Efficient heterogeneously palladium-catalysed synthesis of stilbenes and bibenzyls

Article abstract of DOI:10.2174/157017809787003043

An alternative heterogeneously palladium catalysed procedure for the synthesis of functional stilbenes and bibenzyls is reported. Starting from aryl bromides and using simple commercially available Pd/C catalyst at a low catalytic rate (1 mol%), stilbenes are obtained with 30-100% GC-yields and bibenzyls are produced in a one-pot fashion with 27-100% GC-yields. The procedure showed, however, some limitations when applied to strongly deactivated aryl bromides that could be in some extent overcome by using corresponding iodo derivatives.

Full text of DOI:10.2174/157017809787003043

Letters in Organic Chemistry, 2009, 6, 77-81
77
Efficient Heterogeneously Palladium-Catalysed Synthesis of Stilbenes and
Bibenzyls
Giuseppe Cusati, Anja Wedig and Laurent Djakovitch*
Ircelyon-Institut de recherches sur la catalyse et l'environnement de Lyon, UMR 5256 CNRS-Université de Lyon, 2
Avenue Albert Einstein, F-69626 Villeurbanne, France
Received June 27, 2008: Revised September 18, 2008: Accepted September 19, 2008
Abstract: An alternative heterogeneously palladium catalysed procedure for the synthesis of functional stilbenes and
bibenzyls is reported. Starting from aryl bromides and using simple commercially available Pd/C catalyst at a low cata-
lytic rate (1 mol%), stilbenes are obtained with 30-100% GC-yields and bibenzyls are produced in a one-pot fashion with
27-100% GC-yields. The procedure showed, however, some limitations when applied to strongly deactivated aryl bro-
mides that could be in some extent overcome by using corresponding iodo derivatives.
Keywords: Stilbene synthesis, bibenzyl synthesis, one-pot synthesis, heterogeneous palladium catalyst.
INTRODUCTION
procedure recently applied to the preparation of fragrances
[15].
Stilbenes and bibenzyls are important classes of com-
pounds that found applications in agrochemical and pharma-
ceutical industries. For example stilbenes derivatives like
Resveratrol, Pterostilbene or other Combretastatines A4 and
analogues are recognized to have beneficial health effects
such as cancer-preventive, protection against coronary heart
disease, neuroprotective, anti-aging and anti-inflammatory
[1, 2]. Besides bibenzyls like aminoalkoxy-bibenzyls found
useful applications as inhibitors of platelet aggregation or as
serotonin antagonist [3, 4]. Other applications include liquid
crystals for non-linear optic, polymer materials and lubri-
cants. Additionally, stilbenes and bibenzyls are also known
as substructure of several macrocycles possessing interesting
biological activity like the Marchantins and Riccardins [5-8].
Continuing our effort to develop green syntheses of bio-
active molecules, we decided to investigate the one-pot syn-
thesis of various bibenzyls compounds through the Heck
cross-coupling reaction followed by selective hydrogenation
of the resulting stilbenes.
RESULTS AND DISCUSSION
As catalysts, based on our previous reports, we selected
commercially available Pd/C catalysts (Aldrich 5%wt Pd and
Aldrich 10%wt, Pd-Degussa type E101 NE/W) and a home-
made palladium supported on zeolite
Y catalyst as
[Pd(NH3)4]/NaY (3.7%wt Pd) prepared following a proce-
dure previously described in the literature [16].
All of these bioactive molecules (and substructures) are
naturally available through extraction from plants and fruits.
However, for large availability in target compounds these
methods are not suitable. On the other hand some chemical
total syntheses, mainly based on Wittig and Ullmann proto-
cols, have been reported generally for the most popular one
like the Resveratrol [9-12]. However, these examples remain
limited and methodologies are today not convenient as they
use stoichiometric amount of reagents generating large quan-
tities of wastes (i.e. salts mainly). Therefore, eco-friendly
methods to prepare these structures are still required that can
be achieved using catalytic approaches.
As preliminary study, all catalysts were engaged in a
one-pot synthesis of bibenzyls, coupling styrene with either
bromobenzene or 4-bromobenzonitrile under classical reac-
tion conditions (a. 10 mmol aryl halide, 15 mmol styrene, 15
mmol NaOAc, 1mol% Pd-catalyst,
8
mL N-
methylpyrrolidone (NMP), 140°C, 24 h; b. 1 bar H2)
(Scheme 1). Alternatively, 4-acetoxystyrene was used as the
olefin. The results reported in Table 1 indicate clearly that if
all catalysts are efficient to perform the first step of the syn-
thesis, i.e; the Heck reaction, leading generally to full con-
versions of the aryl bromides, only the Pd/C 5%wt was ef-
fective to perform the hydrogenation of the resulting stil-
benes towards the target bibenzyls with high yields.
We previously reported a catalytic procedure for the one-
pot synthesis of bibenzyl via the intermediate stilbene de-
rivatives [13]. Our strategy was based on the well docu-
mented Heck C-C coupling reaction using commercially
available Pd/C heterogeneous catalyst (Scheme 1) [13, 14]; a
Having these conditions in hands (a. 5 mmol aryl halide,
7 mmol styrene, 7 mmol NaOAc, 1 mol% PdC 5%wt, 4 mL
NMP, 140°C, 24 h; b. 1 bar H2) we extended the procedure
to the synthesis of various stilbenes and bibenzyls starting
from various aryl iodides and bromides (Scheme 2).
*Address correspondence to this author at the Ircelyon-Institut de recher-
ches sur la catalyse et l'environnement de Lyon, UMR 5256 CNRS-
Université de Lyon, 2 Avenue Albert Einstein, F-69626 Villeurbanne,
France; Tel: +33 4 72 44 53 81; Fax: +33 4 72 44 53 99;
The results reported in Table 2 show that generally good
to high yields were achieved under these reactions conditions
for both the stilbenes and the bibenzyls whatever the func-
tional groups present on the starting materials.
E-mail: Laurent.djakovitch@ircelyon.univ-lyon1.fr
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

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Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Cusati et al.
R2
R2
Br
[Pd]
[Pd]
NaOAc, NMP
140°C, 24h
H2 (1 bar), NMP
rt, 24h
R1
R1 = H, CN and R2 = H, OAc
Scheme 1. Pd-catalysed synthesis of bibenzyls following a one-pot procedure.
Table 1. Optimisation of the Reaction Conditions for the Synthesis of Stilbenes and Bibenzyls (Scheme 1)
R2
R1
R1
1 (cis + trans)
2
Entry
Catalyst
R1
R2
GC-yield 1 (%)a
GC-yield 2 (%)a
1
2
H
H
H
OAc
H
100
90c
54
28c
61
46c
100
45c
100
50c
0
Pd/C 10%wtb
3
CN
CN
H
100
100c
100
100c
100
100c
100
86c
4
OAc
H
5
6
H
OAc
H
Pd/C 5%wt
7
CN
CN
H
8
OAc
H
9
10
11
12
H
OAc
H
0
[Pd(NH3)4]/NaY
CN
CN
100
88c
0
OAc
0
aYields were determined by GC with an internal standard (diethylene glycol di-n-butyl ether) (ꢀrel = ± 5%). bThe Pd/C 10%wt - Degussa type E101 NE/W was not effective to per-
form hydrogenation of stilbenes at atmospheric pressure and room temperature as the immobilised palladium is mainly under Pd(II)-oxidation state. However, it was effective under 10
bar hydrogen at 140°C following ref [13]. cPartial de-acetylation was observed under the reaction conditions leading to non-negligible amount of phenol formation (ca. 47-52 %).
R1
R5
R5
R1
R1
R2
R3
X
R2
R3
R2
R3
Pd/C 5%wt
Pd/C 5%wt
R4
NaOAc, NMP
140°C, 24h
R5
H2 (1 bar), NMP
rt, 24h
R4
1 (cis + trans)
R4
2
Scheme 2. Pd-catalysed synthesis of stilbenes and bibenzyls.
Nevertheless, when using the 4-bromophenol as aryl hal-
ide poor conversions were achieved in the Heck coupling
reaction (Table 2, entry 9). This disappointing result could
be overcome by protecting the phenol function as the ben-
zylether derivative. After hydrogenation, the corresponding
4-phenethylphenol was obtained quantitatively (Table 2,
entry 10). Interestingly, we demonstrated that the overall
procedure (i.e. a). benzylation of the phenol using benzyl-
chloride (BnCl), b). Heck coupling, c). hydrogena-
tion/hydrogenolysis) could be performed as a one-pot reac-
tion affording the expected compound in good isolated yield
(86 %) (Scheme 3). Performing thus the synthesis resulted in
higher reaction rate in the coupling step as the Heck reaction
was quantitative after 2 h while it required ca. 24 h when
Br
Br
BnCl
Pd/C 5%wt
Pd/C 5%wt
DMF, K2CO3
HO
BnO
K2CO3, DMF
140°C, 2h
H2 (1 bar), DMF
BnO
rt, 24h
HO
1 (cis + trans)
2
Scheme 3. Efficient one-pot synthesis of 4-phenethylphenol.

Efficient Heterogeneously Palladium-Catalysed Synthesis
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
79
Table 2. Synthesis of Stilbenes and Bibenzyls (Scheme 2)
GC-yield 1 (%)a
GC-yield 2 (%)a
ArX
styrene
Entry
1
100
100 [93]
Br
2
100
100
100
45
100 [84]
50
AcO
3
Br
NC
4
AcO
Br
5
100
100 [92]
Cl
6
100
100
100 [56]b
100c
Br
O2N
7
BnO
Br
8
100
40
100 [86]
H3COC
Br
9
-
HO
Br
10
100
50
100 [86]d
BnO
I
11
-
HO
12
100
100
75
45
I
OH
13
AcO
MeO
Br
14
15
37
34
-
-
OH
MeO
Br
OMe

80
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Cusati et al.
(Table 2). Contd…..
Entry
GC-yield 1 (%)a
GC-yield 2 (%)a
ArX
styrene
MeO
I
16
64
-
OMe
17
18
19
20
89
80
60
35
80
48
H3CO
I
OH
AcO
100
100
O2N
I
OH
AcO
OBn
I
21
30
27d
BnO
aYields were determined by GC with an internal standard (diethylene glycol di-n-butyl ether) (ꢀrel = ± 5%). When available, [isolated yields] are reported. bUnder hydrogenation
conditions, the nitro group is reduced to the corresponding amino derivative. cUnder hydrogenation conditions, both the benzyl group is hydrogenolysed and the nitro group is reduced
giving the 4-(4-aminophenethyl)phenol whose purification failed. dUnder hydrogenation conditions, the benzyl group is hydrogenolysed leading to the direct formation of phenol
derivative.
starting from isolated 4-benzyloxybromobenzene. This was
reasonably attributed to the presence of KCl in the reaction
medium that is known to promote the Heck coupling reac-
tions [17]. Proceeding thus, the 4-phenethylphenol was ob-
tained with 86% isolated yield. Unexpectedly, the use of the
free-OH 4-iodophenol as aryl halide did not improve the
procedure as poor conversion was achieved (Table 2, entry
11) whereas good yield was obtained when using the unpro-
tected 2-iodophenol (Table 2, entry 12).
Current investigations focus on improving the activity of
the heterogeneous catalysts to achieve the one-pot syntheses
of stilbenes and bibenzyls bearing electro-donating groups.
Alternatively we develop new methodology to face the lack
of availability of functional styrenes.
EXPERIMENTAL
All preparations, manipulations and reactions were car-
ried out under argon, including the transfer of the catalysts to
the reaction vessel. All glassware was base- and acid-washed
and oven dried.
While successful this methodology shows, nevertheless,
some limitations when engaging in highly deactivated aryl-
bromides as generally no or poor conversions were observed
(some conversion was observed in few cases; Table 2, en-
tries 14-15). For these cases it was necessary to use costly
and not commercially available iodo-derivatives to achieve
better results (Table 2, entries 16 and 21). But also in these
examples, good results were achieved only when activating
groups were present on the aromatic ring (Table 2, entries
19-20 versus Table 2, entry 21).
The NaY zeolite (LZ-Z-52) was purchased from Sigma-
Aldrich Chemicals and was dried before use at 120°C for
48h under 5.10-2mmHg before palladium loading. The palla-
dium content determination of the catalysts prepared with
this support was performed by AAS spectroscopy from a
solution obtained by treatment of the catalysts with a mixture
of HBF4, HNO3 and HCl in a Teflon reactor at 180°C.
The Pd/C catalyst (5%wt Pd and Aldrich 10%wt Pd on
dry basis {52% water} from Degussa type E101 NE/W) was
purchased from Aldrich Chemicals and used as supplied.
CONCLUSIONS
In conclusion we reported in this communication an al-
ternative route to the synthesis of functional stilbenes and
bibenzyls. Starting from aryl bromides and using simple
commercially available Pd/C catalyst good yields in target
compounds were achieved. However, the procedure showed
some limitations when applied to functional aryl bromides
that could be in some extent overcame by using correspond-
ing iodo derivatives.
All organics and solvents were used as received from the
suppliers (Sigma-Aldrich, Alfa Aesar, Acros Organics) after
deaerating by an argon flow.
NMR spectra were recorded with a Bruker AM 400 spec-
trometer (1H NMR were referenced to the residual protio-
solvent: CDCl3, ꢀ=7.25 ppm; 13C NMR were referenced to
the C-signal of the deutero solvent: CDCl3, ꢀ=77ppm).

Efficient Heterogeneously Palladium-Catalysed Synthesis
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
81
Gas-liquid chromatograms were performed on a HP 6890
series chromatograph equipped with a FID detector and a
HP-1 column (cross-linked methylsiloxane, 30m x 0.25mm x
0.25μm film thickness) using N2 as carrier gas. Alterna-
tively, a Shimadzu GC-MS-QP2010S equipped with a
Sulpelco SLB-5MS column (95% methylpolysiloxane + 5%
phenylpolysiloxane, 30m x 0.25mm x 0.25μm) with He as
carrier gas was used.
Example of NMR Characterisations (Table 2, entry 3)
(E)-4-styrylbenzonitrile
1H NMR (250 MHz, CDCl3): ꢀ ppm: 7.41 (d, 3J = 7.5 Hz,
2H), 7.34 (d, 3J = 7.5 Hz, 2H), 7.27 – 7.09 (m, 5H), 7.01 (d,
3
3J = 16.4 Hz, 1H), 6.87 (d, J = 16.4, 1H). 13C NMR (63
MHz, CDCl3): ꢀ ppm: 141.69, 136.19, 132.35, 132.24,
128.81, 128.59, 126.91, 126.83, 126.57, 119.03, 110.31.
C15H11N : 205,09 g.mol-1. MS: m/z (%) = 205 (100) [M+·].
4-phenethylbenzonitrile
Procedure for the Preparation of the [Pd(NH ) ]/NaY
3 4
1H NMR (250 MHz, CDCl3): ꢀ ppm: 7.51 (d, 3J = 8.3 Hz,
2H), 7.34 (m, 3H), 7.24 (d, 3J = 8.3 Hz, 2H), 7.22 (d, 3J = 7.5
Hz, 2H), 2.98 (m, 4H). 13C NMR (63 MHz, CDCl3): ꢀ ppm:
147.28, 140.67, 132.12, 129.39, 128.49, 126.27, 119.15,
109.76, 37.89, 37.21. C15H13N : 207,10 g.mol-1. MS: m/z (%)
= 207 (20) [M+·]; 91 (100) [M+ - C8H6N.].
Catalyst [16]
The heterogeneous [Pd(NH3)4]/NaY catalyst was pre-
pared as follows:
A 0.1 M ammonia solution of
[Pd(NH3)4]Cl2 -prepared from PdCl2 and a commercial am-
monia solution- was added drop wise (5 mL/g zeolite, corre-
sponding to ca. 5% wt Pd in the final catalyst) to a suspen-
sion of the zeolite NaY in bi-distilled water (100 mL/g zeo-
lite). The mixture was stirred for 24 h at rt and the ex-
changed zeolite was filtered off and washed until no trace of
chloride was detected in the filtrate (AgNO3 test). Then the
zeolite was allowed to dry at room temperature to give the
entrapped [Pd(NH3)4]/NaY catalyst as slightly yellow mate-
rial. ICP-AES analysis: 3.7 % wt Pd.
ACKNOWLEDGEMENTS
GC thanks the "Ministère de l’Education Nationale, de
l'Enseignement Supérieur et de la Recherche for funding.
AW thanks ERASMUS for a grant. We gratefully acknowl-
edge the "Programme interdisciplinaire : Chimie Pour le
Développement Durable - Réseau de Recherche 2: Aller vers
une Chimie Eco-compatible" for funding.
General Procedure for Catalytic Tests
5 mmol of aryl halide, 7 mmol of olefin, 7 mmol of
NaOAc and 1 mol % of Pd-catalyst were introduced in a
pressure tube under argon. 4 mL of solvent NMP previously
deaerated were added and the mixture was deaerated by an
argon flow for 5 min. The reactor was then placed in a pre-
heated oil bath at 140 °C for 24 h under vigorous stirring and
then cooled to room temperature before the reaction mixture
was analyzed by GC. At completion of the reaction, the mix-
ture was filtered on celite, diluted with 50 mL of water and
the resulting mixture was extracted with 3 x 20 mL CH2Cl2.
The combined organic layers were washed with 15 mL of
brine, dried over MgSO4 and evaporated. The residue was
then purified by flash chromatography on silica gel.
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1
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