Synthesis of fluazolate via the application of regioselective [3+2] cyclocondensation and nucleophilic substitution-cyclization strategies

Article abstract of DOI:10.1016/j.tet.2016.08.021

Starting from commercially available 2-chloro-4-fluorobenzoic acid 4, synthesis of fluazolate was achieved in up to 30% overall yield via the key procedure of either regioselective [3+2] cyclocondensation of trifluoromethyl-α,β-ynone 2 with hydrazine hydr

Full text of DOI:10.1016/j.tet.2016.08.021

Accepted Manuscript
Synthesis of fluazolate via the application of regioselective [3+2] cyclocondensation
and nucleophilic substitution-cyclization strategies
Min-Tsang Hsieh, Hui-Chang Lin, Sheng-Chu Kuo
PII:
S0040-4020(16)30779-7
10.1016/j.tet.2016.08.021
TET 28002
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 June 2016
Revised Date: 5 August 2016
Accepted Date: 8 August 2016
Please cite this article as: Hsieh M-T, Lin H-C, Kuo S-C, Synthesis of fluazolate via the application of
regioselective [3+2] cyclocondensation and nucleophilic substitution-cyclization strategies, Tetrahedron
(2016), doi: 10.1016/j.tet.2016.08.021.
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Synthesis of fluazolate via the application of
regioselective [3+2] cyclocondensation and
nucleophilic substitution-cyclization strategies
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Min-Tsang Hsieh,a,b,* Hui-Chang Lin,a and Sheng-Chu Kuoa
a School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C.
b Chinese Medicinal Research and Development Center, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan, R.O.C.

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of fluazolate via the application of regioselective [3+2] cyclocondensation
and nucleophilic substitution-cyclization strategies
Min-Tsang Hsieh,a,b,* Hui-Chang Lin,a and Sheng-Chu Kuoa
a School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C.
b Chinese Medicinal Research and Development Center, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan, R.O.C.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Starting from commercially available 2-chloro-4-fluorobenzoic acid 4, synthesis of fluazolate
was achieved in up to 30% overall yield via the key procedure of either regioselective [3+2]
cyclocondensation of trifluoromethyl-α,β-ynone 2 with hydrazine hydrate or nucleophilic
substitution-cyclization of trifluoromethyl-α,β-dibromoenone 10 with hydrazine hydrate.
Available online
Keywords:
Trifluoromethylpyrazole
[3+2] Cyclocondensation
Fluazolate
Regioselective
N-methylation
1. Introduction
The 3- and 5-trifluoromethylpyrazole substructures are
commonly present in many pharmaceuticals and biologically
active compounds, including the non-steroidal anti-inflammatory
drug celecoxib,1 anticancer agent SC-560,2 anti-viral agent AS-
136A,3 anticoagulant drug razaxaban,4 insecticide DP-235 and
herbicide fluazolate.6 Generally, 3- or 5-trifluoromethylpyrazole
derivatives are prepared via the condensation of 1,1,1-
trifluoromethyl-1,3-diketones, or their synthetic equivalents, with
hydrazines.7 However, when applied to pharmaceutical
manufacturing, these methods often suffer from limitations, such
as low functional-group tolerance and formation of unwanted
Scheme 1. [3+2] cyclocondensation reaction for the selective
synthesis of 3- and 5-trifluoromethylpyrazoles
regioselective N-methylation reaction.9 Alternatively, Harrity et
al. reported a formal synthesis of fluazolate whereby the 5-
trifluoromethylpyrazole core structure could be accessed through
reaction of 4-trifluoromethylsydnone with a suitable alkyne.10 In
continuation of our efforts to synthesize biologically active
trifluoromethylpyrazole compounds, we expanded the
regioisomers. Recently, we developed
a
highly facile
methodology for the regioselective synthesis of 3- and 5-
trifluoromethylpyrazole
cyclocondensation of
compounds
trifluoromethyl-α,β-ynones
via
the
[3+2]
with
hydrazines.8 As shown in Scheme 1, the regioselectivity resulting
from these reactions can be readily shifted via minor
modifications to the reaction procedures to preferentially produce
either 3- or 5-trifluoromethylpyrazole products. The synthetic
procedure is operationally very simple. Yields of products are
generally excellent, and the tolerance of functionality is high.
These features render it an attractive alternative to existing
methods.
aforementioned
regioselective
[3+2]
cyclocondensation,
modifying the trifluoromethyl-α,β-ynone intermediate, to
expedite the preparation of fluazolate. The retrosynthesis of
fluazolate is depicted in Scheme 2. The target molecule is
anticipated to be achieved from the advanced intermediate 1, the
synthesis of which will proceed from trifluoromethyl-α,β-ynone
2
via [3+2] cyclocondensation with hydrazine. A more
Fluazolate (JV-485), developed by Monsanto and Bayer AG, is a
protoporphyrinogen IX oxidase-inhibiting herbicide used on
winter wheat. The commercial route to this product consists of
two key steps: a classic cyclization reaction of the 1,1,1-
trifluoromethyl-1,3-diketone intermediate with hydrazine and a
straightforward pathway which using N-methylhydrazine in the
[3+2] cyclocondensation is not preferred because that compound
is highly toxic and carcinogenic. Compound 2 is proposed to be
prepared from compound 3 via a synthetic sequence of isopropyl
esterification followed by a Sonogashira coupling reaction.

2
Tetrahedron
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from the signal (δ
= 6.82-6.74 ppm) of 5-phenyl-3-
trifluoromethyl-1H-pyrazoles.8 With the key intermediate in hand,
we then attempted to introduce a methyl group at the 1-position
of the pyrazole ring for the synthesis of the penultimate
intermediate 9a. Initial attempts, using general reaction
conditions (1.5 equivalents K2CO3, 1.5 equivalents CH3I, DMF,
rt), yielded two diasteromeric compounds 9a and 9b in a ratio of
3:2. The regiochemistry of 9a and 9b was assigned by
1
comparison of their H NMR spectrum to those of structurally
similar compounds, which were previously reported in the
literature. The 1H NMR spectrum of 9a displayed N-methyl
signals at δ = 4.09 ppm which is consistent with the chemical
shift (δ = 4.03 ppm) of 1-methyl-3-phenyl-5-(trifluoromethyl)-
1
1H-pyrazole.14 In the H NMR spectrum of 9b, a sharp singlet at
δ = 3.88 ppm is attributed to N-methyl group and consistent with
the chemical shift (δ = 3.92 ppm) of 1-methyl-5-phenyl-3-
(trifluoromethyl)-1H-pyrazole.15
Scheme 2 The retrosynthesis of fluazolate
2. Results and discussion
F
F
F
Our endeavor to synthesize fluazolate began with synthesis of
compound 3. Thus, starting with commercially available
compound 4 and treating it with iodine in the presence of sodium
iodate gave the required compound 3 in quantitative yield (99%).
Esterification of compound 3, giving compound 5, was readily
achieved by treating 3 with isopropyl iodide in the presence of
potassium carbonate in DMF. To incorporate the trifluoromethyl
ynone functionality into 5, the procedures involving the coupling
reaction of 1,1,1-trifluoro-4-(trimethylstannyl)but-3-yn-2-one11
with compound 5 were initially examined. Unfortunately, all
attempts failed to directly convert compound 5 to 2. In another
approach, a trimethylsilyl acetylene group was introduced by a
typical Sonogashira cross-coupling reaction,12 wherein compound
5 was mixed with trimethylsilyl acetylene, CuI and Pd(PPh3)4 in
THF to produce the desired compound 6 in 93% yield, which in
turn underwent desilylation using TBAF in THF to give
compound 7 in a virtually quantitative yield (96%). Treatment of
compound 7 with n-BuLi at -60 °C in THF was followed by
trifluoroacetylation with ethyl trifluoroacetate to give the
required intermediate 2 with a yield of 62%. Subsequently, the
key [3+2] cyclocondensation was investigated, following the
procedure described previously for the selective synthesis of 5-
trifluoromethylpyrazoles (vide supra). Unfortunately, treatment
of compound 2 with hydrazine hydrate in DMSO at 110 °C for
12 h provided compound 1 in only 23% yield (method A,
Scheme 3). Attempts to increase the reaction yield by modifying
the reaction temperature and reagent amounts were met with little
success. The consistently low yield of the desired product
prompted us to search for another approach to its preparation. It
was reported that 3-(trifluoromethyl)-1H-pyrazoles tautomerized
into 5-(trifluoromethyl)-1H-pyrazoles under basic condition.13
We then speculated that with the Cu(OAc)2-catalyzed [3+2]
cyclocondensation protocol for the synthesis of the 3-
I
I
K2CO3, i-PrI
I2, NaIO3, H2SO4
rt, 8 h, 99%
Cl
Cl
OH
Cl
OH
DMF, rt, 6 h, 96%
O
O
O
O
5
4
3
F
TMS
F
Pd(PPh3)4, CuI, Et3N
TBAF, THF
Cl
0 oC, 30 min
96%
, THF
TMS
Cl
2 h, reflux, 93%
6
O
7
O
O
O
O
Method A: NH2NH2.H2O,
DMSO, 110 oC, 12 h, 23%
F
n-BuLi, THF, -60 oC, 30 min
F3C
then CF3COOEt, BF3.OEt2,
-60 oC, 1 h, 62%
Method B: NH2NH2.H2O,
Cu(OAc)2, CH2Cl2, reflux,
2 h, 94%
Cl
F
2
O
N
O
HN
F
N
N
Br2, AcOH
fluazolate
80 oC, 70 h
methylation
see Table 1
F3C
F3C
Cl
Cl
85%
1
O
O
F
9a
O
O
N
NH
F3C
Cl
8
O
O
fluoromethylpyrazole congener 8, followed by
a
facile
Scheme 3 Synthesis of fluazolate via [3+2] cyclocondensation of
trifluoromethyl-α,β-ynone 2 with hydrazine hydrate
tautomerization, we could achieve compound 1. In practice, 2.0
mol% Cu(OAc)2 catalyzed the [3+2] cyclocondensation of 2 with
hydrazine hydrate and gave compound 1 in excellent yield (94%,
method B, Scheme 3), but it did not afford the expected 8.
Currently, it remained uncertain that the formation of compound
1 was directly resulted from the Cu(OAc)2 catalyzed-[3+2]
cyclocondensation or through rapid tautomerization from
compound 8. Efforts to single crystal of compound 1 suitable for
X-ray analysis turned out to be fruitless. To verify the
regiochemistry of compound 1, 1H NMR was used as an
analytical technique. Compound 1 showed the presence of the C-
4 proton of pyrazole at δ = 6.98 ppm which is agreeing with the
chemical shift (δ = 7.16-6.97 ppm) of structurally related 3-
phenyl-5-trifluoromethyl-1H-pyrazoles and well-distinguishable
After a brief survey of the reaction conditions, including reagents,
solvents and temperatures, the optimal conditions were
established. As shown in Entry 4 of Table 1, compound 1 was
treated with Me2SO4 in toluene at 80 °C, and the desired
compound 9a was obtained as a major product in 71% yield.
Finally, bromination of 9a with Br2 in acetic acid gave rise to
fluazolate in 85% yield. The spectral data (NMR, IR, and HRMS)
of the synthetic fluazolate were found to agree well with those
reported previously in the literature.16

3
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Table 1. Methylation of 1 under various reaction conditions
The final step of the secondary synthetic route was to introduce
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a methyl group. Disappointingly, using the procedure delineated
previously for the methylation of compound 1 (vide supra), 11
was methylated and gave fluazolate in 50% yield and the
unwanted isomer 12 in 35% yield (Table 2, Entry 1). The low
selectivity could be attributed to the higher acidity of the NH
proton in compound 11, which resulted in reduced activation
energy barrier for interconversion between the tautomers. After
examining several reaction conditions, this problem was finally
circumvented by using a silver(I)-mediated methylation process
(Table 2, Entry 4). Thus, the reaction of 11 with methyl iodide
and silver oxide in acetonitrile at room temperature gave rise to
71% yield of fluazolate and 19% yield of 12.
N
F
N
N
F
N
F3C
F3C
1
+
Cl
Cl
9b
9a
O
O
O
O
Yield (%)[b]
9a
Entry
Conditions[a]
9b
32%
1.5 equiv MeI, 1.5 equiv K2CO3,
DMF, rt, 8 h
1.5 equiv MeI, 1.5 equiv K2CO3,
THF, reflux, 6 h
1.2 equiv Me2SO4, 1.5 equiv
K2CO3, DMF, reflux, 6 h
1.2 equiv Me2SO4, toluene, 80 °C,
10 h
1.5 equiv Me2SO4, 1.5 equiv
LiOH, DMF, reflux, 6 h
1.2 equiv Me2SO4, DMF, 100 °C,
7 h
48%
29%
32%
71%
24%
43%
45%
1
2
3
4
5
6
7
22%
30%
15%
19%
27%
35%
Table 2. Methylation of 11 under various reaction conditions
1.5 equiv MeI, 1.5 equiv Na2CO3,
DMF, rt, 9 h
Yield (%)[b]
Entry
1
Conditions[a]
[a] Substrate 1 (0.28 mmol) and solvent (2 mL)
fluazolate
12
[b] Isolated yield
1.2 equiv Me2SO4, toluene, 80 °C,
10 h
50%
35%
2
3
4
5
6
7
1.5 equiv MeI, 1.5 equiv K2CO3,
THF, reflux, 8 h
1.5 equiv MeI, 1.5 equiv Na2CO3,
DMF, reflux, 8 h
1.5 equiv MeI, 1.0 equiv Ag2O,
CH3CN, rt, 3 h
1.5 equiv MeI, 1.0 equiv Ag2CO3,
CH3CN, rt, 3 h
28%
25%
71%
57%
53%
54%
42%
50%
19%
23%
20%
15%
Recently, Nenajdendo et al. reported a nucleophilic substitution-
cyclization for the synthesis of 4-bromo-5-(trifluoromethyl)-3-
phenyl-1H-pyrazole via the corresponding trifluoromethyl-α,β-
dibromoenone.17 In light of the above results, we turned our
attention to an alternative route to fluazolate. We assumed that
the 4-bromo-5-(trifluoromethyl)-1H-pyrazole, the core structure
of fluazolate, could be assembled via Nenajdendo‘s protocol,
1.5 equiv MeI, 1.0 equiv AgNO3,
CH3CN, rt, 3 h
with
a
subsequent regioselective methylation furnishing
was converted to
fluazolate. Therefore, compound
2
1.5 equiv MeI, 1.0 equiv Ag2O,
CH3CN, 0 oC, 14 h
trifluoromethyl-α,β-dibromoenone 10 in 88% yield as an
inseparable mixture of geometric isomers with a ratio of ca. 5.6 :
1.18 This was carried out simply by exposure of 2 to bromine in
CH2Cl2 at 0 °C. Nucleophilic substitution-cyclization of this
trifluoromethyl-α,β-dibromoenone with hydrazine hydrate was
then performed in toluene at 80 °C to give compound 11 in 66%
yield and compound 1 in 25% yield.19 Other solvents, such as
chlorobenzene, THF, t-BuOH and CH2Cl2, were examined but
gave inferior results in terms of both yield and selectivity.
[a] Substrate 1 (0.28 mmol) and solvent (2 mL)
[b] Isolated yield
3. Conclusion
In summary, two new routes have been developed that are
suitable for the synthesis of fluazolate in up to 30% overall yield.
The first strategy, involves
a Cu(OAc)2-catalyzed [3+2]
cyclocondensation combined with a facile tautomerization and a
regioselective methylation of the resulting adduct, as efficient
key steps in the creation of target compound. This synthetic
endeavor further demonstrates and reinforces the generality of
our [3+2] cyclocondensation to the synthesis of 5-
trifluoromethylpyrazole-based bioactive compounds. The second
strategy, which applied a nucleophilic substitution-cyclization
protocol and a silver (I)-mediated methylation process as key
steps, was also successful in constructing fluazolate. It is
believed that the work reported in this paper will be a valuable
addition to both academic research and industrial application.
4. Experimental section
4.1. General procedure
Scheme 4 Synthesis of compound 11 via nucleophilic
substitution-cyclization of compound 10 with hydrazine hydrate
All reactions were performed under an atmosphere of air unless
otherwise stated. All solvents and reagents were employed as
received. Analytical thin layer chromatography was performed
on SiO2 60 F-254 plates and flash column chromatography was

4
Tetrahedron
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addition of trimethylsilyl acetylene (0.540 g, 5.46 mmol). The
carried out using SiO2 60 (particle size 0.040-0.055 mm, 230–
reaction mixture was stirred at 80 oC for 2 hours and H2O (30 mL)
was added to quench the reaction. The aqueous layer was
separated and extracted with EtOAc (20 x 3 mL). The combined
organic extracts were washed with brine, dried over MgSO4,
filtered and concentrated to give the crude residue, which was
purified by flash chromatography on silical gel with EtOAc/n-
hexane (1:29) to afford compound 6 as a white solid (1.458 g,
400 mesh), both of which are available from E. Merck.
Visualization was performed under UV irradiation at 254 nm
followed by staining with aqueous potassium permanganate
(KMnO4 (3 g) and K2CO3 (20 g) in 300 mL of H2O containing 5
mL of an aqueous solution of NaOH (5%, w/v)) and charring by
heat gun. Fourier transform infrared spectra (IR) were recorded
on Shimadzu spectrum IRPrestige-21 system and expressed in
cm-1. 1H , 19F and 13C NMR spectra were recorded on Bruker 500
FT NMR. Chloroform-d and Methanol-d were used as the solvent
and TMS (δ = 0.00 ppm) as an internal standard. Chemical shifts
are reported as δ values in ppm as referenced to TMS.
Multiplicities are recorded as s (singlet), d (doublet), t (triplet), q
(quartet), quint (quintet), sext (sextet), sept (septet), dd (doublet
of doublets), dt (doublet of triplets), br (broad), m (multiplet).
Coupling constants (J) are expressed in Hz. HRMS were
measured by JEOL JMS-HX110 spectrometer and spectral data
were recorded as m/z values. Melting points were measured
using an Electrothermal instrument.
o
93%). Mp 38-39 C; IR (neat): 1730, 1714, 1583, 1556, 1463,
1455, 1396, 1346, 1282, 1269, 1255 cm-1; H NMR (500 MHz,
1
CDCl3): δ = 7.95 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 9.0 Hz, 1H),
5.28 (septet, J = 6.0 Hz, 1H), 1.41 (d, J = 6.5 Hz, 6H), 0.29 (s,
9H); 13C NMR (125 MHz, CDCl3): δ = 163.6 (d, J = 258.7 Hz),
163.6, 136.6 (d, J = 2.5 Hz), 135.1 (d, J = 10.0 Hz), 126.9 (d, J =
3.7 Hz), 118.5 (d, J = 23.7 Hz), 110.9 (d, J = 16.2 Hz), 102.4 (d,
J = 2.5 Hz), 95.7, 69.7, 21.8 (2xCH3), -0.92 (3xCH3); 19F NMR
(470 MHz, CDCl3): δ = -103.1; HRMS (EI) m/z [M]+ calcd. for
C15H18ClFO2Si: 312.0749; found: 312.0745.
4.5 Isopropyl 2-chloro-5-ethynyl-4-fluorobenzoate (7)
4.2 2-Chloro-4-fluoro-5-iodobenzoic acid (3)
To a stirred solution of 6 (1.400 g, 4.49 mmol) in anhydrous THF
(15 mL) was added TBAF (1 M in THF, 5.84 mL, 5.84 mmol) in
small portions at 0oC. The resulting mixture was stirred at the
same temperature for 0.5 hour and then saturated NH4Cl(aq) (10
mL) was added to quench the reaction. The aqueous layer was
separated and extracted with EtOAc (15 x 3 mL). The combined
organic extracts were washed with brine, dried over MgSO4,
filtered and concentrated to give the crude residue, which was
purified by flash chromatography on silical gel with EtOAc/n-
hexane (1:19) to afford compound 7 as a white solid (1.032 g,
A mixture of 2-chloro-4-fluorobenzoic acid 4 (4.000 g, 22.91
mmol), NaIO3 (0.906 g, 4.58 mmol) and I2 (2.037 g, 8.02 mmol)
in conc. H2SO4 (40 mL) was stirred at room temperature for 8
hours. Chilled water (100 mL) was added to quench the reaction.
The resulting solid was filtered, washed with H2O, dired at 50 oC
in vaccum to give the white solid 3 (6.824 g, 99% yield). Mp
124-126 oC; IR (neat): 1700, 1580, 1558, 1400, 1348, 1298, 1258
cm-1; 1H NMR (500 MHz, CD3OD): δ = 8.33 (d, J = 7.0 Hz, 1H),
7.37 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CD3OD): δ =
164.9, 163.3 (d, J = 250.0 Hz), 142.0 (d, J = 3.7 Hz), 135.1 (d, J
= 10.0 Hz), 128.4, 117.9 (d, J = 28.7 Hz), 78.1 (d, J = 26.2 Hz);
19F NMR (470 MHz, CD3OD): δ = -89.5; HRMS (EI) m/z [M]+
calcd. for C7H3ClFIO2: 299.8850; found: 299.8855.
o
96%). Mp 34-35 C; IR (neat): 1732, 1710, 1606, 1562, 1481,
1
1386, 1294, 1273, 1103 cm-1; H NMR (500 MHz, CDCl3): δ =
7.99 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 5.27 (septet, J
= 6.0 Hz, 1H), 3.40 (s, 1H), 1.40 (d, J = 6.0 Hz, 6H); 13C NMR
(125 MHz, CDCl3): δ = 163.9 (d, J = 260.0 Hz), 163.5, 136.9 (d,
J = 2.5 Hz), 135.8 (d, J = 11.2 Hz), 127.0 (d, J = 3.7 Hz), 118.6
(d, J = 23.7 Hz), 109.8 (d, J = 16.2 Hz), 84.1 (d, J = 3.7 Hz), 75.1,
69.8, 21.8 (2xCH3); 19F NMR (470 MHz, CDCl3): δ = -103.1;
HRMS (EI) m/z [M]+ calcd. for C12H10ClFO2: 240.0353; found:
240.0355.
4.3 Isopropyl 2-chloro-4-fluoro-5-iodobenzoate (5)
To a stirred solution of compound 3 (2.200 g, 7.33 mmol) in
anhydrous DMF (20 mL) was added K2CO3 (0.846 g, 8.06 mmol)
and isopropyl iodide (1.870 g, 10.99 mmol) in sequence at room
temperature. The resulting mixture was stirred at the same
temperature for 6 hours and saturated NH4Cl(aq) (10 mL) was
added to quench the reaction. The aqueous layer was separated
and extracted with EtOAc (20 x 3 mL). The combined organic
extracts were washed with brine, dried over MgSO4, filtered and
concentrated to give the crude residue, which was purified by
flash chromatography on silical gel with EtOAc/n-hexane (1:19)
to afford compound 5 (2.407 g, 96% yield) as white solid. Mp
4.5 Isopropyl 2-chloro-4-fluoro-5-(4,4,4-trifluoro-3-oxobut-1-
yn-1-yl)benzoate (2)
To a stirred solution of 7 (0.560 g, 2.34 mmol) in anhydrous THF
(20 mL) was added n-BuLi (2.21 mL, 1.6M, 3.50 mmol)
dropwise at -60 oC. The resulting solution was stirred at the same
temperature for 30 min, at which time a solution of ethyl
trifluoromethylacetate (0.365 g, 2.56 mmol) and BF3.OEt2 (0.331
g, 2.34 mmol) in anhydrous THF (8 mL) was introduced
dropwise. After reaction was complete (ca. 1h), water (8 mL) and
saturated NH4Cl solution (6 mL) was added. The aqueous layer
was separated and extracted with EA (2 x 25 mL). The combined
organic extracts were washed with brine, dried over MgSO4,
filtered and concentrated to give the crude product, which was
purified by flash chromatography on silica gel with EtOAc/n-
hexane (1:9) to afford compound 2 (0.485 g, 62%) as white solid.
o
43-44 C; IR (neat): 1732, 1714, 1585, 1558, 1463, 1371, 1284,
1
1271, 1255 cm-1; H NMR (500 MHz, CDCl3): δ = 8.23 (d, J =
6.5 Hz, 1H), 7.19 (dd, J = 7.5, 1.0 Hz, 1H), 5.28 (septet, J = 6.0
Hz, 1H), 1.41 (d, J = 6.0 Hz, 6H); 13C NMR (125 MHz, CDCl3):
δ = 163.1, 163.0 (d, J = 252.5 Hz), 141.9 (d, J = 2.5 Hz), 135.5 (d,
J = 10.0 Hz), 128.4 (d, J = 3.7 Hz), 118.4 (d, J = 26.2 Hz), 78.6
(d, J = 26.2 Hz), 69.9, 21.8 (2xCH3); 19F NMR (470 MHz,
CDCl3): δ = -89.5; HRMS (EI) m/z [M]+ calcd. for C10H9ClFIO2:
341.9320; found: 341.9321.
o
Mp 61-63 C; IR (neat): 1730, 1712, 1606, 1568, 1556, 1485,
1
1392, 1294 cm-1; H NMR (500 MHz, CDCl3): δ = 8.15 (d, J =
4.4 Isopropyl 2-chloro-4-fluoro-5-((trimethylsilyl)ethynyl)
benzoate (6)
9.0 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 5.30 (septet, J = 6.5 Hz,
1H), 1.42 (d, J = 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3): δ =
166.8 (q, J = 43.7 Hz), 164.5 (d, J = 265.0 Hz), 162.7, 140.3 (d, J
= 11.2 Hz), 138.0, 128.0 (d, J = 3.7 Hz), 119.4 (d, J = 23.7 Hz),
114.7 (q, J = 285.0 Hz), 106.2 (d, J = 16.2 Hz), 90.6, 88.0, 70.4,
21.7 (2xCH3); 19F NMR (470 MHz, CDCl3): δ = -77.8, -99.5;
A mixture of 5 (1.700 g, 4.96 mmol), CuI (47 mg, 0.25 mmol),
Pd(PPh3)4 (138 mg, 0.12 mmol) was stirred in THF (35 mL) at
room temperature. The resulting mixture was degassed by
bubbling N2 through it for 10 mins. Then Et3N (2.000 g, 19.84
mmol) was added thereto and stirred for another 10 mins before

5
ACCEPTED MANUSCRIPT
HRMS (EI) m/z [M]+ calcd. for C14H9ClF4O3: 336.0176; found:
336.0177.
volatiles were removed in vacuo and the resulting mixture was
ACCEPTED MANUSCRIPT
purified by flash chromatography on silica gel with EtOAc/n-
hexane (1:9) to afford compound 10 (cis + trans mixture, 220 mg,
88% yield) as yellow oil. IR (neat): 1653, 1583, 1560, 1490,
4.6 Isopropyl 2-chloro-4-fluoro-5-(5-(trifluoromethyl)-1H-
pyrazol-3-yl)benzoate (1)
1272, 1188, 1140 cm-1; H NMR (500 MHz, CDCl3): δ = 7.90-
1
7.88 (m, 1H), 7.33 (d, J = 9.0 Hz, 0.14H), 7.24 (d, J = 9.5 Hz,
0.86H), 5.28 (septet, J = 6.5 Hz, 1H), 1.44-1.40 (m, 6H); 13C
NMR (125 MHz, CDCl3) major isomer: δ = 177.8 (q, J = 40.0
Hz), 163.1, 158.6 (d, J = 258.7 Hz), 138.1, 133.8, 130.3, 127.5,
124.0, 119.4, 118.4, 114.9 (q, J = 288.7 Hz), 70.4, 21.7 (2xCH3).
19F NMR (470 MHz, CDCl3) major isomer: δ = -72.3, -104.5.
minor isomer: δ = -72.8, -106.8; HRMS (EI) m/z [M]+ calcd. for
C14H9Br2ClF4O3: 493.8543; found: 493.8535.
To a stirred solution of compound 2 (0.220 g, 0.65 mmol) and
Cu(OAc)2 (3 mg, 0.016 mmol) in CH2Cl2 (4 mL) was added
hydrazine hydrate (39 mg, 0.65 mmol). The resulting mixture
was stirred under reflux for 2 hour. Then saturated NH4Cl
solution (2 mL) was added to quench the reaction. The aqueous
layer was separated and extracted with CH2Cl2 (2 x 4 mL). The
combined organic extracts were washed with brine, dried over
Na2SO4, filtered and concentrated to give the crude residue,
which was purified by flash chromatography on silical gel with
EtOAc/n-hexane (1:5) to afford compound 1 (0.212 g, 94% yield)
4.9 Isopropyl-5-(4-bromo-5-(trifluoromethyl)-1H-pyrazol-3-
yl)-2-chloro-4-fluoro- benzoate (11)
o
as white solid. Mp 56-57 C; IR (neat): 1733, 1714, 1616, 1581,
1
1456, 1378, 1274, 1178 cm-1; H NMR (500 MHz, CDCl3): δ =
A mixture of 10 (102 mg, 0.20 mmol) and hydrazine hydrate (13
8.18 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 10.5 Hz, 1H), 6.98 (s, 1H),
5.31 (septet, J = 6.5 Hz, 1H), 1.41 (d, J = 6.5 Hz, 6H); 13C NMR
(125 MHz, CDCl3): δ = 163.9, 159.8 (d, J = 256.2 Hz), 137.9,
135.7 (d, J = 11.2 Hz), 130.9 (d, J = 5.0 Hz), 128.0 ( (d, J = 2.5
Hz), 120.9 (q, J = 267.5 Hz), 119.5 (d, J = 25.0 Hz), 115.2 (d, J =
12.5 Hz), 103.6, 70.3, 21.7 (2xCH3); 19F NMR (470 MHz,
CDCl3): δ = -62.2, -109.6; HRMS (EI) m/z [M]+ calcd. for
C14H11ClF4N2O2: 350.0445; found: 350.0439
o
mg, 0.26 mmol) in toluene (3 mL) was stirred at 80 C for 10
hours. The volatiles were removed in vacuo and the resulting
mixture was purified by flash chromatography on silica gel with
EtOAc/n-hexane (1:9) to afford compound 1 (22 mg, 25% yield)
and 11 (58 mg, 66% yield) as white solid.Compound 11 Mp 61-
o
62 C; IR (neat): 1730, 1715, 1615, 1571, 1454, 1376, 1272,
1178 cm-1; 1H NMR (500 MHz, CDCl3): δ = 8.40 (d, J = 7.5 Hz,
1H), 7.39 (d, J = 10.0 Hz, 1H), 5.30 (septet, J = 6.0 Hz, 1H), 1.41
(d, J = 6.0 Hz, 6H); 13C NMR (125 MHz, CDCl3): δ = 163.6,
160.2 (d, J = 257.5 Hz), 141.9, 137.2 (d, J = 10.0 Hz), 135.9,
133.3 (d, J = 3.7 Hz), 127.7 ( (d, J = 2.5 Hz), 121.7, 119.4 (d, J =
26.2 Hz), 113.8 (d, J = 13.7 Hz), 92.5, 70.2, 21.8 (2xCH3); 19F
NMR (470 MHz, CDCl3): δ = -62.2, -107.5; HRMS (EI) m/z
[M]+ calcd. for C14H10BrClF4N2O2: 427.9550; found: 427.9555.
4.7 Isopropyl 2-chloro-4-fluoro-5-(1-methyl-5-
(trifluoromethyl) -1H-pyrazol-3-yl)benzoate (9a) and
isopropyl 2-chloro-4-fluoro-5-(1-methyl-3-(trifluoromethyl) -
1H-pyrazol-5-yl)benzoate (9b)
A solution of 1 (104 mg, 0.30 mmol) and Me2SO4 (45 mg, 0.36
mmol) in toluene (3 mL) was stirred at room temperature for 10 h.
The reaction was then quenched with water and the aqueous layer
was separated and extracted with EtOAc (3 x 5 mL). The
combined organic extracts were washed with brine, dried over
MgSO4, filtered and concentrated to give the crude product,
which was purified by flash chromatography on silica gel with
EtOAc/n-hexane (1:9) to afford compound 9a (77 mg, 71%) and
9b (16 mg, 15%).
4.10 Fluazolate and Isopropyl-5-(4-bromo-1-methyl-3-
(trifluoromethyl)-1H-pyrazol-5-yl)-2-chloro-4-fluorobenzoate
(12)
A mixture of 11 (121 mg, 0.28 mmol), Ag2O (63 mg, 0.28 mmol)
and MeI (61 mg, 0.42 mmol) in CH3CN (3 mL) was stirred at
room temperature for 3 h. The reaction was then quenched with
water and the aqueous layer was separated and extracted with
EtOAc (2x3 mL). The combined organic extracts were washed
with brine, dried over MgSO4, filtered and concentrated to give
the crude product, which was purified by flash chromatography
on silica gel with EtOAc/n-hexane (1:9) to afford fluazolate (100
mg, 71%) as white solid and 12 (24 mg, 19%) as white solid.
9a White solid; mp 78-80 oC; IR (neat): 1732, 1716, 1617, 1578,
1
1454, 1380, 1270, 1173 cm-1; H NMR (500 MHz, CDCl3): δ =
8.48 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 11.0 Hz, 1H), 7.05 (s, 1H),
5.31 (septet, J = 6.0 Hz, 1H), 4.09 (s, 3H), 1.42 (d, J = 6.5 Hz,
6H); 13C NMR (125 MHz, CDCl3): δ = 163.6, 160.5 (d, J = 243.5
Hz), 142.1, 141.8, 137.0 (d, J = 7.5 Hz), 134.4, 127.8, 119.3 (d, J
= 25.0 Hz), 118.7 (q, J = 273.7 Hz), 116.1 (d, J = 15.0 Hz), 106.2,
70.1, 38.0, 21.8 (2xCH3); 19F NMR (470 MHz, CDCl3): δ = -62.1,
-106.1; HRMS (EI) m/z [M]+ calcd. for C15H13ClF4N2O2:
364.0602; found: 364.0605.
o
Fluazolate Mp 81-83 C; IR (neat): 1732, 1714, 1618, 1571,
1
1537, 1454, 1375, 1267, 1178, 1145, 1130 cm-1; H NMR (500
MHz, CDCl3): δ = 8.05 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.5 Hz,
1H), 5.30 (septet, J = 6.5 Hz, 1H), 4.12 (s, 3H), 1.41 (d, J = 6.0
Hz, 6H); 13C NMR (125 MHz, CDCl3): δ = 163.8, 161.0 (d, J =
258.7 Hz), 144.3, 136.3 (d, J = 10.0 Hz), 134.8 (d, J = 3.7 Hz),
130.6 (q, J = 38.7 Hz), 127.0 (d, J = 3.7 Hz), 119.5 (q, J = 267.5
Hz), 119.1 (d, J = 25.0 Hz), 117.8 (d, J = 15.0 Hz), 96.2, 69.6,
40.1, 21.8 (2xCH3); 19F NMR (470 MHz, CDCl3): δ = -58.7, -
105.4; HRMS (EI) m/z [M]+ calcd. for C15H12BrClF4N2O2:
441.9707; found: 441.9700.
9b White solid; mp 93-94 oC; IR (neat): 1730, 1716, 1616, 1574,
1
1454, 1375, 1274, 1174 cm-1; H NMR (500 MHz, CDCl3): δ =
7.88 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 6.66 (s, 1H),
5.31 (septet, J = 6.0 Hz, 1H), 3.88 (s, 3H), 1.42 (d, J = 6.0 Hz,
6H); 13C NMR (125 MHz, CDCl3): δ = 164.3, 160.5 (d, J = 256.2
Hz), 143.1, 134.2 (d, J = 10.0 Hz), 131.1 (d, J = 3.7 Hz), 127.5
( (d, J = 3.7 Hz), 119.8 (q, J = 266.2 Hz), 119.0 (d, J = 22.5 Hz),
107.9 (d, J = 10.0 Hz), 69.6, 29.7, 21.8 (2xCH3); 19F NMR (470
MHz, CDCl3): δ = -60.5, -109.8; HRMS (EI) m/z [M]+ calcd. for
C15H13ClF4N2O2: 364.0602; found: 364.0600.
o
Compound 12 Mp 61-63 C; IR (neat): 1732, 1714, 1618, 1574,
1
1454, 1377, 1274, 1170, 1143, 1103 cm-1; H NMR (500 MHz,
CDCl3): δ = 7.93 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H),
5.13 (septet, J = 6.0 Hz, 1H), 3.86 (s, 3H), 1.42 (d, J = 6.5 Hz,
6H); 13C NMR (125 MHz, CDCl3): δ = 163.4, 160.7 (d, J = 257.5
Hz), 140.1 (q, J = 37.5 Hz), 138.0 (d, J = 10.0 Hz), 136.7, 135.2,
127.7 ( (d, J = 3.7 Hz), 120.4 (q, J = 267.5 Hz), 119.5 (d, J = 25
Hz), 114.8 (d, J = 8.7 Hz), 93.6, 70.2, 38.9, 21.7 (2xCH3); 19F
NMR (470 MHz, CDCl3): δ = -62.3, -105.1; HRMS (EI) m/z
[M]+ calcd. for C15H12BrClF4N2O2: 441.9707; found: 441.9702.
4.8 (E) and (Z)-isopropyl-2-chloro-5-(1,2-dibromo-4,4,4-
trifluoro-3-oxobut-1-en-1-yl)-4-fluorobenozoate (10)
A mixture of 2 (170 mg, 0.50 mmol) and Br2 (120 mg, 0.75
o
mmol) in CH2Cl2 (6 mL) was stirred at 0 C for 1 hour. The

6
Tetrahedron
ACCEPTED MANUSCRIPT
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13. (a) Corbett, J. W.; Elliott, R. L.; Bell, A. S. WO
Acknowledgement
2008065508 A1; (b) Day, R. F.; Lafontaine, J. A. US
200252392 A1.
We are grateful to the Taiwan Ministry of Science and
Technology (MOST 103-2113-M-039-002-MY2) and the
Chinese Medicine Research Center, China Medical University
(the Ministry of Education, the Aim for the Top University Plan)
for financial support.
14. Dai, J. J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.-J.; Lu,
X.; Liu, L.; Fu, Y. J. Am. Soc. Chem. 2013, 135, 8436-8439.
15. Dvorak, C. A.; Rudolph, D. A.; Ma, S.; Carruthers, N. I. J.
Org. Chem. 2005, 70, 4188-4190.
16. Rouchaud, J.; Neus, O.; Cools, K.; Bulcke, R. Bull. Environ.
Contam. Toxicol. 2000, 64, 651-658.
17. Muzalevskiy, V. M.; Iskandarov, A. A.; Nenajdenko, V. G.
Mendeleev Commun. 2014, 24, 342-344.
References
18. The ratio of isomers was determined by the relative
1
1. (a) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter,
J. S.; Collins, P. W.; Docter, S; Graneto, M. J.; Lee, L. F.;
Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D.
J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J.
N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert,
K.; Veenhuizen , A. W.; Zhang, Y. Y.; Isakson, P. C. J.
Med. Chem. 1997, 40, 1347-1365; (b) Kaur, K.; Kumar, V.;
Gupta, G. K. J. fluorine Chem. 2015, 178, 306-326.
2. (a) Lee, E.; Choi, M. K.; Youk, H. J.; Kim, C. H.; Han, I.
C.; Yoo, B. C.; Lee, M. K.; Lim, S. J. J. Cancer Res. Clin.
Oncol. 2006, 132, 223-233; (b) Brenneis, C.; Maier, T. J.;
Schmidt, R.; Hofacker, A.; Zulauf, L.; Jakobsson, P. J.;
Scholich, K.; Geisslinger, G. FASEB J. 2006, 20, 1352-
1360.
intensity of the aromatic proton signals in the H NMR
spectrum.
19. Compound 10 could be converted into 2 through a
halophilic reaction mechanism17 followed by [3+2]
cyclocondensation to give compound 1.
3. Sun, A.; Chandrakumar, N.; Yoon, J.-J.; Plemper, R. K.;
Snyder, J. P. Bioorg. Med. Chem. Lett. 2007, 17, 5199-
5203.
4. Wong, P. C.; Crain, E. J.; Watson, C. A.; Wexler, R. R.;
Lam, P. Y.; Quan, M. L.; Knabb, R. M. J. Thromb.
Thrombolysis 2007, 24, 43-51.
5. Lahm, G. P.; Selby, T. P.; Freudenberger, J. H.; Stevenson,
T. M.; Myers, B. J.; Seburyamo, G.; Smith, B. K.; Flexner,
L.; Clark, C. E.; Cordova, D. Bioorg. Med. Chem. Lett.
2005, 15, 4898-4906.
6. Hamper, B. C.; Mao, M. K.; Phillips, W. G. US 6121458 A.
7. For recent articles: (a) Zora, M.; Kivrak, A.; Yazici, C. J.
Org. Chem. 2011, 76, 6726-6742; (b) Janin, Y. L. Chem.
Rev. 2012, 112, 3924-3958; (c) Fustero, S.; Sánchez-
Roselló, M.; Barrio, P.; Simón-Fuentes, A. Chem. Rev. 2011,
111, 6984-7034; (d) Li, F.; Nie, J.; Sun, L.; Zheng, Y.; Ma,
J.-A. Angew. Chem. Int. Ed. 2013, 52, 6255-6258. Angew.
Chem. 2013, 125, 6375-6378; (e) Mykhailiuk, P. K. Chem.
Eur. J. 2014, 20, 1-7; (f) Iminov, R. T.; Mashkov, A. V.;
Vyzir, I. I.; Chalyk, B. A.; Tverdokhlebov, A. V.;
Mykhailiuk, P. K.; Babichenko, L. N.; Tolmachev, A. A.;
Volovenko, Y. M.; Biitseva, A.; Shishkin, O. V.; Shishkina,
S. V. Eur. J. Org. Chem. 2015, 4, 886-891; (g) Rulev, A.
Y.; Romanov, A. R. RSC Adv. 2016, 6, 1984-1988; (h)
Vincent-Rocan, J.-F.; Ivanovich, R. A.; Clavette, C.;
Leckett, K.; Bejjani, J.; Beauchemin, A. M. Chem. Sci.
2016, 7, 315-328; (i) Sloop, J. C.; Holder, C.; Henary, M.
Eur. J. Org. Chem. 2015, 16, 3405-3422; (j) Wen, J. J.;
Ding, C.-K.; Ding, Z.-C.; Li, T.; Zhan, Z.-P. Eur. J. Org.
Chem. 2015, 23, 5230-5235.
8. Hsieh, M.-T.; Kuo, S.-C.; Lin, H.-C. Adv. Synth. Catal.
2015, 357, 683-689.
9. Maxwell, B. D. J. Labelled. Cpd. Radiopharm. 2000, 43,
645-654.
10. Foster, R. S.; Jakobi, H.; Harrity, J. P. A. Org. Lett. 2012,
14, 4858-4861.
11. For the synthesis of 1,1,1-trifluoro-4-(trimethylstannyl)but-
3-yn-2-one, refer to: Koldobskii, A. B.; Tsvetkov, N .P.;
Verteletskii, P. V.; Godovikov, I. A.; Kalinin, V. N. Russ.
Chem. Bull. Int. Ed. 2009, 58, 1431-1437.
12. (a) Zhang, W.; Moore, J. S. J. Am. Chem. Soc. 2004, 126,
12796; (b) Tai, C.-L.; Hung, M.-S.; Pawar, V.-D.; Tseng,
S.-L.; Song, J.-S.; Hsieh, W.-P.; Chiu, H.-H.; Wu, H.-C.;
Hsieh, M.-T.; Kuo, C.-W.; Hsieh, C.-C.; Tsao, J.-P.; Chao,
Y.-S.; Shia, K.-S. Org. Biomol. Chem. 2008, 6, 447-450.