Suzuki-Miyaura cross-coupling of aryl and alkyl halides using palladium/imidazolium salt protocols

Article abstract of DOI:10.1016/j.tetlet.2004.02.134

A simple new protocol for the high yielding Suzuki-Miyaura cross-couplings of aryl chlorides with aryl boronic acids using a palladium/imidazolium salt catalytic system is presented. The first examples of a palladium/imidazolium salt protocol for sp³-sp³ Suzuki-Miyaura couplings of alkyl halides are also disclosed.

Full text of DOI:10.1016/j.tetlet.2004.02.134

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3511–3515
Suzuki–Miyaura cross-coupling of aryl and alkyl halides
using palladium/imidazolium salt protocols
a,
c
Katherine Arentsen,a Stephen Caddick,b,* F. Geoffrey N. Cloke, Adam P. Herring
*
and Peter B. Hitchcocka
aDepartment of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK
bDepartment of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK
cAstraZeneca, R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK
Received 28 January 2004; revised 17 February 2004; accepted 27 February 2004
Abstract—A simple new protocol for the high yielding Suzuki–Miyaura cross-couplings of aryl chlorides with aryl boronic acids
using a palladium/imidazolium salt catalytic system is presented. The first examples of a palladium/imidazolium salt protocol for
sp3–sp3 Suzuki–Miyaura couplings of alkyl halides are also disclosed.
Ó 2004 Elsevier Ltd. All rights reserved.
Palladium-catalysed formation of carbon–carbon and
carbon–heteroatom bonds have become an extremely
powerful tool for the organic chemist.1 Such bond for-
mations, in which an organometallic reagent is coupled
to an organic electrophile, are widely used in the prep-
aration of many natural products,2 as well as in other
branches of synthetic chemistry and materials science.3
Amongst the palladium-catalysed cross-coupling pro-
cesses, the Suzuki–Miyaura reaction has emerged as one
of the most popular,4 owing, in part, to the tolerance of
the reaction to a wide range of functional groups on
both substrates. The ease of separation of the nontoxic
boron containing reaction by-product from the desired
product has ensured that the reaction has found exten-
sive use in the pharmaceutical industry.
tron-neutral as well as electron-rich aryl chlorides to be
achieved.
N-Heterocyclic carbenes (NHCs) are often considered
phosphine mimics and have consequently received a
great deal of attention as alternatives to phosphine-
based ligands in Pd-catalysed chemistry. NHCs are
useful alternative ligands to phosphines because the
increased thermal stability of the Pd–NHC bond avoids
the necessity for excess ligand. This can be a problem in
Pd/phosphine-based catalytic systems due to the facile
Table 1. Imidazolium salt ligands in a Suzuki–Miyaura coupling of an
aryl chloride
Pd(dba)2 (3 mol%)
Ligand (3 mol%)
KOMe (3 mol%)
As with many other Pd-catalysed coupling processes, the
use of aryl chlorides (particularly those that are elec-
tron-rich) in the Suzuki–Miyaura reaction was, until
recently, uncommon.5 New catalytic systems, utilising
palladacyclic complexes,6 electron-rich trialkylphos-
phine ligands7 and the bulky biphenyl-based phosphines
developed by Buchwald and co-workers,8 amongst
others, have allowed couplings of electron-poor, elec-
(HO)2B
2M Na2CO3 (2.5 eq.)
toluene/EtOH
Cl
°
70 C, 5-6 h
Entry
Ligand
Yield (%)a
1
2
3
4
IAdÆHCl
IPrÆHCl
It-BuÆHClb
IPrÆHCl
0
17
0
87c
Keywords: Palladium; Suzuki; Aryl chlorides; Alkyl bromides.
* Corresponding authors. Tel./fax: +44-020-76794694 (S.C.); tel.: +44-
01273-678735; fax: +44-01273-677196 (F.G.N.C.); e-mail addresses:
s.caddick@ucl.ac.uk; f.g.cloke@sussex.ac.uk
a Isolated yield.
b It-BuÆHCl ¼ 1,3-bis(tert-butyl)imidazolium chloride.
c KOMe (3 equiv) used instead of Na2CO3.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.134

3512
K. Arentsen et al. / Tetrahedron Letters 45 (2004) 3511–3515
Table 2. Suzuki–Miyaura reactions of aryl chlorides using IPrÆHCl
Pd(dba)2 (3 mol%)
IPr.HCl (3 mol%)
(HO)2B Ar1
Ar Ar1
Ar Cl
KOMe (3 eq.)a
Toluene/MeOH
TBAB (10 mol%)
40 oC
Entry
1
Ar–Cl
(HO)2B–Ar1
Time (h)b
24
Yield (%)c
0d
O N
2
Cl
Cl
(HO) B
2
2
3
24
24
93
75
O N
2
(HO) B
2
Cl
(HO) B
2
4
5
6
7
8
24
5
91
79
75
75
99
(HO) B
2
Cl
Cl
Cl
(HO) B
2
5
(HO)2B
6
(HO) B
2
MeO
MeO
Cl
23
(HO) B
2
Cl
OMe
Cl
9
29
78
(HO) B
2
10
11
6
91
92
(HO) B
2
OMe
Cl
Cl
29
O
O
(HO)2B
O
12
13
14
10
8
83
82
86
(HO) B
2
Cl
(HO) B
2
CF
3
Cl
N
29
Cl
(HO)2B
(HO)2B
O
S
15
29
61
Cl
aKOMe in MeOH added at 0 °C.
b Reaction time not optimised.
c Isolated yield.
d No TBAB used.

K. Arentsen et al. / Tetrahedron Letters 45 (2004) 3511–3515
3513
degradation of the P–C bond at elevated temperatures.9
In many catalytic processes where NHCs are employed
as the ancillary ligand, the corresponding imidazolium
salt is used and is deprotonated in situ, possibly to give
the NHC, thus avoiding the problems of handling the
air- and moisture-sensitive carbene.
Despite the success we observed with the coupling of
4-chlorotoluene and phenylboronic acid, we were dis-
appointed to find that the coupling of 1-chloro-4-
nitrobenzene with phenylboronic acid was completely
unsuccessful under the optimised reaction conditions
(Table 2, entry 1). Previous work has shown that the use
of tetra-n-butylammonium bromide (TBAB) in the Heck
reaction facilitates the reaction and leads to improved
yields.16 Encouragingly, when a sub-stoichiometric
amount (10 mol %) of TBAB was used in the coupling of
1-chloro-4-nitrobenzene with phenylboronic acid, the
reaction proceeded to 93% conversion (Table 2, entry 2).
Table 2 shows that this methodology is compatible with
a variety of functional groups on both substrates. The
catalytic system, with the TBAB additive, was tolerant
of both electron-donating and electron-withdrawing
substituents, resulting in excellent yields. It is particu-
larly noteworthy that these reactions proceed at 40 °C
and this present protocol offers a practical method for
Suzuki–Miyaura couplings of aryl and hetero-aryl
chlorides.
Work by Herrmann and co-workers,10 Nolan and
12
co-workers11 and Furstner and Leitner has shown that
€
Suzuki–Miyaura couplings can be achieved using Pd/
imidazolium salt protocols. These reactions have been
carried out at elevated temperatures (70–80 °C) and
usually with an excess of organoborane. In this Letter,
we describe our own findings on the Suzuki–Miyaura
reactions of electron-rich and electron-deficient aryl
chlorides at significantly lower temperatures (40 °C)
using a Pd/1,3-bis(2,6-diisopropylphenyl)imidazolium
chloride (IPrÆHCl) catalytic system (1:1 Pd/ligand
ratio).13 These aryl couplings are very sensitive to the
reaction conditions. We also describe the first examples
of Suzuki–Miyaura alkyl–alkyl couplings, employing a
palladium/NHC protocol.
Our working model for the mechanism of this trans-
formation involves the in situ deprotonation of the
imidazolium salt to the free carbene, which is then
believed to bind to palladium to form a mono-ligated
Pd–NHC complex. This complex is considered to be the
catalytically active species, which then undergoes oxi-
dative addition. In order to demonstrate that such a
palladium(0) species is catalytically active in the
reactions, we sought to isolate a bis-carbene Pd(0) spe-
cies, which could be tested in these cross-coupling pro-
cesses.
Initial experiments used the sterically encumbered ada-
mantyl-substituted imidazolium salt, 1,3-bis(adaman-
tyl)imidazolium chloride (IAdÆHCl). This ligand has
been successfully used by Herrmann and co-workers14
and we anticipated that an in situ protocol based on this
imidazolium salt would be particularly facile. However,
when IAdÆHCl was used as an ancillary ligand in the
coupling of 4-chlorotoluene with phenylboronic acid,
none of the desired product, 4-phenyltoluene, was
obtained. Different imidazolium salts were evaluated in
the reaction and, in accordance with the findings of
12
Furstner and Leitner, the best results were obtained
€
The synthesis of 1 was carried out as shown in Scheme
110;14 and crystals suitable for X-ray diffraction were
obtained from a toluene solution at )50 °C (Fig. 1). The
geometry at Pd is essentially linear with a C1–Pd–C2
angle of 175.98° and the angle of torsion between the
planes of the two NHC ligands was found to be 51.7°,
which indicates that the Pd centre is less sterically
crowded than in other Pd(NHC)2 complexes, for
example, 95.6° in bis(1,3-bis(adamantyl)imidazol-2-
ylidene)palladium(0)14 and 90° in bis(1,3-bis(tert-
butyl)imidazol-2-ylidene)palladium(0).17
with the IPrÆHCl imidazolium salt (Table 1). We found
that the use of KOMe (3 equiv) as the sole base vastly
improves the reaction outcome compared to the results
obtained using catalytic amounts of KOMe and
Na2CO3 (Table 1). It is also vital to the success of the
cross-coupling procedure that the exotherm generated
upon addition of base is controlled by prior cooling of
the reaction medium and slow addition.
Studies by Nolan and co-workers have demonstrated
that Suzuki–Miyaura reactions can be sensitive to
changes in Pd(0)/imidazolium salt ratios, with a 1:1 ratio
being optimal.15 However, we found that there was no
apparent difference in product yields when different
Pd(0)/ligand ratios were used; with both the 1:1 ratio
and 1:2 ratio giving yields of 87%.
Complex 1 was able to catalyse the Suzuki–Miyaura
coupling of 4-chloroanisole with phenylboronic acid in
68% yield (Scheme 2), complete conversion was achieved
after 22 h (a similar yield but longer reaction time than
the analogous Pd/IPrÆHCl protocol).
Ar
N
Ar
N
Ar
Ar
N
N
THF
60 o
Pd(P(o-tol)3)2
2
2 P(o-tol)3
Pd
C
N
Ar
N
Ar
1
47%
Ar:
Scheme 1. Synthesis of bis(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)palladium(0) 1.

3514
K. Arentsen et al. / Tetrahedron Letters 45 (2004) 3511–3515
Our attention then turned to alkyl–alkyl couplings using
a Suzuki–Miyaura protocol employing an imidazolium
salt. The major issue associated with methodologies of
this type is that of b-hydrogen elimination.18 In recent
years, Fu and co-workers have exploited the different
steric and electronic properties of various phosphine
ligands to design successful catalytic systems for the
coupling of alkyl halides and tosylates with organo-
boranes.19 Recent work by Fu has also demonstrated
the first examples of the use of an imidazolium salt
protocol to mediate Sonogashira couplings of sp3-
hybridised alkyl halides.20 Here we show the first
application of imidazolium salts for sp3–sp3 Suzuki–
Miyaura cross-couplings.
Initial experiments demonstrated that, in the coupling of
1-bromohexane to B-(4-propylanisole)-9-BBN, KOt-Bu
was the most effective base and Pd(dba)2 the most suc-
cessful palladium source. Elevation of the reaction
temperature to 40 °C was found to be beneficial to the
reaction outcome. A number of different imidazolium
salts were examined in the reaction, however, after
considerable experimentation, we found that IPrÆHCl
Figure 1. X-ray structure of 1 (thermal ellipsoids at the 50% proba-
ꢀ
bility level). Selected bond distances (A) and angles (°): Pd–
C1 ¼ 2.022(4), C1–N2 ¼ 1.377(5), N2–C4 ¼ 1.387(5), C4–C3 ¼
1.338(5), C3–N1 ¼ 1.377(5), N1–C1 ¼ 1.379(4); C1–Pd–C2 ¼ 175.98,
N1–C1–N2 ¼ 101.0(3), C1–N2–C4 ¼ 112.9(3), N2–C4–C3 ¼ 106.2(3),
C4–C3–N1 ¼ 106.9(3), C3–N1–C1 ¼ 112.9(3).
MeO
MeO
(HO)2B
1 (3 mol%)
KOMe (3 eq.)
Cl
TBAB (10 mol%)
68%
toluene
40 oC, 22 h
Scheme 2. Suzuki–Miyaura reaction of an aryl chloride using 1.
Table 3. Suzuki–Miyaura reactions of alkyl bromides using IPrÆHCl
Pd(dba)2 (4 mol%)
IPr.HCl (8 mol%)
R–R1
R
Br
R1 (9-BBN)
KOt-Bu (1.2 eq.)
AgOTf (4 mol%)
°
THF, 40 C, 24 h
Entry
1
R–Br
Br
R1–(9-BBN)a
Yield (%)b
56
(CH ) CH
2 9
3
(9-BBN)
(9-BBN)
2
3
4
46
39
37
Br
MeO
MeO
(9-BBN)
(CH ) CH
2 9
3
3
Br
Br
(9-BBN)
(CH ) CH
2 9
O
5
6
7
53
52
28
(9-BBN)
Br
Br
OEt
CN
4
(9-BBN)
4
(CH ) CH
2 9
3
BnO
(9-BBN)
Br
a Organoboranes prepared from 9-BBN dimer (0.6 equiv) and terminal alkene/alkyne (1.2 equiv), not isolated or purified prior to use.
b Isolated yield.

K. Arentsen et al. / Tetrahedron Letters 45 (2004) 3511–3515
3515
4. Reviews: (a) Suzuki, A. J. Organomet. Chem. 1999, 576,
147–168; (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457–2483; (c) Suzuki, A. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, 1998.
5. For a review on aryl chlorides in cross-coupling reactions,
see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002,
41, 4176–4211.
was optimal. Table 3 shows preliminary results for a
selection of sp3–sp3 Suzuki–Miyaura couplings.
Although the yields are modest for these transforma-
tions, their success is noteworthy. As with the aryl
Suzuki–Miyaura couplings, we were able to confirm that
the isolated complex 1 could be used, although at this
stage the yields are poor (around 20%) and do not yet
represent a practical procedure.
6. Bedford, R. B.; Cazin, C. S. J. Organometallics 2003, 22,
987–999.
In summary, we have developed a new imidazolium salt
protocol for efficient and high yielding aryl Suzuki–
Miyaura cross-couplings, employing aryl chlorides and
boronic acids. We have also confirmed that two-coor-
dinate palladium carbene complexes can promote these
transformations. Key to success has been the use of
TBAB.21 We have also presented the first evidence that
sp3–sp3 Suzuki–Miyaura reactions are possible using
certain imidazolium salt protocols.
7. Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020–4028.
8. (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
1999, 38, 2413–2416; (b) Wolfe, J. P.; Singer, R. A.; Yang,
B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550–
9561.
9. Jafarpour, L.; Nolan, S. P. Adv. Organomet. Chem. 2001,
46, 181–222.
€
€
10. Bohm, V. P. W.; Gstottmayr, C. W. K.; Weskamp, T.;
Herrmann, W. A. J. Organomet. Chem. 2000, 595, 186–
190.
11. Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org.
Chem. 1999, 64, 3804–3805.
€
12. Furstner, A.; Leitner, A. Synlett 2001, 290–292.
Acknowledgements
13. IPrÆHCl available from Strem Chemicals, catalog number:
07-0590.
We thank AstraZeneca and EPSRC for financial sup-
port of this work. We also thank Glaxo-SmithKline and
BBSRC for the support of our program. We also thank
the University of Sussex for providing funds to establish
the Centre for Biomolecular Design and Drug Devel-
opment. We also gratefully acknowledge the contribu-
tions of Dr. A. G. Advent, Dr. A. Abdul-Sada and the
EPSRC Mass Spectroscopy Service at Swansea.
€
€
14. Gstottmayr, C. W. K.; Bohm, V. P. W.; Herdtweck, E.;
Grosche, M.; Herrmann, W. A. Angew. Chem., Int. Ed.
2002, 41, 1363–1365.
15. Grasa, G. A.; Viciu, M. S.; Huang, J.; Zhang, C.; Trudell,
M. L.; Nolan, S. P. Organometallics 2002, 21, 2866–
2873.
16. Caddick, S.; Kofie, W. Tetrahedron Lett. 2002, 43, 9347–
9350.
17. Arnold, P. L.; Cloke, F. G. N.; Geldbach, T.; Hitchcock,
P. B. Organometallics 1999, 18, 3228–3233.
ꢁ
18. Cardenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384–387.
19. (a) Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C.
€
References and notes
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Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chich-
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Principles and Applications of Organotransition Metal
Chemistry; University Science Books: Mill Valley, CA,
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20. Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
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21. For the use of TBAB in Pd free Suzuki reactions, see:
Leadbeater, N. E.; Marco, M. Angew. Chem., Int. Ed.
2003, 42, 1407–1409.