Molybdenum-Mediated One-Pot Synthesis of Pyrazoles from Isoxazoles

Article abstract of DOI:10.1055/s-0039-1690615

A one-pot approach for the direct synthesis of substituted pyrazoles from isoxazoles is reported. The process involves isoxazole N-O bond cleavage mediated by a molybdenum complex, in situ hydrolysis of the resulting β-amino enone to the corresponding 1,3-diketone, followed by pyrazole formation in the presence of hydrazine or substituted hydrazine. Good to excellent yields and regioselectivities are obtained with nonsymmetric isoxazoles. By using readily available starting materials, a wide range of substituted pyrazoles may be synthesized by this method.

Full text of DOI:10.1055/s-0039-1690615

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
paper
A
en
M. Rey, S. Beaumont
Paper
Synthesis
Molybdenum-Mediated One-Pot Synthesis of Pyrazoles from
Isoxazoles
Marine Rey
[Mo]
R4
Stéphane Beaumont*
0
0
0
0-0
0
0
1-
5
9
2
9-2
6
1
6
O
R2
R3
• Aryl
HCl(aq)
N
R2
R3
N
R4
NH2
N
+
N
THF/H2O
70 °C
Galapagos SASU, 102 Avenue Gaston Roussel
93230 Romainville, France
Stephane.Beaumont@glpg.com
H
R1
Mo
CO
R1
OC
OC
one-pot
• Aryl
• Heteroaryl
• H, Alkyl
[Mo]
R1, R2, R3:
R4:
• Heteroaryl
• H, Alkyl
28 examples
64–98%
Received: 23.07.2019
Vasil'ev's work (2007)
Accepted after revision: 02.08.2019
Published online: 26.08.2019
DOI: 10.1055/s-0039-1690615; Art ID: ss-2019-t0415-op
N2H4
Raney-Ni
H
N
N
N
O
MeOH, r.t.
R
R = alkyl, C(O)NHPh
R
Abstract A one-pot approach for the direct synthesis of substituted
pyrazoles from isoxazoles is reported. The process involves isoxazole N–
O bond cleavage mediated by a molybdenum complex, in situ hydroly-
sis of the resulting -amino enone to the corresponding 1,3-diketone,
followed by pyrazole formation in the presence of hydrazine or substi-
tuted hydrazine. Good to excellent yields and regioselectivities are ob-
tained with nonsymmetric isoxazoles. By using readily available starting
materials, a wide range of substituted pyrazoles may be synthesized by
this method.
5 examples
22–92%
Nitta's isoxazole N–O bond cleavage (1982)
N
O
NH2
O
Mo(CO)6
Ph
Ph
Ph
Ph
wet MeCN
reflux
Key words isoxazole, pyrazole, molybdenum, one-pot, -amino
91%
enone
R
This study
[Mo], H+
N
N
N
O
Pyrazole rings are an important family of nitrogen-
based heterocycles.1 Given their biological and pharmaco-
logical properties, pyrazoles constitute an important struc-
tural unit found in several commercial drugs such as Cele-
coxib (Cox-2 inhibitor), Sildenafil (PDE5 inhibitor), and
Apixaban (direct factor Xa inhibitor).2 During the course of
a medicinal chemistry program, a simple and highly effi-
cient synthesis of symmetric pyrazoles A was sought to rap-
idly access N-1 substituted analogues (Scheme 1).
+
R-NHNH2
Ar
Ar
A
NH
O
O
OH
N–O cleavage
Knorr
cyclocondensation
Ar
Ar
Scheme 1 Raney-Ni-based pyrazole synthesis from isoxazoles and Mo-
based N–O bond cleavage
Among the numerous approaches that have been devel-
oped to date, the most common remains the Knorr cyclo-
condensation between a substituted hydrazine and an -
arylated acetylacetone.3 Although significant advances have
been made by Hurtley,4 -arylation5,6 of acetylacetone still
suffers from drawbacks such as the preferred use of highly
activated aryl iodides, reproducibility issues, and the well-
known retro-Claisen reaction, leading to the -arylated ke-
tones.7 To address these liabilities, we have considered an
alternative approach in which isoxazole,8 an acetylacetone
surrogate, could be directly used to give the pyrazole of in-
terest, without isolating the intermediate 1,3-diketone. To
our knowledge, only one recent report describes the
straightforward preparation of pyrazoles from the corre-
sponding isoxazoles.9 However, the process, which is cata-
lyzed by Raney Ni,10 is limited to hydrazine hydrate and few
substituted isoxazoles (Scheme 1).
Several methods have been reported to achieve N–O
bond cleavage of isoxazoles; however, they all have limita-
tions. The most common method for the isoxazole reduc-
tive cleavage to -amino enone involves Pd11 or Pt12 cata-
lyzed hydrogenation, but sensitive functional groups are
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Rey, S. Beaumont
Paper
Synthesis
not tolerated. FeCl2,13 TiCl3,14 or SmI2 have also been re-
ported to cleave N–O bonds, but anhydrous conditions are
necessary to obtain satisfactory yields. More interestingly,
the method reported by Nitta using a reductive ring-open-
ing of isoxazoles with Mo(CO)6 in wet acetonitrile gave -
amino enones in good yields (Scheme 1).16
Table 1 Optimization of the Mo-Based N–O Bond Cleavage and In Situ
Hydrolysis of the -Amino Enonea
15
OH
O
O
N
[Mo]
acid
Ia: Mo(CO)6
Ib: Mo(CO)3(CH3CH2CN)3
Ic: Mo(CO)4(CH3CN)2
Id: Mo(CO)3(cycloheptatriene)
solvent, T °C
16 h
We, thus, took inspiration from this work to design a
one-pot synthesis of substituted pyrazoles in the presence
of a Brønsted acid and substituted hydrazines. We hypothe-
sized that the addition of a Brønsted acid could induce in
situ hydrolysis of the -amino enone to afford the 1,3-dike-
tone, which, in turn, could react with hydrazine to produce
the corresponding substituted pyrazole (Scheme 1).
Our studies were initially devoted to the optimization of
the reaction conditions for the Mo-based isoxazole ring
opening and the subsequent in situ hydrolysis of the -ami-
no enone to the 1,3-dicarbonylated compound 2a. We
aimed to achieve clean and complete conversion of isoxaz-
ole 1a into 1,3-diketone 2a to facilitate the design of an effi-
cient one-pot process.
We first screened several Brønsted acids (Table 1) and
encouraging results were obtained when acetic acid and
oxalic acid were used (entries 1 and 2). Despite the moder-
ate isolated yields, these first results demonstrated the
compatibility between an aqueous acid solution required
for the hydrolysis of the -amino enone, and the molybde-
num complex. Pleasingly, complete conversion was ob-
tained by using citric acid, and the desired 1,3-diketone 2a
was obtained in 83% yield (entry 3). A control experiment
confirmed the requirement for a Mo complex to form 2a
(entry 4). Moreover, the amount of Mo complex was identi-
fied as a key parameter for the reaction. Indeed, incomplete
conversion was observed with 0.5 equivalent of Ia, leading
to a mixture of starting material and expected product (en-
try 5).
2a
1a
Entry [Mo]
(equiv)
Acid
Solvent
Temp. Yield
(°C)
(%)b
1
2
Ia (1)
AcOH
CH3CN/H2O (3:1)
CH3CN/H2O (3:1)
CH3CN/H2O (3:1)
CH3CN/H2O (3:1)
CH3CN/H2O (3:1)
CH3CN/H2O (3:1)
CH3CN/H2O (3:1)
CH3CN/H2O (3:1)
CH3CN/H2O (3:1)
CH3CN/H2O (3:1)
CH3CN/H2O (3:1)
CH3CN/CH3OH (3:1)
dry CH3CN
90
90
90
90
90
90
90
90
90
70
50
70
70
70
70
70
70
58
56
83
0
Ia (1)
oxalic acid
3
Ia (1)
citric acid
citric acid
citric acid
citric acid
citric acid
citric acid
citric acid
citric acid
citric acid
citric acid
citric acid
citric acid
citric acid
citric acid
1 M HCl
4
–
5
Ia (0.5)
Ib (0.5)
Ic (0.5)
Id (0.5)
Id (0.25)
Id (0.5)
Id (0.5)
Id (0.5)
Id (0.5)
Id (0.5)
Id (0.5)
Id (0.5)
Id (0.5)
74c
71d
87
89
40
89
70e
0f
6
7
8
9
10
11
12
13
14
15
16
17
0f
CH3CN/H2O (1:1)
THF/H2O (3:1)
67
86
83
91
EtOH/H2O (3:1)
THF/H2O (3:1)
a Reaction conditions: 1a (0.5 mmol), [Mo] complex (1–0.25 equiv), acid
(1.5 equiv), solvent (2.0 mL).
b Isolated yield after column chromatography.
c 14% of 1a remained, based on 1H NMR analysis of the crude reaction mix-
We then evaluated the ability of commercially available
molybdenum complexes to cleave the isoxazoles N–O bond.
Complex Ib was found to be as efficient as Mo(CO)6 (Table 1,
entry 6), whereas complete conversion was obtained with
0.5 equivalent of complexes Ic and Id, which provide 2a in
87% and 89% yield, respectively (entries 7 and 8). Given that
complex Ic was less chemically stable, we decided to fur-
ther optimize the reaction conditions with Id.
Decreasing the complex loading to 0.25 equivalent led
to a lower conversion (Table 1, entry 9). We also demon-
strated that the reaction could be performed at lower tem-
perature without affecting the yields. Compound 2a was
obtained in 89% yield at 70 °C (entry 10) while decreasing
the temperature to 50 °C led to 70% yield, albeit after a lon-
ger reaction time (24 h) (entry 11).
ture.
d 21% of 1a remained, based on 1H NMR analysis of the crude reaction mix-
ture.
e 18% of 1a remained, based on 1H NMR analysis of the crude reaction mix-
ture.
f Only -amino enone was observed.
ed compound 2a (Table 1, entries 12 and 13). The amount of
water was also key for the conversion (entry 14), while THF
or EtOH could also be used with nearly equal efficiency (en-
tries 15 and 16). Finally, an optimal yield of 91% was ob-
tained by running the reaction in the presence of 1 M HCl in
a 3:1 mixture of THF/H2O at 70 °C (entry 17).
Having determined the best conditions for the forma-
tion of 2a, we then focused on the one-pot formation of
pyrazole in the presence of hydrazine. Gratifyingly, in the
presence of 1.2 equivalents of phenylhydrazine (3a), the
corresponding pyrazole 4a was obtained in very good yield
of 92% (Table 2). A control experiment again revealed the
requirement for the Mo complex to produce the pyrazole
Solvents were also evaluated. Replacing water with
methanol or using anhydrous CH3CN only afforded the -
amino enone without any trace of desired 1,3-dicarbonylat-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–I

C
M. Rey, S. Beaumont
Paper
Synthesis
Table 2 Optimization of the One-Pot Synthesis of 4a
With the optimal conditions in hand, the generality and
the scope of this process were evaluated. A wide range of
commercially available isoxazoles with different electronic
and steric properties afforded the expected symmetric pyr-
azoles in moderate to excellent yields (Scheme 2). Isoxaz-
oles with either electron-donating or electron-withdrawing
groups reacted smoothly to give the expected pyrazoles in
good yields. Sensitive functional groups such as esters,
amines, or nitriles were compatible with the reaction con-
ditions (4b–g; 64–81% yield). By contrast, the nitro group
was not tolerated, with a partial reduction leading to a com-
plex mixture being observed in this case (4h). Heterocycles
such as pyridines, pyrimidines, or pyrazoles were also well
tolerated, giving the N-substituted pyrazoles 4i–m with
65–97% yield. Surprisingly, the Boc protecting group was
not affected by the acidic conditions (4l).
We next investigated the reactivity of various hydra-
zines with substituted isoxazoles. Aryl and heteroaryl hy-
drazines were found to be suitable reagents for this trans-
formation, affording 4n and 4o in 87% and 82% yield, re-
spectively. Hydrazine and alkyl hydrazines afforded N-H
and N-alkyl pyrazoles with yields ranging from 75 to 96%
(4p–u). Interestingly, isoxazole 1v, bearing a free hydroxyl
Ph
N
O
N
N
Id (0.5 equiv.)
HCl(aq) (1.5 equiv.)
+
Ph-NHNH2
THF/H2O (3:1, c = 0.25)
70 °C, 16 h
'standard conditions'
1a
(1.0 equiv.)
3a
4a
(1.2 equiv.)
Entry
Variation of the ‘standard conditions’ Yield (%)a
1
2
3
4
none
92
0
w/o Id
Ib
81
73
CH3CN/H2O (3:1)
a Isolated yield after column chromatography.
(entry 2). A lower yield of 81% was obtained when Ib was
used instead of Id (entry 3). Replacing THF with CH3CN led
to a lower yield of 73% (entry 4).
ld (0.5 equiv.)
HCl(aq) (1.5 equiv.)
R1
N
O
H
N
+
N
N
R
R
R1
NH2
R
R
Ar
THF/H2O (3:1)
70 °C, 16 h
Ar
1
3
4
(1.0 equiv.)
(1.2 equiv.)
EtO2C
Ph
N
N
Ph
N N
Ph
N
N
N
N
N
N
N
Ph
Ph
4b, R = o-OMe, 74%
4c, R = p-OMe, 74%
4d, R = m-CN, 64%
4e, R = p-CO2Me, 75%
4f, R = p-NH2, 72%
4g, R = m,m'-diF, 81%
4h, R = o-NO2, 0%
N
N
Ph
N
N
N
N
N
N
N
N
N
N
O
N
O
N
N
R
N
N
NBoc
F
4i, 65%
4j, 72%
4k, 97%
4l, 88%
4m, 91%
4n, 87%
N
O
S
O
N
Ph
N
N
N
N
N N
CF3
H
N
N
N
N
N N
N
N
N
N
N
N
N
N
N
N
N
O
N
O
N
O
OH
4o, 82%
4p, 68%
4q, 72%
4r, 96%
4s, 75%
4t, 89% (84%)a
4u, 86%
4v, 70%b
Scheme 2 One-pot synthesis of symmetric pyrazoles from isoxazoles. a Reaction performed on 2 mmol scale. b Reaction performed overnight at room
temperature.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–I

D
M. Rey, S. Beaumont
Paper
Synthesis
metrical isoxazoles to evaluate the regioselectivity of the
reaction (Scheme 3). We were very pleased to achieve high
levels of regiocontrol starting from 5-arylisoxazole 5a. The
corresponding 1,5-diarylpyrazoles 6a and 6b were, thus,
isolated in high yields and with regioisomeric ratios of 12:1
and 25:1, respectively, as indicated by the 1H NMR analysis
of the crude product. Similarly, the reactions from 3-aryli-
soxazoles 5b and 5c proved to be as efficient in terms of
conversion, although the regioselectivities were found to
decrease slightly.
Even more efficient were the reactions performed from
di- or trisubstituted isoxazoles (Scheme 4). 1,3,5-Trisubsti-
tuted pyrazole 9a and the 1,2,3,4-tetrasubstituted deriva-
tive 9b were isolated, respectively, in 77% and 78% yields
and with complete regiocontrol (>98:2). The reaction also
proceeded smoothly with trifluoromethylisoxazole 8c, to
give the corresponding trifluoromethyl pyrazole17 9c in 84%
yield and with an excellent regioisomeric ratio of 15:1.18
In summary, we have developed an efficient Mo-medi-
ated one-pot synthesis of polysubstituted pyrazoles from
isoxazoles. Reaction of the latter with substituted hydra-
zines afforded symmetrical pyrazoles in good to excellent
yields. The reaction could be extended to the formation of
non-symmetrical derivatives with equal efficiency and,
importantly, excellent levels of regioselectivity. The
Id (0.5 equiv.)
HCl(aq) (1.5 equiv.)
N
N
N
Ar
Ar
Ar
N
N
O
+
MeO
ArNHNH2
+
Ar
6
THF/H 2O (3:1)
70 °C, 16 h
5a
7
6a, 94%
(6a/7a = 12:1)a
6b, 98%
7bb
7ab
3
3a, Ar =Ph
3b, Ar = p-NCC6H4
(6b/7b > 25:1)a
Id (0.5 equiv.)
HCl(aq) (1.5 equiv.)
N
+
N
Ph-NHNH2
+
O
Ar
Ph
Ar
N
Ar
N
N
THF/H 2O (3:1)
70 °C, 16 h
Ph
5
3a
6
7
5b, Ar = p-CH3OC6H4
5c, Ar = p-ClC6H4
6a,70%
7a, 11%
(6a/7a = 7:1)a
6c, 86%
(6c/7c = 8:1)a
7c, 8%
Scheme 3 Mo-mediated one-pot pyrazole synthesis from 5- and 3-ary-
lated isoxazoles. a Based on 1H NMR analysis of the crude mixture. b Not
isolated.
group, could be converted at room temperature into 4v in
70% yield.
Encouraged by these results, we decided to further ex-
pand the scope of the reaction to more challenging unsym-
OMe
OMe
OMe
N
N
Id (0.5 equiv.)
N
HCl(aq) (1.5 equiv.)
O
+
+
+
+
N
N
N
N
Ph
THF/H2O (3:1)
r.t., 16 h
N
Ph
O
NHNH2
O
Ph
O
8a
3c
9a, 77%
10ab
(9a/10a > 98:2)a
O
O
O
Id (0.5 equiv.)
HCl(aq) (1.5 equiv.)
+
N
N
N
N
Ph
THF/H2O (3:1)
70 °C, 16 h
O
N
NHNH2
Ph
8b
3a
9b, 78%c
(9b/10b > 98:2)a
10bb
CF3
SO2Me
N
N
F3C
N
N
Id (0.5 equiv.)
+
N
F3C
HCl(aq) (1.5 equiv)
THF/H2O (3:1)
r.t., 16 h
O
NHNH2
then 70 °C, 5 h
SO2Me
SO2Me
8c
3d
9c, 84%
10c, 3%
(9c/10c = 15:1)a
Scheme 4 Mo-mediated one-pot pyrazoles synthesis from alkylated isoxazoles. a Based on 1H NMR analysis of the crude mixture. b Not isolated.
c 3 equivalents of 1M HCl used (1.5 mmol).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–I

E
M. Rey, S. Beaumont
Paper
Synthesis
experimental protocol involves simple practical conditions
starting from readily available materials. The transforma-
tion also tolerates a wide range of functional groups, there-
by making this process suitable for the late-stage modifica-
tion of advanced intermediates.
4-(4-Isopropylphenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (4a)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil, 0–15% EtOAc in
heptane) to afford 4a.
Yield: 133 mg (92%); white foam.
1H NMR (400 MHz, CDCl3):  = 7.54–7.44 (m, 4 H), 7.42–7.33 (m, 1 H),
7.33–7.22 (m, 4 H), 2.96 (hept, J = 6.9 Hz, 1 H), 2.37 (s, 3 H), 2.31 (s,
3 H), 1.30 (d, J = 6.9 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 147.4, 147.1, 140.2, 136.4, 131.3,
129.6, 129.2, 127.5, 126.7, 125.1, 121.0, 34.0, 24.2, 12.9, 12.1.
All reagents were of commercial grade and were used as received
without further purification, unless otherwise stated. Isoxazoles were
purchased from commercial sources or were available in the company
collection. All molybdenum complexes were purchased from Strem
Chemicals. All reactions were performed in 2–5 mL Biotage micro-
wave reactions vials unless otherwise stated. Column chromatogra-
phy was performed on silica gel 60 (35–70 m). Thin-layer chroma-
tography was carried out using precoated silica gel F-254 plates
(thickness 0.25 mm).
HRMS (ESI): m/z [M + Na]+ calcd for C20H22N2Na: 313.1681; found:
313.1681.
4-(2-Methoxyphenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (4b)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil, 0–15% EtOAc in
heptane) to afford 4b.
CAUTION: Heating Mo(CO)6 leads to CO extrusion and causes over-
pressure in the microwave vials.
Yield: 103 mg (74%); colorless oil.
Melting points were determined with a Mettler Toledo MP50 melting-
point system for non-amorphous solid. 1H, 13C, and 19F NMR spectra
were recorded with a Bruker DPX 400 NMR spectrometer at 400 MHz
1H NMR (400 MHz, CDCl3):  = 7.55–7.43 (m, 4 H), 7.39–7.30 (m, 2 H),
7.21 (dd, J = 7.4, 1.8 Hz, 1 H), 7.06–6.98 (m, 2 H), 3.84 (s, 3 H), 2.25 (s,
3 H), 2.21 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 157.3, 148.1, 140.1, 137.4, 132.1,
129.0, 128.6, 127.2, 124.9, 122.4, 120.6, 117.3, 111.0, 55.4, 12.7, 12.0.
(
13C: 101 MHz and 19F: 376 MHz). Chemical shifts are given in parts
per million from tetramethylsilane (1H NMR) or CCl3F (19F NMR) as in-
ternal standard. Data are represented as: chemical shift, integration,
multiplicity: s = singlet, d = doublet, t = triplet, q = quartet,
sept = septet, m = multiplet, b = broad, coupling constants in Hertz
(Hz). High-resolution mass spectra (HRMS) were acquired with a Q-
ToF Agilent 1290–6545 spectrometer coupled with an ESI source.
HRMS (ESI): m/z [M + H]+ calcd for C18H18N2O: 279.1497; found:
279.1505.
4-(4-Methoxyphenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (4c)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil, 0–15% EtOAc in
heptane) to afford 4c.
Preparation of 3-(4-Isopropylphenyl)pentane-2,4-dione (2a)
A microwave vial equipped with a magnetic bar was charged with
isoxazole 1a (0.5 mmol, 1 equiv), THF/H2O (3:1, 2 mL) and 1 M HCl
(0.75 mmol, 1.5 equiv). [Mo] Id (0.25 mmol, 0.5 equiv) was added and
the vial was sealed. The reaction mixture was vigorously stirred and
heated at 70 °C for 16 h. The reaction mixture was cooled to r.t., and
concentrated under reduced pressure. The crude material was puri-
fied by flash chromatography (KP-Sil, 0–10% EtOAc in heptane) to give
2a.
Yield: 102 mg (74%); white solid; mp 124–126 °C.
1H NMR (400 MHz, CDCl3):  = 7.52–7.43 (m, 4 H), 7.41–7.31 (m, 1 H),
7.27–7.21 (m, 2 H), 7.01–6.95 (m, 2 H), 3.85 (s, 3 H), 2.32 (s, 3 H), 2.28
(s, 3 H).
13C NMR (101 MHz, CDCl3):  = 158.5, 147.4, 140.1, 136.4, 130.8,
129.2, 127.5, 126.3, 125.1, 120.8, 114.2, 55.5, 12.8, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C18H18N2O: 279.1497; found:
279.1506.
Yield: 99 mg (91%); white foam.
1H NMR (400 MHz, CDCl3):  = 7.24–7.21 (m, 2 H), 7.09–7.05 (m, 2 H),
2.93 (hept, J = 6.9 Hz, 1 H), 1.89 (s, 6 H), 1.28 (d, J = 6.9 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 191.3, 148.2, 134.4, 131.1, 127.0,
3-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)benzonitrile (4d)
115.3, 34.0, 24.4, 24.2.
HRMS (ESI): m/z [M + H]+ calcd for C14H18O2: 219.1385; found:
219.1377.
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
15%) to afford 4d.
Yield: 87 mg (64%); beige solid; mp 102–103 °C.
1H NMR (400 MHz, CDCl3):  = 7.63–7.59 (m, 2 H), 7.58–7.54 (m, 2 H),
Pyrazoles 4, 6, 7a, 7c, 9, and 10c; General Procedure
7.53–7.45 (m, 4 H), 7.43–7.38 (m, 1 H), 2.34 (s, 3 H), 2.30 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 146.9, 139.6, 136.8, 135.4, 133.9,
132.8, 130.1, 129.5, 129.3, 127.9, 125.1, 118.9 (2C), 112.8, 12.7, 11.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H15N3: 274.1344; found:
A microwave vial equipped with a magnetic bar was charged with
isoxazole (0.5 mmol, 1 equiv), hydrazine (0.6 mmol, 1.2 equiv),
THF/H2O (3:1, 2 mL) and 1 M HCl (0.75 mmol, 1.5 equiv). [Mo] Id
(0.25 mmol, 0.5 equiv) was added and the vial was sealed. The reac-
tion mixture was vigorously stirred and heated at 70 °C for 16 h. The
reaction mixture was cooled to r.t., and concentrated under reduced
pressure. The crude material was purified by flash chromatography to
give the pyrazole.
274.1350.
Methyl 4-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)benzoate (4e)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil, 0–20% EtOAc in
heptane) to afford 4e.
Yield: 114 mg (75%); white solid; mp 143–145 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–I

F
M. Rey, S. Beaumont
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.15–8.07 (m, 2 H), 7.50–7.48 (m, 4 H),
13C NMR (101 MHz, CDCl3):  = 153.2, 148.6, 148.0, 145.3, 139.7,
7.44–7.37 (m, 3 H), 3.95 (s, 3 H), 2.38 (s, 3 H), 2.32 (s, 3 H).
139.2, 134.6, 129.2, 128.2, 125.5, 118.2, 108.2, 96.3, 13.9, 12.6.
13C NMR (101 MHz, CDCl3):  = 167.0, 147.1, 139.7, 138.8, 136.7,
HRMS (ESI): m/z [M + H]+ calcd for C17H15N5: 290.1406; found:
129.8, 129.3, 129.2, 128.1, 127.7, 125.0, 120.0, 52.1, 12.8, 11.9.
290.1412.
HRMS (ESI): m/z [M + H]+ calcd for C19H18N2O2: 307.1446; found:
307.1453.
1′-(4-Fluorophenyl)-3,5-dimethyl-1-phenyl-1H,1′H-4,4′-bipyra-
zole (4k)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
20%) to afford 4k.
4-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)aniline (4f)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-NH, CH2Cl2/EtOAc/hep-
tane, 1:1:2) to afford 4f.
Yield: 160 mg (97%); white solid; mp 143–144 °C.
Yield: 95 mg (72%); white solid; mp 186–187 °C.
1H NMR (400 MHz, CDCl3):  = 7.52–7.42 (m, 4 H), 7.41–7.29 (m, 1 H),
7.16–7.10 (m, 2 H), 6.85–6.78 (m, 2 H), 2.31 (s, 3 H), 2.28 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 146.3, 144.0, 139.2, 135.1, 129.6,
128.1, 126.3, 123.9, 122.9, 120.0, 114.3, 11.7, 10.9.
HRMS (ESI): m/z [M + H]+ calcd for C17H17N3: 264.1501; found:
264.1508.
1H NMR (400 MHz, CDCl3):  = 7.89 (s, 1 H), 7.79 (s, 1 H), 7.74–7.66
(m, 2 H), 7.49 (m, 4 H), 7.40 (m, 1 H), 7.22–7.12 (m, 2 H), 2.43 (s, 3 H),
2.38 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 161.3 (d, J = 246.3 Hz), 147.2, 140.7,
139.4, 136.9, 136.6, 129.4, 128.0, 125.2, 124.9, 121.0 (d, J = 8.2 Hz),
116.4 (d, J = 23.3 Hz), 116.0, 111.4, 13.0, 12.1.
19F NMR (376 MHz, CDCl3):  = –115.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H17FN4: 333.1515; found:
333.1523.
4-(3,5-Difluorophenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (4g)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; CH2Cl2/heptane, 0–
50%) to afford 4g.
tert-Butyl 4-[3′,5′-Dimethyl-1′-phenyl-1H,1′H-(4,4′-bipyrazol)-1-
yl]piperidine-1-carboxylate (4l)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-NH; EtOAc/heptane, 0–
40%) to afford 4l.
Yield: 115 mg (81%); beige gum.
1H NMR (400 MHz, CDCl3):  = 7.53–7.44 (m, 4 H), 7.43–7.37 (m, 1 H),
6.88–6.81 (m, 2 H), 6.80–6.72 (m, 1 H), 2.35 (s, 3 H), 2.31 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 163.2 (dd, J = 13.5, 247.9 Hz), 147.1,
139.8, 137.4 (t, J = 10.3 Hz), 136.9, 129.4, 128.0, 125.3, 119.3 (t,
J = 2.6 Hz), 112. 3 (m), 102.0 (t, J = 25.4 Hz), 12.8, 12.0.
19F NMR (376 MHz, CDCl3):  = –110.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H14F2N2: 285.1203; found:
Yield: 185 mg (88%); pale-yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.59 (s, 1 H), 7.52–7.43 (m, 5 H), 7.42–
7.36 (m, 1 H), 4.33 (m, 3 H), 2.92 (t, J = 12.9 Hz, 2 H), 2.38 (s, 3 H), 2.33
(s, 3 H), 2.24–2.14 (m, 2 H), 2.04–1.90 (m, 2 H), 1.48 (s, 9 H).
13C NMR (101 MHz, CDCl3):  = 154.7, 147.2, 139.9, 138.2, 136.2,
129.2, 127.5, 125.0, 124.8, 113.8, 111.8, 80.0, 59.5, 42.9, 32.5, 28.5,
13.0, 12.0.
285.1211.
HRMS (ESI): m/z [M + H]+ calcd for C24H31N5O2: 422.2556; found:
422.2565.
4-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)pyridine (4i)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/CH2Cl2, 0–
50%) to afford 4i.
4-[5-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-
yl]morpholine (4m)
Yield: 81 mg (65%); white solid; mp 93–95 °C.
1H NMR (400 MHz, CDCl3):  = 8.64 (s, 2 H), 7.51–7.41 (m, 4 H), 7.41–
7.34 (m, 1 H), 7.29–7.24 (m, 2 H), 2.36 (s, 3 H), 2.32 (s, 3 H).
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-NH; EtOAc/heptane, 0–
40%) to afford 4m.
13C NMR (101 MHz, CDCl3):  = 148.9, 147.1, 143.1, 139.4, 137.4,
Yield: 153 mg (91%); white solid; mp 154–155 °C.
129.3, 128.1, 125.2, 124.1, 118.0, 12.9, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N3: 250.1344; found:
250.1351.
1H NMR (400 MHz, CDCl3):  = 8.34 (s, 2 H), 7.50–7.44 (m, 4 H), 7.41–
7.34 (m, 1 H), 3.91–3.85 (m, 4 H), 3.84–3.78 (m, 4 H), 2.30 (s, 3 H),
2.27 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.4, 158.0, 147.5, 139.7, 137.0,
129.2, 127.7, 124.9, 116.4, 114.7, 66.9, 44.4, 12.5, 11.7.
HRMS (ESI): m/z [M + H]+ calcd for C19H21N5O: 336.1824; found:
336.1831.
6-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimi-
dine (4j)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-NH; EtOAc/heptane, 0–
30%) to afford 4j.
Methyl 3-[4-(2-Morpholinopyrimidin-5-yl)-3,5-dimethyl-1H-pyr-
azol-1-yl]benzoate (4n)
Yield: 104 mg (72%); white solid; mp 163–165 °C.
1H NMR (400 MHz, CDCl3):  = 8.72 (dd, J = 7.3, 0.9 Hz, 1 H), 8.13 (d,
J = 2.3 Hz, 1 H), 7.55–7.39 (m, 5 H), 6.98 (d, J = 7.3 Hz, 1 H), 6.66 (dd,
J = 2.4, 0.9 Hz, 1 H), 2.56 (s, 3 H), 2.55 (s, 3 H).
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
40%) to afford 4n.
Yield: 177 mg (87%); white solid; mp 103–104 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–I

G
M. Rey, S. Beaumont
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.32 (s, 2 H), 8.14 (t, J = 1.9 Hz, 1 H),
8.06 (dt, J = 7.7, 1.4 Hz, 1 H), 7.69 (ddd, J = 8.0, 2.2, 1.2 Hz, 1 H), 7.56 (t,
J = 7.9 Hz, 1 H), 4.41 (q, J = 7.1 Hz, 2 H), 3.89–3.77 (m, 8 H), 2.31 (s,
3 H), 2.30 (s, 3 H), 1.41 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 165.7, 160.6, 158.0, 147.9, 139.9,
137.0, 131.7, 129.3, 129.0, 128.6, 125.6, 116.1, 115.2, 66.9, 61.4, 53.5,
44.4, 22.7, 14.4, 12.5, 11.7.
1H NMR (400 MHz, CDCl3):  = 7.30–7.24 (m, 2 H), 7.23–7.17 (m, 2 H),
2.94 (hept, J = 6.9 Hz, 1 H), 2.31 (s, 6 H), 1.29 (d, J = 6.9 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 146.8, 142.0, 131.5, 129.4, 126.7,
118.4, 34.0, 24.2, 11.9.
HRMS (ESI): m/z [M + H]+ calcd for C14H18N2: 215.1548; found:
215.1553.
HRMS (ESI): m/z [M + Na]+ calcd for C22H25N5O3: 430.1855; found:
430.1856.
3-[4-(4-Isopropylphenyl)-3,5-dimethyl-pyrazol-1-yl]thiolane 1,1-
dioxide (4s)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
25%) to afford 4s.
4-{5-[3,5-Dimethyl-1-(pyridine-4-yl)-1H-pyrazol-4-yl]pyrimidin-
2-yl}morpholine (4o)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc, 100%) to af-
ford 4o.
Yield: 125 mg (75%); beige foam.
1H NMR (400 MHz, CDCl3):  = 7.30–7.23 (m, 2 H), 7.18–7.10 (m, 2 H),
5.00 (dq, J = 9.1, 7.6 Hz, 1 H), 3.77–3.68 (m, 1 H), 3.64 (ddd, J = 13.2,
8.9, 6.2 Hz, 1 H), 3.45 (ddt, J = 13.3, 7.6, 1.2 Hz, 1 H), 3.20 (dtd, J = 13.2,
7.8, 1.3 Hz, 1 H), 2.94 (hept, J = 7.0 Hz, 1 H), 2.83 (ddt, J = 13.6, 8.9,
7.9 Hz, 1 H), 2.70–2.57 (m, 1 H), 2.27 (s, 3 H), 2.23 (s, 3 H), 1.28 (d,
J = 7.0 Hz, 6 H).
Yield: 138 mg (82%); white solid; mp 199–200 °C.
1H NMR (400 MHz, CDCl3):  = 8.72–8.65 (m, 2 H), 8.29 (s, 2 H), 7.54–
7.48 (m, 2 H), 3.89–3.83 (m, 4 H), 3.82–3.75 (m, 4 H), 2.41 (s, 3 H),
2.29 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.7, 158.1, 151.0, 149.4, 146.5,
13C NMR (101 MHz, CDCl3):  = 147.3, 147.1, 135.9, 130.8, 129.5,
137.1, 117.3, 117.1, 115.4, 66.9, 44.4, 12.6, 12.5.
126.7, 120.3, 55.0, 53.0, 51.2, 34.0, 29.4, 24.2, 12.9, 10.2.
HRMS (ESI): m/z [M + H]+ calcd for C18H20N6O: 337.1777; found:
HRMS (ESI): m/z [M + H]+ calcd for C18H24N2O2S: 333.1638; found:
337.1784.
333.1644.
4-[5-(1-Ethyl-3,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-yl]mor-
1-Isopropyl-4-(4-isopropylphenyl)-3,5-dimethyl-1H-pyrazole (4t)
pholine (4p)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
15%) to afford 4t.
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
60%) to afford 4p.
Yield: 114 mg (89%); colorless oil.
Yield: 98 mg (68%); white solid; mp 162–163 °C.
1H NMR (400 MHz, CDCl3):  = 8.22 (s, 2 H), 4.09 (q, J = 7.3 Hz, 2 H),
3.84–3.73 (m, 8 H), 2.20 (s, 3 H), 2.19 (s, 3 H), 1.41 (t, J = 7.3 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.27 (d, J = 8.1 Hz, 2 H), 7.21–7.16 (m,
2 H), 4.43 (hept, J = 6.7 Hz, 1 H), 2.95 (hept, J = 7.0 Hz, 1 H), 2.29 (s,
3 H), 2.26 (s, 3 H), 1.53 (d, J = 6.7 Hz, 6 H), 1.31 (d, J = 7.0 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 160.4, 158.0, 145.5, 136.2, 116.5,
13C NMR (101 MHz, CDCl3):  = 146.7, 145.1, 134.9, 131.9, 129.7,
113.0, 66.9, 44.4, 44.0, 15.6, 12.2, 10.0.
126.6, 119.0, 49.7, 34.0, 24.2, 22.7, 12.9, 10.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H21N5O: 288.1824; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H24N2: 257.2018; found:
288.1831.
257.2022.
4-[5-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-
1-Trifluoroethyl-4-(4-isopropylphenyl)-3,5-dimethyl-1H-pyra-
yl]morpholine (4q)
zole (4u)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
35%) to afford 4q.
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
15%) to afford 4t.
Yield: 126 mg (72%); pale-yellow oil.
Yield: 128 mg (86%); white foam.
1H NMR (400 MHz, CDCl3):  = 8.24 (s, 2 H), 7.38–7.26 (m, 3 H), 7.19–
7.12 (m, 2 H), 5.27 (s, 2 H), 3.91–3.73 (m, 8 H), 2.25 (s, 3 H), 2.14 (s,
3 H).
1H NMR (400 MHz, CDCl3):  = 7.31–7.25 (m, 2 H), 7.21–7.14 (m, 2 H),
4.63 (q, J = 8.4 Hz, 2 H), 2.95 (hept, J = 6.9 Hz, 1 H), 2.28 (s, 3 H), 2.26
(s, 3 H), 1.30 (d, J = 6.9 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 160.5, 157.9, 145.9, 136.9, 136.7,
128.8, 127.7, 126.9, 116.6, 113.5, 66.8, 53.2, 44.4, 12.5, 10.2.
HRMS (ESI): m/z [M + H]+ calcd for C20H23N5O: 350.1981; found:
350.1989.
13C NMR (101 MHz, CDCl3):  = 147.8, 147.4, 137.7, 130.8, 129.6,
126.8, 123.5 (q, J = 279.9 Hz), 120.8, 50.3 (q, J = 34.9 Hz), 34.0, 24.2,
12.8, 10.3.
19F NMR (376 MHz, CDCl3):  = –70.7.
HRMS (ESI): m/z [M + H]+ calcd for C16H19F3N2: 297.1579; found:
297.1585.
3,5-Dimethyl-4-(4-isopropylphenyl)-1H-pyrazole (4r)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
40%) to afford 4r.
4-[4-(2-Hydroxyethyl)-1H-pyrazol-1-yl]-benzonitrile (4v)
Prepared according to the general procedure performed at r.t.; the
crude material was purified by flash column chromatography (KP-Sil;
EtOAc/heptane, 0–60%) to afford 4u.
Yield: 103 mg (96%); white solid; mp 158–159 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–I

H
M. Rey, S. Beaumont
Paper
Synthesis
Yield: 75 mg (70%); white solid; mp 94–95 °C.
1H NMR (400 MHz, CDCl3):  = 7.72 (d, J = 1.9 Hz, 1 H), 7.39–7.31 (m,
3 H), 7.31–7.25 (m, 4 H), 7.18–7.12 (m, 2 H), 6.51 (d, J = 1.9 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 142.0, 140.6, 140.1, 134.5, 130.2,
1H NMR (400 MHz, CDCl3):  = 7.89 (s, 1 H), 7.80 (d, J = 8.4 Hz, 2 H),
7.73 (d, J = 8.4 Hz, 2 H), 7.67 (s, 1 H), 3.86 (t, J = 6.3 Hz, 2 H), 2.81 (t,
J = 6.3 Hz, 2 H).
129.3, 129.2, 129.0, 127.9, 125.5, 108.2.
13C NMR (101 MHz, CDCl3):  = 143.0, 142.8, 133.7, 125.7, 121.7,
118.6, 118.5, 109.2, 62.7, 27.7.
The data are consistent with those generated from the commercially
available compound (CAS 33064-23-2).
HRMS (ESI): m/z [M + H]+ calcd for C12H11N3O: 214.0980; found:
214.0978.
3-(4-Chlorophenyl)-1-phenyl-1H-pyrazole (7c)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
10%) to afford 7c.
5-(4-Methoxyphenyl)-1-phenyl-1H-pyrazole (6a)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
10%) to afford 6a.
Yield: 10 mg (8%); white solid; mp 120–121 °C.
1H NMR (400 MHz, CDCl3):  = 7.96 (d, J = 2.5 Hz, 1 H), 7.89–7.81 (m,
2 H), 7.80–7.72 (m, 2 H), 7.52–7.43 (m, 2 H), 7.43–7.36 (m, 2 H), 7.35–
7.26 (m, 1 H), 6.75 (d, J = 2.5 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 151.9, 140.3, 133.9, 131.8, 129.6,
129.0, 128.3, 127.2, 126.7, 119.2, 105.1.
Yield: 118 mg (94%); white foam.
1H NMR (400 MHz, CDCl3):  = 7.70 (d, J = 1.8 Hz, 1 H), 7.39–7.24 (m,
5 H), 7.19–7.11 (m, 2 H), 6.87–6.79 (m, 2 H), 6.45 (d, J = 1.8 Hz, 1 H),
3.80 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 159.6, 142.9, 140.3, 140.2, 130.1,
HRMS (ESI): m/z [M + H]+ calcd for C15H11ClN2: 255.0689; found:
128.9, 127.3, 125.2, 123.0, 113.9, 107.4, 55.3.
255.0688.
HRMS (ESI): m/z [M + H]+ calcd for C16H14N2O: 251.1184; found:
The data are consistent with those previously reported.21
251.1190.
The data are consistent with those previously reported.19
3-Methyl-1-(4-methoxyphenyl)-5-[(1-benzoyl)-2-pyrrolidinyl]-
1H-pyrazole (9a)
Prepared according to the general procedure; the reaction was per-
formed at r.t. and the crude material was purified by flash column
chromatography (KP-Sil; EtOAc/heptane, 0–40%) to afford 9a (140 mg,
77%) as a white solid. Mixture of conformers, ratio 2.1:1 in DMSO-d6.
3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazole (7a)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
10%) to afford 7a.
Spectral Data of the Major Conformer
Yield: 14 mg (11%); beige solid; mp 102–104 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.56–7.41 (m, 6 H), 7.26 (t,
J = 7.5 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 2 H), 6.22 (s, 1 H), 5.09 (dd, J = 7.7,
5.3 Hz, 1 H), 3.83 (s, 3 H), 3.78–3.70 (m, 1 H), 3.40–3.33 (m, 1 H), 2.17
(s, 3 H), 2.17–2.11 (m, 1 H), 2.01–1.89 (m, 1 H), 1.81–168 (m, 2 H).
13C NMR (101 MHz, DMSO-d6):  = 168.3, 158.6, 147.3, 146.7, 136.7,
132.7, 130.0, 128.2, 127.1, 126.9, 114.2, 102.8, 55.4, 53.0, 49.6, 32.9,
24.6, 13.4.
1H NMR (400 MHz, CDCl3):  = 7.85 (d, J = 2.5 Hz, 1 H), 7.81–7.73 (m,
2 H), 7.72–7.63 (m, 2 H), 7.43–7.33 (m, 2 H), 7.26–7.15 (m, 1 H), 6.93–
6.85 (m, 2 H), 6.62 (d, J = 2.5 Hz, 1 H), 3.77 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 159.8, 152.9, 140.4, 129.5, 128.0,
127.2, 126.3, 126.1, 119.1, 114.2, 104.7, 55.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H14N2O: 251.1184; found:
251.1190.
The data are consistent with those previously reported.20
HRMS (ESI): m/z [M + Na]+ calcd for C22H23N3O2Na: 384.1688; found:
384.1687.
5-(4-Methoxyphenyl)-1-(4-cyanophenyl)-1H-pyrazole (6b)
3-Methyl-1-phenyl-1,5,6,7-tetrahydro-4H-indazol-4-one (9b)
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
20%) to afford 6b.
Prepared according to the general procedure, using 3 equivalents of
1M HCl; the crude material was purified by flash column chromatog-
raphy (KP-Sil; EtOAc/heptane, 0–20%) to afford 9b.
Yield: 135 mg (98%); white foam.
Yield: 88 mg (78%); white solid; mp 126–127 °C (lit.22 129 °C).
1H NMR (400 MHz, CDCl3):  = 7.74 (d, J = 1.8 Hz, 1 H), 7.65–7.57 (m,
2 H), 7.48–7.40 (m, 2 H), 7.19–7.11 (m, 2 H), 6.93–6.84 (m, 2 H), 6.47
(d, J = 1.8 Hz, 1 H), 3.83 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.0, 143.5, 143.3, 141.4, 132.8,
130.1, 124.8, 122.3, 118.3, 114.3, 110.4, 108.9, 77.5, 77.2, 76.8, 55.3.
1H NMR (400 MHz, CDCl3):  = 7.53–7.46 (m, 4 H), 7.44–7.36 (m, 1 H),
2.94 (t, J = 6.2 Hz, 2 H), 2.55 (s, 3 H), 2.55–2.49 (m, 2 H), 2.15 (p,
J = 6.3 Hz, 2 H).
13C NMR (101 MHz, CDCl3):  = 194.3, 150.2, 150.0, 138.9, 138.7,
129.5, 128.1, 123.8, 118.1, 38.5, 23.9, 23.7, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C17H13N3O: 276.1137; found:
276.1144.
The data are consistent with those generated from the commercially
available compound (CAS 36767-62-1).
5-(4-Chlorophenyl)-1-phenyl-1H-pyrazole (6c)
3-Methyl-1-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-
Prepared according to the general procedure; the crude material was
purified by flash column chromatography (KP-Sil; EtOAc/heptane, 0–
10%) to afford 6d.
pyrazole (9c)
Prepared according to the general procedure. The reaction was per-
formed at r.t. overnight and then heated at 70 °C for 5 h; the crude
material was purified by flash column chromatography (KP-Sil;
EtOAc/heptane, 0–40%) to afford 9c.
Yield: 109 mg (86%); white solid.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–I

I
M. Rey, S. Beaumont
Paper
Synthesis
Yield: 128 mg (84%); white solid; mp 126–127 °C.
1H NMR (400 MHz, CDCl3):  = 8.09–8.02 (m, 2 H), 7.76–7.68 (m, 2 H),
6.68 (s, 1 H), 3.10 (s, 3 H), 2.37 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 150.5, 143.5, 140.6, 133.2 (q, J =
39.4 Hz), 128.7, 125.8, 119.8 (q, J = 269.4 Hz), 110.5, 44.7, 13.5.
19F NMR (376 MHz, CDCl3):  = –57.1.
HRMS (ESI): m/z [M – H]– calcd for C12H11F3N2O2S: 305.0572; found:
A. Chem. Rev. 2011, 111, 6984. (c) Yoon, J.-Y.; Lee, S.; Shin, H.
Curr. Org. Chem. 2011, 15, 657. (d) Fustero, S.; Simon-Fuentes,
A.; Sanz-Cervera, J. F. Org. Prep. Proced. Int. 2009, 41, 253.
(2) For recent reviews on pyrazoles in medicinal chemistry, see:
(a) Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y. N.;
Al-aizari, F. A.; Ansar, M. Molecules 2018, 23, 134. (b) Keter, F.
K.; Darkwa, J. Biometals 2012, 25, 9. (c) Tambe, S. K.; Dighe, N. S.;
Pattan, S. R.; Kedar, M. S.; Musmade, D. S. Pharmacologyonline
2010, 2, 5. (d) Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S.
Targets Heterocycl. Syst. 2002, 6, 52.
305.0559.
(3) Knorr, L. Ber. Dtsch. Chem. Ges. 1883, 16, 2587.
(4) Hurtley, W. R. H. J. Chem. Soc. 1929, 1870.
3-Trifluoromethyl-1-[4-(methylsulfonyl)phenyl]-5-methyl-1H-
pyrazole (10c)
(5) For recent reviews on -arylation of carbonyl compounds, see:
(a) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
(b) Johansson, C. C. C.; Colacot, T. J. Angew. Chem. Int. Ed. 2010,
49, 676. (c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008,
108, 3054.
Prepared according to the general procedure. The reaction was per-
formed at r.t. overnight and then heated at 70 °C for 5 h; the crude
material was purified by flash column chromatography (KP-Sil;
EtOAc/heptane, 0–40%) to afford 10c.
Yield: 5 mg (3%); colorless oil.
(6) Jiang, Y.; Wu, N.; He, M. Synlett 2005, 2731.
1H NMR (400 MHz, CDCl3):  = 8.13–8.05 (m, 2 H), 7.77–7.68 (m, 2 H),
6.52 (s, 1 H), 3.10 (s, 3 H), 2.44 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 144.0 (q, J = 38.3 Hz), 143.3, 141.2,
140.4, 128.9, 125.6, 121.2 (q, J = 269.1 Hz), 106.3, 44.6, 12.8.
19F NMR (376 MHz, CDCl3):  = –62.6.
(7) (a) Xing, Q.; Lv, H.; Xia, C.; Li, F. Chem. Eur. J. 2015, 21, 1. (b) He,
C.; Guo, S.; Huang, L.; Lei, A. J. Am. Chem. Soc. 2010, 132, 8273.
(8) For a recent review on the synthesis and reactivity of isoxaz-
oles, see: Melo, T. Curr. Org. Chem. 2005, 9, 925.
(9) Sviridov, S.; Vasil’ev, A. A.; Shorshnev, S. V. Tetrahedron 2007,
63, 12195.
(10) (a) Calle, M.; Calvo, L. A.; González-Ortega, A.; González-Nogal,
A. M. Tetrahedron 2006, 62, 611. (b) Saxena, R.; Singh, V.; Batra,
S. Tetrahedron 2004, 60, 10311. (c) Akiba, K.; Kashiwagi, K.;
Ohyama, Y.; Yamamoto, Y.; Ohkata, K. J. Am. Chem. Soc. 1985,
107, 2721.
HRMS (ESI): m/z [M – H]– calcd for C12H11F3N2O2S: 303.0415; found:
303.0417.
Pyrazole 4t; Larger Scale Procedure (2 mmol)
A microwave vial equipped with a magnetic bar was charged with
isoxazole 1a (431 mg, 2 mmol, 1 equiv), iPrNHNH2·HCl (266 mg, 2.4
mmol, 1.2 equiv), THF/H2O (3:1, 8 mL) and 1 M HCl (3 mL, 3 mmol, 1.5
equiv). [Mo] Id (272 mg, 1 mmol, 0.5 equiv) was added and then the
vial was sealed. The reaction mixture was vigorously stirred and heat-
ed at 70 °C for 16 h. The reaction mixture was cooled to r.t. then parti-
tioned between water and EtOAc. The organic phase was dried over
Na2SO4 and concentrated under reduced pressure. The crude material
was purified by flash chromatography (KP-Sil; EtOAc/heptane, 0–15%)
to afford 4t.
(11) (a) Caplan, J. F.; Zheng, R. J.; Blanchard, J. S.; Vederas, J. C. Org.
Lett. 2000, 2, 3857. (b) Vergelli, C.; Giovannoni, M. P.; Pieretti, S.;
Di Giannuario, A.; Dal Piaz, V.; Biagini, P.; Biancalani, C.;
Graziano, A.; Cesari, N. Bioorg. Med. Chem. 2007, 15, 5563.
(12) (a) Keserü, G. M.; Dienes, Z.; Nógrádi, M. J. Org. Chem. 1993, 58,
6725. (b) Oster, T. A.; Harris, T. M. J. Org. Chem. 1983, 48, 4307.
(13) Auricchio, S.; Bini, A.; Pastomerlo, E.; Truscello, A. M. Tetrahe-
dron 1997, 53, 10911.
(14) Angibaud, P. R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny, Y.
A.; Muller, P.; Poncelet, V. S.; End, D. W. Eur. J. Org. Chem. 2004,
479.
Yield: 431 mg (1.68 mmol, 84%); colorless oil.
(15) (a) Fan, X. S.; Zhang, Y. M. Tetrahedron Lett. 2002, 43, 7001.
(b) Natale, N. R. Tetrahedron Lett. 1982, 23, 5009.
(16) (a) Nitta, M.; Kobayashi, T. J. Chem. Soc., Chem. Commun. 1982,
877. (b) Nitta, M.; Kobayashi, T. J. Chem. Soc., Perkin Trans. 1
1985, 1, 1401.
Acknowledgment
The Authors would like to thank the Structuralis team (Romainville,
France) and Dr. Valentin Poirier for analytical support (HRMS and
NMR data) and helpful discussion.
(17) Heating at 70 °C is necessary to force the dehydration of the 5-
hydroxy-5-trifluoromethylpyrazoline
intermediate,
see:
Fustero, S.; Román, R.; Sanz-Cervera, J.-F.; Simón-Fuentes, A.;
Cuñat, A. C.; Villanova, S.; Murguía, M. J. Org. Chem. 2008, 73,
3523; and references herein.
Supporting Information
(18) For trifluoromethylated pyrazole synthesis, see: (a) Martins, M.
A. P.; Marzari, M. R. B.; Frizzo, C. P.; Zanatta, M.; Buriol, L.;
Andrade, V. P.; Bonacorso, H. G. Eur. J. Org. Chem. 2012, 7112.
(b) Singh, P. S.; Kumar, D.; Batra, H.; Naithani, R.; Rozas, I.;
Elguero, J. Can. J. Chem. 2000, 78, 1109.
(19) Zora, M.; Kivrak, A. J. Org. Chem. 2011, 76, 9379.
(20) Xu, Z.-L.; Li, H.-X.; Ren, Z.-G.; Du, W.-Y.; Xu, W.-C.; Lang, J.-P.
Tetrahedron 2011, 67, 5282.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690615.
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References
(1) For recent reviews on the synthesis of pyrazoles, see: (a) Ansari,
A.; Ali, A.; Asif, M.; Shamsuzzaman New J. Chem. 2017, 41, 16.
(b) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes,
(21) Voronin, V. V.; Ledovskaya, M. S.; Gordeev, E. G.; Rodygin, K. S.;
Ananikov, V. P. J. Org. Chem. 2018, 83, 3819.
(22) Smith, H. J. Chem. Soc. 1953, 803.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–I