Ligand-free Suzuki-Miyaura coupling using ruthenium(0) nanoparticles and a continuously irradiating microwave system

Article abstract of DOI:10.1039/c7gc01166k

We developed a conceptually and methodologically novel ruthenium(0) nanoparticle catalyst, sulfur-modified Au-supported ruthenium nanoparticles (SARu). SARu is easily prepared through a three-step procedure involving simultaneous in situ metal nanoparticle and nanospace organization. This unique method does not require any conventional preformed template to immobilize and stabilize metal nanoparticles. SARu is an ideal ruthenium catalyst for liquid-phase combinatorial synthesis because it repeatedly catalyzes ligand-free Suzuki-Miyaura coupling of aryl halides, including aryl chlorides, with arylboronic acids with low Ru leaching. Physical analysis of SARu showed that the active species in these reactions were ruthenium (0) nanoparticles with a size of 1-3 nm. Also, we developed a continuously irradiating microwave methodology, which can first time discriminate the heating effect and the microwave effect in microwave experiments.

Full text of DOI:10.1039/c7gc01166k

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: T. Akiyama, T.
Taniguchi, N. Saito, R. Doi, T. Honma, Y. Tamenori, Y. Ohki, N. Takahashi, H. Fujioka, Y. Sato and M.
Arisawa, Green Chem., 2017, DOI: 10.1039/C7GC01166K.
This is an Accepted Manuscript, which has been through the
Volume 18 Number
7 7 April 2016 Pages 1821–2242
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Accepted Manuscripts are published online shortly after
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1463-9262
CRITICAL REVIEW
G. Chatel et al.
Heterogeneous catalytic oxidation for lignin valorization into valuable
chemicals: what results? What limitations? What trends?
rsc.li/green-chem

Page 1 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
Ligand-Free Suzuki–Miyaura Coupling Using Ruthenium(0) Nanoparticles and a Continuously
Irradiating Microwave System†
Toshiki Akiyamaa, Takahisa Taniguchib, Nozomi Saitoc, Ryohei Doib, Tetsuo Honmad, Yusuke Tamenorid,
Yuuta Ohkie, Naoyuki Takahashie, Hiromichi Fujiokaa, Yoshihiro Sato,*b and Mitsuhiro Arisawa*a
aGraduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871
Japan
bFaculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812
Japan
cMeiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588 Japan
dJapan Synchrotron Radiation Research Institute, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5198 Japan
eTokyo Rikakikai Co., Ltd. (Brand: EYELA), TN Koishikawa Bldg. 1-15-17 Koishikawa Bunkyo-ku, Tokyo
112-0002 Japan
*Corresponding Author. Phone: +81-6-6879-8226, Fax: +81-6-6879-8229, E-mail: arisaw@phs.osaka-u.ac.jp
†Electronic supplementary information (ESI) available. See DOI: 10.1###/ ####
Abstract
We developed a conceptually and methodologically novel ruthenium(0) nanoparticle catalyst,
sulfur-modified gold-supported ruthenium nanoparticles (SARu). SARu is easily prepared through a
three-step procedure involving simultaneous in situ metal nanoparticle and nanospace organization.
This unique method does not require any conventional preformed template to immobilize and
stabilize metal nanoparticles. SARu is an ideal ruthenium catalyst for liquid-phase combinatorial
1

Green Chemistry
Page 2 of 41
View Article Online
DOI: 10.1039/C7GC01166K
synthesis because it repeatedly catalyzes ligand-free Suzuki–Miyaura coupling of aryl halides,
including aryl chlorides, with arylboronic acids with low Ru leaching. Physical analysis of SARu
showed that the active species in these reactions were ruthenium (0) nanoparticles with a size of 1–3
nm. Also, we developed a continuously irraditating microwave methodology, which can first time
discriminate the heating effect and the microwave effect in microwave experiments.
Introduction
The development of immobilized transition-metal nanoparticles as catalysts for carbon–carbon
(hetero) bond-forming cross-coupling reactions is an important area in organic synthesis because
these immobilized catalysts have different reactivities and advantages (such as recyclability and low
metal contamination) from those of homogeneous catalytic systems based on transition metals with
ligands such as phosphine and nitrogen-containing heterocyclic carbene (NHC).1 Reported
immobilized nanoparticle catalysts have usually been prepared using various supports with
preformed pores or coordination sites, such as metal oxides, silica materials, ionic liquids,
functionalized polymers, and dendrimers.1b The pores or coordination sites trap metal nanoparticles,
and act as templates to immobilize and stabilize nanoparticles by adsorption, ionic bonding,
coordination, or encapsulation, along with preventing aggregation (Figure 1). Supported palladium
nanoparticle catalysts have been developed for various C–C bond-forming cross-coupling reactions.2
In contrast, although cross coupling without palladium is important to synthesize functional
molecules from the viewpoints of minimizing the demand for this heavy metal and catalyst cost, the
use of immobilized catalysts containing Ru nanoparticles is limited. And only a few studies of
immobilized Ru nanoparticles for Suzuki–Miyaura coupling have been reported, even though Ru is a
good substitute for Pd and much cheaper.1, 3, 4 We envisioned that the development of conceptually
2

Page 3 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
and methodologically novel immobilization methods for Ru nanoparticles with good recyclability
and low Ru leaching would promote future development of organic, inorganic, materials, green, and
medicinal chemistry.
Figure 1. Supports to immobilize nanoparticles via: a) adsorption, b) ionic bonding, c) coordination,
and d) encapsulation.
We previously developed a sulfur-modified Au-supported Pd catalyst (SAPd) and used it to catalyze
Suzuki–Miyaura coupling, Buchwald–Hartwig coupling, C–H functionalization, double
carbonylation, removal of the allyl protecting groups of allyl esters and redox switching.5 We found
that SAPd consists of approximately ten layers of self-assembled Pd(0) nanoparticles with a size of
less than 5 nm on a sulfur-modified Au surface.6 These Pd nanoparticles are encapsulated in a
sulfated p-xylene polymer matrix. 6 We speculated that the self-assembled Pd nanoparticles were
constructed by in situ metal nanoparticle and nanospace simultaneous organization (PSSO). This
method is illustrated in Figure 2; it involves four simultaneous procedures: i) reduction of a
high-valence metal source, ii) growth of transition-metal nanoparticles of appropriate size, iii)
growth of a matrix with appropriate pores, and iv) encapsulation of the metal nanoparticles in matrix
nanopores. This method is quite different from conventional nanoparticle-immobilizing methods
3

Green Chemistry
Page 4 of 41
View Article Online
DOI: 10.1039/C7GC01166K
using solid supports with preformed pores or coordination sites. Based on these results, we
hypothesized that the in situ PSSO method could be extended to immobilize various transition-metal
nanoparticles, including Ru.
transition
metal
source
solvent
+
i) reduction of a high-valence metal source
ii) growth of transition-metal nanoparticles
iii) matrix growth
Δ
iv) encapsulation of
metal nanoparticles
in matrix nanospaces
NPs
matrix
S-Au
Figure 2. The in situ metal nanoparticle and nanospace simultaneous organization (PSSO) method:
In this study, we use the PSSO method to produce Ru nanoparticles with low Ru leaching and good
recyclability, which could be a good catalyst for liquid-phase combinatorial organic synthesis. We
successfully develop sulfur-modified Au-supported Ru nanoparticle (SARu) catalysts using a
combination of the in situ PSSO method and an appropriate reducing agent. We find that SARu can
repeatedly catalyze Suzuki–Miyaura coupling under ligand-free conditions. The chemistry described
here is useful from a synthetic point of view because reactions, including liquid-phase combinatorial
synthesis, can be repeatedly performed under ligand-free conditions with low Ru leaching.
Results and Discussion
SARu preparation and catalytic activity in Suzuki–Miyaura coupling of aryl iodides
First, we developed a suitable method to prepare a SARu catalyst that can be used repeatedly for
4

Page 5 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
ligand-free Suzuki–Miyaura coupling. The three-step method developed to prepare SARu, which is
based on our reported method for SAPd preparation,5 is outlined in Scheme 1.
Step 2
Step 3
Step 1
SARu
S-Au
Ru
p-xylene
H2SO4 aq
Na2S2O8
30 min
Ru: 194 µg
immobilizing
conditions
°
Au (mesh)
12 x 14 mm
135 C, 12 h
Optimized conditions:
Ru(acac)3 (20 mg)
°
4-MeOC6H4CH2OH(0.13 mL), p-xylene (2.3 mL), 135 C, 12 h
Scheme 1. Preparation of SARu.
The first step was the same as that for SAPd preparation. Sulfur-modified Au (S-Au) was prepared
by treating Au mesh (12 × 14 mm, 100 mesh) with piranha solution; i.e., a mixture of sulfuric acid
and sodium persulfate (Scheme 1, step 1).5b The second step involved immobilization of Ru
nanoparticles on S-Au using the in situ PSSO method. We first tried to immobilize Ru nanoparticles
on S-Au under various conditions similar to those used for Pd nanoparticle immobilization in SAPd
preparation. However, when S-Au was treated with Ru(acac)3 instead of Pd(OAc)2 in p-xylene at
100 °C, S-Au was recovered. Considering the redox potentials of Ru and Pd, we assumed that Ru
reduction is more difficult than Pd reduction. Thus, we next focused on the conditions for Ru
nanoparticle synthesis via chemical reduction of Ru(III). It should be noted that the reducing agent
must be able to reduce Ru(III) to Ru(0) at the same rate as the solvent forms the matrix that
encapsulates the Ru nanoparticles. The use of conventional reductants such as LiBEt3H or NaBH4
failed, and a large amount of Ru black was formed in the Ru immobilization step. After screening
various conditions and other reducing agents, we identified suitable immobilization conditions:
treatment of S-Au with Ru(acac)3 as a Ru source and 4-methoxybenzyl alcohol as the Ru
reductant in p-xylene at 135 °C for 12 h (step 2). The third step involved heating in p-xylene at
5

Green Chemistry
Page 6 of 41
View Article Online
135 °C for 12 h to remove unnecessary ruthenium species attached on the cDaOtaI:l1y0s.1t039s/uCr7GfaCc01e1.66K
Inductively coupled plasma mass spectrometry (ICP-MS) of SARu revealed that 194 µg (average of
two samples) of Ru was immobilized on 96.4 mg of S-Au mesh (average of two samples). Also, we
detected no Pd on SARu in this ICP-Mass analysis.
The resulting SARu catalyzed the Suzuki–Miyaura coupling of 4-iodobenzene (1a) (0.25 mmol) and
phenylboronic acid (2a) (1.5 equiv.) repeatedly, as shown in Scheme 2. That is, a mixture of SARu
(1 sheet) and K3PO4 (3.0 equiv.) in dimethoxyethane (DME) was heated at 80 °C for 6 h under
ligand-free conditions. After SARu was removed from the reaction mixture, H2O (1.0 mL) was
added to solve insoluble reagents and then the resulting mixture was stirred at 100 °C for 10 h to
give the corresponding biaryl compound 3a in 99% yield. We have to remove SARu in the end of
Step 1 and add water to the reaction mixture in the beginning of Step 2, because SARu stands for
moisture level of water, but the filn, which seems to involve Ru species, on SARu is destroyed by
solvent amount of water. In the absence of SARu, only a trace amount of 3a was detected in this
Suzuki–Miyaura coupling reaction. These results encouraged us to investigate the recyclability of
SARu in the same Suzuki–Miyaura coupling reaction.
6

Page 7 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
SARu
SARu
I
K3PO4 (3.0 eq.)
+
DME (1.0 mL)
80 oC, 6 h
(HO)2B
100 oC, 10 h
99%
H2O (1.0 mL)
Step 2
1a
(0.25 mmol)
2a
(1.5 eq.)
3a
Step 1
Scheme 2. SARu-catalyzed ligand-free Suzuki–Miyaura coupling of 1a with 2a and its time course
experiments.
The yields of 3a in the first ten runs in recycling experiments are presented in Table 1. The
SARu-catalyzed ligand-free Suzuki–Miyaura coupling proceeded smoothly to afford the products in
91%–99% yield for run 1 to 10; no marked loss of catalytic activity was observed. We next
measured the amount of Ru released into the reaction mixture in each cycle using ICP-MS. The
results showed that the amount of Ru released in each run was 0.11–1.93 µg (0.05–0.83 ppm) (Table
1).
7

Green Chemistry
Page 8 of 41
View Article Online
Table 1. Yields of 3a and amount of Ru released in Suzuki–Miyaura coupling using rDeOcIy: 1c0l.1e0d39S/CA7GRC0u1.166K
SARu
SARu
K3PO4 (3.0 eq.)
+
1a
(0.25 mmol)
2a
(1.5 eq.)
3a
DME (1.0 mL)
80 °C, 6 h
100 °C, 10 h
H2O (1.0 mL)
run
yield of 3a amount of released Ru (µgb, mmol%c, %d)
(%)a
1st
99
99
1.93, 7.64, 0.955
0.48, 1.90, 0.247
2nd
3rd
99
95
97
94
95
92
91
91
0.28, 1.11, 0.144
0.25, 0.989, 0.129
0.25, 0.989, 0.129
0.28, 1.11, 0.144
0.15, 0.594, 0.0773
0.13, 0.514, 0.0670
0.12, 0.475, 0.0619
0.11, 0.435, 0.0567
3.95b
4th
5th
6th
7th
8th
9th
10th
total releasing
used SARuc)
145b
a Yields were determined by HPLC and are average values of two sets of reactions. b The amount of
c
Ru released into the reaction mixture is the average value of two sets of reactions. mmol% of Ru
d
e
species in the reaction mixture. % of Ru employed in the catalysis. The amount of Ru on SARu
after ten cycles of Suzuki–Miyaura coupling.
We next investigated the scope of SARu use by performing liquid-phase combinatorial synthesis
using various iodobenzene derivatives and boronic acid reagents; the results are summarized in Table
2 and 3. Combinatorial synthesis is a useful technique in medicinal chemistry.7 The reactions of
iodobenzene (first cycle), 4-methoxyiodobenzene (second cycle), 4-acetyliodobenzene (third cycle),
4-nitroiodobenzene (fourth cycle), and 4-iodotoluene (sixth cycle), with phenylboronic acid provided
the corresponding biaryl products 3a–3d and 3f in quantitative yields. The reaction of
8

Page 9 of 41
Green Chemistry
View Article Online
1-chloro-4-iodobenzene with phenylboronic acid gave the corresponding product 3e DinOI:8108.%1039y/Cie7GldC0i1n166K
the fifth reaction. In the next three cycles, the reaction proceeded smoothly to give the corresponding
products 3g–3i in yields of 86%–91%. In the tenth cycle, stilbene 3j was obtained in 86% yield.
Table 2. Liquid-phase combinatorial synthesis using SARu and aryl iodides (part 1).
SARu
SARu
K3PO4 (3.0 eq.)
+
Ar-I
DME (1.0 mL)
80 °C, 6 h
100 °C, 10 h
Ar
(HO)2B
1
H2O (1.0 mL)
2a
(1.5 eq.)
3
(0.25 mmol)
run
Ar-I 1
product
run
Ar-I 1
product
(yield, %)a
(yield, %)a
I
I
1
2
3
4
5
1a
3a (99)
3b (99)
3c (98)
3d (98)
3e (88)
6
7
1f
1g
1h
1i
3f (93)
3g (86)
3h (87)
3i (91)
3j (86 )
I
I
MeO
1b
I
I
O
1c
8
I
F3C
I
O2N
CF3
1d
9
I
I
1e
10
1j
Cl
a Isolated Yields
This was likewise the case when the boronic acid derivative was changed (Table 3). These results
9

Green Chemistry
Page 10 of 41
View Article Online
DOI: 10.1039/C7GC01166K
demonstrate that SARu is an effective Ru reservoir for this kind of synthesis without any
contamination of other products or starting materials. When similar combinatorial syntheses are
conducted with polymer-supported metal catalysts, the catalysts have to be washed carefully to
prevent contamination because of the strong adsorption of starting materials and/or products on the
polymers. In contrast, no contamination was observed after simple solvent washing of SARu because
of its low affinity for organic compounds. S-Au is just solid-support and behaves nothing as catalyst
in this Ru nano-particle catalyzed Suzuki-Miyaura coupling. Au mesh itself is recyclable to make
another SARu. Also, there is a possibility that Au in SARu can be replaced by cheep glass, because
we have succeeded to replace Au in SAPd by glass.5g
10

Page 11 of 41
Green Chemistry
View Article Online
Table 3. Liquid-phase combinatorial synthesis using SARu and aryl iodides (part 2). DOI: 10.1039/C7GC01166K
SARu
SARu
K3PO4 (3.0 eq.)
Ar
I
(HO)2B Ar
+
DME (1.0 mL)
80 °C, 6 h
100 °C , 10 h
H2O (1.0 mL)
1a
(0.25 mmol)
2
3
(1.5 eq.)
run (HO)2B-Ar 2
product
run (HO)2B-Ar 2
product
(yield, %)a
(yield, %)a
OMe
(HO)2B
(HO)2B
1
2
3
4
5
2b
3b (99)
3f (98)
3e (90)
3c (94)
3g (92)
6
7
2g
2h
2i
3h (95)
3k (93)
3l (94)
Me
N
(HO)2B
(HO)2B
(HO)2B
(HO)2B
2c
Cl
S
(HO)2B
2d
8 b
Ac
O
(HO)2B
2e
9
2j 3m (89)
Me
(HO)2B
(HO)2B
2f
10
2k
3j (86)
a Isolated Yields. b 2 equiv. of boronic acid was used.
11

Green Chemistry
Page 12 of 41
View Article Online
DOI: 10.1039/C7GC01166K
SARu-catalyzed ligand-free Suzuki–Miyaura coupling of aryl bromides
We next investigated the scope of SARu use by performing liquid-phase combinatorial synthesis
using various bromobenzene derivatives. The results are summarized in Table 4. The reactions of
bromobenzene (first cycle), 4-acetylbromobenzene (third cycle), and 4-nitrobromobenzene (fourth
cycle), with phenylboronic acid provided the corresponding biaryl products 3a, 3c, and 3d in
quantitative yields, although we needed a longer reaction time in the first step because of the
relatively slow oxidative addition of aryl bromides. The reactions of 4-methoxybromobenzene
(second cycle) and 1-chloro-4-bromobenzene (fifth cycle) with phenylboronic acid gave the
corresponding product 3b in 88% yield and 3e in 70% yield, respectively. In the following five
cycles, the reaction proceeded smoothly to give the corresponding products 3f–3i in yields of
82%–91%. These results indicate that SARu is much more reactive than SAPd in ligand-free
Suzuki–Miyaura coupling of aryl bromides, because bromobenzene 1k did not give the coupled
product under the conventional heating conditions with SAPd.8 Furthermore, as indicated in Table 5,
this methodology is very useful to synthesize biaryl compounds with heterocycles, because
numerous heterocyclic aryl bromides are commercially available at reasonable prices.
12

Page 13 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
Table 4. Liquid-phase combinatorial synthesis using SARu and aryl bromides.
SARu
SARu
K3PO4 (3.0 eq.)
+
Ar-Br
DME (1.0 mL)
80 °C, 8 h
Ar
(HO)2B
100 °C, 10 h
H2O (1.0 mL)
1
(0.25 mmol)
2a
(1.5 eq.)
3
run
Ar-Br 1
product
run
Ar-Br 1
product
(yield, %)a
3a (94)
3b (88)
3c (95)
3d (97)
3e (70)
(yield, %)a
Br
Br
1
2
3
4
5
1k
6
7
1p
1q
1r
1s
1t
3f (86)
3g (82)
3h (86)
3i (91)
3j (84)
Br
Br
MeO
1l
Br
Br
O
1m
8
1n
1o
9
10
a Isolated Yields
13

Green Chemistry
Page 14 of 41
View Article Online
DOI: 10.1039/C7GC01166K
Table 5. Liquid-phase combinatorial synthesis using SARu and heterocyclic aryl bromides.
SARu
SARu
K3PO4 (3.0 eq.)
+
Het - Br
DME (1.0 mL)
80 °C, 8 h
Het
(HO)2B
100 °C, 10 h
H2O (1.0 mL)
1
2a
(1.5 eq.)
3
(0.25 mmol)
run
Het-Br 1
product
run
Het-Br 1
product
(yield, %)a
(yield, %)a
Br
Br
Br
Br
O
N
1
2
3
4
1u
1v
1w
1x
1y
3k (87)
3n (89)
3o (92)
3l (90)
3p (89)
6
7
1z
3q (82)
3r (95)
3s (88)
3t (85)
3u (78)
Br
N
N
H
1aa
1ab
1ac
1ad
Br
N
N
H
S
8
Br
S
Br
N
S
9
Br
Br
N
NH2
S
5
10
a Isolated Yields
SARu-catalyzed ligand-free Suzuki–Miyaura coupling of aryl chlorides
Aryl chlorides, which are economical and readily available substrates, have rarely been used in
Suzuki–Miyaura coupling because of the high activation barriers associated with oxidative insertion
of ruthenium(0) species into the C-Cl bond.3, 6 We next investigated the scope of SARu use by
performing Suzuki–Miyaura coupling of aryl chloride 1ae with phenylboronic acid 2a. Although we
14

Page 15 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
tried various traditional heating conditions, only trace amount of the corresponding coupling product
was obtained, as exemplified in Scheme 3.
Scheme 3. SARu-catalyzed ligand-free Suzuki–Miyaura coupling of 1ae with 2a.
SARu
SARu
Cl
K3PO4 (3.0 eq.)
+
DME (1.0 mL)
80 oC, 10 h
100 oC, 10 h
H2O (1.0 mL)
(HO)2B
trace
1ae
(0.25 mmol)
2a
(1.5 eq.)
3a
We previously developed a microwave-assisted strategy for Suzuki–Miyaura cross-coupling
reactions catalyzed by SAPd, which has very low leaching properties.8 The combined use of two
microwaves with different irradiation approaches made this protocol very efficient, because the
leaching induced by microwave-assisted physical etching can be easily controlled during the process.
However, irradiation of the reaction mixture containing 1ae and 2a by traditional microwave reactors
did not deliver the desired product 3a because of the rapid generation of hot spots (Figure 4 a) upon
heating whole the reaction vessel caused the irradiation to turn off within a very short period when
the temperature limit was reached (Figure 3). Then, we envisioned that the expected reaction might
proceed if the whole reaction mixture was continuously irradiated by microwaves. We constructed a
special microwave reactor equipped with a cooling unit for this purpose, as shown in Figure 4b,9 and
used it in the first step reaction. The results are summarized in Table 6. The reaction mixture was
irradiated at a certain microwave power for 2 h (entries 1–4) as the first step and then the whole
reaction mixture was treated in the usual second step. We obtained 3a in 31% yield when we used a
microwave irradiation power of 70 W in the first step. Using this novel microwave reactor fitted with
a cooling system, we achieved continuous microwave irradiation of SARu (Figure 5). We observed
15

Green Chemistry
Page 16 of 41
View Article Online
DOI: 10.1039/C7GC01166K
aggregated Ru in the bottom of the flask (Table 6, entry 4), indicating that stronger irradiation
leached more Ru than needed for the reaction, while weaker irradiation did not work. Entries 1–4
reveal that a microwave irradiation power of 70 W is suitable. When we shortened the irradiation
time to 1 and 1.5 h, the yield of 3a increased to 41% and 38%, respectively. When the reaction time
in the second step was prolonged to 24 h, a quantitative yield of 3a was successfully obtained
(entries 7 and 8).
Figure 3. Microwave irradiation data for SARu-catalyzed ligand-free Suzuki–Miyaura coupling of
1ae with 2a (first step) using a conventional microwave reactor.
16

Page 17 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
Figure 4. Microwave reactor designed for SARu-catalyzed ligand-free Suzuki–Miyaura coupling of
1ae with 2a (first step). Schematics of (a) a conventional microwave reactor and (b) our microwave
reactor with a cooling system.
(a)
① SARu
② thermo sensor
③ magnetic stirring bar
④ test tube (φ15 x 15 cm)
⑤ cooling condensor
⑥ cavity
⑤
⑦ microwave (standing
wave)
⑧ hot area
⑧
④
⑦
①
②
③
⑥
17

Green Chemistry
Page 18 of 41
View Article Online
DOI: 10.1039/C7GC01166K
(b)
① SARu
② thermo sensor
③ magnetic stirring bar
④ test tube (φ15 x 15 cm)
⑤ cooling condensor
⑥ thermostat
⑤
(adjustment range -13~200℃)
⑦ microwave (traveling wave)
⑧ antenna
④
⑦
⑧
⑧
①
②
③
⑥
18

Page 19 of 41
Green Chemistry
View Article Online
Figure 5. Microwave irradiation data for SARu-catalyzed ligand-free Suzuki–MiyaDuOraI: 10c.o10u3p9/lCi7nGgC0o11f66K
1ae with 2a (first step) using our microwave reactor in Figure 4 (b).
19

Green Chemistry
Page 20 of 41
View Article Online
DOI: 10.1039/C7GC01166K
Table 6. Microwave assisted SARu-catalyzed ligand-free Suzuki–Miyaura coupling of 1ae with 2a.
SARu
SARu
Cl
K3PO4 (3.0 eq.)
+
DME (2.5 mL)
80 oC, 8 h
100 oC, 10 h
H2O (2.5 mL)
(HO)2B
microwave heating
with cooling
1ae
(0.25 mmol)
2a
(1.5 eq.)
3a
Entry Time (h) MW (W) Yield (%)a
Entry Time (h) MW (W) Yield (%)a
1
2
3
4
2
2
2
2
10 W
50 W
70 W
100 W
trace
trace
31
5
6
1
70 W
70 W
70 W
70 W
41
38
96
97
1.5
1
7 b
8b
15
1.5
a Determined by HPLC. b The reaction was conducted for 24 h in the second step.
We next investigated the scope of the combined use of SARu and the special microwave reactor by
performing liquid-phase combinatorial synthesis using various chlorobenzene derivatives; the results
are summarized in Table 7. The reactions of chlorobenzene (first cycle) and 4-nitrochlorobenzene
(fourth cycle) with phenylboronic acid provided the corresponding biaryl products 3a and 3d in high
yields. The reactions of 4-methoxychlorobenzene (second cycle) and 2-methylchlorobenzene (third
cycle) with phenylboronic acid gave the corresponding product 3b in 60% yield and 3g in 52% yield,
respectively. In the following four cycles, the reactions proceeded smoothly to give the
corresponding heterocyclic products 3r, 3o, 3k, and 3n in yields of 65%–83%. This methodology is
very useful to make biaryl compounds with heterocycles, because a variety of heterocyclic aryl
chlorides are commercially available at reasonable prices.
20

Page 21 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
Table 7. Liquid-phase combinatorial synthesis using SARu and aryl chlorides.
SARu
SARu
K3PO4 (3.0 eq.)
Cl
+
R
100 oC, 24 h
R
DME (2.5 mL)
80 oC, 1.5 h
MW (70 W)
(H2O)2B
2a
(1.5 eq.)
H2O (1.0 mL)
1 (0.25 mmol)
3
Ar-Cl
Ar-Cl
Run
1
Yield (%)a
Run
Yield (%)a
Cl
Cl
3a (93)
3b (60)
3g (52)
3d (84)
5
6
7
8
3k (76)
N
1ae
1ai
Cl
Cl
2
3
4
3n (83)
3o (70)
3r (65)
N
1aj
MeO
1af
Cl
Cl
S
Me
1ag
1ak
Cl
Cl
N
O2N
1ah
1al
H
a Isolated Yields
SARu characterization
The structure and chemical composition of SARu were investigated using various spectroscopic
methods. We examined the SARu Ru K-edge X-ray absorption near-edge structure (XANES) spectra
before Suzuki–Miyaura coupling (denoted SARu before) and after the tenth cycle of the
SARu-catalyzed reaction (SARu after), and of Ru powder, [RuCl2(p-cymene)]2, Ru(acac)3, RuCl3,
and RuO2 as standard samples. The spectra are shown in Figure 6. The Ru K-edge XANES spectra
of SARu before and after use, and of Ru powder were similar. However, the K-edge XANES spectra
of [RuCl2(p-cymene)]2, Ru(acac)3, RuCl3, and RuO2 showed different chemical shifts. We also
examined the SARu Ru L-edge XANES spectra before Suzuki–Miyaura coupling and of Ru foil as
21

Green Chemistry
Page 22 of 41
View Article Online
standard samples; these spectra are presented in Figure 7. The Ru L-edge XANES sDpOeIc: 1t0r.a10o39f/CS7GACR01u166K
and Ru foil were almost identical. This indicates that the Ru species in SARu are zerovalent Ru or
metallic Ru, and are probably Ru nanoparticles, as in the case of SAPd.
The sizes of the metallic Ru species were determined precisely via theoretical curve fitting of the
extended X-ray absorption fine structure (EXAFS) oscillation for the Ru–Ru peak by Fourier
transforms of EXAFS oscillation spectra.10 The Ru K-edge Fourier transforms of the EXAFS
oscillation spectra in the k range of 2.0–12.0 Å−1 for Ru powder and SARu before and after reaction
are depicted in Figure 8. The curve-fitting analysis revealed that before the coupling reaction, SARu
had an average coordination number (N) of 7.0 ± 1.4, which is lower than that for Ru powder. From
these data, the average size of Ru species with an N of 7.0 was estimated to be approximately 1.0 ±
0.3 nm (Table 8). These results and XANES analyses confirmed that the Ru source in SARu is Ru(0)
nanoparticles. We also estimated the average size of the Ru nanoparticles in SARu after the reaction,
and found that their size was still approximately 2.4 ± 1.6 nm after the tenth cycle. It is worth noting
that the XANES results suggest that the Ru(0) nanoparticles in SARu are stable and tolerate C–C
coupling reaction conditions.
22

Page 23 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
Figure 6. Ru K-edge XANES spectra of SARu before and after use, Ru powder, [RuCl2(p-cymene)]2,
RuCl3, Ru(acac)3, and RuO2.
Figure 7. Ru L-edge XANES spectra of SARu and Ru foil.
23

Green Chemistry
Page 24 of 41
View Article Online
DOI: 10.1039/C7GC01166K
Figure 8. Ru K-edge Fourier transforms of EXAFS oscillation spectra of SARu and Ru powder.
Table 8. Theoretical curve-fitting results for EXAFS spectra of SARu and Ru powder.a
f
CN b
R[Å] c
δ2[Å2] d
E0[eV] e
2.2±1.0
-3.1±1.7
-3.5±2.1
Rfactor
0.003
0.014
0.022
Ru powder
SARu before
SARu after
12 g
2.68±0.01
2.67±0.01
2.67±0.01
0.0034±0.0005
0.0081±0.0011
0.0078±0.0014
7.0±1.4
8.7±2.1
2
a k3: k range = 2.0–12.0 Å−1, r range = 1.7–2.9 Å for Ru–Ru. Intrinsic loss factor, S0 = 0.65 (Ru–Ru
b
c
d
from Ru powder data). First shell coordination number. Interatomic distance. Debye–Waller
factor. e Correction of edge energy. f Goodness-of-fit index. g The coordination number was fixed as
that of a hexagonal close packed lattice.
We then focused on the sulfur in SARu, and recorded the sulfur K-edge XANES spectra of SARu
before and after use in Suzuki–Miyaura coupling reactions and of the standard samples Na2SO4,
24

Page 25 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
Na2S2O8, Na2SO3, Na2S2O3, PdS, and SAPd (Figure 9). The XANES spectra of SARu before and
after reaction display a clear resonance peak at 2481.6 eV. Comparison of the XANES spectrum of
SARu with those of standard materials suggests that the sulfur in SARu is strongly oxidized and
present as SO42−.5 The chemical shift of the sulfur in SARu is similar to that previously reported for
SAPd. These results strongly indicate that SARu consists of a matrix containing SO42− and is similar
to SAPd, which is composed of Pd nanoparticles implanted in a matrix formed by complexation of
SO42− and p-xylene. Based on these spectroscopic analyses, we conclude that SARu consists of Ru
nanoparticles with a size of approximately 1–3 nm and a matrix formed by complexation of SO42−
and p-xylene as the solvent, and that SARu forms a matrix of self-assembled multilayers of Ru
nanoparticles.
25

Green Chemistry
Page 26 of 41
View Article Online
Figure 9. Sulfur K-edge XANES spectra of SARu before and after use, and standard DsaOmI: 1p0.l1e03s9./C7GC01166K
Reaction Mechanism
From the data of SARu characterization, now we consider a plausible reaction mechanism as shown
in Scheme 4.10 Via the oxidative addition between arylhalide and Ru(0) nanopartiel on SARu,
although continuous irradiation of microwacve in Step 1 is critical for arylchloride, Ru(0)
nanoparticle on SARu was released into the reaction mixture in the Step 1 (Scheme 2 and Table 6).
After removing SARu in the end of Step 1 and adding water in the beginning of Step 2, insoluble
base was dissolved in the mixture and Ru(0) nanoparticle catalyzed ligand-free Suzuki-Miyaura
coupling. Soluble base is important for this reaction to be preoceeded. It is also important to make an
appropriate Step 1 conditions to release minimum and sufficient amount of Ru(0) into the reaction
mixture for both ligand-free Suzuki-Miyaura coupling and the repeated use of SARu.
Ar-X
Ar, Ar' = benzene, heterocycle
X = I, Br, Cl
continuoulys irradiating
= Ru(0) nanoparticle
microwave forAr-Cl
oxidative addition
supporting solid
SARu
Step 1
Ar-Ar'
Ar
Ar'-B(OH)2
1
+
K2PO4
X
1
2
Ar
K2PO4
PO4
2
Ar'-B(OH)2
metathesis
Ar'
Ar
B(OH)2PO4
transmetalation
KX
1
2
PO4
Step 2
Scheme 4. A plausible reaction mechanism of SARu catalyzed ligand-free Suzuki-Miyaura coupling.
Conclusion
26

Page 27 of 41
Green Chemistry
View Article Online
DOI: 10.1039/C7GC01166K
We successfully developed sulfur-modified Au-supported Ru(0) nanoparticles, i.e., SARu, for
recyclable, low-leaching, and ligand-free Suzuki–Miyaura coupling. SARu was easily prepared by a
three-step procedure involving Ru immobilization using Ru(acac)3 as a Ru source and
4-methoxybenzyl alcohol as a reductant to produce Ru(0) from Ru(II) via an in situ PSSO method.
SARu catalyzed C–C bond-forming Suzuki–Miyaura coupling of not only aryl iodides and aryl
bromides but also aryl chlorides under microwave irradiation. Detailed spectroscopic analyses
showed that SARu consists of Ru(0) nanoparticles with diameters of approximately 1–3 nm. The
results also showed that the Ru(0) nanoparticles, which are known to be easily oxidized to Ru(III),
are stably immobilized in SARu. These results suggest that our in situ PSSO method could be a
versatile method to immobilize metal nanoparticles. Further studies of in situ PSSO for
immobilization of other metals and its use in synthesizing catalysts for organic synthesis are in
progress.
Experimental
Preparation of SARu
A 12 × 14 mm2 (100 mesh) sample of Au was placed in piranha solution for 30 min and then rinsed
in succession with H2O (2 mL × 5) and EtOH (2mL × 5). The sample was placed in a flask and dried
for 10 min under reduced pressure. The resulting sulfur-modified Au [S-Au] was placed in a solution
of Ru(acac)3 (20.0 mg, 0.050 mmol) and 4-methoxybenzylalcohol (0.13 mL, 1.05 mmol) in p-xylene
(2.3 mL) and stirred at 135 °C for 12 h under a N2 atmosphere. Then the plate was rinsed with
p-xylene (2 mL × 10) and dried under vacuum. The obtained mesh was placed in p-xylene (2.5 mL)
and heated at 135 °C for 12 h three times. The mesh was rinsed with p-xylene (2 mL × 5) and dried
27

Green Chemistry
Page 28 of 41
View Article Online
DOI: 10.1039/C7GC01166K
under vacuum for 20 min to give SARu (Ru: 194 ± 36 μg)
Recycling experiment of SARu-catalyzed ligand-free Suzuki-Miyaura coupling (Table 1, run 1)
A mixture of iodobenzene 1a (51.0 mg, 0.250 mmol), phenylboronic acid 2a (45.7 mg, 0.375 mmol),
and K3PO4 (159 mg, 0.750 mmol) in DME (1.0 mL) was heated in the present of SARu (12 ×14 mm2,
Ru: 194 ± 36 μg) at 80 °C for 6 h under argon atmosphere without stirring. After the reaction
mixture had been cooled to room temperature, the SARu plate was removed from the reaction
mixture and rinsed several time with DME (0.2 mL) and EtOH. Then, H2O (1.0 mL) was added into
the reaction mixture and the whole was stirred at 100 °C for 10 h. The yields of corresponding
compound 3a were determined by using HPLC (Condition: Mightysil-RP18 (150 mm, φ 4.6 mm, 3
μm Kanto Chemical Co. Inc.), MeCN : H2O (70 / 30), 0.80 mL / min, 25 °C, tR 12.8 min).
ICP-Mass analysis
The whole reaction mixture or SARu substrate was treated with concentrated nitric acid, and Ru
species in this mixture was examined by ICP-Mass.
Typical experimental procedure of successively Suzuki-Miyaura coupling for Table 2-5 (Table
2, run 1)
A mixture of iodobenzene (51.0 mg, 0.250 mmol), phenylboronic acid (45.7 mg, 0.375 mmol) and
K3PO4 (159 mg, 0.750 mmol) in DME (1.0 mL) was heated in the presence of SARu (12 × 14 mm2,
Ru: 194 ± 36 μg) at 80 °C for 6 h under argon atmosphere without stirring. After the reaction
mixture had been cooled to room temperature, the SARu plate was removed from the reaction
mixture and rinsed several time with EtOH. Then, H2O (1.0 mL) was added into the reaction mixture
28

Page 29 of 41
Green Chemistry
View Article Online
and the whole was stirred at 100 °C for 10 h. After the reaction mixture had been DcOoIo: 1l0e.1d03t9o/C7rGoCo0m1166K
temperature, sat. NH4Cl (2.0 mL) was added, concentrated in vacuo and extracted with AcOEt. The
organic layer was washed with brine, dried over anhydrous Na2SO4 and concentration under reduced
pressure. The resulting crude product was purified by silica gel column chromatography (100%
hexane) to provide a title compound, biphenyl (3a, 99%) as a colorless plate. The recovered SARu
plate was again subject to above reaction as a next run. This procedure was repeated a total 10 runs.
Typical experimental procedure of successively Suzuki-Miyaura coupling with aryl chlorides
(Table 7, run 1)
A mixture of chlorobenzene 1ae (28.1 mg, 0.250 mmol), phenylboronic acid 2a (45.7 mg, 0.375
mmol) and K3PO4 (159 mg, 0.750 mmol) in DME (2.5 mL) was heated in the presence of SARu (12
× 14 mm2, Ru: 194 ± 36 μg) and irradiated by semi-conductor type microwave machine at 80 °C, 70
W for 1.5 h. After the reaction mixture had been cooled to room temperature, the SARu plate was
removed from the reaction mixture and rinsed several time with EtOH. Then, H2O (2.5 mL) was
added into the reaction mixture and the whole was stirred at 100 °C, conventional heating for 24 h.
After the reaction mixture had been cooled to room temperature, sat. NH4Cl (2.0 mL) was added,
concentrated in vacuo and extracted with AcOEt. The organic layer was washed with brine, dried
over anhydrous Na2SO4 and concentration under reduced pressure. The resulting crude product was
purified by silica gel column chromatography (100% hexane) to provide a title compound, biphenyl
(3a, 93%) as a colorless plate. The recovered SARu plate was again subject to above reaction as a
next run. This procedure was repeated a total 8 runs.
1
Biphenyl 3a112 13: mp. 70.0-70.5 ℃ (lit.13 70.0-71.0 ℃, MeOH), colorless plates. H NMR (400
29