Cycloaddition of Trifluoroacetaldehyde N-Triftosylhydrazone (TFHZ-Tfs) with Alkynes for Synthesizing 3-Trifluoromethylpyrazoles

Article abstract of DOI:10.1021/acs.orglett.0c00395

A transition-metal-free [3 + 2] cycloaddition between trifluoroacetaldehyde N-triftosylhydrazone (TFHZ-Tfs) and alkynes is reported. This protocol provides an operationally simple and general method for the synthesis of diverse 3-trifluoromethylpyrazoles in good to excellent yields with broad substrate scope, including aryl, heteroaryl, and alkyl terminal alkynes, and electron-deficient internal alkynes. The synthetic potential of this method was further demonstrated by the synthesis of an antiarthritic drug Celecoxib in multigram scale.

Full text of DOI:10.1021/acs.orglett.0c00395

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Letter
Cycloaddition of Trifluoroacetaldehyde N‑Triftosylhydrazone (TFHZ-
Tfs) with Alkynes for Synthesizing 3‑Trifluoromethylpyrazoles
Hongwei Wang,§ Yongquan Ning,§ Yue Sun,§ Paramasivam Sivaguru,§ and Xihe Bi*
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ABSTRACT: A transition-metal-free [3 + 2] cycloaddition
between trifluoroacetaldehyde N-triftosylhydrazone (TFHZ-Tfs)
and alkynes is reported. This protocol provides an operationally
simple and general method for the synthesis of diverse 3-
trifluoromethylpyrazoles in good to excellent yields with broad
substrate scope, including aryl, heteroaryl, and alkyl terminal
alkynes, and electron-deficient internal alkynes. The synthetic
potential of this method was further demonstrated by the synthesis
of an antiarthritic drug Celecoxib in multigram scale.
eterocycles holding the trifluoromethyl (CF3) group are
core structures of many bioactive natural and unnatural
compounds, and also exhibit high utility for further design of
bioactive molecules.1 Within this context, 3-trifluoromethyl-
pyrazoles represent valuable synthetic intermediates and
privileged scaffolds found in many drugs, agrochemicals, and
biologically active molecules (Figure 1).2 For example,
treatment of both venous and arterial thrombosis.2i As a result,
their preparation has received significant attention, and many
useful strategies have been disclosed.3,4 Among them, the
intermolecular cycloaddition of 2,2,2-trifluorodiazoethane
(CF3CHN2) with C−C multiple bonds represents a most
powerful and atom-economical approach to access 3-
trifluoromethylpyrazoles (Figure 2a).5−7 For instance, in
2013, the Ma group realized the first regioselective [3 + 2]
H
Figure 1. Biologically active molecules with a 3-trifluoromethylpyr-
azole core.
Figure 2. Previous and current strategies for the synthesis of 3-
trifluoromethylpyrazoles from CF3CHN2.
Celecoxib is a nonsteroidal anti-inflammatory and antiarthritic
drug for the treatment of pain and inflammation;2c,d SC-560
acts as a growth inhibitor of human lung cancer cells;2e AS-
136A serves as a measles virus inhibitor;2f Razaxaban acts as a
significant anticoagulant agent;2g DPC-602 is a potent,
selective, and orally bioavailable factor Xa inhibitor for the
Received: January 31, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00395
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
cycloaddition of CF3CHN2 with alkynes for the synthesis 3-
trifluoromethylpyrazoles.5a Alternatively, the Jamison group
described the same transformation by continuous flow
method.5f,g Very recently, Wang and co-workers achieved
this transformation under transition-metal-free conditions.5h
Limited scope of alkyl alkyne substrates is the common
drawback of these methods. Although CF3CHN2 has emerged
as a highly reactive 1,3-dipole in this reaction, the preparation
of the gaseous CF3CHN2 has remained complicated due to its
hazardous nature and handling issues.8 It is typically generated
in situ in solution by the treatment of CF3CH2NH2·HCl with
NaNO2 under oxidative acidic8b−f or continuous flow
conditions5f,g,8g,h or recycling of gaseous CF3CHN2.8i In
addition, the utility of CF3CHN2 always requires a large
excess of reagent, which makes the synthetic methods rather
expensive. These difficulties remain a general limitation for
their broad applications, especially in a large scale synthesis.
Therefore, developing an operationally safe and nontoxic
reagent that can slowly release CF3CHN2 in situ under mild
conditions is highly appealing to offer an efficient route to
access 3-trifluoromethylpyrazoles via the [3 + 2] cycloaddition
of CF2CHN2 with alkynes.
Table 1. Optimization of the Reaction Conditions
b
entry
base (equiv)
solvent
T (°C)
yield of 2g (%)
1
2
3
4
5
6
7
8
9
10
KOH (4.0)
Cs2CO3 (4.0)
t-BuOK (4.0)
t-BuOLi (4.0)
NaOH (4.0)
KOH (4.0)
KOH (4.0)
KOH (4.0)
KOH (4.0)
KOH (4.0)
KOH (4.0)
KOH (4.0)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH3CN
toluene
THF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
100
100
100
100
100
100
100
100
80
92
60
60
44
52
trace
69
41
58
86
120
100
100
c
11
d
trace
7
12
a
Reaction conditions: 1g (0.3 mmol), TFHZ-Tfs (0.6 mmol, 2.0
equiv), base (1.2 mmol, 4.0 equiv), solvent (1 mL), 10 h, N2.
b
c
d
Isolated yield. Under air. Under oxygen.
In this context and our continued interest in the room-
temperature decomposition of N-sulfonylhydrazones as well as
design, synthesis, and reaction of functionalized diazo-
methanes,9−11 we recently reported trifluoroacetaldehyde N-
triftosylhydrazone (TFHZ-Tfs) as an operationally safe and
nontoxic CF3CHN2 surrogate, which could release CF3CHN2
under basic conditions.10 The utility of TFHZ-Tfs was
successfully employed in the iron-catalyzed gem-difluoroalke-
nylation of X−H (X = N, O, S, Se) bonds, Doyle-Kirmse
rearrangement, and cyclopropanation reactions,10 as well as the
transition-metal-free gem-difluoroolefination of TFHZ-Tfs with
boronic acids.11 Meanwhile, Titanyuk and co-workers reported
the employment of trifluoroacetaldehyde N-tosylhydrazone as
a precursor of trifluorodiazoethane in reactions of insertion
into the heteroatom−hydrogen (X−H) bond.12 In view of the
importance of 3-trifluoromethylpyrazole in medicinal re-
search,2 we herein wish to report a new reaction paradigm of
TFHZ-Tfs in the [3 + 2] cycloaddition with alkynes under
transition-metal-free conditions, allowing for the assembly of 3-
trifluoromethylpyrazoles (Figure 2b). Remarkably, this proto-
col represents a general, operationally safe, and complementary
approach to the existing methods that require additional safety
techniques or lacks substrate generality. Its potential
applications were emphasized by scalable experiment and
expedient preparation of the potential antiarthritic drug
Celecoxib.
To validate our hypothesis, the reaction of TFHZ-Tfs with
4-bromophenylacetylene 1g was used as the model substrates.
The reaction in the presence of KOH in 1,4-dioxane at 100 °C
under nitrogen atmosphere afforded the corresponding
product 2g in 92% yield (Table 1, entry 1). To further
optimize the reaction conditions, we examined other inorganic
bases such as Cs2CO3, t-BuOK, t-BuOLi, and NaOH; however,
no superior results were obtained (Table 1, entries 1 vs 2−5).
Replacement of solvent 1,4-dioxane with toluene or THF gave
moderate yields of the product 2g, while acetonitrile provided
trace amounts of product 2g (Table 1, entries 6−8). When the
reaction temperature was decreased to 80 °C or increased to
120 °C, the yield was dropped to 58% or 86%, respectively
(Table 1, entries 9 and 10). In addition, performing the
reaction under air/oxygen atmosphere gave trace amounts of
product 2g (Table 1, entries 11 and 12). Note that the use of
trifluoroacetaldehyde N-tosylhydrazone (TFHZ-Ts), instead of
TFHZ-Tfs, led to a significant decrease in product yield (63%).
Next, the suitability of this protocol was first investigated
with a range of aryl-substituted terminal alkynes. As shown in
Scheme 1a, phenylacetylenes bearing electron-donating
(methyl, tert-butyl, methoxy, phenoxy), electron-withdrawing
(fluoro, trifluoromethyl, nitro, acetyl), and halide (chloro,
bromo) groups at any of the positions of aryl ring were all
reacted efficiently to give the corresponding products 2a−2s in
good to excellent yields. The structure of compound 2b was
unambiguously confirmed by means of single crystal X-ray
crystallography analysis (CCDC No. 1978283). Generally,
phenylacetylenes bearing electron-withdrawing groups ex-
hibited higher reactivity than their electron-donating groups
(2b−2e vs 2h−2j). Moreover, the slight decrease in yield was
observed with ortho-substituted phenylacetylenes, possibly due
to the steric effect (2b vs 2p, 2f vs 2r, 2h vs 2s). It is
noteworthy that phenylacetylene with a sensitive functional
group (3-amino) was also suitable for this cycloaddition,
affording the expected product 2o in 88% yield. A
disubstituted phenylacetylene (2t) could also be tolerated
under standard conditions. In addition to aryl alkynes, fused
aryl (2-naphthyl), heterocyclic (2-thienyl, 3-thienyl, 3-pyridyl),
and fused heterocyclic (3-dibenzothienyl, 6-(4,4-dimethylth-
iochromanyl)) alkynes were also suitable substrates for the
reaction, giving the pyrazole products 2u−2z in 68−88%
yields. Similarly, alkyne containing a ferrocenyl group was also
smoothly transformed into 2aa in 71% yield. Remarkably, the
activated aryl alkynes, such as 1-bromo-2-(4-chlorophenyl)-
acetylene (2ab) and methyl 3-phenylpropiolate (2ac) were
also tolerated with high efficiency, which exemplified the
versatility of the reaction.
We then turned our attention to extend the scope of this
reaction to alkyl-substituted alkynes (Scheme 1b). Alkyl
terminal alkynes bearing a long chain alkyl (n-hexyl) and a
phenyl group at the terminus of the alkyl chain (benzyl,
phenylethyl) were successfully converted to the desired
products 2ad−2af in moderate to good yields. Similarly,
synthetically relevant functional groups, such as chloro, azido,
B
https://dx.doi.org/10.1021/acs.orglett.0c00395
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a
Scheme 1. Scope of Transition-Metal-Free [3 + 2] Cycloaddition of TFHZ-Tfs with Alkynes
a
Reaction conditions: 1 (0.3 mmol), TFHZ-Tfs (0.6 mmol, 2.0 equiv), KOH (1.2 mmol, 4.0 equiv) in 1 mL of 1,4-dioxane at 100 °C for 10 h
under N2. Yields are of isolated products. Conditions A: 2b (0.3 mmol, 1.0 equiv), CuI (5 mol %), K2CO3 (2.0 equiv), N,N′-
dimethylcyclohexyldiamine (20 mol %), N,N′-dibenzyl-4-iodobenzenesulfonamide (5.0 equiv) in dry 1,4-dioxane (2 mL) at 150 °C for 36 h.
and various aryl ethers at the terminal carbon of alkyl chain of
alkyl terminal alkynes, were all proved to be suitable substrates,
leading to the desired products 2ag−2ak in 49−82% yields.
Moreover, the propargylic ester also showed good reactivity,
and 63% yield the cycloaddition product 2al was obtained. It
should be important to highlight that the substrate bearing a
conjugate diyne and enyne regioselectively underwent the
cycloaddition at the terminal CC bond, affording the desired
products 2am and 2an in 75% and 64% yields, respectively. It
is remarkable that activated internal alkyne was also found to
undergo the cycloaddition reaction efficiently, furnishing
pyrazole product 2ao in 68% yield.
To further evaluate the efficacy and synthetic utility of this
protocol, we carried out the scale-up experiment using 30
mmol (3.48 g) of methyl phenylacetylene, which afforded the
desired product 2b in 67% (4.52 g) yield. The compound 2b is
a key intermediate for the preparation of antiarthritic drug
Celecoxib, which was derived from the Cu-catalyzed N-
arylation of 2b with N,N′-dibenzyl-4-iodobenzenesulfonamide,
and following elimination of the benzyl group delivered
Celecoxib in 71% yield (Scheme 1c).5h
On the basis of the above experimental results and the
related literature precedents,5 a reasonable mechanism for this
[3 + 2] cycloaddition of TFHZ-Tfs with alkynes was proposed
C
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as follows (Scheme 2). The reaction likely proceeds through
the initial formation of CF3CHN2 (A), which exists a charge
Chemistry, Northeast Normal University, Changchun 130024,
China
Yongquan Ning − Jilin Province Key Laboratory of Organic
Functional Molecular Design & Synthesis, Department of
Chemistry, Northeast Normal University, Changchun 130024,
China
Scheme 2. Proposed Reaction Mechanism
Yue Sun − Jilin Province Key Laboratory of Organic Functional
Molecular Design & Synthesis, Department of Chemistry,
Northeast Normal University, Changchun 130024, China
Paramasivam Sivaguru − Jilin Province Key Laboratory of
Organic Functional Molecular Design & Synthesis, Department
of Chemistry, Northeast Normal University, Changchun
130024, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00395
Author Contributions
§H.W., Y.N., Y.S., and P.S. contributed equally to this work.
separation isomer (A′), from the decomposition of TFHZ-Tfs
promoted by a base.10 Then, the 1,3-dipolar cycloaddition of
CF3CHN2 (A′) with alkynes occurs to form a crucial
cycloadduct B. Following 1,3-hydrogen transfer, the target
pyrazole products 2 were formed.5a,h
In conclusion, a highly efficient and operationally simple
method for the synthesis of 3-trifluoromethylpyrazoles has
been developed, through the [3 + 2] cycloaddition of
CF3CHN2, in situ generated from base-promoted TFHZ-Tfs
decomposition, with alkynes. This method features in broad
substrate scope of alkyl and (hetero)aryl alkynes, excellent
functional group tolerance, and high product yields, in
particular avoiding the direct exposure to toxic and explosive
CF3CHN2. Furthermore, the application to multigram scale
preparation of Celecoxib demonstrates the great potency of
this protocol in the medicinal research of the family of 3-
trifluoromethylpyrazole-based drugs in the future.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC (21871043,
21961130376), Department of Science and Technology of
Jilin Province (20180101185JC, 20190701012GH), and the
Fundamental Research Funds for the Central Universities
(2412019ZD001).
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The Supporting Information is available free of charge at
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Experimental procedures and copies of spectra (PDF)
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a, J. L.; Soloshonok, V. A.; Izawa, K.; Liu,
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Accession Codes
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CCDC 1978283 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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AUTHOR INFORMATION
Corresponding Author
■
Xihe Bi − Jilin Province Key Laboratory of Organic Functional
Molecular Design & Synthesis, Department of Chemistry,
Northeast Normal University, Changchun 130024, China;
State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-0002-
6694-6742; Email: bixh507@nenu.edu.cn
Authors
Hongwei Wang − Jilin Province Key Laboratory of Organic
Functional Molecular Design & Synthesis, Department of
D
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