Direct [3+2]-cycloaddition of electron-deficient alkynes with CF3CHN2: Regioselective one-pot synthesis of 3-trifluoromethylpyrazoles

Article abstract of DOI:10.1016/j.tetlet.2017.09.086

A direct and facile cycloaddition reaction of electron-deficient terminal alkynes with 2,2,2-trifluorodiazoethane under mild conditions to afford a series of 5-substituted 3-trifluoromethylpyrazoles in high yields is described. The potential application of this cycloaddition reaction was demonstrated via the efficient synthesis of a key intermediate of the antiviral drug AS-136A and a fluorinated analog of Tebufenpyrad.

Full text of DOI:10.1016/j.tetlet.2017.09.086

Accepted Manuscript
Direct [3+2]-Cycloaddition of Electron-Deficient Alkynes with CF CHN : Re-
3
2
gioselective One-Pot Synthesis of 3-Trifluoromethylpyrazoles
Feng Li, Jingjing Wang, Wenlong Pei, Hong Li, Huiling Zhang, Manman Song,
Linyun Guo, Anan Zhang, Lantao Liu
PII:
S0040-4039(17)31254-6
https://doi.org/10.1016/j.tetlet.2017.09.086
TETL 49356
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 July 2017
26 September 2017
29 September 2017
Please cite this article as: Li, F., Wang, J., Pei, W., Li, H., Zhang, H., Song, M., Guo, L., Zhang, A., Liu, L., Direct
[
3+2]-Cycloaddition of Electron-Deficient Alkynes with CF CHN : Regioselective One-Pot Synthesis of 3-
3
2
Trifluoromethylpyrazoles, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.09.086
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Direct [3+2]-Cycloaddition of Electron-Deficient Alkynes with CF CHN :
3
2
Regioselective One-Pot Synthesis of 3-Trifluoromethylpyrazoles
Feng Li, Jingjing Wang*, Wenlong Pei, Hong Li, Huiling Zhang, Manman Song, Linyun Guo, Anan
Zhang, Lantao Liu*
College of Chemistry and Chemical Engineering, Shangqiu Normal University, 298 Wenhua Road, Shangqiu, Henan 476000, China
e-mail: wangjingjing0918@163.com, liult05@iccas.ac.cn, phone: +86-0370-3115072
ARTICLE INFO
ABSTRACT
Article history:
Received
A direct and facile cycloaddition reaction of electron-deficient terminal alkynes with
2,2,2-trifluorodiazoethane under mild conditions to afford a series of 5-substituted
Received in revised form
Accepted
3-trifluoromethylpyrazoles in high yields is described. The potential application of this
cycloaddition reaction was demonstrated via the efficient synthesis of a key intermediate of the
antiviral drug AS-136A and a fluorinated analog of Tebufenpyrad.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
3 2
CF CHN
electron-deficient terminal alkynes
cycloaddition
3
-trifluoromethylpyrazoles
3
construction of diverse trifluoromethylated building blocks. For
Trifluoromethyl-substituted pyrazoles are valuable synthetic
intermediates as well as important structural motifs in many
example, Ma and co-workers reported
a
silver-mediated
CHN
to afford functionalized 3-trifluoromethyl-pyrazoles, as well as
the metal-free cycloaddition of CF CHN with arynes and
electron-deficient allenic esters to construct CF -substituted
1
pharmaceuticals and bioactive molecules. Many examples of
cycloaddition reaction of various terminal alkynes with CF
3
2
4
bioactive trifluoromethyl-substituted pyrazoles have emerged in
recent years (Fig. 1). For example, AS-136A represent a first-in-
class non-nucleoside inhibitor of the Measles virus RNA-
2
3
2
3
2
a
dependent RNA polymerase (RdRp) complex. Razaxaban and
5
indazoles and pyrazoles. Mykhailiuk and co-workers described
the [3+2]-cycloaddition of electron-deficient alkenes and alkynes
its derivatives are coagulation factor Xa inhibitors, and have been
2
used in the treatment of thrombotic diseases. DP-23 possesses
b
3 2
with CF CHN to give trifluoromethyl-substituted pyrazolines
6
insecticidal activity and represents a potentially new class of
and pyrazoles. In comparison with previously reported methods,
these representative modern protocols employ milder conditions
to afford the desired adducts with improved functional group
tolerance. Despite this promising progress, it is still highly
2
pesticide. Finally, fluorinated analogs of Tebufenpyrad have
c
acaricide activity and may act as adulticides and fertility
2
d
inhibitors. Trifluoromethyl-substituted pyrazoles are promising
molecules for medicinal chemists, and thus, the development of
new methodologies for their construction has become the subject
of intensive research in organic synthesis and drug chemistry.
3 2
desirable to develop new cycloaddition reactions with CF CHN
in order to broaden the diversity of obtainable
trifluoromethylated pyrazole derivatives. As part of our
continued interest in organofluorine chemistry, herein, we report
7
the direct and facile cycloaddition of electron-deficient terminal
3 2
alkynes with CF CHN under mild conditions to obtain the
corresponding 3-trifluoromethylpyrazoles in high yields.
We initiated our study by evaluating the model reaction of
1
-phenylprop-2-yn-1-one 1a with CF
without any metal complexes or additives at room temperature
Table 1). (CAUTION: CF CHN is potentially explosive). To
our delight, phenyl(3-(trifluoromethyl)-1H-pyrazol-5-
yl)methanone 2a was obtained in 96% yield (Entry 1). The use of
other solvents, such as THF, CH Cl and CH CN, led to lower
yields (Entries 2−4). Decreasing the amount of CF CH NH ·HCl
also led to a lower yield (Entry 5), while increasing the
equivalents of CF CH NH ·HCl did not improve the yield (Entry
). Therefore, the combination of CF CH NH ·HCl (3.0 equiv.)
3 2 2
CHN in toluene/H O
(
3
2
Figure 1. Selected 3-trifluoromethylpyrazole-based bioactive
compounds.
2
2
3
3
2
2
The reactions of 2,2,2-trifluorodiazoethane (CF
generated in situ from readily available CF CH NH ·HCl and
NaNO in water, has emerged as a powerful tool for the
3 2
CHN ),
3
2
2
3
2
2
2
6
3
2
2

and NaNO
temperature was determined to be the optimal reaction conditions.
2
(3.0 equiv.) in toluene/H
2
O (v/v = 20:1) at room
3 2
1p with CF CHN also proceeded smoothly to give the
corresponding product 2p in 83% yield.
Table 1. Reaction optimization for the [3+2]-cycloaddition of 1a
a
with CF CHN
3 2
To demonstrate the applicability of this cycloaddition reaction,
we opted to explore the synthesis of 3-trifluoromethyl-pyrazole-
5
the measles virus inhibitor AS-136A and a fluorinated analog of
-carboxylic acid 5 which is a known synthetic intermediate of
9
2
d
Tebufenpyrad (Scheme 3). For example, methylation of ethyl 3-
trifluoromethyl pyrazole-5-carboxylate 2n with iodomethane in
DMF gave ethyl 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-
carboxylate 3 in 94% yield, then subsequent hydrolysis afforded
compound 5 in 95% yield. The reaction of cycloadduct 2n with
benzyl bromide also delivered the corresponding product 4 in
8
3% yield. Unfortunately, we found that compound 4
decomposed into compound 2n in aqueous NaOH. In addition,
we conducted the CuI-catalyzed N-arylation of cycloadduct 2n
with iodobenzene, affording ethyl 1-phenyl-3-(trifluoromethyl)-
a
2
Reagents and conditions: 1a (0.2 mmol), solvent (1.0 mL), H O
50 µL).
(
10
1
H-pyrazole-5-carboxylate 6 in 72% yield (Scheme 4).
b
Isolated yield.
With the optimized conditions in hand, the substrate scope
was investigated using a variety of electron-deficient terminal
alkynes (Scheme 1). The cycloaddition reaction tolerates various
substituents on the aryl ring. Both 1-(p-tolyl)prop-2-yn-1-one and
1-(4-methoxyphenyl)prop-2-yn-1-one exhibited good reactivities,
affording compounds 2b, 2c in 95% and 96% yields, respectively.
When the electron-deficient terminal alkynes were modified by
Figure 2. Single crystal X-ray structure of product 2h.
3
F-, Cl-, Br- and CF -substituents on the phenyl ring, the desired
products 2d-i were also obtained in good yields. The structure of
compound 2h was further confirmed to be 3-trifluoromethyl-5-
(
(
4-bromobenzoyl)-1H-pyrazole by single crystal X-ray analysis
8
Fig. 2).
A
dimethylaryl-substituted alkyne gave the
corresponding product 2j in 92% yield. Furthermore, the 2-
naphthyl-substituted alkyne was also a good substrate, affording
compound 2k in excellent yields. Finally, alkynyl ketone and
alkynyl esters afforded the corresponding products 2l-n in
excellent yields under the same reaction conditions.
Scheme 2. Reaction of a β-substituted alkynyl ketone and
alkynyl ester.
Scheme 1. Reaction scope.
Scheme 3. Further synthetic transformations of compound 2n.
Scheme 4. Further synthetic transformations of compound 2n.
In summary, we have developed a direct and efficient
cycloaddition reaction of electron-deficient terminal alkynes with
a
Reagents and conditions: 1 (0.2 mmol), CF
3
CH
2 2
NH ·HCl (0.6
mmol), NaNO
2
(0.6 mmol), toluene (1.0 mL), H O (50µL).
2
CF
A
3
CHN
series of 5-substituted 3-trifluoromethylpyrazoles were
2
without the need for any metal complexes or additives.
b
Isolated yield.
obtained in high yields under mild reaction conditions. The
reaction is exceptionally regioselective and the products are of
high value for multiple synthetic applications. The scope and
limitations of this reaction, as well as synthetic applications of
these 5-substituted 3-trifluoromethylpyrazoles, are currently
being investigated in our laboratory.
Next, the reactivity of β-substituted alkynyl ketones and
alkynyl esters were examined (Scheme 2). The reaction of ethyl
3-phenylpropiolate 1o with CF
afforded the desired product 2o in 72% yield. Under the same
o
in toluene at 100 C for 6 h
3
CHN
2
reaction condition, the reaction of 1,3-diphenylprop-2-yn-1-one

3
Acknowledgments
Xie, H.; Xu, M.; Zhao, X.; Liu, L.; Zhao, W.-X. Appl.
Organometal. Chem. 2017, 31, e3545.
8
.
CCDC 1575273 (2h) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The authors are grateful for financial support from the
National Natural Science Foundation of China (Nos. 21402116,
The
www.ccdc.cam.ac.uk/data_request/cif.
Cambridge
Crystallographic
Data
Center
via
2
1502111, 21572126), the Key Scientific and Technological
Project of Henan Province (Nos. 172102210099) and the Key
Science Research of Education Committee in Henan Province
9. Sun, A.; Yoon, J.-J.; Yin, Y.; Prussia, A.; Yang, Y.; Min, J.;
Plemper, R. K.; Snyde, J. P. J. Med. Chem. 2008, 51, 3731.
1
0. Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org.
Chem. 2004, 69, 5578.
(
No. 15A150072).
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Highlights
•
•
•
•
Facile access to a variety of 5-substituted 3-
trifluoromethylpyrazole derivatives.
Reaction proceeds regioselectively without
the assistance of any additives.
A one-pot reaction was proposed without
3 2
isolation of the dangerous CF CHN .
Cycloadducts represent
versatile
intermediates for multiple synthetic
applications.

5
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Direct [3+2] Cycloaddition of Electron-
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3 2
Deficient Alkynes with CF CHN : Highly
Regioselective One-Pot Synthesis of 3-
Trifluoromethylpyrazoles
Feng Li, Jingjing Wang*, Wenlong Pei, Hong Li, Huiling Zhang, Manman Song, Linyun Guo, Anan Zhang,
Lantao Liu*