N-Heterocyclic carbene/phosphite synergistically assisted Pd/C-catalyzed Suzuki coupling of aryl chlorides

Article abstract of DOI:10.1002/aoc.3076

An N-heterocyclic carbene and phosphite synergistically enhanced Pd/C catalyst system has been developed for Suzuki coupling of aryl chlorides and aryl boronic acids from commercially available Pd/C with sterically demanding N,N′-bis(2,6-diisopropylphenyl)imidazolylidene and trimethylphosphite. A remarkable increase in catalytic activity of Pd/C was observed when used along with 1 equiv. N,N′-bis(2,6-diisopropylphenyl)imidazolium chloride and 2 equiv. phosphite with respect to palladium in appropriate solvents that were found to play a crucial role in Pd/C-NHC-P(OR)₃-catalyzed Suzuki coupling. A dramatic ortho-substitution effect of carbonyl and nitrile groups in aryl chlorides was observed and explained by a modified quasi-heterogeneous catalysis mechanism. The Pd/C catalyst could be easily recovered from reaction mixtures by simple filtration and only low palladium contamination was detected in the biparyl products. A practical process for the synthesis of 4-biphenylcarbonitrile has therefore been developed using the N-heterocyclic carbene/phosphite-assisted Pd/C-catalyzed Suzuki coupling. Copyright

Full text of DOI:10.1002/aoc.3076

Full Paper
Received: 26 July 2013
Revised: 27 August 2013
Accepted: 1 September 2013
Published online in Wiley Online Library: 6 November 2013
(wileyonlinelibrary.com) DOI 10.1002/aoc.3076
N-Heterocyclic carbene/phosphite synergistically
assisted Pd/C-catalyzed Suzuki coupling of
aryl chlorides
Haihua Ke, Xiaofeng Chen and Gang Zou*
An N-heterocyclic carbene and phosphite synergistically enhanced Pd/C catalyst system has been developed for Suzuki
coupling of aryl chlorides and aryl boronic acids from commercially available Pd/C with sterically demanding N,N′-bis
(2,6-diisopropylphenyl)imidazolylidene and trimethylphosphite. A remarkable increase in catalytic activity of Pd/C was
observed when used along with 1 equiv. N,N′-bis(2,6-diisopropylphenyl)imidazolium chloride and 2 equiv. phosphite
with respect to palladium in appropriate solvents that were found to play a crucial role in Pd/C-NHC-P(OR)3-catalyzed
Suzuki coupling. A dramatic ortho-substitution effect of carbonyl and nitrile groups in aryl chlorides was observed
and explained by a modified quasi-heterogeneous catalysis mechanism. The Pd/C catalyst could be easily recovered from
reaction mixtures by simple filtration and only low palladium contamination was detected in the biparyl products. A
practical process for the synthesis of 4-biphenylcarbonitrile has therefore been developed using the N-heterocyclic
carbene/phosphite-assisted Pd/C-catalyzed Suzuki coupling. Copyright © 2013 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web site.
Keywords: Suzuki coupling; palladium on carbon; N-heterocyclic carbene; phosphite; aryl chloride
Pioneered by Nolan and co-workers,[34–36] palladium catalysts
supported by single sterically demanding N-heterocyclic carbene
Introduction
Suzuki cross-coupling represents the most popular method for
production of unsymmetrical biaryls because of the friendly
properties of organoboronic acids, e.g. non-toxicity, air/moisture
stability and tolerance of a variety of functional groups.[1–4] Since
the discovery of this reaction, innumerable improvements on the
original protocol have been reported, especially with respect to
catalysts, which have led to some highly efficient systems.[5–9]
Potential in industrial applications has become a major concern
in further development of this technique. In this context, the
use of heterogeneous palladium catalysts has attracted increasing
attention because of the drawbacks of homogeneous transition
metal catalysis, such as tedious catalyst separation processes, loss
of expensive noble metal and residual metal impurities in the
products.[10–15] Although a variety of heterogeneous palladium
(NHC) ligands have proven not only highly efficient but also more
practical than air-sensitive palladium/phosphine catalysts in
cross-coupling. Organ and Nolan and co-workers have further
developed an elegant strategy to increase the catalytic activities
of Pd/NHC catalysts by introduction of a secondary labile ancillary
ligand, such as pyridines[37–39] or phosphites.[40] However, to the
best of our knowledge, there is no report on using NHC to
enhance the catalytic activity of Pd/C in Suzuki coupling. We
report herein Suzuki coupling of aryl chlorides catalyzed by
commercially available Pd/C with synergistic assistance from
sterically demanding NHCs and phosphites in environmentally
friendly alcohol solvent.
catalysts have been reported for Suzuki coupling, most of them Results and Discussion
are either less active or more tedious to prepare, and/or give less
reproducible results than their homogeneous counterparts. There-
Establishment of Catalyst System
fore, there has been an increasing interest to use commercially
available Pd/C for development of practical Suzuki coupling
procedures.[16–26] In fact, both of the commercially available
reduced and unreduced Pd/C catalysts have proven to be efficient
for Suzuki coupling of active aryl halides, such as aryl iodides and
bromides. However, it is still a challenge to use Pd/C to catalyze
Suzuki coupling of more practical aryl chlorides unless harsh
conditions or extra additives, such as tetrabutylammonium bro-
mide, were used.[27–30] Alternatively, the activity of Pd/C has to be
enhanced by the introduction of homogeneous phosphine ligands
to effect a so-called quasi-heterogeneous catalysis,[31–33] which is
believed to be, in fact, homogeneous catalysis of ligand-stabilized
palladium species leaching from insoluble Pd/C.
Suzuki coupling of phenylboronic acid (1a) with 4-chloroacetophenone
(2a) was chosen as the model reaction using commercially
available 5% Pd/C as a catalyst to screen reaction conditions
(Table 1). The yields of the desired product, 4-phenylacetophenone
(3aa), increased to 26% using 0.5 mol% palladium (5% Pd/C)
and N,N′-bis(2,6-diisopropylphenyl)imidazolylidene (IPr, used
*
Correspondence to: G. Zou, Department of Fine Chemicals, East China Univer-
sity of Science and Technology, 130 Meilong Rd, Shanghai, China. Email:
zougang@ecust.edu.cn
Department of Fine Chemicals, East China University of Science and Technology,
Shanghai, China
Appl. Organometal. Chem. 2014, 28, 54–60
Copyright © 2013 John Wiley & Sons, Ltd.

Ligand-enhanced heterogeneous catalysis
Table 1. Suzuki coupling of 4-chloroacetophone with phenylboronic acida
Entry
NHC/L
—/—
Cat. mol% (Pd/NHC/L)
Solvent
Baseb
Temp. (°C)c
T (h)
Yield (%)d
1
0.5/—/—
0.5/0.5/—
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/2
0.5/0.5/0.5
0.5/0.5/0.25
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/—/1
DMF
K3PO4.3H2O
K3PO4.3H2O
K3PO4.3H2O
K3PO4.3H2O
K3PO4.3H2O
K3PO4.3H2O
K3PO4.3H2O
K3PO4.3H2O
K2CO3
110
110
110
100
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
10
10
10
10
10
10
10
10
10
6
4
26
53
98
62
99
98
31e
28
98
91
67
60
75
97
95
49
99
83
79
Trace
38
64
88
54
/
2
IPr/—
DMF
3
IPr/P(OPh)3
IPr/P(OPh)3
IPr/P(OPh)3
IPr/P(OPh)3
IPr/P(OPh)3
IPr/P(OPh)3
IPr/P(OPh)3
IPr/P(OPh)3
IPr/P(OPh)3
IPr/Py
DMF
4
Dioxane
tBuOH
iPrOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26f
27g
28
29
30
31h
32i
NaOH
KOH
6
NaOH
10
10
10
6
IPr/Et3N
NaOH
IPr/NMI
NaOH
IPr/P(OPh)3
IPr/P(OPh)3
IPr/P(OPh)3
IPr/P(OMe)3
IPr/P(OEt)3
IPr/P(OiPr)3
—/P(OMe)3
IPr/—
NaOH
NaOH
10
10
4
NaOH
NaOH
NaOH
10
10
10
10
10
10
10
10
10
7
NaOH
NaOH
0.5/0.5/—
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.5/0.5/1
0.3/0.3/0.6
0.2/0.2/0.4
0.1/0.1/0.2
0.5/0.5/1
0.5/0.5/1
NaOH
IMes/P(OMe)3
SIPr/P(OMe)3
SIMes/P(OMe)3
NHC/P(OMe)3
NHC/P(OMe)3
IPr/P(OMe)3
IPr/P(OMe)3
IPr/P(OMe)3
IPr/P(OMe)3
IPr/P(OMe)3
NaOH
NaOH
NaOH
NaOH
NaOH
7
NaOH
96
87
13
98
95
NaOH
10
10
4
NaOH
NaOH
NaOH
4
aReaction run at 1 mmol scale with 5% Pd/C (Sinopharm Chemical Reagent), IPr used in form of IPr.HCl.
b2.0 equiv. K3PO4.3H2O or K2CO3 or 1.3–1.4 equiv. KOH or NaOH.
cBath temperature.
dIsolated yields.
e5% H2O in EtOH.
fNHC = N,N′-bis(butyl)imidazolylidene and no reaction detected.
gNHC = N,N′-bis(butyl)benzimidazolylidene.
h5% Pd/C from Alfa Aesar.
i5% Pd/C from Acros.
in the form of IPr.HCl with Pd/IPr = 1:1 mol/mol) from 4% using
Pd/C alone under a condition, K3PO4 in DMF, that has proven
compatible for homogeneous NHC-Pd(OAc)2 or NHC-PdCl2 sys-
tems.[41] With the assistance of a secondary ancillary ligand –
triphenylphosphite (2.0 equiv. relative to palladium) – the yield
of 3aa further increased to 53% under otherwise identical
conditions (Table 1, entries 1–3). It is well known that bis
(NHC) palladium complexes are overwhelmingly dominating
species in solution in the presence of excess NHC but generally
show low catalytic activities in Suzuki coupling. Therefore, con-
sidering the quasi-heterogeneous catalysis of Pd/C in Suzuki
coupling,[31–33] the unsatisfactory performance of Pd/C-IPr-P
Appl. Organometal. Chem. 2014, 28, 54–60
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

H. Ke et al.
(OPh)3 in the preliminary investigation may be attributed to the
favorable formation of bis(NHC) palladium complexes (IPr)2Pd
over more active heteroligated (IPr)Pd[P(OR)3]n, since only a
small portion of palladium generally leaches into solution from
Pd/C, while a large excess IPr relative to the leached palladium
would be possibly present in solution. We anticipated that an
appropriate solvent, in which the NHC (IPr) and/or its precursor
(IPr.HCl) are also mainly absorbed on to carbon, would solve the
problem. In fact, solvents did affect the catalytic activity of Pd/C-
NHC-P(OPh)3 significantly. When the model reaction was run in
dioxane, the yield of 3aa increased to 98% under otherwise iden-
tical conditions (Table 1, entry 4). We have recently reported a
highly efficient homogeneous Pd/NHC/P(OPh)3 catalyst system for
Suzuki coupling of diaryl borinic acids using K3PO4.3H2O as base
in tert-BuOH.[42] Therefore, we tested alcohol solvents for the Pd/C-
IPr-P(OPh)3 catalyst system. Although it occurred less efficiently in
tert-BuOH, the model reaction proceeded as well in environmentally
friendly alcohol solvents – isopropanol and ethanol – as in dioxane
(Table 1, entries 5–7). No reaction took place when water was used
as solvent. In fact, water appeared to be deleterious to the catalytic
activity of Pd/C-IPr-P(OPh)3 even in alcohol solution. However, no
extra step was needed to remove water from commercial solvents
for the model reaction. Stronger bases, especially cheap NaOH
and KOH, also performed well with appropriate stoichiometry
(1.3 equiv.), while the reaction proceeded much more slowly
with a weaker base such as K2CO3. N-containing ancillary
ligands, such as 3-chloropyridine (3-ClPy),[37–39] Et3N (TEA)[43]
and N-methylimidazole (NMI),[44–47] have been reported to
remarkably improve the efficiency of homogeneous Pd-NHC
catalyst systems in various cross-couplings. For example, the
desired biaryls could be obtained in excellent yields from
Suzuki coupling of aryl chlorides by using the structurally
well-defined complexes (IPr)PdCl2(TEA)[43] or (IPr)PdCl2(NMI)[46]
as catalysts even at room temperature, while the seminal (IPr)
PdCl2(3-ClPy)[9,37,39] performed better in Kumada and Negishi
couplings. However, these N-containing ancillary ligands
appeared to be less compatible with Pd/C in the model reaction,
giving product 3aa only in modest yields (Table 1, entries
12–14). The success of phosphites possibly benefits from a
ligand synergy between the σ-donor NHC and π-acceptor
phosphite originally proposed by Jamison and co-workers.[48]
The influence of structure and stoichiometry of phosphites on
the catalytic activity of the Pd/C-IPr-P(OR)3 catalyst system was
investigated. The system performed consistently well with more
than 1 equiv. of P(OPh)3 (1–4 equiv.) with respect to Pd/C-IPr
loading, while lower stoichiometry, such as 0.5 equiv. P(OPh)3,
showed little effect compared with the Pd/C-IPr combination
alone (Table 1, entries 7 and 15–17). The smallest-volume
phosphite, P(OMe)3, showed a slightly higher activity than
P(OPh)3, while P(OEt)3 and P(OiPr)3 worked less efficiently
in the system (Table 1, entries 18–20). Compared with the re-
sults of control experiments using Pd/C-P(OR)3 and Pd/C-IPr
catalyst systems, the enhanced catalytic efficacy of Pd/C-IPr-P
(OR)3 to aryl chlorides implied that the true catalytic species
should be palladium co-supported by NHC and phosphite
(NHC)Pd[P(OR)3]n (Table 1, entries 21 and 22). From a practical
point of view, trimethylphosphite P(OMe)3 has an obvious
advantage over P(OPh)3 with respect to cost owing to its higher
atom economy and lower price. The structure of NHCs proved
more crucial than that of phosphites to the activity of the
Pd/C-NHC-P(OR)3 catalyst system. With use of less sterically
demanding N,N′-bis(mesityl)imidazolylidene (IMes), both the
rate and product yield of the model reaction decreased signif-
icantly, while only trace product 3aa was detected or isolated
with simple NHCs of N,N′-bis(butyl)imidazolylidene and N,N′-
bis(butyl)benzimidazolylidene under otherwise identical condi-
tions. The saturated analogues of sterically demanding NHCs –
N,N′-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene
(SIPr) and N,N′-bis(mesityl)phenyl)-4,5-dihydroimidazol-2-ylidene
(SIMes) – also displayed lower activity (Table 1, entries 23–27). Re-
ducing the loading of Pd/C-IPr-P(OMe)3 catalyst system from 0.5
to 0.2mol%, the product yields decreased slightly from 98% to
87%. In fact, 0.3mol% palladium loading appeared to be sufficient
to obtain the coupling product 3aa in excellent yield (96%), al-
though the model reaction failed to complete with 0.1mol% cata-
lyst loading (Table 1, entries 28–30). Pd/C catalysts from different
commercial sources showed negligible influence on the activity
of the Pd/C-IPr-P(OMe)3 catalyst system (Table 1, entries 31 and 32).
Scope and Limitation
The scope of the Pd/C-IPr-P(OMe)3-catalyzed Suzuki coupling was
investigated under the optimized conditions (Table 2). Electron-
rich (deactivated) aryl chlorides reacted with more difficulty than
electron-deficient (activated) ones and gave products in poor
yields unless a higher loading (1 mol%) of palladium was used.
An ortho hetero-atom containing unsaturated groups, such as
carbonyls and nitrile, on the aromatic ring of aryl chlorides
unexpectedly blocked the Pd/C-IPr-P(OMe)3-catalyzed Suzuki
coupling. For example, almost no reaction was detected for
2-chloroacetophenone (2c) or even the highly active 2-
bromoacetophenone (2d), although 3-chloroacetophenone (2b)
reacted well, similar to 4-chloroacetophenone (2a), to give cross-
coupling product 3ab in 95% yield under otherwise identical con-
ditions (Table 2, entries 1–5). Similarly, 3- or 4-chlorobenzonitriles
reacted smoothly, while 2-chlorobenzonitrile failed (Table 2,
entries 8–15). Control experiments indicated that the ortho-
substituent effect should be attributed to the heterogeneous
palladium source, since the reactions of 2-chloroacetophenone
(2c) and 2-chlorobenzonitrile (2h) occurred to provide the desired
products 3ac and 3ah, respectively, in excellent yields using Pd
(OAc)2 (94%, 95%) or PdCl2 (93%) as palladium source for the
Pd-IPr-P(OMe)3 catalyst system (Table 2, entries 6, 7 and 16).
Surprisingly, this ortho-substituent effect would appear not to
be from a simple steric hindrance associated with heteroge-
neous catalyst. The reaction of 2-chlorotoluene (2i) proceeded
as smoothly as that of 4-chlorotoluene (2l) and even the
deactivated 2-methoxyphenyl chlorides reacted with 1 mol%
catalyst loading to give 3ak (41%) (Table 2, entries 17–22). These
results implied that the substituent nature beyond steric
hindrance, e.g. absorption on carbon,[27,49] may also play a
key role.
Electronic and steric effects from aryl boronic acids on the
Pd/C-IPr-P(OMe)3-catalyzed reaction were also investigated. In
contrast to aryl chlorides, the electronic effect of aryl boronic
acids on the Pd/C-IPr-P(OMe)3-catalyzed Suzuki reaction was
rather small except for the proton-deboronation side reaction
of electron-deficient aryl boronic acids, which could be com-
pensated for by slightly increasing the loading of aryl boronic
acids. For example, all the investigated aryl boronic acids with
an electron-donating or -withdrawing group at the para posi-
tion on the aromatic ring, e.g. methyl (Me, 92%), methoxyl
(MeO, 96%), fluoro (F, 90%), acetyl (Ac, 78–95%) and cyano
wileyonlinelibrary.com/journal/aoc
Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 54–60

Ligand-enhanced heterogeneous catalysis
Table 2. Scope of the cross-coupling of aryl boronic acids with aryl chloridesa
Entry
R1(1)
H(1a)
X
R2(2)
Pd (mol%)
Time (h)
3
Yield (%)b
1
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
3-COMe(2b)
2-COMe(2c)
2-COMe(2c)
2-COMe(2c)
2-COMe(2d)
2-COMe(2c)
2-COMe(2c)
4-CN(2e)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.03(Pd/C)
0.3(PdCl2)
0.3(Pd(OAc)2)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.03(Pd/C)
0.3/(Pd/C)
0.3/(Pd/C)
0.3/(Pd/C)
0.3/(Pd/C)
0.3(Pd(OAc)2)
1(Pd/C)
4
4
3ab
3ac
3ac
3ac
3ac
3ac
3ac
3ae
3ae
3ae
3ae
3ag
3ah
3ah
3ah
3ah
3ai
95
8c
17c,d
9c,e
5c
2
H(1a)
3
H(1a)
4
4
H(1a)
4
5
H(1a)
4
6
H(1a)
3
93
7
H(1a)
3
94
8
H(1a)
3
93
9
H(1a)
4-CN(2e)
3
97e
95d
98
10
11
12
13
14
15
16
17f
18
19
20 f
21
22
23
24
25
26
27
28
29
30
31
32
33
H(1a)
4-CN(2e)
3
H(1a)
4-CN(2f)
1
H(1a)
3-CN(2g)
6
82
7c
4c,e
11c,d
95
H(1a)
2-CN(2h)
6
H(1a)
2-CN(2h)
6
H(1a)
2-CN(2h)
6
H(1a)
2-CN(2h)
3
H(1a)
2-Me(2i)
10
6
86
H(1a)
2-Me(2j)
0.03(Pd/C)
1(Pd/C)
3ai
96
H(1a)
2-OMe(2k)
4-Me(2l)
10
10
10
10
5
3ak
3al
41
H(1a)
1(Pd/C)
82
H(1a)
4-OMe(2m)
4-OMe(2m)
4-CO2Me(2n)
3-CO2Et(2o)
4-COMe(2a)
4-COMe(2a)
4-COMe(2a)
4-COMe(2a)
4-COMe(2a)
4-COMe(2a)
4-COMe(2a)
4-COMe(2a)
4-COMe(2a)
0.3(Pd/C)
1(Pd/C)
3am
3am
3an
3ao
3ba
3ca
3da
3ea
3fa
31
H(1a)
73
95g
H(1a)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd/C)
0.3(Pd(OAc)2)
H(1a)
5
89
4-Me(1b)
2-Me(1c)
2-Et(1d)
4-F(1e)
4-OMe(1f)
4-COMe(1g)
4-CN(1h)
2-COMe(1i)
2-COMe(1i)
8
92
10
10
8
74
53
90
8
96
5
3ga
3ha
3ia
78(95)h
65(86)h
Tracec
30c
5
5
5
3ia
aReaction run at 1 mmol scale with 5% Pd/C (Sinopharm Chemical Reagent).
bIsolated yields.
cArCl recovered.
d5% Pd/C from Acros.
e5% Pd/C from Alfa Aesar.
f3 equiv. aryl chloride relative to aryl boronic acid due to its low bp.
gEthyl biphenyl-4-carboxylate isolated due to exchange with ethanol.
h1.3 equiv. arylboronic acid used due to proton-deboronation.
(CN, 65–86% ) provided the desired products in good to
excellent yields (Table 2, entries 25 and 28–31). However, an
obvious steric effect was observed. For example, reaction of
2-methylphenyl boronic acid with 4-chloroacetophenone 2a
gave the cross-coupling product 3ca (74%) in significantly
lower yield than 3ba from 4-methylphenyl boronic acid
(92%). The yield of cross-coupling product 3da further decreased
to 53% for the more sterically demanding 2-ethylphenyl boronic
acid (1d) (Table 2, entries 26 and 27). 4-Acetyl and 4-cyanophenyl
boronic acids reacted with 2a to provide 3ga and 3ha in good
yields, respectively, although 1.3 equiv. aryl boronic acids had to
be used due to proton-deboronation of electron-deficient aryl
boronic acids (Table 2, entries 30 and 31). The failure of reaction
of 2-acetylphenyl boronic acid (1i) with 2a using the Pd/C-IPr-P
(OMe)3 system may be at least partly due to the instability of the
former under the reaction conditions since a low yield (30%) was
obtained even using the homogeneous catalyst system Pd(OAc)2-
IPr-P(OMe)3.
Appl. Organometal. Chem. 2014, 28, 54–60
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H. Ke et al.
Mechanistic Explanation
reaction as originally proposed.[32] Therefore, the original
quasi-heterogeneous catalysis mechanism has been slightly
modified (Scheme 2).
The unexpected ortho-substitution effect of carbonyl and nitrile
groups in aryl halides on the Pd/C-IPr-P(OMe)3-catalyzed Suzuki
coupling appeared to be consistent with a quasi-heterogeneous
catalysis proposed by Conlon, Simeone and Sowa and co-workers
for ligand-assisted Pd/C catalysis.[31,32] In the quasi-heterogeneous
catalysis, Pd/C just serves as a reservoir of homogeneous
ligand-stabilized palladium species that forms from the ligand
and palladium leaching from the carbon frame to solution
induced by oxidative addition of ArX to Pd(0) and eventually
redeposits on the carbon surface as the reaction nears com-
pletion. The aryl halides with an ortho-carbonyl or nitrile sub-
stituent on the aromatic ring obviously failed to contact the
active palladium site on carbon, possibly due to steric hin-
drance as well as absorption of the heterogeneous catalyst.[49]
Subsequently, the oxidative-addition induced leaching of
palladium particles from the carbon frame to solution was
blocked, which, in turn, led to failure of the catalysis. According to
the quasi-heterogeneous catalysis mechanism, it is easy to antici-
pate that if there is an appropriate ArX in the reaction solution to
induce palladium leaching from the carbon frame to solution by
oxidative-addition of ArX to Pd(0), then the resulting homogeneous
catalytic species would be able to catalyze the Suzuki coupling of
ortho-carbonyl or nitrile-substituted aryl halides since the homoge-
neous catalyst systems Pd-IPr-P(OMe)3 from Pd(OAc)2 and PdCl2
worked well. To test this, 4-chloroacetophenone (2a) was added
on purpose to the reaction of 2-chloroacetophenone (2c) with
phenylboronic acid catalyzed by 0.5mol% Pd/C-IPr-P(OMe)3, which
had failed under otherwise identical conditions. After 10 h, the
reaction was quenched and the components in the crude reaction
mixture were analyzed by 1H NMR (Scheme 1).
It can be seen that the coupling between 2-chloroacetophenone
(2c) and phenylboronic acid (1a) gave the coupling product
3ac in about 30% yield (by 1H NMR) after 10 h when 1 mol%
4-chloroacetophenone (2a) was added to the reaction mixture,
while almost no reaction occurred in the absence of 2a.
However, the conversion of 2-chloroacetophenone (2c) was only
slightly increased to about 50% when the amount of 2a was
increased to 10 mol%. These results implied that the homoge-
neous catalytic palladium species forming via ligand stabiliza-
tion of the leaching palladium from Pd/C could not constantly
exist in solution during the reaction progress. In other words,
the redeposition of homogeneous catalytic palladium species
on the carbon surface should occur during the whole reaction
progress instead of only taking place near completion of the
In the modified mechanism, the oxidative-addition induced
palladium leaching should occur at the site where palladium
could be ligated by NHC at least, if not NHC and P(OR)3 syn-
ergistically, considering the nearly complete non-activity of
Pd/C in the absence of NHC (Table 1, entry 21). The homoge-
neous catalytic palladium species (NHC)Pd[P(OR)3] could, at
least partly, redeposit on the carbon surface throughout the
progress of the reaction and has to re-leach to solution by
the oxidative-addition of ArX to the Pd(0) process to start a
new catalytic cycle.
Application Exploration
To demonstrate the potential of the NHC/phosphite-promoted
Pd/C-catalyzed Suzuki coupling in practical applications, a process
has been developed for the synthesis of 4-biphenylcarbonitrile
(3ae), the key intermediate for the production of 3,6-di(biphenyl-
4-yl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione (C.I. DPP-264),[50]
a
high-performance red pigment. Currently, 4-biphenylcarbonitrile
is mainly produced on an industrial scale from biphenyl through
Friedel–Crafts acylation or alkylation, followed by a set of functional
group conversions, generating a lot of waste. Therefore, it is
important to develop practical and environmentally friendly
processes. The synthesis of 4-biphenylcarbonitrile (3ae) from
4-halobenzonitriles and phenylboronic acid via the NHC/
phosphite-promoted Pd/C-catalyzed Suzuki coupling was
conducted at a 0.1 mol scale so that the desired biaryl product
could be isolated by recrystallization instead of chromatogra-
phy. Using the Pd/C-IPr-P(OMe)3 catalyst system, the reaction
of 4-chlorobenzonitrile with phenylboronic acid completed in
3 h under the above optimized conditions (Scheme 3). The Pd/
C catalyst was readily separated from the mixture by simple
filtration along with inorganic by-products and recovered by
washing with ethanol and water to remove organic and
inorganic materials, respectively. Elemental analysis (inductively
coupled plasma–atomic emission spectroscopy (ICP-AES)) of
palladium indicated that more than 90% Pd was recovered.
Unfortunately, almost no reactivity was found for the recovered
Pd/C
deactive
NHC
Pd/C*
Ar-Cl
NHC
solid
activation stage
0.5mol%
Pd/C-IPr HCl-P(OMe)3
(1/1/2, mol/mol)
solution
(NHC)Pd[(POR)3]
Ar-Ar'
O
Ar-Cl
P(OR)3
NaOH (1.3equiv.)
EtOH, 80oC, 10h
B(OH)2
Cl
O
catalytic cycle
4-chloroacetophenone (2a)
+
P(OR)3
P(OR)3
3ac
Ar Pd NHC
Ar'
1a
2c
Ar Pd NHC
Cl
reaction mixture after 10h
2a added
0 mol%(2a):
1 mol%(2a):
10 mol%(2a):
3ac(trace) + 2c(>98%)
B(OH)3 + Cl-
Ar'B(OH)2, OH-
3ac(30%) + 2c(70%) + 3aa(trace)
3ac(48%) + 2c(50%) + 3aa(7%) + 2a(2%)
Scheme 2. A slightly modified mechanism for the NHC/phosphite
Scheme 1. Test of the quasi-heterogeneous catalysis mechanism.
synergistically assisted Pd/C-catalyzed Suzuki coupling of aryl chlorides.
wileyonlinelibrary.com/journal/aoc
Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 54–60

Ligand-enhanced heterogeneous catalysis
1.1 equiv.
PhB(OH)2
Experimental
CN
0.03~0.3mol% cat.
1.3 equiv. NaOH
EtOH, 80oC, 1-3 h
X
Materials and Methods
All reactions were carried out under an N2 atmosphere unless
otherwise stated. Commercially available chemicals were used
as received. N,N′-bis(2,6-diisopropylphenyl)imidazolium chloride
(IPr.HCl),[34] N,N′-bis(mesityl)imidazolium chloride (IMes.HCl),[34] N,N′-
bis(butyl)imidazolium chloride,[41] N,N′-bis(butyl)benzimidazolium
NC
X = Cl, 0.3 mol% cat., 3h, 93-95% yields
X = Br, 0.03 mol% cat.,1h, 97% yield
chloride,[41]
N,N′-bis(2,6-diisopropylphenyl)imidazolidinium
Scheme 3. Synthesis of 4-biphenylcarbonitrile by the Pd/C-IPr-P(OMe)3-
catalyzed Suzuki coupling.
bromide (SIPr.HBr)[52] and N,N′-bis(mesityl)imidazolidinium bro-
mide (SIMes.HBr)[52] were prepared according to previously
reported procedures. 1H and 13C NMR spectra were recorded in
CDCl3 at ambient temperature. Chemical shifts in NMR were
reported in ppm (δ), relative to the internal standard of
tetramethylsilane. High-resolution mass spectrometry (HRMS)
was performed on an electron ionization mass spectrometer
with a quadrupole analyzer. Elemental analysis (including
ICP-AES) was conducted at the Analysis Center of ECUST.
The known compounds were identified by their spectral data
of 1H NMR and 13C NMR (see supporting information), while
characterization of the new compound 3da is given below.
Pd/C in the coupling reaction possibly because of redeposition
of palladium on to the carbon support that left the palladium
in a different form.[31,32,51] The filtrate was simply concentrated
to afford crude 3ae, in which the palladium residue was about
40 ppm (about 2–2.5% of the total quantity of palladium load-
ing). The pure product 3ae was obtained after recrystallization
from ethanol as white fine crystals in 93–95% yield over
repeated experiments. The palladium contamination in the
product was less than 5 ppm by ICP-AES. Considering the loss
of activity of recovered Pd/C catalyst in the coupling, we also
investigated the reaction of 4-bromobenzonitrile with
phenylboronic acid to synthesize 3ae, which required much
lower loading of palladium catalyst. It was found that
0.03 mol% Pd/C-IPr-P(OMe)3 catalyst loading with respect to
4-bromobenzonitrile was sufficient for the coupling reaction
to complete within 1 h under otherwise identical conditions
and provide 4-biphenylcarbonitrile (3ae) in 97% yield.
Typical Procedure for Cross-Coupling Reactions of Aryl
Chlorides
Under an N2 atmosphere, to a 10 ml flask were added 4-
chloroacetophenone (130 μl, 1.0 mmol), phenylboronic acid
(0.13 g, 1.1 mmol), 5% Pd/C (0.003 mmol, 6.5 mg dried Pd/C or
13 mg wet Pd/C (containing 50% w/w water), IPr.HCl
(0.003 mmol, 30 μl of 0.1 M stock solution in EtOH), P(OMe)3
(0.7 μl, 0.006 mmol), NaOH (1.3 ml, 1 M stock solution in EtOH)
and EtOH (2.0 ml). The mixture was stirred at 80°C and monitored
by thin-layer chromatography until 4-chloroacetophenone was
completely consumed. The reaction mixture was diluted with
CH2Cl2 (15 ml), filtered and washed with H2O. The organic layer
was dried over Na2SO4, followed by filtration and solvent removal
with a rotavapor to give the crude product. The pure product was
obtained by column chromatography on silica gel with EtOAc/
petroleum ether.
Conclusions
The catalytic activity of commercially available 5% Pd/C in Suzuki
coupling of aryl chlorides has been remarkably increased by
using it along with a synergistic σ-donor and π-acceptor pair of
ligands: N,N′-bis(2,6-diisopropylphenyl)imidazolylidene (IPr) and
trimethylphosphite. For activated aryl chlorides, the coupling
reaction with aryl boronic acids could be effected to give the
desired biaryl products in excellent yields with 0.3 mol%
palladium (5%Pd/C) loading along with 0.3 mol% IPr.HCl and
0.6 mol% P(OMe)3. The structure of the NHCs showed a
significant impact on the activity of the Pd/C-NHC-phosphite
catalyst system. The most sterically demanding N,N′-bis(2,6-
diisopropylphenyl)imidazolylidene performed best among the
tested NHCs. A dramatic ortho-substitution effect of carbonyl
and nitrile groups in aryl chlorides was observed, which
could be attributed to steric hindrance and absorption
associated with heterogeneous Pd/C. The original quasi-
heterogeneous catalysis mechanism for ligand-assisted Pd/
C-catalyzed Suzuki coupling has been modified according to
the experimental results. The potential of the NHC/phosphite
synergistically promoted Pd/C-catalyzed Suzuki coupling in
practical applications has been demonstrated by developing
a practical process for synthesis of 4-biphenylcarbonitrile,
a key intermediate for production of C.I. DPP-264, from
4-halobenzonitriles and phenylboronic acid using sodium
hydroxide as a base in environmentally friendly ethanol
solvent. The Pd/C catalyst could be easily removed from reac-
tion mixtures and less than 5 ppm palladium contamination
was detected in the final product after one recrystallization.
1-(2′-Ethylbiphenyl-4-yl)ethanone (3da)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.01 (d, J = 8.4 Hz,
2H, H-3, H-5), 7.42 (d, J = 8.4 Hz, 2H, H-2, H-6), 7.34–7.33 (m, 2H, H-
3′, H-5′), 7.27–7.23 (m, 1H, H-4’), 7.18 (d, J = 7.2 Hz, 1H, H-6’), 2.65
(s, 3H, COCH3), 2.59 (q, J = 7.6 Hz, 2H, CH2), 1.09 (t, J = 7.6 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ (ppm):197.9(C O), 147.1 (C-1),
141.4 (C-2′), 140.5 (C-1′), 135.6 (C-4), 129.6 (Ar), 129.5 (Ar),
128.8 (Ar), 128.2 (Ar), 128.1 (Ar), 125.8 (C-6’), 26.7 (COCH3), 26.1
(ArCH2), 15.7, CH3; HRMS (EI) m/z (M+) calcd for C16H16O:
224.1201, found: 224.1200. Anal. for 3da: calcd for C16H16
O
(%): C, 85.68; H, 7.19; found (%): C, 85.60; H, 7.28.
Synthesis of 4-biphenylcarbonitrile at 0.1 mol scale
Chlorobenzonitrile (13.75 g, 100 mmol), phenylboronic acid
(13.40 g, 110 mmol), 5% Pd/C (0.64 g, 0.3 mmol), IPr.HCl (0.13 g,
0.3 mmol), P(OMe)3 (70 μl, 0.6 mmol), NaOH (5.20 g, 130 mmol)
and EtOH (200 ml). The mixture was stirred at 80°C for 2 h and
filtered directly. The residual solid was washed twice with hot
EtOH (2 × 20 ml). The filtrate was evaporated under reduced
pressure to give a crude product, which was recrystallized from
EtOH/H2O to give 4-biphenylcarbonitrile (16.83 g, 94%).
Appl. Organometal. Chem. 2014, 28, 54–60
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

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Supporting Information
Additional supporting information may be found in the online
version of this article at the publisher’s web site.
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