take place one-pot with only carbon
dioxide as waste. Additionally, a palladium-catalyzed Heck coupling strategy was developed by using
ferrocenyl phosphane ligands, and multi-functionalized hydroxylated stilbenes were obtained without
the need of any protection/deprotection sequence. Up to six functional groups are introduced by these
procedures, which limit the number of reactions steps, the waste toxicity, and the use of costly reagents.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 February 2012
Received in revised form 5 March 2012
Accepted 7 March 2012
Available online 15 March 2012
Keywords:
Hydroxylated stilbenes
Wittig reaction
Protective group
Heck coupling
Ferrocenyl phosphane
1. Introduction
coupling,10 benefits from many commercially available starting
reagents and may be more convenient to scale-up.11 Thus, we re-
The interest in trans-resveratrol, as a polyphenolic natural
product present in several plants is related to its potent antioxidant
properties and influence onto infection or oxidative stress (Fig. 1).1
Reduced risks of cardiovascular disease have been documented and
correlated with the moderate consumption of beverages rich in this
polyphenol.2 The various ways, by which resveratrol targets the
signalling cell elements explain the versatile therapeutic properties
it may exhibit.3 Natural and synthetic analogues of resveratrol
bearing at least one phenolic function have shown promising
benefits to human health.4 However, the systematic investigation
of biological and therapeutic properties of polyphenols is some-
what limited by their general accessibility.
port herein new protocols based on Wittig and palladium-
catalyzed Heck reactions, which deliver a large range of poly-
functionalized resveratrol analogues of formula I or II (Fig. 1).
2. Results and discussion
Wittig reaction applied to the synthesis of hydroxylated stil-
benes requires a preliminary protection of phenolic functions of
the starting aromatic compounds. Several research teams have
previously used tert-butyldimethylchlorosilane as protective
group.9 This group was efficiently introduced to form the corre-
sponding arylsilyl ethers, and was found very stable towards protic
solvents. However, in our hands both the separation of silylated
compounds by column chromatography and the deprotection of
phenolic functions by using [n-Bu4Nþ,Fꢀ] were unsatisfactory,
giving intractable mixtures.12 In the search for a more flexible
protection, the trimethylsilyl group attracted our attention. A few
examples of protection of phenolic functions in stilbenes by a tri-
methylsilyl group have been described, unfortunately giving
very poor yields.13,14 We nevertheless investigated the synthesis
of hydroxylated stilbenes by using the more sensitive
trimethylsilyl protective group with cheap starting materials:
4-hydroxybenzaldehyde and functionalized benzyl bromides,
under strictly anhydrous conditions and inert atmosphere along
the protocol. The aryltrimethylsilyl ether 1 (Scheme 1) was
easily prepared by the reaction of chlorotrimethylsilane with
Beside extraction from plants,5,6 the development of efficient
and clean synthetic methods towards functionalized resveratrol
analogues is highly desirable.7 In particular, the antitumoral activity
of resveratrol derivatives incorporating phenolic functions and/or
methoxy groups,8 make these stilbenes pertinent targets. In this
context, the development of syntheses avoiding tedious sequences
of functional groups protection/deprotection is also valuable. The
preparation of stilbenes based on Wittig reaction,9 or Heck cross-
* Corresponding authors. Tel.: þ33 3 80399036; fax: þ33 3 80393682 (D.V.-F.);
tel.: þ33 3 80396107; fax: þ33 3 80393682 (J.-C.H.); e-mail addresses: domi-
nique.vervandier-fasseur@u-bourgogne.fr (D. Vervandier-Fasseur), jean-cyr-
ille.hierso@u-bourgogne.fr (J.-C. Hierso).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.025

3900
M. Chalal et al. / Tetrahedron 68 (2012) 3899e3907
OH
R4
R1
(I)
R2
R1, R3, R4 = H or OMe
OH
R2 = H, OH, OMe, Br, or -CH=CH2
R3
HO
OMe
(II)
trans-resveratrol
OH
R1, R3 = H, OH or OMe
R1
R3
R2 = H, OH, OMe, -CH2OH
R2
unnatural resveratrol analogues
Fig. 1. Resveratrol and targeted artificial analogues.
Scheme 1. Synthesis of hydroxylated and O-alkylated functionalized stilbenes via improved Wittig protocol.
4-hydroxybenzaldehyde in the presence of pyridine. After distilla-
tion, 1 was reacted with substituted benzyl triphenylphosphonium
bromides 2aed and iodide 2e to give the protected stilbenes 3aee.
The sensitiveness of trimethylsilyl group towards protic
solvents allowed a clean and quantitative cleavage during workup
procedure in aqueous medium to give from 3 the expected func-
tionalized hydroxylated stilbenes 4 in overall good to excellent
conversion (77e91%, Fig. 2). This procedure based on Wittig re-
action was used to synthesize and isolate Z and E-stilbenes 4aee.
It presents several practical and cost-effective advantages: (i)
Fig. 2. Functionalized resveratrol analogues synthesized by Wittig reaction using 4-trimethylsilyloxybenzaldehyde derivatives 3aee.

M. Chalal et al. / Tetrahedron 68 (2012) 3899e3907
3901
chlorotrimethylsilane for protection is considerably cheaper than t-
butyldimethylchlorosilane with a lower mass, (ii) the workup
procedure in aqueous medium allows to avoid an additional
deprotection step, (iii) due to a very clean reaction, the separation
of isomers Z and E is easily made by simple crystallization with no
need for column chromatography and consumption of large
quantity of solvent.
Recently, new promising O-alkylated stilbenes have been syn-
thesized and these resveratrol derivatives afforded in medicinal
applications increased antitumour activity,15 better solubility in
water,16 and a surprising affinity with human serum albumin of
high interest with regards to their bioavailability.17 However,
several reactants used in phenols alkylation have some disadvan-
tages: dibromide alkyls promote polymerization reactions,15
chloroalcohols generate chloride waste,18 and ethylene oxide is
a harmful and explosive reagent.19 Conversely, hydroxyethylation
of phenols,20 or of acidic alcohols,21 in neutral or basic conditions
may be done with lesser toxic ethylene carbonate. Arylsilyl ether 3b
afford polyhydroxylated esters and fluorinated analogues of
resveratrol.26 MatsudaeHeck arylation of styrenes was recently
described with arenediazonium salts.10b In these reports, the
phenolic functions are always protected by a methyl or an acetyl
group. We investigated Heck coupling without protection/
deprotection sequences of phenolic functions by using a conve-
nient palladium/ligand/base catalytic system. Heck vinylation of
substituted iodoarenes were first tested by using simplistic sys-
tems combining palladium and triphenylphosphane in the pres-
ence of a soluble base. However, optimized conditions had to be
determined to produce in a satisfactory yield the targeted stil-
benes. For catalysts screening (Table 1), a challenging couple of
substrates was preferred with the view to identify a system
having a sufficiently extended scope and synthetic utility. We
choose the coupling of the electron-rich hindered 3,4,5-(trime-
thoxy)iodobenzene 6, or its bromide analogue 7a, to the styrene
substrate 8a, functionalized with an unprotected hydroxyl group
and a methoxy function.
Table 1
Screening of palladium-catalyzed system for Heck vinylation of electron-rich methoxy(hydroxy)styrene 8aa
Entry
Catalysteligand
Halide X
Yield (%)
Selectivity E/Z
1
2
3
4
5
6
7
8
/
I or Br
I or Br
I
Br
I
I
I
I
Br
Br
Br
Br
0
0
15
5
40
58
51
13
36
73
55
10
d
Pd/no ligand
Pd/PPh3
Pd/PPh3
Pd/L1
d
b
63/37
60/40
82/18
70/30
80/20
55/45
79/21
82/18
84/16
88/12
b
Pd/L2
Pd/dppf
Pd/P(2-furyl)3
Pd/L1
Pd/L2
Pd/dppf
Pd/P(2-furyl)3
9
10
11
12
a
Reaction conditions: [PdCl(h
3-C3H5)]2/ligand (1:2, 0.65x10ꢀ2 mmol), aryl halide (1.3 mmol), styrene 8a (1.3 mmol), Cs2CO3 (1.3 mmol), DMF 10 mL, 100 ꢁC, 16 h. Yields of
isolated E products reported.
b
1:3 Pd/L.
(R¼OMe) was reacted with this electrophile in the presence of [n-
Bu4Nþ,Fꢀ] (Scheme 1).22 After 4 h refluxing, the reaction was
quenched by adding water. The pure isomer E of the stilbene 5b was
isolated in 36% yield after workup. By this original way, Wittig re-
action and hydroxyethylation takes place one-pot and the final
alkylation only produces carbon dioxide as waste. This method was
successfully extended to 3c and 3d leading to 5c and 5d, in re-
spectively, 47 and 37% yield.
Despite the satisfactory results obtained regarding our primary
synthetic targets, general limitations attached to the Wittig pro-
tocol subsist. The diversity in the functionalization of hydroxyl-
ated stilbenes is restricted by benzaldehyde and benzylic bromide
starting reagents. The protection sequence and the synthesis of
phosphonium salt diminish the convergence of the synthesis,
while undesired stoichiometric phosphane waste is produced. The
moderate stereoselectivity of the reaction diminishes the isolated
yield in desired E isomer. The development of a palladium-
catalyzed Heck coupling strategy from suitable styrenes and
haloarenes was thus envisaged. This method has been previously
used to form resveratrol,23 glucopyranosides of resveratrol24
and polymethoxystilbenes.25 Heck decarbonylative coupling can
Whatever the aryl halide used, in the absence of catalytic system,
or under ligand-less conditions, no coupling reaction was observed
(entries 1, 2). The use of PPh3 as ligand improved the results since
5e15% yield of stilbene 9a was then obtained (entries 3, 4). Changing
the base or the solvent, for instance by the cheaper base K2CO3 or
a less polar solvent as toluene, was ineffective. The catalytic systems
based on ferrocenyl phosphane ligands L1 and L2 (Fig. 3) were then
tested under the best conditions identified with PPh3 as ligand.
These ligands have shown excellent performances in the
Heck reaction of demandingdbut poorly-functionalizeddsub-
strates.27,28 In the Pd-catalyzed coupling of iodide 6a with styrene
8a, ligands L1 and L2 much improved the Heck vinylation, with
a higher activity for L2 and a slightly better selectivity in E isomer
for L1 (entries 5,6). In relation with the structural features of L2 we
examined the performances of the commercially available parent
ligands 1,10-bis(diphenylphosphino)ferrocene, dppf, and trifur-
ylphosphane, P(2-furyl)3. Less satisfaying results were obtained,
with yields of coupling product 9a of 51% and 13%, respectively
(entries 7, 8). Due to the deleterious dehalogenation side-reaction
observed with aryl iodide 6a we tested the related aryl bromide
7a with better success (entries 9e12). The superiority of ligand L2

3902
M. Chalal et al. / Tetrahedron 68 (2012) 3899e3907
Methoxylated aryl bromides were efficiently vinylated (78e91%,
entries 1e3) with high stereoselectivity in E product (83e99%)
depending on the ortho, meta or para position of the OMe group.
We were glad to see that bromides hydroxylated in these three
positions were also coupled in good yield (66e86%, entries 4e6)
with excellent regioselectivity (84e91% E), and without the need for
any protection/deprotection sequence. A lower yield of 9g (entry 7)
was obtained due to a moderate conversion of 5-bromo-2-hydroxy-
benzylalcohol. In general, a much better selectivity was obtained
with Heck reactions compared to Wittig protocol, as attested by the
synthesis of 4b (Table 2 entry 4, and Fig. 2). Interestingly, less re-
active aryl bromides circumvented the dehalogenation side-
reactions observed with iodides. The use of bromoarenes is also
profitable in terms of atomic mass economy and cost of reagents.29
The coupling of partners, in which hydroxyl group is hold by the
styrene derivative reagent was also efficiently achieved, as reported
in Table 3. The E isomer of stilbenes 9he9j were isolated in 45e95%
yield following the same protocol avoiding hydroxyl protection.
Notably, the presence of both methoxy and hydroxyl functions was
tolerated with sometimes remarkable performances as obtained for
9j (entry 3).
Fig. 3. Ferrocenyl tetra- and diphosphane ligands L1 and L2.
over the other phosphanes tested regarding activity and selectivity
was clearly established (entry 10), with a very good yield of 73% in
9a and a good regioselectivity (E/Z 82:18). The combination of steric
hindrance from ferrocenyl backbone and electron-withdrawing
properties from furyl substituants on phosphorus donors in L2
outperform the existence of only one of these features in ligands
dppf and P(2-furyl)3. Since the synthesis of L2 is straightforward
at multigram scale,28 this ligand was preferred for further stilbenes
synthesis by Heck reaction. Hydroxylated bromoarenes were
then found suitable substrates for stilbenes construction (Table 2).
The synthetic methods reported herein give a practical access to
polyfunctionalized artificial-resveratrol derivatives in fairly good to
Table 2
Methoxylated and hydroxylated stilbenes synthesis from functionalized bromoarenes 7beI and methoxystyrene 8ba
Entry
1
R1, R2
Isolated product
Conversion (%)
85
E/Z
Yield (%)b
65
3-OMe, H
83/17
2
3
2-OMe, H
4-OMe, H
78
91
92/8
99/1
50
80
4
4-OH, H
86
84/16
78
5
6
3-OH, H
2-OH, H
70
66
89/11
91/9
61
57
7
4-OH, 3-CH2OH
50
97/3
25
a
Same reaction conditions as Table 1.
Yields of isolated E products.
b

M. Chalal et al. / Tetrahedron 68 (2012) 3899e3907
3903
Table 3
Stilbenes synthesis from hydroxylated styrenesa
Entry
1
Aryl halide
Isolated product
Conv. (%)
E/Z
Yield (%)b
87
45
80/20
65
35
2
75/25
93/7
3
95
85
a
Same reaction conditions as Table 2.
Yields of isolated E products.
b
excellent isolated yields. Products 4d, 4e, 5b, 5c, 5d, 9a, and 9g are
reported for the first time, and X-ray structures are disclosed for 5c,
9a, and 9j. TMS was proved a cheap and convenient protection in
Wittig protocol. Additionally, an efficient and selective palladium/
diphosphane catalytic system in DMF, in the presence of Cs2CO3,
was identified for Heck reaction using hydroxylated styrenes or
bromoarenes, which circumvents the use of protective groups in
a straightforward stilbenes synthesis.
128.84 (s, 3C), 128.75 (s, 2C), 128.37 (s, 1C), 30.57 (s, 1C); 31P {1H}
NMR (121.47 MHz, CDCl3): (ppm) 23.14 (s, 1P).
d
3.2.2. 4-Methoxybenzyltriphenylphosphonium bromide (2b). 98%;
1H NMR (300 MHz, CDCl3):
(ppm) 7.80e7.50 (m, 15H), 6.98 (dd,
2H), 6.64 (dd, 2H), 5.29e5.25 (d, 2H), 3.70 (s, 3H); 13C NMR
(75 MHz, CDCl3): (ppm) 154.32 (s, 1C), 134.92e130.05 (m, 18C),
d
d
128.91 (s, 1C), 118.49 (s, 2C), 114.22 (s, 2C), 128.75 (s, 2C), 55.26 (s,
1C), 37.80 (s, 1C); 31P {1H} NMR (121.47 MHz, CDCl3):
(s, 1P).
d (ppm) 22.34
3. Experimental
3.2.3. 3,5-Dimethoxybenzyltriphenylphosphonium bromide (2c).
95%; 1H NMR (300 MHz, CDCl3):
(ppm) 7.80e7.50 (m, 15H), 6.31
(d, 2H), 6.25 (t, 1H), 5.20e5.30 (d, 2H), 3.50 (s, 6H); 13C NMR
(75 MHz, CDCl3): (ppm) 160.62 (s, 2C), 134.96e129.99 (m, 18C),
129.03 (s, 1C), 109.24 (s, 2C), 101.33 (s, 1C), 55.54 (s, 2C), 31.28 (s,
1C); 31P {1H} NMR (121.47 MHz, CDCl3):
(ppm) 22.51 (s, 1P).
d
3.1. General experimental procedures
d
All reactions and workup procedures were performed under
inert atmosphere of argon using conventional vacuum-line and
glasswork techniques. THF, diethylether, and hexane were degassed
and distilled by refluxing over sodium benzophenone under argon.
DMF and Pyridine were distilled over molecular sieves before use.
Caesium carbonate (99%þ) was used without drying. The organic
and organometallic products were received from commercial
sources, and used without further purification. Separations by flash
d
3.2.4. 4-Bromobenzyltriphenylphosphonium bromide (2d).30 93%;
1H NMR (300 MHz, CDCl3):
(ppm) 7.80e7.55 (m, 15H), 7.15 (d, 2H),
7.04 (d, 2H), 5.56 (d, 2H);31P {1H} NMR (121.47 MHz, CDCl3):
(ppm) 23.20 (s, 1P).
d
d
chromatography were performed on silica gel (230e400 mesh).
ˇ
Spectroscopic analyses were performed at the ‘Pole Chimie
3.3. Preparation of the 4-
Moleculaire’ of our University: 1H, 13C, 31P NMR spectra on Bruker
vinylbenzyltriphenylphosphoniumphosphonium iodide (2e)31
ꢀ
300 and AMX 400, IR spectra on IRFT Vectra-22, HRMS on MicroTOF
Q-Bruker (ESI ionization).
A mixture of 4-vinylbenzylchloride (11 g, 71.2 mmol) and NaI
(32 g, 213 mmol) in acetonitrile was refluxed for 12 h. After cooling,
the mixture was poured into water and extracted with CH2Cl2. The
excess of iodine was neutralized with a solution of Na2S2O3; the
organic layer was washed with water and dried over MgSO4. Re-
moval of the solvent in vacuum yielded 4-vinylbenzyliodide (92%).
3.2. General procedure for the preparation of the
phosphonium bromides 2ae2d9a
To a solution of benzylbromide (33 mmol) in toluene (20 mL)
was added a solution of triphenylphosphine (36.3 mmol) in toluene
(25 mL). After being heated at reflux for 5 h, the reaction mixture
was cooled at room temperature and a first crop of product was
collected by filtration. The filtrate was then refluxed for additional
5 h and a second crop of product precipitated (10e20%). The col-
lected crops were crystallized from ethanol to give pure phospho-
nium bromide in high yield.
1H NMR (300 MHz, CDCl3):
d (ppm) 7.40e7.30 (m, 4H), 6.68 (dd, 1H,
3J¼17.6 Hz, 3J¼10.9 Hz), 5.75 (dd, 1H, 3J¼17.6 Hz, 2J<1 Hz), 5.26 (dd,
3
2
1H, J¼10.9 Hz, J<1 Hz), 4.47 (s, 2H).
To a solution of 4-vinylbenzyliodide (10 g, 41 mmol) in dieth-
ylether (20 mL) was added a solution of triphenylphosphine (12.8 g,
49.2 mmol) in diethylether (50 mL). After being heated at reflux for
5 h, the reaction mixture was cooled at room temperature and the
product was collected by filtration. The filtrate was refluxed again
for 5 h and precipitation of the product occurred. The product was
collected and crystallized from ethanol (88%); 1H NMR (300 MHz,
3.2.1. Benzyltriphenylphosphonium bromide (2a). 97% yield; 1H
NMR (300 MHz, CDCl3):
7.16 (t, 1H), 7.07 (t, 2H), 5.32 (d, 2H); 13C NMR (75 MHz, CDCl3):
(ppm) 135.00 (s, 3C), 134.44 (s, 6C), 130.06 (s, 3C), 131.46 (s, 2C),
d
(ppm) 7.77e7.56 (m, 15H), 7.19 (t, 2H),
CDCl3): d (ppm) 7.70e7.50 (m, 15H), 7.15e7.00 (m, 4H), 6.56 (dd, 1H,
3J¼17.6, 3J¼10.9 Hz), 5.64 (d, 1H, 3J¼17.6 Hz), 5.10e5.30 (m, 3H); 31
P
d
{1H} NMR (121.47 MHz, CDCl3):
d (ppm) 22.30 (s, 1P).

3904
M. Chalal et al. / Tetrahedron 68 (2012) 3899e3907
3.4. Preparation of 4-trimethylsilyloxybenzaldehyde (1)
275.14). HRMS (ESI): m/z 272.99081 (MꢀHþ), calculated mass:
272.99205 (
s
¼0.007).
The synthesis, the filtration and the vacuum distillation were
carried out under Argon atmosphere. Freshly distilled pyridine
(10 mL, 123 mmol) was added to 4-hydroxybenzaldehyde (3.9 g,
32 mmol); the mixture was stirred until complete homogeniza-
tion of both reactants. Chlorotrimethylsilane (6.35 mL, 50 mmol)
was slowly added and the mixture was heated at 50 ꢁC for
a night. After cooling at room temperature, freshly distilled tet-
rahydrofuran (20 mL) was added and the pyridinium chloride
was filtered. A vacuum distillation apparatus was directly adap-
ted to the flask containing the silylated compound in THF; the
solvent was slowly removed under reduced pressure and the
4-trimethylsilyloxybenzaldehyde was distilled, yield 87%, bp
3.5.5. (E)-4-Hydroxy-40-vinylstilbene (4e). Yield 51%, mp 241 ꢁC; 1H
NMR (300 MHz, CDCl3): d (ppm) 7.42e7.39 (m, 6H), AB system 7.10
(d, 1H, 3J¼16.8 Hz), 6.96 (d, 1H, 3J¼16.8 Hz), 6.81 (d, 2H), 6.69 (dd,
1H), 5.71 (d, 1H), 5.22 (d, 1H), 5.33 (s, 1H); 13C NMR (75 MHz,
CDCl3):
(s, 1C), 126.94 (s, 1C), 126.66 (s, 1C), 125.69 (s, 2C), 124.36 (s, 2C),
124.15 (s, 2C), 122.95 (s, 1C), 113.43 (s, 2C), 110.24 (s, 1C); IR (cmꢀ1
d (ppm) 155.83 (s, 1C), 135.88 (s, 1C), 134.82 (s, 1C), 134.38
)
3329, 3020, 1593, 1246, 959, 902, 829; C16H14O (MW 222.28).
HRMS (ESI): m/z 221.09653 (MꢀHþ), calculated mass: 221.09719
(
s
¼0.005).
118 ꢁC/6 mmHg; 1H NMR (300 MHz, CDCl3):
7.72 (2H, d), 6.86 (2H, d), 0.25 (9H, s).
d
(ppm) 9.82 (1H, s),
3.6. Typical procedure of preparation of stilbenes 5be5d by
Wittig reaction
3.5. Typical procedure of preparation of stilbenes 4ae4e by
Wittig reaction
3.6.1. (E)-4-(2-O-hydroxyethyl)-40-methoxystilbene (5b). Under ar-
gon atmosphere, butyllithium (1.6 M, 20 mL, 32 mmol) was slowly
added to a solution of (4-methoxybenzyl)triphenylphosphonium
bromide (13.8 g, 33 mmol) in THF (70 mL) at ꢀ78 ꢁC. The resulting
reddish solution was allowed to warm at room temperature.
Freshly distilled 4-trimethylsilyloxybenzaldehyde (6.37 g,
33 mmol) was added dropwise and the reaction mixture was stir-
red for a night. A solution of ethylene carbonate (2.9 g, 33 mmol) in
THF (20 mL) and a solution of tetrabutylammoniumfluoride in THF
(1 M, 3.3 mL, 33 mmol) were added under argon atmosphere. The
mixture was refluxed for 10 h, then hydrolyzed with ice-cold water
and stirred for an additional hour. The aqueous layer was extracted
with ethylacetate; the combined organic layers were washed with
water and dried on MgSO4. Removal of the solvent in vacuum
yielded a crude mixture of isomers Z and E as brown oil. The isomer
E was isolated by chromatography (CH2Cl2/CH3CN: 9/1), yield 36%
3.5.1. (E)-4-Hydroxy-40-methoxystilbene (4b). Under argon atmo-
sphere, butyllithium (1.6 M, 20 mL, 32 mmol) was slowly
added to a solution of (4-methoxybenzyl)triphenylphosphonium
bromide (13.8 g, 33 mmol) in THF (70 mL) at ꢀ78 ꢁC. The
resulting reddish solution was allowed to warm at room tem-
perature. Freshly distilled 4-trimethylsilyloxybenzaldehyde
(6.37 g, 33 mmol) was added dropwise and the reaction mix-
ture was stirred for a night, diluted with ice-cold water (200 mL)
and stirred for an additional hour. The aqueous layer was
extracted with ethylacetate; the combined organic layers were
washed with water and dried. After evaporating the solvent, 6.4 g
(86%) of a crude mixture of isomers Z and E was isolated as brown
oil. Pure isomer E, which was crystallized from ethanol (2.4 g,
32%); mp 211e212 ꢁC; 1H NMR (300 MHz, CDCl3):
d
(ppm) 7.38 (d,
mp 214e215 ꢁC; 1H NMR (300 MHz, DMSO-d6):
4H), 7.07 (s, 2H), 6.96 (d, 4H), 3.84 (t, 2H), 3.81 (s, 3H), 3.76 (td, 2H),
2.10 (t, 1H); 13C NMR (75 MHz, DMSO-d6):
(ppm) 170.2 (s, 2C),
d (ppm) 7.53 (dd,
2H), 7.34 (d, 2H), 6.85 (d, 2H), 6.78 (d, 2H), AB system 6.89 (d, 1H,
3J¼16.6 Hz), 6.87 (d, 1H, 3J¼16.6 Hz), 4.74 (s, 1H), 3.80 (s, 3H), OH
d
proton resonance obscured; 13C NMR (75 MHz, CDCl3):
d
(ppm)
130.2 (s, 4C), 127.3 (s, 2C), 125.8 (s, 2C), 114.6 (s, 2C), 114.0 (s, 2C),
59.6 (s, 1C), 20.9 (s, 1C), 13.9 (s, 1C); C17H18NaO3 (MW 270.32).
HRMS (ESI): m/z 293.11617 (MþNaþ), calculated mass: 293.11482
127.60 (s, 2C), 127.40 (s, 2C), 126.10 (s, 2C), 115.50 (s, 2C), 114.10 (s,
2C), 55.3 (s, 1C); IR (cmꢀ1) 3380, 1596, 958, 825; C15H13O2 (MW
226.27). HRMS (ESI): m/z 225.0914 (MꢀHþ), calculated mass
(s¼0.021).
225.0921 (
s
¼0.007).
3.6.2. (E)-4-(2-O-hydroxyethyl)-30,50-dimethoxystilbene (5c). Yield
3.5.2. (E)-4-Hydroxystilbene (4a). Yield 62%, mp 102e104 ꢁC; 1H
47%, mp 187 ꢁC; 1H NMR (300 MHz, CDCl3):
d (ppm) 7.43 (d, 2H), AB
NMR (300 MHz, CDCl3):
d
(ppm) 7.46 (d, 2H), 7.39 (t, 2H), 7.34 (t,
system 7.01 (d,1H, 3J¼15.9 Hz), 6.93 (d,1H, 3J¼15.9 Hz), 6.90 (d, 2H),
1H), 7.30 (d, 2H), AB system 7.02 (d, 1H, 3J¼16.3 Hz), 6.98 (d, 1H,
6.64 (d, 2H), 6.38 (t, 1H), 4.09 (t, 2H), 3.97 (td, 2H), 3.83 (s, 6H), 2.10
3J¼16.3 Hz), 6.81 (d, 2H), 4.99 (s, 1H); 13C NMR (75 MHz, CDCl3):
(t,1H); 13C NMR (75 MHz, CDCl3):
d (ppm) 160.9 (s, 2C),158.4 (s,1C),
d
(ppm) 155.42 (s, 1C), 137.63 (s, 1C), 130.25 (s, 1C), 128.63 (s, 2C),
139.6 (s, 1C), 130.4 (s, 1C), 128.6 (s, 1C), 127.8 (s, 2C), 126.8 (s, 1C),
114.8 (s, 2C), 104.3 (s, 2C), 99.7 (s, 1C), 69.2 (s, 1C), 61.5 (s, 1C), 55.3
(s, 2C); C18H20O4 (MW 300.35). HRMS (ESI): m/z 323.12567
(MþNaþ), calculated mass: 323.12538 (Err¼0.897 ppm).
128.18 (s, 1C), 127.90 (s, 2C), 127.21 (s, 1C), 126.63 (s, 1C), 126.24 (s,
2C), 115.62 (s, 2C); IR (cmꢀ1) 3374, 1596, 1498, 1450, 1240, 966, 830;
C14H12O (MW 196.24). HRMS (ESI): m/z 195.0808 (MꢀHþ), calcu-
lated mass: 195.0815 (
s
¼0.0102).
3.6.3. (E)-4-(2-O-hydroxyethyl)-40-bromostilbene (5d). Yield 37%,
3.5.3. (E)-4-Hydroxy-(30,50)-dimethoxystilbene (4c).32 Yield 38%,
mp 211 ꢁC; 1H NMR (300 MHz, CDCl3):
d (ppm) 7.45 (d, 2H), 7.42 (d,
mp 92e94 ꢁC; 1H NMR (300 MHz, CDCl3):
d
(ppm) 7.35 (d, 2H), 6.79
2H), 7.33 (d, 2H), AB system 7.01 (d, 1H, 3J¼16.2 Hz), 6.93 (d, 1H,
(d, 2H), 6.61 (d, 2H), 6.34 (d, 1H), AB system 6.94 (d, 1H, 3J¼16.5 Hz),
3J¼16.2 Hz), 6.90 (d, 2H), 4.11 (t, 2H), 3.98 (td, 2H), 2.00 (t, 1H); 13
C
6.84 (d, 1H, 3J¼16.5 Hz), 3.77 (s, 6H); 13C NMR (75 MHz, CDCl3):
NMR (75 MHz, CDCl3):
d (ppm) 131.7 (s, 2C), 127.8 (s, 2C), 127.7 (s,
d
(ppm) 160.9 (s, 2C),155.5 (s,1C),139.7 (s,1C),130.1 (s, 2C),128.8 (s,
2C), 114.8 (s, 2C), 69.2 (s, 1C), 61.5 (s, 1C); C16H15BrO2 (MW 319.19).
HRMS (ESI): m/z 341.01486 (MþNaþ), calculated mass: 341.01476
(Err¼0.283 ppm).
1C), 126.5 (s, 2C), 115.8 (s, 2C), 104.5 (s, 2C), 99.7 (s, 1C), 55.4 (s, 2C).
3.5.4. (E)-4-Bromo-40-hydroxystilbene (4d). Yield 51%, mp 181 ꢁC;
1H NMR (300 MHz, CDCl3):
d
(ppm) 7.44 (d, 2H), 7.38 (d, 2H), 7.32
3.7. Typical procedure of preparation of stilbenes 9ae9j and
(d, 2H), AB system 7.00 (d, 1H, 3J¼16.5 Hz), 6.91 (d, 1H, 3J¼16.5 Hz),
4b by Heck reaction28
6.81 (d, 2H), 4.86 (s,1H). 13C NMR (75 MHz, CDCl3);
d (ppm) 155.5 (s,
1C), 136.6 (s, 1C), 131.7 (s, 2C), 130.0 (s, 1C), 128.6 (s, 1C), 128.0 (s,
2C), 127.9 (s, 1C), 127.7 (s, 2C), 125.4 (s, 1C), 115.6 (s, 2C); IR (cmꢀ1
3342, 1592, 1508, 1445, 1230, 1070, 966, 825; C14H10BrO (MW
3.7.1. (E)-4-Hydroxy-3,30,40,50-tetramethoxystilbene (9a). Under an
argon atmosphere, a mixture of 1-bromo-3,4,5-trimethoxybenzene
(1.82 g, 7.4 mmol), Cs2CO3 (2.4 g, 7.36 mmol), allylpalladium (II)
)

M. Chalal et al. / Tetrahedron 68 (2012) 3899e3907
3905
chloride dimer [Pd(
h
-C3H5)Cl]2 (27 mg, 7.5 10ꢀ2 mmol) and 1,10-bis
(MW 226.27). HRMS (ESI): m/z 249.0890 (MþNaþ), calculated
[di(5-methyl-2-furyl)phosphino]ferrocene (170 mg, 3.10ꢀ1 mmol,
this ligand is prepared following literature procedure5 or available
from STREM catalogue 2012) in freshly distilled DMF (15 mL) was
heated at 40 ꢁC for 20 min. After adding 2-methoxy-4-vinylphenol
(1.11 g, 7.5 mmol) the solution was heated at 110 ꢁC for a night. After
cooling, the product was extracted with ethylacetate. GC/MS: 73%;
E/Z: 88/12. After crystallization from ethanol, 58% of isomer E was
mass: 249.0886 (
s
¼0.006).
3.7.7. (E)-2-Hydroxy-40-methoxystilbene (9f) (Table 2, entry 6). GC/
MS: 66%; E/Z: 91/9. Crystallization from ethanol, 58% of isomer E,
mp 153 ꢁC; 1H NMR (300 MHz, CDCl3):
d (ppm) 7.47 (d, 2H), 7.45 (d,
1H), 7.18 (t, 1H), 7.12 (t, 1H), AB system 7.08 (d, 1H, 3J¼16.7 Hz), 6.94
(d, 1H, 3J¼16.7 Hz), 6.88 (d, 2H), 6.79 (d, 1H), 3.83 (s, 3H), OH proton
isolated, mp 192 ꢁC; 1H NMR (300 MHz, CDCl3):
d
(ppm) 7.03 (d,
resonance obscured; 13C NMR (75 MHz, CDCl3):
d (ppm) 159.3 (s,
2H), 6.91 (d, 1H), 6.73 (s, 2H), AB system 6.95 (d, 1H, 3J¼16 Hz), 6.84
1C),152.8 (s,1C),130.4 (s,1C),129.9 (s,1C),128.2 (s,1C),127.7 (s, 2C),
127.1 (s, 1C), 124.9 (s, 1C), 121.5 (s, 1C), 120.9 (s, 1C), 115.8 (s, 1C),
114.1 (s, 2C), 55.33 (s, 1C); IR (cmꢀ1) 3355, 1587, 964, 814, 747;
C15H13O2 (MW 226.27). HRMS (ESI): m/z 225.0911 (MꢀHꢀ), calcu-
(d, 1H, 3J¼16 Hz), 5.69 (s, 1H), 3.95 (s, 3H), 3.91 (s, 6H), 3.86 (s, 3H);
13C NMR (75 MHz, CDCl3):
d
(ppm)¼153.42 (s, 2C), 146.74 (s, 1C),
145.62 (s, 1C), 137.75 (s, 1C), 133.34 (s, 1C), 129.88 (s, 1C), 128.16 (s,
1C), 126.47 (s, 1C), 120.39 (s, 1C), 114.60 (s, 1C), 108.22 (s, 1C), 103.38
(s, 2C), 60.96 (s,1C), 56.13 (s, 2C), 55.92 (s,1C); IR (cmꢀ1) 3390,1596,
1501, 1466, 1238, 1104, 1055, 1026, 965, 817; C18H20O5 (MW 316.35).
HRMS (ESI): m/z 339.12096 (MþNaþ), calculated mass: 339.12029
lated mass: 225.0921 (
s
¼0.011).
3.7.8. (E)-3-Carbinol-4-hydroxy-40-methoxystilbene (9g) (Table 2,
entry 7). GC/MS: 50%; E/Z: 93/7. Crystallization from ethanol, 25%
(s
¼0.030).
of isomer E, mp 156 ꢁC; 1H NMR (300 MHz, CDCl3):
d (ppm) 7.39
(2H, d), 7.33 (dd, 1H), 7.17 (d, 1H), 6.89 (s, 2H), 6.88 (s, 1H), 6.87 (d,
2H), 4.91 (s, 2H), 3.83 (s, 3H), OH proton resonance obscured;
C16H16O3 (MW 256.30). HRMS (ESI): m/z 279.0970 (MþNaþ), cal-
3.7.2. (E)-3,40-Dimethoxystilbene (9b) (Table 2, entry 1). GC/MS:
85%; E/Z: 83/17. Crystallization from ethanol, 76% of isomer E, mp
167 ꢁC; 1H NMR (300 MHz, CDCl3):
d
(ppm) 7.44 (d, 2H), 7.25 (t, 1H),
culated mass: 279.0992 (
s
¼0.0118).
AB system 7.24 (d, 1H, 3J¼15.81), 6.97 (d, 1H, 3J¼15.81), 7.09 (t, 1H),
7.03 (s, 1H), 6.89 (d, 2H), 6.77 (dd, 1H), 3.85 (s, 3H), 3.83 (s, 3H); 13C
3.7.9. (E)-4,40-Dihydroxy-3-methoxystilbene (9h) (Table 3, entry
1). GC/MS: 87%; E/Z: 80/20. Crystallization from ethanol, 65%
NMR (75 MHz, CDCl3):
d (ppm) 159.9 (s, 1C), 159.3 (s, 1C), 139.1 (s,
1C), 129.5 (s, 1C), 128.5 (s,1C), 127.7 (s, 2C), 126.5 (s, 2C), 119.0 (s, 1C),
114.1 (s, 2C), 112.9 (s, 1C), 111.5 (s, 1C), 55.8 (s, 1C), 55.3 (s, 1C); IR
(cmꢀ1) 1587, 1171, 1025, 968, 781, 686; C16H16O2 (MW 240.30).
HRMS (ESI): m/z 263.1033 (MþNaþ), calculated mass: 263.1043
of isomer E, mp 220 ꢁC; 1H NMR (300 MHz, CDCl3):
d (ppm)
7.28 (d, 2H), 7.00 (s, 1H), 6.93 (d, 1H), 6.88 (d, 1H), AB system
6.82 (d, 1H, 3J¼15.2 Hz), 6.84 (d, 1H, 3J¼16 Hz), 6.79 (d, 2H),
5.29 (s, 2H), 3.94 (s, 3H); 13C NMR (75 MHz, CDCl3):
d
(ppm)¼
(s
¼0.014).
153.42 (s, 2C), 146.74 (s, 1C), 145.62 (s, 1C), 137.75 (s, 1C),
133.34 (s, 1C), 129.88 (s, 1C), 128.16 (s, 1C), 126.47 (s, 1C),
120.39 (s, 1C), 114.60 (s, 1C), 108.22 (s, 1C), 103.38 (s, 2C), 60.96
(s, 1C), 56.13 (s, 2C), 55.92 (s, 1C); IR (cmꢀ1) 3399, 2938, 2840,
1594, 1511, 1455, 1238, 1127, 1120, 965, 812, 741; C15H14O3
(MW 242.27). HRMS (ESI): m/z 241.08694 (MꢀHꢀ), calculated
3.7.3. (E)-2,40-Dimethoxystilbene (9c) (Table 2, entry 2). GC/MS:
68%; E/Z: 92/8. Crystallization from ethanol, 50% of isomer E, mp
134 ꢁC; 1H NMR (300 MHz, CDCl3):
d (ppm) 7.56 (dd, 1H), 7.46 (d,
2H), AB system 7.32 (d, 1H, 3J¼16.47), 7.03 (d, 1H, 3J¼16.47), 7.22
(t, 1H), 6.96 (t, 1H), 6.88 (dd, 1H), 6.87 (d, 2H), 3.89 (s, 3H), 3.83
mass: 241.08702 (
s
¼0.018).
(s, 3H); 13C NMR (75 MHz, CDCl3):
d (ppm) 159.1 (s, 1C), 156.7 (s,
1C), 130.9 (s, 1C), 128.7 (s, 1C), 128.2 (s, 1C), 127.7 (s, 2C), 126.8 (s,
2C), 126.1 (s, 1C), 121.4 (s, 2C), 120.7 (s, 1C), 114.0 (s, 2C), 110.9 (s,
1C), 55.5 (s, 1C), 55.3 (s, 1C); IR (cmꢀ1) 2938, 2840, 1595, 1455,
1497, 1103, 1027, 969, 818, 741; C16H16O2 (MW 240.30). HRMS
(ESI): m/z 263.1049 (MþNaþ), calculated mass: 263.1043
3.7.10. (E)-4-Acetoxy-40-hydroxy-30-methoxystilbene (9i) (Table 3,
entry 2). GC/MS: 77%; E/Z: 84/16. Crystallization from ethanol, 54%
of isomer E, mp 164 ꢁC; 1H NMR (300 MHz, CDCl3):
d (ppm) 7.84 (d,
2H), 7.3 (d, 2H), 7.28 (s, 1H), 7.25 (d, 1H), 7.07 (d, 1H), AB system 7.01
(d,1H, 3J¼16.6 Hz), 6. 97 (d,1H, 3J¼16.6 Hz), 5.33 (s,1H), 3.82 (s, 3H),
(
s
¼0.012).
2.29 (s, 3H); 13C NMR (75 MHz, CDCl3):
d (ppm) 169.11 (s, 1C),
150.53 (s, 1C), 149.99 (s, 1C), 147.92 (s, 1C), 134.46 (s, 1C), 130.38 (s,
1C), 129.76 (s, 2C), 127.42 (s, 2C), 122.94 (s, 1C), 121.51 (s, 2C), 116.84
(s, 1C), 109.28 (s, 1C), 21.69 (s, 1C).
3.7.4. (E)-4,40-Dimethoxystilbene (9d) (Table 2, entry 3). GC/MS:
91%; E/Z: 79/21. Crystallization from ethanol, 72% of isomer E, mp
108e110 ꢁC; 1H NMR (300 MHz, CDCl3):
d
(ppm) 7.41 (d, 4H), 6.87
(d, 4H), 6.93 (s, 2H), 3.82 (s, 6H); 13C NMR (75 MHz, CDCl3):
d
(ppm)
3.7.11. (E)-4-Hydroxy-3,40-dimethoxystilbene (9j) (Table 3, entry
3). GC/MS: 95%; E/Z: 93/7. Crystallization from ethanol, 60% of
160.3 (s, 2C), 128.5 (s, 2C), 127.4 (s, 4C), 130.1 (s, 2C), 126.8 (s, 2C),
114.2 (s, 4C), 55.3 (s, 2C); IR (cmꢀ1) 2957, 1601, 1460, 1153, 1027, 957,
829. C16H16O2 (MW 240.30). HRMS (ESI): m/z 263.1029 (MþNaþ),
isomer E, mp 172e173 ꢁC; 1H NMR (300 MHz, CDCl3):
d (ppm) 7.41
(d, 2H), 7.01 (s, 1H), 6.99 (s, 1H), 6.98 (s, 1H), 6.90 (s, 2H), 6.87 (d,
calculated mass: 263.1043 (
s
¼0.0107).
2H), 3.95 (s, 3H), 3.82 (s, 3H), OH proton resonance obscured; 13C
NMR (75 MHz, CDCl3): d (ppm) 159.02 (s, 1C), 146.73 (s, 1C), 145.39
3.7.5. (E)-4-Hydroxy-40-methoxystilbene (4b) (Table 2, entry 4). GC/
MS: 86%; E/Z: 84/16. Crystallization from ethanol, 72% of isomer E
(characterization data see above).
(s, 1C), 130.42 (s, 2C), 127.46 (s, 1C), 126.68 (s, 2C), 126.17 (s, 1C),
120.12 (s, 1C), 114.54 (s, 1C), 114.13 (s, 1C), 108.08 (s, 1C), 55.98 (s,
1C), 55.31 (s, 1C); IR (cmꢀ1) 3042, 1602, 1157, 1120, 963, 821 cmꢀ1
;
C16H15O3 (MW 256.30). HRMS (ESI): m/z 255.10382 (MꢀHꢀ), cal-
3.7.6. (E)-3-Hydroxy-40-methoxystilbene (9e) (Table 2, entry 5). GC/
MS: 70%; E/Z: 89/11. Crystallization from ethanol, 61% of isomer E,
culated mass: 255.10267 (s¼0.012).
mp 151 ꢁC; 1H NMR (300 MHz, CDCl3):
d (ppm) 7.43 (d, 2H), 7.21 (t,
1H), 7.07 (d, 1H), 7.01 (d, 2H), AB system 6.96 (d, 1H, 3J¼16.8 Hz),
6.93 (d, 1H, 3J¼16.8 Hz), 6.88 (s, 1H), 6.69 (d, 1H), 4.71 (s, 1H), 3.82
3.8. X-ray structures
(s, 3H); 13C NMR (75 MHz, CDCl3):
d (ppm) 159.4 (s, 1C), 155.7 (s,
1C), 139.4 (s, 1C), 129.9 (s, 1C), 129.6 (s, 1C), 128.7 (s, 1C), 127.7 (s,
2C), 126.1 (s, 1C), 119.2 (s, 1C), 114.2 (s, 1C), 114.1 (s, 2C), 112.6 (s, 1C),
55.33 (s, 1C); IR (cmꢀ1) 3308, 1592, 969, 814, 778, 684; C15H13O2
The X-ray structures of compounds 5c, 9a and 9j were de-
termined (see details in Supplementary data) and corresponding
ORTEP are gathered in Fig. 4. Characterization data for all new

3906
M. Chalal et al. / Tetrahedron 68 (2012) 3899e3907
Fig. 4. Molecular structure of stilbenes 5c, 9a and 9j.
compounds, as well as details of X-ray structure for 5c, 9a and 9j are
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