Ligand-Dependent Site-Selective Suzuki Cross-Coupling of 4-Bromopyrazol-5-yl Triflates

Article abstract of DOI:10.1021/acs.joc.9b01306

Ligand-dependent Suzuki cross-coupling of 4-bromopyrazol-5-yl triflates has been developed. This approach enabled selective introduction of an aryl substituent at the C4 or C5 position in pyrazoles. This protocol is the first example in which the cross-coupling proceeded predominantly at the C4 position in pyrazoles, which is generally recognized as the least reactive position. The selection of phosphine ligands switched the order of arylation. This method should be highly useful for preparing diverse poly-substituted pyrazole derivatives.

Full text of DOI:10.1021/acs.joc.9b01306

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Article
Ligand-Dependent Site-Selective Suzuki Cross-
Coupling of 4-Bromopyrazol-5-yl Triflates
Ryo Sakakibara, Kennosuke Itoh, and Hideaki Fujii
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01306 • Publication Date (Web): 16 Jul 2019
Downloaded from pubs.acs.org on July 16, 2019
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Ligand-Dependent Site-Selective Suzuki Cross-
Coupling of 4-Bromopyrazol-5-yl Triflates
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Ryo Sakakibara†,‡, Kennosuke Itoh†,§, Hideaki Fujii*,†,§
† Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane,
Minato-ku, Tokyo 108-8641, Japan
‡ Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50,
Kawagishi, Toda, Saitama, 335-8505, Japan
§ Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane,
Minato-ku, Tokyo, 108-8641, Japan
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ABSTRACT
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Ligand-dependent Suzuki cross-coupling of 4-bromopyrazol-5-yl triflates has been developed.
This approach enabled selective introduction of an aryl substituent at the C4 or C5 position in the
pyrazoles. This protocol is the first example in which the cross-coupling proceeded
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predominantly at the C4 position in pyrazoles, which is generally recognized as the least reactive
position. The selection of phosphine ligands switched the order of the arylation. This method
should be highly useful for preparing diverse poly-substituted pyrazole derivatives.
INTRODUCTION
Pyrazoles appear as potent scaffolds in many pharmaceuticals with a wide range of biological
activities.1 The most general methods for their preparation are the condensation of 1,3-dicarbonyl
compounds with hydrazine derivatives or the cycloaddition of diazoalkanes with alkynes.2
Although these methods are reliable and straightforward, one must prepare precursors bearing
the desired substituents for the condensation or cycloaddition reactions. For these reasons, there
has been a growing interest in new synthetic methods which allow for the efficient synthesis of
poly-substituted pyrazole derivatives from a common intermediate. Pd-catalyzed cross-coupling
is one of the useful approaches for installing aryl substituents to fully assembled pyrazoles in a
late stage of the reaction sequence. Especially, site-selective cross coupling of
poly(pseudo)halopyrazoles is an attractive approach for preparation of poly-substituted
pyrazoles, which enables the production of pyrazoles with various substituents from common
intermediates.
Collins and coworkers reported that 1-methyl-3-bromopyrazol-5-yl nonaflate underwent highly
selective Pd-catalyzed cross-couplings at the C-O bond in the nonaflate moiety, followed by
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coupling at the C-Br bond, achieving selective introduction of two distinct aryl substituents at the
C3 and C5 positions in pyrazoles.3 Langer and coworkers reported site-selective Suzuki cross-
coupling of N-protected tribromopyrazoles.4 Under the reported reaction conditions, arylation
proceeded sequentially at C5, C3, and C4 positions with very good selectivity to afford mono-,
di-, or tri-arylated pyrazoles, depending on the amount of aryl boronic acids. Diarylation of
pyrazole derivatives at the C4 and C5 positions via C-H bond activation was also reported by
Doucet and coworkers; the C4 halo-substituted pyrazole derivatives were selectively arylated at
the C5 position by Pd-catalyzed C-H bond arylation and the the remaining C-halogen bond at the
C4 position are arylated by Suzuki cross-coupling.5 Site-selectivity of these reactions is based on
the different reactivity of the two or three carbon-(pseudo)halogen bonds or carbon-hydrogen
bonds in the substrates. Furthermore, an alternative approach, ligand-dependent site-selective
Suzuki cross-coupling, has been also reported for several dihaloarenes. Dai and coworkers
examined the effect of different phosphine ligands on the site-selectivity of Suzuki cross-
coupling of 3,5-dichloropyridazines and discovered that dppf and Qphos ligands promoted
coupling at C5 and C3, respectively.6 Similarly, Strotman and Chobanian and coworkers reported
ligand-dependent Suzuki cross-coupling of 2,4-diiodooxazoles and 2,4-diiodoimidazoles.7 In
addition to examples of dihaloarenes with the identical halogens, Fu and coworkers reported
ligand-dependent site-selective Suzuki cross-coupling of 4-chlorophenyl triflate.8 Although their
approaches are attractive because a line of analogues can be obtained from common
intermediates by changing only the ligand used, no examples of di(pseudo)halopyrazoles have
been reported.
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Here, we describe a general method for ligand-dependent highly selective Suzuki cross-
coupling of di(pseudo)halopyrazoles, 4-bromopyrazol-5-yl triflates (Figure 1). In this approach,
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two distinct aryl substituents could be introduced selectively to the C4 and C5 positions of
pyrazoles and the order of C4- and C5-arylations could be switched by simply changing the
phosphine ligand.
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Figure 1. Ligand-dependent site-selectivity switching in Suzuki cross-coupling of 4-
bromopyrazol-5-yl triflates.
R3
Ar2
R3
R3
N
N
N R1
N R1
R3
N
Br
Ar1
Ar1
N R1
Ar1B(OH)2
Ar2B(OH)2
4
Br
R3
5
N
N
OTf
N R1
N R1
Ar1
Ar1
Ar2
OTf
RESULT AND DISCUSSION
Pyrazole-5-yl triflates are useful substrates for Suzuki cross-coupling and can be readily
prepared from 5-pyrazolones.9 Because the -position of 5-pyrazolone can be easily
brominated,10 we chose 4-bromopyrazol-5-yl triflates 2 as substrates for investigating site-
selective Suzuki cross-coupling. We first prepared 4-bromopyrazol-5-yl triflate derivatives 2a,
2b from commercially available 5-pyrazolones 1a, 1b. 5-Pyrazolone derivatives are generally
obtained by the condensation of -ketoesters with alkyl or arylhydrazines.2 Combined with the
methodology of -bromination of 5-pyrazolones9 and triflation of 5-pyrazolones,11 we
established a very efficient one-pot method to prepare 4-bromopyrazol-5-yl triflates. We treated
5-pyrazolones 1a, 1b with equal equivalents of N-bromosuccinimide (NBS) in dichloromethane
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followed by the reaction of triflic anhydride in the presence of 2,6-lutidine in one pot to afford
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the corresponding 4-bromopyrazol-5-yl triflate derivatives 2a, 2b in good yields (Table 1).
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Table 1. Synthesis of 4-bromopyrazol-5-yl triflates 2a, 2b.
NBS (1.05 eq)
N
N
CH2Cl2, 0 oC or rt
N R1
N R1
then
Br
2,6-lutidine (1.5 eq)
O
OTf
Tf2O (1.2 eq), 0 oC
1
2
pyrazolone 1
R1
Ph
Me
triflate 2
yield (%)
1a
1b
2a
2b
86
66
Next, we examined the effect of the ligand for Suzuki cross-coupling of 4-bromopyrazol-5-yl
triflates 2a with phenylboronic acid (Table 2). Monodentate ligands showed marked ligand-
dependent selectivity (Table 2, entries 1−4). The PPh3 ligand predominantly gave C5 coupling
product 4a, whereas the selectivity was completely reversed by using P(Cy)3, PtBu3, and
Amphos ligands. Especially, the electron-rich and sterically demanding monodentate ligand
Amphos gave the C4 coupling product 3a in excellent yield with prefect site-selectivity (entry 4).
Therefore, Amphos was an optimal ligand for the C4 coupling. In the case of bidentate ligands,
electron-deficient ligands Xantphos, DPPF, and DPPP preferentially coupled at C5, but their
selectivities were inferior to that of PPh3 ligand (entries 5−7 vs. entry 1). Meanwhile, the
electron-rich ferrocene-type bidentate ligand DTBPF had the opposite selectivity compared to
the DPPF ligand (entry 8). The modification of the reaction conditions (the use of Pd(PPh3)4
instead of Pd(OAc)2 with PPh3, the higher loading of the catalyst and elevation of the reaction
temperature) using PPh3 ligand improved the conversion of the reaction with retention of high
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C5-selectivity (entry 11). It is noteworthy that Buchwald’s ligands Xphos and Sphos
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preferentially gave bis-coupling product 5a (entries 9−10).
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Table 2. Effect of ligand for Suzuki coupling of 4-bromopyrazol-5-yl triflate and phenylboronic
acida
10 mol% Pd(OAc)2
10 or 20 mol% ligand
N
PhB(OH)2
1.5 equiv.
+
N
K3PO4 (2.5 equiv.)
toluene, 60 oC, 2 h
Br
OTf
2a
N
N
N
N
N
N
Br
OTf
3a
4a
5a
ratio of productb
3a : 4a : 5a
<1 : 99 : 1
entry
ligand
conversion (%)b
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9
PPh3
P(Cy)3
PtBu3 HBF4
Amphos
Xantphos
DPPF
40
70
8
97
51
13
7
81
75
28
>99
91 : <1 : 9
>99 : <1 : <1
>99 : <1 : <1
1.5 : 96 : 3
29 : 71 : <1
33 : 67 : <1
95 : <1 : 5
34 : 29 : 35
15 : 22 : 63
<1 : 99 : 1
DPPP
DTBPF
Xphos
10
11
Sphos
c
PPh3
a 1:2 Pd/ligand ratio for monodentate ligands and 1:1 Pd/ligand ratio for bidentate ligands. b
Conversion and ratio of products were determined by HPLC analysis. c The reaction was
performed using 20 mol% Pd(PPh3)4 instead of Pd(OAc)2 and ligand at 100 C.
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With the optimal ligands for C4 (Amphos) and C5 (PPh3) selective Suzuki cross-coupling in
hand, we then investigated the scope of the reactions. Table 3 shows the results of Suzuki cross-
coupling using the Amphos ligand. 4-Bromopyrazol-5-yl triflate 2a could be coupled with
electron-neutral or electron-rich phenylboronic acids in good yields (entries 1−4), whereas the
yields were moderate when either electron-deficient phenylboronic acids or heteroaryl boronic
acids were used. In such cases, substrate 2a was not consumed completely since catalysts were
deactivated as a result of the formation of inactive palladium black (entries 5−8). We also
examined the Suzuki cross-coupling of the N-methyl substrate 2b to obtain C4 coupling products
3i−3l in good yields without any C5 coupling products (entries 9−12).
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Table 3. Scope of Suzuki cross-coupling using Amphos ligand.
10 mol%Pd(OAc)2
20 mol% Amphos
N
N
N R1
N R1
Ar-B(OH)2
1.5 equiv.
+
K3PO4 (2.5 equiv.)
toluene, 60 oC, 2 h
Br
Ar
OTf
OTf
2
3
entry
1
2
3
4
5
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8
2
R1
Ar
Ph
product 3
yield%
86
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
4-MePh
3-Me2NPh
2-MeOPh
2,4-F2Ph
3-ClPh
3-Furyl
3-Thienyl
Ph
67
90
82
52
49
33
53
78
9
10
11
12
3-Me2NPh
2-MeOPh
3-Thienyl
3j
3k
3l
82
92
87
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The results of Suzuki cross-coupling with various boronic acids under Pd(PPh3)4 conditions
are summarized in Table 4. The scope of the boronic acids was broad and the C5 selectivity as
compared to C4 was complete in all reactions. Furthermore, yields of cross-coupling with
electron-deficient boronic acids and heteroaryl boronic acids under Pd(PPh3)4 conditions were
improved in comparison with those under Amphos conditions (Table 4, entries 5−8 vs. Table 3,
entries 5−8). N-Methyl substrate 2b also coupled with various boronic acids to afford C5
coupling products in good yields (entries 9−12).
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Table 4. Scope of Suzuki cross-coupling using PPh3 ligand.
N
N
20 mol% Pd(PPh3)4
N R1
N R1
Ar-B(OH)2
1.5 equiv.
+
K3PO4 (2.5 equiv.)
toluene, 100 oC, 1 h
Br
Br
OTf
Ar
2
4
entry
1
2
3
4
5
6
7
8
2
R1
Ar
Ph
product 4
yield%
77
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-MePh
3-Me2NPh
2-MeOPh
2,4-F2Ph
3-ClPh
3-Furyl
3-Thienyl
Ph
85
84
81
80
65
39
92
75
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10
11
12
3-Me2NPh
2-MeOPh
3-Thienyl
4j
4k
4l
97
90
82
The second arylation of the obtained bromide 4 and triflate 3 progressed smoothly (Tables 5
and 6). Under Amphos conditions, the various aryl substituents were installed at the C4 position
of the obtained bromide 4 (entries 1−5), but higher reaction temperature was required. Similarly,
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the second arylation of the obtained triflates 3 under Pd(PPh3)4 conditions proceeded easily to
afford 4,5-diarylpyrazoles 5 in good yields (Table 6, entries 1−5). The order of sequential
diarylation at the C4 and C5 positions provided almost no influence on the efficiency of 4,5-
diarylpyrazole 5b−5e synthesis from 4-bromopyrazol-5-yl triflate 2b (Table 5, entries 1−4 vs.
Table 6, entries 1−4). Two distinct aryl substituents can be introduced efficiently by each
method.
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Table 5. Second arylation using Amphos ligand.
10 mol%Pd(OAc)2
20 mol% Amphos
N
N
Ar4-B(OH)2
2.0 equiv.
+
N
N
Ar4
K3PO4 (2.5 equiv.)
toluene, 100 oC, 2 h
Br
Ar5
Ar5
4
5
entry
4
4i
4i
4k
4j
4i
Ar4
2-MeOPh
3-Me2NPh
Ph
Ph
4-MePh
Ar5
Ph
Ph
product 5
yield% a
86 (65)
97 (73)
72 (65)
52 (50)
83 (62)
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2
3
4
5
5b
5c
5d
5e
5f
2-MeOPh
3-Me2NPh
Ph
a Yields in parentheses were calculated for two steps: 1st arylation (Table 4) and 2nd arylation
(Table 5).
Table 6. Second arylation using PPh3 ligand.
N
N
20 mol% Pd(PPh3)4
Ar5-B(OH)2
2.0 equiv.
+
N
N
Ar4
Ar4
K3PO4 (2.5 equiv.)
toluene, 100 oC, 1 h
OTf
Ar5
3
5
entry
3
Ar4
2-MeOPh
3-Me2NPh
Ph
Ar5
Ph
Ph
product 5
yield% a
55 (51)
89 (73)
67 (52)
1
2
3
3k
3j
3i
5b
5c
5d
2-MeOPh
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4
5
3i
3i
Ph
Ph
3-Me2NPh
4-MePh
5e
5g
87 (68)
88 (69)
a Yields in parentheses were calculated for two steps: 1st arylation (Table 3) and 2nd arylation
(Table 6).
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The oxidative addition step in Suzuki cross-coupling is generally considered as the site-
selectivity determining step, and the bond dissociation energies (BDEs) are one of the important
factors determining the oxidative addition site.12 The calculated C-Cl BDEs of 1H-pyrazole are
reported to be higher at the C4 position than at the C3 and C5 positions.13,14 Indeed the order of
the calculated BDEs is consistent with the order of the reacted sites of N-protected
tribromopyrazole reported by Langer.4 The gas-phase homolytic dissociation energy of the C-
OTf bond was much larger than that of the C-Br bond using DFT calculations in 4-bromophenyl
triflate.15 As 4-bromopyrazol-5-yl triflates 2 are heterocycles having different kinds of
(pseudo)halides, it is difficult to predict the more reactive site due to both the inherent relative
site reactivities of pyrazole and the nature of the (pseudo)halide. However, Langer’s results4
suggested that the C4-Br bond in N-substituted pyrazoles was the least reactive. To the best of
our knowledge, these Amphos reaction conditions are the first report of the site-selective Suzuki
cross-coupling of pyrazoles with the C4 selectivity. In our developed method, the ligand
demonstrated remarkable effects on the site-selective Suzuki cross-coupling at the C4 (C-Br
bond) and C5 (C-OTf bond) positions of pyrazoles. Influences of the ligand for site-selectivity
were examined using DFT calculations by Houk and Schoenebeck; the site-selectivity by these
kinds of ligands was explained by the ligation state between mono-ligated Pd complex (PdL) and
di-ligated Pd complex (PdL2); PdL preferred the C-halogen bond with lower BDE (the
distortion-controlled reaction): PdL2 favored the C-OTf bond with lower LUMO energy (the
interaction-controlled reaction).16 Subsequent theoretical and experimental studies have
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concluded that the sterically bulky ligands were generally advantageous for the formation of
PdL, whereas the sterically less-hindered ligands generally stabilized the PdL2 state.17 These
well-recognized studies explain our results (Table 2); bulky ligands such as Amphos, PtBu3, and
DTBPF would interact with the substrate in the PdL state to provide the C4 coupling products
(activation of the C4-Br bond), whereas less sterically demanding ligands such as PPh3, DPPF,
and Xantphos would react with the substrate in the PdL2 state to afford the C5 coupling product
(activation of the C-OTf bond).
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CONCLUSIONS
We developed the ligand-dependent site-selective Suzuki cross-coupling of 4-bromopyrazol-5-
yl triflates. The selective cross-coupling at C4 (C-Br bond) and C5 (C-OTf bond) was achieved
by using the Amphos ligand and the PPh3 ligand, respectively. These reaction conditions were
applicable to coupling of a wide range of phenyl boronic acids with various substituents and
heteroaryl boronic acids. The second aryl substituent could also be introduced smoothly. Our
developed methods would be highly useful for preparing diverse pyrazole derivatives.
Additionally, the method provided the first examples of the ligand-dependent C4 site-selective
Suzuki cross-coupling of pyrazoles having different kinds of (pseudo)halides.
EXPERIMENTAL SECTION
General Information. All reagents and solvents were obtained from commercial suppliers and
were used without further purification. For reactions that require heating, a heating mantle was
used. Nuclear magnetic resonance (NMR) spectra were recorded on an Agilent Technologies
VXR-400NMR for 1H NMR and 13C NMR. Chemical shifts were reported as δ values (ppm)
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reference to tetramethylsilane. Mass spectra (MS) were obtained on JMS-AX505HA, JMS-700
MStation, or JMS-100LP instrument by applying an electrospray ionization (ESI)/TOF or fast
atom bombardment (FAB)/double-focusing magnetic sector mass spectrometer method. The
progress of the reaction was determined on Merck Silica Gel Art. 5715 (TLC). Purification was
carried out using a EPCLC W-prep 2XY purification system (Yamazen Corporation) with
prepacked normal phase SiO2 cartridges eluted with optimized gradients of either n-hexane-ethyl
acetate or chloroform-methanol as described.
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Synthesis of 4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a).
N-Bromosuccinimide (2150 mg, 12.1 mmol) was added to a solution of 3-methyl-1-phenyl-1H-
pyrazol-5-one (2000 mg, 11.5 mmol) in dichloromethane (40 mL) at 0 °C and allowed to warm
to room temperature. After stirring at the same temperature for 1 h, 2,6-lutidine (2.00 mL, 17.2
mmol) and triflic anhydride (2.32 mL, 13.8 mmol) were added to the mixture at 0 °C. After
stirring at the same temperature for 30 min, the reaction mixture was poured into saturated
NaHCO3 aqueous solution, extracted with chloroform. Combined organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica
gel chromatography (n-hexane/ethyl acetate, 100:0 to 96:4) to yield compound 2a (3870 mg,
10.0 mmol, 87%) as a colorless solid. mp: 43.0-44.0 ºC. 1H-NMR (400 MHz, CDCl3):
 7.40−7.51 (m, 5H), 2.34 (s, 3H). 13C-NMR (100 MHz, CDCl3):  148.5, 138.8, 136.8, 129.5,
128.9, 123.9, 118.1 (q, JC-F = 320 Hz), 87.6, 13.2. HRMS-FAB m/z [M+H]+ calcd. for
C11H9BrF3N2O3S, 384.9469; found 384.9462.
Synthesis of 4-bromo-1,3-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2b). N-
Bromosuccinimide (3330 mg, 18.7 mmol) was added to a solution of 1,3-dimethyl-1H-pyrazol-
5-one (2000 mg, 17.8 mmol) in dichloromethane (60 mL) at 0 °C. After stirring at the same
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temperature for 30 min, 2,6-lutidine (4.15 mL, 35.7 mmol) and triflic anhydride (3.60 mL, 21.4
mmol) were added to the mixture at 0 °C. After stirring at the same temperature for 30 min, the
reaction mixture was poured into saturated NaHCO3 aqueous solution, extracted with
chloroform. Combined organic layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate,
98:2 to 92:8) to yield compound 2b (3830 mg, 11.9 mmol, 66%) as a colorless oil. 1H-NMR (400
MHz, CDCl3):  3.79 (s, 3H), 2.23 (s, 3H). 13C-NMR (100 MHz, CDCl3):  147.2, 139.0, 118.4
(q, JC-F = 320 Hz), 84.9, 36.2, 13.0. HRMS-FAB m/z [M+H]+ calcd. for C6H7BrF3N2O3S,
322.9313; found 322.9305.
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General Procedure: Screening Suzuki cross-coupling conditions with respect to ligand
(Table 2). A mixture of 4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate
(2a, 100 mg, 0.26 mmol), phenyboronic acid (48mg, 0.39 mmol), palladium(II) acetate (5.8 mg,
0.026 mmol), indicated ligand (0.052 mmol for monodentate ligand, 0.026 mmol for bidentate
ligand), and potassium phosphate (138 mg, 0.65 mmol) in toluene (3.0 mL) was heated at 60 °C
for 2 h under an Ar atmosphere. The mixture was cooled to room temperature and diluted with
chloroform. After filtration through Celite pad, the filtrate was concentrated under reduced
pressure. The conversion and the ratio of products were determined by normal phase HPLC
analysis (column: Senshu Pak PEGASIL Silica SP100-3 (4.6φ x 250 mm) , mobile phase:
isocratic n-hexane/i-PrOH = 99.8/0.2, flow rate: 0.5 mL/min, Wavelength of UV detection: 254
nm) of the residue using an external standard.
Representative Procedure: Suzuki cross-coupling using Amphos ligand (Table 3, entry 9,
3i). A mixture of 4-bromo-1,3-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2b, 800 mg,
2.48 mmol), phenylboronic acid (453 mg, 3.72 mmol), palladium(II) acetate (56 mg, 0.25
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mmol), 4-(di-tert-butylphosphino)-N,N-dimethylaniline (132 mg, 0.50 mmol), and potassium
phosphate (1580 mg, 7.43 mmol) in toluene (20 mL) was heated at 60 °C for 2 h under an Ar
atmosphere. The mixture was cooled to room temperature and diluted with chloroform. After
filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (n-hexane/ethyl acetate, 100:0 to 94:6) to yield 1,3-
dimethyl-4-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (3i, 621 mg, 1.94 mmol, 78%) as
a colorless liquid. 1H-NMR (400 MHz, CDCl3):  7.39−7.44 (m, 2H), 7.29−7.36 (m, 3H), 3.84
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(s, 3H), 2.28 (s, 3H). 13C-NMR (100 MHz, CDCl3):  146.1, 138.0, 129.7, 129.0, 128.7, 127.6,
118.2 (q, JC-F = 319 Hz), 110.6, 35.5, 13.4. HRMS-ESI m/z [M+H]+ calcd. for C12H12F3N2O3S,
321.0521; found 321.0506.
3-Methyl-1,4-diphenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (3a). From 4-bromo-3-
methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol) and
phenylboronic acid (48 mg, 0.39 mmol), 3a (85 mg, 0.22 mmol, 86%) was obtained as a
colorless solid. mp: 55.5-57.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.57−7.61 (m, 2H), 7.35−7.54
(m, 8H), 2.39 (s, 3H). 13C-NMR (100 MHz, CDCl3):  147.7, 137.6, 137.0, 129.5, 129.4, 129.1,
128.8, 128.5, 127.9, 123.9, 117.9 (q, JC-F = 320 Hz), 112.6, 13.6. HRMS-ESI m/z [M+H]+ calcd.
for C17H14F3N2O3S, 383.0677; found 383.0667.
3-Methyl-1-phenyl-4-(p-tolyl)-1H-pyrazol-5-yl trifluoromethanesulfonate (3b). From 4-
bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol)
and p-tolylboronic acid (53 mg, 0.39 mmol), 3b (69 mg, 0.17 mmol, 67%) was obtained as a
colorless solid. mp: 64.5-66.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.56−7.60 (m, 2H), 7.48−7.54
(m, 2H), 7.42 (tt, J = 6.6, 1.3 Hz, 1H), 7.25−7.33 (m, 4H), 2.41 (s, 3H), 2.38 (s, 3H). 13C-NMR
(100 MHz, CDCl3):  147.7, 137.7, 137.5, 137.0, 129.5, 129.4, 128.9, 128.4, 126.4, 123.9, 117.9
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(q, JC-F = 320 Hz), 112.6, 21.3, 13.6. HRMS-ESI m/z [M+H]+ calcd. for C18H16F3N2O3S,
397.0834; found 397.0817.
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4-(3-(Dimethylamino)phenyl)-3-methyl-1-phenyl-1H-pyrazol-5-yl
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trifluoromethanesulfonate (3c). From 4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl
trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol) and (3-(dimethylamino)phenyl)boronic acid
(64 mg, 0.39 mmol), 3c (100 mg, 0.24 mmol, 90%) was obtained as a colorless solid. mp: 87.0-
89.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.56−7.62 (m, 2H), 7.48−7.54 (m, 2H), 7.14 (tt, J = 7.4,
1.3 Hz, 1H), 7.28−7.34 (m, 1H), 6.72−6.79 (m, 3H), 3.00 (s, 6H), 2.41 (s, 3H). 13C-NMR (100
MHz, CDCl3):  150.8, 147.8, 137.5, 137.0, 130.0, 129.4, 129.4, 128.4, 123.9, 117.9 (q, JC-F
320 Hz), 117.2, 113.4, 113.0, 112.0, 40.5, 13.8. HRMS-ESI m/z [M+H]+ calcd. for
C19H19F3N3O3S, 426.1099; found 426.1090.
=
4-(2-Methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (3d).
From 4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26
mmol) and (2-methoxyphenyl)boronic acid (59 mg, 0.39 mmol), 3d (88 mg, 0.21 mmol, 82%)
was obtained as a pale yellow liquid. 1H NMR (CDCl3) 1H-NMR (400 MHz, CDCl3):
 7.58−7.62 (m, 2H), 7.47−7.54 (m, 2H), 7.36−7.44 (m, 2H), 7.28 (dd, J = 7.5, 1.7 Hz, 1H), 7.04
(ddd, J = 7.4, 7.4, 1.0 Hz, 1H), 6.99 (dd, J = 8.3, 0.9 Hz, 1H), 3.87 (s, 3H), 2.29 (s, 3H). 13C-
NMR (100 MHz, CDCl3):          , 120.6,
118.1, 117.9 (q, JC-F = 320 Hz), 110.9, 108.9, 55.4, 13.7. HRMS-ESI m/z [M+H]+ calcd. for
C18H16F3N2O4S, 413.0783; found 413.0768.
4-(2,4-Difluorophenyl)-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (3e).
From 4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26
mmol) and (2,4-difluorophenyl)boronic acid (62 mg, 0.39 mmol), 3e (57 mg, 0.14 mmol, 52%)
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was obtained as a colorless solid. mp: 57.0-58.0 ºC. 1H NMR (CDCl3) 1H-NMR (400 MHz,
CDCl3):  7.56−7.61 (m, 2H), 7.49−7.54 (m, 2H), 7.43 (tt, J = 7.4, 1.4 Hz, 1H), 7.35 (ddd, J =
8.5, 8.5, 6.3 Hz, 1H), 6.93−7.03 (m, 2H), 2.31 (d, J = 0.8 Hz, 3H). 13C-NMR (100 MHz, CDCl3):
 163.1 (dd, JC-F = 251, 14 Hz), 160.3 (dd, JC-F = 249, 12 Hz), 148.4, 138.0, 136.8, 132.3 (dd, JC-
F = 9.7, 4.4 Hz), 129.5, 128.7, 124.0, 118.0 (q, JC-F = 320 Hz), 113.4 (dd, JC-F = 16, 3.8 Hz),
111.8 (dd, JC-F = 21, 3.8 Hz), 105.7, 104.6 (dd, JC-F = 26, 26 Hz), 13.4 (d, JC-F = 2.4 Hz). HRMS-
ESI m/z [M+H]+ calcd. for C17H12F5N2O3S, 419.0489; found 419.0472.
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4-(3-Chlorophenyl)-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (3f).
From 4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26
mmol) and (3-chlorophenyl)boronic acid (61 mg, 0.39 mmol), 3f (53 mg, 0.13 mmol, 49%) was
obtained as a colorless liquid. 1H-NMR (400 MHz, CDCl3):  7.56−7.60 (m, 2H), 7.49−7.55 (m,
2H), 7.34−7.46 (m, 4H), 7.31 (ddd, J = 7.3, 1.6, 1.6 Hz, 1H), 2.39 (s, 3H). 13C-NMR (100 MHz,
CDCl3):          , 128.0, 127.2, 124.0,
117.9 (q, JC-F = 320 Hz), 111.3, 13.6. HRMS-ESI m/z [M+H]+ calcd. for C17H13ClF3N2O3S,
417.0288; found 417.0287.
4-(Furan-3-yl)-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (3g). From 4-
bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol)
and 3-furylboronic acid (44 mg, 0.39 mmol), 3g (32 mg, 0.086 mmol, 33%) was obtained as pale
brown solid. mp: 95.0-97.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.62 (dd, J = 1.4, 0.9 Hz, 1H),
7.47−7.56 (m, 5H), 7.42 (dddd, J = 8.1, 6.4, 1.6, 1.6 Hz, 1H), 6.61 (dd, J = 1.9, 0.9 Hz, 1H), 2.39
(s, 3H). 13C-NMR (100 MHz, CDCl3):  147.7, 143.6, 140.3, 137.3, 136.9, 129.4, 128.5, 123.9,
118.0 (q, JC-F = 320 Hz), 113.8, 110.0, 104.4, 14.0. HRMS-ESI m/z [M+H]+ calcd. for
C15H12F3N2O4S, 373.0470; found 373.0479.
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3-Methyl-1-phenyl-4-(thiophen-3-yl)-1H-pyrazol-5-yl trifluoromethanesulfonate (3h). From
4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26
mmol) and 3-thienylboronic acid (50 mg, 0.39 mmol), 3h (54 mg, 0.14 mmol, 53%) was
obtained as a colorless solid. mp: 80.0-81.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.55−7.59 (m,
2H), 7.48−7.54 (m, 2H), 7.39−7.46 (m, 2H), 7.38 (dd, J = 2.9, 1.3 Hz, 1H), 7.23 (dd, J = 5.0, 1.2
Hz, 1H), 2.41 (s, 3H). 13C-NMR (100 MHz, CDCl3):  147.7, 137.4, 136.9, 129.4, 129.1, 128.5,
127.4, 126.2, 123.9, 123.4, 117.9 (q, JC-F = 320 Hz), 108.1, 13.9. HRMS-ESI m/z [M+H]+ calcd.
for C15H12F3N2O3S2, 389.0241; found 389.0237.
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4-(3-(Dimethylamino)phenyl)-1,3-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (3j).
From 4-bromo-1,3-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2b, 84 mg, 0.26 mmol)
and (3-(dimethylamino)phenyl)boronic acid (64 mg, 0.39 mmol), 3j (77 mg, 0.21 mmol, 82%)
was obtained as a colorless solid. mp: 59.5-60.5 ºC. 1H-NMR (400 MHz, CDCl3):  7.24−7.30
(m, 1H), 6.64−6.74 (m, 3H), 3.83 (s, 3H), 2.96 (s, 6H), 2.30 (s, 3H). 13C-NMR (100 MHz,
CDCl3):  150.7, 146.2, 137.9, 130.3, 129.3, 118.2 (q, JC-F = 320 Hz), 117.3, 113.1, 111.8, 111.4,
40.5, 35.4, 13.6. HRMS-FAB m/z [M+H]+ calcd. for C14H17F3N3O3S, 364.0943; found 364.0942.
4-(2-Methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (3k). From 4-
bromo-1,3-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2b, 84 mg, 0.26 mmol) and (2-
methoxyphenyl)boronic acid (59 mg, 0.39 mmol), 3k (84 mg, 0.24 mmol, 92%) was obtained as
a pale yellow liquid. 1H-NMR (400 MHz, CDCl3):  7.35 (ddd, J = 8.3, 7.5, 1.8 Hz, 1H), 7.18
(dd, J = 7.5, 1.7 Hz, 1H), 6.99 (ddd, J = 7.4, 7.4, 1.1 Hz, 1H), 6.95 (dd, J = 8.2, 0.8 Hz, 1H), 3.83
(s, 3H), 3.81 (s, 3H), 2.19 (s, 3H). 13C-NMR (100 MHz, CDCl3):  157.0, 147.0, 138.4, 131.4,
129.6, 120.5, 118.4, 118.2 (q, JC-F = 319 Hz), 110.8, 106.8, 55.3, 35.3, 13.4. HRMS-ESI m/z
[M+H]+ calcd. for C13H14F3N2O4S, 351.0626; found 351.0611.
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1,3-Dimethyl-4-(thiophen-3-yl)-1H-pyrazol-5-yl trifluoromethanesulfonate (3l). From 4-
bromo-1,3-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2b, 84 mg, 0.26 mmol) and 3-
thienylboronic acid (50 mg, 0.39 mmol), 3l (74 mg, 0.23 mmol, 87%) was obtained as a pale
yellow liquid. 1H-NMR (400 MHz, CDCl3):  7.40 (dd, J = 5.0, 3.0 Hz, 1H), 7.26 (dd, J = 3.0,
1.2 Hz, 1H), 7.13 (dd, J = 5.0, 1.2 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.19 (s, 3H). 13C-NMR
(100 MHz, CDCl3):  146.1, 137.8, 129.4, 127.5, 125.9, 123.0, 118.3 (q, JC-F = 319 Hz), 106.2,
35.5, 13.7. HRMS-ESI m/z [M+H]+ calcd. for C10H10F3N2O3S2, 327.0085; found 327.0076.
Representative Procedure: Suzuki cross-coupling using Amphos ligand (Table 4, entry 9,
4i). A mixture of 4-bromo-1,3-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2b, 800 mg,
2.48 mmol), phenylboronic acid (453 mg, 3.72 mmol), tetrakis(triphenylphosphine)palladium(0)
(570 mg, 0.496 mmol) and potassium phosphate (1580 mg, 7.43 mmol) in toluene (20 mL) was
heated at 100 °C for 1 h under an Ar atmosphere. The mixture was cooled to room temperature
and diluted with chloroform. After filtration through Celite, the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate,
100:0 to 92:8) to yield 4-Bromo-1,3-dimethyl-5-phenyl-1H-pyrazole (4i, 467 mg, 1.86 mmol,
75%) as a colorless solid. mp: 45.0-46.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.38−7.50 (m, 5H),
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3.76 (s, 3H), 2.29 (s, 3H). 13C-NMR (100 MHz, CDCl3):  146.5, 141.6, 129.7, 129.1, 129.0,
128.7, 94.0, 37.9, 12.3. HRMS-ESI m/z [M+H]+ calcd. for C11H12BrN2, 251.0184; found
251.0169.
4-Bromo-3-methyl-1,5-diphenyl-1H-pyrazole (4a). From 4-bromo-3-methyl-1-phenyl-1H-
pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol) and phenylboronic acid (48 mg,
0.39 mmol), 4a (63 mg, 0.20 mmol, 77%) was obtained as a pale yellow solid. mp: 72.0-74.0 ºC.
1H-NMR (400 MHz, CDCl3):  7.32−7.36 (m, 3H), 7.17−7.31 (m, 7H), 2.39 (s, 3H). 13C-NMR
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(100 MHz, CDCl3):  148.4, 140.7, 139.9, 129.9, 129.1, 128.8, 128.8, 128.4, 127.3, 124.7, 96.9,
12.5. HRMS-ESI m/z [M+H]+ calcd. for C16H14BrN2, 313.0340; found 313.0323.
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4-Bromo-3-methyl-1-phenyl-5-(p-tolyl)-1H-pyrazole (4b). From 4-bromo-3-methyl-1-phenyl-
1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol) and p-tolylboronic acid (53
mg, 0.39 mmol), 4b (71 mg, 0.22 mmol, 85%) was obtained as a colorless solid. a colorless
solid. mp: 80.0-82.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.18−7.32 (m, 5H), 7.14−7.17 (m, 4H),
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2.38 (s, 3H), 2.36 (s, 3H). 13C-NMR (100 MHz, CDCl3):  148.4, 140.7, 140.0, 138.8, 129.7,
129.2, 128.8, 127.2, 126.2, 124.7, 96.7, 21.4, 12.5. HRMS-ESI m/z [M+H]+ calcd. for
C17H16BrN2, 327.0497; found 327.0469.
3-(4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N,N-dimethylaniline (4c). From 4-bromo-3-
methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol) and (3-
(dimethylamino)phenyl)boronic acid (64 mg, 0.39 mmol), 4c (78 mg, 0.22 mmol, 84%) was
obtained as a pale yellow liquid. 1H-NMR (400 MHz, CDCl3):  7.15−7.32 (m, 6H), 6.70 (ddd, J
= 8.6, 2.3, 1.3 Hz, 1H), 6.67−6.62 (m, 2H), 2.85 (s, 6H), 2.39 (s, 3H). 13C-NMR (100 MHz,
CDCl3):  150.2, 148.3, 141.5, 140.2, 129.6, 129.0, 128.7, 127.1, 124.7, 117.9, 114.0, 112.7,
96.6, 40.3, 12.6. HRMS-ESI m/z [M+H]+ calcd. for C18H19BrN3, 356.0762; found 356.0740.
4-Bromo-5-(2-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazole (4d). From 4-bromo-3-
methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol) and (2-
methoxyphenyl)boronic acid (59 mg, 0.39 mmol), 4d (72 mg, 0.21 mmol, 81%) was obtained as
a colorless solid. mp: 128.0-129.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.38 (ddd, J = 8.4, 7.5, 1.7
Hz, 1H), 7.31 (dd, J = 7.5, 1.7 Hz, 1H), 7.16−7.26 (m, 5H), 7.02 (ddd, J = 7.5, 7.5, 1.1 Hz, 1H),
6.82 (d, J = 8.4 Hz, 1H), 3.41 (s, 3H), 2.39 (s, 3H). 13C-NMR (100 MHz, CDCl3):  156.8, 148.1,
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140.8, 138.2, 131.8, 131.0, 128.5, 126.8, 123.3, 120.7, 118.5, 111.4, 97.6, 55.1, 12.6. HRMS-ESI
m/z [M+H]+ calcd. for C17H16BrN2O, 343.0446; found 343.0433.
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4-Bromo-5-(2,4-difluorophenyl)-3-methyl-1-phenyl-1H-pyrazole (4e). From 4-bromo-3-
methyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol) and (2,4-
difluorophenyl)boronic acid (62 mg, 0.39 mmol), 4e (73 mg, 0.21 mmol, 80%) was obtained as a
pale yellow solid. mp: 81.5-83.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.23−7.33 (m, 4H),
7.18−7.22 (m, 2H), 6.94 (ddd, J = 9.5, 8.9, 2.5 Hz, 1H), 6.82 (dddd, J = 8.7, 7.9, 2.6, 0.9 Hz,
1H), 2.39 (s, 3H). 13C-NMR (100 MHz, CDCl3):  161.3 (dd, JC-F = 252, 12 Hz), 157.5 (dd, JC-F
= 253, 13 Hz), 148.5, 139.8, 134.8, 133.0 (dd, JC-F = 9.7, 3.8 Hz), 129.0, 127.6, 123.8, 113.8 (dd,
JC-F = 15, 4.0 Hz), 111.9 (dd, JC-F = 21, 3.8 Hz), 104.7 (dd, JC-F = 18, 18 Hz), 98.5, 12.5. HRMS-
ESI m/z [M+H]+ calcd. for C16H12BrF2N2, 349.0152; found 349.0135.
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4-Bromo-5-(3-chlorophenyl)-3-methyl-1-phenyl-1H-pyrazole (4f). From 4-bromo-3-methyl-
1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol) and (3-
chlorophenyl)boronic acid (61 mg, 0.39 mmol), 4f (59 mg, 0.17 mmol, 65%) was obtained as a
colorless liquid. 1H-NMR (400 MHz, CDCl3):  7.24−7.35 (m, 6H), 7.17−7.22 (m, 2H), 7.10
(ddd, J = 7.7, 1.4, 1.4 Hz, 1H), 2.39 (s, 3H). 13C-NMR (100 MHz, CDCl3):  148.6, 139.6, 139.2,
134.4, 130.9, 129.8, 129.7, 129.0, 129.0, 128.1, 127.6, 124.7, 97.2, 12.5. HRMS-ESI m/z
[M+H]+ calcd. for C16H13BrClN2, 346.9951; found 346.9937.
4-Bromo-5-(furan-3-yl)-3-methyl-1-phenyl-1H-pyrazole (4g). From 4-bromo-3-methyl-1-
phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol) and 3-furylboronic
acid (44 mg, 0.39 mmol), 4g (31 mg, 0.10 mmol, 39%) was obtained as a colorless liquid. 1H-
NMR (400 MHz, CDCl3):  7.62 (dd, J = 1.5, 0.9 Hz, 1H), 7.31−7.42 (m, 6H), 6.16 (dd, J = 1.9,
0.8 Hz, 1H), 2.36 (s, 3H). 13C-NMR (100 MHz, CDCl3):  148.5, 142.6, 142.0, 140.0, 133.7,
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129.0, 128.1, 125.4, 114.1, 110.2, 96.2, 12.5. HRMS-ESI m/z [M+H]+ calcd. for C14H12BrN2O,
303.0133; found 303.0128.
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4-Bromo-3-methyl-1-phenyl-5-(thiophen-3-yl)-1H-pyrazole (4h). From 4-bromo-3-methyl-1-
phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2a, 100 mg, 0.26 mmol) and 3-
thienylboronic acid (50 mg, 0.39 mmol), 4h (76 mg, 0.24 mmol, 92%) was obtained as a pale
yellow liquid. 1H-NMR (400 MHz, CDCl3):  7.39 (dd, J = 3.0, 1.3 Hz, 1H), 7.22−7.36 (m, 6H),
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6.90 (dd, J = 5.1, 1.3 Hz, 1H), 2.37 (s, 3H). 13C-NMR (100 MHz, CDCl3):  148.5, 140.0, 136.5,
129.0, 128.8, 127.9, 127.7, 126.2, 125.5, 124.9, 96.6, 12.5. HRMS-ESI m/z [M+H]+ calcd. for
C14H12BrN2S, 318.9905; found 318.9893.
3-(4-Bromo-1,3-dimethyl-1H-pyrazol-5-yl)-N,N-dimethyl-aniline (4j). From 4-bromo-1,3-
dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2b, 84 mg, 0.26 mmol) and (3-
(dimethylamino)phenyl)boronic acid (64 mg, 0.39 mmol), 4j (74 mg, 0.25 mmol, 97%) was
obtained as a colorless solid. mp: 59.0-61.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.33 (dd, J = 8.0,
8.0 Hz, 1H), 6.78−6.82 (m, 1H), 6.68−6.72 (m, 2H), 3.77 (s, 3H), 2.99 (s, 6H), 2.29 (s, 3H). 13C-
NMR (100 MHz, CDCl3):  150.4, 146.4, 142.5, 129.7, 129.3, 117.4, 113.6, 112.9, 93.8, 40.4,
37.9, 12.3. HRMS-ESI m/z [M+H]+ calcd. for C13H17BrN3, 294.0606; found 294.0631.
4-Bromo-5-(2-methoxyphenyl)-1,3-dimethyl-1H-pyrazole (4k). From 4-bromo-1,3-dimethyl-
1H-pyrazol-5-yl trifluoromethanesulfonate (2b, 84 mg, 0.26 mmol) and (2-
methoxyphenyl)boronic acid (59 mg, 0.39 mmol), 4k (66 mg, 0.21 mmol, 90%) was obtained as
a colorless liquid. 1H-NMR (400 MHz, CDCl3):  7.45 (ddd, J = 8.4, 7.5, 1.8 Hz, 1H), 7.26 (dd, J
= 7.5, 1.8 Hz, 1H), 7.07 (ddd, J = 7.5, 7.5, 1.0 Hz, 1H), 7.01 (dd, J = 8.4, 0.8 Hz, 1H), 3.82 (s,
3H), 3.65 (s, 3H), 2.29 (s, 3H). 13C-NMR (100 MHz, CDCl3):  157.2, 146.1, 138.9, 132.1,
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131.1, 120.7, 117.8, 111.3, 94.6, 55.5, 37.7, 12.4. HRMS-ESI m/z [M+H]+ calcd. for
C12H14BrN2O, 281.0290; found 281.0285.
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4-Bromo-1,3-dimethyl-5-(thiophen-3-yl)-1H-pyrazole (4l). From 4-bromo-1,3-dimethyl-1H-
pyrazol-5-yl trifluoromethanesulfonate (2b, 84 mg, 0.26 mmol) and 3-thienylboronic acid (50
mg, 0.39 mmol), 4l (55 mg, 0.21 mmol, 82%) was obtained as a pale yellow solid. mp: 54.0-55.0
ºC. 1H-NMR (400 MHz, CDCl3):  7.49 (dd, J = 3.0, 1.4 Hz, 1H), 7.46 (dd, J = 4.9, 3.0 Hz, 1H),
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7.24 (dd, J = 5.0, 1.4 Hz, 1H), 3.81 (s, 3H), 2.28 (s, 3H). 13C-NMR (100 MHz, CDCl3):  146.5,
137.1, 128.8, 127.8, 126.1, 126.0, 94.2, 38.1, 12.3. HRMS-ESI m/z [M+H]+ calcd. for
C9H10BrN2S, 256.9748; found 256.9740.
Representative Procedure: The second Suzuki cross-coupling using Amphos ligand (Table
5, entry 1, 5b). A mixture of 4-bromo-1,3-dimethyl-5-phenyl-1H-pyrazole (4i, 75 mg, 0.30
mmol), 2-methoxyphenylboronic acid (91 mg, 0.60 mmol), palladium(II) acetate (6.7 mg, 0.030
mmol), 4-(di-tert-butylphosphino)-N,N-dimethylaniline (16 mg, 0.060 mmol), and potassium
phosphate (159 mg, 0.75 mmol) in toluene (3.0 mL) was heated at 100 °C for 2 h under an Ar
atmosphere. The mixture was cooled to room temperature and diluted with chloroform. After
filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (n-hexane/ethyl acetate, 90:10 to 70:30) to yield 4-(2-
Methoxyphenyl)-1,3-dimethyl-5-phenyl-1H-pyrazole (5b, 72 mg, 0.26 mmol, 86%) as a pale
yellow liquid. 1H-NMR (400 MHz, CDCl3):  7.27−7.34 (m, 3H), 7.16−7.23 (m, 3H), 6.99 (dd, J
= 7.4, 1.8 Hz, 1H), 6.81−6.86 (m, 2H), 3.81 (s, 3H), 3.55 (s, 3H), 2.19 (s, 3H). 13C-NMR (100
MHz, CDCl3):  157.1, 146.6, 141.9, 132.2, 131.0, 129.4, 128.2, 128.1, 127.9, 122.5, 120.3,
115.9, 110.8, 55.0, 37.1, 12.5. HRMS-ESI m/z [M+H]+ calcd. for C18H19N2O, 279.1497; found
279.1523.
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3-(1,3-Dimethyl-5-phenyl-1H-pyrazol-4-yl)-N,N-dimethyl-aniline (5c). From 4-bromo-1,3-
dimethyl-5-phenyl-1H-pyrazole (4i, 75 mg, 0.30 mmol) and (3-(dimethylamino)phenyl)boronic
acid (90 mg, 0.60 mmol), 5c (85 mg, 0.29 mmol, 97%) was obtained as a yellow solid. mp:
118.0-120.0 ºC. 1H-NMR (400 MHz, CDCl3):  7.31−7.39 (m, 3H), 7.23−7.27 (m, 2H), 7.11 (dd,
J = 7.9, 7.9 Hz, 1H), 6.57 (ddd, J = 8.2, 2.7, 0.8 Hz, 1H), 6.53 (ddd, J = 7.6, 1.5, 1.1 Hz, 1H),
6.41 (dd, J = 2.5, 1.6 Hz, 1H), 3.76 (s, 3H), 2.77 (s, 6H), 2.38 (s, 3H). 13C-NMR (100 MHz,
CDCl3):  150.3, 145.6, 141.2, 134.1, 130.9, 130.1, 128.7, 128.5, 128.2, 120.2, 118.0, 114.3,
110.4, 40.4, 36.9, 12.9. HRMS-ESI m/z [M+H]+ calcd. for C19H22N3, 292.1814; found 292.1802.
5-(2-Methoxyphenyl)-1,3-dimethyl-4-phenyl-1H-pyrazole (5d). From 4-bromo-5-(2-
methoxyphenyl)-1,3-dimethyl-1H-pyrazole (4k, 51 mg, 0.18 mmol) and phenylboronic acid (44
mg, 0.36 mmol), 5d (36 mg, 0.13 mmol, 72%) was obtained as a pale yellow liquid. 1H-NMR
(400 MHz, CDCl3):  7.36 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.18−7.24 (m, 2H), 7.13 (tt, J = 7.5,
1.4 Hz, 1H), 7.06−7.10 (m, 2H), 7.01 (dd, J = 7.5, 1.7 Hz, 1H), 6.96 (dd, J = 8.7, 0.8 Hz, 1H),
6.89 (ddd, J = 7.5, 7.5, 1.1 Hz, 1H), 3.73 (s, 3H), 3.66 (s, 3H), 2.37 (s, 3H). 13C-NMR (100 MHz,
CDCl3):  157.7, 145.3, 138.1, 134.0, 132.2, 130.4, 129.1, 128.0, 125.7, 120.7, 120.0, 119.4,
111.1, 55.4, 36.7, 12.9. HRMS-ESI m/z [M+H]+ calcd. for C18H19N2O, 279.1497; found
279.1506.
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3-(1,3-Dimethyl-4-phenyl-1H-pyrazol-5-yl)-N,N-dimethyl-aniline (5e). From 3-(4-bromo-1,3-
dimethyl-1H-pyrazol-5-yl)-N,N-dimethyl-aniline (4j, 37 mg, 0.13 mmol) and phenylboronic acid
(31 mg, 0.25 mmol), 5e (19 mg, 0.065 mmol, 52%) was obtained as a colorless liquid. 1H-NMR
(400 MHz, CDCl3):  7.19−7.27 (m, 3H), 7.11−7.18 (m, 3H), 6.70 (ddd, J = 8.5, 2.7, 0.7 Hz,
1H), 6.58 (ddd, J = 7.5, 1.0, 1.0 Hz, 1H), 6.50 (dd, J = 2.6, 1.5 Hz, 1H), 3.79 (s, 3H), 2.84 (s,
6H), 2.34 (s, 3H). 13C-NMR (100 MHz, CDCl3):  150.3, 145.5, 142.1, 133.9, 131.0, 129.6,
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129.1, 128.0, 125.8, 119.4, 118.0, 114.2, 112.3, 40.3, 37.0, 12.7. HRMS-ESI m/z [M+H]+ calcd.
for C19H22N3, 292.1814; found 292.1817.
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1,3-Dimethyl-5-phenyl-4-(p-tolyl)-1H-pyrazole (5f). From 4-bromo-1,3-dimethyl-5-phenyl-
1H-pyrazole (4i, 75 mg, 0.30 mmol) and p-tolylboronic acid (82 mg, 0.60 mmol), 5f (65 mg,
0.25 mmol, 83%) was obtained as a pale yellow solid. mp: 147.0-148.0 ºC. 1H-NMR (400 MHz,
CDCl3):  7.32−7.40 (m, 3H), 7.20−7.24 (m, 2H), 7.02−7.06 (m, 2H), 6.96−7.00 (m, 2H), 3.76
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(s, 3H), 2.33 (s, 3H), 2.30 (s, 3H). 13C-NMR (100 MHz, CDCl3):  145.6, 141.1, 135.5, 130.6,
130.6, 130.1, 129.4, 128.9, 128.5, 128.3, 119.5, 36.9, 21.1, 12.7. HRMS-ESI m/z [M+H]+ calcd.
for C18H19N2, 263.1548; found 263.1548.
Representative Procedure: The second Suzuki cross-coupling using PPh3 ligand (Table 6,
entry 1, 5b). A mixture of 4-(2-methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-yl
trifluoromethanesulfonate (3k, 74 mg, 0.21 mmol), phenylboronic acid (52 mg, 0.42 mmol),
tetrakis(triphenylphosphine)palladium(0) (49 mg, 0.042 mmol) and potassium phosphate (112
mg, 0.53 mmol) in toluene (3.0 mL) was heated at 100 °C for 2 h under an Ar atmosphere. The
mixture was cooled to room temperature and diluted with chloroform. After filtration through
Celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica
gel chromatography (n-hexane/ethyl acetate, 90:10 to 70:30) to yield 4-(2-methoxyphenyl)-1,3-
dimethyl-5-phenyl-1H-pyrazole (5b, 32 mg, 0.12 mmol, 55%) as a pale yellow liquid.
3-(1,3-Dimethyl-5-phenyl-1H-pyrazol-4-yl)-N,N-dimethyl-aniline (5c). From 4-(3-
(dimethylamino)phenyl)-1,3-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (3j, 56 mg,
0.15 mmol) and phenylboronic acid (38 mg, 0.21 mmol), 5c (40 mg, 0.14 mmol, 89%) was
obtained as a yellow solid.
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5-(2-Methoxyphenyl)-1,3-dimethyl-4-phenyl-1H-pyrazole (5d). From 1,3-dimethyl-4-phenyl-
1H-pyrazol-5-yl trifluoromethanesulfonate (3i, 96 mg, 0.30 mmol) and 2-methoxyphenylboronic
acid (91 mg, 0.60 mmol), 5d (56 mg, 0.20 mmol, 67%) was obtained as a pale yellow liquid.
3-(1,3-Dimethyl-4-phenyl-1H-pyrazol-5-yl)-N,N-dimethyl-aniline (5e). From 1,3-dimethyl-4-
phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (3i, 96 mg, 0.30 mmol) and (3-
(dimethylamino)phenyl)boronic acid (99 mg, 0.60 mmol), 5e (76 mg, 0.26 mmol, 87%) was
obtained as a colorless liquid.
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1,3-Dimethyl-4-phenyl-5-(p-tolyl)-1H-pyrazole (5g). From 1,3-dimethyl-4-phenyl-1H-pyrazol-
5-yl trifluoromethanesulfonate (3i, 96 mg, 0.30 mmol) and p-tolylboronic acid (82 mg, 0.60
mmol), 5g (69 mg, 0.26 mmol, 88%) was obtained as a pale yellow solid. mp: 68.5-69.5 ºC. 1H-
NMR (400 MHz, CDCl3):  7.26−7.20 (m, 2H), 7.13−7.19 (m, 3H), 7.07−7.12 (m, 4H), 3.76 (s,
3H), 2.36 (s, 3H), 2.34 (s, 3H). 13C-NMR (100 MHz, CDCl3):  145.6, 141.3, 138.2, 133.8,
129.9, 129.6, 129.3, 128.1, 127.5, 125.9, 119.4, 36.9, 21.3, 12.7. HRMS-ESI m/z [M+H]+ calcd.
for C18H19N2, 263.1548; found 263.1569.
3-Methyl-1,4,5-triphenyl-1H-pyrazole (5a). A mixture of 4-bromo-3-methyl-1-phenyl-1H-
pyrazol-5-yl trifluoromethanesulfonate (100 mg, 0.26 mmol), phenylboronic acid (160 mg, 1.30
mmol), palladium(II) acetate (5.8 mg, 0.026 mmol), 2-dicyclohexylphosphino-2',4',6'-
triisopropylbiphenyl (25 mg, 0.052 mmol) and potassium phosphate (138 mg, 0.65 mmol) in
toluene (3.0 mL) was heated at 60 °C for 2 h under an Ar atmosphere, and then warmed to 80 °C
for 2 h. Then, additional phenylboronic acid (160 mg, 1.30 mmol), palladium(II) acetate (5.8 mg,
0.026 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (25 mg, 0.052 mmol) and
potassium phosphate (138 mg, 0.65 mmol) were added to the mixture. After stirring at 80 °C for
1.5 h, the reaction mixture was poured into water, extracted with ethyl acetate. The combined
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organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (n-hexane/ethyl acetate, 98:2 to 90:10) to yield
compound 5a (61 mg, 0.20 mmol, 76%) as a colorless solid. mp: 179.0-181.0 ºC. 1H-NMR (400
MHz, CDCl3):  7.12−7.30 (m, 13H), 7.02−7.06 (m, 2H), 2.40 (s, 3H). 13C-NMR (100 MHz,
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CDCl3):  147.8, 140.3, 140.0, 133.3, 130.3, 130.3, 129.9, 128.7, 128.3, 128.2, 128.0, 126.9,
126.4, 125.1, 121.4, 12.8. HRMS-ESI m/z [M+H]+ calcd. for C22H19N2, 311.1548; found
311.1548.
ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C NMR spectrum and synthetic procedure of compound 5a as reference
standard of HPLC analysis. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: fujiih@pharm.kitasato-u.ac.jp
ORCID
Sakakibara, R.: 0000-0003-1852-039X
Itoh, K.: 0000-0002-6096-304X
Fujii, H.: 0000-0002-0049-0084
ACKNOWLEDGMENT
The authors thank Dr. Ken Tokunaga (Kogakuin University) for insightful discussion, and Dr.
Kenichiro Nagai (Kitasato University) for analytical support.
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REFERENCES
7
8
9
(1) For reviews (a) Naim, M. J.; Alam, O.; Nawaz, F.; Alam, M. J.; Alam, P. Current status of
pyrazole and its biological activities. J Pharm Bioallied Sci. 2016. 8. 2−17. (b) Ansari, A.;
Ali, A.; Asif, M.; Shamsuzzaman. Review: biologically active pyrazole derivatives. New J.
Chem. 2017, 41, 16−41. For recent examples (c) Le, T. G.; Kundu, A.; Ghoshal, A.; Nguyen,
N. H.; Preston, S.; Jiao, Y.; Ruan, B.; Xue, L.; Huang, F.; Keiser, J.; Hofmann, A.; Chang, B.
C. H.; Garcia-Bustos, J.; Wells, T. N. C.; Palmer, M. J.; Jabbar, A.; Gasser, R. B.; Baell, J. B.
Novel 1-Methyl-1H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity.
J. Med. Chem. 2019, 62, 3367−3380. (d) Sakakibara, R.; Sasaki, W.; Onda, Y.; Yamaguchi,
M.; Ushirogochi, H.; Hiraga, Y.; Sato, K.; Nishio, M.; Egi, Y.; Takedomi, K.; Shimizu, H.;
Ohbora, T.; Akahoshi, F. Discovery of Novel Pyrazole-Based Selective Aldosterone
Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of
CYP11B2. J. Med. Chem. 2018, 61, 5594−5608. (e) Procopiou, P. A.; Anderson, N. A.;
Barrett, J.; Barrett, T. N.; Crawford, M. H. J.; Fallon, B. J.; Hancock, A. P.; Le, J.; Lemma,
S.; Marshall, R. P.; Morrell, J.; Pritchard, J. M.; Rowedder, J. E.; Saklatvala, P.; Slack, R. J.;
Sollis, S. L.; Suckling, C. J.; Thorp, L. R.; Vitulli, G.; Macdonald, S. J. F. Discovery of (S)-3-
(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-
2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for theInhaled
Treatment of Idiopathic Pulmonary Fibrosis. J. Med. Chem. 2018, 61, 8417−8443.
10
11
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14
15
16
17
18
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20
21
22
23
24
25
26
27
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29
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33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) (a) Elguero, J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Eds.; Pergamon Press: Oxford, U.K., 1984; Vol. 5, p 167. (b) Elguero, J. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon
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Page 28 of 31
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5
6
7
8
9
Press: Oxford, U. K., 1996; Vol. 3, p 1. (c) Stanovnik, B.; Svete, J. In Pyrazoles; Neier, R.,
Ed.; Science of Synthesis, Houben-Weyl, Methods of Organic Transformations, Georg
Thieme: Stuttgart, Germany, 2002; Vol. 12, pp 15−225. (d) Yet, L. In Comprehensive
Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J.
K., Eds.; Elsevier: Oxford, U.K., 2008; Vol. 4, p 1.
10
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18
19
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22
23
24
25
26
27
28
29
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) Bourrain, S.; Ridgill, M.; Collins, I. Regioselective Rapid Analogue Syntheses of 1-Methyl-
3,5-diarylpyrazoles via Palladium-catalysed Coupling to 3(5)-Pyrazolyl Nonaflates. Synlett
2004, 5, 795−798.
(4) Khera, R. A.; Ali, A.; Rafique, H.; Hussain, M.; Tatar, J.; Saeed, A.; Villinger, A.; Langer, P.
Suzuki-Miyaura reactions of N-protected tribromopyrazoles. Efficient and site-selective
synthesis of 3,4,5-triaryl-pyrazoles, 3,5-diaryl-4-bromopyrazoles and 5-aryl-3,4-
dibromopyrazoles. Tetrahedron 2011, 67, 5244−5253.
(5) Brahim, M.; Smari, I.; Ammar, H. B.; Hassine, B. B.; Soule, J-F.; Doucet, H. Conditions for
palladium-catalyzed direct arylations of 4-bromo and 4-iodo N-substituted pyrazoles without
C-Br or C-I bond cleavage. Org. Chem. Front. 2015, 2, 917−926.
(6) Dai, X.; Chen, Y.; Garrell, S.; Liu, H.; Zhang, L-K.; Palani, A.; Hughes, G.; Nargund, R.
Ligand-Dependent Site-Selective Suzuki Cross-Coupling of 3,5-Dichloropyridazines. J. Org.
Chem. 2013, 78, 7758−7763.
(7) Strotman, N. A.; Chobanian, H. R.; He,J.; Guo, Y.; Dormer, P. G.; Jones,C. M.; Steves, J. E.
Catalyst-Controlled Regioselective Suzuki Couplings at Both Positions of Dihaloimidazoles,
Dihalooxazoles, and Dihalothiazoles. J. Org. Chem. 2010, 75, 1733−1739.
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9
(8) Littke, A. F.; Dai, C. Y.; Fu, G. C. Versatile Catalysts for the Suzuki Cross-Coupling of
Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Mild Conditions. J. Am.
Chem. Soc. 2000, 122, 4020−4028.
10
11
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53
54
55
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60
(9) Dvoak, C. A.; Rudolph, D. A.; Ma, S.; Carruthers, N. I. Palladium-Catalyzed Coupling of
Pyrazole Triflates with Arylboronic Acids. J. Org. Chem. 2005, 70, 4188−4190.
(10) (a) Abdelhamid, A. O.; Riad, B. Y. Reactions with 4-Bromo-3-methyl-1-phenyl-2-
pyrazolin-5-one: New Fused Pyrazole Derivatives. Archiv der Oharmazie, 1987, 320,
1010−1014. (b) El-Shehry, M. F.; El-Telbani, E. M.; Swellem, R. H. Synthesis of
polyfunctional substituted pyrazoles. J. Chem. Res. Synop. 2009, 10, 625−629.
(11) (a) Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.; Hickey, E. Klaus,
B.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis, C.; Pav, S.; Proto, A.; Swinamer, A.; Tong,
L.; Torcellini, C. Pyrazole Urea-Based Inhibitors of p38 MAP Kinase: From Lead
Compound to Clinical Candidate. J. Med. Chem. 2002, 45, 2994−3008. (b) Tokumaru, K.;
Ito, Y.; Nomura, I.; Nakahata, T.; Shimizu, Y.; Kurimoto, E.; Aoyama, K.; Aso, K. Design,
synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel
GPR52 agonists. Bioorg. Med. Chem. 2017, 25, 3098−3115.
(12)
(a) Almond-Thynne, J.; Blakemore, D. C.; Pryde. D. C.; Spivey, A. C. Site-selective
Suzuki-Miyaura coupling of heteroaryl halides – understanding the trends for
pharmaceutically important classes. Chem. Sci. 2017, 8, 40−62. (b) Legault, C. Y.; Garcia,
Y.; Merlic, C. A.; Houk, K. N. Origin of Regioselectivity in Palladium-catalyzed Cross-
Coupling Reactions of Polyhalogenated heterocycles. J. Am. Chem. Soc. 2007, 129,
12664−12665. (c) Grushin, V. V.; Alper, H. Transformations of Chioroarenes, Catalyzed by
Transition-Metal Complexes. Chem. Rev. 1994, 94, 1047-1062.
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