Development of a Unique Heterogeneous Palladium Catalyst for the Suzuki–Miyaura Reaction using (Hetero)aryl Chlorides and Chemoselective Hydrogenation

Article abstract of DOI:10.1002/adsc.201700156

A unique heterogeneous palladium catalyst (7% Pd/WA30) supported on an anion exchange resin, which contains N,N-dimethylaminoalkyl functionalities on the polymer backbone, was developed. 7% Pd/WA30 could smoothly catalyze Suzuki–Miyaura reactions of even less reactive heteroaryl chlorides and heteroarylboronic acids to afford various (hetero)biaryls due to the electron-donating effect of the tert-amines on WA30 to Pd species. It was also applicable as a chemoselective hydrogenation catalyst, showing inactivity for the hydrogenolysis of tert-butyldimethylsilyl (TBS) ethers, alkyl benzyl ethers, and benzyl alcohols. The tert-amines on WA30 acted as moderate catalyst poisons for Pd, resulting in chemoselective hydrogenation. 7% Pd/WA30 was reused for at least five times without any loss of the hydrogenation catalytic activity. (Figure presented.).

Full text of DOI:10.1002/adsc.201700156

Title: Development of a unique heterogeneous palladium catalyst
for Suzuki–Miyaura reaction using (hetero)aryl chlorides and
chemoselective hydrogenation
Authors: Tomohiro Ichikawa, Moeko Netsu, Masahiro Mizuno,
Tomoteru Mizusaki, Yukio Takagi, Yoshinari Sawama,
Yasunari Monguchi, and Hironao Sajiki
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700156
Link to VoR: http://dx.doi.org/10.1002/adsc.201700156

10.1002/adsc.201700156
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Development of a unique heterogeneous palladium catalyst for
Suzuki–Miyaura reaction using (hetero)aryl chlorides and
chemoselective hydrogenation
Tomohiro Ichikawa,a Moeko Netsu,a Masahiro Mizuno,a Tomoteru Mizusaki,b Yukio
Takagi,b Yoshinari Sawama,a Yasunari Monguchia* and Hironao Sajikia*
a
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
Phone/Fax: (+81)-58-230-8109; e-mails: monguchi@gifu-pu.ac.jp and sajiki@gifu-pu.ac.jp
Chemical Catalysts R & D Department, Catalyst Development Center, N.E. Chemcat Corporation, 25-3 Kojindaira,
b
Bando, Ibaraki 306-0608, Japan
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A unique heterogeneous palladium catalyst (7% tert-butyldimethylsilyl (TBS) ethers, alkyl benzyl ethers,
Pd/WA30) supported on an anion exchange resin, which and benzyl alcohols. The tert-amines on WA30 acted as
contains N,N-dimethylaminoalkyl functionalities on the moderate catalyst poisons for Pd, resulting in
polymer backbone, was developed. 7% Pd/WA30 could chemoselective hydrogenation. 7% Pd/WA30 was reused
smoothly catalyze Suzuki–Miyaura reaction of even less for at least five times without any loss of the
reactive heteroaryl chlorides and heteroaryl boronic acids hydrogenation catalytic activity.
to afford various (hetero)biaryls due to the electron-
donating effect of the tert-amines on WA30 to Pd species.
It was also applicable as a chemoselective hydrogenation
catalyst, showing inactivity for the hydorogenolysis of
Keywords: Chemoselectivity; Heterogeneous catalysis;
Hydrogenation; Palladium; Suzuki–Miyaura reaction
hydrogenation of a wide variety of reducible
functionalities.[5b] However, specific functionalities
that coexist with multiple reducible functional groups
in a single molecule could not be selectively reduced,
because of the high catalyst activity.
Introduction
Development of heterogeneous Pd catalysts has been
investigated for a long time in termes of process
chemistry, due to their notable advantages over
homogeneous Pd catalysts, such as recoverability,
reusability, and less residual metal property, which
are directly linked to the reduction of environmental
and economic burdens.[1] The Pd-catalyzed Suzuki-
Miyaura reaction between aryl halides and
arylboronic acids has been widely applied for the
synthesis of biaryls, which are often present in many
biologically active compounds.[2,3] The addition of
phosphine or amine ligands favors the smooth
reaction progress, although they are often expensive
and toxic. As opposed to the number of ligand-free
Suzuki-Miyaura reactions of aryl iodides or bromides
Chemoselective hydrogenation is an important
topic in synthetic chemistry because of its
contribution to the development of new synthetic
pathways.[9,10] To date, various heterogeneous Pd
catalysts have been developed for the chemoselective
hydrogenation of alkenes, alkynes, carbonyl, and
nitro functionalities in the presence of protecting
groups,[11–18] such as benzyl ethers,[16a,16b,16p,18b–e,18h–j]
benyl esters,[16b,18c–e,18h–j] and N-benzyloxycarbonyls
(Cbz),[16a,18c,18e,18h–j] hydrogenation of alkenes in the
presence of carbonyl[16c–e,18c,18e,18h–i] or nitro
groups,[16a,18e,18h–j] and semi-hydrogenation of alkynes
to the corresponding alkenes.[16f–o,18g] Furthermore,
using heterogeneous catalysts,[4,5] only
a
few
heterogeneous
Pd-catalyzed
chemoselective
heterogeneous catalysts could be applied to the
ligand-free protocols of less reactive chloroarenes[6,7]
despite their versatility and low cost. We have
already developed a heterogeneous Pd catalyst
immobilized on a synthetic adsorbent, DIAION HP20
hydrogenolysis methods for the deprotection have
also been reported; e.g., the deprotection of benzyl
ethers in the presence of trisubstituted olefines,[17] and
the removal of N-Cbz and O-benzyl protections to the
corresponding amines, phenols, and carboxylic acids
without hydrogenation of carbonyl functionality.[18f]
We have established various Pd/C-catalyzed
chemoselective hydrogenation systems using
[(HP20,
Mitsubishi
Chemical
Corporation),
Pd/HP20],[8] which is a polystyrene-divinylbenzene
polymer without special functionalities on the
polymer backbone. Pd/HP20 indicates the high
catalytic activity for the ligand-free Suzuki-Miyaura
reaction of bromoarenes in aqueous alcohols,
although aryl chlorides are still inappropriate as
substrates.[5b,5d] Pd/HP20 also catalyzes the
NH4OAc,[18a]
ethylenediamine,[18b]
and
diphenylsulfide[18c] as catalytic poisons. Moreover,
we developed catalyst support-dependent
chemoselective hydrogenation methods using Pd on
1
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10.1002/adsc.201700156
Advanced Synthesis & Catalysis
ceramic,[18d,18e] monolithic ion exchange resin,[18f]
fibroin as a protein,[18g,18h] molecular sieves 3Å,[18e,18h–
j]
boron nitride,[18e,18h–k] and the chelate resins,
DIAION CR11 or CR20 bearing a diiminoacetate or
polyamine moiety, respectively.[18e,18l] The catalyst
activity of such catalysts basically depends on the
ingredients of supports, which can interact or
coordinate with Pd species, and the chemoselectivity
could be achieved by the appropriate reduction of the
inherent activity of Pd species.[18h]
A commercially available anion exchange resin,
DIAION WA30 (WA30, Mitsubishi Chemical
Corporation),[19,20] bearing N,N-dimethylaminoalkyl
groups on the polystyrene-divinylbenzene backbone
was a preferable target as a catalyst support, because
the tert-amino functionalities of WA30 would act as
moderate ligands to Pd metal. 7% Pd/WA30 was
prepared by the adsorption of palladium diacetate
[Pd(OAc)2] to the colorless WA30 in ethyl acetate
and its subsequent reduction using hydrazine.[21–23] It
is noteworthy that it could effectively catalyze the
Suzuki-Miyaura reaction of chloroarenes. We have
reported the preliminary results focusing on the
Fig. 1 XRD spectrum of 7% Pd/WA30
coupling
chlorides
between
non-heterocyclic
aromatic
Although
and
boronic
acids.[21]
heterogeneous catalysts for Suzuki–Miyaura reaction
of chloroarenes with a ligand function on their
support display the greatest catalyst activity, such
intramolecular ligands may act as a catalyst poison in
hydrogenation reactions.[7] Therefore, we expected
that the effective catalyst for the Suzuki–Miyaura
reaction may be applicable to the chemoselective
hydrogenation as a less active catalyst.
In this paper, we describe the 7% Pd/WA30-
catalyzed Suzuki-Miyaura reaction using aryl and
heteroaryl chlorides and its new application for
chemoselective hydrogenation.
Results and Discussion
The properties of 7% Pd/WA30 were analyzed by X-
ray photoelectron spectroscopy (XPS), scanning
transmission electron microscope (STEM),[21] X-ray
diffraction (XRD) spectroscopy, and electron probe
microanalysis (EPMA). 7% Pd/WA30 consisted of
both Pd(II) and Pd(0) species even after reduction
with hydorazine, as shown in the XPS image (see the
Supporting information and also reference 21). The
particle size of Pd species was estimated to be
approximately 3–20 nm by means of the STEM
image (see the Supporting information and also
reference 21).The XRD analysis indicated that the
existence of crystalline palladium in the 7%
Pd/WA30 (Figure 1), and the particle size of Pd
species was evaluated to be ca. 4 nm, which were
virtually conformed to that estimated from STEM
image.[24] Furthermore, the EPMA indicated that the
Pd species were securely fastened to the surface layer
of WA30 (Figure 2).
Fig. 2 EPMA spectrum of 7% Pd/WA30
As we preliminarily reported in the communication,
7% Pd/WA30 could catalyze the Suzuki–Miyaura
coupling reaction between various aryl chlorides and
arylboronic acids in the presence of Cs2CO3 in N,N-
dimethylacetamide (DMA) at 80 °C (Table 1).[21]
Phenylation of chloroarenes bearing an electron-
withdrawing group such as Ac (3a–c), CO2Et (3d),
NO2 (3e), and CF3 (3f) on the aromatic ring smoothly
occurred to afford the corresponding biaryls in high
to excellent yields. Although it is difficult to react
chloroanisoles (3g and 3h) bearing an electron-rich
aromatic ring with phenylboronic acid, the yield was
improved by increasing the amounts of the catalyst,
phenylboronic acid, and Cs2CO3. However, the yield
of 2-methoxybiphenyl did not improve in spite of
using increased amounts of such reagents, probably
because of the electronic and steric properties of 2-
2
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10.1002/adsc.201700156
Advanced Synthesis & Catalysis
chloroanisole. Substituted phenylboronic acids were
also used for the cross-coupling reaction (3i–q).[25]
Even unfavorable combinations of the coupling
reagents, such as electron-rich chlorotoluenes and
electron-poor acetylphenylboronic acids (3p and 3q),
afforded the desired biaryls in good to high yields.
conditions, have been reported in the literature.[6g–h]
Heteroaryl halides and heteroaryl boronic acids are
generally less reactive than non-heteroaromatic
halides and boronic acids owing to the potential
coordination of heteroatoms with Pd species. Thus,
we precisely investigated the catalytic activity of 7%
Pd/WA30 for the Suzuki–Miyaura coupling reaction
for the preparation of heterobiaryls. A coupling of 4-
or 3-chloropyridine and non-heteroaryl boronic acids
afforded the corresponding 4- or 3-arylated pyridine
in high yields (6a–d) in the presence of Cs2CO3 in
DMA at 80 °C (conditions A). A relatively low yield
(30%) of 2-pheylpyridine (6e) was obtained from 2-
chloropyridine under conditions A despite using
increased amounts of 7% Pd/WA30, phenylboronic
acid, and Cs2CO3. However, the yield of 6e increased
to 56% yield when K3PO4 was used as a base and
iPrOH as a solvent (conditions B). The coupling of 2-
chloropyridine and non-heteroaryl boronic acids was
also feasible (6e–g). The yield of 2-arylated pyridines
increased to good to high yields using more reactive
2-bromopyridines as the substrate. The arylation of 2-
chloroquinoline smoothly proceeded to yield the
corresponding heterobiaryls in excellent yields
regardless of the electron density of the benzene ring
of aryl boronic acids (6h and 6i): the sterically
hindered 2-methoxyphenylboronic acid was also
applicable to this arylation (6j). Reactions of non-
heteroaryl chlorides and heteroaryl boronic acids
were successfully performed under conditions A (6k
and 6l), although the corresponding heteroaryl
boronic acids were unstable under conditions B and
the yields greatly decreased because of the
decomposition of the boronic acids before the cross-
coupling reaction. It was remarkable that 7%
Pd/WA30 could also catalyze the formation of
heterobiaryls (6m and 6n). However, the coupling of
2-chloropyridine with 2-benzofuranylboronic acid
was unsuccessful under both conditions A and B (6o).
Table 1. Coupling of chloroarenes and boronic acidsa
R1
7% Pd/WA30 (5 mol%)
Cs2CO3 (2.0 equiv)
Cl
B(OH)2
R2
R1
DMA
80 °C, Ar
R2
2 (1.5 equiv)
1
3
Ph
Ph
Ac
Ph
Ac
100%, 6 h (3a)
Ac
80%, 24 h (3b)b)
Ph
89%, 24 h (3c)b)
Ph
Ph
F3C
O2N
97%, 6 h (3e)
EtO2C
94%, 6 h (3d)
96%, 6 h (3f)
Ph
Ph
MeO
Ph
MeO
64%, 24 h (3g)c)
OMe
15%, 24 h (3i)c)
83%, 24 h (3h)c)
OMe
Ac
OMe
Ac
Ac
EtO2C
96%, 4 h (3j)
100%, 24 h (3k)d)
91%, 4 h (3l)
OMe
Me
OMe
OMe
Me
Me
Table 2. Suzuki–Miyaura reaction of (hetero)aryl halide
78%, 24 h (3m)
79%, 24 h (3n)
66%, 24 h (3o)
with (hetero)aryl boronic acidsa
Ac
Ac
Me
Me
59%, 24 h (3q)
71%, 24 h (3p)
a) Reactions were carried out on a 0.25 mmol scale in 1 mL
b)
of DMA. The reaction was performed using 2 equiv of
c)
phenylboronic acid. The reaction was carried out using
10 mol% of 7% Pd/WA30, 3 equiv of Cs2CO3, and 3 equiv
of phenylboronic acid. d) The reaction was performed using
2 equiv of 3-methoxyphenylboronic acid.
Heterobiaryls are of particular interest as
fundamental scaffolds of a variety of medicines,
natural products, functional materials, etc. Although
the Suzuki–Miyaura reaction has been one of the
most effective synthetic methods of non-heterobiaryl
units, only a few successful couplings of heteroaryl
chlorides, especially under ligand-free heterogeneous
3
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10.1002/adsc.201700156
Advanced Synthesis & Catalysis
OMe
Ac
as Me2NBn (Entry 3), Et3N (Entry 5), and N,N,N',N'-
tetramethylethylenediamine (TMEDA, Entry 7),
without solvents at room temperature for 1 h under an
Ar atmosphere for the Pd species on the 10%
Pd/HP20 directly to interact with the tert-amines.[26]
The same pre-treatment experiments using 7%
Pd/WA30 were also conducted as the control
experiments (Entries 4, 6, 8). 10% Pd/HP20 catalyzed
the reaction to provide 4-acetylbiphenyl in 75% yield
without pre-treatments by additives, while the use of
the pre-treated catalysts for the reaction provided the
virtually same results (Entries 3, 5, 7 vs. 1).
Similarly, the effect of the pre-treatment of the
catalyst with amines was barely observed in the case
of 7% Pd/WA30 (Entries 4, 6, 8 vs. 2). It has also
been proposed that the single-electron transfer (SET)
process is involved in the activation of a carbon-
halogen bond as the reaction mechanism.[27–31] We
have reported that SET from Pd species to aromatic
chlorides caused the activation and cleavage of the C-
Cl bond in the presence of amines.[32,33] Since the
N
N
N
X = Cl (6a)
100%, 12 ha,b)
X = Cl (6b)
71%, 10 ha,b)
X = Cl (6c)
100%, 12 ha,b)
N
N
N
OMe
6d
6e
6f
X = Cl
X = Cl
92%, 12 ha)
X = Cl
30%, 24 ha,c)
56%, 24 hd)
47%, 24 hd)
X = Br
94%, 3 hd)
N
N
N
Ac
OMe
Ac
addition of
a
radical scavenger (2,2,6,6-
6g
X = Cl
6h
6i
X = Cl
X = Cl
tetramethylpiperidine 1-oxyl, TEMPO) never affected
the reaction yield (Entry 5), the tert-amine
functionality on WA30 would not facilitate the SET
from Pd to substrates. These results indicate that
external amines would neither function as ligands to
Pd nor initiate the SET process; we considered that
the Pd species accepted an electron pair from tert-
amino group via an intramolecular coordination as a
ligand, rather than an intermolecular Pd-tert-amine
interaction, in addition to the π-electrons of the
polystyrene backbone aromatic ring due to strong
coordination. The combination of the two interaction
ways would result in the excellent catalytic activity of
7% Pd/WA30.
40%, 24 hd)
X = Br
100%, 12 hd)
90%, 24 hd)
52%, 5 hd)
OMe
O
N
Ac
6j
6k
X = Cl
X = Cl
55%, 24 hd)
85%, 24 ha)
9%, 24 hd)
O
O
O2N
N
Table 3. Mechanistic study of tert-amino group on WA30
6l
6m
X = Cl
X = Br
96%, 13 ha)
100%, 3.5 ha)
18%, 6 hd)
Ac
Cl
Additive
PhB(OH)2 (1.5 equiv)
(35 mol%) Cs2CO3 (2.0 equiv)
OMe
Pd catalyst
(5 mol%)
3a
N
neat, rt, 1 h DMA, 80 °C, Ar, 24 h
N
N
Entry
1
Catalyst
Additive
none
none
Me2NBn
Me2NBn
Et3N
Yield (%)a)
N
10% Pd/HP20
7% Pd/WA30
10% Pd/HP20
7% Pd/WA30
10% Pd/HP20
7% Pd/WA30
10% Pd/HP20
7% Pd/WA30
7% Pd/WA30
75
6o
2b)
3
100c)
80
6n
X = Br
0%a)
0%d)
X = Cl
95%, 24 ha,b)
4b)
5
100
80
a)
b)
The reaction was carried out under conditions A. 4-
Chloropyridine hydrochloride salt was used as a substrate
6d)
7
Et3N
88e)
70
c)
and 3 equiv of Cs2CO3 was used.
The reaction was
TMEDA
TMEDA
TEMPO
carried out using 10 mol% of 7% Pd/WA30, 3 equiv of
Cs2CO3, and 3 equiv of phenylboronic acid. d) The reaction
was carried out under conditions B.
8b)
9b)
93
96
a) The yield was determined by 1H NMR using 1,4-dioxane
b)
as an internal standard. The reaction was completed in 6
h. c) Isolated yield. d) The reaction was carried out for 6 h. e)
We used 10% Pd/HP20 pre-treated with amine
derivatives for the Suzuki–Miyaura reaction of 4'-
chloroacetophenone and phenylboronic acid to
investigate whether the tert-aminoalkyl group on
WA30 has actually act as a ligand to Pd (Table 3).
10% Pd/HP20 was stirred with tertiary amines, such
f)
8% of starting material was recovered. The coupling
reaction
phenylboronic acid (1.5 equiv) was carried out in the
presence of 7% Pd/WA30 (5 mol%), Cs2CO3 (2.0 equiv),
and 2,2,6,6-tetramethylpiperidine (10 mol%) without pre-
between
4'-chloroacetophenone
and
treatment of 7% Pd/WA30. TMEDA
=
N,N,N',N'-
4
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10.1002/adsc.201700156
Advanced Synthesis & Catalysis
tetramethylethylenediamine.
tetramethylpiperidine 1-oxyl.
TEMPO
=
2,2,6,6-
Fig. 3 EPMA spectrum after Suzuki–Miyaura reaction
The catalytic activity of 7% Pd/WA30 for the
hydrogenation was evaluated in MeOH using
substrates bearing a variety of reducible groups. The
hydrogenation of alkynes (Table 4, Entries 1, 9, and
10), azido (Entry 2), alkene (Entries 3, 7, 11, 15, 18,
and 23), and nitro (Entries 3 and 4) functionalities
smoothly proceeded at room temperature under
ordinary hydrogen pressure. Aryl ketones (Entries 5
and 6) and an aldehyde (Entry 7) were reduced at
40 °C to obtain the corresponding benzyl alcohols
without any further hydrogenolysis of the benzyl
alcohol functionality even after being stirred for 24 h.
Benzyl alcohols (Entries 8 and 9) are likewise inert
during the 7% Pd/WA30-catalyzed hydrogenation.
The N-Cbz protecting group of both aliphatic and
aromatic amines could be removed (Entries 10–14).
The deprotection of aryl benzyl ethers and benzyl
esters was easily performed at room temperature
(Entries 15–19). It is noteworthy that aliphatic benzyl
ethers could be tolerant under the same reaction
In our preliminary report, we proved that 7%
Pd/WA30 could be quantitatively recovered by a
simple filtration after the Suzuki–Miyaura reaction,
and no leached Pd species from 7% Pd/WA30 to the
reaction media were detected by inductively coupled
plasma-atomic emission spectrometry (ICP-AES).[21]
However,
the
coupling
reaction
of
4'-
chloroacetophenone with phenylboronic acid slightly
but surely proceeded in the filtrate obtained after the
removal of 7% Pd/WA30 by the filtration without
cooling. These results strongly suggest the "release
and capture" process of the Pd species from and on
the support (WA30). During the reuse test of 7%
Pd/WA30, its catalytic activity decreased drastically
even in the second reuse of the catalyst. According to
the XPS spectra of 7% Pd/WA30 before and after the
reaction, the ratio of Pd(0)/Pd(II) increased after the
reaction (see the Supporting information).
Furthermore, the EPMA spectrum of 7% Pd/WA30
after the reaction indicates that Pd species were
uniformly distributed from the surface to the inside of
WA30 (Figure 3), although this distribution was
obviously deflected to the surface of the WA30
support (Figure 2). Therefore, we have concluded that
the decrease of Pd species on the WA30 surface,
which directly catalyze the coupling reaction, caused
the decrease of the catalytic activity due to the
difficult uptake of substrates inside the support,
owing to the comparatively small surface area (15 m2
g–1) and pore volume (1.3 mL g–1) of WA30.[6,20]
conditions
(Entries
19–21).
The
selective
hydrogenolysis of the benzyl ester of Boc-Ser(Bn)-
OBn was achieved without the deprotection of the
coexisting aliphatic benzyl ether (Entry 19).
Furthermore, epoxide adjacent to aromatic rings
easily opened to afford the corresponding benzyl
alcohol (Entry 22). tert-butyldimethylsilyl (TBS)
protecting group could also tolerate under the
reaction conditions (Entry 23).
Table 4. 7% Pd/WA30-catalyzed hydrogenation
7% Pd/WA30 (1 mol%)
H2
Substrate
Product
MeOH
5
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10.1002/adsc.201700156
Advanced Synthesis & Catalysis
Entry
Substrate
Temp.
(°C)
rt
Time
(h)
5
Product
Ratioa)
(SM : Pro)
0 : 100 (100)
Ph
1
2
Ph
Ph
Ph
rt
18
0 : 100 (100)
trace : 99 (89)
EtO2C
N3
EtO2C
NH2
NH2
NO2
3
4
rt
24
Ph
Me
Ph
Me
rt
24
0 : 100 (81)
NO2
NH2
Me
O
Me
OH
5
6
40
40
6
0 : 100 (100)
0 : 100 (100)
O
O
OH
24
Et
Et
CHO
7
8
40
rt
24
24
0 : 100 (94)
OH
PrO
OH
No Reaction
100 (100) : 0
Me
H2N
Me
OH
Me
OH
Et
9
rt
24
24
0 : 100 (99)
0 : 100 (89)
H
N
NH2
10
40
Cbz
Me
Cbz
H
11
12
13
rt
rt
rt
24
7
0 : 100 (98)
0 : 100 (100)
0 : 100 (100)
N
Me
N
H
N
H2N
Cbz
Me
OMe
Me
OMe
8
N
N
Cbz
N
NH
NHCbz
NH2
14
15
50
rt
24
7
0 : 100 (76)
0 : 100 (98)
O
O
OBn
OH
16
17
18
rt
rt
rt
6
0 : 100 (100)
0 : 100 (94)
0 : 100 (100)
BnO
OH
CN
HO
OH
6
BnO
MeO
HO
CN
Me
MeO
Me
18
BnO
HO
BocHN
CO2Bn
BocHN
CO2H
OBn
19
20
rt
rt
24
24
0 : 100 (75)
100 (96) : 0
OBn
OBn
No Reaction
BnO
6
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10.1002/adsc.201700156
Advanced Synthesis & Catalysis
Me
OBn
21
rt
24
No Reaction
100 (91) : 0
Me
O
OH
22
rt
rt
18
24
0 : 100 (98)
0 : 100 (98)
Ph
Ph
Ph
Ph
Ph
23
OTBS
Ph
OTBS
a) Ratio was determined by 1H NMR. Isolated yields are indicated in parentheses.
Next, the reuse of 7% Pd/WA30 under the
hydrogenation conditions was examined using
cinnamyl alcohol as a substrate (Table 5). The
catalyst could be readily recovered and reused for at
least five times without any loss of the catalytic
activity. Furthermore, the leached Pd species in the
filtrate of the reaction mixture were never detected by
ICP-AES (detection limit: <1 ppm).
We have developed a new heterogeneous palladium
catalyst embedded in an anion exchange resin
(WA30). tert-Amino functionalities on the WA30
skeleton act as an ancillary ligand for Pd species and
accelerate the Suzuki–Miyaura coupling reaction
using readily available chloroarenes. The 7%
Pd/WA30-catalyzed coupling is also applicable to the
coupling of heteroaryl chlorides and heteroaryl
boronic acids. It was particularly important that less
reactive 2-chloropyridines can be also applied to the
7% Pd/WA30-catalyzed Suzuki–Miyaura reaction.
On the other hand 7% Pd/WA30-catalyzed
hydrogenation at room temperature under ordinary
hydrogen pressure could achieve the specific
chemoselectivity induced by the moderate catalyst
poison effect of WA30 tert-amino groups. The
catalyst is recoverable by simple filtration. Although
the activity of the recovered catalyst in the Suzuki–
Miyaura reaction decreased because of its inevitable
structural changes, 7% Pd/WA30 could be reused in
hydrogenation, without any loss of the activity.
Furthermore, it could be used for practical
applications involving the wide range of utility in
industries and reserch laboratories.
Table 5. Reuse of 7% Pd/WA30
7% Pd/WA30 (1 mol%)
H2
OH
OH
MeOH, rt, 5 h
Run
1st
97
2nd
100
3rd
97
4th
97
5th
96
Recovered
7% Pd/WA30
Yield (%)
100
100
100
100
100
Figure 4 displays the activity of 7% Pd/WA30 and
some selected heterogeneous catalysts for
hydrogenation. The reducible functionalities in each
frame could be reduced using the corresponding
catalyst. 7% Pd/WA30 catalyzed the hydrogenation
of a relatively large number of functionalities, except
for TBS ethers, benzyl alcohols, and aliphatic benzyl
ethers.[34] Although the activity of 7% Pd/WA30 for
hydrogenation was similar to that of Pd/C in the
presence of amines or ammonium acetate as a
moderate catalyst poison, the reaction never required
the removal of such additives to obtain the pure
product.
Experimental Section
General
All reagents and solvents were obtained from commercial
sources and used without further purification. Pd(OAc)2
was obtained from N.E. Chemcat Co. (Tokyo, Japan).
Melting points (uncorrected) were determined on a Sansyo
melting point apparatus SMP-300. IR spectra (neat) were
measured using a Bruker Alpha FT-IR spectrometer. The
1H NMR and 13C NMR spectra were recorded on a JEOL
1
JNM ECA-500 (500 MHz for H NMR and 125 MHz for
13C NMR), ECS-400 (400 MHz for 1H NMR and 100 MHz
1
for 13C NMR), or AL-400 (400 MHz for H NMR and 100
MHz for 13C NMR) spectrometer. CDCl3 or CD3OD was
used as the solvent for NMR measurement. Chemical shifts
(δ) are expressed in part per million and internally
1
referenced (0.00 ppm for tetramethylsilane for H NMR
and 77.0 ppm for 13C NMR for CDCl3, and 3.30 ppm for
1H NMR and 49.0 ppm for 13C NMR for CD3OD). Mass
spectra (EI) were taken on a JEOL JMS Q1000GC Mk II
Quad GC/MS. High resolution mass spectra were
measured by Shimadzu hybrid LCMS-IT-TOF (LCMS-IT-
TOF). The Hitachi HD-2000 STEM, ULVAC-PHI PHI
QuanteraSXM, Shimadzu ICPS-8100, and PANalytical
X'Pert PRO-MPD were used for the scanning transmission
electron microscope (STEM) analysis, X-ray photoelectron
spectroscopy (XPS), inductively coupled plasma-atomic
emission spectroscopy (ICP-AES), and X-ray diffraction
Fig. 4 Chemoselectivity of 7% Pd/WA30 in hydrogenation
Pd/C(en) = Pd/C-ethylenediamine complex, Pd/C(Ph2S) =
Pd/C-diphenylsulfide complex.
1
analysis (XRD), respectively. All of H NMR spectra of
known products were identical with those in the literature.
Conclusion
Typical procedure for the coupling reaction between
aryl chlorides and arylboronic acids (Table 1)
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700156
Advanced Synthesis & Catalysis
7% Pd/WA30 (19.0 mg, 12.5 μmol), the aryl chloride (250
μmol), the arylboronic acid (375 μmol), Cs2CO3 (163 mg,
500 μmol) and DMA (1 mL) were added in a test tube. The
mixture was stirred at 80 °C under Ar atmosphere. The
reaction progress was monitored by thin layer
chromatography (TLC) (hexane/EtOAc, 5:1). After
complete consumption of the aryl chloride or 24 h (if the
reaction was incomplete), the mixture was cooled to rt,
diluted with Et2O (5 mL), and filtered through a cotton
filter. The catalyst on the filter was washed with Et2O (15
mL × 2) and H2O (10 mL × 3). The combined filtrates
were separated into two layers. The aqueous layer was
extracted with Et2O (20 mL), and the combined organic
layers were washed with H2O (20 mL × 4) and brine (20
mL), dried over Na2SO4, filtered, and concentrated in
vacuo. CDCl3 (ca. 1 mL) and 1,4-dioxane (8.53 μL, 100
μmol) were added to the residue. After the determination
of the reaction yield by 1H NMR, the product was purified
by silica gel column chromatography using hexane/EtOAc
(10:1) as eluents to afford the corresponding biaryl.
and H2O (10 mL × 3). The combined filtrates were
separated into two layers. The aqueous layer was extracted
with Et2O (20 mL), and the combined organic layers were
washed with H2O (20 mL × 4) and brine (20 mL), dried
over Na2SO4, filtered, and concentrated in vacuo. CDCl3
(ca. 1 mL) and 1,4-dioxane (8.53 μL, 100 μmol) as an
internal standard were added to the residue, and the yield
of 3a was determined by 1H NMR analysis.
Typical procedure for the hydrogenation reaction
(Table 4)
A mixture of the substrate (250 μmol) and 7% Pd/WA30
(3.8 mg, 2.50 μmol) in MeOH (1 mL) was stirred under H2
atmosphere (balloon) at room temperature. After a specific
time, the mixture was passed through a cotton filter. The
catalyst on the filter was washed with MeOH (5 mL × 3).
The filtrate was concentrated in vacuo to afford the
corresponding spectrometrically pure reduced product. If
the reaction was incomplete after 24 h, the temperature
was raised to 40 or 50 °C.
Typical procedure for the synthesis of heterobiaryls
(Table 2)
Reuse test of 7% Pd/WA30 in hydrogenation (Table 5)
Conditions A: The conditions were the same as for the
coupling between aryl chlorides and arylboronic acids. The
residue was purified by silica gel column chromatography
using hexane/EtOAc as eluents to afford the corresponding
heterobiaryl.
For the first run shown in Table 1, a mixture of cinnamyl
alcohol (335 mg, 2.50 mmol) and 7% Pd/WA30 (38.0 mg,
25.0 μmol) in MeOH (10 mL) was stirred under H2
atmosphere (balloon). After 5 h, the mixture was filtered
using a Kiriyama funnel (1 μm filter paper). The catalyst
on the filter was washed with EtOAc (3 mL × 5), and the
filtrate was concentrated in vacuo to afford 3-phenyl-1-
propanol in 100% yield (342 mg, 2.51 mmol). The
recovered catalyst was dried at room temperature under
reduced pressure overnight, and then weighed (36.9 mg,
97 % recovery). The reaction for the second run was
carried out similarly to the first run except for the amount
of cinnamyl alcohol (326 mg, 2.43 mmol) and 7%
Pd/WA30 (36.9 mg, 24.3 μmol). 3-Phenyl-1-propanol was
obtained in 100% yield (330 mg, 2.42 mmol). The
reactions for the runs 3–5 were also carried out in a manner
similar to the first run except for the amount of the
substrate and the catalysts used. The results are
summarized in the Supporting information.
Conditions B: 7% Pd/WA30 (19.0 mg, 12.5 μmol), the aryl
chloride [or the heteroaryl chloride (250 μmol)], the aryl
boronic acid [or the heteroaryl boronic acid (375 μmol)],
K3PO4 (106 mg, 500 μmol) and iPrOH (1 mL) were added
in a test tube. The mixture was stirred at 80 °C under Ar
atmosphere. The reaction progress was monitored with
TLC (hexane/EtOAc, 5:1). After complete consumption of
the aryl chloride or after 24 h (if the reaction was
incomplete), the mixture was cooled to rt, diluted with
EtOAc (5 mL), and passed through a cotton filter. The
catalyst on the filter was washed with EtOAc (15 mL × 2)
and H2O (10 mL × 3). The combined filtrates were
separated into two layers. The aqueous layer was extracted
with EtOAc (20 mL), and the combined organic layers
were washed with H2O (20 mL) and brine (20 mL), dried
over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
to afford the corresponding heterobiaryl.
Acknowledgements
This work was partially supported by JSPS KAKENHI Grant
number 15K07863. We sincerely appreciate the N. E. Chemcat
Co. and Mitsubishi Chemical Co. for providing the Pd(OAc)2 and
DIAION WA30, respectively.
Procedure for the mechanistic study (Table 3)
For entries 3–8: A mixture of Pd catalyst (12.5 μmol) and
amine (87.5 μmol) in a test tube was stirred at room
temperature under an Ar atmosphere. After 1 h, 4'-
chloroacetophenone (32.4 μL, 250 μmol), phenylboronic
acid (45.7 mg, 375 μmol), Cs2CO3 (163 mg, 500 μmol) and
DMA (1 mL) was added to the mixture. It was stirred at
80 °C under an Ar atmosphere. After the specific time, the
mixture was cooled to room temperature, diluted with Et2O
(5 mL), and passed through a cotton filter. The catalyst on
the filter was washed with Et2O (15 mL × 2) and H2O (10
mL × 3). The combined filtrates were separated into two
layers. The aqueous layer was extracted with Et2O (20 mL),
and the combined organic layers were washed with H2O
(20 mL × 4) and brine (20 mL), dried over Na2SO4, filtered,
and concentrated in vacuo. CDCl3 (ca. 1 mL) and 1,4-
dioxane (8.53 μL, 100 μmol) as an internal standard were
added to the residue, and the yield of 3a was determined
by 1H NMR analysis.
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9
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700156
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(1,1,1) 39.862
(2,0,0) 46.288
(2,2,0) 67.827
2.062
2.971
3.047
1.992
2.900
2.968
4.2
3.0
3.2
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The amount of amino Surface area
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Pore volume
1.3 mL g–1
4.96 mmol g–1
15 m2 g–1
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wt% by the measurement of Pd species in the filtrates
10
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10.1002/adsc.201700156
Advanced Synthesis & Catalysis
FULL PAPER
Development of a unique heterogeneous palladium
catalyst for Suzuki–Miyaura reaction using
(hetero)aryl chlorides and chemoselective
hydrogenation
Adv. Synth. Catal. Year, Volume, Page – Page
Tomohiro Ichikawa,a Moeko Netsu,a Masahiro
Mizuno,a Tomoteru Mizusaki,b Yukio Takagi,b
Yoshinari Sawama,a Yasunari Monguchia* and
Hironao Sajikia*
11
This article is protected by copyright. All rights reserved.