Silver-catalyzed synthesis of 5-aryl-3-trifluoromethyl pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2019.151455

A silver-catalyzed synthesis of 5-aryl-3-trifluoromethyl pyrazoles from reaction of various N′-benzylidene tolylsulfonohydrazides with ethyl 4,4,4-trifluoro-3-oxobutanoate is described. The reaction proceeds via sequential nucleophilic addition, intramole

Full text of DOI:10.1016/j.tetlet.2019.151455

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Silver-catalyzed synthesis of 5-aryl-3-trifluoromethyl pyrazoles
Yihui Xu, Qiaoling Chen, Yishi Tian, Wei Wu, Yi You, Zhiqiang Weng
PII:
S0040-4039(19)31254-7
DOI:
https://doi.org/10.1016/j.tetlet.2019.151455
TETL 151455
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 October 2019
22 November 2019
25 November 2019
Please cite this article as: Xu, Y., Chen, Q., Tian, Y., Wu, W., You, Y., Weng, Z., Silver-catalyzed synthesis of 5-
aryl-3-trifluoromethyl pyrazoles, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151455
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Silver-catalyzed synthesis of 5-aryl-3-
trifluoromethyl pyrazoles
Yihui Xu, Qiaoling Chen, Yishi Tian, Wei Wu,* Yi You, and Zhiqiang Weng*
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†
†
†
H
N
HN
N
AgOTf (10 mol%)
Me2phen (12 mol%)
N
Ts
O
O
CF3
+
R
F3C
OEt
KH (15 mol%)
Toluene, 60 °C
O
R
EtO
B-
[Ag]
AgLn
Ts
N
Ts
LnAg
N
CF3
N
N
CF3
OAgLn
N
N
Ts
N
N
O
CF3
H
R
R
R
R
O
O
O
EtO
EtO
EtO

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Silver-catalyzed synthesis of 5-aryl-3-trifluoromethyl pyrazoles
†
†
†
Yihui Xu, Qiaoling Chen, Yishi Tian, Wei Wu,* Yi You, and Zhiqiang Weng
State Key Laboratory of Photocatalysis on Energy and Environment, and Fujian Provincial Key Laboratory of Electrochemical Energy Storage Materials,
College of Chemistry, Fuzhou University, Fuzhou, 350108, China
—
——
ARTICLE INFO
ABSTRACT

Corresponding author. Tel.: + 86 591 22866247; fax: + 86 591 22866247; e-mail: 1096258149@qq.com (W. Wu), zweng@fzu.edu.cn (Z.
Weng).
Article history:
Received
Received in revised form
Accepted
Available online
A silver-catalyzed synthesis of 5-aryl-3-trifluoromethyl pyrazoles from reaction of various N'-
benzylidene tolylsulfonohydrazides with ethyl 4,4,4-trifluoro-3-oxobutanoate is described. The
reaction proceeds via sequential nucleophilic addition, intramolecular cyclization, elimination,
and [1,5]-H shift steps to afford the trifluoromethylated pyrazole products in moderate to
excellent yields. The reaction is compatible with a variety of functional groups.
†
These authors contributed equally.
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
Trifluoromethyl
Pyrazole
Silver
The pyrazoles are ubiquitous structural motifs present in a
number of natural products and drugs that exhibit a wide range of
biological activities. Particularly, the trifluoromethylated
further development for the efficient construction of such
molecules.
1
pyrazoles have been gaining much attention in recent years as
potential pharmaceuticals and agrochemicals.2 Representative
examples of bioactive molecules containing trifluoromethylated
pyrazole motifs with various pharmacological properties are
enlisted below in Figure 1: Celecoxib is a nonsteroidal anti-
inflammatory drug used in the treatment of pain or
O
S
NH2
OMe
O
N
N
N
F3C
N
F3C
3
4
inflammation; SC-560 exhibits significant anticancer activities;
Cl
Razaxaban is a factor Xa inhibitor for the treatment of
SC-560
Celecoxib
5
thrombosis; Fluazolate is a broad spectrum preemergent
herbicide used on winter wheat.6
O
F3C
N
N
N
The development of efficient methodologies for the synthesis
of trifluoromethyl pyrazole derivatives is of great importance for
N
N
F3C
Br
F
H
NH2
N
7
N
academic research, as well as for chemical industries. The most
O
O
common route to access this class of heterocycles is the
condensation of 1,1,1-trifluoromethyl-1,3-diketones, or their
F
NMe2
O
Cl
8
N
synthetic equivalents, with hydrazines. Several new synthetic
Razaxaban
Fluazolate
methods have also been developed in recent years, including the
cycloaddition of alkynes with 2,2,2-trifluorodiazoethane,9 the
Figure 1. Biologically important trifluoromethylated
pyrazoles.
We have been interested for several years in the utility of
readily available and inexpensive fluorinating reagents for the
construction of trifluoromethylated heterocyclic compounds.
a copper-catalyzed chemoselective
synthesis of 4-trifluoromethyl pyrazoles from the reaction of N-
cyclocondensation
of
trifluoromethyl-,-ynones
with
1
0
hydrazines,
trifluoromethylation/cyclization of ,-alkynic
1
1
hydrazones,
intramolecular
cyclization
of
N-
propargylhydrazones,12 the cyclization of trifluoromethyl
alkenone with tosylhydrazone,13 the cycloaddition of
trifluoroacetonitrile imines with enol ethers.14 These
transformations provide efficient and flexible methods for the
synthesis of 3-trifluoromethylpyrazoles. However, some of them
suffered from serious limitations, such as the formation of
regioisomeric mixtures, narrow substrate scopes, the requirement
of using expensive reagents. As a result, there remains a need for
15
Recently, we reported
arylsydnone derivatives with 2-bromo-3,3,3-trifluoropropene
1
6
under mild conditions. As part of this initial investigation, we
extended this condensation strategy to the reaction between N'-
benzylidene tolylsulfonohydrazides and ethyl 4,4,4-trifluoro-3-

2
Tetrahedron
oxobutanoate, which led to the formation of the corresponding
5
-aryl-3-trifluoromethyl pyrazoles in good yields.
Table 1 Optimization of the reaction a
N
H
N
HN
N
Ts
CF3
O
O
Conditions
+
O
F3C
OEt
EtO
1
2b
3b
Entry
[Cat.]
Ligand
Base
KH
KH
KH
KH
KH
KH
KH
NaH
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
THF
Temp. (C)
Yield (%)b
1
2
3
4
5
6
7
8
9
AgOTf
AgOTf
AgOTf
Cu(OTf)
-
40
60
70
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
62
69
59
60
33
12
9
-
-
2
-
Fe(OTf)
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
-
3
-
-
-
Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
-
8
-
K
2
CO
3
63
52
14
51
30
57
92
>99
86
63
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
-
KOt-Bu
-
NaOt-Bu
KH
-
-
AgOTf
AgOTf
AgOTf
AgOTf
Cu(OTf)
Cu(OTf)
-
bpy
phen
KH
KH
KH
KH
KH
Me
bpy
phen
2
phen
2
2
a
Reaction conditions: 1 (0.25 mmol, 2.5 equiv), 2b (0.10 mmol, 1.0 equiv), [cat.] (10 mol%), ligand (12
mol%), base (0.15 equiv), solvent (1.0 mL), 20 h, under N atmosphere; bpy = 2,2-bipyridine, phen = 1,10-
phenanthroline, Me phen = neocuproine.
The yield was determined by 19F NMR spectroscopy with PhOCF
2
2
b
3
as internal standard.
We initiated our investigation by utilizing tosyl-protected
(Entries 8, 10, and 11). In the absence of either the silver species
or KH, the reaction efficiency was significantly decreased
(Entries 12 and 13). To further improve the product yield, the
cyclization was examined in the presence of some bidentate
benzylidene hydrazine 2b, easily prepared from commercially
available p-tolualdehyde, as a substrate to react with 1 for the
optimization of the reaction conditions (Table 1). A mixture of
2
b (0.10 mmol) and 1 (0.25 mmol) in toluene (1.0 mL) in the
2
dinitrogen ligands. The use of Me phen as the ligand gave the
presence of AgOTf (10 mol%) and KH (0.15 equiv) was stirred
at 40 C. The desired trifluoromethylated pyrazole product 3b
was formed in 62% NMR yield (Entry 1). The yield of the 3b
was further improved to 69% by raising the reaction temperature
to 60 C (Entry 2). However, further increasing the reaction
temperature to 70 C only resulted in lower yield (59%; Entry 3).
Other transition-metal catalysts were also examined, and it was
best yield (>99%; Entry 16), while a 57% or 92% yield was
achieved by using bpy or phen as the ligand, respectively (Entries
14 and 15). However, in the presence of bpy or phen ligand,
Cu(OTf) provided relatively low yields of the desired product
2
(Entries 17 and 18).
With the optimized conditions in hand, we investigated the
substrate
tolylsulfonohydrazides 2 and ethyl 4,4,4-trifluoro-3-oxobutanoate
. As showed in Table 2, the cyclization reaction worked
scope
using
various
N'-benzylidene
found that the reaction using Cu(OTf)
comparable yield (60%; Entry 4), while Fe(OTf)
2
afforded product 3b in
was ineffective
3
1
for this reaction (Entry 5). The choice of solvent proved crucial
for this transformation. The use of THF or dioxane gave poor
yield of the product (Entries 6 and 7). Other bases were tested,
efficiently to afford the corresponding 5-aryl-3-trifluoromethyl
pyrazole products in good to high yields. For instance, excellent
yield was obtained when a simple hydrazine substrate 2a was
reacted with 1 to give 3a (96% yield). N'-benzylidene
tolylsulfonohydrazides 2b2d containing alkyl groups such as
and K
2 3
CO also proved to be an effective base for the reaction
(Entry 9), while NaH, KOt-Bu, and NaOt-Bu were less efficient

3
methyl and tert-butyl reacted smoothly with 1 under silver
catalysis, furnishing the expected 5-aryl-3-trifluoromethyl
pyrazoles 3b3d in 88%98% yields. Similarly, N'-benzylidene
tolylsulfonohydrazides 2e–2h having electron-donating and -
withdrawing groups, such as 4-benzyloxy, 4-methoxy, 4-
dimethylamine, and 3-trifluoromethyl on the aromatic rings,
exhibited good reactivity, generating 3e–3h in excellent yields.
yield (30%). Likewise, the substrates bearing heteroaryl
moieties, such as furyl, thienyl, pyrrolyl, quinolyl, and indolyl
were also efficiently converted to the desired products 3q3v in
30%90% yields. The structure of product 3r was
unambiguously
determined
by
single-crystal
X-ray
crystallography demonstrating the successful synthesis of the
trifluoromethylated pyrazole compound (Figure 2).
As
an
exception,
N'-(4-cyanobenzylidene)-4-
2i afforded the
The scope of the cyclization reaction was then further
methylbenzenesulfonohydrazide
explored
with
a
range
of
4-methyl-N'-(3-
trifluoromethylated pyrazole product 3i in only 21% yield. It is
worthy of note that the sulfonohydrazide substrates bearing
halogen substituents such as F (2j–2l), Cl (2m), and Br (2l, 2n,
and 2o) on the phenyl rings were also tolerated and furnished the
desired products 3j3o in moderate to excellent yields
phenylallylidene)benzenesulfonohydrazides (Table 2). The
cyclization reaction of these substrates with 1 provided the
desired trifluoromethylated pyrazole products 3w3z in 44%-
8
2% yields. Various functional groups including methyl, chloro,
and nitro substituents on the aromatic rings were well tolerated.
In addition, a menthadiene-containing substrate reacted smoothly
with 1 to furnish the corresponding pyrazole product 3aa in 47%
yield.
(73%93%), thereby providing possibilities for further
elaboration. The cyclization of 4-methyl-N'-(naphthalen-2-
ylmethylene)benzenesulfonohydrazide 2p with 1 also took place
to give the corresponding product 3p, albeit in somewhat lower
Table 2. Scope of reaction a, b
H
N
HN N
AgOTf (10 mol%)
CF3
N
Ts
O
O
Me phen (12 mol%)
2
+
R
F3C
OEt
KH (15 mol%)
Toluene, 60 °C
O
R
EtO
2
1
3
N
N
N
N
HN
HN N
HN
HN
HN
CF3
CF3
CF3
CF3
CF3
O
O
O
O
O
EtO
EtO
EtO
t-Bu
EtO
O
EtO
3a, 96%
3b, 98%
3c, 88%
3d, 97%
3e, 97%
N
N
N
N
HN
HN
HN
HN
N
HN
CF3
CF3
CF3
CF3
F3C
CF3
O
O
O
O
O
MeO
EtO
Me N
F
2
EtO
EtO
NC
EtO
i, 21%
EtO
3
f, 98%
3g, 98%
3h, 95%
3j
, 73%
3
N
N
N
N
N
N
HN
F
HN
F
HN
HN
HN
Br HN
CF3
CF3
CF3
CF3
CF3
CF3
O
O
O
O
O
O
F
EtO
EtO
Cl
Br
EtO
3o, 78%
EtO
EtO
EtO
Br
3
k, 75%
3l, 85%
3m, 93%
3n, 81%
3p, 30%
N
N
N
HN
HN
HN
N
N
N
HN
HN
HN
H
CF3
CF3
CF3
O
S
N
CF3
CF3
CF3
N
O
O
O
N
O
O
N
O
EtO
EtO
3r
EtO
3s
EtO
EtO
EtO
3
q, 87%
,
58%
, 62%
3t, 30%
3u, 36%
3v, 90%
N
N
N
N
N
HN
HN
HN
HN
NO2
HN
CF3
CF3
Cl
CF3
CF3
CF3
O
O
O
O
O
EtO
w, 82%
Reaction conditions: 1 (1.25 mmol), 2 (0.50 mmol), AgOTf (0.050 mmol, 10 mol%), Me
EtO
EtO
EtO
EtO
3
3x, 63%
3y, 48%
3z, 44%
3aa, 47%
a
2
phen (0.060 mmol, 12 mol%), KH (0.075 mmol, 15 mol%), toluene
2
(3.0 mL), 60 C, 20 h, under N atmosphere.
b
Isolated yields.

4
Tetrahedron
The reaction was also evaluated for the scalability by reacting
-methyl-N'-(4-methylbenzylidene)benzenesulfonohydrazide 2b
with ethyl 4,4,4-trifluoro-3-oxobutanoate 1 on a 5.0 mmol scale
Scheme 1). As anticipated, the reaction proceeded smoothly to
4
(
give the desired product 3b in 92% yield (1.37 g).
A plausible reaction mechanism for the formation of the
trifluoromethylated pyrazoles is depicted in Scheme 2. Initially,
the complexation of silver species with hydrazine would form the
silver complex I. Subsequently, complex I underwent an
nucleophilic addition with an anion of 1 to generate the
intermediate II. Finally, intramolecular cyclization of the amine
moiety with the ketone C=O bond in II could furnish III, which
underwent elimination and subsequent [1,5]-H shift to afford the
trifluoromethylated pyrazole product 3.
Figure 2. ORTEP drawing of 3r. Thermal ellipsoids are
In conclusion, we have developed a silver-catalyzed synthesis
of 5-aryl-3-trifluoromethyl pyrazoles starting from easily
accessible N'-benzylidene tolylsulfonohydrazides and ethyl 4,4,4-
trifluoro-3-oxobutanoate under basic conditions. The sequential
nucleophilic addition, intramolecular cyclization, elimination,
and [1,5]-H shift afforded the trifluoromethylated pyrazole
products in moderate to excellent yields in a single operation.
This work provides a complementary method to access 3-
trifluoromethyl pyrazoles.
drawn at 40% probability.
N
H
HN
N
AgOTf (10 mol%)
Me2phen (12 mol%)
CF3
N
Ts
+
O
O
O
F3C
OEt
KH (15 mol%)
Toluene, 60 °C, 20 h
EtO
2b
1
3b
1.44 g
2.30 g
1.37, 92%
Scheme 1. Gram scale experiment.
H
N
[AgLn]
N
Ts
Ts
Ts
AgLn
O
O
O
O
N
CF3
OAgLn
B-
N
N
HN
N
N
N
F3C
OEt
F3C
OEt
N
Ts
CF3
CF3
[1,5]-H shift
H
1
1'
O
O
O
EtO
EtO
EtO
I
III
IV
3
Ts
N
LnAg
N
CF3
O
O
EtO
II
Scheme 2. Plausible reaction mechanism.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21772022), and Fuzhou University.
Chem. 2016, 120, 170; (c) Xu, Z.; Gao, C.; Ren, Q.-C.;
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2

6
Tetrahedron
Highlights:



A silver-catalyzed synthesis of 5-aryl-3-
trifluoromethyl pyrazoles was developed.
Various 5-aryl-3-trifluoromethyl pyrazoles
were obtained in moderate to excellent yields.
A variety of functional groups were tolerated.