An extremely active and general catalyst for Suzuki coupling reaction of unreactive aryl chlorides

Article abstract of DOI:10.1021/ol102677r

β-Diketiminatophosphane Pd complex 2a acted as a powerful catalyst which allows easy access to the Suzuki coupling reaction of less reactive aryl chlorides under mild conditions. A wide range of sterically hindered and deactivated aryl chlorides could be efficiently coupled at a low catalyst loading of 0.1 mol %. Furthermore, this catalytic system also proved to be highly effective in one-pot multiple couplings.

Full text of DOI:10.1021/ol102677r

ORGANIC
LETTERS
2
011
Vol. 13, No. 2
52-255
An Extremely Active and General
Catalyst for Suzuki Coupling Reaction
of Unreactive Aryl Chlorides
2
Dong-Hwan Lee and Myung-Jong Jin*
Department of Chemical Science and Engineering, Inha UniVersity,
Incheon 402-751, South Korea
mjjin@inha.ac.kr
Received November 4, 2010
ABSTRACT
ꢀ-Diketiminatophosphane Pd complex 2a acted as a powerful catalyst which allows easy access to the Suzuki coupling reaction of less
reactive aryl chlorides under mild conditions. A wide range of sterically hindered and deactivated aryl chlorides could be efficiently coupled
at a low catalyst loading of 0.1 mol %. Furthermore, this catalytic system also proved to be highly effective in one-pot multiple couplings.
Palladium-catalyzed coupling reactions, inspired by the 2010
Nobel Laureates’ discoveries, are powerful and convenient
one-step tools for the construction of carbon-carbon bonds.
Especially, Pd catalysts derived from electron-rich, bulky di-
4
5
or trialkylphosphanes and N-heterocyclic carbenes have led
to considerable progress in this area. Most of the prominent
catalysts display excellent reactivity for the coupling of
deactivated aryl chlorides, while a relatively high catalyst
loading and high temperature are often required to attain
satisfactory results. There is still a need for more efficient
catalysts which can significantly lower the catalyst loading
and improve the reactivity with broad substrate generality.
In this communication, we describe our discovery of a highly
active palladium catalyst that facilitates the Suzuki reaction
1
The Suzuki coupling reaction of aryl halides with arylboronic
acids represents one of the most synthetically valuable
2
methods for the synthesis of biaryl derivatives. Early studies
on the coupling have performed predominantly with aryl
3
iodides and bromides as substrates. From a practical point
of view, the use of aryl chlorides is typically more attractive
due to their low cost and wide availability. However, the
high C-Cl bond strength makes their activation difficult.
The emergence of highly active catalysts provides new
opportunities for the Suzuki coupling of these substrates.
(4) (a) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2006, 45, 3484. (b) Fleckenstein, C.; Plenio, H. Chem.sEur.
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73, 3236. (d) Hoshi, T.; Nakazawa, T.; Saitoh, I.; Mori, A.; Suzuki, T.;
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(
1) For reviews, see: (a) Bedford, R. B.; Cazin, C. S. J.; Holder, D.
Coord. Chem. ReV. 2004, 248, 2283. (b) deMeijere, A., Diederich, F. Eds.
Metal Catalyzed Cross-Coupling Reactions, Vol 2; Wiley-VCH: Weinheim,
2
(
004. (c) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366.
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1
(
AdV. Synth. Catal. 2006, 348, 609. (b) Martin, R.; Buchwald, S. L. Acc.
Chem. Res. 2008, 41, 1461. (c) Tobisu, M.; Chatani, N. Angew. Chem.,
Int. Ed. 2009, 48, 3565.
(5) (a) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. Angew.
Chem., Int. Ed. 2003, 42, 3690. (b) Altenhoff, G.; Goddard, R.; Lehmann,
C. W.; Glorius, F. J. Am. Chem. Soc. 2004, 126, 15195. (c) Marion, N.;
Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; S. Nolan, P. J. Am.
Chem. Soc. 2006, 128, 4101. (d) Diebolt, O.; Braunstein, P.; Nolan, S. P.;
Cazin, C. S. J. Chem. Commun. 2008, 3190. (e) Organ, M. G.; Calimsiz,
S.; Sayah, M.; Hoi, K. H.; Lough, A. J. Angew. Chem., Int. Ed. 2009, 48,
2383.
(
3) (a) Zhang, T.; Wang, W.; Gu, X.; Shi, M. Organometallics 2008,
2
7, 753. (b) Lipke, M. C.; Woloszynek, R. A.; Ma, L.; Protasiewicz, J. D.
Organometallics 2009, 28, 188. (c) Zhang, X.; Qiu, Y.; Rao, B.; Luo, M.
Organometallics 2009, 28, 3093. (d) Chalker, J. M.; Wood, C. S. C.; Davis,
B. G. J. Am. Chem. Soc. 2009, 131, 16346.
10.1021/ol102677r  2011 American Chemical Society
Published on Web 12/13/2010

of less reactive substrates under mild conditions and low
catalyst loadings.
Table 1. Suzuki Coupling of 2-Chloro-1,3-dimethylbenzene with
p-Tolylboronic Acid
Transition metal ꢀ-diketiminates have gained much interest
a
6
in the fields of metallo-organic chemical vapor deposition
7
and catalytic olefin polymerization. However, they have
received much less attention in other processes. A new class
of air- and moisture-stable ꢀ-diketiminato-phosphane Pd
complexes 2 could be easily prepared in three steps (Scheme
e
entry
1
2 (mol %)
base
t (°C)
time (h)
yield (%)
1
). Acetylacetone reacted with primary amines under mild
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
K
2
K
2
K
2
K
2
K
2
K
2
K
3
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
50
50
50
50
40
25
50
50
50
50
50
50
8
6
6
24
10
24
24
8
8
8
8
8
91
95
90
70
83
60
82
61
53
49
53
72
b
2
c
3
d
4
Scheme 1. Synthesis of ꢀ-Diketiminatophosphine Pd Catalysts 2
5
6
7
8
9
PO
4
Na
Cs
NaOMe
2
CO
3
2
CO
3
10
11
12
a
K
K
2
CO
CO
3
2
3
General conditions: 2-chloro-1,3-dimethylbenzene (1.0 mmol), p-
tolylboronic acid (1.2 mmol), 2 (0.1 mol %), base (2.0 mmol), EtOH-H
2
O
b
c
d
(
2 mL, 1:1). DMF-H
2
O (2 mL, 1:1). DMA-H
2
O (2 mL, 1:1). In the
e
presence of 0.01 mol % of 2a. Isolated yield.
microwave irradiation to give ꢀ-diketimines 1 in high yields.
Interestingly, this reaction could be complete within 30 min
under solvent-free conditions. Deprotonation of 1 with EtOTl
The use of K
CO gave inferior results under the same conditions
entries 7-10). It was noted that catalyst 2b and 2c led to
an significant decrease in the rate (entries 11 and 12). This
difference could be explained by the fact that the stronger
electron-donating triethylphosphine ligand on the Pd metal
lowers the activation energy for the oxidation step of the
catalytic cycle more compared to triphenylphosphine. In
addition, methyl groups on the phenyl rings also have a
beneficial effect in enhancing the reactivity.
3 4 2 3 2 3
PO , Na CO , Cs CO , and NaOMe instead of
K
(
2
3
in THF followed by treatment with Pd
2
(µ-Cl)
2 2 2
Me L (L )
8
PPh , PEt ) led to the formation of the corresponding Pd
3 3
complexes 2.
A great deal of interest has recently been devoted to
exploring the hindered Suzuki reaction due to the presence
of di-ortho-substituted biaryls in numerous natural products,
biologically active compounds, and valuable polymeric
9
materials. Despite considerable research effort, the coupling
of hindered aryl chlorides with di-ortho-substitution has so
The Suzuki coupling of less reactive aryl chlorides was
then investegated under the optimized reaction conditions
4
a,f
far brought only limited success.
Our main interest is
concerned with activation of sterically hindered as well as
electron-rich aryl chlorides under mild conditions.
Thus, we chose the coupling of 1-chloro-2,6-dimethyl-
benzene and p-tolyboronic acid as a model system for the
optimization study (Table 1). The reaction was carried out
(Figure 1). Deactivated aryl chlorides possessing electron-
donating groups reacted with p-tolyboronic acid in the
presence of 0.1 mol % of 2a at 50 °C (3a-d). Noteworthy
is that the catalyst system could promote the coupling of
2
-chloroaniline bearing a free amino group (3e). Regardless
2 3
in the presence of 0.1 mol % of 2a and 2.0 equiv of K CO
of the substituent, all of the coupling reactions were carried
out rapidly and efficiently to afford the desired biaryls in
high yields. It was also observed that catalyst 2a worked
well for the coupling of more challenging di-ortho-substituted
aryl chlorides while offering unprecedented reactivity and
wide substrate scope under the mild conditions (3f-k).
Additionally, hindered and electron-rich 4-chloro-3,5-dim-
ethylphenol having a free hydroxy group was successfully
combined with hindered 2,6-dimethylphenyl boronic acid to
give a tetra-ortho-substituted biaryl (3l). To the best of our
knowledge, catalyst 2a shows the highest catalytic activity
reported for the Suzuki coupling of sterically demanding aryl
chlorides.
as a base. We used aqueous ethanol as a reaction media for
economic benefit, even though the activity was accelerated
in other organic solvents (entries 1-3). To our delight, the
coupling proceeded very well at 50 °C to give the product
in excellent yield. A catalyst loading as low as 0.01 mol %
was also shown to be effective, although a comparatively
long reaction time was needed (entry 4). Moderate conver-
sions were observed even at 40-25 °C (entries 5 and 6).
(
6) (a) Bourget-Merle, L.; Lappert, M. F.; Severn, J. R. Chem. ReV. 2002,
02, 3031. (b) Franceschini, P. L.; Morstein, M.; Berke, H.; Schmalle, H. W.
Inorg. Chem. 2003, 42, 7273.
7) (a) Hadzovic, A.; Song, D. Organometallics 2008, 27, 1290. (b)
1
(
Holland, P. L. Acc. Chem. Res. 2008, 41, 905.
The Suzuki reaction has been used previously in the
(
8) Ladipo, F. T.; Anderson, G. K. Organometallics 1994, 13, 303.
10
(
9) (a) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
application of convenient diarylation of dibromobenzenes.
(
4
b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
From the viewpoint of efficiency, a one-pot double coupling
of inexpensive aryl dichlorides would be highly valuable for
4, 4442. (c) Yokoyama, A.; Suzuki, H.; Kubota, Y.; Ohuchi, K.;
Higashimura, H.; Yokozawa, T. J. Am. Chem. Soc. 2007, 129, 7236.
Org. Lett., Vol. 13, No. 2, 2011
253

Figure 1
Reaction conditions: Aryl chloride (1.0 mmol), arylboronic acid
1.3 mmol), 2a (0.1 mol %), K CO (2.0 mmol), EtOH-H O (2
mL, 1:1); Isolated yield.
. Suzuki coupling of aryl chlorides with arylboronic acids.
Figure 2
Reaction conditions: Aryl dichloride (1.0 mmol), arylboronic acid
2.5 mmol), 2a (0.15 mol %), K CO (3.0 mmol), EtOH-H O (3
mL, 1:1); Isolated yield.
. One-pot double Suzuki coupling of aryl dichlorides.
(
2
3
2
(
2
3
2
the synthesis of functionalized terphenyls. We proceeded to
investigate the double coupling with 0.15 mol % of 2a
Pd. 1,3,5-Triarylbenzenes were obtained exclusively in the
coupling of 1,3,5-trichlorobenzene with different arylboronic
acids at 60 °C (Figure 3).
(
Figure 2). An array of aryl dichlorides reacted with
arylboronic acids in a single pot to give the dicoupled
products in excellent yields (4a-h). In particular, we were
able to dicouple highly deactivated aryl dichlorides having
a strong electron-donating group such as a hydroxy and an
amino group (4i-l). During the diarylation, the monocoupled
adduct was scarcely formed. This catalytic system shows
great practical potential for the facile synthesis of terphenyls
via one-pot double couplings. To our knowledge, this is the
first example of a challenging double Suzuki reaction of aryl
dichlorides.
We further extended this concept to a one-pot quadruple
coupling (Figure 4). 1,2,4,5-Tetrachlorobenzene was coupled
uneventfully with arylboronic acids in the presence of 0.5
mol % Pd. All chlorine atoms were replaced by aryl groups
in high yields. Under these conditions, relatively hindered
2-chloro-1,3-dimethylbenzene was also found to be a capable
coupling partner in this reaction. These transformations open
up a one-step route to polyaryl-substituted aromatic com-
pounds from readily available and inexpensive polychlo-
robenzenes.
Polyarylbenzenes have attracted much attention in the field
1
1
of organic optical and electronic devices. A one-pot
multiple Suzuki coupling leading to such polyarylbenzenes
can be more challenging. It was possible to achieve a one-
pot triple coupling at a catalyst level as low as 0.3 mol %
All couplings of di-, tri-, and tetrachlorobenzenes with
various arylboronic acids in the presence of low catalyst
loadings of 2a afford the corresponding products in high
(
11) (a) Goal, A.; Singh, F. V.; Dixit, M.; Verma, D.; Raghunandan,
(
10) (a) Berthiol, F.; Kondolff, I.; Doucet, H.; Santelli, M. J. Organomet.
Chem. 2004, 689, 2786. (b) Dong, C.-G.; Hu, Q.-S. J. Am. Chem. Soc.
005, 127, 10006. (c) Hung, N. T.; Hussain, M.; Malik, I.; Villinger, A.
R.; Maulik, P. R. Chem.sAsian J. 2007, 2, 239. (b) Sergeyev, S.; Pisula,
W.; Geerts, Y. H. Chem. Soc. ReV 2007, 36, 1902. (c) Mahler, C.; M u¨ ller,
U.; M u¨ ller, W. M.; Enkelmann, V.; Moon, C.; Brunklaus, G.; Zimmermann,
H.; H o¨ ger, S. Chem. Commun. 2008, 4816. (d) Rathore, R.; Vyas, V. S.
Chem. Commun. 2010, 46, 1065.
2
Tetrahedron Lett. 2010, 51, 2420. (d) Sharif, M.; Zeeshan, M.; Reimann,
S.; Villinger, A.; Langer, P. Tetrahedron Lett. 2010, 51, 2810.
254
Org. Lett., Vol. 13, No. 2, 2011

Figure 4
robenzene. Reaction conditions: 1,2,4,5-tetrachlorobenzene (1.0
mmol), arylboronic acid (5.2 mmol), 2a (0.5 mol %), K CO (6.0
mmol), EtOH-H O (5 mL, 1:1).
. One-pot quadruple Suzuki coupling of 1,2,4,5-tetrachlo-
Figure 3
Reaction conditions: 1,3,5-trichlorobenzene (1.0 mmol), arylboronic
acid (3.9 mmol), 2a (0.3 mol %), K CO (5.0 mmol), EtOH-H
4 mL, 1:1).
. One-pot triple Suzuki coupling of 1,3,5-trichlorobenzene.
2
3
2
3
2
O
2
(
palladium species which promotes the cleavage of the inert
Ar-Cl bond in the rate-limiting oxidation step.
yields. This method would offer the attraction of reducing
the number of steps required to access highly aryl-substituted
arenes. These results represent a significant advancement in
the Suzuki coupling reaction.
In conclusion, we have developed a highly active and
general catalyst system for the Suzuki reactions of deacti-
vated or hindered aryl chlorides. Under these conditions,
efficient one-pot multiple Suzuki couplings were realized.
We anticipate that the application of this catalyst can be
extended to other catalytic processes.
An interesting structural feature of 2a concerns the
presence of bulky diketimine and an electron-rich trieth-
ylphosphine ligand exerting a positive influence on the redox
catalytic properties of palladium. However, it is unlikely that
both of these ligands simultaneously coordinate on palladium
through the catalytic cycle because the palladium complex
is not able to undergo the coupling alone with the one
remaining coordination site. It is envisaged that the catalytic
system will facilitate the formation of a catalytically active
Acknowledgment. This work was supported by a National
Research Foundation of Korea grant funded by the Korean
Government (2009-0072013).
Supporting Information Available: General experimental
procedures, synthesis characterization details, and copies of
1
13
31
1
c
H NMR, C NMR, and P NMR spectra. This material is
monophosphine complex. Although the mechanism of the
present coupling reaction is not yet obvious, the high activity
is probably attributed to the enhanced nucleophilicity of the
available free of charge via the Internet at http://pubs.acs.org.
OL102677R
Org. Lett., Vol. 13, No. 2, 2011
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