An efficient palladium-catalyzed Heck coupling of aryl chlorides with alkenes

Article abstract of DOI:10.1016/j.tetlet.2006.02.040

Catalyst system PdCl₂(PCy₃)₂/Cs ₂CO₃ in dioxane was found to be the efficient catalyst system for Heck cross-coupling reactions of deactivated, neutral, and activated aryl chlorides with a variety of alkenes under mild conditions to afford selectively E-arylated alkenes in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2006.02.040

Tetrahedron Letters 47 (2006) 2573–2576
An efficient palladium-catalyzed Heck coupling
of aryl chlorides with alkenes
Chenyi Yi and Ruimao Hua*
Department of Chemistry, Tsinghua University, Innovative Catalysis Program, Key Laboratory of Organic Optoelectronics
and Molecular Engineering of Ministry of Education, Beijing 100084, China
Received 16 December 2005; revised 7 February 2006; accepted 8 February 2006
Available online 24 February 2006
Abstract—Catalyst system PdCl2(PCy3)2/Cs2CO3 in dioxane was found to be the efficient catalyst system for Heck cross-coupling
reactions of deactivated, neutral, and activated aryl chlorides with a variety of alkenes under mild conditions to afford selectively
E-arylated alkenes in good to excellent yields.
Ó 2006 Elsevier Ltd. All rights reserved.
Palladium-catalyzed Heck reactions of aryl halides with
alkenes have become one of the most powerful tools in
organic synthesis for the construction of carbon–carbon
bond. Generally, aryl bromides, iodides, and activated
alkenes are typically employed as the cross-coupling
reactants, and a variety of the efficient palladium cata-
lyst systems have been developed.1 Aryl chlorides are
cheaper and more easily available than bromides and
iodides, but less reactive. Recent years attempts to estab-
lish the efficient catalyst systems for the Heck reactions
of aryl chlorides have been made extensively, but among
the reported catalytic procedures, in order to achieve the
satisfactory yields of the cross-coupling reactions, either
the activated aryl chlorides, or the activated alkenes
were employed.2 The catalyst systems which show the
high catalytic activity in Heck reactions of deactivated
aryl chlorides are still few.3 The aim of our research
work is to develop the efficient catalyst system for the
cross-coupling of deactivated, neutral and activated aryl
chlorides with both activated and deactivated alkenes.
coupling reaction to give a small amount of stilbene 3a
(entries 1–3). Complex PdCl2(PEt3)2, which contains
the electron-rich phosphine ligands of PEt3, displayed
the mild catalytic activity to afford the coupled products
in 55% GC yield (entry 4). In this case, the analysis of
the reaction mixture by GC–MS disclosed that the
cross-coupling reaction produced three coupled prod-
ucts, and the selectivity of the major product 3a was
85%. Further investigation found that PdCl2(PPCy3),
which bears the electron-rich and bulky phosphine
ligands of PCy3, catalyzed the cross-coupling reaction
with high activity and selectivity to furnish the cross-
coupled products in 80% GC yield with 90% selectivity
of 3a (entry 5). Dioxane could promote the reaction
greatly when it was used as the solvent. In this case,
cross-coupled products were formed in quantitative
yield, and the selectivity of 3a was in 93% (entry 6).
As revealed in Table 1, under the solvent-free condition,
the cross-coupling of 1a with 2a also proceeded
smoothly, but the selectivity of 3a was decreased (entry
7 vs entries 5 and 6). In addition, the use of DMF to
replace dioxane as solvent resulted in decreasing the
catalytic activity of PdCl2(PCy3)2 (entry 8), and in
CHCl2CHCl2, the formation of 3a could not be deter-
mined at all (entry 9). Among the base chosen, Cs2CO3
is the best one. PdCl2(PCy3)2 showed very low or no cata-
lytic activity when K2CO3, Na3PO4, piperidine, or
Et3N were used as bases, or in the absence of base (en-
tries 10–14). Therefore, we carried out the reactions of
1a with a variety of alkenes, and a number of aryl chlo-
rides with ethyl acrylate in the presence of PdCl2(PCy3)2
in dioxane with the use of Cs2CO3 as base to examine
the scope of the present catalyst system for the Heck
We chose the reaction of chlorobenzene 1a with styrene
2a as the model reaction to screen the catalyst and opti-
mize the reaction conditions (Table 1). Initial studies re-
vealed that in the presence of Cs2CO3 and in toluene at
120 °C (sealed tube, oil bath temperature) for 12 h, com-
plexes PdCl2(PPh3)2 and NiCl2(dppp) showed no cata-
lytic activity at all, and Pd(PPh3)4 catalyzed the cross-
Keywords: Alkene; Aryl chloride; Catalysis; Heck coupling; Palladium.
*
Corresponding author. Tel./fax: +86 10 62792596; e-mail: ruimao@
mail.tsinghua.edu.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.040

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C. Yi, R. Hua / Tetrahedron Letters 47 (2006) 2573–2576
Table 1. Palladium-catalyzed Heck coupling of chlorobenzene with styrenea
cat. 3.0 mol%
120 oC for 12 h
Cl
+
1a
2a
Solvent
3a
Entry
Catalyst
Base
Yieldb (%)
Selectivityc (%)
1
2d
3
4
5
6
7
8
9
10
11
12
13
14
PdCl2(PPh3)2
NiCl2(dppp)
Pd(PPh3)4
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
—
Cs2CO3
NR
NR
<5
55
80
>99(90)
90
60
NR
30
10
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na3PO4
Piperidine
Et3N
PdCl2(PEt3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
85
90
93
81
95
DMF
CHCl2CHCl2
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
92
<5
NR
NR
—
a Reactions were carried out at 120 °C for 12 h using 0.66 mmol of 1a, 0.6 mmol of 2a, 0.66 mmol of base and 0.018 mmol of catalyst in 0.8 mL of
solvent.
b GC yields are based on the amount of 2a used. Number in parentheses is isolated yield.
c By GC.
d DPPP = 1,3-bis(diphenylphosphino)propane.
reaction of aryl chlorides with alkenes as summarized in
Tables 2 and 3.
Table 2. Palladium-catalyzed Heck coupling of chlorobenzene with
alkenesa
PdCl2(PCy3)2
The results of the cross-coupling of chlorobenzene with
deactivated (electron-rich) and activated (electron-defi-
cient) alkenes are shown in Table 2, and the catalytic
reactions appeared quite general with respect to the nat-
ure of the alkenes. For example, the cross-coupling of
chlorobenzene with 2-methylstyrene 2b, 4-methylstyrene
2c, 2-vinylnaphthalene 2d, and 1,1-diphenylethylene 2e
afforded the desired product in good to high yields with
high selectivity of 3b–e (entries 1–4). The formation of
3e in moderate yield might be due to the existence of
two bulky phenyl groups in 3e. It was worthy to note
that the normally inactive 1-octene 2f and 2-methyl-3-
butyn-2-ol 2g could also proceed the cross-coupling
reaction smoothly under the same reaction conditions
to afford the cross-coupled products in quantitative
yields (entries 5–6). In the case of 2f used, the selectivity
of 3f was in only 60% arising from the cross-coupling
reactions occurring not only at the alkenic C–H bond,
but also at C–H bond of a-CH2 of alkene.4 The success-
ful cross-coupling of 2g with chlorobenzene indicated
that hydroxyl group was tolerated under the reaction
conditions. As expected, the activated alkene ethyl acryl-
ate 2h reacted with 2a produced quantitatively the
desired cross-coupling product 3h as an exclusive
coupled product (entry 7).
(3.0 mol%)
R
Cl
+
R
dioxane
120 oC for 12 h
1a
Entry
2
3
Alkene
Yieldb
(%)
Selectivityc
(%)
1
2
3
2b
2c
2d
90(81)
94(89)
95(90)
3b
3c
3d
93
95
95
Me
Me
Ph
Ph
4
5
2e
2f
65(59)
3e
3f
95
60
>99(83)
n-C6H13
6
2g
>99(96)
3g
100
HO
O
7
2h
>99(93)
3h
100
In order to assess the scope of PdCl2(PCy3)2-catalyzed
Heck reaction, the cross-coupling of a variety of aryl
chlorides, deactivated as well as activated aryl chlorides
with 2h was investigated. As seen from Table 3, both
electron-rich and electron-deficient aryl chlorides were
compatible with the coupling reaction to afford arylated
alkenes 3i–m in high yields with high selectivity.
O
a Reactions were carried out at 120 °C for 12 h using 0.66 mmol of 1a,
0.6 mmol of 2, 0.66 mmol of Cs2CO3 and 0.018 mmol of catalyst in
0.8 mL of solvent.
b GC yields are based on the amount of 2 used. Numbers in paren-
theses are isolated yields.
c By GC.

C. Yi, R. Hua / Tetrahedron Letters 47 (2006) 2573–2576
Table 3. Palladium-catalyzed Heck coupling of aryl chlorides with ethyl acrylatea
2575
PdCl2(PCy3)2
(3.0 mol%)
R
O
COOEt
+
Cl
dioxane
120 oC for 12 h
O
2h
3
1
Entry
1
Aryl chlorides
Yieldb (%)
Selectivityc (%)
1b
1c
>99(94)
98(93)
3i
3j
97
97
Me
Cl
MeOOC
Cl
2
3
4
1d
1e
96(89)
92(85)
3k
97
98
PhCO
Cl
Cl
3l
F
F
F
F
Cl
F
5
1f
94(87)
3m
97
a Reactions were carried out at 120 °C for 12 h using 0.66 mmol of 1, 0.6 mmol of 2h, 0.66 mmol of Cs2CO3 and 0.018 mmol of catalyst in 0.8 mL of
solvent.
b GC yields are based on the amount of 2h used. Numbers in parentheses are isolated yields.
c By GC.
The mechanism of Heck reaction has been well docu-
mented.5 The high catalytic activity of the present cata-
lyst system for aryl chlorides was considered to be the
use of the electron-rich and bulky phosphine ligand of
PCy3,5b combined with the choice of Cs2CO3 as the
base, as well as dioxane as the solvent.
89%). The results of GC analysis of the reaction mixture
revealed that the cross-coupling reaction gave three
products in a ratio of 2:1:97 (3k) in 96% GC yield. Ethyl
(E)-4-benzoyl-cinnamate 3k: 1H NMR (300 MHz,
CDCl3): d 7.95–7.43 (m, 10H), 6.54 (d, 1H, J =
16.1 Hz), 4.27 (q, 2H, J = 7.2 Hz), 1.35 (t, 3H, J =
7.2 Hz); 13C NMR (75.4 MHz, CDCl3): d 195.9, 166.6,
143.2, 138.3, 138.2, 138.0, 132.7, 130.6, 130.0, 128.4,
127.9, 120.7, 60.8, 14.3; GCMS m/z (% rel. inten.)
280(M+, 42), 252(9), 235(18), 203(56), 175(25), 129(11),
105(100), 91(12), 77(76). HRMS calcd for C18H16O3
280.1099, found 280.1097.
In summary, we developed a practical and efficient
PdCl2(PCy3)2-catalyzed cross-coupling of aryl chlorides
with alkenes at 120 °C in dioxane using Cs2CO3 as base.
The advantages of this catalyst system include its gener-
ality and high catalytic activity for not only electron-
deficient (activated), but also electron-neutral and elec-
tron-rich (deactivated) aryl chlorides under mild and
convenient conditions.
Other products are known compounds and were charac-
1
terized by H, 13C NMR, 19F NMR (for 3m) and mass
spectra.
A typical experimental procedure for cross-coupling of
4-chlorobenzophenone 1d with ethyl acrylate (Table 3,
entry 3): A mixture of 1d (143 mg, 0.66 mmol), ethyl
acrylate (60 mg, 0.60 mmol), Cs2CO3 (215 mg, 0.66
mmol) and PdCl2(PCy3)2 (14.5 mg, 0.018 mmol) in diox-
ane (0.8 mL) under nitrogen in a sealed tube was heated
with stirring at 120 °C (oil bath temperature) for 12 h.
After cooling, the reaction mixture was diluted with
CH2Cl2 to 2.0 mL and octadecane (51.0 mg, 0.2 mmol)
was added as internal standard for GC analysis. After
GC and GC–MS analyses, removing the solvents and
volatiles under vacuum, the residue was subjected to
preparative TLC isolation (silica, eluted with cyclohex-
ane) to give 3k as colorless oil (150 mg, 0.54 mmol,
Acknowledgements
This project (20573061) was supported by National Natu-
ral Science Foundation of China.
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