A practical method for heterogeneously-catalyzed Mizoroki–Heck reaction: Flow system with adjustment of microwave resonance as an energy source

Article abstract of DOI:10.1016/j.tet.2018.02.044

The microwave-assisted and continuous-flow Mizoroki–Heck reaction using a heterogeneous palladium catalyst supported on the anion-exchange resin DIAION WA30 (7% Pd/WA30) is described. The microwave resonance is finely adjusted to 2.4 GHz according to the electric permittivity of the reaction medium for efficient heating. Organic solvents, such as acetonitrile, N,N-dimethylacetamide, and toluene, can be sufficiently heated even with a low intensity of microwave irradiation in a 7% Pd/WA30-packed, glass tube-shaped catalyst cartridge, which was designed based on the electric permittivity of the solvents. The catalyst cartridge can be continuously reused at least 5 runs without exchange.

Full text of DOI:10.1016/j.tet.2018.02.044

Accepted Manuscript
A practical method for heterogeneously-catalyzed Mizoroki–Heck reaction: Flow
system with adjustment of microwave resonance as an energy source
Tomohiro Ichikawa, Masahiro Mizuno, Shun Ueda, Noriyuki Ohneda, Hiromichi
Odajima, Yoshinari Sawama, Yasunari Monguchi, Hironao Sajiki
PII:
S0040-4020(18)30189-3
10.1016/j.tet.2018.02.044
TET 29315
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 October 2017
Revised Date: 7 February 2018
Accepted Date: 20 February 2018
Please cite this article as: Ichikawa T, Mizuno M, Ueda S, Ohneda N, Odajima H, Sawama Y, Monguchi
Y, Sajiki H, A practical method for heterogeneously-catalyzed Mizoroki–Heck reaction: Flow system
with adjustment of microwave resonance as an energy source, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.02.044.
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A practical method for heterogeneously-
catalyzed Mizoroki–Heck reaction: flow
system with adjustment of microwave
resonance as an energy source
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Tomohiro Ichikawa, Masahiro Mizuno, Shun Ueda, Noriyuki Ohneda, Hiromichi Odajima, Yoshinari Sawama,
Yasunari Monguchi,* and Hironao Sajiki*

1
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Tetrahedron
journal homepage: www.elsevier.com
A practical method for heterogeneously-catalyzed Mizoroki–Heck reaction: flow
system with adjustment of microwave resonance as an energy source
Tomohiro Ichikawaa, Masahiro Mizunoa, Shun Uedaa, Noriyuki Ohnedab, Hiromichi Odajimab, Yoshinari
Sawamaa, Yasunari Monguchia,c,*, and Hironao Sajikia
a Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
b Saida FDS, Inc.143-10 Isshiki, Yaizu 425-0054, Japan
c Laboratory of Organic Chemistry, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The microwave-assisted and continuous-flow Mizoroki–Heck reaction using a heterogeneous
palladium catalyst supported on the anion-exchange resin DIAION WA30 (7% Pd/WA30) is
described. The microwave resonance is finely adjusted to 2.4 GHz according to the electric
permittivity of the reaction medium for efficient heating. Organic solvents, such as acetonitrile,
N,N-dimethylacetamide, and toluene, can be sufficiently heated even with a low intensity of
microwave irradiation in a 7% Pd/WA30-packed, glass tube-shaped catalyst cartridge, which
was designed based on the electric permittivity of the solvents. The catalyst cartridge can be
continuously reused at least 5 runs without exchange.
Available online
Keywords:
Heck reaction
Heterogeneous catalysis
Microwave chemistry
Palladium
2009 Elsevier Ltd. All rights reserved
.
Polymers
———
Corresponding author. Tel.: +81-58-230-8109; fax: +81-58-230-8109; e-mail: monguchi@daiichi-cps.ac.jp; sajiki@gifu-pu.ac.jp

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
method for the Mizoroki–Heck reaction using the same flow
reactor equipped with a MW heating device and a catalyst
cartridge (Fig. 1a–c), which is heterogeneously catalyzed by
our recently developed N,N-dimethylamino-functionalized
anion-exchange resin-embedded Pd (7% Pd/WA30).16–18
The development of heterogeneous Pd catalysts has long
been underway in the field of process chemistry because of
their recoverability, reusability, and lower metal contaminated
property to the product based on their insolubility, which in
turn reduce environmental and economic burden.
Heterogeneous Pd catalysts have been used for various cross-
coupling reactions,1–4 including the Pd-catalyzed Mizoroki–
Heck reaction between aryl halides and alkenes for the
preparation of multi-substituted alkene moieties, which are
often contained in key intermediates of organic syntheses.5 The
practical progress in the heterogeneously catalyzed Mizoroki–
Heck reaction in the last decade concerns the use of flow6–14
and microwave (MW) heating technologies.7,8,10,11,14
The application of heterogeneous Pd catalysts to the flow
reaction has several advantages resulting from the narrow and
closed reaction path, including sufficient contact between the
reagents and catalysts packed in the cartridge and prevention of
ignition by the combustible catalyst that is totally sealed from
air (oxygen). The reported flow-type Mizoroki–Heck reaction
8c,10a,12
uses Pd(OAc)2
as a homogeneous system and of Pd/C12,
Pd(0) on an ion-exchange-functionalized monolithic polymer13,
and poly(vinylpyridine)-doped Pd11a as a heterogeneous system.
Although MW heating has also been attractive because of its
specific characteristics, such as direct and rapid heating leading
to a short reaction time, increased product yield, and energy and
resource savings, MW-assisted syntheses have generally been
inappropriate for the scale-up in the batch system because of
the limited penetration depth of the MW.12,15a The combination
of flow technology with MW heating would be a solution, but
only a few examples of the MW-assisted continuous-flow
Mizoroki–Heck reaction have been reported to date.8a,10,11c,14 In
particular, the use of a heterogeneous Pd catalyst for the flow-
MW Mizoroki–Heck reaction is limited to Organ’s study,
where the reaction was carried out using their own equipment
with an attached Pd-coated capillary as a flow path, at the flow
rate of 0.010 mL min–1 under 2.45 GHz MW irradiation of 0–
300 W (~200 °C).14c Although the method could be used for the
Mizoroki–Heck reaction of aryl iodides to afford the desired
coupling products in moderate to excellent yields, there is room
for improvement from the perspective of use of a readily
exchangeable catalyst cartridge and reaction conditions, such as
the energy efficiency of MW heating, flow rates, and
temperature, for the practical utility of the MW-assisted
continuous-flow chemistry.
Fig. 1 (a) System for the continuous-flow MW-assisted synthesis: 1)
pumping system and backpressure regulator, 2) MW generator and resonant
cavity, 3) control devise, and 4) PC. (b) 7% Pd/WA30 (203 mg) packed in a
cartridge (cartridge A), which was developed for using MeCN as the
solvent and coated by a polytetrafluoroethylene tubular film for safety
reasons. (c) 7% Pd/WA30 (~600 mg) packed in a cartridge (cartridge B)
which was developed for the use of toluene as the solvent.
2. Results and discussion
2.1. Solvent heating efficiency in the presence of 7% Pd/WA30
A glass coiled tube was used by Akai et al. in the resonant
cavity for the reactions to achieve efficient heating based on the
long residence time of the reaction mixture in the MW heating
space; however, heterogeneous catalysts were extremely
difficult to be packed into and removed from the coiled tube.
We examined two kinds of straight glass tubes as catalyst
cartridges instead of the coiled tube. A straight glass tube
(internal diameter, 3 mm; internal volume, approximately 2
mL) with a glass filter to fix the catalyst (cartridge A) was
designed for maintaining the resonant frequency at 2.40–2.50
GHz in the absence of the Pd catalyst based on the electric
permittivity of acetonitrile (MeCN), which is used as the
solvent. Likewise, the other tube (cartridge B) with a partially
bugging section (internal diameter, 8 mm) at the center was
tuned for toluene (internal volume, 3.6 mL), and the glass filter
was placed at the bottom of the bulging part. These catalyst
Recently, well-improved stoichiometric methods were
developed for the Fischer indole synthesis and Diels-Alder
reaction by Akai15a and for the Wolf-Staudinger reaction by
Ley15b using a MW-applied continuous-flow reactor prepared
by Saida FDS, Inc. This reactor consists of 1) a pumping
system together with a backpressure regulator, 2) a single-mode
MW generator and resonant cavity, 3) a control device for the
MW generation, and 4) a personal computer (PC) to manage
the conditions including the MW irradiation (Fig. 1a). A
distinctive feature of this instrument is that it can generate a
uniform electromagnetic field in the resonant cavity by a solid-
state device for telecommunications; the irradiation frequency
could be quickly and finely adjusted by the immediate feedback
on the reflected power and electric field in the cavity. The best
resonance was maintained based on the changes in the electric
permittivity of the reaction mixture. We now describe a novel

3
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6b
DMA
0.3
10
5
91
cartridges A and B were selected according to the electric
permittivity of reaction solvents.
7b
DMA
0.15
0.15
0.15
0.15
0.15
0.15
0.3
69
8b
DMA
10
5
94
On the bottom side of cartridge A were placed glass beads
(0.991–1.397 mm diameter) and a cotton plug (entrance side) as
a platform, so that the Pd catalyst could be located in the
middle of the tube. 7% Pd/WA30 was then densely packed over
the cotton plug, and then, another cotton plug (exit side) was
placed on the catalyst, which would not be moved under the
increased pressure by a flow of solvent or reaction mixture.
Glass beads were again placed on the second cotton plug to fill
the vacant space and stabilize the MW resonance (Fig. 1b).
Glass beads and 7% Pd/WA30 were also placed in cartridge B
using a procedure similar to that in the case of cartridge A, and
7% Pd/WA30 was located in the bulging part (Fig. 1c).
9b
EtOAc
EtOAc
CPME
CPME
Toluene
Toluene
79
10b
11b
12b
13c
14c
10
5
111
90
10
5
119
95
0.3
10
126
a Solvent temperature at the steady state was directly measured using a
thermocouple installed at the exit of the cartridge.
b Cartridge A developed for MeCN was used.
c Cartridge B developed for toluene was used.
Table 1 shows the influence of the flow rate and the output
power of the MW on the solvent temperature at the exit of the
7% Pd/WA30-packed cartridge using a thermocouple at a
backpressure of 1 MPa. When MeCN was allowed to flow
through cartridge A at 0.3 mL min–1, the solvent temperature
increased to 70 °C under 5 W MW irradiation (Table 1, Entry
1) and 114 °C under 10 W MW irradiation (entry 2). A
decrease in the flow rate to 0.15 mL min–1 hardly affected the
temperature (entries 1 vs. 3 and 2 vs. 4). A similar heating
effect was observed in N,N-dimethylacetamide (DMA); the
temperature was increased by the raised MW output power
(entries 5 vs. 6 and 7 vs. 8), while the flow rate from 0.15 to 0.3
mL min–1 was not very important for the temperature change
(entries 5 vs. 7, and 6 vs. 8). EtOAc, cyclopentyl methyl ether
(CPME), and toluene were also effectively heated under 10 W
MW irradiation rather than under 5 W MW irradiation (Entries
9 vs. 10, 11 vs. 12, and 13 vs. 14). The Mizoroki–Heck reaction
was conducted at the conditionally controlled temperature
below 100 °C by taking into account the thermostability of the
DIAION WA30 catalyst support (ca. 100 °C).16
2.2. 7% Pd/WA30-catalyzed Mizoroki–Heck reaction
When a solution of 4'-iodoacetophenone 1 (0.1 M), n-butyl
acrylate (1.2 equiv), and tributylamine (Bu3N, 1.5 equiv) in
MeCN was once passed through the 7% Pd/WA30 in cartridge
A at the flow rate of 0.3 mL min–1 under MW irradiation (5 W),
a
mixture of the starting material 1, butyl 3-(4-
acetylphenyl)acrylate 2, 4,4'-diacetylbiphenyl 3, and
acetophenone 4 was obtained in 46%, 30%, 16%, and 5%
yields, respectively (Table 2, Entry 1).19 A decrease in the flow
rate to 0.15 mL min–1 led to a better conversion yield of 2
(53%) by extension of the contact time of the reagents with the
catalyst during the MW irradiation (Entry 2). DMA could also
be used as a solvent to afford 2 in 59% yield under 10 W MW
irradiation without any detection of 4 (Entry 4). However,
further decease in the flow rate to 0.05 mL min–1 resulted in the
increase of the yields of byproducts 3 and 4. Although 1 was
well consumed in toluene, significant amounts of the
byproducts 3 and 4 were generated (Entry 6). To minimize the
formation of byproducts, DMA was chosen as the appropriate
solvent. When the amounts of n-butyl acrylate (2 equiv) and
Bu3N (3 equiv) were increased, an excellent conversion yield of
1 (92%) was achieved (Entries 7 and 8). Furthermore, the
Table 1. Temperature of solvents heated at the exit of the
7% Pd/WA30-packed cartridge under the continuous-flow
and MW irradiation conditions
Entry
Solvent
Flow rate
Microwave
(W)
Temperature
(mL min–1)
(°C)a
1b,c
2b
MeCN
MeCN
MeCN
MeCN
DMA
0.3
5
70
reaction successfully proceeded even under
a
higher
concentration (0.25 M) leading to a reduction in the amount of
solvent and a facile increase in the production scale (Entry 9).
However, the yield of 2 decreased at a higher concentration (0.5
M), and serious deiodization of 1 was observed (Entry 10).20
0.3
10
5
114
70
3b
0.15
0.15
0.3
4b
10
5
115
65
5b
Table 2. 7% Pd/WA30-catalyzed flow-type Mizoroki–Heck reaction assisted by microwave irradiation
CO2Bu
I
Ac
7% Pd/WA30
Bu3N (z equiv)
CO2Bu
y equiv
DMA
Microwave
flow
Ac
Ac
Ac
Ac
Single-pass
1 (x M)
2
3
4
Entry
1
x
y
z
Solvent
MeCN
Microwave
(W)
Flow rate (mL
min–1)
Temperature Yield (%)b
(°C)a
1
2
3
4
0.1
1.2
1.5
5
0.3
80–98
46
30
16
5

4
Tetrahedron
ACCEPTED MANUSCRIPT
2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.25
0.5
1.2
1.2
1.2
1.2
1.2
2
1.5
1.5
1.5
1.5
1.5
1.5
3
MeCN
DMA
DMA
DMA
5
0.15
0.15
0.15
0.05
0.15
0.15
0.15
0.15
0.15
65–80
80–87
83–96
80–132
63–71
78–92
80–95
80–100
80–106
27
55
33
12
5
53
9
5
3
5
36
4
0
4
10
10
59
9
0
5
46
31
17
6
11
33
0
6c
Toluene 10
44
7
DMA
DMA
DMA
DMA
10
10
10
10
0
87
8
2
4
92
4
0
9
2
3
trace
0
93 (91)d
0
0
10
2
3
60
1
25
a The temperature, which was raised by the passing of only solvent through the catalyst cartridge, is indicated as a lower temperature in each entry. The
temperature increased up to the higher one during the reaction by the passing of the reaction mixture through the cartridge.21
b Yields were determined by 1H NMR using 1,4-dioxane as the internal standard.
c 7% Pd/WA30 (600 mg) was packed in cartridge B.
d Isolated yield.
The coupling reaction of 3'-iodoacetophenone with n-butyl
acrylate under 10 W MW irradiation afforded the desired cross-
coupling product in a better yield when using a 0.25 M solution
compared with that in the reaction using 0.1 M solution (34% vs.
62%; Table 3, Entries 3 and 4) in the same manner as the case of
4'-iodoacetophenone (Table 2, entries 6 and 8 and Table 3,
entries 1 and 2). The yield of the product was significantly
increased by circulation of the reaction solution (0.25 M) for 7.5
h (93% isolated yield, Entry 5).
bromobenzene as the substrates for the reaction with n-butyl
acrylate, respectively.
Table 3. Scope of substrates
7% Pd/WA30
Conditions A: Bu3N (1.5 equiv)
DMA (10 mL)
Single-pass
Conditions B: Bu3N (3 equiv)
DMA (4 mL)
Single-pass
Conditions C: Bu3N (5 equiv)
DMA (4 mL)
R2
I
To expand the substrate scope, three sets of reaction condition
were used: 1) condition A, where a solution of an aryl iodide (0.1
M), n-butyl acrylate (2 equiv), and Bu3N (1.5 equiv) in DMA
was passed through the 7% Pd/WA30-packed cartridge A only
once (single-pass manner) under MW irradiation; 2) condition B,
where a solution of an aryl iodide (0.25 M), n-butyl acrylate (2
equiv), and Bu3N (3 equiv) in DMA was passed through the 7%
Pd/WA30-packed cartridge A only once (single-pass manner)
under MW irradiation; 3) condition C, a solution of an aryl iodide
(0.25 M), n-butyl acrylate (2 equiv), and Bu3N (5 equiv) in DMA
was passed through the 7% Pd/WA30-packed cartridge A by
circulation under MW irradiation, when the conditions A and B
are ineffective.
Circulation
R2
R1
Microwave irradiation
0.15 mL min-1
R1
2 equiv
1 mmol
Entry
R1
R2
Condition
Temperat
Yield (%)a
ure (°C)
78–92
80–104
70–89
80–101
77–97
80–98
67–97
80–94
62–97
80–100
80-121
73–93
70–119
80–96
80–90
80–95
68–90
80–100
70-–95
1
4-Ac
4-Ac
3-Ac
3-Ac
3-Ac
2-Ac
4-NO2
4-NO2
4-CO2Et
4-CO2Et
4-Br
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
A
B
A
B
C
C
A
C
A
C
B
A
C
A
C
C
A
C
A
87
2
93 (91)b
3
34
4c
62
5
100 (93)b
15 (15)b
16
6d
7
The aryl iodides except for 1 showed poor reaction efficiency,
regardless of the electron density of their aromatic rings under
the single-pass conditions (entries 3, 4, 7, 9, 11, 12, 14, 17, and
19). The electron-deficient nitro-, ester-, and halogen-substituted
iodobenzenes were coupled with n-butyl acrylate to give the
desired Mizoroki–Heck products in good to excellent yields
under condition C (entries 8, 10, 13, and 15). In the case of 2'-
iodoacetophenone, the reaction proceeded with difficulty even
under condition C, probably because of the steric hindrance
around the reaction center (entry 6). Unsubstituted and electron-
enriched iodoarenes were also good substrates for the reaction
and produced the corresponding cinnamates in good yields under
condition C (entries 16, 18, 20, and 21). In addition to the
acrylates (entries 2 and 22), styrene, which is less reactive in the
Mizoroki–Heck reaction as compared to the electron-deficient
alkenes, was applicable to the present reaction (condition C, entry
24). The reactions generally proceeded in a clean manner without
any formation of byproducts except in three cases, wherein
homo-coupling biaryls (entries 8 and 10)22 or dialkene (entry
11)23,24 were generated by using iodoarenes or 4-iodo-
8
76 (76)b
9
33
10
11
12
13e
14
15
16f
17
18g
19
– (78)b
– (69)
65
4-Cl
4-Cl
88 (91)b
4-F
36
4-F
57 (57)b
86 (86)b
13
H
4-Me
4-Me
4-MeO
70 (65)b
31

5
20f,g
21
4-MeO
3-MeO
4-Ac
CO2Bu
CO2Bu
CO2Bn
Ph
C
C
B
A
C
80–100
69 (73)b
acrylate (2 equiv), and Bu3N (3 equiv) in DMA was passed
ACCEPTED MANUSCRIPT
80–95
80–100
70–95
80–97
- (51)b
86 (91)b
11
through the 7% Pd/WA30-packed cartridge at the flow rate of 0.1
mL min–1 at 100 °C to produce the mixture of the unreacted 1
(9%), desired Mizoroki–Heck product (2, 87%), and homo-
coupling product (3, 4%). This result indicated that the MW
irradiation facilitated the Mizoroki–Heck reaction because of the
rapid and efficient heating properties (Scheme 1 vs. Table 2,
entry 8).26
22
23
4-Ac
24
4-Ac
Ph
30 (30)b
a Yields were determined by 1H NMR using 1,4-dioxane as the internal
standard.
7% Pd/WA30
b Isolated yield.
Bu3N (3 equiv)
1
2
3
4
CO2Bu
2 equiv
c 5 equivalents of Bu3N were used.
d 12 W Microwave irradiation was used.
e 15 W Microwave irradiation was used.
f 14 W Microwave irradiation was used.
g 3 equivalents of Bu3N were used.
DMA, 100 °C
0.1 mL min-1
0.25 M
1H NMR yield
1 / 2 / 3 / 4
Single-pass
= 9 / 87 / 4 / 0
Scheme 1 Flow Mizoroki–Heck reaction using a heating oven
(without MW irradiation)
The MW effect for heating the DMA solutions of aryl iodide
derivatives under the flow conditions was investigated to clarify
whether the MW heating affects the efficiency of the Mizoroki–
Heck reaction (Table 4). When the DMA solutions of para-
substituted iodoacetophenone and iodoanisole were passed
through the 7% Pd/WA30-packed cartridge A at the rate of 0.15
mL min–1 under the 10 W MW-irradiated conditions, the
temperature increased to 105 °C and 99 °C, respectively (entries
Significant Pd leaching may emerge as an important issue in
heterogeneously catalyzed cross-coupling reactions, especially
under flow conditions.9a After the 7% Pd/WA30-catalyzed cross-
coupling reaction between 1 and n-butyl acrylate under the
present MW-assisted flow conditions, the Pd concentration in the
recovered reaction mixture was measured by the atomic
absorption analysis. As the result, revealed that the Pd species
were hardly leached from the catalyst in the cartridge (~1%,
1.249 ppm). The small amount of contaminating Pd species in the
recovered mixture could be removed during the process of 2
using silica-gel column chromatography; no Pd species were
observed in the purified 2 (< 1 ppm; detection limit).
1
and 3). On the other hand, the meta-substituted
iodoacetophenone and iodoanisole were heated up to 95 °C and
94 °C, respectively (entries 4 and 5). Effective heating was
observed in the case of the electron-deficient iodobenzene
derivatives, which were more reactive than the electron-rich
derivatives, regardless of the para- or meta-substitution (entries 1
and 2 vs. 3; entries 4 vs. 5). A distinctive observation was that
para-substitution of iodobenzene with a methoxy group led to a
greater increase in the temperature of the DMA solution and the
reaction yield as compared to those for meta-substitution (entries
3 vs. 5; Table 3, entries 20 vs. 21), although iodoarenes bearing
an electron-enriched substituent at the meta-position are
generally more reactive than the corresponding para-isomers in
palladium-catalyzed cross-coupling reactions using conventional
heating apparatus.17,18,25 These results indicate that the heating
efficiency by MW irradiation would be dependent on the
structure of the iodoarenes and closely related to their reactivity
toward the present Mizoroki–Heck reaction. The heating test
using other substances, n-butyl acrylate and Bu3N, was also
carried out as a background, but these compounds had a smaller
effect on heating than iodoarenes (entry 6).
Next, the reuse of 7% Pd/WA30-packed cartridge under the
Mizoroki–Heck reaction conditions was examined using 1 and n-
butyl acrylate (Table 5). The catalyst cartridge could be
repeatedly used for at least five runs without exchange of 7%
Pd/WA30.27
Table 5. Reuse test of catalyst cartridge
7% Pd/WA30
Bu3N (3 equiv)
1
2
3
CO2Bu
2 equiv
DMA (4 mL)
10 W Microwave
0.15 mL min-1
1 mmol
Single-pass
Runs
Temperature (°C)a
Yield (%)b
1
0
0
0
0
0
2
3
2
2
6
2
5
1st
111
107
108
112
106
98
98
92
98
87
Table 4. Effect of MW irradiation on heating of DMA
solution of aryl iodides under flow conditions
2nd
3rd
4th
5th
Entry
Solute
Temperature (°C)a
1
4-Ac-C6H4-I
105
100
99
2
4-Cl-C6H4-I
3
4-MeO-C6H4-I
3-Ac-C6H4-I
a The top temperature is indicated.
4
95
b Yields were determined by 1H NMR using 1,4-dioxane as the internal
standard.
5
3-MeO-C6H4-I
n-Butyl acrylate + Bu3N
94
6b
91
3. Conclusion
a The highest temperature is indicated.
We have developed a heterogeneously-catalyzed Mizoroki–
Heck reaction using a MW-assisted continuous-flow reactor.
Organic solvents could be effectively heated in the Pd/WA30-
packed cartridge under mild MW irradiation (5–15 W), which
was precisely adjusted for the best resonance. Various aryl
iodides and alkenes could be used for the present reactions. Since
Pd species were hardly leached into the reaction mixture and the
b A solution of n-butyl acrylate (2 mmol) and Bu3N (3 mmol) in DMA (4 mL)
was used
A comparative experiment of the heating systems was carried
out using KeyChem-H® (YMC Co., Ltd.), which is a continuous
flow-device equipped with a heating oven (hot air-mediated
heating system) (Scheme 1). The mixture of 1 (0.25 M), n-butyl

6
Tetrahedron
ACCEPTED MANUSCRIPT
trace amount of Pd species was easily removed by purification,
the vial had passed through the catalyst cartridge, additional
the reaction system would be suitable for practical application.
The 7% Pd/WA30-packed cartridge could be used 5 times
without exchange. Further research aimed at extending the MW-
assisted continuous flow system to other types of heterogeneous
catalysis is in progress in our laboratory.
DMA (15 mL) was passed through the path to wash out the
remaining reagents (total operation time: ca. 140 min). To the
collected mixture were added EtOAc (20 mL) and H2O (10 mL),
and the layers were separated. The aqueous layer was extracted
with EtOAc (20 mL). The combined organic layers were washed
with H2O (20 mL × 4) and brine (20 mL), dried over Na2SO4, and
concentrated in vacuo. To the residue was added CDCl3 (ca. 1.5
mL) and 1,4-dioxane (8.53 ꢀL, 100 ꢀmol) as an internal standard,
4. Experimental section
4.1. General
1
1
and the yield was determined by H NMR. The H NMR sample
was diluted with EtOAc (15 mL), washed three times with sat.
aq. CuSO4 (5 mL) and H2O (10 mL), dried over Na2SO4,
concentrated in vacuo. The residue was purified by silica gel
column chromatography using hexane/EtOAc (10 : 1) as the
eluent to give the corresponding substituted alkenes as the
Mizoroki–Heck reaction product.
All reagents and solvents were obtained from commercial
sources and used without further purification. 7% Pd/WA30 was
prepared according to our previous study.18a The microwave-
applied continuous-flow reactor was made by Saida FDS Inc.
The melting point was determined on a Sansyo melting point
apparatus SMP-300. IR spectra (neat) were measured using a
1
Bruker Alpha FT-IR spectrometer. The H and 13C NMR spectra
Circulation manner (condition C): When the TLC analysis
revealed that the aryl iodide still remained unreacted after a
single-pass of the reaction solution through the catalyst cartridge,
both the starting and ending parts of the flow path were dipped
into the reaction solution in a reservoir for circulation. After 7.5 h
of circulation at the flow rate of 0.15 mL min–1, the flow path
was washed with DMA (15 mL). The recovered mixture was
treated according to a procedure similar to that described for the
single-pass setup.
were recorded on JEOL AL 400 (400 MHz for 1H NMR and 100
1
MHz for 13C NMR) or JEOL ECA-500 (500 MHz for H NMR
and 125 MHz for 13C NMR). Chemical shifts (δ) were expressed
in ppm and internally referenced (δ = 0.00 ppm for TMS/CDCl3
for 1H NMR and 77.0 ppm for CDCl3 for 13C NMR). High
resolution mass spectra were measured by Shimadzu hybrid
LCMS-IT-TOF (LCMS-IT-TOF).
4.2. Preparation of catalyst cartridge
4.5. Heating efficiency of aryl iodides
7% Pd/WA30-packed cartridge A: Glass beads (0.991–1.397
mm diameter, 25 mg) were put on the glass filter, which was
placed in a straight glass tube (cartridge A), then a small amount
of cotton (ca. 7 mg) was placed on the glass beads. The 7%
Pd/WA30 (203 mg) was tightly filled on the cotton plug by
tapping the tube (3.8 cm catalyst layer in height), and another
cotton plug (ca. 7 mg) was then placed on the catalyst to prevent
movement of the 7% Pd/WA30 from the cartridge. Finally, more
glass beads (250 mg) were placed on the cotton plug.
Into the 7% Pd/WA30-packed cartridge A was flowed a
solution of iodoarene (1 mmol) in DMA (4 mL) from an
Erlenmeyer flask acting as a reservoir at the flow rate of 0.15 mL
min–1 along with irradiation of 10 W MW under a 1 MPa back-
pressure. The temperature was measured using a thermocouple at
the exit of the cartridge to avoid MW irradiation of the
thermocouple. The MW irradiation was maintained until the
temperature reached the steady state. The heating efficiency of a
solution of n-butyl acrylate (2 mmol) and Bu3N (3 mmol) in
DMA (4 mL) was also investigated in a procedure similar to that
for iodoarenes.
7% Pd/WA30-packed cartridge B: The 7% Pd/WA30 of (600
mg) was placed on a glass filter attached to the bottom of the
bulging part (internal diameter, 8 mm) of the straight tube
(internal diameter, 3 mm) (cartridge B), and glass beads (ca. 400
mg) were then placed on the catalyst.
4.6. Flow Mizoroki–Heck reaction using a heating oven (without
MW irradiation)
4.3. Solvent heating test
A solution of 4'-iodoacetophenone (246 mg, 1 mmol), n-butyl
acrylate (285 ꢀL, 2 mmol), and Bu3N (716 ꢀL, 3 mmol) in DMA
(4 mL) was prepared in a vial and passed through the 7%
Pd/WA30-packed (203 mg) cartridge in heated oven at 100 °C at
the flow rate of 0.1 mL min–1 in a single-pass manner using
KeyChem-H® (YMC Co., Ltd). After the whole solution of in the
vial was flowed to the catalyst cartridge, additional DMA (15
mL) was passed through the path to wash out the remaining
reagents. To the collected mixture were added EtOAc (20 mL)
and H2O (10 mL), and the layers were separated. The aqueous
layer was extracted with EtOAc (20 mL). The combined organic
layers were washed with H2O (20 mL × 4) and brine (20 mL),
dried over Na2SO4, concentrated in vacuo. To the residue was
added CDCl3 (ca. 1.5 mL) and 1,4-dioxane (8.53 ꢀL, 100 ꢀmol)
as an internal standard. The desired product was produced in 87%
yield determined by 1H NMR analysis.
Into the 7% Pd/WA30-packed cartridge A was flowed MeCN
(50 mL) from an Erlenmeyer flask acting as a reservoir at the
flow rate of 0.30 or 0.15 mL min–1 along with irradiation of 5 or
10 W MW under a 1 MPa back-pressure. The temperature was
measured using a thermocouple at the exit of the cartridge to
avoid MW irradiation of the thermocouple. The MW irradiation
was maintained until the temperature reached the steady state.
DMA, EtOAc, and CPME (10 mL) was also flowed into the 7%
Pd/WA30-packed cartridge A and the temperature was measured
by a procedure similar to that for the MeCN.
In the case of toluene (50 mL), the temperature change was
investigated in a setup similar to MeCN and DMA except for the
use of cartridge B.
4.4. General procedure for Mizoroki–Heck reaction
4.7. Pd-leaching test
Single-pass manner (conditions A and B): A solution of
iodoarene (1 mmol), alkene (2 mmol), and Bu3N (condition A,
1.5 mmol; condition B, 3 mmol) in DMA (condition A, 10 mL;
condition B, 4 mL) was prepared in a vial and flowed into
cartridge A packed with 7% Pd/WA30 at the flow rate of 0.15
mL min–1 along with the MW irradiation (10 W) under the 1 MPa
back-pressure in a single-pass manner. After the entire solution in
A solution of 4'-iodoacetophenone (246 mg, 1 mmol), n-butyl
acrylate (285 ꢀL, 2 mmol), and Bu3N (716 ꢀL, 3 mmol) in DMA
(4 mL) was prepared in a vial and passed through the 7%
Pd/WA30-packed [203 mg (14.21 mg as Pd species)] cartridge at
the flow rate of 0.15 mL min–1 under MW irradiation (10 W) at 1
MPa back-pressure in a single-pass manner. After the entire

7
7. In Flow Chemistry, Darvas, F.;Dorman, G.; Hesel, V., Eds.,
solution in the vial had passed through the catalyst cartridge, the
path was rinsed with additional DMA (15 mL) to wash out the
remaining reagents. The combined DMA solution was diluted
with EtOAc (20 mL) and washed with H2O (10 mL), and the
layers were separated. The aqueous layer was further extracted
with EtOAc (20 mL). The combined organic layers were washed
with H2O (20 mL × 4) and brine (20 mL), and was transferred to
a 100 mL volumetric flask together with additional EtOAc. Its
atomic absorption analysis indicated that 1.249 ppm (124.9 ꢀg)
of Pd species were eluted from the 7% Pd/WA30-packed
cartridge into the organic layers. The combined aqueous layers
were also transferred to a 100 mL volumetric flask together with
additional H2O and its atomic absorption analysis indicated that
Pd species were not detected in the aqueous layer (< 1 ppm;
detection limit). The total Pd amounts leached from the catalyst
was found to be 124.9 ꢀg (ca. 1% of Pd).
ACCEPTED MANUSCRIPT
Walter de Gruyter GmbH, Berlin and Boston, 2014, vol 1.
8. (a) Achanta, S.; Liautard, V.; Paugh, R.; Organ, M. G. Chem. Eur.
J. 2010, 16, 12797–12800; (b) Noël, T.; Buchwald, S. Chem. Soc.
Rev. 2011, 40, 5010–5029; (c) Viviano, M.; Glasnov, T. N.;
Reichart, B.; Tekautz, G.; Kappe, C. O. Org. Process Res. Dev.
2011, 15, 858–870.
9. (a) Cantillo, D.; Kappe, C. O. ChemCatChem 2014, 6, 3286–3305;
(b) Frost, C. G.; Mutton, L. Green, Chem. 2010, 12, 1687–1703;
(c) Kirschning, A.; Solodenko, W.; Mennecke, K. Chem. Eur. J.
2006, 12, 5972–5990.
10. (a) Ӧhrngren, P.; Fardost, A.; Russo, F.; Schanche, J.-S.; Fagrell,
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Moseley, J. D.; Woodman, E. K. Org. Process. Res. Dev. 2008, 12,
967–981.
11. For Mizoroki–Heck reaction using heterogeneous catalyst in flow
system: (a) K. Mennecke, W. Solodenko, A. Kirschning,
Synthesis, 2008, 10, 1589–1599; (b) Mennecke, K.; Kirschning, A.
Beilstein J. Org. Chem. 2009, 5, No. 21; (c) Konda, V.; Rydfjord,
J.; Sӓvmarker, J.; Larhed, M. Org. Process Res. Dev. 2014, 18,
1413–418.
The crude compounds obtained from the reaction using a
solution of 4'-iodoacetophenone (246 mg, 1 mmol), n-butyl
acrylate (285 ꢀL, 2 mmol), and Bu3N (716 ꢀL, 3 mmol) in DMA
(4 mL) under condition B was purified by silica gel column
chromatography using hexane/EtOAc (10 : 1) as the eluent to
give 2 (223 mg). The purified 2 was solved in EtOAc (100 mL)
using 100 mL volumetric flask. Its atom absorption analysis
indicated that no Pd species were observed (< 1 ppm; detection
limit).
12. Glasov, T. N.; Findernig, S.; Kappe, C. O. Chem. Eur. J. 2009, 15,
1001–1010.
13. Singh, B. K.; Kaval, N.; Tomar, S.; Eycken, E. V.; Parmar, V. S.
Org. Process. Res. Dev. 2008, 12, 468–474.
14. Microwave-assisted coupling reaction using heterogeneous
catalyst in flow system: (a) Shore, G.; Morin, S.; Mallik, D.;
Organ, M. G. Chem. Eur. J. 2008, 14, 1351–1356; (b) Ullah, F.;
Zhang, Q.; Javed, S.; Porubsky, P.; Neuenswander, B.;
Lushiznton, G. H.; Harson, P. R.; Organ, M. G. Synthesis 2012,
44, 2547–2554; (c) Sore, G.; Morin, S.; Organ, M. G. Angew.
Chem. int. Ed. 2006, 45, 2761–2766.
Acknowledgements
15. (a) Yokozawa, S.; Ohneda, N.; Muramatsu, K.; Okamoto, T.;
Odajima, H.; Ikawa, T.; Sugiyama, J.; Fujita, M.; Sawai, T.;
Egami, H.; Hamashima, Y.; Egi, M.; Akai, S. RSC Adv. 2015, 5,
10204–10210; (b) Musio, B.; Mariani, F.; Śliwiński, E. P.;
Kabeshov, M. A.; Odajima, H.; Ley, S. V. Synthesis 2016, 48,
3515–3526.
This work was partially supported by JSPS KAKENHI Grant
number 15K07863 and 16K15100. We sincerely appreciate the
N.E. Chemcat Co. and Mitsubishi Chemical Co. for providing the
Pd(OAc)2 and DIAION WA30, respectively.
16. For more information of DIAION WA30, see:
http://www.diaion.com/en/products/ion_exchange_resins/weakly_
basic_anion/index.html.
References and notes
17. (a) Monguchi, Y.; Ichikawa, T.; Netsu, M.; Hattori, T.; Mizusaki.
T.; Sawama, Y.; Sajiki, H. Synlett 2015, 26, 2014–2018; (b)
Ichikawa, T.; Netsu, M.; Mizuno, M.; Mizusaki, T.; Takagi, Y.;
Sawama, Y.; Monguchi, Y.; Sajiki, H. Adv. Synth. Catal. 2017,
359, 2269–2279.
1.
In Metal-Catalyzed Cross-Coupling Reaction 2nd Ed., Meilere,
A. de.; Diederich, F., Eds., Willy-VCH, Weinheim, 2004, vols. 1
and 2.
2. (a) Mizoroki, T.; Mori, K.; Ozaki, A.; Bull. Chem. Soc. Jpn. 1971,
44, 581; (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37,
2320–2322.
3. Beletstskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009–3066.
18. In comparison with the Pd catalyst embedded on the unsubstituted
polystyrene-divinylbenzene polymer (10% Pd/HP20), 7%
Pd/WA30 was found to much more effectively catalyze the
Suzuki–Miyaura reaction of 4'-chloroacetophenone with
phenylboronic acid under the batch conditions due to the ligand
effect of tert-amino groups on DIAION WA30, see References
and notes 17b. For 10% Pd/HP20, see (a) Monguchi, Y.; Fujita,
Y.; Endo, K.; Takao, S.; Yoshimura, M.; Takagi, Y.; Maegawa,
T.; Sajiki, H. Chem. Eur. J. 2009, 15, 834–837; (b) Monguchi, Y.;
Sakai, K.; Endo, K.; Fujita, Y.; Niimura, M.; Yoshimura, M.;
Mizusaki, T.; Sawama, Y.; Sajiki, H. ChemCatChem 2012, 4,
546–558. A piece of DIAION WA30 is not finely powdered but
spherically shaped, and the future is an advantage for the flow
reactions to maintain the continuous, stable, and smooth flow of
reaction mixtures in the catalyst cartridge.
19. The homo-coupling reaction of 1 to generate 3 would have
proceeded in a similar manner to that of Ullman-type reaction.
Although the mechanism of the hydrodeiodination of 1 is not
clear, the deiodination of iodoarenes under Mizoroki–Heck
reaction conditions were reported; e.g., (a) Alonso, D. A.; Nájera,
C.; Pacheco, C. J. Org. Chem. 2002, 67, 5588–5594; (b) Perosa,
A.; Tundo, P.; Selvia, M.; Zinovyev, S.; Testa, A. Org. Biomol.
Chem. 2004, 2, 2249–2252.
20. The use of EtOAc (4 mL) or CPME (4 mL) as a solvent for the
present Mizoroki–Heck reaction of 1 (1 mmol) with n-butyl
acrylate (2 mmol) in the presence of Bu3N (3 mmol) under 10 W
MW irradiation at the 0.15 mL min–1 flow rate led to a poor
formation of 2 in only a 19% or 29% yield, respectively.
21. The heating effect of the MW irradiation depends on an electric
permittivity of the solution or solvent passing through a catalyst
cartridge. Since the reaction mixture contains aryl halide, alkene,
tributylamine, and products, which have each inherent electric
permittivity, the electric permittivity of the mixture differs from
4. For heterogeneous catalyst: (a) Yin, L.; Liebscher, J. Chem. Rev.
2007, 107, 133–173; (b) Climent, M. J.; Corma, A.; Iborra, S.
Chem. Rev. 2011, 111, 1072–1133; (c) Hussain, I.; Capricho, J.;
Yawer, M. A. Adv. Synth. Catal. 2016, 358, 3320–3349; (d)
Pascanu, V.; Hansen, P.R.; Gómez, A. B.; Ayats, C.; Platero–
Prats, A. E.; Johansson, M. J.; Periàs, M. À.; Martin–Matute, B.
ChemSusChem 2015, 8, 123–130.
5. For recent reports for the Mizoroki–Heck reaction using
heterogeneous catalyst: (a) Monguchi, Y.; Sakai, K.; Endo, K.;
Fujita, Y.; Niimura, M.; Yoshimura, M.; Mizusaki, T.; Sawama,
Y.; Sajiki, H. ChemCatChem 2012, 4, 546–558; (b) Naghipour,
A.; Fakhri, A. Catal. Commun. 2016, 73, 39–45; (c) Sienkiewicz,
N.; Strzelec, K.; Pospiech, P.; Cypryk, M.; Szmechtyk, T. Appl.
Organomet. Chem. 2016, 30, 4–11; (d) Hajipour, A.; Khorsandi,
Z. Appl. Organomet. Chem. 2016, 30, 256–261; (e)
Marulasiddeshwara, M. B.; Kumar, P. R. Int. J. Biol. Macromol.
2016, 83, 326–334; (f) Movassagh, B.; Parvis, F. S.; Navidi, M.
Appl. Organomet. Chem. 2015, 29, 40–44; (g) Taira, T.;
Yanagimoto, T.; Sakai, K.; Sakai, H.; Endo, A.; Imura, T.
Tetrahedron 2016, 71, 4117–4122; (h) Khazaei, A.; Khazaei, M.;
Rahmati, S. J. Mol. Cat. A 2015, 29, 241–247; (i) Putta, C.;
Sharvath, V.; Sarkar, S.; Ghosh, S. RSC Adv. 2015, 5, 6652–6660;
(j) Dong, Z.; Ye, Z. Appl. Catal. A 2015, 489, 61–71; (k) Yamada,
Y. M. A.; Yuyama, Y.; Sato, T.; Fujikawa, S.; Uozumi, Y. Angew.
Chem. Int. Ed. 2014, 53, 127–131.
6. Glasnov, T.; In Continuous-Flow Chemistry in the Research
Laboratory, Springer, Berlin, 2016.

8
Tetrahedron
that of DMA. The change of the permittivity of the reaction
ACCEPTED MANUSCRIPT
solution as well as exothermic phenomenon of the reaction would
cause the change of temperature during the reaction.
22. 4,4'-Dinitro-1,1'-biaryl was observed in the 1H NMR spectrum of
the crude product when 4-iodonitrobenzene was used as the
substrate. The homo-coupling product from ethyl 4-iodobenzoate
was also obtained in 5% yield.
23. Di-n-butyl (E,E)-p-benzenediacrylate was obtained in 11% yield
during the reaction of n-butyl acrylate with 4-iodo-bromobenzene.
24. The use of 4'-bromoacetophenone or 3-iodopyridne as the
substrate for the reaction with n-butyl acrylate resulted in the
recovery of haloarene under the present reaction conditions. The
coupling reaction of 1 with cinnamaldehyde as a disubstituted
alkene intricately proceeded. The use of (2-iodophenyl)acrylate
for the intramolecular cross-coupling reaction led to a formation
of complex mixture.
25. (a) Lauer, M. G.; Thompson, M. K.; Shaughnessy, K. H. J. Org.
Chem. 2014, 79, 10837–10848; (b) Lee, H.–S.; Pai, S.–H.; Liao,
W.–T.; Yang, X.–J.; Tsai, F.–Y. RSC Adv. 2017, 7, 34293–34299.
26. Although the difference between the MW heating and hot air-
mediated heating in the reactivity might be attributed to the
selective heating of substrates or products by the former MW
heating, it could not be clarified because the actual temperature in
the catalyst cartridge during the reaction under the latter air-
mediated heating conditions could not be measured.
27. Although the temperature rose over 100 °C, which is the
maximum operating temperature of DIAION WA30 (see
References and notes 16), in each run during the reuse study, the
catalyst could be reused without any loss of the catalyst activity.