Direct palladium/copper oxidative cross-coupling of α-methylstyrene with acrylates

Article abstract of DOI:10.1007/s11426-010-4096-7

Fully palladium/copper catalytic oxidative cross-coupling of acrylates with α-methylstyrene was performed in a DMSO/AcOH (1:1) mixture at 60 °C in the air. This improves previous procedures which employed stoichiometric amounts of copper and oxygen. Thus

Full text of DOI:10.1007/s11426-010-4096-7

SCIENCE CHINA
Chemistry
September 2010 Vol.53 No.9: 1927–1931
doi: 10.1007/s11426-010-4096-7
• ARTICLES •
Direct palladium/copper oxidative cross-coupling of
-methylstyrene with acrylates
AL-MAKSOUD Walid, DJAKOVITCH Laurent*, JAHJAH Mohamad & PINEL Catherine
Université de Lyon, CNRS, UMR 5256, IRCELYON, Institut de recherches sur la catalyse et l’environnement de Lyon,
2 avenue Albert Einstein, F-69626 Villeurbanne, France
Received April 28, 2010; accepted June 14, 2010
Fully palladium/copper catalytic oxidative cross-coupling of acrylates with -methylstyrene was performed in a DMSO/AcOH
(1:1) mixture at 60 °C in the air. This improves previous procedures which employed stoichiometric amounts of copper and
oxygen. Thus various acrylates were effectively coupled to -methylstyrene giving the expected compounds in moderate to
good yields (44%–65%) as a mixture of E and Z isomers.
direct cross-coupling, oxidative couplings, palladium, copper, catalytic procedures, olefin cross-coupling
cross-coupling, elimination of product) before substrate
decomposition [8, 9].
1 Introduction
There were few studies due to the difficulties in solving
such issue. Ishii et al. reported an elegant Pd(II)-catalysed
oxidative cross-coupling of acrylates with vinyl carboxy-
lates in presence of vanadomolybdophosphonic acids (2 mol%)
under oxygen in 2004. Thus, working in acetic acid at 90 °C
with 10 mol% Pd(OAc)2 associated to H4PMo11VO40 (2 mol%)
under oxygen, good to high conversion (65%–90%) leading
to useful yields (45%–76%) for the coupling reaction of
various acrylates (i.e. methyl, ethyl, butyl, iso-butyl) with
vinyl acetate were achieved [10]. Lately, Loh et al. reported
the direct cross-coupling between -methylstyrene and tert-
butylacrylate using 20 mol% Pd(OAc)2 in the presence of 2
equiv Cu(OAc)2 under oxygen (1 atm) in DMSO/AcOH
(1:1) at 60 °C. Thus target compounds were obtained in
moderate to good yields (33%–87%) [11].
In our ongoing research, we developed several catalytic
systems applied to the direct cross-coupling of indoles with
olefins under oxidative conditions [3, 5]. Generally, using a
catalytic system based both on palladium and copper in a
DMF/H2O/AcOH mixture, high conversions and good iso-
lated yields were achieved for the coupling of the indole
nucleus with the n-butylacrylate. Therefore, we planned to
The cross-coupling reactions have become one of the most
powerful methods for the construction of carbon-carbon
bonds in organic syntheses including naturally occurring
compounds and pharmaceuticals [1] for two decades. How-
ever, one of the main limitations is related to the use of ac-
tivated reagents, generally as halogenated or metallic de-
rivatives that are linked to the co-production of undesirable
wastes.
In order to solve such limitation, several research groups
have investigated both direct and oxidative cross-coupling
reactions. In these reactions, one takes advantages of the
natural reactivity of CH bonds affording good alternative
to the use of halide or metallic compounds. However, these
procedures based on CH activation are generally limited to
heterocycles [2–7].
For alkene substrates, the main difficulty in such CH
activation based protocols concerns generally the rate at
which the catalytic system performs of each elementary
steps of the cross-coupling reaction (i.e. CH activation,
*Corresponding author (email: Laurent.Djakovitch@ircelyon.univ-lyon1.fr)
© Science China Press and Springer-Verlag Berlin Heidelberg 2010
chem.scichina.com
www.springerlink.com

1928
AL-MAKSOUD Walid, et al. Sci China Chem September (2010) Vol.53 No.9
adapt these systems to the oxidative direct coupling of
olefins.
6.8 Hz, 2H), 1.45 (sx, J=7.8 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H).
Data agree with those reported for this compound; CAS
[943613-81-8].
2 Experimental
(2E)-tert-Butyl 5-phenylhexa-2,4-dienoate (3b)
This compound was prepared by the procedure described
2.1 General experimental
above and was obtained as a mixture (EE:ZE = 90:10) as a
1
colourless oil. Yield = 49%. H NMR (250 MHz, CDCl3) 
The qualitative and quantitative analysis of the reactants and
the products were made by gas chromatography (GC). Con-
versions and yields were determined by GC based on the
relative area of GC signals referred to an internal standard
(biphenyl) calibrated to the corresponding pure compound.
Liquid NMR spectra were recorded on a Bruker AC-250
spectrometer. All chemical shifts were measured relative to
7.6–7.75 (dd, J = 11.7, 15.0 Hz, 1H), 7.45 (d, J = 7.2 Hz,
2H), 7.29–7.35 (m, 3H), 6.51 (d, J = 11.6 Hz, 1H), 5.90 (d,
J = 15.4 Hz, 2H), 2.28 (s, 3H), 1.50 (s, 9H). Data agree with
those reported for this compound; CAS [1110610-05-3].
(2E)-tert-Butyl 5-phenylhexa-2,4-dienoate (3c)
1
This compound was prepared by the procedure described
residual H resonances in the deuterated solvents: CDCl3, d
7.25 ppm for 1H.
above and was obtained as a mixture (EE:ZE = 87:13) as a
1
colourless oil. Yield = 38%. H NMR (250 MHz, CDCl3) 
Flash chromatography was performed at a pressure slightly
greater than atmospheric pressure using silica (Merck Silica
Gel 60, 230–400 mesh). Thin layer chromatography was
performed on Fluka Silica Gel 60 F254. The compounds are
generally obtained as a mixture of two isomers [trans/trans:
cis/trans], noticed hereafter [EE:ZE].
7.6–7.75 (dd, J = 11.7, 15.0 Hz, 1H), 7.45 (d, J = 7.2 Hz,
2H), 7.29–7.35 (m, 3H), 6.51 (d, J = 11.6 Hz, 1H), 5.90 (d,
J = 15.4 Hz, 2H), 3.76 (s, 3H), 2.28 (s, 3H). Data agree with
those reported for this compound; CAS [131070-56-9].
GC analyses were performed on a HP 4890 chromatograph
equipped with a FID detector, a HP 6890 autosampler and
a HP-5 column (cross-linked 5% phenyl-methylsiloxane,
30 m × 0.25 mm i.d. × 0.25 m film thickness). Nitrogen is
used as carrier gas. The mass spectra were obtained by a
Shimadzu GC-MS-QP2010S equipped with a Sulpelco
SLB-5MS column (95% methylpolysiloxane + 5% phenyl-
polysiloxane, 30 m × 0.25 mm ×0.25 m) with He as carrier
gas was used. The experimental error was estimated to be
± 5%.
3 Results and discussion
The influence of the nature of palladium source, solvent and
atmosphere were studied for the cross-coupling of -
methylstyrene with acrylate esters.
Table 1 summarized the representative results for the re-
action of the -methylstyrene 1 (2 equiv) with n-butyl acry-
late 2a (1 equiv) in the presence of different Pd-salts/
complexes and Cu(OAc)2 under various solvent and reac-
tion conditions. The desired product, i.e. the n-butyl
5-phenylhexa-2,4-dienoate, was formed in 59% isolated
yield in the mixed solvent system DMSO/HOAc (v/v 1/1)
when using 20 mol% Pd(OAc)2 at 60 °C (Table 1, entry 4).
By contrast, when applying the reaction conditions de-
scribed by Loh et al. [11], i.e. under O2 atmosphere, 3a was
obtained in slightly lower 48% yield (Table 1, entry 7).
When the Pd(OAc)2 loading was decreased to 10 mol%, the
yield in 3a decreased to 38% (Table 1, entry 5), and 15%
with 5 mol% of Pd(OAc)2 (Table 1 entry 6). Moving from
DMSO to apolar iso-octane resulted in moderate yield
(50%); however after longer reaction time (i.e. 48 h) (Table
1, entry 2). Poor yields were observed in pure H2O (Table 1,
entries 1 and 10) or H2O/HOAc (1:1) mixture (Table 1, en-
tries 3, 9 and 11) whatever the palladium precursor used.
This can be attributed to low solubility of styrene deriva-
tives in aqueous medium.
2.2 General procedure for the catalytic tests
A 5 mL dry round bottom flask was charged sequentially
with a stirring bar, Pd(OAc)2 (mol%), Cu(OAc)2 (mol%),
mixed solvents DMSO/HOAc (v/v 1/1) (1 mL). The -
methylstyrene (2 equiv, 1 mmol) and acrylate (1 equiv, 0.5
mmol) were added into the solution in sequence. The reac-
tion mixture was stirred at 60 °C under atmospheric pres-
sure for 24 h. After cooling down, the mixture was diluted
with ethyl acetate, filtered and washed with distilled water
and brine. The organic layer was dried with anhydrous
MgSO4, filtered and concentrated to give the crude product
which was directly applied to a flash column chromatogra-
phy (EtOAc/Hexanes mixtures).
(2E)-Butyl 5-phenylhexa-2,4-dienoate (3a)
This compound was prepared by the procedure described
The nature of palladium source also played a significant
role on the yield of 3a. Under identical conditions, the
Herrmann palladacycle did not exhibited activities (Table 1,
entry 11), while 9% and 28% yields were achieved with [12]
and PdCl2, respectively (Table1, entries 8 and 9).
above and was obtained as a mixture (EE:ZE = 80:20) as a
1
colourless oil. Yield = 78%. H NMR (250 MHz, CDCl3) 
7.7–7.8 (dd, J = 12.1, 14.7 Hz, 1H), 7.40 (d, J=7.3 Hz, 2H),
7.15–7.30 (m, 3H), 6.45 (d, J = 11.9 Hz, 1H), 5.85 (J=15.1
Hz, 2H), 4.10 (t, J = 7.5 Hz, 2H), 2.20 (s, 3H), 1.65 (qn, J=
Next, we optimised the reaction conditions working with

AL-MAKSOUD Walid, et al. Sci China Chem September (2010) Vol.53 No.9
1929
Table 1 Direct cross-coupling reaction of -methyl styrene with n-butyl
acrylate
Table 2 Pd(OAc)2 catalyzed direct cross-coupling reaction of -methyl
styrene with n-butyl acrylate
Entry
Pd(OAc)2 (mol%)
Yield a)
77
Entry
1
Pd(II) (mol%)
Pd(OAc)2/20
Pd(OAc)2/20
Pd(OAc)2/20
Pd(OAc)2/20
Pd(OAc)2/10
Pd(OAc)2/5
Pd(OAc)2/20
Pd(NH3)4Cl2/10
PdCl2/10
Solvent
H2O
Yield a)
11
1
5
5
5
2
2
5
2
2
2
2 b)
3 c)
4
5 d)
6 e)
7 e)
8 e, g, f)
9 f)
13
2
isooctane/HOAc
H2O/HOAc
50 c)
52
3
26
62
4
DMSO/HOAc
DMSO/HOAc
DMSO/HOAc
DMSO/HOAc
DMSO/HOAc
DMSO/HOAc
H2O
59
57
5
38
79
6
15
72
7 b)
48
62
8
9
22
Reaction conditions unless otherwise specified: 1 (2 equiv), 2a (1 equiv,
0.5 M) and oxidant (1 equiv Cu(OAc)2) at 60 °C in the mixture solvent
DMSO/HOAc (1:1), 4 days. a) Isolated yields as a mixture of isomers
(ratio [trans/trans:cis/trans] = 80:20). b, c) The reaction was performed at
25 °C (b) and 80 °C (c). d) Cu(OAc)2 (1 equiv.) + O2. e) 1 equiv of 1 and 1
equiv of 2a. f) 1 equiv of 1 and 2 equiv of 2a. g) The concentration of 2a is
0.25 M.
9
28
10
11
PdCl2/10
16
palladacycle/10
DMSO/HOAc
–
Reaction conditions unless otherwise specified: 1 (2 equiv), 2a (1 equiv,
0.5 M) and oxidant: Cu(OAc)2 (1 equiv) at 60 °C in the mixture solvent
(1:1), 24 h. a) Isolated yields as a mixture of isomers (ratio [trans/trans:
cis/trans] = 80:20). b) Cu(OAc)2 (1 equiv.) + O2. c) Reaction time: 48 h.
Table 3 Direct cross-coupling reaction of -methyl styrene with various
acrylates catalyzed by Pd(OAc)2
lower Pd(OAc)2 loading. With a longer reaction time (4
days), the coupling reactions afforded the desired product in
good yield (77%) using only 5 mol% Pd(OAc)2 (Table 2,
entry 1). Under these conditions, working even at low load-
ing as 2 mol% resulted to useful yields (62%, Table 2, entry
4). Furthermore, no influence of the atmosphere (i.e. air or
pure O2) was observed (Table 2, entry 5).
With these new conditions (i.e. 5 mol% Pd(OAc)2) we
were able to decrease the substrates ratio to an equimolar
mixture of 1:2a that afforded high product yield (i.e. 79%)
(Table 2, entry 6). This could be further optimised by using
only 2 mol% Pd(OAc)2 (Table 2, entry 8).
Entry
2
b
c
c
c
Pd(OAc)2 (mol%)
Pd(OAc)2/2
Oxidant
Cu(OAc)2
Yield a
1
2
3
4
42 (90:10)
38 (87:13)
21 (87:13)
36 (87:13)
Pd(OAc)2/5
Cu(OAc)2
Pd(OAc)2/2
Cu(OAc)2
Pd(OAc)2/5
Cu(OAc)2 + O2
At room temperature, the reaction proceeded very slowly
as only 13% yield was obtained even after prolonged stirring
(Table 2, entry 2). However, higher reaction temperature
(i.e. 80 °C) resulted in decreased 52% yield due to the for-
mation of numerous side products because of the oxidation
of -methylstyrene and acrylate decomposition (Table 2,
entry 3).
With the optimized conditions (Pd(OAc)2 (2–5 mol%),
Cu(OAc)2 (1 equiv), DMSO/HOAc (1:1), 60 °C), we evalu-
ated various olefins as coupling partners. However, besides
acrylates (Table 3), all other evaluated olefins (i.e. 1-octen,
cycloocten, 2-vinylpyridine, cyclohexen, 3-methylcyclohexen)
failed to couple.
Optimized reaction conditions: 1 (1 equiv), 2 (1 equiv, 0.5 M) and oxi-
dant Cu(OAc)2 (1 equiv) at 60 °C for 96 h in the mixture solvent: DMSO/
HOAc (1:1). a) Isolated yields as a mixture of isomers (ratio [trans/trans:
cis/trans] is given in brackets).
conditions, the methyl acrylate 2c gave only the desired
product in 21% yield (Table 3, entry 3). Again, no influence
of O2 pressure on chemical yields was observed (Table 3,
entry 2 versus 4).
Having demonstrated the applicability of the protocol for
the catalyzed direct cross-coupling of -methylstyrene with
acrylates, we explored the possibility to perform it in a fully
catalytic procedure (i.e. both for palladium and copper) us-
ing copper salts as co-catalyst to re-oxidise the palladium
species under air. Table 4 summarized the representative
results for this study using -methylstyrene 1 (1 equiv) and
The reaction between -methylstyrene 1 and tert-butyl
acrylate 2b afforded the corresponding product in 42% yield
using 2 mol% Pd(OAc)2 (Table 3, entry 1). Under the same

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AL-MAKSOUD Walid, et al. Sci China Chem September (2010) Vol.53 No.9
Table 4 Direct cross-coupling reaction of -methyl styrene with various
acrylates catalysed by Pd(OAc)2
under oxygen atmosphere or continuous air bubbling (Table
4, entry 3). Surprisingly, while the copper chloride used as
oxidant is somewhat ineffective (Table 4, entries 5 and 7), it
was found valuable when used in catalytic amount and
working under air. To date, the best explanation accounting
for these observations is related to a possible poisoning of
palladium species (i.e. mainly palladium colloids and ag-
gregates) by metallic copper surrounding when copper
chloride is used in high concentration. Such palladium par-
ticles poisoning by copper was previously observed when
engaging supported metallic palladium in presence of cop-
per salts (CuCl2, CuI) [13]. Thus optimisation of the condi-
tions led to a new fully catalytic protocol working with
Pd(OAc)2 (10 mol%) and CuCl2 (2 mol%) at 60 °C. These
conditions led to useful product yields, up to 65% depend-
ing on the acrylate. Interestingly, these conditions did not
modify the selectivity of the cross-coupling reaction (i.e.
E/Z, noticed trans/trans:cis/trans) that depend essentially on
the nature of the acrylate according to previous reports [10,
11].
Entry
1
2
a
a
a
a
a
a
a
a
a
b
b
c
Pd(OAc)2 (mol%)
CuX2/mol%
Cu(OAc)2/1 equiv
Cu(OAc)2/5 mol%
Cu(OAc)2/5 mol%
Cu(OAc)2/40 mol%
CuCl2/1 equiv
Yield a)
48 (80:20)
–
20
5
2
3 b)
5
–
4
5
8 (nd)
5
6 c)
2
5 (nd)
2
CuCl2/2 mol%
15 (80:20)
25 (80:20)
58 (80:20)
65 (80:20)
20 (90:10)
46 (90:10)
28 (87:13)
44 (87:13)
7
10
10
10
10
10
10
10
CuCl2/1 equiv
8
CuCl2/10 mol%
CuCl2/2 mol%
9
10
11
12
13
CuCl2/10 mol%
CuCl2/2 mol%
4 Conclusions
CuCl2/10 mol%
CuCl2/2 mol%
c
In this paper we described an improved protocol for the
oxidative direct cross-coupling of -methylstyrene with
acrylates. We demonstrated that the use of Pd(OAc)2 (10
mol%) associated to CuCl2 (2 mol%) allowed to convert
almost fully the starting material used in a ratio (1:1) toward
the expected compounds within 48 h. working in a DMSO/
AcOH (1:1) mixture at 60 °C , with yields ranging from 44
to 65%. Though Loh’s procedure previously reported was
already an efficient one, it is shown that a fully catalytic
system in both copper and palladium could be used, and that
air can be simply used. Current investigations are in pro-
gress to extend the method to other olefins and environ-
mentally friendly solvents.
Reaction conditions: 1 (1 equiv), 2 (1 equiv, 0.5 M) and Pd(OAc)2 at
60 °C for 48 h in the mixture solvent: DMSO/HOAc (1:1). a) Isolated
yields as a mixture of isomers (ratio [trans/trans:cis/trans] is given in
brackets). b) With air bubbling. c) Time = 96 h.
The authors gratefully acknowledge the National Agency of Research
(CATAQ N° ANR-07-CP2D-0167-01/02) for funding. MJ and WAL thank
ANR for a grant.
1
2
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3
4
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