Copper-catalyzed chemoselective synthesis of 4-trifluoromethyl pyrazoles

Article abstract of DOI:10.1039/c9ra07694h

A series of 4-trifluoromethyl pyrazoles have been prepared via the copper-catalyzed cycloaddition of 2-bromo-3,3,3-trifluoropropene with a variety of N-arylsydnone derivatives under mild conditions. This new protocol under optimized reaction conditions [C

Full text of DOI:10.1039/c9ra07694h

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Copper-catalyzed chemoselective synthesis of 4-
trifluoromethyl pyrazoles†
Cite this: RSC Adv., 2019, 9, 30952
a
a
a
a
a
Yuning Man, Yabin Zhang, Bo Lin, Qi Lin b and Zhiqiang Weng
*
*
Jiaqing Lu,
Received 26th July 2019
Accepted 24th September 2019
A series of 4-trifluoromethyl pyrazoles have been prepared via the copper-catalyzed cycloaddition of 2-
bromo-3,3,3-trifluoropropene with a variety of N-arylsydnone derivatives under mild conditions. This
new protocol under optimized reaction conditions [Cu(OTf)2/phen, DBU, CH3CN, 35 ꢀC] afforded 4-
trifluoromethyl pyrazoles in moderate to excellent yields with excellent regioselectivity.
DOI: 10.1039/c9ra07694h
rsc.li/rsc-advances
synthetic methods that allow effectively access to 4-tri-
uoromethyl pyrazoles. Conventionally, 4-triuoromethyl
Introduction
pyrazoles were synthesized by the cycloaddition/cyclization
reaction with CF3-containing building blocks.20–23 For
example, the synthesis of 4-(triuoromethyl)pyrazole deriva-
tives from cycloaddition of hydrazines to b-tri-
uoromethylated vinamidinium salt or 2-(triuoromethyl)-
1,3-diketones was independently reported by the research
groups of Yamanaka and Yamakawa (Scheme 1a).20,21 Recently,
Tsui and co-workers developed a copper-mediated synthesis of
4-(triuoromethyl)pyrazoles from reaction of a,b-alkynic
tosylhydrazones with triuoromethyltrimethylsilane through
domino cyclization, triuoromethylation, and deprotection
sequence (Scheme 1b).24 Meazza and co-workers reported the
preparation of triuoromethyl-substituted pyrazoles via 1,3-
dipolar cycloaddition from sydnones and 1-aryl-3,3,3-triuoro-
propynes (Scheme 1c).22 The methods described above and
some other reported methods are useful,25–30 and have found
extensive applications in synthesis; however, some of reac-
tions suffered from tedious procedures for the synthesis of
triuoromethylated sources, the requirement of a stoichio-
metric amount of metal catalyst, and harsh reaction condi-
tions, as well as poor regioselectivities. Therefore, the
development of more general and practical approaches
Methods for introduction of a uorine atom or uorinated
group into organic molecules have emerged over the last
decade as powerful synthetic tools that allow the construc-
tion of organouorine compounds, which are of immense
interest in materials sciences, agrochemical development,
and medicinal chemistry.1–4 Indeed, derivatization of organic
compounds with uorinated units oen alters their chem-
ical, physical, and biological properties, by comparison with
the corresponding non-uorinated derivative and oen
improves their pharmacological properties.5–10
Among organouorinated molecules, triuoromethylated
pyrazoles11 are particularly important compounds because
many of them exhibit diverse biological activities and have
found applications as drugs and agrochemicals (Fig. 1). Key
examples include Celecoxib,
a
nonsteroidal anti-
inammatory drug used to treat pain or inammation,12
and Razaxaban, a factor Xa inhibitor potentially for the
treatment of thrombosis.13 In addition, triuoromethylated
pyrazoles form the core of several agrochemicals currently in
development. Specically, penthiopyrad has shown fungi-
cidal activity against foliar pathogens and soilborne patho-
gens,14 compounds A have shown insecticidal activity for
control of Spodoptera littoralis,15 and compounds B has
potential application as an acaricide for control of Tetra-
nychus urticae.16
While the vast array of procedures to synthesize 3-tri-
uoromethyl pyrazoles have been established,17–19 there were
considerably less efforts devoted to the development of
aFujian Provincial Key Laboratory of Electrochemical Energy Storage Materials,
College of Chemistry, Fuzhou University, Fuzhou, 350108, China. E-mail: zweng@
fzu.edu.cn; Fax: +86 591 22866247; Tel: +86 591 22866247
bOcean College, Minjiang University, Fuzhou, 350108, China. E-mail: qlin1990@163.
com
† Electronic supplementary information (ESI) available. CCDC 1934789. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9ra07694h
Fig. 1 Some biologically active trifluoromethylated pyrazoles.
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employing easily accessible starting materials under mild
conditions is highly desirable.
As part of our ongoing research into the development of
copper-catalyzed reactions for the preparation of organo-
uorine compounds,31,32 we aimed to investigate an alter-
native protocol for the synthesis of these scaffolds using
easy-to-operate synthetic tools. Based on the fact that
3,3,3-triuoropropyne could be generated in situ from
a
dehydrobromination reaction of readily available 2-
bromo-3,3,3-triuoropropene (1) under base conditions,33
and our recent work on 1,3-dipolar cycloaddition reac-
tion,34–36 we wondered if 2-bromo-3,3,3-triuoropropene
could be used for the selective synthesis of 4-tri-
uoromethyl pyrazoles (Scheme 1d). We report here a new
method for the synthesis of 4-triuoromethyl pyrazoles
through copper-catalyzed reaction of sydnones with 2-
bromo-3,3,3-triuoropropene (1).
Scheme 1 Recent examples for the preparation of 4-trifluoromethyl
pyrazoles.
Table 1 Optimization of the reaction conditionsa
Entry
[Cu]
Ligand
Base
Solvent
Temp. (ꢀC)
Time (h)
Yieldb (%)
3a:3a0
1
2
3
4
5
6
7
8
CuI
CuBr
CuSCN
CuTc
phen
phen
phen
phen
phen
phen
phen
bpy
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
NEt3
NaOt-Bu
KOt-Bu
NaOH
KOH
K3PO4
DBU
DBU
DBU
DBU
DBU
DBU
DBU
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
THF
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
25
35
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
2
47
36
71
74
9
99
85
22
27
23
0
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
97 : 3
99 : 1
99 : 1
—
—
—
—
—
—
—
100 : 0
—
—
CuSO4
Cu(OTf)2
Cu(TFA)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
—
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
9
dmbpy
tmeda
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
0
<1
<1
<1
<1
0
50
<1
0
<1
<1
44
60
Toluene
Dioxane
DMF
CH3CN
CH3CN
—
—
100 : 0
100 : 0
a
Reaction conditions: 1 (0.30 mmol, 3.0 equiv.), 2a (0.10 mmol), solvent (1.0 mL), N2; DBU ¼ 1,8-diazabicyclo[5.4.0]undec-7-ene; phen ¼ 1,10-
b
phenanthroline; bpy ¼ 2,20-bipyridine; dmbpy
¼
4,40-dimethyl-2,20-bipyridine; TMEDA ¼ tetramethylethylenediamine. The yield was
determined by 19F NMR spectroscopy with PhOCF3 as internal standard.
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With the optimised conditions in hand, the substrate scope
of the reaction was evaluated using a range of electronically and
sterically differentiated N-arylsydnone derivatives (Table 2).
Overall, it was observed that the reaction could tolerate a variety
of functional groups on the phenyl rings of sydnones. For
example, N-arylsydnones bearing para- or meta-alkyl-substituted
aromatic rings all reacted well with 1 to give the corresponding
products 3b–3d in 70–92% yields. As an exception, ortho-alkyl-
substituted on phenyl rings of N-arylsydnones afforded the
products 3e and 3f in lower yields (21% and 58%, respectively),
probably due to steric hindrance. The dimethyl-substituted N-
arylsydnone also took part in the reaction to afford the desired
product 3g in 65% yield. N-arylsydnone substrates bearing
electron-donating substituents, such as methoxy at the para-
position on the aryl ring was smoothly converted to the corre-
sponding product 3i in 83% yield, with the exception of
substrate bearing a OMe group at the ortho position (3h, 60%
yield). However, reactions of N-arylsydnones containing
electron-withdrawing substituents, such as ester, cyano, and
nitro groups on the aryl ring furnished the desired products 3j–
3n in relatively low yields (14–55%). Likewise, N-arylsydnone
derivatives bearing electron-withdrawing halogen groups, such
as uoro, chloro, bromo, and iodo on the aryl rings were
accommodated and furnished the desired products 3o–3v in
22–80% yields, thereby providing possibilities for following
chemical transformations. Analogously, the reaction with pol-
yaromatic sydnones provided the corresponding tri-
uoromethylated product 3w, 3y, and 3z in 63–88% yields. In
the case of the N-1-naphthylsydnone substrate, the desired
product 3x could only be obtained in 15% isolated yield, with
the majority of the remaining material attributed to unreacted
starting material. This may be due to the steric bulk of the 1-
naphthyl group hindering access to the cycloaddition site. The
process was applied also to heteroaromatic sydnones, such as N-
pyridyl- and cumarin sydnone derivatives, the corresponding
products 3aa-3ae were obtained in low to moderate yields (5–
41%). Notably, a N-benzylsydnone derivative was also proved to
be suitable substrate, producing the corresponding tri-
uoromethylated pyrazole 3af in promising yield (40%).
Results and discussion
We commenced our investigation by using N-phenylsydnone
(2a) as a model substrate in the reaction with 3.0 equiv. of 1 in
the presence of CuI (10 mol%)/phen (10 mol%) as a catalyst and
2.0 equiv. of DBU as a base (Table 1). Gratifyingly, aer 4 h at
35 ꢀC in CH3CN under
a nitrogen atmosphere, 4-tri-
uoromethylated pyrazole 3a was obtained in 47% yield with
excellent regioselectivity (Entry 1). The structure of 3a was
unambiguously determined by NMR spectroscopy and X-ray
crystallography (Fig. 2). Encouraged by this initial result, we
carried out the reaction under different conditions to optimize
the product yield. First, copper catalysts and ligands were
screened (Entries 2–10), and the results showed that the use of
Cu(OTf)2/phen presented the highest catalytic activity for this
reaction, providing product 3a in 99% yield (Entry 6). It is worth
mentioning that no product formation was observed in the
absence of copper salts and ligands (Entry 11), thus implying
the importance of the copper catalyst in this transformation.
The effects of the base were also examined. When DBU was
replaced with NEt3, NaOt-Bu, KOt-Bu, NaOH, KOH, or K3PO4 the
reactions only produced trace amounts or no desired product
(Entries 12ꢁ17). Commonly used organic solvents were also
screened. It was found that CH3CN gave the best yield (Entry 6);
solvents such as DMSO gave moderate yields of the product
(Entry 18), and THF, toluene, dioxane, and DMF retarded the
reaction (Entries 19–22). Reactions performed either at lower
temperatures (25 ꢀC) or reducing the reaction time to 2 h
resulted in substantially lower product yields (44% and 60%
yields, respectively; Entry 23 and 24).
To illustrate the further synthetic utility of this method,
a gram-scale reaction of N-phenylsydnone (2a) with 2-bromo-
3,3,3-triuoropropene (1) was performed, and the correspond-
ing 4-triuoromethyl pyrazole product 3a was given in 80%
isolated yield (Scheme 2). This result demonstrates the scal-
ability of the reaction.
Based on the above results and previous reports by Taran,37
Gomez-Bengoa, and Harrity,38 a plausible reaction mechanism
is proposed in Scheme 3. Firstly, the copper species reacted with
the in situ generated 3,3,3-triuoropropyne to give Cu(I) acety-
lide species I. In the second step, the cycloaddition of I with the
sydnone 2 would form the transition state II. The tight copper–
nitrogen interaction in II is probably responsible for its lower
the activation barrier compared with other modes of interaction
between arylsydnone and Cu(I) acetylide.38,39 Subsequently, the
Cu–N dissociation and C–N bond formation could generate III,
which upon CO2 elimination provided 3-copper(I) pyrazolide IV.
Finally, protonation of IV with new 3,3,3-triuoropropyne
Fig. 2 ORTEP drawing of 3a. Thermal ellipsoids are drawn at 40%
probability.
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Table 2 Scope of the reactiona
Scheme 2 Gram scale experiment.
Scheme 3 Plausible reaction mechanism.
produced the desired 4-triuoromethyl pyrazole regiomer 3
along with regeneration of the starting copper species to
complete the catalytic cycle.
Conclusions
In summary, we have developed a simple and efficient method
for the synthesis of 4-triuoromethyl pyrazole derivatives from
the copper-catalyzed cycloaddition of 2-bromo-3,3,3-
triuoropropene with a variety of N-arylsydnones under mild
conditions. This approach allowed the rapid assembly of
a
small library of potentially medicinally relevant 4-tri-
uoromethylated pyrazoles in moderate to excellent yields with
excellent regioselectivity. Investigations directed towards the
extension of the scope of the reaction are underway in our
laboratory.
a
Reaction conditions: 1 (1.5 mmol, 3.0 equiv.), 2 (0.50 mmol, 1.0
equiv.), Cu(OTf)2 (0.050 mmol, 10 mol%), phen (0.050 mmol,
10 mol%), DBU (1.0 mmol, 2.0 equiv.), CH3CN (5.0 mL), 35 ꢀC, 4 h,
N2; isolated yields.
Conflicts of interest
There are no conicts to declare.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21772022) and Fuzhou University.
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