Ligand-free Suzuki-Miyaura cross-coupling with low Pd content: rapid development by a fluorescence-based high-throughput screening method

Article abstract of DOI:10.1039/d0ob02359k

Suzuki-Miyaura (SM) cross-coupling is one of the most effective strategies for carbon-carbon bond formation, but previous methods have several drawbacks, such as the requirement of complicated ligands, toxic organic solvents, and high-content-Pd catalysts. Thus, in this study, a highly efficient SM cross-coupling was developed using metal oxide catalysts: 0.02 mol% Pd, aqueous solvent, no ligand, and room temperature. Metal oxides containing low Pd content (ppm scale) were prepared by a simple co-precipitation method and used as a catalyst for the SM reaction. A fluorescence-based high-throughput screening (HTS) method was developed for the rapid evaluation of catalytic activity and reaction conditions. Among the various metal oxides, Pd/Fe₂O₃showed the highest activity for the SM reaction. After further optimization by HTS, various biaryl compounds were obtained under optimal conditions: Pd/Fe₂O₃(0.02 mol% Pd) in aqueous ethanol at mild temperature without any ligands.

Full text of DOI:10.1039/d0ob02359k

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Ligand-free Suzuki–Miyaura cross-coupling with
low Pd content: rapid development by a
fluorescence-based high-throughput screening
method†
Cite this: Org. Biomol. Chem., 2021,
19, 1009
Taeho Lim,
Jeong Yup Ryoo, Mingyeong Jang and Min Su Han
*
Suzuki–Miyaura (SM) cross-coupling is one of the most effective strategies for carbon–carbon bond for-
mation, but previous methods have several drawbacks, such as the requirement of complicated ligands,
toxic organic solvents, and high-content-Pd catalysts. Thus, in this study, a highly efficient SM cross-
coupling was developed using metal oxide catalysts: 0.02 mol% Pd, aqueous solvent, no ligand, and room
temperature. Metal oxides containing low Pd content (ppm scale) were prepared by a simple co-precipi-
tation method and used as a catalyst for the SM reaction. A fluorescence-based high-throughput screen-
ing (HTS) method was developed for the rapid evaluation of catalytic activity and reaction conditions.
Among the various metal oxides, Pd/Fe2O3 showed the highest activity for the SM reaction. After further
optimization by HTS, various biaryl compounds were obtained under optimal conditions: Pd/Fe2O3
(0.02 mol% Pd) in aqueous ethanol at mild temperature without any ligands.
Received 26th November 2020,
Accepted 23rd December 2020
DOI: 10.1039/d0ob02359k
rsc.li/obc
eco-friendly solvents to replace toxic organic solvents plays a
vital role in the sustainability of the reaction process. Palladium
Introduction
Suzuki–Miyaura (SM) cross-coupling, generally defined as a is a commonly used transition metal in the SM reactions.
Pd-catalyzed cross-coupling between organohalides and orga- However, its use incurs high cost and the supply of Pd resources
noboron, is one of the most effective approaches for carbon– is limited. Moreover, the use of large amounts of the Pd catalyst
carbon bond formation because of its advantages such as can result in residual Pd in the final organic product, which is
functional group compatibility and low toxicity of reactants undesirable in pharmaceutical chemistry.6 Therefore, a new SM
and by-products. Therefore, the SM reaction has been widely reaction using low-content-Pd catalyst must be developed. The
used to prepare biaryl derivatives that serve as important Lipshutz group developed an efficient SM reaction that allowed
chemicals for various natural products, pharmaceuticals, and the coupling of aryl halides and aryl boronic acids in a water
polymers.1–3 Over the past four decades, numerous catalysts system (2 wt% surfactants) with extremely low Pd content.7,8
showing high activity and selectivity have been developed for However, the use of a phosphine ligand was essential for their
the SM reaction. However, the previously reported catalysts reaction. At mild temperatures, a ligand-free SM reaction was
have several disadvantages such as the requirement of compli- performed using Pd nanoparticles stabilized by polyvinylpyrroli-
cated ligands, toxic organic solvents, and high content of Pd. done.9 However, 0.5 mol% Pd content was required. Recently,
Ligands are widely used in SM reactions, but they are often Ishida et al. developed a Pd-nanoparticle-based SM reaction.10
sensitive to water and/or air. Although several ligands can Using a catalyst, halides were coupled with a boronic acid in an
work in water and/or air systems, the high-cost and multi-step aqueous methanol solution without a phosphine ligand, but at
synthesis procedures have hindered the application of ligand- a high temperature (100 °C). Therefore, an eco-friendly SM reac-
based SM reactions.4,5 Because solvents form a large pro- tion that requires low catalyst loading, an eco-friendly solvent,
portion of the reaction process, the use of toxic solvents has mild temperature, and ligand-free is desired.11–14
an adverse effect on the environment. Therefore, the use of
The development of a new synthetic method consists of
numerous parameters such as catalysts, ligands, solvents, and
additives. Because of these parameters, there are various trials
and errors, and it leads to waste of human and materials
resources. Therefore, high-throughput screening (HTS)
methods for organic reactions have been developed, and they
facilitate the rapid analysis of reaction conditions. In general,
Department of Chemistry, Gwangju Institute of Science and Technology (GIST),
Gwangju 61005, Republic of Korea. E-mail: Happyhan@gist.ac.kr
†Electronic supplementary information (ESI) available: Tables S1, S2, Fig. S1, S2,
and characterization of compounds, 1H and 13C NMR spectra of compounds.
See DOI: 10.1039/d0ob02359k
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Scheme 1 Schematic representation of the fluorescence-based high-throughput screening method for the Suzuki–Miyaura cross-coupling.
various automated techniques such as high-performance
Results and discussion
liquid chromatography (HPLC),15,16 gas chromatography
(GC),17–19 mass spectrometry,20–22 and nuclear magnetic reso- The proposed fluorescence-based HTS method was developed
nance (NMR)23,24 have been used as HTS methods. However, to evaluate the efficiency of the reaction conditions for the SM
these methods have some drawbacks: the high cost of auto- reaction. Naphthalimide derivatives have been widely used as
mated instruments and the long time taken to analyze each chemosensors because they can readily introduce several func-
sample. To overcome these drawbacks, colorimetric25–28 and tional groups by tuning the naphthalene or imide structure
fluorescence29–35 HTS methods have been developed. These and show diverse photophysical properties because of such
methods facilitate shorter analysis time and are less expensive, tuning.44 Furthermore,
a useful precursor, 4-bromo-1,8-
thus incurring relatively low operation costs. We have pre- naphthalic anhydride, is commercially accessible. Therefore,
viously developed several chemosensor-based HTS methods we selected naphthalimide derivative 1a as a fluorophore for
for organic reactions,36–43 and the effects of reaction para- the fluorescence-based HTS method. The bromo group in 1a
meters, including additives, catalysts, and solvents, were evalu- is the reaction site of the SM reaction, and it is expected that
ated rapidly from the optical changes in the chemosensor. We fluorescence will increase when the bromo group is substi-
believe that chemosensor-based HTS methods could enhance tuted with a phenyl group by the SM reaction because high
the efficiency of the development process for the SM reaction.
fluorescence is typically observed in naphthalimide deriva-
Herein, we developed a fluorescence-based HTS method tives with other functional groups such as phenyl, ether, and
and an efficient catalytic method for the SM reaction. The fluo- amino groups at the 4-position instead of the bromine
rescence-based HTS method for the SM reaction was designed atom.45,46 As expected, the fluorescence intensity at 412 nm
using the chemosensor 4-bromo-N-n-butyl-1,8-naphthalimide increased with the ratio of 2a, and a linear standard curve for
(1a) to rapidly screen the efficiency of the catalysts (Scheme 1). 2a was obtained (Fig. S1†). The standard curve was used to
Chemosensor 1a was easily prepared through a simple one- calculate the yield of 2a. After the SM coupling between 1a
step procedure starting with a commercially available precur- and phenylboronic acid under various reaction conditions,
sor. As a catalyst, metal oxides with or without Pd were pre- the fluorescence of 2a in the reaction mixture was analyzed
pared following our previous research.43 In the case of Pd/ using a fluorescence spectrophotometer. The fluorescence of
MxOy, Pd at the ppm level was used, and 24 metal oxides were the reaction mixture was converted to yield using the stan-
prepared by co-precipitation. The activity of the catalysts and dard curve, and the obtained yield was denoted as the fluo-
reaction conditions were rapidly evaluated with the naked eye rescence yield. The proposed HTS method enables the rapid
or through fluorescence spectrophotometry using the fluo- analysis of the efficiency of metal oxides and reaction
rescence-based HTS method. After optimization, various biaryl conditions.
compounds were obtained under mild reaction conditions
without any ligands.
The first screening was performed using 0.1 mmol of 1a,
0.1 mmol of phenylboronic acid, 0.2 mmol of K2CO3, and
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Table 1 Optimization of reaction conditionsa
1 mg of metal oxides at room temperature (Fig. 1). To test
environmentally friendly conditions, we used 1 mL of mixed
EtOH/H2O (3 : 1) solvent, and the ligand was not used. After
12 h, H2O and toluene were added to the reaction mixture. An
aliquot of the toluene layer was collected and diluted using
toluene. There was no significant difference between the
diluted samples, but when irradiated with 365 nm UV light,
several fluorescent samples could be observed with the naked
eye. Furthermore, to confirm the fluorescence, a dark field
image was obtained, and 3o and 3r were found to exhibit dis-
tinct fluorescence (the number of metal oxide catalysts is
listed in Table S1†). Low fluorescence was observed for 3n and
3t, and the catalyst without Pd showed no catalytic activity
(3a–3l). Therefore, 3o and 3r were selected as ideal catalysts.
After the first screening, the reaction conditions were opti-
mized (Table 1). In this case, the overall reaction scale was
increased, and 1.2 equivalents of phenylboronic acid were
used. The fluorescence yield of 2a was proportional to the
amount of catalyst, and 3r showed higher activity than 3o
(Table 1, entries 1–6). Without the catalyst, the reaction did
not proceed. (Table 1, entry 7). Thus, 3r (Pd/Fe2O3) was
selected as the optimal catalyst. Furthermore, the effect of the
base was studied. Without the base, 1a could not be coupled
with phenylboronic acid. Sodium and potassium hydroxide
showed slightly lower activity than K2CO3 (Table 1, entries 8
and 9). Other carbonate bases (Na2CO3 and CsCO3) and
acetate bases showed a low fluorescence yield (Table 1, entries
10–13). NaOMe, t-BuOK, triethylamine, and tribasic phosphate
Entry
Catalyst
Base
Fluorescence yieldb (%)
1
2
3
4
5
6
7
8
3o 3 mg
3o 4 mg
3o 5 mg
3r 3 mg
3r 4 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 5 mg
3r 6 mg
3r 7 mg
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
NaOH
KOH
Na2CO3
Cs2CO3
NaOAc
KOAc
Na3PO4
K3PO4
NaOMe
t-BuOK
TEA
K2CO3
K2CO3
K2CO3
K2CO3
21
39
44
50
58
72
1
66
57
49
37
12
16
35
49
40
69
2
9
10
11
12
13
14
15
16
17
18
19c
20d
21
22
61
65
82
93
a Reaction conditions: 1a (0.5 mmol), phenylboronic acid (0.6 mmol),
base (2 equiv.), catalyst, and 5 mL of EtOH/H2O (3 : 1) at room tempera-
ture. b Fluorescence yield calculated from the standard curve. c K2CO3
(1 equiv.). d K2CO3 (1.5 equiv.).
bases also showed low catalytic activity (Table 1, entries
14–18). After the base screening, K2CO3 was selected as the
most appropriate base. Furthermore, on reducing the amount
of K2CO3, the fluorescence yield decreased (Table 1, entries 19
and 20). The solvent effect was also quickly analyzed using the
fluorescence-based HTS method (Table S2†). Several organic
solvents, H2O, or mixed solvents were used. In most cases,
exceptionally low fluorescence yields of <10% were obtained,
and EtOH or 1,4 dioxane showed a fluorescence yield of ∼40%.
The amount of 3r was adjusted to increase the fluorescence
yield of 2a, depending on the loading amount of 3r (Table 1,
entries 21 and 22). It was observed that 7 mg of 3r facilitated a
high fluorescence yield; thus, 7 mg was considered as the
optimal catalyst amount. This result highlighted the high cata-
lytic activity of 3r: 7 mg of 3r (Pd/Fe2O3) per 0.5 mmol of sub-
strate corresponds to only 0.02 mol% Pd (Pd content in 3r:
1356 ppm estimated by ICP-OES). The requirement of low Pd
content is one of the most significant features of this catalyst.
Furthermore, to evaluate the scope of this method, several
coupling reactions were performed under optimized reaction
conditions determined by HTS (Fig. 2). Aryl bromides contain-
Fig. 1 High-throughput screening of metal oxides.
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Fig. 3 XPS spectra of 3r (Pd/Fe2O3). (a) Survey XPS spectrum. High-
resolution XPS spectra of (b) Fe 2p, (C) O 1s, and (d) Pd 3d.
Fig. 2 Evaluation of the scope of the SM reaction. Reaction conditions:
aryl bromide (0.5 mmol), arylboronic acid (0.6 mmol), K2CO3
(1.0 mmol), 7 mg of 3r (Pd/Fe2O3, 0.02 mol% Pd), and 5 mL of EtOH/
H2O (3 : 1) at room temperature. Isolated yield. a50 °C. b0.7 mg of 3r (Pd/
Fe2O3, 0.002 mol% Pd) at 80 °C.
ing an electron-withdrawing group (EWG) were reacted with
phenylboronic acid. In the case of nitrile (2b), nitro (2c), alde-
hyde (2d), and methyl ester (2e), the reaction proceeded
rapidly and gave biphenyl products in excellent yields. The
selectivity between the halides is crucial in the coupling reac-
tion. Therefore, we investigated the selectivity between the
halides. We found that this coupling method has high selecti-
vity for bromide (2f and 2g), and no dehalogenation products
were formed. Aryl bromides with an electron-donating group
were investigated. Consequently, methoxy biphenyl (2h) was
obtained in 80% yield but required a longer reaction time than
EWG-containing aryl bromides. Furthermore, for hydroxyl and
dimethylamine substrates, the reactions were performed at
50 °C, and the products were obtained in 65% (2i) and 99%
(2j) yields, respectively. Moreover, the naphthaleneboronic
acid derivative was coupled with aryl bromide. After SM coup-
ling, 2k was obtained in 97% yield under optimal conditions.
Interestingly, a high yield (2k, 98%) could be confirmed even
under very low catalytic conditions (0.002 mol% Pd) in the
case of heating conditions. In the case of bulky boronic acid,
pyrene derivative 2l was obtained after 24 h and afforded a
high yield (87%). Notably, ortho-methyl substitution did not
affect the reaction (2m).
To investigate the surface and valence states of 3r, XPS
measurements were performed. The XPS spectra are presented
Fig. 4 (a) TEM image of 3r (Pd/Fe2O3); (b) HAADF-STEM and elemental
in Fig. 3. In the high-resolution XPS spectrum of Fe 2p, there mapping images of Pd/Fe2O3; (c) Fe; (d) O; and (e) Pd.
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were two major peaks at 710.8 and 724.2 eV. These peaks were loading in the catalyst sample was determined by ICP-OES
assigned to Fe 2p3/2 and Fe 2p1/2. Furthermore, there was a sat- (Avio 500, PerkinElmer).
ellite peak at 718.6 eV. The binding energies of Fe 2p and the
Preparation of 4-bromo-N-n-butyl-1,8-naphthalimide (1a)
satellite peak are typically indicative of Fe3+. This result is in
good agreement with the chemical composition of Fe2O3.47 In A mixture of 4-bromo-1,8-naphthalic anhydride (100 mmol,
the O 1s region, three peaks are located at 529.9, 531.9, and 27.71 g) and n-butylamine (110 mmol, 8.05 g) in EtOH
533.4 eV. The peak at 529.9 eV is assigned to O in Fe2O3. The (200 mL) was refluxed in an oil bath. The reaction was moni-
peaks at 531.9 and 533.4 eV are assigned to a hydroxyl group tored by TLC. After the consumption of 4-bromo-1,8-naphtha-
on the surface and the adsorbed water molecules, lic anhydride (26 h), the reaction mixture was cooled to room
respectively.48,49 The Pd 3d region showed two peaks at 337.7 temperature. The solid was filtered and washed with cold
and 342.9 eV.50 These binding energies were slightly higher EtOH. The solid was further purified by recrystallization using
than the Pd 3d binding energy of PdO and metallic Pd.51 The EtOH and 1a was obtained in quantitative yield. 1H NMR
high binding energy of Pd 3d was observed in Pd2+ in solid (400 MHz, CDCl3) δ 8.45 (dd, J = 7.3, 1.2 Hz, 1H), 8.32 (dd, J =
solution.52,53 Furthermore, this result was very similar to the 8.5, 1.2 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.9 Hz,
XPS results of Pd/CuO.43
1H), 7.67 (dd, J = 8.2, 7.3 Hz, 1H), 4.06 (t, J = 7.6 Hz, 2H),
Fig. 4 shows the TEM and HAADF-STEM images of 3r. The 1.68–1.60 (m, 2H), 1.39 (td, J = 15.0, 7.4 Hz, 2H), 0.93 (t, J = 7.3
average size of 3r was 191 nm. Elemental mapping images Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.4, 163.4, 132.9,
showed that Fe and O were evenly distributed. In the case of 131.8, 131.0, 131.0, 130.3, 130.0, 128.7, 128.0, 123.0, 122.1,
Pd, there were only background signals that were not well- 40.4, 30.2, 20.5, 13.9. The NMR data were consistent with
matched with the HAADF image of 3r because of the low reported data.54
content of Pd (1356 ppm Pd in 3r). The TEM results supported
the XPS spectra of 3r. 3r contained low Pd content. In the SEM
Preparation of N-n-butyl-4-phenyl-1,8-naphthalimide (2a)
images, 3r (Pd/Fe2O3) and Fe2O3 showed the same morphology A mixture of 1a (1 mmol, 0.33 g), phenylboronic acid (1 mmol,
and size distribution (Fig. S2†).
0.12 g), K2CO3 (2 mmol, 0.28 g), and Pd(PPh3)4 (0.05 mmol,
0.06 g) in EtOH/H2O (3 : 1, 10 mL) was stirred at room tempera-
ture for 10 hours. After the reaction, the reaction mixture was
diluted with H2O and CHCl3. The organic layer was collected
and washed with brine. The organic layer was dried with
Na2SO4, filtered and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography
(eluent: CHCl3/n-hexane = 2 : 1) and further purified by recrys-
tallization (EtOH) to afford pure 2a as a white solid (0.1724 g,
52%). 1H NMR (400 MHz, CDCl3) δ 8.62–8.58 (m, 2H), 8.23
(dd, J = 8.5, 1.2 Hz, 1H), 7.68–7.64 (m, 2H), 7.55–7.46 (m, 5H),
4.18 (t, J = 7.5 Hz, 2H), 1.76–1.68 (m, 2H), 1.45 (td, J = 15.0, 7.5
Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
164.4, 164.2, 146.9, 138.9, 132.7, 131.2, 130.9, 130.1, 130.0,
128.8, 128.6, 127.9, 126.9, 123.0, 121.9, 40.4, 30.3, 20.5, 14.0;
Conclusions
In this work, we developed an efficient SM reaction in which
various Pd-containing metal oxides were prepared by a simple
co-precipitation method and used as catalysts for SM reac-
tions. Furthermore, a fluorescence-based HTS method for the
SM reaction was developed by using 1a to facilitate the rapid
screening of reaction conditions. The activity of the catalysts
for the SM reaction was evaluated rapidly by the fluorescence-
based HTS method. We found that 3r (Pd/Fe2O3) showed the
highest activity for the SM reaction. After optimization, various
biaryl compounds were successfully obtained by using Pd/
Fe2O3 (0.02 mol% Pd) at room temperature under mild reac-
tion conditions without any ligands.
HRMS-ESI (m/z): [M + H]+ calcd for C22H20NO2 : 330.1489;
+
found: 330.1486.
General procedure for the high-throughput screening method
for Suzuki–Miyaura cross-coupling
The metal oxide catalyst was added to a reaction vial contain-
ing a PTFE-coated magnetic stirring bar. To the reaction vial,
the solvent was added and sonicated about 20 seconds to dis-
Experimental section
Materials and instruments
All chemical reagents were purchased from commercial perse a catalyst. A base was added to the reaction mixture. The
sources (Sigma-Aldrich, Tokyo Chemical Industry, and Alfa pre-fluorescent chemosensor 1a and phenylboronic acid were
Aesar) and used as received without further purification. added to the suspension. The reaction mixture was stirred vig-
Catalysts (MxOy and Pd/MxOy) were prepared following our pre- orously at room temperature. After 12 h, the stirring bar was
vious research.43 NMR spectra were recorded using a JEOL stopped, and H2O and toluene were added to the mixture. The
(400 MHz) NMR spectrometer. Fluorescence spectra were reaction mixture was shaken gently by hand for about 10
recorded on an Agilent Cary Eclipse fluorescence spectro- seconds. The reaction mixture was separated into two layers.
photometer. XPS studies were carried out with a Thermo An aliquot of the toluene layer was collected and diluted with
Scientific K-Alpha. SEM images were obtained on a Hitachi toluene. The solution was further diluted with toluene (5 µM
SU-70. TEM images were collected on a FEI Tecnai F20 UT. Pd based on 1a). The solution was analyzed with a fluorescence
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spectrophotometer. The fluorescence value of the solution was
converted to the fluorescence yield using a standard curve.
7 S. Handa, Y. Wang, F. Gallou and B. H. Lipshutz,
Sustainable Fe–ppm Pd nanoparticle catalysis of Suzuki-
Miyaura cross-couplings in water, Science, 2015, 349, 1087.
8 S. Handa, M. P. Andersson, F. Gallou, J. Reilly and
B. H. Lipshutz, HandaPhos: A General Ligand Enabling
Sustainable ppm Levels of Palladium-Catalyzed Cross-
Couplings in Water at Room Temperature, Angew. Chem.,
Int. Ed., 2016, 55, 4914.
9 F. Mäsing, H. Nüsse, J. Klingauf and A. Studer, Visible-
Light-Enabled Preparation of Palladium Nanoparticles and
Application as Catalysts for Suzuki–Miyaura Coupling, Org.
Lett., 2018, 20, 752.
10 J. Ishida, M. Nakatsuji, T. Nagata, H. Kawasaki, T. Suzuki
and Y. Obora, Synthesis and Characterization of N,
N-Dimethylformamide-Protected Palladium Nanoparticles
and Their Use in the Suzuki–Miyaura Cross-Coupling
Reaction, ACS Omega, 2020, 5, 9598.
11 S. E. Hooshmand, B. Heidari, R. Sedghi and R. S. Varma,
Recent advances in the Suzuki–Miyaura cross-coupling
reaction using efficient catalysts in eco-friendly media,
Green Chem., 2019, 21, 381.
12 W. Dong, L. Zhang, C. Wang, C. Feng, N. Shang, S. Gao and
C. Wang, Palladium nanoparticles embedded in metal–
organic framework derived porous carbon: synthesis and
application for efficient Suzuki–Miyaura coupling reactions,
RSC Adv., 2016, 6, 37118.
13 Y. Qian, J. So, M. Y. Lee, S. Hwang, M.-J. Jin and S. E. Shim,
Synthesis of novel and room temperature-operable palla-
dium complexes on graphene oxide: An efficient recyclable
catalyst for Suzuki-Miyaura coupling reactions, J. Ind. Eng.
Chem., 2019, 75, 253.
General procedure for Suzuki–Miyaura cross-coupling
Pd/Fe2O3 (7 mg) was added to a reaction vial containing a
PTFE-coated magnetic stirring bar. To the reaction vial, 5 mL
of mixed EtOH/H2O (3 : 1) solvent was added and sonicated for
about 20 seconds to disperse Pd/Fe2O3. To this suspension,
K2CO3 (1.0 mmol), phenyl boronic acid (0.6 mmol), and aryl
bromide (0.5 mmol) were added. The reaction mixture was
stirred vigorously at room temperature. The reaction was moni-
tored by thin layer chromatography (TLC). After the starting
material was consumed, the reaction mixture was diluted with
H2O and ethyl acetate. The organic layer was collected and
washed with brine. The organic layer was dried with Na2SO4,
filtered and evaporated under reduced pressure. The residue
was purified by silica gel column chromatography.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MSIT)
(NRF-2020R1A2B5B01002392).
14 A. Mohan, L. Rout, A. M. Thomas, J. Peter, S. Nagappan,
S. Parambadath and C.-S. Ha, Palladium nanoparticles-
anchored dual-responsive SBA-15-PNIPAM/PMAA nanoreac-
References
1 J. Sakamoto, M. Rehahn, G. Wegner and A. D. Schlüter,
tor:
a
novel heterogeneous catalyst for
a
green
Suzuki Polycondensation: Polyarylenes
Macromol. Rapid Commun., 2009, 30, 653.
à
la Carte,
Suzuki–Miyaura cross-coupling reaction, RSC Adv., 2020,
10, 28193.
2 C. Torborg and M. Beller, Recent Applications of 15 C. Cai, J. Y. L. Chung, J. C. McWilliams, Y. Sun, C. S. Shultz
Palladium-Catalyzed
Pharmaceutical, Agrochemical, and Fine Chemical
Industries, Adv. Synth. Catal., 2009, 351, 3027.
Coupling
Reactions
in
the
and M. Palucki, From High-Throughput Catalyst Screening
to Reaction Optimization: Detailed Investigation of
Regioselective Suzuki Coupling of 1,6-Naphthyridone
Dichloride, Org. Process Res. Dev., 2007, 11, 328.
3 A. T. K. Koshvandi, M. M. Heravi and T. Momeni, Current
Applications of Suzuki–Miyaura Coupling Reaction in The 16 H. Fang, Q. Xiao, F. Wu, P. E. Floreancig and S. G. Weber,
Total Synthesis of Natural Products: An update, Appl.
Organomet. Chem., 2018, 32, e4210.
Rapid Catalyst Screening by
Microreactor Interfaced with Ultra-High-Pressure Liquid
a
Continuous-Flow
4 Y.-Y. Peng, J. Liu, X. Lei and Z. Yin, Room-temperature
Chromatography, J. Org. Chem., 2010, 75, 5619.
highly efficient Suzuki–Miyaura reactions in water in the 17 O. Trapp, Gas chromatographic high-throughput
presence of Stilbazo, Green Chem., 2010, 12, 1072.
5 C. Liu, Q. Ni, F. Bao and J. Qiu, A simple and efficient pro-
screening techniques in catalysis, J. Chromatogr., 2008,
1184, 160.
tocol for a palladium-catalyzed ligand-free Suzuki reaction 18 Y. Uozumi and Y. Nakai, An Amphiphilic Resin-Supported
at room temperature in aqueous DMF, Green Chem., 2011,
13, 1260.
Palladium Catalyst for High-Throughput Cross-Coupling in
Water, Org. Lett., 2002, 4, 2997.
6 C. E. Garrett and K. Prasad, The Art of Meeting Palladium 19 X.-B. Jiang, P. W. N. M. van Leeuwen and J. N. H. Reek,
Specifications in Active Pharmaceutical Ingredients
Produced by Pd-Catalyzed Reactions, Adv. Synth. Catal.,
2004, 346, 889.
SUPRAphos-based palladium catalysts for the kinetic
resolution of racemic cyclohexenyl acetate, Chem.
Commun., 2007, 2287.
1014 | Org. Biomol. Chem., 2021, 19, 1009–1016
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
20 M. T. Reetz, M. H. Becker, H.-W. Klein and D. Stöckigt, A
Method for High-Throughput Screening of Enantioselective
Catalysts, Angew. Chem., Int. Ed., 1999, 38, 1758.
21 J. W. Szewczyk, R. L. Zuckerman, R. G. Bergman and
J. A. Ellman, A Mass Spectrometric Labeling Strategy for
Regioselectivity Using Fluorescence Spectroscopy, Adv.
Synth. Catal., 2006, 348, 1193.
34 H.-M. Guo and F. Tanaka, A Fluorogenic Aldehyde Bearing
a 1,2,3-Triazole Moiety for Monitoring the Progress of Aldol
Reactions, J. Org. Chem., 2009, 74, 2417.
High-Throughput Reaction Evaluation and Optimization: 35 B. Xia, B. Gerard, D. M. Solano, J. Wan, G. Jones II and
Exploring C−H Activation, Angew. Chem., Int. Ed., 2001, 40,
216.
22 C. Markert and A. Pfaltz, Screening of Chiral Catalysts and
Catalyst Mixtures by Mass Spectrometric Monitoring of
J. A. Porco Jr., ESIPT-Mediated Photocycloadditions of
3-Hydroxyquinolinones: Development of a Fluorescence
Quenching Assay for Reaction Screening, Org. Lett., 2011,
13, 1346.
Catalytic Intermediates, Angew. Chem., Int. Ed., 2004, 43, 36 E. Jung, S. Kim, Y. Kim, S. H. Seo, S. S. Lee, M. S. Han and
2498.
S. Lee, A Colorimetric High-Throughput Screening Method
for Palladium-Catalyzed Coupling Reactions of Aryl Iodides
Using a Gold Nanoparticle-Based Iodide-Selective Probe,
Angew. Chem., Int. Ed., 2011, 50, 4386.
23 M. T. Reetz, A. Eipper, P. Tielmann and R. Mynott, A
Practical NMR-Based High-Throughput Assay for Screening
Enantioselective Catalysts and Biocatalysts, Adv. Synth.
Catal., 2002, 344, 1008.
24 K. Mori, Y. Ichikawa, M. Kobayashi, Y. Shibata,
M. Yamanaka and T. Akiyama, Prediction of suitable cata-
lyst by 1H NMR: asymmetric synthesis of multisubstituted
biaryls by chiral phosphoric acid catalyzed asymmetric bro-
mination, Chem. Sci., 2013, 4, 4235.
25 O. Lavastre and J. P. Morken, Discovery of Novel Catalysts
for Allylic Alkylation with a Visual Colorimetric Assay,
Angew. Chem., Int. Ed., 1999, 38, 3163.
26 M. Kawatsura and J. F. Hartwig, Transition Metal-Catalyzed
Addition of Amines to Acrylic Acid Derivatives. A High-
37 S. Kim, E. Jung, M. J. Kim, A. Pyo, T. Palani, M. S. Eom,
M. S. Han and S. Lee, A simple, fast, and easy assay for
transition metal-catalyzed coupling reactions using
a
paper-based colorimetric iodide sensor, Chem. Commun.,
2012, 48, 8751.
38 A. Pyo, S. Kim, M. R. Kumar, A. Byeun, M. S. Eom,
M. S. Han and S. Lee, Palladium-catalyzed hydrodehalo-
genation of aryl halides using paraformaldehyde as the
hydride source: high-throughput screening by paper-based
colorimetric iodide sensor, Tetrahedron Lett., 2013, 54,
5207.
Throughput Method for Evaluating Hydroamination of 39 M. S. Eom, J. Noh, H.-S. Kim, S. Yoo, M. S. Han and S. Lee,
Primary and Secondary Alkylamines, Organometallics, 2001,
20, 1960.
High-Throughput Screening Protocol for the Coupling
Reactions of Aryl Halides Using Colorimetric
a
27 O. Löber, M. Kawatsura and J. F. Hartwig, Palladium-
Catalyzed Hydroamination of 1,3-Dienes: A Colorimetric
Chemosensor for Halide Ions, Org. Lett., 2016, 18,
1720.
Assay and Enantioselective Additions, J. Am. Chem. Soc., 40 H.-S. Kim, M. S. Eom, M. S. Han and S. Lee, Paper-Based
2001, 123, 4366.
28 D. F. Kennedy, B. A. Messerle and S. L. Rumble,
Application of UV-Vis spectroscopy to high throughput
Colorimetric Sensor System for High-Throughput
Screening of C−H Borylation, Chem. – Eur. J., 2017, 23,
6282.
screening of hydroamination catalysts, New J. Chem., 2009, 41 Y. Son, S. Lee, H.-S. Kim, M. S. Eom, M. S. Han and S. Lee,
33, 818.
Organosilane-Patterned Paper-based Colorimetric Sensors
for High-Throughput Screening of Cross-Coupling
Reactions with Aryl Bromides, Adv. Synth. Catal., 2018, 360,
3916.
29 K. H. Shaughnessy, P. Kim and J. F. Hartwig,
A
Fluorescence-Based Assay for High-Throughput Screening
of Coupling Reactions. Application to Heck Chemistry,
J. Am. Chem. Soc., 1999, 121, 2123.
42 H. Noh, T. Lim, B. Y. Park and M. S. Han, A Fluorescence-
Based High-Throughput Screening Method for Olefin
Metathesis Using a Ratiometric Fluorescent Probe, Org.
Lett., 2020, 22, 1703.
30 J. P. Stambuli, S. R. Stauffer, K. H. Shaughnessy and
J. F. Hartwig, Screening of Homogeneous Catalysts by
Fluorescence Resonance Energy Transfer. Identification of
Catalysts for Room-Temperature Heck Reactions, J. Am. 43 T. Lim and M. S. Han, Preparation of Metal Oxides
Chem. Soc., 2001, 123, 2677.
Containing ppm Levels of Pd as Catalysts for the Reduction
of Nitroarene and Evaluation of Their Catalytic Activity by
the Fluorescence-Based High-Throughput Screening
Method, Catalysts, 2020, 10, 542.
31 S. R. Stauffer, N. A. Beare, J. P. Stambuli and J. F. Hartwig,
Palladium-Catalyzed Arylation of Ethyl Cyanoacetate.
Fluorescence Resonance Energy Transfer as a Tool for
Reaction Discovery, J. Am. Chem. Soc., 2001, 123, 4641.
32 S. R. Stauffer and J. F. Hartwig, Fluorescence Resonance
Energy Transfer (FRET) as a High-Throughput Assay for
Coupling Reactions. Arylation of Amines as a Case Study,
J. Am. Chem. Soc., 2003, 125, 6977.
44 R. M. Duke, E. B. Veale, F. M. Pfeffer, P. E. Kruger and
T. Gunnlaugsson, Colorimetric and fluorescent anion
sensors: an overview of recent developments in the use of
1,8-naphthalimide-based chemosensors, Chem. Soc. Rev.,
2010, 39, 3936.
33 G. Angelovski, M. D. Keränen, P. Linnepe, S. Grudzielanek 45 N. Meher and P. K. Iyer, Functional group engineering in
and P. Eilbracht,
A
Rapid and Reliable Assay for
naphthalimides: a conceptual insight to fine-tune the
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1009–1016 | 1015

View Article Online
Paper
Organic & Biomolecular Chemistry
supramolecular self-assembly and condensed state lumine- 50 X. Xu, J. Luo, L. Li, D. Zhang, Y. Wang and G. Li,
scence, Nanoscale, 2019, 11, 13233.
46 H.-Q. Dong, T.-B. Wei, X.-Q. Ma, Q.-Y. Yang, Y.-F. Zhang,
Y.-J. Sun, B.-B. Shi, H. Yao, Y.-M. Zhang and Q. Lin, 1,8-
Unprecedented catalytic performance in amine syntheses
via Pd/g-C3N4 catalyst-assisted transfer hydrogenation,
Green Chem., 2018, 20, 2038.
Naphthalimide-based fluorescent chemosensors: recent 51 M. Zhao, X. Li, L. Zhang, C. Zhang, M. Gong and Y. Chen,
advances and perspectives, J. Mater. Chem. C, 2020, 8,
13501.
47 J.-C. Wang, J. Ren, H.-C. Yao, L. Zhang, J.-S. Wang,
Catalytic decomposition of methanol to carbon monoxide and
hydrogen over palladium supported on Ce0.65Zr0.30La0.05O2 and
La–Al2O3, Catal. Today, 2011, 175, 430.
S.-Q. Zang, L.-F. Han and Z.-J. Li, Synergistic photocatalysis 52 R. V. Gulyaev, A. I. Stadnichenko, E. M. Slavinskaya,
of Cr(VI) reduction and 4-Chlorophenol degradation over
hydroxylated α-Fe2O3 under visible light irradiation,
J. Hazard. Mater., 2016, 311, 11.
A. S. Ivanova, S. V. Koscheev and A. I. Boronin, In situ
preparation and investigation of Pd/CeO2 catalysts for the
low-temperature oxidation of CO, Appl. Catal., A, 2012,
439–440, 41.
48 X. Xu, Z. Gao, Z. Cui, Y. Liang, Z. Li, S. Zhu, X. Yang and
J. Ma, Synthesis of Cu2O Octadecahedron/TiO2 Quantum 53 G. L. Christensen and M. A. Langell, Characterization of
Dot Heterojunctions with High Visible Light Photocatalytic
Activity and High Stability, ACS Appl. Mater. Interfaces,
2016, 8, 91.
Copper Palladium Oxide Solid Solutions by X-ray
Diffraction, X-ray Photoelectron Spectroscopy, and Auger
Electron Spectroscopy, J. Phys. Chem. C, 2013, 117, 7039.
49 W. Fu, Y. Cao, Q. Feng, W. R. Smith, P. Dong, M. Ye and 54 L. Song, Y. Yang, Q. Zhang, H. Tian and W. Zhu, Synthesis
J. Shen, Pd–Co nanoalloys nested on CuO nanosheets for
efficient electrocatalytic N2 reduction and room-tempera-
ture Suzuki–Miyaura coupling reaction, Nanoscale, 2019,
11, 1379.
and
Photochromism
of
Naphthopyrans
Bearing
Naphthalimide Chromophore: Predominant Thermal
Reversibility in Color-Fading and Fluorescence Switch,
J. Phys. Chem. B, 2011, 115, 14648.
1016 | Org. Biomol. Chem., 2021, 19, 1009–1016
This journal is © The Royal Society of Chemistry 2021