Regioselective Synthesis of 3-Trifluoromethylpyrazole by Coupling of Aldehydes, Sulfonyl Hydrazides, and 2-Bromo-3,3,3-trifluoropropene

Article abstract of DOI:10.1021/acs.orglett.9b04228

A general and practical strategy for 3-trifluoromethylpyrazole synthesis is reported that occurs by the three-component coupling of environmentally friendly and large-tonnage industrial feedstock 2-bromo-3,3,3-trifluoropropene (BTP), aldehydes, and sulfonyl hydrazides. This highly regioselective three-component reaction is metal-free, catalyst-free, and operationally simple and features mild conditions, a broad substrate scope, high yields, and valuable functional group tolerance. Remarkably, the reactions could be performed on a 100 mmol scale and smoothly afforded the key intermediates for the synthesis of celecoxib, mavacoxib, SC-560, and AS-136A. Preliminary mechanism studies indicated that a 1,3-hydrogen atom transfer process was involved in this transformation.

Full text of DOI:10.1021/acs.orglett.9b04228

pubs.acs.org/OrgLett
Letter
Regioselective Synthesis of 3‑Trifluoromethylpyrazole by Coupling
of Aldehydes, Sulfonyl Hydrazides, and 2‑Bromo-3,3,3-
trifluoropropene
Chuanle Zhu,* Hao Zeng, Chi Liu, Yingying Cai, Xiaojie Fang, and Huanfeng Jiang*
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ABSTRACT: A general and practical strategy for 3-trifluoromethylpyrazole synthesis is reported that occurs by the three-
component coupling of environmentally friendly and large-tonnage industrial feedstock 2-bromo-3,3,3-trifluoropropene (BTP),
aldehydes, and sulfonyl hydrazides. This highly regioselective three-component reaction is metal-free, catalyst-free, and operationally
simple and features mild conditions, a broad substrate scope, high yields, and valuable functional group tolerance. Remarkably, the
reactions could be performed on a 100 mmol scale and smoothly afforded the key intermediates for the synthesis of celecoxib,
mavacoxib, SC-560, and AS-136A. Preliminary mechanism studies indicated that a 1,3-hydrogen atom transfer process was involved
in this transformation.
rifluoromethylpyrazole, especially 3-trifluoromethylpyra-
Tzole, is a privileged core structure in many pharmaceut-
icals and agrochemicals (Scheme 1a),1 such as celecoxib2a and
mavacoxib2b (COX-2 inhibitors), SC-560 (human lung cancer
inhibitor),2c DPC-602 (arterial thrombosis),2d AS-136A
(measles virus inhibitor),2e razaxaban (anticoagulant),2f and
DP-23 (insecticidal activity).2g Owing to the immense
applications of 3-trifluoromethylpyrazole derivatives, the
development of efficient methods to construct the 3-
trifluoromethylpyrazole moiety has gained much attention.3−5
Traditionally, the 3-trifluoromethylpyrazole framework could
be constructed by dehydrative condensation between
hydrazines and 1,3-dicarbonyl compounds or ynones via C3−
N2 and C5−N1 bond formation, which often suffers from the
formation of regioisomeric mixtures.3 In 2013, Ma reported a
highly regioselective [3 + 2] cycloaddition of 2,2,2-
trifluorodiazoethane with alkynes4a or allenes4b for the
synthesis of 3-trifluoromethylpyrazoles via C3−C4 and C5−
N1 bond formation, which was promoted by superstoichio-
metric amounts of silver salts.4 Later in 2017, Jamison realized
the same transformation using an elegant continuous flow
strategy.5 However, owing to its gaseous and potential
explosive properties, 2,2,2-trifluorodiazoethane needs to be in
situ generated. In particular, these reported strategies focused
on two-component coupling (Scheme 1b). Thus despite this
progress, the development of more general and practical
methods for the synthesis of 3-trifluoromethylpyrazole is
always in high demand.
enable the direct construction of useful and complex molecules
from simple and readily available raw materials.6 2-Bromo-
3,3,3-trifluoropropene (BTP) is a stable liquid at room
temperature and is an environmentally friendly and large-
tonnage industrial feedstock that is not classified as an ozone
depletion compound and is thought to be an ideal alternative
to Halon fire suppressant.7 Thus we envision constructing 3-
trifluoromethylpyrazole from BTP by a multiple-component
reaction. The logical following retrosynthetic analysis shows
that the coupling of BTP with a C1 synthon and a N2 moiety
via C3−N2, C4−C5, and C5−N1 bond formation is the most
promising strategy to construct this 3-trifluoromethylpyrazole
core; however, to the best of our knowledge, this BTP-involved
three-component strategy has never been reported before.
Thus the choice of a suitable reaction system and control over
the regioselectivity are the main challenges in this trans-
formation. We herein report a highly regioselective coupling
reaction of aldehydes, sulfonyl hydrazides, and BTP, delivering
various useful 3-trifluoromethylpyrazole derivatives in high
yield (Scheme 1c). Remarkably, this three-component reaction
is metal-free, catalyst-free, scalable, and operationally simple
and features mild conditions, a broad substrate scope, and
valuable functional group tolerance.
Received: November 25, 2019
Multiple-component reactions are regarded as one of the
most attractive protocols in synthetic chemistry because they
https://dx.doi.org/10.1021/acs.orglett.9b04228
© XXXX American Chemical Society
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A

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Letter
a
Scheme 1. 3-Trifluoromethylpyrazole
Table 1. Optimization of the Reaction Conditions
b
entry
solvent
toluene
base
yield (%)
1
2
3
4
5
6
7
8
Cs2CO3
K2CO3
Li2CO3
t-BuOK
t-BuOLi
MeONa
DBU
trace
trace
0
0
24
trace
63 (61)
0
0
0
38
38
40
43
39
31
58
91 (88)
91
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
MeCN
1,4-dioxane
THF
DMF
DMSO
EtOH
DABCO
Et3N
9
10
11
12
13
14
15
16
17
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
c
18
c d
,
toluene
toluene
19
a
Reaction conditions: 1a (0.5 mmol), TsNHNH2 (1.2 equiv), bases
(3 equiv), BTP (2 equiv), and solvent (3 mL) were stirred in a 25 mL
b
c
test tube at room temperature for 12 h. 19F NMR yields. At 60 °C
d
for 6 h. Under N2 with anhydrous toluene as the solvent. Isolated
The initial experiment of this three-component reaction for
3-trifluoromethylpyrazole synthesis was carried out with
benzaldehyde 1a, p-toluenesulfonyl hydrazide (TsNHNH2),
and BTP under the treatment of Cs2CO3 in toluene at room
temperature (Table 1, entry 1). A trace amount of new species
was detected by GC−MS with a base peak at m/z = 212.03,
which has the same m/z value with respect to our desired 3-
trifluoromethylpyrazole product 2a. To identify the structure
of this new species, different inorganic bases such as K2CO3,
Li2CO3, t-BuOK, t-BuOLi, and MeONa and organic bases such
as DBU, DABCO, and Et3N were first examined to improve its
yield (Table 1, entries 2−9). To our delight, a base of DBU
gave the new species in 61% isolated yield. Thus its structure
was confirmed to be our desired 3-trifluoromethylpyrazole
product 2a by nuclear magnetic resonance (NMR) analysis.
Without a base, no product 2a was detected (Table 1, entry
10). Next, different types of solvent such as 1,2-dichloroethane
(DCE), MeCN, 1,4-dioxane, THF, DMF, DMSO, and EtOH
were investigated to optimize the yield of 2a (Table 1, entries
11−17); however, no superior results were obtained.
Furthermore, increasing the reaction temperature to 60 °C
enhanced the isolated yield of 2a to 88% in 6 h (Table 1, entry
18). In addition, performing the reaction under anhydrous
toluene and a N2 atmosphere did not increase the yield of 2a,
indicating that this three-component reaction was not air- or
moisture-sensitive (Table 1, entry 19). In particular, this three-
component coupling reaction is highly regioselective, and no
other regioisomers were detected.
yields are presented in the parentheses.
pyrazole products 2a−g in high yield. Benzaldehyde derivatives
with electron-donating substituents such as alkyl, alkoxy,
hydroxy, amino, morpholinyl, and methylthio and electron-
withdrawing substituents such as fluoro, chloro, bromo, iodo,
cyano, trifluoromethyl, formic ester, sulfonyl, nitro, and ethynyl
groups on the phenyl ring all smoothly afforded the
corresponding products 2h−al. Symmetric 3-trifluoromethyl-
pyrazole products 2am−an derived from the corresponding
symmetric aldehydes were obtained in high yield. It is
noteworthy that this reaction was not sensitive to steric
hindrance (2c, 2e, 2k, 2o, 2af, and 2am), and acid-free O−H
and N−H bonds could also be tolerated under the standard
reaction conditions (2q and 2r). α,β-Unsaturated aldehydes
such as (S)-perillaldehyde and (E)-tigladehyde also gave 2ao−
ap in high yield. Furthermore, different heteroaromatic
aldehydes, such as furanyl-, thienyl-, pyridyl-, and quinolyl-
bearing aldehydes, were also found to be good substrates, and
the desired products 2aq−ax were isolated in high yield. In
addition, aliphatic aldehydes such as cyclohexanaldehyde and
lilialdehyde were also tested under the standard reaction
conditions, and the corresponding products 2ay and 2az were
obtained in reasonable yield.
Next, four different 100 mmol scale experiments were
performed under the standard reaction conditions. By simple
extraction and recrystallization, products 2h, 2v, and 2aa were
obtained in high yield, which were independently key
intermediates for colecoxib, mavacoxib, and SC-560 (Scheme
3a).8 Importantly, product 2ar derived from biomass derivative
2-furaldehyde was also obtained in 78% yield (15.76 g).9
Further N−H methylation of 2ar gave product 3 in 70% yield,
which was used for the preparation of AS-136A (Scheme
3b).2e,3g,4 It is noteworthy that these 100 mmol scale
With the optimized reaction conditions in hand, we then
turned our attention to the generality of this three-component
reaction with a variety of aldehydes, and the results are
outlined in Scheme 2. In general, electron-neutral aromatic
aldehyde derivatives such as benzaldehyde, [1,1′-biphenyl]-
carbaldehyde, naphthaldehyde, anthracene-9-carbaldehyde,
and pyrene-1-carbaldehyde gave the desired 3-trifluoromethyl-
B
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a
Scheme 2. Scope of Aldehydes
Scheme 3. Scale Experiments and Synthetic Applications
Scheme 4. Control Experiments
previously reported reactions, a two-step protocol is necessary
for these transformations because N-tosylhydrazones first need
to be in situ generated to ensure the efficiency of these
reactions.11 Furthermore, an intermediate featuring δ = −70.2
(d, J = 7.52 Hz) was detected by a 19F NMR analysis
experiment to monitor the reaction (Scheme 4b), indicating
that a proton was transferred to the α-position of the CF3
group during the reaction. (For details, see the Supporting
Information.) N-Tosylhydrazone 4a derived from benzalde-
hyde could be slowly decomposed at room temperature and
fully decomposed at 60 °C under the treatment of DBU for 6 h
(Scheme 4c). Additionally, when N-tosylhydrazone 5 derived
from acetophenone was treated with BTP under the standard
reaction conditions, N-tosylhydrazone 5 decomposed com-
pletely, and a complex mixture was obtained (Scheme 4d).
The proposed reaction mechanism is illustrated in Scheme
5. The condensation of benzaldehyde 1a with p-toluenesul-
fonyl hydrazide in-situ-generated N-tosylhydrazone 4a, which
then decomposed to diazo compound A in the presence of
bases.12 The regioselective [3 + 2] cycloaddition of dizao
compound A with BTP afforded intermediate B,13 which
a
Reaction conditions: 1a (1 mmol), TsNHNH2 (1.2 equiv), BTP (2
equiv), DBU (3 equiv), and toluene (6 mL) were stirred at 60 °C for
b
c
6 h. Isolated yields. p-Nitrobenzaldehyde (1 mmol), TsNHH2 (1.2
equiv), toluene (6 mL), 60 °C, 30 min, then DBU (3 equiv), BTP (2
equiv).
experiments were almost not exothermic, providing ample
potential for the larger scale synthesis of 3-trifluoromethylpyr-
azoles.
The condensation of aldehydes with TsNHNH2 would
afford the corresponding N-tosylhydrazones.10 Thus N-
tosylhydrazone 4a derived from benzaldehyde was tested
under the standard reaction conditions and provided the
desired product 2a in 98% yield (Scheme 4a). Interestingly,
although carbonyl compounds and TsNHNH2 could be used
instead of the corresponding N-tosylhydrazones in some
C
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pubs.acs.org/OrgLett
Letter
Notes
Scheme 5. Proposed Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Program on
Key Research Project (2016YFA0602900), the National
Natural Science Foundation of China (21702064,
21420102003), the Pearl River S&T Nova Program of
Guangzhou (201806010138), and the Fundamental Research
Funds for the Central Universities (2019ZD19).
further converted to trifluoromethylated diazo intermediate C
via the elimination of HBr in the presence of base. The
subsequent facile and chemoselective 1,3-hydrogen atom
transfer (1,3-HAT) of trifluoromethylated diazo intermediate
C provided diazo intermediate D, which featured a proton at
the α-position of the CF3 group.14 Finally, the 1,3-HAT of
intermediate D afforded the desired product 2a.4a
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In summary, we have reported a general and practical
strategy for 3-trifluoromethylpyrazole synthesis by coupling
environmentally friendly and large-tonnage industrial feedstock
BTP with aldehydes and sulfonyl hydrazides. This highly
regioselective three-component coupling reaction is metal-free,
catalyst-free, and operationally simple and features mild
conditions, a broad substrate scope, high yields, and valuable
functional group tolerance. Remarkably, the reactions could be
performed on a 100 mmol scale and smoothly afforded the key
intermediates for the synthesis of celecoxib, mavacoxib, SC-
560, and AS-136A. Preliminary mechanism studies indicated
that a 1,3-HAT process was involved in this transformation. An
investigation of the mechanistic details and an exploration of
other potential applications of BTP are currently underway in
our laboratory, the results of which will be reported in due
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AUTHOR INFORMATION
Corresponding Authors
■
Chuanle Zhu − South China University of Technology,
Guangzhou, P. R. China; orcid.org/0000-0002-0096-
258X; Email: cechlzhu@scut.edu.cn
Huanfeng Jiang − South China University of Technology,
Guangzhou, P. R. China; orcid.org/0000-0002-4355-
0294; Email: jianghf@scut.edu.cn
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Other Authors
Hao Zeng − South China University of Technology,
Guangzhou, P. R. China
Chi Liu − South China University of Technology,
Guangzhou, P. R. China
Yingying Cai − South China University of Technology,
Guangzhou, P. R. China
Xiaojie Fang − South China University of Technology,
Guangzhou, P. R. China
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Complete contact information is available at:
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