Oxone-mediated facile access to substituted pyrazoles

Article abstract of DOI:10.1016/j.tet.2015.11.035

An Oxone-mediated transition-metal-free oxidative C-N bond formation has been achieved for the regioselective synthesis of substituted pyrazoles. The reactions accompany the chelation-controlled ortho-oxidation of N-substituted aromatic ring to provide ph

Full text of DOI:10.1016/j.tet.2015.11.035

Accepted Manuscript
Oxone-mediated facile access to substituted pyrazoles
Mitsuhiro Kashiwa, Yoshiyuki Kuwata, Motohiro Sonoda, Shinji Tanimori
PII:
S0040-4020(15)30220-9
10.1016/j.tet.2015.11.035
TET 27292
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 April 2015
Revised Date: 14 November 2015
Accepted Date: 17 November 2015
Please cite this article as: Kashiwa M, Kuwata Y, Sonoda M, Tanimori S, Oxone-mediated facile access
to substituted pyrazoles, Tetrahedron (2015), doi: 10.1016/j.tet.2015.11.035.
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ACCEPTED MANUSCRIPT
Oxone-mediated facile access to substituted pyrazoles
Mitsuhiro Kashiwa, Yoshiyuki Kuwata, Motohiro Sonoda, and Shinji Tanimori*
Department of Bioscience and Informatics, Graduate School of Life and Environmental
Sciences, Osaka Prefecture University, 1-1 Gakuencho, Sakai, Osaka 599-8531, Japan
Corresponding authors. Tel.: +81 72 254 9469; fax: +81 72 254 9469; e-mail address:
tanimori@bioinfo.osakafu-u.ac.jp (S. Tanimori).
Keywords:
Oxone
Transition-metal-free
Pyrazole
Oxidative coupling
Ortho-oxidation
ABSTRACT
An Oxone-mediated transition-metal-free oxidative C−N bond formation has been
achieved for the regioselective synthesis of substituted pyrazoles. The reactions
accompany the chelation-controlled ortho-oxidation of N-substituted aromatic ring to
provide phenol derivatives in some cases. This method displays a facile access to
diverse range of substituted pyrazoles from readily accessible hydrazones.
1. Introduction
Pyrazole and its derivatives are well known to be an important structural unit for the
development of pharmaceuticals and agrochemicals.1 For instances, pyrazoles exhibit
antimicrobial, ant-inflammatory, analgesic, anticonvulsant, anticancer, and herbicidal
activities.1 To date, huge amount of synthetic methods of pyrazoles have been
documented2,3 including traditional approach based on the condensation of
1,3-dicarbonyl compounds with hydrazines and 1,3-dipolar cycloaddition of
dipolarophiles with appropriate dipoles. However, the former affords pyrazoles as
mixtures of two regioisomers when substituted hydrazines and 1,3- dicarbonyl
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substrates are used. The latter requires the unstable reagents such as diazo
compounds.
Recently, oxidative cyclization of hydrazones 1 by hypervalent iodine (III)4a or
DDQ4b to provide substituted pyrazoles 2 have been published (eq 1). This
transformation was also achieved by transition-metal-catalyzed aerobic oxidation.3j,3u,3n
More recently, I2 mediated one-pot transformations from α,β- unsaturated
aldehydes/ketones and hydrazines have also been accomplished.5 However, there are
still limitations associated with these methods, such as limited substrate scope, harsh
reaction conditions, and unsatisfactory overall yields. Thus, more general and
practical protocols for the synthesis of pyrazole and derivatives are still desirable.
Previously, we have developed iodobenzene-catalyzed oxidative C–H amination for the
construction of 1H-indazole core from arylhydrazones by using Oxone
(2KHSO ·KHSO ·K SO ) as a terminal oxidant under mild reaction conditions.6 As
5
4
2
4
a part of our continuing research on the oxidative C−N bond formation to access useful
heterocycles, herein, we report a practical and regioselective synthesis of pyrazole via
the oxidative annulation of allylidene- and butenylidenehydrazones under the presence
of Oxone7 as an single reagent without the use of iodine source (eq 2).
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2. Results and discussion
The reaction
conditions
were
evaluated
by
using
(E)-1-phenyl-2-((E)-3-phenylallylidene)hydrazone 1a as a model substrate (Table 1).
At first we applied the conditions previously utilized for the synthesis of 1H-indazoles.6
Reaction of 1a in the presence of iodobenzene (30mol%) and Oxone (1.5 equiv.) in
trifluoroacetic acid (TFA) at -10 oC for 30 min afforded the desired pyrazole 2a in 75%
yield (Table 1, run 1). To our surprise, reaction of 1a without iodobenzene under
otherwise same conditions also afforded pyrazole 2a in 54% yield along with phenol 3a
(24%) (run 2). The formation of phenol 3a has been reduced when the same reaction
o
was performed at 0 C to provide 78% yield of pyrazole 2a and still 12% of phenol 3a
(run 3). Further lowering the temperature resulted in the remarkable decrease of
reactivity (run 4). Less effective results have been observed when 1.0 and 2.0
equivalent of Oxone was introduced (runs 5 and 6). Interestingly, phenol 3a was
formed as a major product with the use of 30% H2O2 aq. instead of Oxone to afford
pyrazole 2a (16%) and phenol 3a (56%), respectively (run 7). The use of other
oxidants (mCPBA, K2S2O8, and TBHP) displayed the unsatisfactory transformations
(runs 8-10). In addition, another solvents instead of TFA were found to be less
effective (runs 11-15) to afford pyrazole 2a as a sole product, which indicate the
participation of TFA and/or trifluoroperacetic acid derived from TFA with Oxone for
the formation of phenol 3a (vide infra). The present method without the use of
iodobenzene would be more practical because it can avoid the tedious chromatographic
separation to remove organics derived from iodobenzene. The separation of phenol
derivative was easy by extractive work-up and/or chromatography.
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Table 1
Evaluation of the reaction conditions for the synthesis of pyrazolesa
Run Oxidant (equiv) Additive (equiv) Solvent
Temp (°C) Time (h) Yield 2a (%)b
Yield 3a (%)b
1
2
3
4
5
6
7
Oxone (1.5)
Oxone (1.5)
Oxone (1.5)
Oxone (1.5)
Oxone (1.0)
Oxone (2.0)
PhI (0.1)
TFA
TFA
TFA
TFA
TFA
TFA
TFA
-10
RT
0
0.5
0.5
2
75
54
78
54
50
53
16
0
-
-
-
-
-
-
24
12
16
9
-10
0
5
2
0
2
11
55
30% H2O2 aq.
(1.5)
RT
0.5
8
mCPBA (1.5)
-
-
-
TFA
TFA
TFA
RT
RT
RT
0.5
0.5
0.5
23
5
0
0
9
K2S2O8 (1.5)
trace
0
10
70% TBHP aq.
(1.5)
11
12
13
14
15
Oxone (1.5)
Oxone (1.5)
Oxone (1.5)
Oxone (1.5)
Oxone (1.5)
TsOH (1.5)
TsOH (1.5)
TsOH (1.5)
TsOH (1.5)
TFA (1.5)
CHCl3
EtOH
PhMe
MeCN
MeCN
RT
RT
RT
RT
RT
6
28
25
22
27
31
0
0
0
0
0
24
24
3
3
TFA=trifluoroacetic acid, TBHP=tert-butylhydroperoxide, Oxone=2KHSO5・KHSO4・
K2SO4.
a Reaction Conditions: Substrate 1a, oxidant (1.5 equiv.), in TFA (0.33 M).
b Isolated yield.
Another hydrazones (1b-1s)8 were examined for the cyclization reaction under the
conditions (Table 1, run 3). Substrates with electron-donating group on the
N-substituted aromatic ring provided moderate yields of expected pyrazoles (2b, 2c, and
2d) along with phenols (3b, 3c, and its regioisomer 3’c). The preferential formation of
phenol 3’c in the transformation of hydrazine 1c would be attributed to the steric and
electronic effects (para-position of electron-donating group). Phenol product was not
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observed when hydrazine 1d with ortho-substituent was employed to afford pyrazole 2d
in moderate yield, probably due to the steric congestion. Better yields were observed
when substrates with electron-deficient benzene ring (1e and 1f) were applied.
Interestingly, exclusive formation of pyrazole 2f was observed with excellent yield
(83%) when 2-fluorophenylhydrazone 1f was applied. Hydrazone 1g derived from
tert-butylhydrazine also afforded a corresponding pyrazole 2g in moderate yield.
Pyrazoles with substituted aromatic ring at the 5-position were also formed smoothly in
moderate to good yields (51-82%) still as a mixture of pyrazoles (2h, 2i, and 2j) and
phenols (3h, 3i, and 3j) except for nitro- and fluoro-substituted substrates (1k and 1l).
In the case of hydrazine 1k, the oxidation would be inhibited by the strong inducting
effect of electron-withdrawing nitro group, which would lower the electron density of
N-phenyl group, to afford 2k, exclusively. Moreover, butenylidenehydrazones (1m,
1n, 1o, 1p, and 1q) were tested to provide corresponding 1,3,5-trisubstituted pyrazoles
(2p and 2q) and phenols (3m, 3n, 3o, 3p, and 3q) in good yields. Intriguingly,
substrates with N-phenyl group (1m, 1n, and 1o) gave phenols as a sole product (3m,
3n, and 3o), while the other substrates with substituted N-aromatics (1p and 1q) were
transferred to the mixtures of pyrazoles and phenols (2p+3p and 2q+3q). It is
assumed that the oxidations of N-substituted aryl group would be easier in the case of
1m-1q due to the additional substitution of methyl group which would enhance the
electron density of aromatic ring by its electron-donating nature. Therefore, rich
amount of phenol products (3m, 3n, 3o, 3p, and 3q) have been produced. In all cases,
mixtures of two classes of compounds (pyrazole 2 and phenol 3) were separated easily
through the work-up process and/or silica gel column chromatography.
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Table 2
The reaction substrate scope of di- and tri-substituted pyrazolesa
a Reaction Conditions: Substrate 1, Oxone (1.5 equiv.), at 0 oC in TFA (0.33 M).
b Reaction at room temperature for 0.5 h.
c The ratios were determined by 1H-NMR.
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To examine the reaction pathway for the formation of pyrazole and phenol, the
reaction of benzylideneacetone and 4-chlorophenylhydrazine hydrochloride in ethanol
without oxidant was conducted to afford 4,5-dihydro-1H-pyrazole 4 in 90% yield,9
which was subjected to the condition to provide pyrazole 2q as a sole product (Scheme
1, eq. 1). Furthermore, isolated pyrazole 2q did not transform to phenol 3q under the
conditions. While hydrazone 1q gave pyrazole 2q and phenol 3q in 58% yield in a
ratio of 56:44 (Table 2). On the other hand, the same results was observed when in
situ generated trifluoroperacetic acid derived from trifluoroacetic anhydride with
hydrogen peroxide10 was applied to the reaction to form pyrazole 2q and phenol 3q in
47 and 28% yield, respectively (Scheme 1, eq. 2), which is close results obtained in
Table 2. These results suggested that oxidation of ortho-position of nitrogen-substituted
aromatic ring could occur prior cyclization and also triflioroperacetic acid would
participate the transformation.
Scheme 1. Examination of the reaction pathway.
Considering the phenomenon, a possible reaction pathway for the formation of
pyrazole 2 and phenol 3 has been illustrated in Scheme 2. Ortho-oxidation of
hydrazine 1 would afford intermediate phenol 5 with the aid of trifluoroperacetic acid
derived from triflioroacetic acid and Oxone.9 While the reaction of Oxone and
trifluoroacetic acid should form complex 6 which would suffer from nucleophilic attack
by nitrogen atom of hydrazine to produce trifluoroacetoxyhydrazone 7 which would
cyclize to give phenol 3 after deprotonation.11 Pyrazole 2 would form directly by
skipping the ortho-oxidation step.
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Scheme 2. Proposed reaction mechanism.
3. Conclusions
In conclusion, we have discovered the first simple and divergent synthesis of
pyrazoles and phenols by employing an inexpensive and environmentally benign Oxone
as a single oxidant in moderate to excellent yields. A range of functional groups has
been tolerated through this transformation. Diverse range of di- and tri-substituted
pyrazole derivatives along with phenol compounds has been synthesized from readily
accessible starting materials by simple operations. The present method would
effectively complement the previous synthesis and serve as combinatorial synthesis of
diverse pyrazole scaffolds and drug discovery.
4. Experimental section
4.1. General
Unless stated otherwise, reactions were monitored by thin layer chromatography
(TLC) on silica gel plates (60 F254), visualizing with ultraviolet light or iodine spray.
Column chromatography was performed on silica gel (60–120 mesh) using hexane and
1
ethyl acetate. H and 13 C NMR spectra were determined in CDCl3 solution using 400
and 100 MHz spectrometers, respectively. Proton chemical shifts (δ) are relative to
tetramethylsilane (TMS, d = 0.0) as the internal standard and expressed in parts per
million. Spin multiplicities are given as s (singlet), d (doublet), t (triplet), and m
(multiplet) as well as b (broad). Coupling constants (J) are given in hertz. Infrared
spectra were recorded on a FT-IR spectrometer. Melting points were determined by
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using a Büchi melting point B-540 apparatus and are uncorrected. MS spectra were
obtained on a mass spectrometer. HR-MS was determined using JEOL JNM-AX 500
mass spectrometer.
4.2. General procedures for the synthesis of pyrazoles and phenols
4.2.1. Condition A. Oxone (0.75 mmol, 1.5 equiv) was added to a stirred solution of
hydrazine 1 (0.5 mmol, 1.0 equiv) in TFA (1.5 mL) at 0 ºC, and the mixture was stirred
for 2 h at the same temperature. The reaction mixture was quenched with water (5
mL) and diluted with CHCl3 (5 mL), and extracted with CHCl3 (3 x 15 mL). The
organic layers were washed with water (3 x 15 mL), dried over Na2SO4 and the solvent
was evaporated in vacuo.
The residue was purified by silica gel column
chromatography to afford pure substituted pyrazoles 2 and/or 3.
4.2.2. Condition B. Oxone (0.75 mmol, 1.5 equiv) was added to a solution of hydrazine
1 (0.5 mmol, 1.0 equiv) in TFA (1.5 mL) to stir for 30 min at ambient temperature.
The reaction mixture was quenched with water (5 mL) and diluted with CHCl3 (5 mL),
and extracted with CHCl3 (3 x 15 mL). The organic layers were washed with water (3
x 15 mL), dried over Na2SO4 and the solvent was removed in vacuo. The residue was
purified by silica gel column chromatography to afford pure substituted pyrazoles 2
and/or 3.
If it is required for further purification, the residue was added 1N NaOH aq. (15 mL),
and extracted with Et2O (3 x 15 mL). The organic layers were washed with 1N citric
acid aq. (15 mL) and brine (15 mL). Drying over Na2SO4 followed by evaporation of
the solvent afforded almost pure pyrazoles 2. The aqueous layer was treated with 1N
citric acid aq. (20 mL) to acidify, and extracted with Et2O (3 x 20 mL) and the layers
were washed with sat. NaHCO3 aq. (20 mL) and brine (20 mL). Drying over Na2SO4
followed by evaporation of the solvent gave almost pure phenols 3.
4.2.3. 1,5-Diphenylpyrazole (2a)5. Following the condition A. Pale yellow oil; yield
78%; Rf 0.50 (hexane : AcOEt = 4 : 1); 1H NMR (400 MHz, CDCl3) δ = 7.72 (d, J = 1.7
Hz, 1H), 7.38–7.26 (m, 8H), 7.26–7.19 (m, 2H), 6.51 (d, J = 1.7 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ = 143.0, 140.3, 140.1, 130.6, 128.9 (2C), 128.7 (2C), 128.4
(2C), 128.2 (2C), 127.4, 125.2, 107.8 ppm.
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4.2.4. 2-(5-Phenylpyrazol-1-yl)phenol (3a). Following the condition A. Pale yellow oil;
yield 12%; Rf 0.39 (hexane : AcOEt = 4 : 1); 1H NMR (400 MHz, CDCl3) δ = 7.79 (d, J
= 2.0 Hz, 1H), 7.42–7.33 (m, 3H), 7.33–7.27 (m, 2H), 7.20–7.09 (m, 2H), 6.75–6.67 (m,
1H), 6.67–6.58 (m, 1H), 6.53 (d, J = 2.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ =
150.4, 143.6, 140.0, 130.1, 128.8 (2C), 128.6, 128.5, 128.3, 125.3 (2C), 124.4, 119.0,
+
118.4, 108.1 ppm; HRMS (FAB) calcd for C15H13N2O: 237.1024, [M+H] found:
237.1027.
4.2.5. 1-(4-Tolyl)-5-phenylpyrazole (2b)5. Following the condition A. Yellow oil; yield
45%; Rf 0.50 (hexane : AcOEt = 4 : 1); 1H NMR (400 MHz, CDCl3) δ = 7.70 (d, J = 1.5
Hz, 1H), 7.34–7.27 (m, 3H), 7.27–7.20 (m, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.12 (d, J =
8.3 Hz, 2H), 6.49 (d, J = 1.5 Hz, 1H), 2.35 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
= 142.8, 140.0, 137.7, 137.3, 130.7, 129.4 (2C), 128.7 (2C), 128.4 (2C), 128.1, 125.0
(2C), 107.6, 21.1 ppm.
4.2.6. 5-Methyl-2-(5-phenylpyrazol-1-yl)pyrazole (3b). Following the condition A.
1
White solid; yield 22%; Rf 0.41 (hexane : AcOEt = 4 : 1); mp 119–121 ºC; H NMR
(400 MHz, CDCl3) δ = 7.76 (d, J = 1.2 Hz, 1H), 7.40–7.26 (m, 5H), 6.95 (s, 1H), 6.56
(d, J = 8.0 Hz, 1H), 6.50 (d, J = 1.2 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 2.29 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ = 150.2, 143.5, 139.9, 138.7, 130.3, 128.9 (2C), 128.64
(2C), 128.58, 124.1, 123.0, 119.9, 118.8, 108.0, 21.1 ppm; HRMS (FAB): m/z [M+H]+
calcd for C16H15ON2: 251.1185; found: 251.1157.
4.2.7. 5-Phenyl-1-(4-tolyl)pyrazole (2c). Following the condition A. Yellow oil; yield
12%; Rf 0.32 (hexane : AcOEt = 9 : 1); 1H NMR (400 MHz, CDCl3) δ = 7.71 (d, J = 1.7
Hz, 1H), 7.37–7.27 (m, 3H), 7.27–7.21 (m, 3H), 7.17 (t, J = 7.6 Hz, 1H), 7.10 (d, J =
13
7.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.50 (d, J = 1.7 Hz, 1H), 2.32 (s, 3H) ppm; C
NMR (100 MHz, CDCl3) δ = 142.9, 140.1, 140.0, 139.0, 130.6, 128.7 (2C), 128.5,
128.4 (2C), 128.2, 128.1, 125.8, 122.3, 107.7, 21.3 ppm; IR (NaCl) ν 3445, 3057, 1605,
1493, 760, 694 cm-1; HRMS (FAB): m/z [M+H]+ calcd for C16H15N2: 235.1236; found:
235.1292.
4.2.8. 2-Methyl-6-(5-phenylpyrazol-1-yl)phenol (3c). Following the condition A.
Yellow oil; yield 10%; Rf 0.44 (hexane : AcOEt = 9 : 1); 1H NMR (400 MHz, CDCl3) δ
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= 9.17 (s, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.48–7.31 (m, 3H), 7.31–7.22 (m, 2H), 7.02 (d,
J = 8.3 Hz, 2H), 6.95 (d, J = 8.3 Hz, 1H), 6.52 (d, J = 1.5 Hz, 1H), 6.48 (s, 1H), 2.00 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 148.2, 143.6, 140.0, 130.2, 128.9, 128.8
(2C), 128.6, 128.5 (2C), 127.4, 125.0, 124.9, 118.0, 108.0, 20.3 ppm; IR (NaCl) ν 3058,
2931, 1731, 1604, 1485, 1245, 767, 694 cm-1; HRMS (FAB): m/z [M+H]+ calcd for
C16H15ON2: 251.1184; found: 251.1182.
4.2.9. 4-Methyl-2-(5-phenylpyrazol-1-yl)phenol (3’c). Followed the condition A.
1
Yellow solid; yield 19%; Rf 0.21 (hexane : AcOEt = 9 : 1); mp 108–110 ºC; H NMR
(400 MHz, CDCl3) δ = 9.45 (s, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.40–7.30 (m, 3H), 7.30–
7.22 (m, 2H), 7.03 (t, J = 4.4 Hz, 1H), 6.58–6.44 (m, 3H), 2.35 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ = 148.7, 143.8, 140.0, 130.2, 129.6, 128.9 (2C), 128.6, 128.5 (2C),
127.7, 124.9, 122.3, 118.4, 108.1, 16.2 ppm; HRMS (FAB): m/z [M+H]+ calcd for
C16H15ON2: 251.1184; found: 251.1186.
4.2.10. 1-(2-Methoxyphenyl)-5-phenylpyrazole (2d): Following the condition A.
Yellow oil; yield 34%; Rf 0.23 (hexane : AcOEt = 4 : 1); 1H NMR (400 MHz, CDCl3) δ
= 7.74 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 7.6, 1.5 Hz, 1H), 7.34 (dt, J = 8.3, 1.5 Hz, 1H),
7.28–7.15 (m, 5H), 7.01 (t, J = 7.6 Hz, 1H) 6.87 (d, J = 8.3 Hz, 1H), 6.52 (d, J = 2.0 Hz,
13
1H), 3.45 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ = 154.1, 144.7, 140.2, 131.0,
129.9, 129.4, 128.8, 128.1 (2C), 127.8, 127.5, 120.8 (2C), 112.1, 105.9, 55.3 ppm; IR
(KBr) ν 3068, 2937, 1711, 1600, 1508, 1278, 1025, 759, 695 cm-1;HRMS (FAB): m/z
[M+H]+ calcd for C16H15ON2: 251.1184; found: 251.1205.
4.2.11. 1-(3-Fluorophenyl)-5-phenylpyrazole (2e): Following the condition A. Yellow
oil; yield 37%; Rf 0.50 (hexane : AcOEt = 4 : 1); 1H NMR (400 MHz, CDCl3) δ = 7.73
(d, J = 1.7 Hz, 1H), 7.38–7.30 (m, 3H), 7.30–7.18 (m, 3H), 7.09 (dd, J = 9.8, 4.4 Hz,
1H), 7.05 (d, J = 8.3 Hz, 1H), 7.00 (dt, J = 8.3, 2.4 Hz, 1H), 6.51 (d, J = 1.7 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ = 162.5 (d, 1JCF = 246.2 Hz), 143.1, 141.3, 140.7,
130.2, 130.0 (d, 3JCF = 9.0 Hz), 128.7 (2C), 128.6 (2C), 128.5, 120.6 (d, 4JCF = 3.3 Hz),
114.3 (d, 2JCF = 20.6 Hz), 112.5 (d, 2JCF = 23.8 Hz), 108.3 ppm; IR (NaCl) ν 3071, 1737,
1606, 1494, 1194, 761, 691 cm-1; HRMS (FAB): m/z [M+H]+ calcd for C15H12N2F:
239.0985; found: 239.1014.
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4.2.12. 4-Fluoro-2-(5-phenylpyrazol-1-yl)phenol (3e): Following the condition A.
1
Yellow solid; yield 32%; Rf 0.46 (hexane : AcOEt = 4 : 1); mp 120–122 ºC; H NMR
(400 MHz, CDCl3) δ = 9.47 (s, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.50–7.34 (m, 3H), 7.34–
7.21 (m, 2H), 7.07 (dd, J = 9.3, 5.4 Hz, 1H), 6.87 (dt, J = 7.8, 2.9 Hz, 1H), 6.53 (d, J =
1.7 Hz, 1H), 6.41 (dd, J = 9.3, 2.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ = 154.9
(d, 1JCF = 255.2 Hz), 153.8, 146.7, 143.9, 140.3, 129.7, 129.1, 128.8 (4C), 119.1 (d, 3JCF
= 9.1 Hz), 114.9 (d, 2JCF = 23.0 Hz), 111.1 (d, 2JCF = 26.3 Hz), 108.5 ppm; FT-IR: 3087,
1613, 1451, 1269, 1175, 975, 925, 863, 783, 690 cm-1; HRMS (FAB): m/z [M+H]+
calcd for C15H12ON2F: 255.0934, found: 255.0887.
4.2.13. 1-(2-Fluorophenyl)-5-phenylpyrazole (2f): Following the condition A. Yellow
solid; yield 83%; Rf 0.50 (hexane : AcOEt = 4 : 1); mp 77–78 ºC; 1H NMR (400 MHz,
CDCl3) δ = 7.77 (d, J = 1.5 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.35 (q, J = 6.3 Hz, 1H),
13
7.31–7.12 (m, 6H), 7.08 (t, J = 9.1 Hz, 1H), 6.55 (d, J = 1.5 Hz, 1H) ppm; C NMR
(100 MHz, CDCl3) δ = 156.6 (d, 1JCF = 251.1 Hz), 144.8, 141.0, 130.1 (d, 3JCF = 8.2 Hz,
2C), 128.9, 128.4 (2C), 128.3 (2C), 127.8 (2C), 124.6 (d, 4JCF = 3.3 Hz), 116.6 (d, 2JCF
= 19.7 Hz), 106.7 ppm; HRMS (FAB): m/z [M+H]+ calcd for C15H12N2F: 239.0985;
found: 239.0923.
4.2.14. 1-tert-Butyl-5-phenylpyrazole (2g): Following the condition A. White solid;
1
yield 52%; Rf 0.61 (hexane : AcOEt = 4 : 1); mp 97–99 ºC; H NMR (400 MHz,
CDCl3) δ = 7.47 (d, J = 1.7 Hz, 1H), 7.42–7.30 (m, 5H), 6.14 (d, J = 1.7 Hz, 1H), 6.14
13
(s, 9H) ppm; C NMR (100 MHz, CDCl3) δ = 142.6, 136.3, 134.3, 130.4 (2C), 128.3,
127.7 (2C), 109.2, 61.0, 31.1 (3C) ppm; IR (KBr) ν 3052, 2991, 2937, 1652, 1448, 1369,
1347, 771, 709 cm-1; HRMS (FAB): m/z [M+H]+ calcd for C13H17N2: 201.1392, found:
201.1353.
4.2.15. 5-(4-Methoxyphenyl)-1-phenylpyrazole (2h)12: Following the condition A.
Yellow oil; yield 49%; Rf 0.32 (hexane : AcOEt = 4 : 1); 1H NMR (400 MHz, CDCl3) δ
= 7.70 (d, J = 1.8 Hz, 1H), 7.39–7.24 (m, 5H), 7.15 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8
13
Hz, 2H), 6.45 (d, J = 1.8 Hz, 1H), 3.79 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ =
159.5, 142.8, 140.2 (2C), 130.0 (2C), 128.8 (2C), 127.3, 125.2 (2C), 113.9, 197.3, 55.2
ppm.
12

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4.2.16. 2-[5-(4-Methoxyphenyl)pyrazol-1-yl]phenol (3h): Following the condition A.
1
White solid; yield 23%; Rf 0.27 (hexane : AcOEt = 4 : 1); mp 163–164 ºC; H NMR
(400 MHz, CDCl3) δ = 9.50 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H),
7.17–7.04 (m, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.0 Hz, 1H), 6.64 (dt, J = 7.0,
2.4 Hz, 1H), 6.47 (d, J = 1.7 Hz, 1H), 3.82 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
= 159.9, 150.6, 143.5, 140.0, 130.2 (2C), 128.3, 125.4, 124.4, 122.4, 119.1, 118.5, 114.0
(2C), 107.7, 55.3 ppm; HRMS (FAB): m/z [M+H]+ calcd for C16H15O2N2: 267.1133,
found: 267.1062.
4.2.17. 5-(4-Dimethylaminophenyl)-1-phenylpyrazole (2i): Following the condition A.
Yellow oil; yield 32%; Rf 0.31 (hexane : AcOEt = 4 : 1); 1H NMR (400 MHz, CDCl3) δ
= 7.69 (d, J = 1.8 Hz, 1H), 7.41–7.22 (m, 5H), 7.08 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4
13
Hz, 2H), 6.42 (d, J = 1.8 Hz, 1H), 2.95 (s, 6H) ppm; C NMR (100 MHz, CDCl3) δ =
150.0, 143.5, 140.4, 140.1, 129.5 (2C), 128.8 (2C), 127.1, 125.2 (2C), 111.8, 106.6,
104.1, 40.2 ppm; HRMS (FAB): m/z [M+H]+ calcd for C17H18N3: 264.1500, found:
264.1566.
4.2.18. 2-[5-(4-Dimethylaminophenyl) pyrazol-1-yl]phenol (3i): Following the
condition A. Yellow oil; yield 22%; Rf 0.31 (hexane : AcOEt = 4 : 1); 1H NMR (400
MHz, CDCl3) δ = 7.74 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 9.0 Hz, 2H), 7.20–7.00 (m, 2H),
6.83 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 9.0 Hz, 2H), 6.67–6.52 (m, 1H), 6.43 (d, J = 2.0
Hz, 1H), 2.98 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ = 150.6, 150.3, 144.3, 139.9,
129.7 (2C), 128.1, 125.8, 124.5, 119.1, 118.3, 117.4, 111.8 (2C), 107.1, 40.2 ppm;
HRMS (FAB): m/z [M]+ calcd for C17H17ON3: 279.1371, found: 279.1360.
4.2.19. 5-(4-Fluorophenyl)-1-phenylpyrazole (2j): Following the condition A. Yellow
oil; yield 62%; Rf 0.38 (hexane : AcOEt = 4 : 1); 1H NMR (400 MHz, CDCl3) δ = 7.72
(d, J = 1.7 Hz, 1H), 7.40–7.24 (m, 5H), 7.21 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.5 Hz,
1H), 7.01 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.49 (d, J = 1.7 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ = 162.5 (d, 1JCF = 247.8 Hz), 141.9, 140.3, 139.9, 130.5
(d, 3JCF = 8.3 Hz, 2C), 128.9 (2C), 127.5, 126.7 (d, 4JCF = 3.3 Hz), 125.2, 115.6 (d, 2JCF
= 21.4 Hz, 2C), 107.8 ppm; HRMS (FAB): [M+H]+ calcd. for C15H12N2F: 239.0985,
found: 239.0989.
13

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4.2.20. 2-[5-(4-Fluorophenyl)pyrazol-1-yl]phenol (3j): Following the condition A.
1
White solid; yield 17%; Rf 0.26 (hexane : AcOEt = 4 : 1); mp 184–186 ºC; H NMR
(400 MHz, CDCl3) δ = 9.39 (s, 1H), 7.78 (s, 1H), 7.45–7.21 (m, 2H), 7.21–7.10 (m, 2H),
7.10–6.90 (m, 2H), 6.79–6.57 (m, 2H), 6.51 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ = 162.8 (d, 1JCF = 247.8 Hz), 150.6, 142.6, 140.1, 130.7 (d, 3JCF = 8.2 Hz, 2C), 128.6,
4
2
126.2 (d, JCF = 3.3 Hz), 125.2, 124.4, 119.2, 118.6, 115.8 (d, JCF = 21.5 Hz, 2C),
108.2 ppm; HRMS (FAB): [M+H]+ calcd. for C15H12ON2F: 255.0934, found: 255.0870.
4.2.21. 5-(2-Nitrophenyl)-1-phenylpyrazole (2k)13: Following the condition A. Orange
solid; yield 51%; Rf 0.22 (hexane : toluene = 1 : 1); mp 113–115 ºC (lit.11 120–122 ºC);
1H NMR (400 MHz, CDCl3) δ = 7.90 (dd, J = 8.0, 1.2 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H),
7.61 (dt, J = 7.6, 1.5 Hz, 1H), 7.72 (dt, J = 8.0, 1.2 Hz, 1H), 7.72 (dd, J = 7.6, 1.5 Hz,
1H), 7.34–7.16 (m, 5H), 6.48 (d, J = 1.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ =
140.4, 139.2, 137.9, 132.9, 132.6, 129.8, 129.0 (2C), 127.6, 125.9, 125.2, 124.53,
124.45 (2C), 108.4 ppm.
4.2.22. 1-(2-Fluorophenyl)-5-(4-methoxyphenyl)pyrazole (2l): Following the condition
1
A. Yellow solid; yield 82%; Rf 0.25 (hexane : AcOEt = 4 : 1); mp 123–125 ºC; H
NMR (400 MHz, CDCl3) δ = 7.75 (d, J = 1.7 Hz, 1H), 7.45 (dt, J = 7.6, 1.7 Hz, 1H),
7.40–7.29 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.15–7.01 (m, 1H), 7.14 (d, J = 9.0 Hz, 2H),
13
6.80 (d, J = 9.0 Hz, 2H), 6.48 (d, J = 1.7 Hz, 1H), 3.78 (s, 3H) ppm; C NMR (100
1
3
MHz, CDCl3) δ = 159.5, 156.6 (d, JCF = 251.1 Hz), 144.6, 141.0, 130.0 (d, JCF = 7.5
Hz), 129.1 (2C), 129.0, 128.4 (d, 3JCF = 11.5 Hz), 124.5 (d, 4JCF = 4.2 Hz), 122.6, 116.7
2
(d, JCF = 19.8 Hz), 113.8 (2C), 106.2, 55.2 ppm; HRMS (FAB): [M]+ calcd. for
C16H13ON2F: 268.1012, found: 268.0969.
4.2.23. 2-(3-Methyl-5-phenylpyrazol-1-yl)phenol (3m): Following the condition B.
1
Yellow solid; yield 69%; Rf 0.47 (hexane : AcOEt = 4 : 1); mp 135–136 ºC; H NMR
(400 MHz, CDCl3) δ = 9.73 (s, 1H), 7.38–7.31 (m, 3H), 7.30–7.23 (m, 2H), 7.11 (d, J =
13
3.9 Hz, 1H), 6.68–6.55 (m, 2H), 6.30 (s, 1H), 2.39 (s, 3H) ppm; C NMR (100 MHz,
CDCl3) δ = 150.4, 149.6, 144.3, 130.3, 128.8 (2C), 128.61 (2C), 128.57, 127.9, 125.4,
14

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124.1, 119.0, 118.3, 180.1, 13.5 ppm; HRMS (FAB): m/z [M+H]+ calcd for C16H15ON2:
251.1184, found: 251.1188.
4.2.24. 2-(3-Methyl-5-p-tolylpyrazol-1-yl)phenol (3n): Following the condition B.
1
White solid; yield 64%; Rf 0.46 (hexane : AcOEt = 4 : 1); mp 177–179 ºC; H NMR
(400 MHz, CDCl3) δ = 9.75 (s, 1H), 7.35–7.24 (m, 1H), 7.22–7.05 (m, 5H), 6.67 (d, J =
7.8 Hz, 1H), 6.64–6.53 (m, 1H), 6.27 (s, 1H), 2.38 (s, 3H), 2.36 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ = 150.4, 149.5, 144.4, 138.6, 129.3 (2C), 128.6 (2C), 127.8, 127.4,
125.5, 124.1, 119.0, 118.3, 107.9, 21.3, 13.5 ppm; HRMS (FAB): m/z [M+H]+ calcd for
C17H17ON2: 265.1340, found: 265.1343.
4.2.25. 2-[5-(4-Chlorophenyl)-3-Methylpyrazol-1-yl]phenol (3o): Following the
condition B. Yellow solid; yield 62%; Rf 0.38 (hexane : AcOEt = 4 : 1); mp 214–216
ºC; 1H NMR (400 MHz, CDCl3) δ = 9.57 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.21 (d, J =
8.4 Hz, 1H), 7.17–7.08 (m, 2H), 6.63 (d, J = 2.9 Hz, 2H), 6.30 (s, 1H), 2.39 (s, 3H)
13
ppm; C NMR (100 MHz, CDCl3) δ = 150.4, 149.8, 143.0, 134.7, 130.0 (2C), 128.9
(2C), 128.8, 128.2, 125.2, 124.1, 119.2, 118.5, 108.2, 13.5 ppm; HRMS (FAB): m/z
[M]+ calcd for C16H13ON2Cl: 284.0717, found: 284.0707.
4.2.26. 3-Methyl-5-phenyl-1-p-tolylpyrazole (2p): Following the condition B. Yellow
oil; yield 16%; Rf 0.44 (hexane : AcOEt = 4 : 1); 1H NMR (400 MHz, CDCl3) δ = 7.33–
7.16 (m, 5H), 7.15 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.29 (s, 1H), 2.38 (s,
3H), 2.33 (s, 3H) ppm; IR (NaCl) ν 3016, 2925, 1670, 1607, 1516, 1450, 1199, 975,
761, 698 cm-1; HRMS (FAB): m/z [M]+ calcd for C17H16N2: 248.1313, found: 248.1320.
4.2.27. 5-Methyl-2-(3-Methyl-5-phenylpyrazol-1-yl)phenol (3p): Following the
1
condition B. Yellow oil; yield 43%; Rf 0.44 (hexane : AcOEt = 4 : 1); H NMR (400
MHz, CDCl3) δ = 9.58 (s, 1H), 7.40–7.31 (m, 3H), 7.31–7.24 (m, 2H), 6.92 (s, 1H),
6.51 (d, J = 7.6 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 6.28 (s, 1H), 2.38 (s, 3H), 2.27 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 151.5, 147.9, 146.4, 141.1, 129.6, 128.7
(2C), 128.6 (2C), 128.4, 128.2, 126.0, 120.8, 119.3, 107.3, 21.3, 12.4 ppm; IR (NaCl)
ν 3060, 2920, 1738, 1592, 1517, 1244, 763, 697 cm-1; HRMS (FAB): m/z [M+H]+ calcd
for C17H17ON2: 265.1341, found: 265.1341.
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4.2.28. 1-(4-Chlorophenyl)-3-methyl-5-phenylpyrazole (2q)14: Following the condition
1
B. Yellow oil; yield 78%; Rf 0.57 (hexane : AcOEt = 4 : 1); H NMR (400 MHz,
CDCl3) δ = 7.34–7.23 (m, 5H), 7.23–7.10 (m, 4H), 2.38 (s, 3H) ppm.
4.2.29. 5-Chloro-2-(3-Methyl-5-phenylpyrazol-1-yl)phenol (3q): Following the
condition B. White oil; yield 12%; Rf 0.54 (hexane : AcOEt = 4 : 1); mp 133–135 ºC;
1H NMR (400 MHz, CDCl3) δ = 7.42–7.30 (m, 3H), 7.30–7.18 (dd, J = 7.2, 2.0 Hz, 2H),
13
7.12 (d, J = 2.0 Hz, 1H), 6.60–6.46 (m, 2H), 6.30 (s, 1H), 2.38 (s, 3H) ppm; C NMR
(100 MHz, CDCl3) δ = 151.3, 149.8, 144.4, 132.8, 130.1, 128.9, 128.76 (2C), 128.74
(2C), 124.4, 124.1, 119.1, 118.6, 108.4, 14.2, 13.5 ppm; IR (KBr) ν 3038, 2930, 1597,
1511, 1424, 1264, 1091, 767, 701 cm-1; HRMS (FAB): m/z [M+H]+ calcd for
C16H13ON2Cl: 284.0717, found: 284.0733.
4.2.30. 4-Methyl-1,5-diphenylpyrazole (2r)15: Following the condition A. Pale yellow
oil; yield 63%; Rf 0.44 (hexane : AcOEt = 4 : 1); 1H NMR (400 MHz, CDCl3) δ = 7.61
(s, 1H), 7.38–7.30 (m, 3H), 7.29–7.24 (m, 2H), 7.24–7.20 (m, 3H), 7.20–7.13 (m, 2H),
13
2.12 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ = 141.1, 140.2, 139.8, 130.5, 129.8
(2C), 128.7, 128.4 (2C), 127.9 (2C), 126.7, 124.6 (2C), 116.3, 9.2 ppm.
4.2.31. 4-Bromo-1,5-diphenylpyrazole (2s): Following the condition A. Pale yellow oil;
1
yield 47%; Rf 0.38 (hexane : AcOEt = 4 : 1); H NMR (400 MHz, CDCl3) δ = 7.76 (s,
13
1H), 7.39–7.33 (m, 3H), 7.31–7.24 (m, 5H), 7.24–7.18 (m, 2H) ppm; C NMR (100
MHz, CDCl3) δ = 141.0, 140.4, 139.8, 130.0 (2C), 128.89, 128.87 (2C), 128.5 (2C),
127.6, 124.7 (2C), 95.8 ppm; IR (NaCl) ν 3059, 1596, 1498, 1381, 1068, 950, 764, 696
cm-1; HRMS (FAB): m/z [M]+ calcd for C15H11N2Br: 298.0106, found: 298.0103.
4.2.32. The procedure for synthesis of pyrazoline 4. Benzylideneacetone (5.0 mmol,
1.0 equiv) and p-chlorophenylhydrazine hydrochloride (5.0 mmol, 1.0 equiv) was
mixed in EtOH (6 mL) to stir at ambient temperature for 7 h. After the reaction
mixture was quenched with sat. NaHCO3 aq. (5 mL), a lot of solid precipitated from the
solution. The solid was collected by filtration and washed with EtOH, to give the pure
1-(4-chloro-phenyl)-3-methyl-5-phenylpyrazoline 416.
16

ACCEPTED MANUSCRIPT
1
White solid; yield 90%; Rf 0.63 (hexane : AcOEt = 4 : 1); H NMR (400 MHz,
CDCl3) δ = 7.43–7.17 (m, 5H), 7.06 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 4.98
(dd, J = 11.9, 8.0 Hz, 1H), 3.42 (dd, J = 17.6, 11.9 Hz, 1H), 2.72 (dd, J = 17.6, 8.0 Hz,
1H), 2.06 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 149.0, 144.4, 142.4, 129.1
(2C), 128.7 (2C), 127.5, 125.8 (2C), 123.2, 114.1 (2C), 64.6, 47.9, 15.9 ppm.
4.2.33. The procedure for synthesis of 2q and 3q by (CF3CO)2O and H2O2. 30%
Hydrgen peroxide (0.085 mL, 2.8 mmol, 5.6 eq) was added slowly at 0 °C to
trifluoroacetic anhydride (0.48 mL, 3.4 mmol, 6.8 eq.), then the mixuture was stirred at
room temperature for 1 hour. After hydrazone 1q (135 mg, 0.5 mmol) was added little
by little to the mixture, the reaction mixture was stirred at the same temperature for 30
min. The reaction mixture was quenched with water (5 mL) and diluted with CHCl3 (5
mL), and extracted with CHCl3 (3 x 15 mL). The organic layers were washed with
water (3 x 15 mL), dried over Na2SO4 and the solvent was evaporated in vacuo. The
residue was purified by silica gel column chromatography (hexane:EtOAc=19:1) to
afford the mixture of pyrazoles 2q and phenol 3q. For further purification, the mixture
was added 1N NaOH aq. (15 mL), and extracted with Et2O (3 x 15 mL). The organic
layers were washed with 1N citric acid aq. (15 mL) and brine (15 mL). Drying over
Na2SO4 followed by evaporation of the solvent afforded almost pure pyrazoles 2 (63 mg,
47%). The aqueous layer was treated with 1N citric acid aq. (20 mL) to acidify, and
extracted with Et2O (3 x 20 mL) and the layers were washed with sat. NaHCO3 aq. (20
mL) and brine (20 mL). Drying over Na2SO4 followed by evaporation of the solvent
gave almost pure phenols 3 (40 mg, 28%).
Acknowledgments
This work was financially supported by JSPS KAKENHI Grant Number
25410051.
References and notes
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8. Synthesis of hydrazones, please see supplementary content.
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Graphical abstract:
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