Suzuki-Miyaura cross-coupling of aryl chlorides in water using ligandless palladium on activated carbon

Article abstract of DOI:10.1055/s-2005-869877

Aqueous reaction conditions that activate various aryl chlorides in Suzuki-Miyaura cross-coupling have been developed. These environment friendly conditions utilize ligandless Pd/C (Pd concentrations 0.2-2 mol%) that allow easy separation of the catalyst at the end of the reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869877

LETTER
1671
Suzuki–Miyaura Cross-Coupling of Aryl Chlorides in Water Using Ligandless
Palladium on Activated Carbon
S
M
uzuki–Miyaura Cross
o
-Coupling of
r
A
ryl Ch
t
lorides
e
in
W
ater n Lysén,*a,b Klaus Köhlera
a
Department Chemie, Anorganische Chemie, TU München, Lichtenbergstr. 4, 85747 Garching, Germany
b
The Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark
Fax +45(35)306040; E-mail: mly@dfuni.dk
Received 1 April 2005
We chose to investigate the applicability of a hetero-
geneous Pd/C catalyst in the Suzuki–Miyaura reaction of
aryl chlorides without addition of ligands. This would
Abstract: Aqueous reaction conditions that activate various aryl
chlorides in Suzuki–Miyaura cross-coupling have been developed.
These environment friendly conditions utilize ligandless Pd/C (Pd
concentrations 0.2–2 mol%) that allow easy separation of the cata- lead to a cleaner reaction and also offer simple removal of
lyst at the end of the reaction.
the palladium after the reaction as it was previously
10
reported that palladium leaches from the carbon support
during the reaction and then reprecipitates on the charcoal
at the end of the reaction.
Key words: aryl chlorides, water, palladium, cross-coupling,
biaryls
In our initial experiments we focused on a Pd/C catalyst
Activation of aryl chlorides in the Suzuki–Miyaura cross- possessing high Pd dispersion, high degree of unreduced
1
coupling reactions is of great interest as these can serve Pd [Pd(II)] and a high water content >50%. Tetrabutyl-
as cheap and readily available starting materials in the ammonium bromide (TBAB) was added to the reaction
synthesis of fine chemicals and pharmaceuticals. Unfortu- since tetrabutylammonium salts have been reported11 to
nately, they are much more difficult to activate than aryl heighten the efficiency by stabilizing palladium nano-
iodides and aryl bromides. Effort has been invested in de- particles. Applying this catalyst using low palladium con-
2
veloping catalysts and ligands that can activate the less centration (0.2 mol%) and addition of 0.5 equivalents
reactive aryl chlorides. Some drawbacks are the availabil- TBAB in the reaction of 4-chloroacetophenone and
ity of the palladium complexes and the stability of some phenylboronic acid gave diverse results proving that the
of the ligands. Furthermore, these ligands and catalysts choice of reaction condition is of major importance.
can be difficult to separate from the end product. Proto-
NMP–water mixture (Table 1, entry 1a), which in several
cols that use ligandless palladium in aryl chloride activa-
cases with heterogeneous catalysts has been the condition
3
tion have been demonstrated. Pd/C, minerals containing
3
of choice, showed moderate conversion and selectivity.
4
5
palladium, and Pd(OAc) have been reported effective
2
Dioxane and dioxane–water worked very sluggishly, as
did methanol and acetone–water (entries 1b, 1c, 1e, 1h,
although organic solvents and long reaction times were
6
needed. In 1997 Badone et al. showed that aryl bromides
1
i). DMF–water (entries 1f and 1g) proved to facilitate the
oxidative addition but the selectivity was low and led to a
0:50 mixture of the biaryl product and dehalogenated
coupled readily in water using Pd(OAc) and tetrabutyl-
2
ammonium bromide (TBAB) as additive but did not
5
report any aryl chloride activation. Bumagin and Bykov7
starting material. Turning to water without organic co-sol-
vent (entries 1d, 1j–1m) the reaction went smoothly with
full conversion in only 1.5 hours with very high selectivity
showed that PdCl could catalyze the reaction of sodium
2
tetraphenyl borate and aryl chlorides in water. Arcadi and
8
coworkers published a few examples of aryl chloride ac-
(
8
(
>99%, entry 1k). Lowering the reaction temperature to
0 °C for two hours resulted in almost full conversion
87%, entry 1l) but at room temperature no reaction was
tivation using Pd/C in water with surfactants and recently
9
it was reported that some aryl chlorides could be coupled
using homogeneous Pd(OAc) in molten TBAB in the
2
observed. The amount of TBAB was tested and 0.5 equiv-
alents were found to be optimal and in the absence of
TBAB poor conversion was observed (entry 1n). Using
these very active and selective reaction conditions, scope
and limitations of the reaction were investigated.
presence of water. In both cases long reaction times (17–
2
4 h) were needed. We wish to report a general procedure
for aryl chloride activation, including ones containing
sensitive functional groups, in water under ambient atmo-
sphere using ligandless palladium on activated carbon.
This general procedure generates the corresponding
biaryls in good to excellent yield.
As summarized in Table 2 various aryl chlorides coupled
–1
nicely under these conditions (TOF 300 h ) although the
different reactivity of the aryl chlorides is reflected in the
reaction conditions. As higher conversions were observed
on electron-rich chloroarenes using NaOH as the base
experiments in Table 2 were performed with NaOH. All
reactions were performed under ambient atmosphere, as
biphenyl formation was minimal. Electron deficient aryl
SYNLETT 2005, No. 11, pp 1671–1674
0
7
.0
7
.2
0
0
5
Advanced online publication: 09.06.2005
DOI: 10.1055/s-2005-869877; Art ID: D08405ST
©
Georg Thieme Verlag Stuttgart · New York

1
672
M. Lysén, K. Köhler
LETTER
Table 1 Optimization of the Reaction Conditions in the Reaction of 4-Chloroacetophenone and Phenylboronic Acid
O
O
Pd/C 0.2 mol%
TBAB 0.5 equiv
base 2.5 equiv
B(OH)2
solvent
Cl
Entrya
Solvent
Base
Temp (°C)
Time (h)
Conversion (%)b
Yield (%)
1
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
NMP–H O, 3:1
NaOH
K PO
140
140
140
100
100
140
140
100
100
100
100
80
4
72
10
8
54
5
2
Dioxane
4
3
4
4
Dioxane–H O, 3:1
K PO
4
5
2
3
H O
K CO
4
100
8
>99
5
2
2
3
3
3
H O–acetone, 1:1
K CO
4
2
2
DMF–H O, 5:1
K CO
4
100
100
21
3
41
56
3
2
2
g
h
i
DMF–H O, 5:1
KF
4
2
MeOH
MeOH
K CO
4
2
3
KF
4
1
j
H O
K CO
2
100
100
87
0
>99
>99
86
0
2
2
3
3
3
3
3
k
l
H O
K CO
1.5
2
2
2
H O
K CO
2
2
m
n
H O
K CO
r.t.
24
3
2
2
1
H O
K CO
100
13
10c
2
2
a
Reaction conditions: 2 mmol 4-chloroacetophenon, 2.2 mmol phenylboronic acid, 1 mmol TBAB in 4–6 mL solvent under argon,
Pd/C (E105CA/W 5% Pd).
b
Determined by GC analysis with diethyleneglycol dibutylether as internal standard.
No TBAB added.
c
chlorides reacted nicely at low palladium concentrations sion and hydrolysis during the reaction. Chlorobenzene
(
0.2–0.5 mol%), and only 1.1 equivalents of phenyl- could be satisfactory coupled with 4-tolylboronic acid
boronic acid were needed to reach full conversion. Elec- using only 0.5 mol% palladium at 140 °C for 6 hours
tron-rich chloroarenes required higher catalyst loading giving 73% yield (entry 2f). Coupling of deactivated 4-
(
2.0 mol%), 1.5 equivalents phenylboronic acid, higher chlorotoluene and 4-chloroanisole produced high yields,
temperature and longer reaction times (6 h).
-Chloroacetophenone and 4-chlorobenzonitrile showed
the highest reactivity giving high yield (Table 2, entry 2a
81% and 83%, respectively, and even the sterically
demanding 2-chlorotoluene could be nicely converted
although the product was contaminated with biphenyl.
4
and 2b) at 100 °C with low catalyst loading. In the case 4-Chloroaniline coupled nicely with only 2 mol% Pd at
with the benzonitriles and the methyl benzoates it was 140 °C but several attempts to isolate the product failed.
1
necessary to change the base due to substantial hydrolysis Estimations based on H NMR revealed a yield of ca.
to the corresponding benzoic acid. K CO and K PO both 66%.
2
3
3
4
led to benzoic acid formation but KF proved efficient to
activate the phenylboronic acid without causing severe
hydrolysis of the ester or nitrile.
In summary we have developed a procedure that facili-
tates efficient coupling of various aryl chlorides, includ-
ing electron-rich and ortho-substituted derivatives, in
1
2
Using KF as base 4-chlorobenzonitrile and 2-chloro- water using ligandless supported palladium. This proce-
benzonitrile gave excellent yields (98% and 89%, respec- dure is a very attractive way of accessing multifunctional
tively, entry 2b and 2c). The methyl benzoates (entries 2d biaryls as sensitive functional groups like ester and nitrile
and 2e) could also be effectively coupled giving 87% and groups are tolerated. Comparisons of different palladium
6
3% yield, respectively. The lower yield from 2-chloro- sources and the recycling of the catalysts are currently
benzoic acid methyl ester was due to incomplete conver- under survey in our laboratories.
Synlett 2005, No. 11, 1671–1674 © Thieme Stuttgart · New York

LETTER
Suzuki–Miyaura Cross-Coupling of Aryl Chlorides in Water
1673
Table 2 Suzuki Cross-Coupling of Aryl Chlorides in Water13
Pd/C
TBAB 0.5 equiv
Cl
B(OH)2
R
NaOH
R
H2O, temperature, time
Entrya
R
Pd (%)
0.2
Temp (°C) Time (h)
Ph-B(OH)2 NaOH
Product
Isolated yield
(%)
b
(
equiv)
(equiv)
2a
4-COOH3
100
2
1.1
2.5
O
99
2
b
c
4-CN
2-CN
0.5
0.5
100
140
3
3
1.1
1.1
2.5
2.5
98c
89c
NC
2
CN
2
d
e
4-CO CH3 0.5
140
140
3
3
1.1
1.1
2.5
2.5
O
O
87c
2
O
O
2
2-CO CH3 0.5
63c,d
2
2
f
H
0.5
2.0
140
140
6
6
1.1
1.5
2.5
5
73e
81
H3C
2g
4-CH3
H3C
CH3
2
2
2
h
2-CH3
2.0
2.0
2.0
140
140
140
6
6
6
1.5
1.5
1.5
5
5
5
74f
83
i
4-OCH3
4-NH2
MeO
H2N
j
66g
a
b
c
d
e
f
Reaction conditions: 4 mmol arylhalide in H O (6mL) in a pressure tube under ambient atmosphere.
Yield of chromatographically pure products.
KF used as base.
2
Product contaminated with 6% of 2-chlorobenzoic acid methyl ester.
4
-Tolylboronic acid was used as nucleophile.
Product contaminated with 5% of biphenyl.
g
1
Determined by H NMR.
References
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4
(
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(
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(
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Synlett 2005, No. 11, 1671–1674 © Thieme Stuttgart · New York

1
674
M. Lysén, K. Köhler
LETTER
(
10) Heidenreich, R. G.; Krauter, J. G. E.; Pietsch, J.; Köhler, K.
acetophenone (4 mmol). Then, H O (6 mL) was added and
2
J. Mol. Catal. A.: Chem. 2002, 182-183, 499.
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the flask was sealed with a Teflon screw cap and stirred at
100 °C for 2 h. After cooling to r.t., CH Cl (15 mL) was
(
(
2
2
added and the reaction was filtered through a plug of celite
to remove the catalyst. The filter was flushed with CH Cl
1994, 59, 6095.
2
2
(
13) Representative Procedure.
(2 × 15 mL) and the combined organic phase was dried
A pressure tube was charged with Pd/C (0.2 mol%;
commercially available E105CA/W 5% Pd, product of
(MgSO ), evaporated on Celite and purified by flash
chromatography to yield 1-biphenyl-4-yl-ethanone (entry
2a, 776 mg, ca. 99%).
4
1
4
Degussa AG, or self-prepared ), TBAB (2 mmol), NaOH
10 mmol), phenylboronic acid (4.4 mmol) and 4-chloro-
(
(14) Pearlman, W. Tetrahedron Lett. 1967, 1663.
Synlett 2005, No. 11, 1671–1674 © Thieme Stuttgart · New York