Unsymmetric-1,3-disubstituted imidazolium salt for palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of aryl bromides

Article abstract of DOI:10.1016/j.molcata.2006.01.034

A series of 1-(ferrocenylethyl)-3-substituted-imidazolium salts [3-substitute = 2,6-di(iso-propyl)phenyl (1a), 2,4,6-trimethylphenyl (1b), tert-butyl (1c), 1-Ad (1d), cyclohexyl (1e)] have been synthesized from a racemic ferrocenylethyl acetate and the corresponding N-substituted imidazole in high yields (70-94%). A combination of Pd(OAc)₂ and 1a-d was found to form an excellent catalyst system for the Suzuki-Miyaura cross-coupling reactions of aryl bromides with phenylboronic acid in the presence of Cs₂CO₃.

Full text of DOI:10.1016/j.molcata.2006.01.034

Journal of Molecular Catalysis A: Chemical 250 (2006) 15–19
Unsymmetric-1,3-disubstituted imidazolium salt for palladium-catalyzed
Suzuki–Miyaura cross-coupling reactions of aryl bromides
Hong-Wei Yua,b, Ji-Cheng Shib,∗, Hong Zhanga,b, Peng-Yu Yangb, Xin-Ping Wanga, Zi-Lin Jina
a State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, China
b State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
Received 10 October 2005; received in revised form 18 January 2006; accepted 19 January 2006
Available online 21 February 2006
Abstract
A series of 1-(ferrocenylethyl)-3-substituted-imidazolium salts [3-substitute = 2,6-di(iso-propyl)phenyl (1a), 2,4,6-trimethylphenyl (1b), tert-
butyl (1c), 1-Ad (1d), cyclohexyl (1e)] have been synthesized from a racemic ferrocenylethyl acetate and the corresponding N-substituted imidazole
in high yields (70–94%). A combination of Pd(OAc)2 and 1a–d was found to form an excellent catalyst system for the Suzuki–Miyaura cross-
coupling reactions of aryl bromides with phenylboronic acid in the presence of Cs2CO3.
© 2006 Elsevier B.V. All rights reserved.
Keywords: Palladium; Imidazol-2-ylidene; Suzuki–Miyaura reaction; Aryl bromides; Catalysis
1. Introduction
geneous catalysis, they require of air-free handling to prevent
their oxidation. Besides, they are subject to P C bond degrada-
tion at elevated temperatures [7], leading to that much excess
of phosphine is often practiced in such catalytic processes to
overcome these problems.
Since the discovery of stable N-heterocyclic carbene (NHC)
by Arduengo et al. [13], increasing attention has been focused
on using them as ancillary ligands; they are alternatives to
phosphines, and have been used for a variety of catalytic reac-
tions, including for palladium-catalyzed cross-coupling reac-
tions [7,14–17].
NHCs are characteristics of electron-rich nature, leading to
favoring oxidative addition and coordinating more tightly to the
Pd. Importantly, their steric properties are easily tunable through
the size of the substituents linking to the N atoms. Steric hin-
drance resulted from the size of the substituents to the N atoms
plays a crucial role for the catalytic performance of the palla-
dium catalyst coordinated by NHCs [7], and the couplings of
deactivated aryl chlorides with various arylboronic acids are
realized [7,16,17]. For 1,3-bis(2,6-dialkylphenyl)-imidazol-2-
ylidene ligating palladium catalysts, the catalytic performance
with iso-propyl substituent is much better than that with methyl
for the Suzuki–Miyaura cross-coupling reaction [7]. However,
the rigid steric bulkiness may disfavor the couplings between
the substrates with ortho substituents. Recently, Glorius and co-
workers introduced the notion of the flexible steric bulkiness,
Transition metal-catalyzed reactions dominate a funda-
mental roll in the modern organic chemistry [1]. Among
them, palladium-catalyzed cross-coupling reactions represent
an extremely versatile tool in organic synthesis [2]. Coupling
between organoboron reagents and aryl halides (or pseudo
halides), named as the Suzuki–Miyaura reaction [3], is one of
the most successful strategies for forming C C bonds. Many of
organoboron reagents used for the reaction are air- and moisture-
stable, and many of them are commercially available. Further-
more, the by-products produced from boron reagents, unlike the
tin-containing by-products of the Stille process [4], are nontoxic
and easily separated from the desired products.
The importance of the Suzuki–Miyaura reaction has attracted
muchattentiontoelevatetheefficiencyofthepalladiumcatalysts
[5–12]. Recently, employing sterically demanding and electron-
rich monodentate tertiary phosphines as supporting ligands has
resulted in the activation of inexpensive aryl chlorides as cou-
pling partners in the Suzuki–Miyaura reaction at room tempera-
ture [12]. Despite tertiary phosphines are effective in controlling
reactivity and selectivity in organometallic chemistry and homo-
∗
Corresponding author. Tel.: +86 591 8346 5225.
E-mail address: jchshi@fjnu.edu.cn (J.-C. Shi).
1381-1169/$ – see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2006.01.034

16
H.-W. Yu et al. / Journal of Molecular Catalysis A: Chemical 250 (2006) 15–19
Table 1
of which could vary in a range: to be large to meet steric hin-
drance required for the high activity of catalyst; to be small to
favor the couplings with sterically hindered substrates [14,15].
The exciting result with the flexible steric bulkiness is to be able
to realize to couple terically hindered aryl chlorides with aryl-
boronic acids. Along with the flexible notion, we were interested
in unsymmetric NHCs which may possess flexible steric hin-
drance produced by the different size of the two substituents on
the two sides of NHC. Here we report the catalytic performance
of some unsymmetric NHCs with different steric bulkiness at
one side for the Suzuki–Miyaura cross-coupling reactions.
Effect of imidazolium salts on Pd(OAc)2 catalyzed Suzuki–Miyaura cross-
coupling of 4-bromoanisole with phenylboronic acida
Entry
Ligand
Time (h)
Yieldb (%)
1
2d
3
4
5
1a
1a
1b
1c
1d
1e
3
3
3
3
3
9
94c
91c
93c
95c
2. Results and discussion
96(91)c
67e
6
2.1. Synthesis of unsymmetric
a
1,3-disubstituted-imidazolium iodides
Reaction conditions: 1.0 mmol of 4-bromoanisole; 1.5 mmol of phenyl-
boronic acid; 2.0 mmol of Cs2CO3; 3.0 mL of dioxane.
b
GC yield against a calibrated internal standard (undecane). Isolated yields
1,3-Disubstituted-imidazolium salts are conventional pre-
cursors of NHCs. Alkylation of N-substituted imidazole is a
convenient route to produce unsymmetric 1,3-disubstituted-
imidazolium salts [18]. With readily accessible racemic
ferrocenylethyl acetate (2) as alkylation reagent [19], five
of unsymmetric 1,3-disubstituted-imidazolium salts (1) with
different steric hindrance were obtained in 70–94% of yields
(Scheme 1). The structures of 1 are consistent with their
characteristic spectroscopic data.
in parentheses.
c
1–2% of biphenyl was observed.
Pd/L = 1/2.
3% of biphenyl was observed.
d
e
above reaction condition, although 1d is a little better (Table 1,
entry 5), achieving >90% of conversions of 4-bromoanisole,
an deactivated aryl bromide substrate, within 3 h. However, the
imidazolium salt 1e with cyclohexyl substituent only achieved
67% of conversion of 4-bromoanisole even after 9 h (Table 1,
entry 6). This trend of the catalytic reactivities of the synthesized
unsymmetric imidazolium salts is in agreement with the larger
hindrance of N-substituents enhancing activity [7]. The influ-
ence of ligand-to-palladium ratio was also investigated, found
that the 1:1 ratio of imidazolium salt to palladium is better than
2:1 in catalytic activity (Table 1, entry 2), which is consistent
with the observation by Nolan [7].
2.2. Influence of the imidazolium salts on Suzuki–Miyaura
cross-coupling reaction
We first compared the reaction between 4-bromoanisole and
phenylboronic acid using Pd(OAc)2 in dioxane with Cs2CO3
as base at 110 ◦C to test the effect of the imidazolium salts
(1) with different steric hindrance; the combination of palla-
dium source, base, and solvent is a classic reaction condition for
the Suzuki–Miyaura cross-coupling reaction using imidazolium
salts as a precursor of NHC ligands [7]. The NHC supported pal-
ladium catalysts could be produced in situ in the above reaction
condition; Cs2CO3 is an effective base to deprotonate imida-
zolium salts to generate NHCs, which subsequently coordinate
to palladium. The results were summarized in Table 1. The imi-
dazolium salts (1a–d) are comparable effective ligands in the
2.3. Effect of the base on Suzuki–Miyaura cross-coupling of
4-bromoanosole with phenylboronic acid
An brief investigation of the influence of a variety of bases
on the Pd(OAc)2/1d-catalyzed Suzuki–Miyaura cross-coupling
suggested that Cs2CO3 was the reagent of choice (Table 2,
Table 2
Effect of the base on Pd(OAc)2/1d catalyzed Suzuki–Miyaura cross-coupling
reaction of 4-bromoanisole with phenylboronic acid
Entry
Base
Time (h)
Yielda,b (%)
1
2
3
4
Cs2CO3
K2CO3
NaOtBu
KF
3
3
12
3
96
93
67
<10
Reaction conditions: 1.0 mmol of 4-bromoanisole; 1.5 mmol of phenylboronic
acid; 2.0 mmol of bases ; 2.0 mol% Pd (OAc)2; 3.0 mL of dioxane.
a
GC yields against a calibrated internal standard (undecane).
1–2% of biphenyl was observed.
b
Scheme 1. Synthesis of unsymmetric 1,3-disubstituted-imidazolium salts.

H.-W. Yu et al. / Journal of Molecular Catalysis A: Chemical 250 (2006) 15–19
17
Table 3
entry 1). K2CO3 [20] was also a comparably effective base
as Cs2CO3, and 93% of conversion for 4-bromoanisole was
achieved. As a generally used base for palladium-catalyzed
C–N formation, NaOtBu [21] only exhibited moderate
effect for palladium-catalyzed Suzuki–Miyaura reaction
with 1d as precursor of NHC. KF, a very effective base for
Pd2(dba)3/phosphine Suzuki–Miyaura reactions [22,23], in
turn, proved not efficient in the present system with 10% of con-
version for 4-bromoanisole. Since Pd(OAc)2 and imidazolium
salts could form NHC coordinating palladium complexes
without base in DMSO at 50 ◦C [24], the poor performance
of KF for Pd(OAc)2/1d system may not the reason that the
weak base cannot deprotonate imidazolium salts to form
NHC.
Pd(OAc)2/1d-catalyzed cross-coupling of aryl bromides with phenylboronic
acida
ArBr
Product
Time
2
Yieldb,c (%)
99(97)
1
2
3
96(91)
3
4
9
2
96(92)
99(94)
2.4. Substitution patterns and functional group tolerance
on aryl bromides
Since the Pd(OAc)2/1d system in the presence Cs2CO3 as
a base proves optimum for the coupling of the deactivated
4-bromoanisole with phenylboronic acid, it is not surprising
that the catalyst system is very effective for the nonactivated
and activated aryl bromides, as shown in Table 3. Compared
to MeO group at para-position, the aryl bromides with the
H, Me, and CF3 substituents are more easily converted with
high isolated yields of desired products (Table 3, entries 1,
4, and 11). However, the extension of reaction time was nec-
essary for the sterically congested substrates to achieve high
yields. For example, for the aryl bromides with one ortho-
methyl substitute, 6 h was consumed for achieving 98–99% of
conversions (entries 6 and 7); even for the activated aryl bro-
mide with withdrawing substitutes at ortho-position, 9 h was
needed for reaching 99% of conversion of 2-bromobenzonitrile
(entry 9). To our delight, 95% of conversion could be achieved
with the unsymmetric NHC supported palladium catalyst, even
for the aryl bromide with two ortho-methyl substituents [14],
which is a very sterically congested substrate. As expected,
nitrilo and keto functional groups were found to be compat-
ible under these reaction conditions (entries 9 and 10). In
all cases examined, only traces of homocoupling and dehalo-
genation product were found (1–2%). Unfortunately, attempts
to couple 4-chlorotoluene with phenylboronic acid were not
successful.
5
2
97(93)
6
7
6
6
98(93)
98(93)
8
9
16
95(90)
9
1
99(94)
99(97)
10
11
1
9
99(96)
99(92)
12
a
Reaction conditions: 1.0 mmol of ArBr; 1.5 mmol of phenylboronic acid;
2.0 mmol of Cs2CO3; 3.0 mL of dioxane; 110 ◦C (oil bath).
2.5. Conclusion
b
GC yields against a calibrated internal standard (undecane). Isolated yields
in parentheses.
c
A series of unsymmetric 1,3-disubstituted-imidazolium salts
derived from ferrocene were prepared and their prelimi-
nary behaviors as precursors of NHC ligands for palladium-
catalyzed cross-coupling of aryl bromides with phenylboronic
acid were examined. The bulkiness of NHC is an impor-
tant factor for realizing high activity of its supporting pal-
ladium catalyst. Excellent yields (>90%) were achieved
for a broad of aryl bromides, ranging from steric con-
gested, inactivated, to nitrilo and keto functionalized sub-
strates, at 1 mol% of loading of Pd(OAc)2/1d in the presence
Cs2CO3.
1–2% of biphenyl was observed.
3. Experimental
Unless stated otherwise, all reactions were carried out
using standard Schlenk-type glassware under an atmosphere
of nitrogen. Solvents were dried and distilled according to the
standard methods. Reagents were used as received. 1-(2,6-
Diisopropylphenyl)imidazole [25], 1-(2,4,6-trimethylphenyl)
imidazole [25] 1-tert-butylimidazole [25], 1-cyclohexy-

18
H.-W. Yu et al. / Journal of Molecular Catalysis A: Chemical 250 (2006) 15–19
limidazole [26], 1-(1-admantyl)imidazole [27], and ferro-
cenylethyl acetate [19] were synthesized according to literature
methods. Flash column chromatography was performed on
silica gel (200–300 mesh). 1H NMR and 13C NMR nuclear
magnetic resonance spectra were recorded on a Varian-400
spectrometer in CDCl3.
3.1.5. Synthesis of 1-(cyclohexyl)-3-
ferrocenylethylimidazolium iodide (1e)
Yield: 70%. 1H NMR (CDCl3, 400 MHz, TMS): δ 1.20–2.20
(11H, m), 1.92 (3H, d, J = 6.8 Hz), 4.10–4.40 (9H, m), 5.95–6.05
(1H, m), 7.14 (1H, s), 7.32 (1H, s), 10.1 (1H, s); 13C NMR
(CDCl3, 100 MHz): δ 21.5, 24.5, 24.8, 33.5, 56.5, 60.0, 66.1,
68.8, 68.9, 69.4, 69.6, 85.2, 119.9, 120.1, 133.8.
3.1. Synthesis of
1-(ferrocenylethyl)-3-substituted-imidazolium salt iodides
3.2. General protocol used for Suzuki–Miyaura
cross-coupling reaction with Pd(OAc)2
General procedure: ferrocenylethyl acetate (0.28 g,
1.0 mmol) and the corresponding substituted imidazole
(1.2 mmol) were stirred in 10 mL of CH3CN and 5 mL of H2O
for 24 h at 23 ◦C. Volatiles were evaporated, and a solution
of NaI (0.76 g, 5.0 mmol) in 20 mL of absolute ethanol was
added. After 24 h, the solvent was evaporated. The residue was
dissolved in CH2Cl2 and filtered through celite, and purified by
flash column chromatography (CH2Cl2/MeOH, 96:4).
Under an atmosphere of nitrogen, a Schlenk tube was charged
with 1,4-dioxane (3.0 mL), 1.0 mol% Pd(OAc)2 (4.6 mg,
0.01 mmol), 1.0 mol% 1 and base (2.0 mmol). After 30 min at
80 ◦C, the reaction mixture was cooled to room temperature and
the aryl halide (1.0 mmol), phenylboronic acid (1.5 mmol) were
addedinturn. TheSchlenktubewasplacedin110 ◦Coilbathand
stirred. The reaction was monitored by GLC. The mixture was
filtered through a pad of Celite, and the solvent was removed.
The residue was purified by flash chromatography (petroleum
ether/ethyl acetate, 15:1).
3.1.1. Synthesis of
1-(2,6-diisopropylphenyl)-3-ferrocenylethylimidazolium
iodide (1a)
Acknowledgements
Yield: 72%. 1H NMR (CDCl3, 400 MHz, TMS): δ 1.00–1.30
(12H, m), 2.08 (3H, d, J = 6.0 Hz), 2.10–2.30 (2H, m), 4.20–4.60
(9H, m), 6.70–6.75 (1H, m), 7.14 (1H, s), 7.30 (2H, d,
J = 4.4 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.78 (1H, s), 9.82 (1H, s);
13C NMR (CDCl3, 100 MHz): δ 21.3, 24.0, 24.1, 24.3, 24.4,
24.5, 24.6, 28.2, 28.7, 56.9, 65.8, 68.8, 68.9, 69.6, 69.9, 85.0,
121.2, 124.0, 124.2, 124.7, 130.1, 130.5, 131.9, 135.9, 145.2
[19].
This work was financially supported by the Knowledge Inno-
vation Program of the Chinese Academy of Sciences (DICP
R200309), the National Basic Research Program of China
(2003CB61615803), the National Natural Science Foundation
of China (20473089).
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