High-Throughput Screening Protocol for the Coupling Reactions of Aryl Halides Using a Colorimetric Chemosensor for Halide Ions

Article abstract of DOI:10.1021/acs.orglett.6b00300

Mercury complex of 4-(2-pyridylazo)resorcinol (PAR-2Hg²⁺), a halide-ion chemosensor, was prepared and its efficiency as a tool for high-throughput screening (HTS) of transition-metal-catalyzed coupling reactions was investigated. It showed a high selectivity for halide ions. When the PAR-2Hg²⁺ complex was used in the Suzuki coupling reaction and C-H activated coupling reaction with aryl bromides, the quantitative and qualitative conversions of aryl halides were obtained from the reaction mixture color change.

Full text of DOI:10.1021/acs.orglett.6b00300

Letter
pubs.acs.org/OrgLett
High-Throughput Screening Protocol for the Coupling Reactions of
Aryl Halides Using a Colorimetric Chemosensor for Halide Ions
Min Sik Eom,†,§ Jieun Noh,‡,§ Han-Sung Kim,‡ Soyeon Yoo,† Min Su Han,*,† and Sunwoo Lee*,‡
†Department of Chemistry, Gwangju Institute of Science of Technology (GIST), Gwangju 61005, Republic of Korea
‡Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
S
* Supporting Information
ABSTRACT: Mercury complex of 4-(2-pyridylazo)resorcinol
(PAR-2Hg2+), a halide-ion chemosensor, was prepared and its
efficiency as a tool for high-throughput screening (HTS) of
transition-metal-catalyzed coupling reactions was investigated.
It showed a high selectivity for halide ions. When the PAR−
2Hg2+ complex was used in the Suzuki coupling reaction and
C−H activated coupling reaction with aryl bromides, the
quantitative and qualitative conversions of aryl halides were
obtained from the reaction mixture color change.
he development of efficient reaction methodologies is an
important topic in pharmaceutical and fine chemical
In particular, diphenylcarbazone−Hg2+ complex has been used as
a chemosensor for halide ions.14 However, the chemosensor
cannot be used in HTS for the coupling reactions of aryl halides
because it rapidly decomposes in assay solutions.14b The
instability of a chemosensor can affect the reproducibility and
accuracy of HTS. Previously, the mercury complex of 4-(2-
pyridylazo)resorcinol (PAR−2Hg2+) was used as a chemosensor
for cyanide ions with a high binding affinity to Hg2+ ion and high
stability in an assay solution.15 The PAR−2Hg2+ complex can be
expanded to detect halide ions because halide ions exhibit high
binding affinity to Hg2+.16 We envisioned that PAR−2Hg2+
would be converted to free PAR in the presence of halide ions,
and the ligand exchange reaction would change the assay solution
color. This would allow a general screening protocol for the
coupling reactions of aryl halides by easily measuring the color
changes even though it has some limitations17 (Scheme 1).
T
industries.1 Among many organic reactions, transition-metal-
catalyzed coupling reactions have been widely used in synthetic
chemistry.2 Modified coupling reactions and new conceptually
advanced methods are being continuously developed.3 Because
of the demand for the fast analysis of reaction leads to synthetic
methodology development, several high-throughput screening
(HTS) methods have been developed.4 Recently, Hartwig and
MacMillan independently reported efficient screening methods
for efficient unbiased screening methods using GC−MS.5 Gas
chromatography,6 high-performance liquid chromatography,7
mass spectrometry,8 and NMR spectroscopy9 are convenient for
this purpose as they do not require prefunctionalization for
analysis. However, the analysis times highly depend on the
automation and still require minutes per sample. The
fluorescence method has a fast analysis time; however, special
fluorescent substrates are needed.10 The colorimetric method is
also a good method; however, it does not provide quantitative
information about the yield or conversion of a reaction.11
To solve these problems, we previously developed colori-
metric analysis methods using Au nanoparticles and paper-based
colorimetric iodide sensors (PBCIS). Although these methods
were used efficiently for screening transition-metal-catalyzed
coupling reactions, they are limited to aryl iodides.12 In the
coupling reactions of aryl halides, aryl bromides are most
frequently used; aryl chlorides are inexpensive, but challenging
substrates. Therefore, HTS methods should be developed for
coupling aryl halides such as aryl iodides, aryl bromides, and aryl
chlorides.
Scheme 1. Schematic Representation of the Halide Probe
Based on a High-Throughput Screening Method for the
Coupling Reaction of Aryl Halides
To achieve this objective, we developed a chemosensor for
halide ions. Organic dye−metal ion complexes have been
developed as ligand-exchange-based chemosensors for various
anions, including phosphate derivatives, halides, and cyanide.13
Received: January 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00300
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Organic Letters
Letter
The PAR−2Hg2+ complex was prepared by mixing PAR (50
μM) and Hg2+ (100 μM) in a pH 7.2 phosphate buffer solution
(EtOH/H2O = 1:1 v/v, Tween 20 0.1%) because the color
change of PAR was directly proportional to the Hg2+
concentration, and the stoichiometry of PAR−2Hg2+ is 2:1
(metal to ligand ratio).18 To evaluate the PAR−2Hg2+ complex
as a chemosensor for halide ions, its optical properties (change in
the absorbance) were measured in the presence of Br−. The
absorbance intensity of the PAR-2Hg2+ complex increased at 408
nm and decreased at 506 nm with the increase in Br−
concentration (Figure 1). The chemosensor also exhibited a
Table 1. Conversion Yields from PAR−2Hg2+ Complex and
a
Gas Chromatography in Suzuki Reaction
b
c
d
e
e
entry ArX ligand
UV abs.
conv (%)
conv (%)
yield (%)
1
1
1
1
1
1
1
2
2
2
2
2
2
3
3
3
3
3
3
L1
1.009
1.403
1.137
1.010
0.312
1.178
1.037
1.174
1.178
1.261
0.862
1.118
0.383
1.371
0.497
1.277
0.691
0.399
55
94
67
55
47
92
75
64
6
40
95
75
67
2
2
L4
3
L5
4
L7
f
5
L11
L12
L1
0(−14)
6
71
37
55
55
74
23
46
0
75
53
56
56
92
20
49
3.3
44.8
4.5
53.7
2.5
0.3
73
49
49
50
95
19
43
0.7
54
3
7
8
L4
9
L5
10
11
12
13
14
15
16
17
18
L7
L11
L12
L1
L4
55
4
Figure 1. (a) Absorbance spectra were measured after adding various
concentrations of Br− to a pH 7.2 phosphate buffer 0.01 M solution
(EtOH/H2O = 1:1, Tween 20 0.1%) containing PAR (50 μM) and Hg2+
(100 μM). Inset: plot of absorbance intensities at 408 nm vs various
concentrations of Br−. (b) Absorbance spectra at 408 nm were measured
after adding various anions (1 mM) to a pH 7.2 phosphate buffer
solution 0.01 M (EtOH/H2O = 1:1, Tween 20 0.1%) containing PAR
(50 μM) and Hg2+ (100 μM).
L5
L7
45
11
1
63
0
L11
L12
0
a
Reaction conditions: ArX (0.3 mmol), PhB(OH)2 (0.3 mmol),
Pd(OAc)2 (0.003 mmol), ligand (0.003 mmol), base (0.45 mmol),
b
c
d
solvent (1.0 mL), 3 h. See Figure 2a. Absorbance at 408 nm. The
value was calculated from the titration curves of halide ions.
high selectivity for Br− over other anions such as AcO−, CO3
,
2−
e
Determined by gas chromatography using an internal standard.
The value below 0 was treated as 0% conversion.
f
F−, and PO4 in the coupling reactions of aryl halides. The
dynamic ranges of PAR−2Hg2+ for the detection of Cl− and I−
are different because of different affinities of halide ions to Hg2+
compared to Br−, whereas the other optical properties of the
chemosensor for Cl− and I− were similar to those for Br−.19 The
detection of Cl− equally worked at high concentration.20
3−
both the quantitative and qualitative conversions of aryl halides
in the coupling reactions. (2) The halide sensor well tolerated Pd,
ligand, base, and organic solvent. Therefore, PAR−2Hg2+ can be
used as a suitable sensor for the conversion of aryl halides such as
aryl iodides, aryl bromides, and aryl chlorides in coupling
reactions. Moreover, this protocol was evaluated for the
screening of Williamson ether synthesis using alkyl chlorides
and phenol derivatives. It was found that this protocol was also
suitable for the sensor for the conversion of alkyl halides.20
We attempted to use PAR−2Hg2+ in the coupling reactions of
aryl bromides in C−H activation.21 We selected heterocyclic
substrates such as benzoxazoles, benzothiazoles, N-methylin-
doles, and benzothiophenes for C−H activated coupling
reactions with aryl bromides. We envisioned that PAR−2Hg2+
would act as a simple and fast tool to determine the optimized
conditions for the coupling reactions of aryl bromides and C−H
activated substrates. Twelve types of ligands (L1−L12) and
bases (B1−B12) were selected for the coupling reaction because
it is important to find a suitable ligand and base for this reaction.
Using these ligands and bases, the coupling reactions were
conducted in the presence of Pd(OAc)2 (5 mol %) and t-
BuCO2H (10 mol %) in DMF at 120 °C for 15 h (Figure 2a).
The reaction mixture was diluted with water, and the resulting
solution was treated with PAR−2Hg2+ solution. Figure 2b shows
the colorimetric results of 96 reactions. These samples were
analyzed by UV/vis spectroscopy, and the conversion of 4-
bromotoluene was determined using the colorimetric change of
PAR−2Hg2+. We found that all the conversions correlated well
with those obtained from the GC analysis.22
This indicates that the chemosensor can detect Cl−, Br−, and
I− and determine the concentration of halide ions released after
the coupling reactions of various aryl halides. Therefore, the
coupling reaction of aryl halides can be easily evaluated by
measuring the color changes of the chemosensor. To evaluate the
capability of PAR−2Hg2+ in measuring the conversion of aryl
halides in coupling reactions, the Pd-catalyzed Suzuki coupling
reaction was selected as the model reaction.
The results are summarized in Table 1. 4-Iodotoluene, 4-
bromoanisole, and 4-chlorobenzonitrile were used as aryl halides
and reacted with phenylboronic acid in the presence of a Pd
catalyst. Three types of bases (K3PO4, K2CO3, and KOAc) and
solvents (DMSO, DMF, and THF) were used. Four types of
ligands were investigated. After 3 h reaction time, distilled water
and EtOAc (1:5 v/v) were added to the reaction mixture. The
reaction mixtures were analyzed by using PAR−2Hg2+ and GC.
All the samples were diluted and treated with PAR−2Hg2+; the
resulting solutions were analyzed by UV/vis spectroscopy. The
conversions of aryl halides were determined from the titration
curves of the halide ions. All the conversions obtained from
halide-sensor analysis exhibited good correlation with those
obtained from the GC analysis (Table 1). Moreover, the
conversion of aryl halide was determined from the solution color
without using any instrument. The conversion increased as the
solution changed from red to yellow. The results indicate the
following: (1) The PAR−2Hg2+ provided information about
B
DOI: 10.1021/acs.orglett.6b00300
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Scheme 2. Coupling Reactions with Aryl Bromides and C−H
Activated Substrates
2,4,5-trimethylbenzene afforded the corresponding products in
65%, 71%, and 61% yields, respectively. For N-methylindole, aryl
bromide 11c afforded the product in 58% yield, and substrates
11i and 11j afforded the desired coupled products in moderate-
to-good yields. The coupling of benzothiophene and 3-
bromopyridine afforded the corresponding product in 48% yield.
In summary, the PAR−2Hg2+ complex was used as a
chemosensor for halide ions; the sensor exhibited a high
selectivity for halide ions. The conversions of aryl iodides, aryl
bromides, and aryl chlorides in Suzuki coupling reactions were
determined using PAR-2Hg2+; the conversions of aryl halides
obtained using this sensor by UV/vis spectroscopy correlated
well with those obtained from GC analysis using an internal
standard. Moreover, the colorimetric change in the reaction
mixture provided information about the conversions of aryl
halides. We used PAR−2Hg2+ for the HTS of the coupling
reactions with aryl bromides and C−H activated substrates such
as benzoxazoles, benzothiazoles, N-methylindoles, and benzo-
thiophenes. When 96 samples of coupling reactions were treated
with PAR−2Hg2+, the conversions of aryl bromides were easily
determined from the colorimetric change and UV/vis spectros-
copy. The results provided information about the suitable ligand
and base in each coupling reaction.
Figure 2. (a) Conditions for ligands and bases in the coupling of azoles
with 4-bromotoluene. (b) Detected colors in colorimetric assay. A: L1−
L12 with K3PO4. B: B1−B12 with dppbz. C: L1−L12 with Cs2CO3. D:
B1−B12 with dppbz. E: L1−L12 with Cs2CO3. F: B1−B12 with phen.
G: L1−L12 with K3PO4. H: B1−B12 with Xantphos.
From the HTS results, the best ligand and base were selected
for each substrate as follows; dppbz (L6) and K3PO4 for
benzoxazoles (condtion I), dppbz (L6) and Cs2CO3 for
benzothiazoles (condtion II), phen (L11) and Cs2CO3 for N-
methylindoles (condtion III), and Xantphos (L7) and K3PO4 for
benzothiophenes (condtion IV). The coupling reactions were
carried out under these conditions, and the desired products
were isolated. As expected, substrates 7, 8, and 9 afforded the
corresponding products, 2-p-tolylbenzoxazole (12a), 2-p-
tolylbenzothiazole (13a), and 2-p-tolyl-1-methylindole (14a),
in good yields. Benzothiophene (10) afforded the coupled
product 15a in 69% yield.23
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00300.
Experimental procedures (chemosensor and coupling
reactions) and spectral data for the products (PDF)
By comparing with previous reports,24 we found that dppbz
(L6) increased the yields of the products in the reactions of
azoles 7 and 8. However, phen (L11) ligand was superior to
other phosphine ligands in the reaction of N-methylindole (9).
The coupling reactions with benzothiophene showed lower
yields. With these optimized conditions, the substrate scope was
investigated. Diverse aryl bromides were used in the coupling
reactions with benzoxazoles, benzothiazoles, N-methylindoles,
and benzothiophenes. The results are summarized in Scheme 2.
The reactions with benzoxazole, 4-bromobenzonitrile (11b), 4′-
bromoacetophenone (11c), 4′-bromobiphenyl (11d), and 1-
bromonaphthalene (11e) afforded the desired coupled products
12b, 12c, 12d, and 12e with good-to-excellent yields.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: happyhan@gist.ac.kr.
*E-mail: sunwoo@chonnam.ac.kr.
Author Contributions
§These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The coupling of benzothiazole with 11c afforded 13c in 88%
yield; however, the coupling reactions with aryl halides such as 3-
bromoquinoline, 1-bromo-4-tert-butylbenzene, and 1-bromo-
This research was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korea
government (MSIP) (NRF-2015R1A4A1041036, NRF-
C
DOI: 10.1021/acs.orglett.6b00300
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Organic Letters
Letter
(19) (a) The titration plots between the absorbance and the
concentration of iodide and chloride were presented in Supporting
Information (S4−1 and S4−2). The selectivity assays for iodide and
chloride were presented in Supporting Information (S4−3 and S4−4)..
(b) Amini, M. K.; Ghaedi, M.; Rafi, A.; Habibi, M. H.; Zohory, M. M.
Sensors 2003, 3, 509.
2014R1A2A1A11050018, NRF-2013R1A2A2A01007000, NRF-
2014H1A8A1022253-Fostering Core Leaders of the Future
Basic Science Program/Global Ph.D. Fellowship Program). The
spectral data were obtained from the Korea Basic Science
Institute, Gwangju branch.
(20) See Supporting Information.
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