Synthesis of N-Arylpyrazoles by Palladium-Catalyzed Coupling of Aryl Triflates with Pyrazole Derivatives

Article abstract of DOI:10.1021/acs.joc.9b00673

A method for the synthesis of N-arylpyrazoles by palladium-catalyzed coupling of aryl triflates with pyrazole derivatives is described. Using tBuBrettPhos as a ligand, the palladium-catalyzed C-N coupling of a variety of aryl triflates including ortho-substituted ones with pyrazole derivatives proceeded efficiently to give N-arylpyrazole products in high yields. 3-Trimethylsilylpyrazole was found to be an excellent pyrazole substrate for the coupling, and the corresponding product, 1-aryl-3-trimethylsilylpyrazole, also served as a great template for the syntheses of N-arylpyrazole derivatives, as demonstrated by regioselective halogenation at the 3-, 4-, and 5-positions of the pyrazole ring.

Full text of DOI:10.1021/acs.joc.9b00673

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Note
Synthesis of N-Arylpyrazoles by Palladium-Catalyzed
Coupling of Aryl Triflates with Pyrazole Derivatives
Shunsuke Onodera, Takuya Kochi, and Fumitoshi Kakiuchi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00673 • Publication Date (Web): 26 Apr 2019
Downloaded from http://pubs.acs.org on April 26, 2019
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Synthesis of N-Arylpyrazoles by Palladium-Catalyzed Coupling of Aryl Triflates with
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Pyrazole Derivatives
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Shunsuke Onodera, Takuya Kochi, and Fumitoshi Kakiuchi*
Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
kakiuchi@chem.keio.ac.jp
Table of Contents/Abstract Graphic
Abstract
A method for synthesis of N-arylpyrazoles by palladium-catalyzed coupling of aryl triflates
with pyrazole derivatives is described. Using tBuBrettPhos as a ligand, the palladium-catalyzed
C–N coupling of a variety of aryl triflates including ortho-substituted ones with pyrazole
derivatives proceeded efficiently to give N-arylpyrazole products in high yields. 3-
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Trimethylsilylpyrazole was found as an excellent pyrazole substrate for the coupling, and the
corresponding product, 1-aryl-3-trimethylsilylpyrazole, also served as a great template for
syntheses of N-arylpyrazole derivatives, as demonstrated by regioselective halogenation at 3-, 4-
and 5-positions of the pyrazole ring.
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N-Arylpyrazoles are a class of important compounds because of their interesting biological
activities as agrochemicals and pharmaceuticals.1 A variety of strategies have been developed for
preparation of N-arylpyrazoles,2,3 and one of the most efficient methods for the synthesis of N-
arylpyrazoles is transition-metal-catalyzed cross-coupling of aryl halides with 1H-pyrazoles
(Figure 1).2 Copper catalysts have been frequently used in the C–N coupling reaction to form N-
arylpyrazoles, and many researchers have developed new copper catalyst systems to improve the
reaction efficiency.4 On the other hand, synthesis of N-arylpyrazoles by palladium-catalyzed C–
N coupling of aryl halides with 1H-pyrazoles has been relatively less explored,5,6 and for
example, only a few examples of the coupling of ortho-substituted aryl halides has been reported
in publications.5c,5f
Aryl triflates are also common electrophiles in palladium-catalyzed C–N coupling reactions,
while copper catalysts have rarely been applied to the reaction of aryl triflates7,8 because of their
reluctance to react with this class of substrates.6a The use of aryl triflates in the cross-coupling
reactions is sometimes advantageous because aryl triflates can be easily prepared from phenolic
compounds, which are more widely accessible than aryl halides.9 However, metal-catalyzed
coupling of aryl triflates with 1H-pyrazoles have been achieved only for limited sets of
substrates,8 and development of a general protocol for synthesis of N-arylpyrazoles by the C–N
coupling is still desired.10 During the course of our study of the rhodium-catalyzed deallylative
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alkenylation reactions,11 we envisioned that a method for the C–N coupling reactions of ortho-
substituted aryl triflates with a pyrazole derivative would provide an efficient route to prepare
substrates for the deallylative alkenylation. After screening of the reaction conditions, we found
that the palladium-catalyzed C–N coupling of an aryl triflates derived from an ortho-prenylated
phenol with 3-trimethylsilylpyrazole proceeded efficiently, but the generality of the C–N
coupling reaction was not investigated.
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Herein, we report the details of the C–N coupling reaction to form N-arylpyrazoles including
modification of the previous reaction conditions and wide substrate scope. The great utility of 3-
trimethylsilylpyrazole was also demonstrated by the excellent reactivity in the C–N coupling
reaction and the applicability of the coupling products for regiodivergent halogenation at all 3-,
4-, and 5-positions on the pyrazole ring.
Figure 1. Metal-catalyzed C–N coupling of aryl (pseudo)halides with pyrazole derivatives.
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In our previous publication showing one example of the aryl triflate/pyrazole coupling, 10
mol % of 1/2 Pd2(dba)3 and 20 mol % of tBuBrettPhos were used to achieve 85% yield of the
product.11 We began our investigation of the general protocol of the C–N coupling reaction by
modification of the previous protocol, especially to reduce the amounts of palladium catalysts
and ligands. We first examined the coupling of simple aryl triflate substrate 1a with 3-
trimethylsilylpyrazole (2a) to see if the catalyst loading can be reduced. When the reaction of p-
tolyl triflate (1a) with 2a was performed using 4 mol % of 1/2 Pd2(dba)3 and 8 mol % of
tBuBrettPhos in 1,4-dioxane in the presence of potassium phosphate as a base at 70 ºC for 24 h,
the desired N-arylpyrazole product 3aa was obtained in 96% NMR yield (Table 1, entry 1). The
use of Pd(dba)2 instead of Pd2(dba)3 was also effective to give 3aa in 94% NMR yield (entry 2).
Reduction of the amount of tBuBrettPhos was then investigated, and the reactions were found to
proceed efficiently using only 6 mol % of the ligand with either Pd2(dba)3 or Pd(dba)2 (entries 3
and 4). Particularly, the reaction with 4 mol % of Pd(dba)2 and 6 mol % of tBuBrettPhos
provided 3aa in 98% NMR yield (entry 4). The use of other ligands such as tBuXPhos,
BrettPhos, and XPhos gave either lower yield or no detectable amount of 3aa (entries 5-7). The
reaction using the tBuXPhos/NaOtBu system, developed for aryl bromide/pyrazole coupling,5a
did not give 3aa and resulted in decomposition of the aryl triflate substrate (entry 8). The
reaction in toluene also provided 3aa only in 58% NMR yield (entry 9). Therefore, the reaction
conditions shown in entry 4 were determined to be optimum and used for further examination.
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Table 1. Palladium-Catalyzed C–N Coupling of Aryl Triflate 1a with Pyrazole Derivative
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2aa
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entry
Pd catalyst
1/2 Pd2(dba)3
Pd(dba)2
phosphine
base
solvent
NMR yield
96%
94%
94%
98%
63%
ndb
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4
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9
8 mol % tBuBrettPhos
8 mol % tBuBrettPhos
6 mol % tBuBrettPhos
6 mol % tBuBrettPhos
6 mol % tBuXPhos
6 mol % BrettPhos
6 mol % XPhos
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
NaOtBu
K3PO4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
1/2 Pd2(dba)3
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
ndb
Pd(dba)2
6 mol % tBuXPhos
6 mol % tBuBrettPhos
ndb
Pd(dba)2
58%
aReaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), Pd catalyst (0.012 mmol), phosphine
(0.018 or 0.024 mmol), solvent (1.5 mL), 70 ºC, 24 h. bNot detected.
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The C–N coupling was then examined for various sets of substrates by isolating the N-
arylpyrazole products (Table 2). Product 3aa formed by the reaction of p-tolyl triflate (1a) with
2a under the standard conditions was isolated in 98% yield (entry 1), and in this case, reduction
of the catalyst loading to 2 mol % of Pd(dba)2 and 3 mol % of tBuBrettPhos had little effect on
the yield (entry 2). The C–N coupling of 1a with 3-substituted pyrazoles such as those bearing
tert-butyl (2b), phenyl (2c), and methyl (2d) groups gave the desired products 3ab-3ad in high
yields (entries 3-5). In addition, pyrazoles with no substituents at the 3-position were also
applicable to this reaction, and the coupling of 1a with pyrazole (2e) and 4-trimethylsilylpyrazole
(2f) provided the corresponding products 3ae and 3af in 84 and 69% yields, respectively (entries
6 and 7). The reaction of o-tolyl triflate (1b) with various pyrazoles was next examined. Under
the standard reaction conditions, 3-substituted pyrazoles 2a-2c were coupled smoothly even with
the sterically-congested aryl triflate 1b to give products 3ba-3bc in excellent yields (entries 8-
10).12 However, the reaction of 1b with pyrazole derivatives possessing a smaller group such as
H or Me group, at the 3-position (2d-2f) resulted in low yields (entry 11-13). It is unclear why
the reactivity of the pyrazole derivatives with large substituents at the 3-position is higher than
those with a small group in this reaction, but as Buchwald and coworkers reported for a
palladium-catalyzed coupling reaction,13 formation of pyrazolyl-bridged palladium dimers,
which may inhibit the reaction, are less likely to occur, when the 3-position possesses a large
substituent.
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Table 2. Palladium-Catalyzed C–N Coupling of Aryl Triflates with 3-Substituted Pyrazole
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Derivativesa
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entry aryl triflate 1
R1
Me
Me
Me
Me
Me
Me
Me
H
R2
H
pyrazole 2
R3
TMS
TMS
tBu
Ph
R4
H
product 3
3aa
yield
98%
97%
quant
97%
90%
84%
69%
95%
95%
92%
25%
trace
trace
1
2b
3
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
2a
2a
2b
2c
2d
2e
2f
H
H
3aa
H
H
3ab
3ac
4
H
H
5
H
Me
H
H
3ad
3ae
6
H
H
7
H
H
TMS
H
3af
8
Me
Me
Me
Me
Me
Me
TMS
tBu
Ph
2a
2b
2c
2d
2e
2f
3ba
3bb
3bc
9
H
H
10
11
12
13
H
H
H
Me
H
H
3bd
3be
H
H
H
H
TMS
3bf
aReaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), Pd(dba)2 (0.012 mmol), tBuBrettPhos (0.018
mmol), 1,4-dioxane (1.5 mL), 70 ºC. bPerformed with 0.006 mmol (2 mol %) Pd(dba)2 and 0.009
mmol (3 mol %) tBuBrettPhos.
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The C–N coupling reaction was applicable to aryl triflates possessing a variety of functional
groups (Table 3). The reaction of 2,3,5-trimethylphenyl triflate (1c) afforded 93% yield of
product 3ca. A substrate possessing an ortho-prenyl group (1d) coupled with 2a effectively to
give 3da in 91% yield by using 6 mol % of the palladium catalyst. Aryl triflate 1e bearing an
ortho-methoxy group showed excellent reactivity to give 3ea in 99% yield. Substrates bearing
electron-withdrawing trifluoromethyl and cyano groups reacted with 2a as well to afford the
corresponding N-arylpyrazoles 3fa and 3ga in 81% and 93% yields, respectively. 1-
Naphthyltriflate (1h) could also be applied for the C–N coupling reaction to form 3ha in 88%
yield.14 The reactions of aryl triflates with various para substituents such as chloro, acetyl, and
methoxy groups proceed in the presence of only 2 mol % of the palladium catalyst to give the
corresponding N-arylpyrazoles 3ia-3ka in 74-97% yields. The coupling of 1i resulted in lower
yield than others, because further C–N coupling at the chlorinated carbon of 3ia partially
occurred as a side reaction. The reaction of 2-pyridyl triflate (1l) with 2a gave 3la in 92% yield
using 2 mol % of the palladium catalyst. In the coupling of 3-pyridyl triflate (1m), pyrazole 2a
was used as a limiting reagent because 3ma and 2a were difficult to separate by silica gel
column chromatography and 95% yield of 3ma was obtained. In the reactions with 3-substituted
pyrazoles, two regioisomeric N-arylation products, 3- and 5-substituted N-arylpyrazoles could be
obtained theoretically, but only 3-substituted N-arylpyrazoles were observed in the coupling
reactions described here. The structures of the products were determined by 1H NMR using a
coupling constant analysis method reported by Cristau and Taillefer.4b
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Table 3. Palladium-Catalyzed C–N Coupling of Various Aryl Triflates with 2a
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aReaction conditions: 1 (0.3 mmol), 2a (0.36 mmol), Pd(dba)2 (0.012 mmol, 4 mol %),
tBuBrettPhos (0.018 mmol, 6 mol %), K3PO4 (1.5 equiv), 1,4-dioxane (1.5 mL), 70 ºC, 24 h.
bPerformed with 0.018 mmol of Pd(dba)2 (6 mol %) and 0.027 mmol of tBuBrettPhos (9 mol %).
cPerformed with 0.006 mmol of Pd(dba)2 (2 mol %) and 0.009 mmol of tBuBrettPhos (3 mol %).
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dPerformed with 0.36 mmol of 1m, 0.3 mmol of 2a, 0.006 mmol of Pd(dba)2 (2 mol %) and
0.009 mmol of tBuBrettPhos (3 mol %).
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The 1-aryl-3-trimethylsilylpyrazole framework, formed by the C–N coupling with 2a, found to
serve as a great template for the synthesis of various N-arylpyrazole derivatives (Figure 2). First,
deprotection of the trimethylsilyl group of 3aa was readily accomplished by treatment with
ethanolic KOH solution to give 3ae in 89% yield. Regioselective introduction of halogeno
groups at all 3-, 4-, and 5-positions were also possible, because each of these positions has
mutually different character and orthogonal reactivities.15 The 3-position of 3aa has the
trimethylsilyl group and its removal under mild conditions would generate a carbanion at the 3-
position, which may react with electrophilic halogenating agents. Therefore, the reaction of 3aa
with N-chlorosuccinimide (NCS) in the presence of silver fluoride in acetonitrile provided 1-
aryl-3-chloropyrazole 4 in 86% yield. The use of 1,2-dibromotetrachloroethane (DBTCE) instead
of NCS also gave the corresponding bromination product 5 in 45% yield. The 4-position of 3aa
is the most nucleophilic, and direct reaction of N-bromosuccinimide (NBS) with 3aa, followed
by deprotection of the trimethylsilyl group led to the formation of 1-aryl-4-bromopyrazole 6 in
87% yield. The 5-position of 3aa bears the most acidic proton on the pyrazole ring. The reaction
of 3aa with n-butyllithium and then with tetrabromomethane installed a bromo group at the 5-
position, and subsequent deprotection of the trimethylsilyl group formed 1-aryl-5-bromopyrazole
7 in 45% yield (70% NMR yield).
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Figure 2. Regiodivergent derivatization of 1-aryl-3-trimethylsilylpyrazole 3aa
In summary, we developed a protocol for the C–N coupling between aryl triflates and pyrazole
derivatives using 2-6 mol % of a palladium catalyst and 3-9 mol % of tBuBrettPhos. The
reaction was applicable to various sets of substrates including sterically-congested aryl triflates
bearing ortho substituents and various reactive functional groups tolerated the reaction
conditions. The 1-aryl-3-trimethylsilylpyrazole framework, readily formed by the C–N coupling
developed here, can serve as a useful template for the synthesis of various N-arylpyrazole
derivatives, as demonstrated by regiodivergent halogenation at all 3-, 4-, and 5-positions.
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Experimental Section
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Unless otherwise noted, all reactions were carried out under nitrogen, and commercial
reagents were used as received. Pd2(dba)3 was purchased from Aldrich and used as received.
Pd(dba)2 was purchased from Tokyo Chemical Industry Co., Ltd. and used as received.
tBuBrettPhos, tBuXPhos, BrettPhos and XPhos were purchased from Aldrich and used as
received. K3PO4 was purchased from Junsei Chemical Co., Ltd. and dried by Kugelrohr prior to
use. 1,4-Dioxnae was purchased from FUJIFILM Wako Pure Chemical Corporation and used as
received. Pyrazoles 2a11, 2b16 and 2f17 were prepared according to the literature procedures.
Pyrazoles 2c and 2d were purchased from Tokyo Chemical Industry Co., Ltd. and used as
received. Pyrazole 2e was purchased from Nacalai Tesque, Inc. and used as received. Aryl
triflates 1a, 1b, 1e-1k were prepared according to the literature procedure using corresponding
phenol derivatives.18 Heteroaryl triflates 1l9b and 1m9b were prepared according to the literature
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1
13
procedures. H and C{1H} spectra were recorded on a JEOL ECX-400, AL-400, or ALPHA-
400 spectrometer. IR spectra were recorded on a JASCO FT/IR-410 infrared spectrometer. Flash
chromatography was performed using a EPCLC-AI-580S (Yamazen Corporation) with silica gel
40 μm. ESI-MS was performed on a JEOL JMS-T100LCS.
Preparation of 2,3,5-Trimethylphenyl Trifluoromethanesulfonate (1c). To a solution of 2,4,5-
trimethylphenol (2.72 g, 20.0 mmol) and 2.4 mL of pyridine in 50 mL dichloromethane at 0 ºC
was added Tf2O (6.41 g, 22.7 mmol) dropwise, and the mixture was stirred for 2 h at room
temperature. After this period, 1 M HCl aq was added to the mixture, which was then extracted
three times with dichloromethane. The combined organic layers were washed with brine, dried
over MgSO4, filtered and concentrated. Kugelrohr distillation of the crude material afforded 4.79
1
g of 1c (17.9 mmol, 90% yield) as a colorless oil; H NMR (400 MHz, CDCl3): δ 2.22 (s, 3H),
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2.28 (s, 3H), 2.31 (s, 3H), 6.90 (s, 1H), 6.99 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) : δ 12.5,
20.1, 20.8, 118.6 (q, J = 320.0 Hz), 119.1, 126.1, 130.5, 136.8, 139.4, 148.3; IR (neat): 2927 w,
2871 w, 1623 w, 1574 w, 1495 w, 1451 w, 1420 , 1281 w, 1248 s, 1213 s, 1143 s, 1040 s, 1018
w, 968 m, 917 s, 853 m, 823 s, 766 w, 748 w, 711 w, 661 w, 610 m cm-1; HRMS (ESI-TOF)
m/z: [M+Na+] Calcd for C10H11F3NaO3S+ 291.0273; Found 291.0265.
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Preparation of 4-Methyl-2-(3-methylbut-2-en-1-yl)phenol. 4-Methyl-2-(3-methylbut-2-en-1-
yl)phenol was prepared according to the literature procedure.19 To a solution of p-cresol (4.32 g,
39.9 mmol) in 80 mL Et2O was added Na (1.95 g, 84.8 mmol) portionwise, and the mixture was
stirred at room temperature for 30 min. Prenyl chloride (4.16 g, 39.8 mmol) was added to the
resulting mixture and heated to reflux for 1 h. After this period, the mixture was acidified with
0.1 N HCl aq and extracted three times with Et2O. The combined organic layers were washed
with brine, dried over MgSO4, filtered and concentrated. Purification of the crude material by
silica gel column chromatography (hexane:AcOEt = 91:9) afforded 5.88 g of 4-methyl-2-(3-
methylbut-2-en-1-yl)phenol (33.4 mmol, 84% yield) as a colorless oil. The analytical data for 4-
methyl-2-(3-methylbut-2-en-1-yl)phenol are in good agreement with those reported in
literature.20
Preparation of 4-Methyl-2-(3-methylbut-2-en-1-yl)phenyl Trifluoromethanesulfonate (1d). To
a solution of 4-methyl-2-(3-methylbut-2-en-1-yl)phenol (0.798 g, 4.53 mmol) and 0.6 mL of
pyridine in 20 mL dichloromethane at 0 ºC was added Tf2O (1.57 g, 5.56 mmol) dropwise, and
the mixture was stirred for 4.5 h at room temperature. After this period, 1 M HCl aq was added
to the mixture, which was then extracted three times with dichloromethane. The combined
organic layers were washed with brine, dried over MgSO4, filtered and concentrated.
Purification of the crude material by silica gel column chromatography (hexane:AcOEt = 98:2)
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afforded 1.32 g of 1d (4.28 mmol, 94% yield) as a colorless oil.; 1H NMR (400 MHz, CDCl3): δ
1.71 (s, 3H), 1.77 (d, J = 1.2 Hz, 3H), 2.34 (s, 3H), 3.38 (d, J = 7.1 Hz, 2H), 5.21-5.26 (m, 1H),
7.03-7.12 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) : δ 17.8, 20.9, 25.7, 28.3, 118.6 (q, J = 325
Hz), 120.5, 120.8, 128.1, 131.4, 134.0, 134.4, 138.3, 145.9; IR (neat): 3014 m, 2969 s, 2917 s,
1860 s, 1612 m, 1507 s, 1448 s, 1376 s, 1347 m, 1260 s, 1203 s, 1149 m, 1108 s, 1040 w, 985 w,
922 m, 879 m, 848 m, 811 s, 787 s, 737 w, 717 w cm-1; HRMS (ESI-TOF) m/z: [M+Na+] Calcd
for C13H15F3NaO3S+ 331.0586; Found 331.0588.
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General Procedure A for Palladium-Catalyzed Amination of Aryl Triflates with Pyrazole
Derivatives. In a glove box, Pd(dba)2, (2-6 mol %) tBuBrettPhos (3-9 mol %), K3PO4 (1.5
equiv) and 1,4-dioxane (1.5 mL) were placed in an oven-dried 10 mL Schlenk flask containing a
stirring bar. After taken out of the glove box, the mixture was heated with an oil bath whose
temperature was maintained at 120 ºC for 5 min, and then cooled to room temperature. In the
glove box, aryl triflates 1 (0.3 mmol) and pyrazole derivatives 2 (0.36 mmol) were added to the
premixed solution, and the reaxtion mixture was stirred at 70 ºC for 24 h. After this period, the
resulting mixture was diluted with dichloromethane, passed through a pad of Celite, and
concentrated in vacuo. Silica gel column chromatography of the crude material followed by
drying in vacuo afforded N-arylpyrazoles 3.
1-(4-Methylphenyl)-3-(trimethylsilyl)-1H-pyrazole (3aa). General Procedure A was followed
with 1a (72.9 mg, 0.303 mmol) and 2a (50.0 mg, 0.356 mmol). Silica gel column
chromatography (hexane:AcOEt = 96:4) afforded 68.1 mg of 3aa (0.296 mmol, 98% yield) as a
1
white solid: Mp = 32-34 ºC; H NMR (400 MHz, (CD3)2CO): δ 0.30 (s, 9H), 2.36 (s, 3H), 6.62
13
(d, J = 2.7 Hz, 1H), 7.28-7.30 (m, 2H), 7.72-7.76 (m, 2H), 8.26 (d, J = 2.4 Hz, 1H); C{1H}
NMR (100 MHz, (CD3)2CO) : δ -0.9, 20.8, 114.1, 119.6, 127.7, 130.6, 136.5, 139.1, 154.6.; IR
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(KBr): 3143 m, 3116 w, 3052 m, 2956 s, 2898 s, 1906 w, 1707 w, 1609 m, 1594 m, 1523 s, 1488
s, 1457 m, 1408 s, 1381 w, 1354 s, 1308 s, 1292 , 1248 s, 1213 m, 1192 s, 1120 m, 1110 s, 1067
m, 1039 s, 971 s, 946 m, 840 s, 813 s, 754 s cm-1; HRMS (ESI-TOF) m/z: [M+H+] Calcd for
C13H19N2Si+ 231.1312; Found 231.1310.
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3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazole (3ab). General Procedure A was followed with
1a (71.5 mg, 0.298 mmol) and 2b (43.0 mg, 0.346 mmol). Silica gel column chromatography
(hexane:AcOEt = 95:5) afforded 63.8 mg of 3ab (0.298 mmol, quant) as a white solid: Mp =
1
34.5-36 ºC; H NMR (400 MHz, (CD3)2CO): δ 1.33 (s, 9H), 2.34 (s, 3H), 6.37 (d, J = 2.4 Hz,
13
1H), 7.25-7.28 (m, 2H), 7.67-7.70 (m, 2H), 8.12 (d, J = 2.7 Hz, 1H); C{1H} NMR (100 MHz,
(CD3)2CO) : δ 20.8, 30.8, 32.9, 104.7, 118.9, 127.7, 130.6, 135.9, 139.2, 163.6; IR (KBr): 3149
m, 3128 w, 3044 m, 2959 s, 2865 s, 1902 w, 1701 w, 1608 s, 1531 s, 1483 s, 1457 s, 1391 s,
1381 s, 1365 s, 1342 m, 1317 m, 1270 s, 1206 m, 1184 m, 1171 s, 1120 m, 1110 m, 1073 m,
1046 s, 982 s, 949 s, 836 s, 812 s, 755 s, 723 m cm-1; HRMS (ESI-TOF) m/z: [M+H+] Calcd for
+
C14H19N2 215.1543; Found 215.1544.
3-Phenyl-1-(4-methylphenyl)-1H-pyrazole (3ac).21 General Procedure A was followed with 1a
(72.6 mg, 0.302 mmol) and 2c (52.1 mg, 0.361 mmol). Silica gel column chromatography
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(hexane:AcOEt = 97:3) afforded 68.3 mg of 3ac (0.292 mmol, 97% yield) as a white solid; H
NMR (400 MHz, (CD3)2CO): δ 2.38 (s, 3H), 6.94 (d, J = 2.4 Hz, 1H), 7.32-7.36 (m, 3H), 7.42-
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7.46 (m, 2H), 7.79-7.82 (m, 2H), 7.95-7.98 (m, 2H), 8.34 (d, J = 2.4 Hz, 1H); C{1H} NMR
(100 MHz, (CD3)2CO) : δ 20.8, 105.5, 119.3, 126.4, 128.7, 129.2, 129.5, 130.7, 134.3, 136.7,
139.0, 153.0.
3-Methyl-1-(4-methylphenyl)-1H-pyrazole (3ad).22 General Procedure A was followed with 1a
(72.5 mg, 0.302 mmol) and 2d (30.2 mg, 0.368 mmol). Silica gel column chromatography
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(hexane:AcOEt = 97:3) afforded 46.6 mg of 3ad (0.271 mmol, 90% yield) as a white solid; H
NMR (400 MHz, (CD3)2CO): δ 2.28 (s, 3H), 2.34 (s, 3H), 6.26 (d, J = 2.4 Hz, 1H), 7.24-7.28 (m,
2H), 7.65-7.68 (m, 2H), 8.12 (d, J = 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, (CD3)2CO) : δ 13.7,
20.8, 107.9, 118.9, 128.1, 130.6, 136.0, 139.1, 150.4.
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1-(4-Methylphenyl)-1H-pyrazole (3ae).4b General Procedure A was followed with 1a (73.0 mg,
0.304 mmol) and 2e (24.7 mg, 0.363 mmol). Silica gel column chromatography (hexane:AcOEt
1
= 96:4) afforded 40.2 mg of 3ae (0.254 mmol, 84% yield) as a pale yellow oil; H NMR (400
MHz, (CD3)2CO): δ 2.36 (s, 3H), 6.48 (dd, J = 2.5 Hz, 1.8 Hz, 1H), 7.28-7.31 (m, 2H), 7.66 (d, J
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= 1.6 Hz, 1H), 7.70-7.74 (m, 2H), 8.26 (dd, J = 2.5 Hz, 0.6 Hz, 1H); C{1H} NMR (100 MHz,
(CD3)2CO) : δ 20.8, 108.1, 119.4, 127.6, 130.7, 136.6, 139.1, 141.3.
1-(4-Methylphenyl)-4-(trimethylsilyl)-1H-pyrazole (3af). General Procedure A was followed
with 1a (72.3 mg, 0.301 mmol) and 2f (51.5 mg, 0.367 mmol). Silica gel column
chromatography (hexane:AcOEt = 97:3) afforded 47.9 mg of 3af (0.208 mmol, 69% yield) as a
1
white solid: Mp = 51-53 ºC; H NMR (400 MHz, (CD3)2CO): δ 0.26 (s, 9H), 2.36 (s, 3H), 7.29
13
(d, J = 8.2 Hz, 2H), 7.67 (s, 1H), 7.72-7.75 (m, 2H), 8.26 (s, 1H); C{1H} NMR (100 MHz,
(CD3)2CO) : δ -0.2, 20.8, 117.2, 119.5, 130.7, 132.3, 136.6, 138.9, 145.8; IR (KBr): 3112 w,
2954 s, 2897 m, 1527 s, 1424 w, 1400 m, 1359 m, 1326 m, 1299 w, 1249 s, 1214w, 1199 m,
1183 w, 1156 s, 1119 w, 1107 w, 1038 m, 986 w, 960 m, 833 s, 814 s, 753 s cm-1; HRMS (ESI-
TOF) m/z: [M+H+] Calcd for C13H19N2Si+ 231.1312; Found 231.1313.
1-(2-Methylphenyl)-3-(trimethylsilyl)-1H-pyrazole (3ba). General Procedure A was followed
with 1b (73.0 mg, 0.304 mmol) and 2a (50.6 mg, 0.361 mmol). Silica gel column
chromatography (hexane:AcOEt = 98:2 to 97:3) afforded 66.4 mg of 3ba (0.288 mmol, 95%
1
yield) as a colorless oil; H NMR (400 MHz, (CD3)2CO): δ 0.29 (s, 9H), 2.24 (s, 3H), 6.60 (d, J
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= 2.0 Hz, 1H), 7.29-7.39 (m, 4H), 7.88 (d, J = 2.4 Hz, 1H); 13C{1H} NMR (100 MHz,
(CD3)2CO) : δ -0.8, 18.4, 112.9, 126.4, 127.3, 128.8, 131.4, 132.1, 134.1, 141.2, 153.8; IR (neat):
3045 w, 2957 s, 2898 m, 1604 w, 1584 m, 1505 s, 1461 m, 1421 m, 1382 w, 1351 w, 1301 s,
1249 s, 1180 s, 1122 m, 1033 m, 971 s, 950 w, 839 s, 755 s, 716 m cm-1; HRMS (ESI-TOF) m/z:
[M+H+] Calcd for C13H19N2Si+ 231.1312; Found 231.1313.
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3-tert-Butyl-1-(2-methylphenyl)-1H-pyrazole (3bb). General Procedure A was followed with
1b (72.2 mg, 0.301 mmol) and 2b (45.0 mg, 0.362 mmol). Silica gel column chromatography
(hexane:AcOEt = 97:3 to 95:5) afforded 61.5 mg of 3bb (0.287 mmol, 95% yield) as a colorless
oil; 1H NMR (400 MHz, (CD3)2CO): δ 1.33 (s, 9H), 2.27 (s, 3H), 6.35 (d, J = 2.4 Hz, 1H), 7.29-
7.35 (m, 4H), 7.72 (d, J = 2.4 Hz, 1H); 13C{1H} NMR (100 MHz, (CD3)2CO) : δ 18.7, 30.9, 32.8,
103.3, 126.2, 127.3, 128.4, 131.5, 132.2, 133.9, 141.4, 163.0; IR (neat): 3033 w, 2960 s, 2929 s,
2902 s, 2866 m, 1606 w, 1584 m, 1524 s, 1499 s, 1480 m, 1461 s, 1393 m, 1362 s, 1263 s, 1206
m, 1166 m, 1124 w, 1068 w, 1048 s, 982 m, 951 s, 861 w, 799 w, 758 s, 718 s, 677 m, 639 w cm-
+
1; HRMS (ESI-TOF) m/z: [M+H+] Calcd for C14H19N2 215.1543; Found 215.1544.
3-Phenyl-1-(2-methylphenyl)-1H-pyrazole (3bc).23 General Procedure A was followed with 1b
(72.2 mg, 0.301 mmol) and 2c (52.2 mg, 0.362 mmol). Silica gel column chromatography
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(hexane:AcOEt = 96:4) afforded 64.8 mg of 3bc (0.277 mmol, 92% yield) as a colorless oil; H
NMR (400 MHz, (CD3)2CO): δ 2.34 (s, 3H), 6.92 (d, J = 2.4 Hz, 2H), 7.30-7.45 (m, 7H), 7.92-
13
7.95 (m, 3H); C{1H} NMR (100 MHz, (CD3)2CO) : δ 18.5, 104.3, 126.3, 126.5, 127.5, 128.5,
129.0, 129.4, 132.2, 133.2, 134.0, 134.6, 141.1, 152.7.
3-Methyl-1-(2-methylphenyl)-1H-pyrazole (3bd).22 General Procedure A was followed with 1b
(73.8 mg, 0.307 mmol) and 2d (30.3 mg, 0.369 mmol). Silica gel column chromatography
(hexane:AcOEt = 97:3) afforded 13.1 mg of 3bd (0.0761 mmol, 25% yield) as a colorless oil; 1H
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NMR (400 MHz, (CD3)2CO): δ 2.26 (s, 3H), 2.27 (s, 3H), 6.24 (d, J = 2.4 Hz, 1H), 7.27-7.36 (m,
4H), 7.72 (d, J = 2.4 Hz, 1H); 13C{1H} NMR (100 MHz, (CD3)2CO) : δ 13.7, 18.5, 106.6, 126.5,
127.3, 128.5, 132.07, 132.11, 133.9, 141.3, 149.7.
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1-(2,4,5-Trimethylphenyl)-3-(trimethylsilyl)-1H-pyrazole (3ca). General Procedure A was
followed with 1c (82.0 mg, 0.306 mmol) and 2a (51.2 mg, 0.365 mmol). Silica gel column
chromatography (hexane:AcOEt = 98:2 to 97:3) afforded 73.8 mg of 3ca (0.286 mmol, 93%
1
yield) as a colorless oil; H NMR (400 MHz, (CD3)2CO): δ 0.28 (s, 9H), 1.98 (s, 3H), 2.30 (s,
6H), 6.58 (d, J = 2.4 Hz, 1H), 6.97 (s, 1H), 7.08 (s, 1H), 7.77 (d, J = 2.0 Hz, 1H); 13C{1H} NMR
(100 MHz, (CD3)2CO) : δ -0.8, 14.1, 20.3, 20.7, 112.6, 125.2, 130.1, 131.2, 131.7, 136.1, 138.8,
141.3, 153.4; IR (neat): 2956 m, 2921 w, 2898 w, 2864 w, 1617 w, 1580 w, 1494 m, 1452 w,
1385 w, 1354 w, 1302 w, 1248 m, 1157 m, 1124 w, 1050 w, 976 w, 940 w, 842 s, 755 m, 718 w,
698 w, 632 w cm-1; HRMS (ESI-TOF) m/z: [M+H+] Calcd for C15H23N2Si+ 259.1625; Found
259.1626.
1-[4-Methyl-2-(3-methylbut-2-en-1-yl)phenyl]-3-(trimethylsilyl)-1H-pyrazole (3da). General
Procedure A was followed with 1d (95.7 mg, 0.310 mmol) and 2a (50.9 mg, 0.363 mmol). Silica
gel column chromatography (hexane:AcOEt = 97:3) afforded 84.2 mg of 3da (0.282 mmol, 91%
1
yield) as a colorless oil; H NMR (400 MHz, (CD3)2CO): δ 0.28 (s, 9H), 1.52 (s, 3H), 1.62 (d, J
= 1.2 Hz, 3H), 2.36 (s, 3H), 3.25 (d, J = 7.4 Hz, 2H), 5.08-5.13 (m, 1H), 6.58 (d, J = 2.4 Hz, 1H),
7.11-7.13 (m, 1H), 7.17-7.19 (m, 2H), 7.78 (d, J = 2.4 Hz, 1H); 13C{1H} NMR (100 MHz,
(CD3)2CO) : δ -0.8, 17.8, 21.1, 25.8, 30.7, 112.7, 123.7, 126.8, 127.9, 131.6, 131.8, 132.7, 138.0,
138.5, 138.9, 153.7; IR (neat): 3026 w, 2958 s, 2924 s, 2857 m, 1611 w, 1510 s, 1439 m, 1376 w,
1353 w, 1304 m, 1248 s, 1184 s, 1154 w, 1122 w, 1099 w, 1058 m, 1035 m, 971 s, 913 w, 843 s,
755 s cm-1; HRMS (ESI-TOF) m/z: [M+H+] Calcd for C18H27N2Si+ 299.1938; Found 299.1938.
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1-(2-Methoxyphenyl)-3-(trimethylsilyl)-1H-pyrazole (3ea). General Procedure A was followed
with 1e (76.0 mg, 0.297 mmol) and 2a (50.3 mg, 0.359 mmol). Silica gel column
chromatography (hexane:AcOEt = 97:3) afforded 72.3 mg of 3ea (0.293 mmol, 99% yield) as a
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colorless oil; H NMR (400 MHz, (CD3)2CO): δ 0.29 (s, 9H), 3.93 (s, 3H), 6.58 (d, J = 2.4 Hz,
1H), 7.05-7.10 (m, 1H), 7.22 (dd, J = 8.4 Hz, 1.4 Hz, 1H), 7.30-7.35 (m, 1H), 7.79 (dd, J = 7.8
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Hz, 1.6 Hz, 1H), 8.21 (d, J = 2.7 Hz, 1H); C{1H} NMR (100 MHz, (CD3)2CO) : δ -0.9, 56.3,
112.9, 113.4, 121.7, 125.5, 128.5, 130.7, 132.2, 151.6, 153.4; IR (neat): 2956 m, 2898 w, 2839 w,
1598 w, 1509 s, 1484 w, 1470 m, 1420 w, 1352 w, 1321 w, 1301 m, 1283 m, 1246 s, 1184 m,
1161 w, 1124 m, 1049 m, 1027 m, 970 m, 948 w, 842 s, 794 w, 753 s, 698 w, 672 w, 632 w cm-
1; HRMS (ESI-TOF) m/z: [M+Na+] Calcd for C13H18N2NaOSi+ 269.1081; Found 269.1081.
1-[2-(Trifluoromethyl)phenyl]-3-(trimethylsilyl)-1H-pyrazole (3fa). General Procedure A was
followed with 1f (89.2 mg, 0.303 mmol) and 2a (50.0 mg, 0.356 mmol). Silica gel column
chromatography (hexane:AcOEt = 96:4) afforded 69.3 mg of 3fa (0.244 mmol, 81% yield) as a
1
pale yellow oil; H NMR (400 MHz, (CD3)2CO): δ 0.29 (s, 9H), 6.63 (d, J = 2.4 Hz, 1H), 7.60-
7.62 (m, 1H), 7.68-7.73 (m, 1H), 7.80-7.85 (m, 1H), 7.90-7.93 (m, 2H); 13C{1H} NMR (100
MHz, (CD3)2CO) : δ -1.0, 113.5, 124.3 (q, J = 272.8 Hz), 126.0 (q, J = 31.3 Hz), 128.1 (q, J =
5.3 Hz), 129.5, 129.7, 132.4 (q, J = 1.9 Hz), 134.1, 140.0, 154.9; IR (neat): 2958 m, 2899 w,
1609 m, 1588 m, 1509 s, 1464 s, 1422 w, 1355 w, 1316 s, 1273 m, 1250 s, 1187, 1136 s, 1113 s,
1077 m, 1054 s, 1039 s, 970 m, 843 757 s, 700 m, 677 w, 647 w, 632 m; HRMS (ESI-TOF) m/z:
[M+H+] Calcd for C13H16F3N2Si+ 285.1029; Found 285.1030.
2-[3-(Trimethylsilyl)-1H-pyrazol-1-yl]benzonitrile (3ga). General Procedure A was followed
with 1g (76.4 mg, 0.304 mmol) and 2a (49.7 mg, 0.354 mmol). Silica gel column
chromatography (hexane:AcOEt = 95:5) afforded 68.4 mg of 3ga (0.283 mmol, 93% yield) as a
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colorless oil; 1H NMR (400 MHz, (CD3)2CO): δ 0.33 (s, 9H), 6.73 (d, J = 2.4 Hz, 1H), 7.55-7.59
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(m, 1H), 7.82-7.88 (m, 2H), 7.92-7.94 (m, 1H), 8.33 (d, J = 2.4 Hz, 1H); C{1H} NMR (100
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MHz, (CD3)2CO) : δ -1.1, 106.6, 114.7, 117.7, 124.7, 128.2, 130.4, 134.9, 135.6, 142.7, 156.4;
IR (neat): 3112 w, 2957 m, 2898 w, 1601 m, 1579 m, 507 s, 1487 m, 1461 m, 1417 w, 1318 s,
1299 m, 1250 s, 1185 m, 1164 w, 1113 w, 1067 w, 1044 m, 1023 m, 968 s, 946 w, 844 s, 758 s,
700 w, 667 m, 633 m cm-1; HRMS (ESI-TOF) m/z: [M+Na+] Calcd for C13H15N3NaSi+
264.0928; Found 264.0927.
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1-(Naphthalen-1-yl)-3-(trimethylsilyl)-1H-pyrazole (3ha). General Procedure A was followed
with 1h (81.5 mg, 0.295 mmol) and 2a (50.1 mg, 0.357 mmol). Silica gel column
chromatography (hexane:AcOEt = 96:4) afforded 69.6 mg of 3ha (0.261 mmol, 88% yield) as a
colorless oil; 1H NMR (400 MHz, (CD3)2CO): δ 0.33 (s, 9H), 6.72 (d, J = 2.0 Hz, 1H), 7.53-7.64
13
(m, 4H), 7.88-7.91 (m, 1H), 8.02-8.05 (m, 2H), 8.06 (d, J = 2.4 Hz, 1H); C{1H} NMR (100
MHz, (CD3)2CO) : δ -0.8, 113.3, 123.6, 124.4, 126.2, 127.4, 127.8, 129.0, 129.4, 129.9, 132.7,
135.4, 138.6, 154.6; IR (neat): 3055 w, 2956 m, 2897 m, 1560 w, 1577 w, 1513 m, 1491 m, 1466
w, 1428 m, 1395 m, 1301 m, 1249 s, 1196 w, 1171 w, 1120 m, 1020 w, 1003 w, 968 m, 934 w,
842 s, 800 s, 771 s, 757 s, 698 w, 663 w, 632 m cm-1; HRMS (ESI-TOF) m/z: [M+Na+] Calcd for
C16H18N2NaSi+ 289.1132; Found 289.1130.
1-(4-Chlorophenyl)-3-(trimethylsilyl)-1H-pyrazole (3ia). General Procedure A was followed
with 1i (78.3 mg, 0.300 mmol) and 2a (50.1 mg, 0.357 mmol). Silica gel column
chromatography (hexane:AcOEt = 98:2) afforded 55.7 mg of 3ia (0.222 mmol, 74% yield) as a
colorless oil; 1H NMR (400 MHz, (CD3)2CO): δ 0.30 (s, 9H), 6.66 (d, J = 2.7 Hz, 1H), 7.50-7.54
(m, 2H), 7.89-7.92 (m, 2H), 8.35 (d, J = 2.4 Hz, 1H); 13C{1H} NMR (100 MHz, (CD3)2CO): δ -
1.0, 114.7, 121.0, 128.0, 130.2, 131.7, 140.0, 155.6; IR (neat): 2957 m, 2898 w, 1598 m, 1505 s,
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1433 w, 1407 w, 1356 w, 1314 m, 303 m, 1249 s, 1220 w, 1191 s, 1095 m, 1067 w, 1036 m,
1011 w, 969 s, 947 m, 842 s, 753 s, 699 w, 633 m cm-1; HRMS (ESI-TOF) m/z: [M+H+] Calcd
for C12H16ClN2Si+ 251.0766; Found 251.0765.
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1-{4-[3-(Trimethylsilyl)-1H-pyrazol-1-yl]phenyl}ethan-1-one (3ja). General Procedure A was
followed with 1j (79.6 mg, 0.297 mmol) and 2a (51.2 mg, 0.365 mmol). Silica gel column
chromatography (hexane:AcOEt = 95:5 to 90:10) afforded 70.6 mg of 3ja (0.273 mmol, 92%
1
yield) as a colorless oil; H NMR (400 MHz, (CD3)2CO): δ 0.32 (s, 9H), 2.61 (s, 3H), 6.71 (d, J
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= 2.4 Hz, 1H), 8.01-8.04 (m, 2H), 8.10-8.14 (m, 2H), 8.47 (d, J = 2.4 Hz, 1H); C{1H} NMR
(100 MHz, (CD3)2CO) : δ -1.1, 26.6, 115.1, 119.0, 128.3, 130.7, 135.5, 144.2, 156.4, 196.7; IR
(neat): 3135 w, 3114 w, 3003 w, 297 m, 2898 w, 1683 s, 1604 s, 1519 s, 1493 w, 1435 s, 1411 s,
1360 s, 1308 s, 1266 s, 1193 s, 1177 m, 1114 w, 1065 w, 1034 m, 967 s, 944 m, 842 s, 757 s,
724 w cm-1; HRMS (ESI-TOF) m/z: [M+Na+] Calcd for C14H18N2NaOSi+ 281.1081; Found
281.1082.
1-(4-Methoxyphenyl)-3-(trimethylsilyl)-1H-pyrazole (3ka). General Procedure A was followed
with 1k (76.0 mg, 0.297 mmol) and 2a (50.0 mg, 0.356 mmol). Silica gel column
chromatography (hexane:AcOEt = 97:3) afforded 70.9 mg of 3ka (0.288 mmol, 97% yield) as a
white solid: Mp = 39-41 ºC ; 1H NMR (400 MHz, (CD3)2CO): δ 0.29 (s, 9H), 3.84 (s, 3H), 6.60
13
(d, J = 2.0 Hz, 1H), 7.02-7.06 (m, 2H), 7.74-7.78 (m, 2H), 8.20 (d, J = 2.4 Hz, 1H); C{1H}
NMR (100 MHz, (CD3)2CO) : δ -0.9, 55.8, 114.0, 115.2, 121.1, 127.7, 135.0, 154.3, 159.0; IR
(KBr): 3114 w, 3058 m, 2959 m, 2838 m, 1935 w, 1905 w, 1871 w, 1698 w, 1667 w, 1608 m,
1521 s, 1446 m, 1311 s, 1296 s, 1247 s, 1183 s, 1114 m, 1068 m, 1041 s, 971 s, 950 m, 847 s,
755 s, 696 m, 634 s cm-1; HRMS (ESI-TOF) m/z: [M+H+] Calcd for C13H19N2OSi+ 247.1261;
Found 247.1263.
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2-[3-(Trimethylsilyl)-1H-pyrazol-1-yl]pyridine (3la). General Procedure A was followed with
1l (69.4 mg, 0.306 mmol) and 2a (50.3 mg, 0.359 mmol). Silica gel column chromatography
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(hexane:AcOEt = 97:3) afforded 61.4 mg of 3la (0.282 mmol, 92% yield) as a colorless oil; H
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NMR (400 MHz, (CD3)2CO): δ 0.32 (s, 9H), 6.65 (d, J = 2.7 Hz, 1H), 7.30 (ddd, J = 7.2 Hz, 4.9
Hz, 1.2 Hz, 1H), 7.96 (ddd, J = 8.3 Hz, 7.3 Hz, 1.9 Hz, 1H), 8.06 (dt, J = 8.4 Hz, 0.9 Hz, 1H),
8.44 (ddd, J = 4.8 Hz, 1.7 Hz, 0.9 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H).; 13C{1H} NMR (100 MHz,
(CD3)2CO) : δ -1.1, 113.1, 114.3, 122.4, 127.5, 139.7, 149.1, 152.6, 156.7; IR (neat): 3065 w,
3017 w, 2957 s, 2898 w, 1614 m, 1595 s, 1578 s, 1497 s, 1471 s, 1457 s, 1410 w, 1310 s, 1249 s,
1223 w, 1197 s, 1145 m, 1099 w, 1048 s, 1035 m, 992 w, 966 s, 952 m, 842 s, 777 s, 759 s, 739
w, 717 m cm-1; HRMS (ESI-TOF) m/z: [M+H+] Calcd for C11H16N3Si+ 218.1108; Found
218.1110.
3-[3-(Trimethylsilyl)-1H-pyrazol-1-yl]pyridine (3ma). General Procedure A was followed
with 1m (81.2 mg, 0.357 mmol) and 2a (41.8 mg, 0.298 mmol). Silica gel column
chromatography (hexane:AcOEt = 92:8 to 80:20) afforded 61.4 mg of 3ma (0.282 mmol, 95%
yield) as a colorless oil; 1H NMR (400 MHz, (CD3)2CO): δ 0.32 (s, 9H), 6.71 (d, J = 2.4 Hz, 1H),
7.51 (ddd, J = 8.4 Hz, 4.7 Hz, 0.6 Hz, 1H), 8.24 (ddd, J = 8.4 Hz, 2.5 Hz, 1.6 Hz, 1H), 8.43 (d, J
= 2.4 Hz, 1H), 8.51 (dd, J = 4.7 Hz, 1.6 Hz, 1H), 9.13 (d, J = 2.4 Hz, 1H).; 13C{1H} NMR (100
MHz, (CD3)2CO) : δ -1.0, 114.9, 124.8, 126.7, 128.2, 137.5, 141.3, 148.1, 156.2; IR (neat): 3106
w, 3045 w, 2957 m, 2898 w, 1587 s, 1502 s, 1479 m, 1458 m, 1430 m, 1359 w, 1311 s, 1250 s,
1181 m, 1121 w, 1101 w, 1074 w, 1048 m, 1019 m, 969 s, 947 m, 843 s, 805 m, 755 s, 718 m,
704 s cm-1; HRMS (ESI-TOF) m/z: [M+H+] Calcd for C11H16N3Si+ 218.1108; Found 218.1108.
Deprotection of 3aa to Form 1-(4-Methylphenyl)-1H-pyrazole (3ae).4b A solution of 3aa (34.6
mg, 0.150 mmol) in 20% ethanolic KOH (1.5 mL) was refluxed for 12 h under air. After this
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period, water was added to the mixture, which was then extracted three times with AcOEt. The
combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated.
Silica gel column chromatography (hexane:AcOEt = 95:5) of the crude material afforded 21.0
mg (0.133 mmol, 89% yield) of 3ae as a pale yellow oil.
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Desilylative Chlorination to Form 3-Chloro-1-(4-methylphenyl)-1H-pyrazole (4).24 In a glove
box, 3aa (23.2 mg, 0.101 mmol), N-chlorosuccinimide (40.5 mg, 0.303 mmol), AgF (37.9 mg,
0.299 mmol), and 0.2 mL of MeCN were placed in an oven-dried sealed tube containing
magnetic stirring bar. The mixture was stirred in the dark at room temperature for 20 h. After this
period, the resulting mixture was diluted with dichloromethane, passed through a pad of Celite,
and concentrated in vacuo. Silica gel column chromatography (hexane:AcOEt = 99:1) of the
crude material afforded 16.8 mg (0.0872 mmol, 86% yield) of 4 as a white solid: Mp = 77-79
ºC ; 1H NMR (400 MHz, (CD3)2CO): δ 2.37 (s, 3H), 6.50 (d, J = 2.7 Hz, 1H), 7.32 (d, J = 7.8 Hz,
2H), 7.67 (d, J = 8.6 Hz, 2H), 8.31 (d, J = 2.7 Hz, 1H); 13C{1H} NMR (100 MHz, (CD3)2CO) : δ
20.8, 107.6, 119.3, 130.2, 130.8, 137.4, 138.4, 141.4; IR (KBr): 3164 m, 3119 m, 3049 m, 2920
m, 2855 w, 1902 w, 1720 w, 1607 m, 1518 s. 1499 s, 1431 m, 1408 s, 1369 s, 1350 s, 1278 w,
1216 m, 1200 s, 1110 m, 1046 s, 970 m, 942 s, 862 w, 817 s, 757 s cm-1; HRMS (ESI-TOF) m/z:
+
[M+H+] Calcd for C10H10ClN2 193.0527; Found 193.0527.
Desilylative Bromination to Form 3-Bromo-1-(4-methylphenyl)-1H-pyrazole (5).24 In a glove
box, 3aa (23.1 mg, 0.100 mmol), 1,2-dibromo-1,1,2,2-tetrachloroethane (163 mg, 0.501 mmol),
AgF (63.3 mg, 0.499 mmol), and 0.2 mL of MeCN were placed in an oven-dried sealed tube
containing magnetic stirring bar. The mixture was stirred in the dark at 40 ºC for 20 h. After this
period, the resulting mixture was diluted with dichloromethane, passed through a pad of Celite,
and concentrated in vacuo. Silica gel column chromatography (hexane:AcOEt = 98:2) of the
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crude material afforded 10.7 mg (0.0451 mmol, 45% yield) of 5 as a white solid: Mp = 69-71
ºC ; 1H NMR (400 MHz, (CD3)2CO): δ 2.37 (s, 3H), 6.58 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.6 Hz,
2H), 7.68 (d, J = 8.6 Hz, 2H), 8.27 (d, J = 2.7 Hz, 1H); 13C{1H} NMR (100 MHz, (CD3)2CO) : δ
20.8, 111.0, 119.3, 128.1, 130.3, 130.8, 137.5, 138.4; IR (KBr): 3154 w, 3127 w, 2919 m, 2854
w, 1610 w, 1594 w, 1524 s, 1495 m, 1407 m, 1364 s, 1342 s, 1266 w, 1214 w, 1193 m, 1119 w,
106 w, 1045 s, 956 s, 939 m, 849 w, 835 w, 809 s, 749 s cm-1; HRMS (ESI-TOF) m/z: [M+H+]
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+
Calcd for C10H10BrN2 237.0022; Found 237.0021.
4-Bromination of 3aa Followed by Deprotection to Form 4-Bromo-1-(4-methylphenyl)-1H-
pyrazole (6). In a glove box, 3aa (22.9 mg, 0.0994 mmol), N-bromosuccinimide (19.8 mg, 0.111
mmol), and 0.2 mL of MeCN were placed in an oven-dried sealed tube containing magnetic
stirring bar. The mixture was stirred at room temperature for 1 h, and the resulting mixture was
concentrated in vacuo. Then a solution of the crude material solution in 20% ethanolic KOH (1.5
mL) was refluxed for 8 h under air. After this period, water was added to the mixture, which was
then extracted three times with AcOEt. The combined organic layers were washed with brine,
dried over MgSO4, filtered and concentrated. Silica gel column chromatography (hexane:AcOEt
= 97:3) of the crude material afforded 20.6 mg (0.0869 mmol, 87% yield) of 6 as a white solid:
Mp = 88-90 ºC ; 1H NMR (400 MHz, (CD3)2CO): δ 2.37 (s, 3H), 7.32 (d, J = 8.2 Hz, 2H), 7.70-
13
7.72 (m, 3H), 8.44 (s, 1H); C{1H} NMR (100 MHz, (CD3)2CO) : δ 20.8, 95.7, 119.4, 128.3,
130.8, 137.5, 138.5, 141.7; IR (KBr): 3112 s, 3044 m, 2918 m, 1697 w, 1608 w, 1525 s, 1509 s,
1426 m, 1398 s, 1380 s, 1335 s, 1244 m, 1214 w, 1193 m, 1150 m, 1109 m, 1033 s, 950 s, 850 s,
+
816 s cm-1; HRMS (ESI-TOF) m/z: [M+H+] Calcd for C10H10BrN2 237.0022; Found 237.0024.
5-Bromination of 3aa Followed by Deprotection to Form 5-Bromo-1-(4-methylphenyl)-1H-
pyrazole (7).25 To a solution of 3aa (23.4 mg, 0.102 mmol) in 1 mL of THF at -40 ºC was added
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nBuLi in hexane (1.50 M, 0.150 mmol) dropwise and the mixture was stirred for 2 h. The
resulting mixture was then cooled to -60 ºC, and tetrabromomethane in THF solution was added
dropwise (1.00 M, 0.250 mmol) to the mixture, which was stirred for 1 h at this temperature and
for another 1 h at room temperature. After this period, water was added to the reaction mixture,
which was then extracted with three times with Et2O. The combined organic layers were washed
with brine, dried over MgSO4, filtered, concentrated and purified by silica gel column
chromatography (hexane:AcOEt = 98:2) to give a mixture of 3aa and the 5-bromination product.
To a round bottom flask charged with the obtained mixture was added KHF2 (39.8 mg, 0.510
mmol) and MeOH 4 mL, and the mixture was stirred for 3 h at 70 ºC. After this period, water
was added to the resulting mixture, which was extracted three times with AcOEt. The combined
organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Silica gel
column chromatography (hexane:AcOEt = 97:3) of the crude material afforded a mixture of 3ae
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and 7, and the NMR yield of 7 (0.0709 mmol, 70% NMR yield) was determined by H NMR
analysis. Gel permeation chromatography (GPC) of the mixture afforded 10.8 mg of pure 7
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(0.0456 mmol, 45% yield) as a pale yellow oil: H NMR (400 MHz, (CD3)2CO): δ 2.42 (s, 3H),
6.58 (d, J = 2.0 Hz, 1H), 7.35-7.37 (m, 2H), 7.42-7.45 (m, 2H), 7.68 (d, J = 2.0 Hz, 1H); 13C{1H}
NMR (100 MHz, (CD3)2CO): δ 21.1, 111.0, 113.0, 126.3, 130.3, 137.7, 139.4, 142.0; IR (neat):
3040 w, 2922 w, 2855 w, 1518 s, 1407 m, 1391 s, 1237 w, 1178 w, 1111 w, 1040 w, 1020 w,
967 m, 917 m, 872 w, 820 m, 799 w, 772 m, 711 w cm-1; HRMS (ESI-TOF) m/z: [M+H+] Calcd
+
for C10H10BrN2 237.0022; Found 237.0026.
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org.
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Copies of 1H and 13C{1H} NMR spectra (PDF)
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Corresponding Author
*E-mail: kakiuchi@chem.keio.ac.jp
ORCID
Takuya Kochi: 0000-0002-5491-0566
Fumitoshi Kakiuchi: 0000-0003-2605-4675
Notes
The authors declare no competing financial interest.
Acknowledgements
This work was supported in part by JSPS KAKENHI Grant Numbers JP17K19126,
JP16H04150 and JP15H05839 (Middle Molecular Strategy). T. K. is also grateful for support by
JSPS KAKENHI Grant Number JP16H01040 (Precisely Designed Catalysts with Customized
Scaffolding). S. O. is also grateful for support by the Research Grant of Keio Leading-edge
Laboratory of Science & Technology.
References and Notes
(1) (a) Ansari, A.; Ali, A.; Asif, M.; Shamsuzzaman. Review: Biologically Active Pyrazole
Derivatives. New. J. Chem. 2017, 41, 16-41. (b) Faria, J. V.; Vegi, P. F.; Miguita, A. G. C.; dos
Santos, M. S.; Boechat, N.; Bernardino, A. M. R. Recently Reported Biological Activities of
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Pyrazole Compounds. Bioorg. Med. Chem. 2017, 25, 5891-5903. (c) Devendar, P.; Qu, R.-Y.;
Kang, W.-M.; He, B.; Yang, G.-F. Palladium-Catalyzed Cross-Coupling Reactions: A Powerful
Tool for the Synthesis of Agrochemicals. J. Agric. Food Chem. 2018, 66, 8914-8934.
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(2) (a) Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A. From 2000 to Mid-
2010: A Fruitful Decade for the Synthesis of Pyrazoles. Chem. Rev. 2011, 111, 6984-7034.
(3) For recent examples: (a) Romero, N. A.; Margrey, K. A.; Tay, N. E.; Nicewicz, D. A. Site-
Selective Arene C–H Amination via Photoredox Catalysis. Science 2015, 349, 1326-1330. (b)
Gonda, Z.; Novák, Z. Transition-Metal-Free N-Arylation of Pyrazoles with Diaryliodinium Salts.
Chem. Eur. J. 2015, 21, 16801-16806. (c) Muzalevskiy, V. M.; Rulev, A. Y.; Romanov, A. R.;
Kondrashov, E. V.; Ushakov, I. A.; Chertkov, V. A.; Nenajdenko, V. G. Selective, Metal-Free
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