Room-temperature activation of aryl chlorides in Suzuki-Miyaura coupling using a [Pd(μ-Cl)Cl(NHC)]2 complex (NHC = N-heterocyclic carbene)

Article abstract of DOI:10.1039/b804695f

A straightforwardly synthesised complex, [Pd(μ-Cl)Cl(NHC)]₂ (NHC = bis(2,6-diisopropylphenyl)imidazol-2-ylidene, IPr), has been employed to mediate Suzuki-Miyaura reactions involving aryl chlorides at very low catalyst loadings and at room temperature. The Royal Society of Chemistry.

Full text of DOI:10.1039/b804695f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Room-temperature activation of aryl chlorides in Suzuki–Miyaura
coupling using a [Pd(l-Cl)Cl(NHC)] complex
2
(
NHC = N-heterocyclic carbene)w
a
b
a
ab
Olivier Diebolt, Pierre Braunstein, Steven P. Nolan and Catherine S. J. Cazin*
Received (in Cambridge, UK) 19th March 2008, Accepted 11th April 2008
First published as an Advance Article on the web 12th May 2008
DOI: 10.1039/b804695f
A straightforwardly synthesised complex, [Pd(l-Cl)Cl(NHC)]
NHC = bis(2,6-diisopropylphenyl)imidazol-2-ylidene, IPr),
2
solvents could be quite beneficial in the Suzuki–Miyaura
1
0
(
reaction with [PdCl(allyl)(NHC)] pre-catalysts. The trans-
formation of the Pd(II) complex into the ‘‘active’’ Pd(0) species
is key and the selection of the solvent/base couple is crucial in
generating the active species. Indeed, when moving to isopro-
has been employed to mediate Suzuki–Miyaura reactions invol-
ving aryl chlorides at very low catalyst loadings and at room
temperature.
t
panol as solvent and KO Bu as base, the desired biphenyl
The Suzuki–Miyaura reaction has become a classic in modern
1
molecular assembly protocols. It is used to synthesise speci-
product was obtained in 80% yield using 1 mol% of 1
(Table 1, entry 3). Screening of other alcohols (methanol,
ethanol) was performed (Table 1, entries 4 and 5) and ethanol
provided a yield of 87%, which is especially interesting in view
of economic and environmental issues.
2
alty polymers, agrochemical and pharmaceutical com-
3
4
pounds. The successful development of catalysts enabling
5
the Suzuki–Miyaura reaction with aryl chlorides started in
t
998 when Littke and Fu first reported the use of P Bu
1
3
to
In order to test the limits of this system, the catalyst
concentration was decreased by one order of magnitude. Here
again, an excellent result was obtained in ethanol and 87% of
4-methylbiphenyl was formed in the presence of 0.1 mol% of 1
after 4 h at r.t. (Table 1, entry 6). With the inexpensive
facilitate the Pd-mediated activation of the strong C–Cl aryl
6
halide bond.
A different class of ligands, the N-heterocyclic carbenes
7
NHC), can also enable this transformation. One of us, and
(
8
11
others, have contributed to this area with the development of
well-defined mono-NHC palladium complexes. Amongst
them, the air- and moisture-stable complex [Pd(m-Cl)Cl(IPr)]2
NaOMe, the catalyst also performed well but more slowly.
Indeed, after 4 h only 68% of biaryl was formed (Table 1,
a
Table 1 Optimisation (aerobic and anaerobic conditions)
1
(IPr = bis(2,6-diisopropylphenyl)imidazol-2-ylidene) has
been reported as an efficient pre-catalyst for the Buch-
9
wald–Hartwig reaction even under aerobic conditions. It
seemed thus of great interest to assess the catalytic perfor-
mance of 1 in the powerful C–C bond-forming reaction that is
the Suzuki–Miyaura coupling. Herein, we report that this
transformation can be achieved under mild reaction condi-
tions at low catalyst loading.z
b
t/h Conv. (%)
Entry Cat. loading (mol%) Solvent
Base
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1,4-Dioxane Cs CO
2
3
1
1
1
1
1
4
4
4
4
4
4
4
4
4
0
t
1,4-Dioxane KO Bu
PrOH
i
t
KO Bu
80
60
87
87
68
0
t
KO Bu
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
As shown in Table 1, the study begins with an optimisation
of the operating conditions on a model reaction involving
t
KO Bu
1
t
KO Bu
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
4
-chlorotoluene and phenylboronic acid. The first solvent/base
NaOMe
NaOH
mixture tested was 1,4-dioxane/Cs CO as it has proven to be
2
3
Cs
2
CO
CO
PO
3
6
efficient for in situ generated Pd–NHC catalysts and for
0
1
K
K
2
3
66
67
96
95
t
Pd–P Bu
only a small amount of coupling product was observed
Table 1, entry 1). We then moved to alkoxide bases that are
3
systems. However, with the well-defined system 1,
3
4
c
c
12
NaOMe
t c
KO Bu
1
1
1
16
17
1
1
2
3
4
5
(
d
1
NaOMe 0.5 82
known to facilitate the Suzuki–Miyaura reaction promoted by
well-defined NHC systems. Here again, no coupling product
was observed when 1,4-dioxane was used as the solvent
d
c
1
K
2
CO
3
0.5 55
0.5 38
0.5 57
d
c
1
K PO
4
3
c
d
1
CsF
d
ce
8
9
0
1
0.1
NaOMe 0.5 91
ce
(
Table 1, entry 2). It was recently reported that alcoholic
d
NaOMe
6
69
ce
1
NaOMe 0.5 99
d
t
KO Bu
ce
ce
ce
a
21
2
2
1
0.5
2
6
92
Institute of Chemical Research of Catalonia (ICIQ) Av. Paı¨sos
Catalans 16, Tarragona, 43007, Spain. E-mail: ccazin@iciq.es;
Fax: +34 977 920 244; Tel: +34 977 920 243
d
t
KO Bu
2
3
1
t
KO Bu
1
0.5 92
b
a
Laboratoire de Chimie de Coordination, Institut de Chimie (UMR
2
Reaction conditions: ArCl (0.5 mmol), ArB(OH) (0.525 mmol), base
b
(0.55 mmol), solvent (1 mL). Conversion to coupling product, based
7
177 CNRS), Universite´ Louis Pasteur, 4 rue Blaise Pascal,
Strasbourg, F-67070. E-mail: ccazin@chimie.u-strasbg.fr
c
on ArCl, determined by GC. Base 0.75 mmol. Aerobic conditions.
d
w Electronic supplementary information (ESI) available: Character-
isation data for all organic products. See DOI: 10.1039/b804695f
e
2
ArCl = 0.6 mmol, ArB(OH) = 0.5 mmol.
3
190 | Chem. Commun., 2008, 3190–3192
This journal is ꢀc The Royal Society of Chemistry 2008

View Article Online
a
entry 7) whereas after 6 h the yield reached 83%. It is
noteworthy that some inorganic bases allow for the formation
of the coupling product under these conditions. This is of great
importance as it shows that alkoxide-sensitive substrates could
still be efficiently coupled using catalyst 1 (Table 1, entries 10
and 11). However, for the latter cases, longer reaction times
did not lead to further conversion to product. Using an excess
of alkoxide base, in ethanol, led to a slightly improved catalyst
performance, as the coupling product was obtained in an
almost quantitative yield within 4 h at r.t. (Table 1, entries
Table 2 Coupling of hindered substrates with arylboronic acids
0
b
t/h Yield (%)
Entry R
n
R
n
Product
1
3-OMe H
20 87
2
2-OMe H
20 96
1
2 and 13). To our delight, with 1 mol% of 1, the test reaction
rapidly led to product at r.t. in air (Table 1, entries 14–18).
This was also observed when inorganic bases were used. The
optimum and most economical base, NaOMe, also permits the
aerobic reaction to be performed with 0.1 mol% of 1 (Table 1,
entry 19). As shown in entry 20, conducting the reaction under
an argon atmosphere leads to a slight increase in activity when
NaOMe is used. Indeed, almost complete conversion is ob-
tained after 0.5 h compared to 91% under aerobic conditions
3
4
2-Me
H
24 86
24 72
2,6-Me H
(
entry 18). In contrast, when carrying out such experiments in
t
the presence of KO Bu, a deleterious effect of the presence of
air is seen (see entries 21–23). This poor catalytic performance
t
might be attributed to the known instability of KO Bu in air
5
6
4-Me 2,4,6-Me
4-Me 2,4-(OMe)
24 82
and moisture conditions.
The assessment of the efficiency of a catalytic system is its
performance with challenging substrates. Some of these are
listed in Table 2 and present sterically hindered C–C biaryl
junctions. Only a few palladium systems are capable of
c
24 78
1
2
performing these couplings. The optimised reaction condi-
tions (0.1 mol% of 1, EtOH/NaOMe) were then employed to
perform Suzuki–Miyaura reactions with the substrates listed
in Table 2. Entries 2 and 3 clearly illustrate that the coupling is
feasible with singly ortho-substituted coupling partners as the
product is formed at room temperature in good isolated yields.
A double substitution in ortho positions to the carbon atom to
be coupled is also tolerated under these conditions (Table 2,
entries 4 and 5). As shown in entry 6, the presence of OMe
groups in ortho positions results in more sluggish reactions.
This can be explained by the propensity of oxygen to act as a
donor atom thus stabilising the Pd-centre. This slow kinetic
profile can be overcome by heating the reaction mixture to
7
8
9
2,6-Me 2-Me
24 80
24 36
2-Me 2,6-Me
c
20 84
2-Me 2,6-(OMe)
6
0 1C since the catalyst is thermally stable. Tri-ortho-substi-
tuted biaryls can also be generated at r.t. (Table 2, entries 7
and 8). Again, the presence of OMe groups led to slower
reactions. The system can generate tri-ortho substituted biaryls
containing two MeO groups (Table 2, entry 9) in good isolated
yields while products bearing three ortho-MeO groups
c
24 29
1
0
2-OMe 2,6-(OMe)
(
Table 2, entry 10) proved difficult to obtain.
Furthermore, other interesting substrates, as they are ubi-
quitously encountered in the pharmaceutical industry, and
also considered as ‘‘challenging’’, are the heteroaromatic
halides. It seemed thus relevant to test 1 in a number of
cross-couplings involving pyridines and thiophenes. The reac-
tions carried out using 2- and 3-chloropyridines (2-Clpy,
a
Reaction conditions: ArCl (0.5 mmol), ArB(OH)
2
(0.525 mmol),
NaOMe (0.75 mmol), EtOH (1 mL), r.t., 0.1 mol% [Pd(m-Cl)-
Cl(IPr)]
b
c
Isolated yields are the average of two runs. Reaction
2
.
performed at 60 1C.
3
-Clpy), with non-optimised reaction times, led from good
to excellent isolated yields at a low catalyst concentration
Table 3, entries 1–4). The coupling depicted in entry 1 proved
proved facile as almost complete conversion is reached at r.t.
after 20 h. This suggests that the catalytic cycle goes through
an o-tolyl–Pd–aryl intermediate complex, which drives the
reductive elimination of the product because of steric pressure
(
difficult at r.t. (17% isolated yield after 20 h) but led to 69%
after 20 h at 60 1C. In contrast, the coupling depicted in entry 2
This journal is ꢀc The Royal Society of Chemistry 2008
Chem. Commun., 2008, 3190–3192 | 3191

View Article Online
Table 3 Coupling of heterocycles, 2-chloropyridine (2-Clpy), 3-chloro-
Fund administered by the ACS and the Ministerio de Educa-
pyridine (3-Clpy) and 2-chlorothiophene (2-ClC
arylboronic acids
4 3
H S), with
cion y Ciencia for financial support and Umicore for gifts of
´
a
chemicals. S. P. N. is an ICREA Research Professor.
b
Yield (%)
Entry Heterocycle ArB(OH)
2
Product
c
1
2
2-Clpy
2-Clpy
PhB(OH)
2
69
Notes and references
z Optimised protocol for Suzuki–Miyaura reactions: In a glovebox, a
o-tolylB(OH)
2
2
2
99
4
mL screwcap-vial containing a magnetic stirring bar was charged
with sodium methoxide (40.5 mg, 0.75 mmol), the boronic acid (0.525
mmol) and fitted with a septum. Outside the glovebox, the required
amount of catalyst solution (catalyst loading 0.1 mol%) was injected
through the septum, followed by addition of technical grade degassed
ethanol (1 mL). The mixture was then stirred at room temperature
unless otherwise indicated. After 15 min, the aryl halide (0.5 mmol)
was injected, and the reaction was monitored by gas chromatography.
When the reaction reached completion, or no further conversion was
observed by gas chromatography, the solvent was removed under
vacuum and the resulting solid was filtered on a pad of silica (using
hexanes–ethyl acetate mixtures, depending on the polarity of the
product). When necessary, the product was purified by flash chroma-
tography on silica gel.
c
3
4
3-Clpy
3-Clpy
PhB(OH)
2
91
c
70
o-tolylB(OH)
5
6
2-ClC
4
4
H
3
3
S
S
PhB(OH)
2
87
79
For reactions carried out under aerobic conditions, all solids were
weighed in air. The solvents were dried over molecular sieves and all
liquids were injected in vials opened to air.
2-ClC
H
o-tolylB(OH)
1
. N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–2483;
A. Suzuki, J. Organomet. Chem., 1999, 576, 147–168; A. Suzuki,
Chem. Commun., 2005, 4759–4763.
2
. A. Yokoyama, H. Suzuki, Y. Kubota, K. Ohuchi,
H. Higashimura and T. Yokozawa, J. Am. Chem. Soc., 2007,
a
2
Reaction conditions: ArCl (0.5 mmol), ArB(OH) (0.525 mmol),
129, 7236–7237.
. S. L. Hargreaves, B. L. Pilkington, S. E. Russell and
P. A. Worthington, Tetrahedron Lett., 2000, 41, 1653–1656.
NaOMe (0.75 mmol), EtOH (1 mL), 20 h, r.t., 0.1 mol%
c
3
b
[
Pd(m-Cl)Cl(IPr)]
2
.
Isolated. Reaction performed at 60 1C.
4
. K. C. Nicolaou, J. M. Ramanjulu, S. Natarajan, S. Bra
H. Li, C. N. C. Boddy and F. Rubsam, Chem. Commun., 1997,
899.
¨
se,
¨
brought about by the presence of the ortho methyl group.
Entry 3 involves a fragment where the heteroatom is in a
position meta with respect to the chloride. These have been
1
5
6
7
. R. B. Bedford, C. S. J. Cazin and D. Holder, Coord. Chem. Rev.,
2004, 248, 2283–2321.
. A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 1998, 37,
1
3
historically more difficult to couple due to electronic effects.
3
387–3388.
Finally, entry 4 highlights the extent of this electronic deacti-
vation that overrides the steric pressure-release caused by the
ortho methyl substituent.
. N. Marion, O. Navarro, J. Mei, E. D. Stevens, N. M. Scott and
S. P. Nolan, J. Am. Chem. Soc., 2006, 128, 4101–4111;
O. Navarro, N. Marion, J. Mei and S. P. Nolan, Chem.–Eur. J.,
2006, 12, 5142–5148.
. J. W. Sprengers, J. Wassenaar, N. D. Clement, K. G. Cavell and
C. J. Elsevier, Angew. Chem., Int. Ed., 2005, 44, 2026–2029;
Thiophenes also represent an important class of compounds
since they can be used in a Suzuki–Miyaura protocol to form
8
1
4
conducting polymers. The examples illustrated in Table 3
with 2-chlorothiophene (2-ClC H S) (entries 5 and 6) clearly
R. Jackstell, M. Go
A. Zapf, H. Klein, A. Spannenberg, D. Ro
R. Karch and M. Beller, Angew. Chem., Int. Ed., 2002, 41,
86–989.
´
mez Andreu, A. Frisch, K. Selvakumar,
¨
ttger, O. Briel,
4
3
show thiophenes to be tolerated and compatible with the
present method as high yields of coupling products were
obtained at r.t. with 0.1 mol% catalyst loading.
9
9
. M. S. Viciu, R. M. Kissling, E. D. Stevens and S. P. Nolan, Org.
Lett., 2002, 4, 2229–2231.
1
0. O. Navarro, R. A. Kelly, III and S. P. Nolan, J. Am. Chem. Soc.,
003, 125, 16194–16195.
2
In conclusion, [Pd(m-Cl)Cl(IPr)] 1, is an excellent pre-
2
1. Prices for 500 g of bases: NaOMe: 21.40h; NaOEt: 33.50h;
catalyst for the Suzuki–Miyaura coupling involving challen-
ging aryl chlorides at low catalyst loading and under mild and
economical reaction conditions. Studies aimed at extending
the scope of 1 to other types of cross-coupling and related
reactions are currently ongoing in our laboratories.
1
t
KO Bu: 78.80h (Prices taken from the 2007/2008 Aldrich
catalogue).
1
2. G. Altenhoff, R. Goddard, C. W. Lehmann and F. Glorius,
Angew. Chem., Int. Ed., 2003, 42, 3690–3693.
3. I. J. S. Fairlamb, Chem. Soc. Rev., 2007, 36, 1036–1045.
1
We thank the C.N.R.S., the Ministe
`
re de la Recherche
14. R. Miyakoshi, A. Yokoyama and T. Yokozawa, J. Polym. Sci.,
Part A: Polym. Chem., 2008, 46, 753–765.
(
Paris), the ICIQ Foundation (OD), the Petroleum Research
3
192 | Chem. Commun., 2008, 3190–3192
This journal is ꢀc The Royal Society of Chemistry 2008