Highly effective recyclable palladium-catalyzed ligand-free heck reactions under aerobic conditions

Article abstract of DOI:10.1055/s-0031-1290099

An effective protocol was developed for the Heck coupling reactions between various aryl halides and olefins. In the presence of 2 mol% of Pd(OAc) ₂, the desired products could be obtained in good yields under ligand-free and aerobic conditions. The catalytic system could be easily recycled for five times with high efficiency. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1290099

1
50
LETTER
Highly Effective Recyclable Palladium-Catalyzed Ligand-Free Heck
Reactions under Aerobic Conditions
R
P
ecyclable Pa
e
a
n
k
g
Reactions Sun, Xiaoming Qu, Tingyi Li, Yan Zhu, Hailong Yang, Zeyong Xing, Jincheng Mao*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. of China
Fax +86(512)65880403; E-mail: jcmao@suda.edu.cn
Received 3 September 2011
ane, THF, and dichloromethane, could not afford the
Abstract: An effective protocol was developed for the Heck cou-
corresponding product (Table 1, entries 2–7). It is possi-
bly attributed to palladium nanoparticles, which were in
pling reactions between various aryl halides and olefins. In the pres-
ence of 2 mol% of Pd(OAc) , the desired products could be obtained
2
situ generated in PEG-400. Different bases, including in-
in good yields under ligand-free and aerobic conditions. The cata-
lytic system could be easily recycled for five times with high effi- organic bases and organic bases, were introduced into the
ciency.
coupling reaction (Table 1, entries 8–15), and K CO3
Key words: coupling reactions, Heck reaction, aryl halides, ole- proved to be the best. Since PEG-400 as the solvent af-
2
fins, ligand-free
forded the good result, several simple polyols, such as
glycol and glycerine, were employed into the reaction.
However, a trace amount of the product was acquired
The Heck cross-coupling reaction between aryl or vinyl (Table 1, entries 16 and 17). In addition, other PEG were
halides and olefins is well-known as being one of the most used as the solvent, including PEG-200 and PEG-600
important and useful reactions for the construction of C– (Table 1, entries 18 and 19). In contrast, PEG-400 gave
1
C bonds in many areas, including natural products, phar- best yield. Increasing the reaction temperature from room
2
temperature to 40 °C, a better result was obtained
maceuticals, and fine-chemical syntheses. During the
past decades, many effective protocols have been devel-
(
Table 1, entry 20). In order to improve the catalytic ef-
3
fect, various palladium catalysts were screened (Table 1,
oped for such coupling reaction. Among them, palladi-
entries 21 and 22), and Pd(OAc) was the best one. Dou-
um–phosphine catalytic systems have been preferentially
employed as an effective catalyst in controlling the reac-
tivity and selectivity in the Heck reaction. Recently, we
2
ble catalyst loading did not lead to obvious improvement
of the catalytic efficiency (Table 1, entry 23). Thus the
have found that tridentate Pd(II) salicylaldiminato thio- best catalyst loading is 2 mol%. Then different types of
semicarbazone complexes of type [Pd(O,N,S-thiosemi- the additives were employed for possible better results,
carbazone)(PPh )] could catalyze the Heck coupling including iodine, tetra-n-butylammonium bromide
3
reaction between a variety of aryl halides and olefins, af- (TBAB), tetra-n-butylammonium fluoride (TBAF), LiCl,
fording the desired products with good to excellent Ag O, Bu NOAc, and ZnCl (Table 1, entries 24–30). It
2 4 2
4
yields. However, phosphine ligands are often air-sensi- can be seen that the influence is quite different, and TBAF
gave the highest yield (61%, Table 1, entry 26). Based on
this encouraging result, we just made a creative attempt:
TBAF was employed not only as the additive but also as
the solvent. Considering that the melting point of TBAF is
about 58 °C, the relative experiment was performed using
tive, toxic, and quite expensive. In view of possible appli-
cations in large scale or industry, one question raised:
5
How to reduce the cost of the catalytic system? Two pos-
sible solutions for this problem were developed: ligand-
6
free conditions and recovery as well as recycling of Pd
7
2
grams of TBAF as the solvent at 60 °C. To our surprise,
catalyst. Therefore, in this paper, we will report such an
good result was obtained (90% yield, Table 1, entry 31).
Under the same conditions, PEG-400 instead of TBAF as
the solvent afforded the desired product in 66% yield
example of highly effective and reusable Heck reactions
in the absence of a ligand.
Our initial studies used PEG-400 as the solvent in order to
meet the demands for recyclability and environmental
concerns, since it is a facile way to immobilize the catalyst
in a liquid phase by dissolving it into a nonvolatile and
low-toxicity liquid, such as poly(ethylene)glycols (PEG).8
At room temperature, the desired product was obtained in
(
Table 1, entry 32), which shows the special effect of
TBAF. Increasing the reaction temperature from 60 °C to
0 °C, almost quantitative yield of the corresponding
7
product was obtained (Table 1, entry 33). A decreased
amount of K CO led to lower yield of the desired product
2
3
(
Table 1, entries 34 and 35). The controlled experiments
3
(
7% yield from iodobenzene and methyl acrylate
Table 1, entry 1). Under the same conditions, the com-
monly used solvents, such as toluene, DMSO, DMF, diox-
were carried out: The reaction could not occur in the ab-
sence of Pd(OAc) (Table 1, entry 36), and slightly re-
2
duced yield was obtained without K CO as the base
2
3
9
(
Table 1, entry 37). Under the same conditions, the typi-
SYNLETT 2012, 23, 150–154
x
x.
x
x.
2
0
1
1
cal catalytic system (DMF/Et N) afforded the correspond-
3
Advanced online publication: 09.12.2011
DOI: 10.1055/s-0031-1290099; Art ID: W19111ST
ing product in 48% yield (Table 1, entry 38).
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Recyclable Palladium-Catalyzed Heck Reactions
151
Table 1 Screening of Catalytic Conditions in the Heck Coupling
between Iodobenzene and Methyl Acrylate
Table 1 Screening of Catalytic Conditions in the Heck Coupling
between Iodobenzene and Methyl Acrylate (continued)
a
a
O
O
I
I
Pd cat.
Pd cat.
OMe
OMe
+
O
+
O
solvent, base, additive
solvent, base, additive
OMe
OMe
Entry Pd cat. (mol%)
Solvent
Base
Temp
°C)
Yield
Entry Pd cat. (mol%)
Solvent
Base
Temp
(°C)
Yield
b
b
(
(%)
37
–
(%)
99
82
77
–
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
Pd(OAc) (2)
PEG-400 K CO
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
40
40
40
40
40
40
40
40
40
40
60
33
Pd(OAc) (2)
TBAF
TBAF
TBAF
TBAF
TBAF
DMF
K CO
70
70
70
70
70
70
2
2
3
3
3
3
3
3
3
2
2
3
3
3
3
34j
35k
36
Pd(OAc) (2)
K CO
Pd(OAc) (2)
toluene
DMSO
DMF
K CO
2
2
2
2
Pd(OAc) (2)
K CO
–
Pd(OAc) (2)
K CO
2
2
2
2
Pd(OAc) (2)
K CO
trace
–
–
K CO
2
2
2
Pd(OAc) (2)
dioxane
THF
K CO
37
Pd(OAc) (2)
–
75
48
2
2
2
Pd(OAc) (2)
K CO
–
38
Pd(OAc) (2)
Et N
2
2
2
3
a
Pd(OAc) (2)
CH Cl
K CO
–
Reaction conditions: iodobenzene (0.5 mmol), methyl acrylate (3.0
mmol), base (1.0 mmol), solvent (2 mL), in air, 18 h, r.t., –70 °C.
2
2
2
2
Pd(OAc) (2)
PEG-400 K PO
17
1
b
2
3
4
Isolated yield (based on iodobenzene).
Iodine as the additive.
TBAB as the additive.
TBAF as the additive.
c
Pd(OAc) (2)
PEG-400 KOt-Bu
PEG-400 KOH
PEG-400 Cs CO
d
2
e
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
Pd(OAc) (2)
5
2
f
LiCl as the additive.
g
Ag O as the additive.
Pd(OAc) (2)
35
–
2
2
2
3
h
i
Bu NOAc as the additive.
4
Pd(OAc) (2)
PEG-400 KF
PEG-400 Na CO
ZnCl as the additive.
2
2
j
K CO (0.75 mmol).
2
3
Pd(OAc) (2)
5
k
2
2
3
K CO (0.5 mmol).
2 3
Pd(OAc) (2)
PEG-400 NaOAc
12
trace
trace
trace
31
34
47
34
27
48
trace
45
61
44
37
44
56
90
2
The optimized procedure was subsequently used to inves-
tigate the scope of the coupling between various aryl ha-
lides and olefins (Table 2). It can be seen that for the
couplings of aryl iodides different types of olefins, such as
acrylates, styrenes, and acrylamide, afforded the desired
products in excellent yields (90–99%, Table 2, entries 1–
Pd(OAc) (2)
PEG-400 Et N
2
3
Pd(OAc) (2)
glycol
K CO
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Pd(OAc) (2)
glycerine K CO
2
2
Pd(OAc) (2)
PEG-200 K CO
2
2
1
4). In addition, challenging aryl bromides were em-
Pd(OAc) (2)
PEG-600 K CO
2
2
ployed into the Heck reaction and relatively decreased
yields of the desired products were obtained (Table 2, en-
tries 15–19).
Pd(OAc) (2)
PEG-400 K CO
2
2
PdCl (2)
PEG-400 K CO
2
2
Table 2 Various Heck Reactions between Aryl Halides and Olefins
Pd (dba) (1)
PEG-400 K CO
a
2
3
2
Using Pd(OAc) /TBAF as Catalytic System
2
3
Pd(OAc) (4)
PEG-400 K CO
Pd(OAc)2 (2 mol%)
2
2
R
R
ArX
+
Ar
4c
K2CO3 (2 equiv), TBAF
8–36 h, 70–90 °C, air
Pd(OAc) (2)
PEG-400 K CO
2
2
1
X = I, Br
5d
6e
7f
8g
9h
0i
1
Pd(OAc) (2)
PEG-400 K CO
2
2
Entry ArX
Olefin
Temp Time Yield
b
Pd(OAc) (2)
PEG-400 K CO
(°C)
(h) (%)
2
2
Pd(OAc) (2)
PEG-400 K CO
O
2
2
1
2
70
18 97
I
I
Pd(OAc) (2)
PEG-400 K CO
OEt
O
2
2
Pd(OAc) (2)
PEG-400 K CO
70
70
18 99
18 99
2
2
OMe
O
Pd(OAc) (2)
PEG-400 K CO
2
2
Pd(OAc) (2)
TBAF
K CO
3
2
2
I
On-Bu
3
2
Pd(OAc) (2)
PEG-400 K CO
60
66
2
2
3
©
Thieme Stuttgart · New York
Synlett 2012, 23, 150–154

1
52
P. Sun et al.
LETTER
Table 2 Various Heck Reactions between Aryl Halides and Olefins
Subsequently, our methodology was applied to the cou-
pling between 1,3-diiodobenzene and methyl acrylate.
From Scheme 1 it can be seen that 99% yield of the de-
sired product was obtained. However, none of the corre-
sponding products were afforded when 1,2- or 1,4-
diiodobenzene was employed as the substrate.
a
Using Pd(OAc) /TBAF as Catalytic System (continued)
2
Pd(OAc)2 (2 mol%)
R
R
ArX
+
Ar
K2CO3 (2 equiv), TBAF
18–36 h, 70–90 °C, air
X = I, Br
Entry ArX
Olefin
Temp Time Yield
b
(
°C)
(h) (%)
O
I
I
4
5
6
7
70
70
70
70
18 96
I
I
I
I
0.5 mmol
+
Pd(OAc)2
(2 mol%)
NMe2
MeOOC
COOMe
K2CO3 (2 equiv)
TBAF, 36 h,
18 99
18 99
36 91
99%
COOMe
COOH
70 °C, air
O
3.0 mmol
Scheme 1 Coupling of 1,3-diiodobenzene and methyl acrylate using
the Pd(OAc) /K CO /TBAF system
Ot-Bu
2
2
3
As shown in Schemes 2, 82% of conversion was ob-
served for the coupling of iodobenzene and a-methacry-
late using the Pd(OAc) /K CO /TBAF system. No doubly
arylated product was obtained in this case. The H NMR
spectroscopy and GC suggests that the E-regioisomer
with an internal double bond was observed (36% selectiv-
ity), and the terminal regioisomer was also found (64% se-
lectivity).10
8
9
70
70
36 99
36 95
I
I
2
2
3
1
Cl
Me
O
1
1
1
1
0
1
2
3
70
70
70
70
36 92
36 97
18 90
18 92
Me
MeO
F
I
As presented in Scheme 3, the coupling of iodobenzene
OMe
and a-methylacrylate using our catalytic system was per-
1
formed, and 50% conversion could be observed. The H
I
NMR spectroscopy and GC suggests that there are two
possible pathways, one leading to a-methylcinnamic acid
ester with an internal double bond (59% selectivity), and
another that leads to a-benzyl acrylate with a terminal
O
I
OMe
O
10
double bond (41% selectivity).
Cl
I
OMe
In order to explain the high efficiency of this coupling re-
action, the nature of the catalytic system was investigated
in situ using transmission electron microscopy (TEM).
The TEM micrograph shows that the average diameters of
palladium nanoparticles were over 200 nm before the re-
action, and the average diameters of palladium nanoparti-
cles were about 100 nm after the reaction (Figure 1). The
smaller size led to a higher catalytic efficiency. The sys-
tem of the in situ generated palladium nanoparticles in
TBAF in aerobic conditions was stable for several
months, and no palladium black was observed. These pal-
ladium nanoparticles showed much higher catalytic activ-
I
O
1
4
70
18 91
OMe
O
1
1
1
5
6
7
70
90
90
18 44
24 30
24 33
Br
OMe
O
Me
Br
OMe
O
O
Cl
Br
OMe
11
ity than the common ones.
F3C
1
8
9
90
90
24 38
24 30
Br
OMe
OMe
Br
O
1
N
a
Reaction conditions: Pd(OAc) (2 mol%), aryl halide (0.5 mmol),
2
olefin (3.0 mmol), K CO (1.0 mmol), TBAF (2 g), in air, 18–36 h,
2
3
7
0–90 °C.
b
Isolated yield based on aryl halide (average of two runs).
Figure 1 The TEM image of catalytic system (before the reaction
and after reaction in air, respectively)
Synlett 2012, 23, 150–154
© Thieme Stuttgart · New York

LETTER
Recyclable Palladium-Catalyzed Heck Reactions
153
Pd(OAc)2 (2 mol%)
I
+
+
K2CO3 (2 equiv)
TBAF, 36 h, 70 °C, air
0.5 mmol
3.0 mmol
82% conv.
36%
64%
Scheme 2 Coupling of iodobenzene and a-methylstyrene using the Pd(OAc) /K CO /TBAF system
2
2
3
O
O
Pd(OAc)2 (2 mol%)
I
OMe
OMe
OMe
+
+
K2CO3 (2 equiv)
O
TBAF, 36 h, 70 °C, air
50% conv.
59%
41%
Scheme 3 Coupling of iodobenzene and a-methylacrylate using the Pd(OAc) /K CO /TBAF system
2
2
3
To check the reusability of the solvent as well as the cata- Synthesis of Jiangsu Province for financial support. This project
was also funded by the Priority Academic Program Development of
lytic system, the coupling between iodobenzene and me-
Jiangsu Higher Education Institutions. We thank Dr. Marc Creus
thyl acrylate was carried out in TBAF in the presence of
from University of Basel, Switzerland for helpful discussions.
Pd(OAc) (2 mol%), K CO (2 equiv) at 70 °C for 24
2
2
3
hours under air. As shown in Scheme 4, this catalytic sys-
tem could be reused for five times. The desired product References and Notes
could be easily isolated by simple extraction with diethyl
(
1) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn.
ether, and the Pd(OAc) /K CO /TBAF system was sub-
2
2
3
1971, 44, 581. (b) Dieck, H. A.; Heck, R. F. J. Am. Chem.
Soc. 1974, 96, 1133. (c) Dieck, H. A.; Heck, R. F. J. Org.
Chem. 1975, 40, 1083.
jected to the second run by charging it with the same sub-
strates in the remnant. Although the effect of TBAF in
these reactions has not been clear until now, it is apparent
that TBAF acted as a base, solvent, and phase-transfer ca-
talysis (PTC) to favor the desired reaction.
(2) For examples, see (a) Gaudin, J.-M. Tetrahedron Lett. 1991,
2, 6113. (b) Overman, L. E.; Ricca, D. J.; Tran, V. D.
3
J. Am. Chem. Soc. 1993, 115, 2042. (c) Tietze, L. F.; Buhr,
W. Angew. Chem., Int. Ed. Engl. 1995, 34, 1366. (d)Bader,
R. R.; Baumeister, P.; Blaser, H. U. Chimia 1996, 50, 99.
O
(
e) Wu, T. C. US 5536870, 1996. (f) Eisenstadt, A. In
Catalysis of Organic Reactions; Herkes, F. E., Ed.; Marcel
Dekker: New York, 1998.
(3) (a) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed.
Engl. 1995, 33, 2379. (b) Beletskaya, I. P.; Cheprakov,
A. V. Chem. Rev. 2000, 100, 3009. (c) Donnay, A. B.;
Overman, L. E. Chem. Rev. 2003, 103, 2945.
O
Pd(OAc)2 (2 mol%)
OMe
I +
K2CO3 (2 equiv)
TBAF, 24 h, 70 °C, air
OMe
run no.
0
1
2
3
4
5
isolated yield (%)
99
94
97
95
90
86
(
2
d) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetradedron
001, 57, 7449.
Scheme 4 Reuse of the catalytic system
(
4) Xie, G.; Chellan, P.; Mao, J.; Chibale, K.; Smith, G. S. Adv.
Synth. Catal. 2010, 352, 1641.
In summary, palladium-catalyzed Heck coupling reac-
tions were successfully performed in TBAF without the
need of a phosphine ligand. Generally, good yields were
obtained for the coupling of various aryl halides and ole-
fins, including acrylates, acrylic acid, styrenes, and acryl-
amides. It is noteworthy that the catalyst system could be
recycled at least five times without the loss of catalytic ac-
tivity. Studies concerning the mechanism and further ap-
plication of the reaction will be the focus of future work.
(
(
5) Farina, V. Adv. Synth. Catal. 2004, 346, 1553.
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132, 79. (b) Reetz, M. T.; de Vries, J. G. Chem. Commun.
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(
8
Org. Lett. 2008, 10, 3215. (d) Bernini, R.; Cacchi, S.;
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(
(
8) Poly(ethylene glycol): Chemistry and Biological
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9) General Procedure for the Ligand-Free Palladium-
Catalyzed Heck-Type Coupling Reactions of Aryl Halide
and Terminal Olefin
Acknowledgment
We are grateful to the grants from Natural Science Foundation of
China (20802046), International S&T Cooperation Program of
Jiangsu Province (BZ2010048), and the Key Laboratory of Organic
A mixture of aryl halide (0.5 mmol), olefin (3.0 mmol),
©
Thieme Stuttgart · New York
Synlett 2012, 23, 150–154

1
54
P. Sun et al.
LETTER
+
+
Pd(OAc) (2 mol%), K CO (2 equiv), and TBAF (2 g) in a
167.8 ppm. HRMS (ESI ): m/z calcd for [C H O ] :
2
2
3
10 10
2
sealed tube was stirred under air atmosphere at 70 °C for the
desired time until complete consumption of starting material
as monitored by TLC. After the mixture was poured into
Et O, then the mixture was washed with H O, extracted with
162.0681; found: 162.0679.
(10) (a) Beller, M.; Riermeier, T. H. Eur. J. Inorg. Chem. 1998,
29. (b) Caló, V.; Nacci, A.; Monopoli, A.; Detomaso, A.;
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(b) Han, W.; Liu, C.; Jin, Z.-L. Adv. Synth. Catal. 2008, 350,
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Chem. 2005, 229, 7. (d) Du, Z.; Zhou, W.; Bai, L.; Wang, F.;
Wang, J.-X. Synlett 2011, 369. (e) Han, W.; Liu, N.; Liu, C.;
Jin, Z. L. Chin. Chem. Lett. 2010, 21, 1411.
2
2
EtOAc, dried over anhyd Na SO , filtered and evaporated
2
4
under vacuum, and the residue was purified by flash column
chromatography (PE or PE–EtOAc) to afford the
corresponding coupling products.
(
E)-Methyl Cinnamate
1
H NMR (400 MHz, CDCl ): d = 3.82 (s, 3 H), 6.45 (d,
J = 16.0 Hz, 1 H), 7.39 (t, J = 3.2 Hz, 3 H), 7.52–7.55 (m, 2
H), 7.71 (d, J = 16.0 Hz, 1 H) ppm. C NMR (100 MHz,
3
1
3
CDCl ): d = 52.1, 118.0, 128.4, 129.2, 130.6, 134.6, 145.2,
3
Synlett 2012, 23, 150–154
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