Aqueous Flow Hydroxycarbonylation of Aryl Halides Catalyzed by an Amphiphilic Polymer-Supported Palladium-Diphenylphosphine Catalyst

Article abstract of DOI:10.1055/s-0037-1611769

An aqueous continuous-flow reaction system is developed for the palladium-catalyzed hydroxycarbonylation of aryl halides. Flow hydroxycarbonylation of aryl halides in aqueous solution proceeds efficiently in a flow reactor containing a palladium-diphenylphosphine complex immobilized on an amphiphilic polystyrene-poly(ethylene glycol) resin to give the corresponding benzoic acids in excellent yields.

Full text of DOI:10.1055/s-0037-1611769

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
letter
A
en
T. Osako et al.
Letter
Synlett
Aqueous Flow Hydroxycarbonylation of Aryl Halides Catalyzed by
an Amphiphilic Polymer-Supported Palladium–Diphenylphos-
phine Catalyst
Takao Osako*
Reinhard Kaiser
Kaoru Torii
PS
O
O
P
Ph2
Pd
n
CO
Cl
packed in column cartridges
Yasuhiro Uozumi*
O
R
R
I
Institute for Molecular Science (IMS) and JST-ACCEL, Okazaki,
OH
K2CO3 (2 equiv), H2O/CH3CN
100 °C, system pressure: 5 bar
solution flow rate: 1.0 mL/min
contact time: 58 s
Aichi 444-8787, Japan
osakot@ims.ac.jp
uo@ims.ac.jp
73–99%
Continuous Flow Reactor
Received: 26.02.2019
Accepted after revision: 07.03.2019
Published online: 26.03.2019
Palladium-catalyzed carbonylation of aryl halides with
CO gas is an efficient and useful method for preparing car-
bonyl compounds.4 Although CO gas is a versatile building
block in organic synthesis and is readily available from in-
dustrial processes,5 there are potential risks in handling this
substance because of its toxicity and flammability.6 More-
over, because CO gas has a low solubility in many solvents,
harsh reaction conditions (high temperatures and/or high
pressures of CO) are usually required in conventional batch
carbonylation reactions in flasks or autoclaves. To overcome
these drawbacks of conventional carbonylation processes,
the use of continuous-flow technology in carbonylations
with CO gas has recently been investigated.7 Although effi-
cient biphasic gas–liquid continuous-flow carbonylation re-
actions mediated by homogeneous palladium catalysts are
well developed,8 triphasic gas–liquid–solid continuous-
flow carbonylation on heterogeneous palladium catalysts
for cleaner and more practical synthesis of benzoic acids
still remains an immature technology.9
We have previously developed a palladium–triphenyl-
phosphine complex immobilized on an amphiphilic poly-
styrene–poly(ethylene glycol) resin through an amide bond
(Pd-PEP) (Scheme 1).10 The polymer-supported palladium–
triphenylphosphine Pd-PEP efficiently catalyzed the batch
hydroxycarbonylation of aryl halides under green and mild
conditions in H2O under CO at atmospheric pressure to af-
ford the corresponding benzoic acids in excellent yields and
with high recyclability. On the basis of these results, we
surmised that the application of the polystyrene–poly(eth-
ylene glycol)-supported palladium–phenylphosphine com-
plex to a continuous-flow system might realize a more effi-
cient and more practical triphasic gas–liquid–solid continu-
ous-flow carbonylation. However, our preliminary attempts
at continuous-flow carbonylation on Pd-PEP in the pres-
ence of strong bases suffered from leaching of the palladi-
DOI: 10.1055/s-0037-1611769; Art ID: st-2019-w0115-l
Abstract An aqueous continuous-flow reaction system is developed
for the palladium-catalyzed hydroxycarbonylation of aryl halides. Flow
hydroxycarbonylation of aryl halides in aqueous solution proceeds effi-
ciently in a flow reactor containing a palladium–diphenylphosphine
complex immobilized on an amphiphilic polystyrene–poly(ethylene gly-
col) resin to give the corresponding benzoic acids in excellent yields.
Key words continuous-flow reaction, hydroxycarbonylation, aryl ha-
lides, palladium catalysis, benzoic acids, catalyst support, heterogenous
catalysis
Continuous-flow transformation has recently attracted
significant attention in organic chemistry and has been rec-
ognized as a powerful technology for realizing efficient,
practical, and green sustainable processes.1 In comparison
with conventional batch reactions, continuous-flow reac-
tions have several advantages in terms of improved safety,
high efficiency, precise control of reaction conditions, and
simple scale-up. In particular, the application of continu-
ous-flow technology to gas–liquid reactions permits effi-
cient gas mixing because of the high interfacial area be-
tween the gas and liquid in a flow stream, resulting in high-
ly efficient reactions.2 Consequently, the development of
continuous-flow systems for gas–liquid reactions has been
investigated extensively in this field of research. As our con-
tribution, we have successfully developed continuous-flow
systems for various gas–liquid reactions, including the aer-
obic oxidation of alcohols with O2 gas and the hydrogena-
tion of olefins, nitroarenes, or aldehydes with H2 gas cata-
lyzed by platinum nanoparticles immobilized on an amphi-
philic polystyrene–poly(ethylene glycol) resin.3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

B
T. Osako et al.
Letter
Synlett
um–triphenylphosphine complex due to cleavage of the
amide bond at the junction between the polymer and
triphenylphosphine ligand. In this study, we report the suc-
cessful development of an efficient and practical triphasic
continuous-flow system for the carbonylation of aryl ha-
lides by using a modified amphiphilic polymer-supported
palladium–diphenylphosphine complex. The flow hydroxy-
carbonylation of aryl halides proceeded efficiently in aque-
ous solutions in a flow reactor containing palladium–di-
phenylphosphine immobilized on polystyrene–poly(eth-
ylene glycol) resin under a system pressure of 5 bar to give
the corresponding benzoic acids in yields of up to 99%.
nBuLi (2.5 mmol), THF
–78 °C, 1 h
1.
2.
O
O
PPh2
PS
HP
n
3
O
O
Br
PS
n
31P NMR: –14.4 ppm
1
2
(1.0 mmol)
THF, –78 °C, then rt, 3 h
(2.5 mmol)
[Pd(allyl)Cl]2
O
O
P
Pd
PS
n
Ph2
Cl
THF, rt
2 h
4
31P NMR: 14.8 ppm
O
R
Pd-PEP (3–10 mol% Pd)
R
Scheme 2 Preparation of the palladium–diphenylphosphine complex
immobilized on an amphiphilic PS–PEG resin 4
X
CO (1 atm)
K2CO3 or KOH, H2O
25 °C, 12–20 h
OH
(X = I, Br)
45–100%
Batch conditions
Next, we examined the optimal conditions for the car-
bonylation of iodobenzene (5a) in a flow reactor system
(Phoenix Flow Reactor; ThalesNano Inc., Budapest, Hunga-
ry) containing the PS–PEG-supported palladium–diphenyl-
phosphine complex 4 (Figure 1, a). A solution of 5a and
K2CO3 (2 equiv) in a 1:2 mixture of H2O and EtOH was
pumped into the reactor at a flow rate of 1.0 mL/min by us-
ing an HPLC pump. CO gas was simultaneously introduced
through a gas mixer equipped with a titanium frit (Figure 1,
b) by a mass-flow controller system (Gas Module; Thale-
sNano Inc., Budapest, Hungary) and the resulting mixture
was passed sequentially through two catalyst cartridges
(internal diameter: 4 mm; length: 70 mm) (Figure 1, c),
each charged with the PS–PEG-supported palladium–di-
phenylphosphine complex 4 (2 × 250 mg; total: 0.084
mmol Pd). Under these conditions, the total contact time of
the solution with the catalyst was 58 seconds. However,
flow carbonylation of iodobenzene (5a) at 25 °C and a sys-
tem pressure of 20 bar with continuous introduction of CO
(flow rate: 40 mL/min) resulted in no conversion of 5a (Ta-
ble 1, entry 1). Increasing the reaction temperature pro-
moted flow carbonylation (entries 2–4). In a reaction at
100 °C, full conversion of 5a was observed (entry 4). Reduc-
ing the system pressure from 20 to 5 bar did not affect the
flow carbonylation (entries 5 and 6). In addition, the flow
rate of CO could be reduced from 40 to 10 mL/min (entries 7
and 8). In the flow carbonylation of 5a at a system pressure
of 5 bar and a CO flow rate of 10 mL/min, 5a was fully con-
sumed to afford the ethoxycarbonylation product, ethyl
benzoate (6a), in 76% isolated yield (entry 8). Increasing the
solution flow rate from 1.0 to 3.0 mL/min resulted in lower
conversions (entries 9 and 10).
O
PS
O
O
N
C
P
Pd
Pd-PEP =
n
H
Ph2
Cl
Amide junction
Cleavage occurs in flow system
Scheme 1 Our previous batch hydroxycarbonylation with the catalyst
Pd-PEP
To suppress the cleavage of the phosphine ligand from
the polymer support, we designed and prepared the palla-
dium–diphenylphosphine complex 4 immobilized on am-
phiphilic PS–PEG resin through a stable C–P bond (Scheme
2). Diphenylphosphine (1) was treated with a solution of n-
butyllithium in THF at –78 °C for one hour under an N2 at-
mosphere. The resulting mixture was added dropwise to a
THF solution containing bromo-functionalized PS–PEG res-
in 2 at –78 °C. After warming to room temperature, the re-
sulting mixture was shaken at room temperature for three
hours to give PS–PEG-supported diphenylphosphine ligand
3.11 Complexation of 3 with allylpalladium(II) chloride di-
mer in THF at room temperature for two hours afforded
pale-yellow beads of the PS–PEG-supported palladium–di-
phenylphosphine complex 4.12 In a 31P NMR study, the peak
for the phosphine group in complex 4 was observed at
+14.8 ppm, whereas the peak for the phosphine group in
the polymer diphenylphosphine ligand 3 was detected at –
14.4 ppm. This result clearly indicated successful formation
of the polymer-supported palladium–diphenylphosphine
complex. Inductively coupled plasma (ICP) analysis showed
that the polymer catalyst 4 had a palladium content of
0.168 mmol/g.
The presence of H2O in the solvent mixture was essen-
tial for promoting the flow carbonylation. When the flow
carbonylation of iodobenzene (5a) was carried out in neat
EtOH containing Et3N or DBU as an organic base (Table 1,
entries 11 and 12, respectively), the reactions were sluggish
(7 and 11% conversion, respectively). Note that, because of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

C
T. Osako et al.
Letter
Synlett
Table 1 Optimization of the Flow Ethoxycarbonylation of Iodobenzene
(5a) Using CO in a Mixture of H2O and EtOH Catalyzed by PS–PEG-Sup-
ported Palladium–Diphenylphosphine Complex 4a
CO
PS
O
O
P
Pd
(10–40 mL/min)
n
Ph2
Cl
4 (total 500 mg, 0.084 mmol Pd)
O
I
OEt
K2CO3 (2 equiv)
5a
6a
25–100 °C, system pressure: 5–20 bar
solution flow rate: 1.0–3.0 mL/min
contact time: 19–58 s
25 mM
in H2O/EtOH
Continuous Flow Reactor
Entry H2O/EtOH Temp System pres- CO flow
Solution Conver-
flow rate sion of
(°C)
sure (bar)
rate
(mL/min) (mL/min) 5a (%)
1
2
3
4
5
6
7
8
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
25
50
75
20
20
20
20
10
5
40
40
40
40
40
40
20
10
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0
11
44
100
100
100
100
100
100
100
100
100
5
Figure 1 Schematic diagrams of (a) the Phoenix flow system (P: pres-
sure sensor, M: gas mixer), (b) the gas mixer, and (c) a photograph of
the catalyst cartridge ( 4.0 × 70 mm)
5
100
(76)b
9
1:2
1:2
0:1
100
100
100
100
100
100
5
5
5
5
5
5
10
10
10
10
10
10
2.0
3.0
1.0
1.0
1.0
1.0
71
26
7
10
11c
its low solubility, K2CO3 could not be used in a flow reaction
in neat EtOH. Flow carbonylation of 5a in a 1:9 or a 1:4 mix-
ture of H2O and EtOH proceeded in 30% and 70% conver-
sions (entries 13 and 14). Therefore, the use of a 1:2 mix-
ture of H2O and EtOH was most effective for the flow
ethoxycarbonylation to obtain ethyl benzoate (6a) in high
yield (entry 8).
12d 0:1
11
30
70
13
14
1:9
1:4
a Reaction conditions: PhI (5a) (25 mM solution in H2O/EtOH), K2CO3 (2
equiv), 4 (two cartridges: 500 mg, 0.084 mmol of Pd), CO (flow rate: 10–40
mL/min), system pressure: 5–20 bar, solution flow rate: 1.0–3.0 mL/min,
contact time: 19–58 s.
Replacement of EtOH with nPrOH in the flow carbonyla-
tion of iodobenzene (5a) gave propyl benzoate (7a) in 73%
isolated yield under the optimized flow conditions (Scheme
3). Notably, flow carbonylation in a 1:2 mixture of H2O and
b Isolated yield.
c Et3N was used instead of K2CO3.
d DBU was used instead of K2CO3.
Notably, 1-bromo-4-iodobenzene (5f) was converted exclu-
sively into 4-bromobenzoic acid (9f) with the bromo group
remaining intact. Ketone, ester, and amide functionalities
were tolerated to provide the corresponding products 9j–l
in excellent yields. Iodobenzenes with other substitution
patterns (ortho- or meta-substitution or disubstitution)
also underwent flow hydroxycarbonylations giving prod-
ucts 9m–q. The flow hydroxycarbonylation of naphthyl and
phenanthryl iodides 5r–t proceeded smoothly to give the
corresponding carboxylic acids 9r–t in yields of 87–99%.
Cinnamic acid (9u) was obtained in 82% yield by flow hy-
droxycarbonylation of [(E)-(2-bromoethenyl)]benzene (5u).
When (2-iodophenyl)methanol (5v) was exposed to the
continuous-flow conditions, carbonylation was followed by
intramolecular cyclization to give 2-benzofuran-1(3H)-one
(9v) in 94% yield.
i
sterically hindered PrOH provided the desired isopropyl
benzoate (8a) in only 15% NMR yield; instead, benzoic acid
(9a; R = H) was obtained in 40% yield as the major product
after work-up of the resulting solution with 2 N aqueous HCl.
This result prompted us to optimize the reaction sol-
vents for exclusive formation of carboxylic acids. Gratify-
ingly, when the flow hydroxycarbonylation of iodobenzene
(5a) was performed in a 2:1 mixture of H2O and CH3CN, 5a
was fully converted into benzoic acid (9a) in 82% isolated
yield (Scheme 4).13 Using these conditions, we examined
the scope of the hydrocarbonylation of various aryl iodides.
Iodobenzenes 5b–i bearing various electron-donating or
electron-withdrawing substituents at the para-position un-
derwent flow hydroxycarbonylation to afford the corre-
sponding benzoic acids 9b–i in isolated yields of 81–99%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

D
T. Osako et al.
Letter
Synlett
O
4 (500 mg, 0.084 mmol Pd)
+
I
CO
K2CO3 (2 equiv), 100 °C
system pressure: 5 bar
solution flow rate: 1.0 mL/min
contact time: 58 s
OR
5a
10 mL/min
6a (R = Et): 100% conversion, 76% isolated yield
7a (R = nPr): 100% conversion, 73% isolated yield
8a (R = iPr): 83% conversion, 15% NMR yield
[Benzoic acid (9a) (R = H) was obtained in
40% NMR yield]
25 mM
in H2O/ROH (1:2)
Scheme 3 Flow hydrocarbonylation of iodobenzene with various alcohols
CO
(10 mL/min)
PS
O
O
P
Ph2
Pd
n
Cl
4 (total 500 mg, 0.084 mmol Pd)
O
R
R
I
OH
K2CO3 (2 equiv)
100 °C, system pressure: 5 bar
solution flow rate: 1.0 mL/min
contact time: 58 s
5
9
11–25 mM
in H2O/CH3CN
(2:1)
Continuous Flow Reactor
O
O
O
O
MeO
Me
OH
F
OH
OH
OH
9b 99%a
9d 96%a
9h 85%c
9a 82%
9c 84%
O
O
O
O
Cl
Br
F3C
O2N
OH
9e 90%b
O
OH
OH
OH
9f 93%b
9g 96%d
O
O
EtO
O
O
NC
BocHN
OH
O
OH
OH
OH
9j 93%a
9k 99%a
9i 81%b
9l 85%d
O
O
O
O
OH
Me
OH
OH
OH
Me
Cl
Cl
9m 86%a
9n 98%a
9o 74%b
9p 81%b
O
F3C
F3C
OH
O
OH
OH
O
OH
O
9q 79%c
9r 87%c
9s 98%c
9t 99%
OH
O
O
Br
I
O
OH
5u
5v
9u 82%
9v 94%
Scheme 4 Scope of aryl iodides in flow hydroxycarbonylation by CO in aqueous CH3CN catalyzed by PS–PEG-supported palladium–diphenylphosphine
complex 4. Reaction conditions: 5 [25 mM solution in H2O/CH3CN (2:1)], K2CO3 (2 equiv), 4 (two cartridges; 500 mg, 0.084 mmol of Pd), CO (flow rate:
10 mL/min), system pressure: 5 bar, solution flow rate: 1.0 mL/min, contact time: 58 s. a A 22 mM solution of 5 in H2O/CH3CN (1.4:1) was used. b An
18.8 mM solution of 5 in H2O/CH3CN (1:1) was used. c A 16.7 mM solution of 5 in H2O/CH3CN (1:1.3) was used. d An 11 mM solution of 5 in
H2O/CH3CN/tBuOH (2.9:2.1:1) was used
Under the standard flow conditions (5 bar, 100 °C, 58 s),
the hydroxycarbonylation of aryl bromides did not proceed
at all. However, when 50 mL of a 10.4 mM solution of 1-bro-
mo-4-(trifluoromethyl)benzene (10g) in H2O/CH3CN/tBuOH
(2.9:2.1:1.0) containing K2CO3 (2 equiv) was continuously
circulated for seven hours in the flow reaction system at
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

E
T. Osako et al.
Letter
Synlett
Scheme 5 Circulating-flow hydroxycarbonylation of aryl bromides catalyzed by PS–PEG-supported palladium–diphenylphosphine complex 4
120 °C, a system pressure of 40 bar, a CO flow rate of 10
mL/min, and a solution flow rate of 0.5 mL/min, 4-(trifluo-
romethyl)benzoic acid (9g) was obtained in 85% yield
(Scheme 5). Similarly, circulation of 40 mL of a 12.5 mM
solution 1-bromo-4-methylbenzene (10c) in H2O/CH3CN
(2:1) for nine hours in the flow system gave 4-methylben-
zoic acid (9c) in 52% yield. Other aryl halides, including het-
erocyclic halides and aryl chlorides, exhibited moderate re-
activity under similar catalytic conditions, requiring further
screening of conditions and optimization which will be re-
ported in due course.
Next, we examined the long-term flow hydroxycarbon-
ylation of iodobenzene (5a) in a flow reaction system con-
taining the PS–PEG-supported palladium–diphenylphos-
phine complex 4 (Scheme 6). Collection of the solution pro-
duced by the flow hydroxycarbonylation of 5a under the
optimized flow conditions over 2758 minutes provided 6.0
g of benzoic acid (9a) in 71% yield. After 2758 minutes, the
catalytic activity of 4 decreased. A second collection of the
resulting solution between 2758 and 5794 minutes afford-
ed 9a in 24% yield. A further decrease in the yield of 9a was
observed in a third collection between 5794 and 6173 min-
utes (14% yield). After 6173 minutes, the catalytic activity of
4 was lost, and no benzoic acid was formed. The long-term
hydroxycarbonylation for 6173 minutes produced a total of
8.3 g of benzoic acid with a turnover number (TON) of 475.
To obtain insight into the deactivation of the catalyst, we
recovered the polymer-supported palladium catalyst after
long-term flow hydroxycarbonylation, and we subjected it
to 31P NMR and ICP analyses. The phosphine peak of the re-
covered catalyst was observed at 33.3 ppm in the 31P NMR
spectrum, suggesting that phosphine was oxidized to the
corresponding phosphine oxide during the long-term reac-
tion due to exposure to air, although the catalyst was ther-
mally stable at 100–120 °C. ICP analysis revealed that 20%
of palladium content had leached out during long-term hy-
droxycarbonylation for 6173 minutes. Therefore, both oxi-
dation of the phosphine ligand and leaching of palladium
from the polymeric catalyst were responsible for the deacti-
vation.
In conclusion, we have developed an efficient continu-
ous-flow system for the hydroxycarbonylation of aryl ha-
lides on a heterogeneous palladium–diphenylphosphine
complex immobilized on an amphiphilic copolymer. The
hydroxycarbonylation proceeded efficiently in aqueous
solutions in a flow system containing a column cartridge of
the supported palladium–diphenylphosphine complex to
give the corresponding benzoic acids in excellent yields.
CO
(10 mL/min)
PS
O
O
P
Pd
n
Ph2
Cl
4 (total 500 mg, 0.084 mmol Pd)
O
I
OH
K2CO3 (2 equiv)
100 °C, system pressure: 5 bar
solution flow rate: 1.0 mL/min
contact time: 58 s
5a
9a
0–2758 min: 71%
2758–5794 min: 24%
5794–6173 min: 14%
25 mM
in H2O/CH3CN
(2:1)
Continuous Flow Reactor
total 8.3 g, average 44% yield
TON = 475
for 6173 mL
Scheme 6 Long-term flow hydroxycarbonylation of iodobenzene (5a) by CO, catalyzed by PS–PEG-supported palladium–diphenylphosphine complex 4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

F
T. Osako et al.
Letter
Synlett
Funding Information
Fukuyama, T. Chem. Lett. 2014, 43, 1456. (f) Mallia, C. J.; Walter,
G. C.; Baxendale, I. R. Beilstein J. Org. Chem. 2016, 12, 1503.
(g) Moore, J. S.; Smith, C. D.; Jensen, K. F. React. Chem. Eng. 2016,
1, 272.
This work was supported by the JST-ACCEL program (JPMJAC401). We
are also grateful for funding from the JSPS KAKENHI [Grant-in-Aid for
Challenging Exploratory Research (No. 26620090) and for Scientific
(9) For typical examples of flow carbonylations using heteroge-
neous catalysts, see: (a) Miller, P. W.; Long, N. J.; de Mello, A. J.;
Vilar, R.; Audrain, H.; Bender, D.; Passchier, J.; Gee, A. Angew.
Chem. Int. Ed. 2007, 46, 2875. (b) Csajágo, C.; Borcsek, B.; Niesz,
K.; Kovács, I.; Székelyhidi, Z.; Bajkó, Z.; Ürge, L.; Darvas, F. Org.
Lett. 2008, 10, 1589. (c) Balogh, J.; Kuik, Á.; Ürge, L.; Darvas, F.;
Bakos, J.; Skoda-Földes, R. J. Mol. Catal. A: Chem. 2009, 302, 76.
(10) Uozumi, Y.; Watanabe, T. J. Org. Chem. 1999, 64, 6921.
(11) PS–PEG-Supported Diphenylphosphine 3
Research (C) (No. 16K05876)].
J
a
p
a
n
S
c
i
e
n
c
e
a
n
d
T
e
c
h
n
o
l
o
g
y
A
g
e
n
c
y
(J
P
M
J
A
C
4
0
1)J
a
p
a
n
S
o
c
i
ety
f
orth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(2
6
6
2
0
0
9
0)J
a
p
a
n
S
o
c
i
etyforth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(1
6
K
0
5
8
7
6)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611769.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
Ph2P (1) (469 mg, 2.5 mmol) was added to degassed anhyd THF
(20 mL) under N2, and the solution was cooled to –78 °C. A 1.6
M solution of n-BuLi in hexane (1.6 mL, 2.5 mmol) was added
dropwise, and the mixture was stirred for 1 h at –78 °C. The
resulting mixture was added to a suspension of bromo-func-
tionalized PS–PEG resin 2 (TentaGel S Br purchased from Rapp
Polymere; average diameter 0.90 m; Br content: 0.32 mmol/g;
3.1 g, 1.0 mmol) in THF (30 mL) at –78 °C. The resulting mixture
was warmed to rt and shaken for 3 h. The solvent was removed
by filtration and the solid was washed sequentially with H2O
(3 × 5 mL) and CH2Cl2 (3 × 5 mL) under an inert atmosphere,
then dried under vacuum to give the PS–PEG-supported
References and Notes
(1) (a) Frost, C. G.; Mutton, L. Green Chem. 2010, 12, 1687.
(b) Newman, S. G.; Jensen, K. F. Green Chem. 2013, 15, 1456.
(c) Pastre, J. C.; Browne, D. L.; Ley, S. V. Chem. Soc. Rev. 2013, 42,
8849. (d) Yoshida, J.; Takahashi, Y.; Nagaki, A. Chem. Commun.
2013, 49, 9896. (e) Vaccaro, L.; Lanari, D.; Marrocchi, A.;
Strappaveccia, G. Green Chem. 2014, 16, 3680. (f) Gutmann, B.;
Cantillo, D.; Kappe, C. O. Angew. Chem. Int. Ed. 2015, 54, 6688.
(g) Munirathinam, R.; Huskens, J.; Verboom, W. Adv. Synth.
Catal. 2015, 357, 1093. (h) Brzozowski, M.; O’Brien, M.; Ley, S.
V.; Polyzos, A. Acc. Chem. Rev. 2015, 48, 349. (i) Kobayashi, S.
Chem. Asian J. 2016, 11, 425. (j) Plutschack, M. B.; Pieber, B.;
Gillmore, K.; Seeberger, P. H. Chem. Rev. 2017, 117, 11796.
(k) Akwi, F. M.; Watts, P. Chem. Commun. 2018, 54, 13894.
(l) Masuda, K.; Ichitsuka, T.; Koumura, N.; Sato, K.; Kobayashi, S.
Tetrahedron 2018, 74, 1705.
(2) Mallia, C. J.; Baxendale, I. R. Org. Process Res. Dev. 2016, 20, 327.
(3) (a) Osako, T.; Torii, K.; Uozumi, Y. RSC Adv. 2015, 5, 2647.
(b) Osako, T.; Torii, K.; Tazawa, A.; Uozumi, Y. RSC Adv. 2015, 5,
45760. (c) Osako, T.; Torii, K.; Hirata, S.; Uozumi, Y. ACS Catal.
2017, 7, 7371.
(4) (a) Barnard, C. F. J. Organometallics 2008, 27, 5402.
(b) Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem. Int.
Ed. 2009, 48, 4114. (c) Wu, X.-F.; Neumann, H.; Beller, M. Chem.
Soc. Rev. 2011, 40, 4986. (d) Gadge, S. T.; Bhanage, B. M. RSC Adv.
2014, 4, 10367. (e) Bai, Y.; Davis, D. C.; Dai, M. J. Org. Chem.
2017, 82, 2319.
(5) Weissermel, K.; Arpe, H.-J. Industrial Organic Chemistry, 4th ed;
Wiley-VCH: Weinheim, 2012, 127.
(6) Lewis, R. J. Sr Sax’s Dangerous Properties of Industrial Materials,
11th ed; Wiley-Interscience: New Jersey, 2004, 708.
(7) Fukuyama, T.; Totoki, T.; Ryu, I. Green Chem. 2014, 16, 2042.
(8) For typical examples of flow carbonylations using homoge-
neous catalysts, see: (a) Glasnov, T. N.; Findenig, S.; Kappe, C. O.
Chem. Eur. J. 2009, 15, 1001. (b) Kelly, C. B.; Lee, C. X.;
Mercadante, M. A.; Leadbeater, N. E. Org. Process Res. Dev. 2011,
15, 717. (c) Gong, X.; Miller, P. W.; Gee, A. D.; Long, N. J.; de
Mello, A. J.; Vilar, R. Chem. Eur. J. 2012, 18, 2768. (d) Gross, U.;
Koos, P.; O’Brien, M.; Polyzos, A.; Ley, S. V. Eur. J. Org. Chem.
2014, 6418. (e) Akinaga, H.; Masaoka, N.; Takagi, K.; Ryu, I.;
diphenylphosphine ligand 3.31
CDCl3):  = –14.4.
P SR-MAS NMR (162 MHz,
(12) PS–PEG-Supported Palladium–Diphenylphosphine Complex 4
The PS–PEG-supported diphenylphosphine ligand 3 (2.0 g) was
treated with allylpalladium(II) chloride dimer (117 mg, 0.32
mmol) in THF (20 mL) at rt for 2 h under N2. The resulting poly-
meric material was collected by filtration, washed with THF
(3 × 5 mL), and dried under vacuum to afford pale-yellow
polymer beads.31P SR-MAS NMR (162 MHz, CDCl3):  = 14.8. ICP
analysis showed the presence of 0.168 mmol/g of Pd.
(13) Flow Hydroxycarbonylation of Iodobenzene (5a); Typical
Procedure
A 25 mM solution of iodobenzene (5a) and K2CO3 (2 equiv) in
H2O/CH3CN (2:1) was pumped at a flow rate of 1.0 mL/min
(contact time: 58 s) through a Phoenix flow reactor system
equipped with two cartridges of 4 (total 500 mg; 0.084 mmol
Pd). Flow hydroxycarbonylation with CO gas introduced from a
gas module (10 mL/min) was conducted at 100 °C and a system
pressure of 5 bar. The resulting solution was collected for 50
min (50 mL) and the solvent was removed by evaporation. 2 N
aq HCl (10 mL) was added and the resulting solid was collected
by filtration, washed with H2O (3 × 10 mL), and dried under
vacuum to give benzoic acid (9a) as a white solid without any
further purification.Yield: 125 mg (82%); mp 122 °C; 1H NMR
(400 MHz, DMSO-d6):  = 12.96 (br s, 1 H, COOH), 7.93 (d, J = 7.2
Hz, 2 H, PhH-2 and PhH-6), 7.62 (t, J = 7.2 Hz, 1 H, PhH-4), 7.49 (t, J =
7.2 Hz, 2 H, PhH-3 and PhH-5); 13C NMR (101 MHz, DMSO-d6):
 = 167.32 (COOH), 132.87 (Ph), 130.76 (Ph), 129.26 (Ph),
128.57 (Ph); ESI-TOF-MS (neg.): m/z = 121 [M – H]–.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F