Preparation of 5-Fluoropyrazoles from Pyrazoles and N -Fluorobenzenesulfonimide (NFSI)

Article abstract of DOI:10.1021/acs.joc.8b00199

Facile synthesis of 5-fluoropyrazoles by direct fluorination of pyrazoles with N-fluorobenzenesulfonimide (NFSI) was elaborated. This approach was used to prepare the unsubstituted 5-fluoro-1H-pyrazole, the known fungicide Penflufen, and many functionaliz

Full text of DOI:10.1021/acs.joc.8b00199

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Article
Preparation of 5-fluoropyrazoles from pyrazoles and NFSI.
Vitalina Levchenko, Yurii V. Dmytriv, Andriy V. Tymtsunik, Konstantin Liubchak,
Alexander Rudnichenko, Anton V. Melnyk, Stanislav Y. Veselovych, Yurii V.
Borodulin, Oleksandr M. Otsalyuk, Andrei A. Tolmachev, and Pavel K. Mykhailiuk
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00199 • Publication Date (Web): 27 Feb 2018
Downloaded from http://pubs.acs.org on February 27, 2018
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Preparation of 5-fluoropyrazoles from pyrazoles and NFSI.
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Vitalina Levchenko,a Yurii V. Dmytriv,a,b Andriy V. Tymtsunik,a,b Konstantin Liubchak,a
Alexander Rudnichenko,a,c Anton V. Melnyk,a Stanislav Y. Veselovych,a Yurii V. Borodulin,a
Oleksandr M. Otsalyuk,a Andrei A. Tolmachev,a,c and Pavel K. Mykhailiuk*a,c
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a Enamine Ltd., Chervonotkatska 78, Kyiv 02094 (Ukraine), www.enamine.net, www.mykhailiukchem.org
b Department of Chemical Technology, National technical university of Ukraine "Igor Sikorsky Kyiv Polytechnic Institute",
Prosp. Peremohy 37, Kyiv 03056 (Ukraine)
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c Department of Chemistry, National Taras Shevchenko University of Kyiv, Volodymyrska 64, Kyiv 01033 (Ukraine)
ABSTRACT: Facile synthesis of 5ꢀfluoropyrazoles by direct fluorination of pyrazoles with NFSI, was elaborated. This approach
was used to prepare the unsubstituted 5ꢀfluoroꢀ1Hꢀpyrazole, the known fungicide Penflufen and many functionalized 5ꢀ
fluoropyrazoles: building blocks for medicinal chemistry and agrochemistry.
INTRODUCTION
Since the discovery of the anticancer agent 5ꢀfluorouracil by Heidelberger in 1957,1 the stable growth of fluorineꢀcontaining
drugs was observed. As a fact, in 1970 there were only about 2% of fluorineꢀcontaining compounds on the market, while the
current number has grown up to about 20%.2,3 Incorporation of a single fluorine atom into organic molecules affects their metabolic
stability, cellular permeability, lipophilicity, and water solubility. Therefore, elaboration of novel methods to prepare the fluorineꢀ
containing organic compounds is of high importance.4
In 2011, Bayer CS launched the novel fungicide with the fragment of 5ꢀfluoropyrazole: Penflufen.5 The single fluorine
substitution made the compound more potent and metabolically stable over the nonꢀfluorinated analogue. Since then, the core of
5ꢀfluoropyrazole has been playing an important role in agrochemical projects, as reflected in an everꢀincreasing number of the
corresponding patents.6 Diverse pharmaceutical and agrochemical companies have actively started to use derivatives of
5ꢀfluoropyrazoles in their research (Figure 1).
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Figure 1. Bioactive compounds with the motif of 5ꢀfluoropyrazole.
,
In spite of the huge current interest in fluoropyrazoles,7 8 the number of the corresponding synthetic approaches to
5ꢀfluoropyrazoles remains still limited.9 They rely mainly on four approaches. An efficient practical method was developed by
Pazenok and Neeff from Bayer CS towards an industrial production of Penflufen.10 At high temperature, 5ꢀchloropyrazoles reacted
with KF ꢀ propably the cheapest source of a nucleophilic fluorine atom nowadays ꢀ to provide 5ꢀfluoropyrazoles (Scheme 1, 1).
The second approach requires the fluorinated synthon for 1,3ꢀdicarbonyl compounds. With hydrazines, the activated CF3/CF2ꢀ
groups act as
a hidden equivalent for the carbonyl group to form 5ꢀfluoropyrazoles accompanied with HFꢀ
elimination/heteroaromatization. The groups of Yamakawa,11 Ichikawa/Minami,12 Schlosser,13 and Chiba14 used different starting
compounds to synthesize the target products (Scheme 1, 2)). Perfluoro(2ꢀmethylꢀ2ꢀpentene) also reacts with hydrazines to provide
polyfluorinated 5ꢀfluoropyrazoles (Scheme 1, 2).15
In 2016, Taran and colleagues elaborated the “ultrafast” copperꢀcatalyzed clickꢀreaction of fluorosydnones with alkynes to give
5ꢀfluoropyrazoles.16 The high potential of this reaction was demonstrated by the radiolabelling of pyrazoles with 18Fꢀisotope
(Scheme 1, 3).
Finally, in 2017, Tang demonstrated that electronꢀrich heteroaromatic carboxylic acids reacted with 1ꢀchloromethylꢀ4ꢀfluoroꢀ1,4ꢀ
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) to form fluoroheterocycles accompanied with decarboxylation.17 In
many cases, however, formation of the side dimeric products was also observed (Scheme 1, 4).
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We were very much surprised since very little was known on the direct incorporation of the electrophilic fluorine atom into
pyrazoles. In recent years, this reaction was mentioned in many patents of agrochemical and pharmaceutical companies using
diverse fluorination agents: XeF2,18 Nꢀfluorobenzenesulfonimide (NFSI)19 and Selectfluor20 with the yields typically below 30%.
However, to the best of our knowledge no systematic study in the open literature has been performed so far.21 In this context, and
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within our current interest in fluorinated heterocycles,22 23 24 2526 herein we have elaborated an efficient practical method to
5ꢀfluoropyrazoles from pyrazoles and NFSI. The high potential of this approach was demonstrated by the synthesis of
5ꢀfluoropyrazole and Penflufen.
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Scheme 1. Approaches to 5ꢀfluoropyrazoles.
RESULTS AND DISCUSSION
Validation of the hypothesis and scale up. First, we tried to perform fluorination of the model noneꢀfunctional pyrazole 1 with
NFSI. Initial attempts to directly introduce fluorine atom in the absence of a strong base were unsuccessful. Therefore, we next
treated the starting material with nꢀBuLi at −78 °C followed by a transfer of a preꢀcooled solution of NFSI in THF (−78 °C) via a
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cannula. After the addition, the reaction mixture was stirred for 2 h under cooling. The crude product contained ca. 85% of product
1a and 15% of the starting material. Unfortunately, all attempts to improve the conversion of the reaction by increasing the reaction
time, amount of NFSI and the reaction temperature did not help. Gratifyingly, however pyrazole 1a was isolated in 65% yield after
the column chromatography (Scheme 2). Importantly, the procedure was still effective on a gram scale, as we easily synthesized 20
g of the product in a single run.
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Scheme 2. Synthesis of 5ꢀfluoropyrazole 1a.
Reaction Scope. Having a validated procedure in hand, we next studied its scope and limitations. Diverse Nꢀaryl substituted
pyrazoles 2ꢀ9 were tested (Table 1, Entry 2ꢀ9). To avoid the bromineꢀlithium exchange in pyrazoles 6 and 7, LDA was used instead
of BuLi. Under the above described conditions, according to LCꢀMS data all reaction mixtures contained ca. 80% of the needed
fluoropyrazoles, the starting materials and the side products: PhSO2ꢀpyrazoles.27 For all tested compounds 2-9, except for 7, the
needed substituted 5ꢀfluoropyrazoles 2a-6a and 8a, 9a were isolated from the reaction mixtures by column chromatography in
appropriate yields of 60ꢀ65%. Pyrazole 7 gave mainly the side product 7b and only 5% of the needed fluoropyrazole 7a, as detected
by LCꢀMS (Scheme 3b).
Next, we studied the fluorination of Nꢀalkyl substituted pyrazoles (Table 1, Entry 10ꢀ18). NꢀIsopropylpyrazole 10 gave a
fluorinated product 10a in a moderate yield of 51%. In case of pyrazole 11 no reaction was observed. Due to a sterically bulky tertꢀ
butyl substituent, anion A did not react with NFSI. The LCꢀMS and GCꢀMS analysis of the reaction mixture showed that a major
component of the reaction was the starting pyrazole 11 (Scheme 3b). With more active electrophile ꢀ carbon dioxide, ꢀ the
corresponding acid 19 was obtained in 75% yield.
Substrates 12-18 smoothly underwent lithiation/fluorination and gave the desired products 12a-18a in 50ꢀ73% yield. LDA was
used instead of BuLi in case of pyrazoles 14, 15 and also 17, 18 to avoid the halogenꢀlithium exchange. All Nꢀalkyl fluorinated
pyrazoles were volatile. The product 16a was very volatile, and we did not isolate it in the individual state. Its solution in THF was
directly used for subsequent transformations (Scheme 7).
Table 1. Scope and limitations of the reaction.
Pyrazole
Product
Yield
65%
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no reaction
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55%
~57%c
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a) LDA was used instead of BuLi. b) Yield by LCꢀMS. C) Yield by 1H NMR. The compound was not isolated due to a high volatility, but was used next as a solution in THF.
Scheme 3. Limitation of the method.
Synthesis of 5-fluoropyrazole. 5ꢀFluoropyrazole 20 was described in 1996 by Reimlinger and Van Overstraeten.28 The authors
thermally decomposed pyrazolyl diazonium tetrafluoroborate in the presence of NaF to obtain the product 20 in 0.3% yield. So far,
this is the only known method towards compound 20. It is not surprising therefore, that in spite of huge practical potential, no one
used pyrazole 20 in medicinal chemistry, agrochemistry or organic synthesis. Because of the lack of synthetic approaches, pyrazole
1a is also not commercially available.
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The above results on Nꢀprotected pyrazoles 14a and 15a suggested us a good method to 20 (Scheme 4). Treatment of compound
15a with TBAF at room temperature during 64 h gave only 65% of conversion. In strict contrast, treatment of compound 15a with
trifluoracetic acid at ꢀ10 °C gave the corresponding salt, and a further hydrolysis with sodium acetate in ethanol afforded product 20
in 21% isolated yield. When we treated compound 14a with trifluoracetic acid, we received the pure pyrazole 20 in 54% isolated
yield.
We believe that with this novel synthetic strategy, pyrazole 20 will find soon a wide practical application in organic synthesis as a
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building block, and also in coordination chemistry as a ligand for transition metals.29 30
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Scheme 4. Synthesis of 5ꢀfluoropyrazole 20.
Synthesis of building blocks. Next, we transformed several products into the representative functionalized building blocks for
organic synthesis. Reaction of bromide 17a with gaseous carbon monoxide in the presence of cat. Pd(dppf)Cl2·CH2Cl2 in dry
methanol in a steel autoclave gave an intermediate ester that after the hydrolysis with 10% aq. NaOH afforded the target acid 21 in
76% yield. Treatment of pyrazole 17a with NBS in acetonitrile at room temperature gave compound 22 in 93% yield (Scheme 5).
The difference in activity of F, Cl and Br atoms in pyrazole 22 makes it an interesting target for further functionalization by
sequential metalꢀcatalyzed crossꢀcouplings.
Scheme 5. Synthesis of pyrazoles 21 and 22.
Different classes of organic compounds were next synthesized from pyrazole 1a (Scheme 6). First, we treated compound 1a with
Nꢀiodosuccinimide under heating at reflux in acetonitrile during two days to obtain iodide 23 in 63% yield. Treatment of pyrazole
1a with a mixture of the fuming nitric acid and acetic anhydride led to a nitro product 29 in good yield of 68%. Further reduction of
the nitro group with hydrogen over Pd/C as a catalyst in methanol at room temperature produced a mixture of 30 and the undesired
product 5ꢀmethoxyꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀamine in 1:1 ratio. When we replaced methanol with THF, the target amine 30 was
isolated in 92% yield. Next, we treated pyrazole 1a with Nꢀbromosuccinimide in acetonitrile at room temperature to obtain bromide
27 in 93% yield.
Pyrazole 1a did not react with acetic anhydride in the presence of Lewis acids even under the heating. Therefore, we treated
bromide 27 with nꢀBuLi, followed by an addition of MeCHO. The intermediate crude alcohol 25 was oxidized with pyridinium
chlorochromate in an overall yield of 48%. To synthesize sulfonyl chloride 24, we mixed bromide 28 with nꢀBuLi, followed by an
addition of a solution of SO2 and NCS. Compound 27 was also a subject for the reaction with 2ꢀisopropoxyꢀ4,4,5,5ꢀtetramethylꢀ
1,3,2ꢀdioxaborolane in the presence of nꢀBuLi to give ester 28 in 73% yield. The structure of compound 28 was confirmed by Xꢀray
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analysis (Figure 2). We also changed bromine atom in pyrazole 27 by a carboxylic acid group with nꢀBuLi and dry ice to get 31 in
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75% yield (Scheme 6).
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I
SO2Cl
F
O
N
N
N
F
F
N
N
O
N
H
C
e
Ph
Ph
Ph
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M
,
i
C
L
C
u
P
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24
B
-
)
%
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n
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4
)
1
n-BuLi
SO2, NCS
64%
NIS 63%
O
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Br
B
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NBS
93%
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N
N
N
N
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F
F
O
iPr-O
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O
Ph
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Ph
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73%
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n
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u
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i
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HNO3
Ac2O
C
68%
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%
NO2
F
NH2
F
CO2H
F
H2, Pd/C
N
N
N
THF
92%
N
N
N
Ph
Ph
Ph
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Scheme 6. Synthetic utility of pyrazole 1a.
Figure 2. Xꢀray crystal structure of pyrazole 28.31
Synthesis of Penflufen. Finally, we developed an alternative synthesis of the commercialized fungicide Penflufen (Figure 1,
Scheme 7). Bromination of pyrazole 16a with NBS in acetonitrile afforded bromide 32 in 42% yield. Treatment of 32 with BuLi,
followed by an addition of dry ice gave acid 33 in 81% yield. The last step of the synthesis was an amide coupling between acid 33
and aniline 34 in the presence of 1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide (EDCI). Penflufen was obtained in 50% yield.
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Scheme 7. Synthesis of fungicide Penflufen.
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CONCLUSIONS
We elaborated a oneꢀstep synthesis of 5ꢀfluoropyrazoles by direct lithiation/fluorination of pyrazoles with NFSI. The procedure
was scalable, and 20 g of pyrazole 1a was synthesized in one run. The obtained products were transformed into the representative
acids, amines, sulfonyl chlorides and boronates. Also, novel synthetic approaches towards 5ꢀfluoropyrazole 20, and the known
fungicide Penflufen were developed. Given the high efficiency, simplicity, and low costs of our method, we believe that 3/5ꢀ
fluoropyrazoles will find soon a wide application in agrochemistry and medicinal chemistry as valuable building blocks, while
pyrazole 20 ꢀ in coordination chemistry as a ligand for transition metals.
EXPERIMENTAL SECTION
General methods
All starting materials were taken at Enamine Ltd. Autoclaves were provided by UOSLab (en.uoslab.com). Column chromatography
was performed using Kieselgel Merck 60 (230ꢀ400 mesh) as the stationary phase. Reverse phase column chromatography was
performed using C18ꢀmodified silica gel as a stationary phase, column: SunFire Waters, 5 µm, 19 mm × 100 mm. Hꢀ, 19Fꢀ, 13Cꢀ
1
NMR spectra were recorded on at 500 or 400 MHz, 376 MHz and 125 or 101 MHz respectively. Chemical shifts are reported in
ppm downfield from TMS (1H, 13C) or CFCl3 (19F) as internal standards. Mass spectra were recorded on an LCꢀMS instrument with
chemical ionization (CI). LCꢀMS data were acquired on Agilent 1200 HPLC system equipped with DAD/ELSD/LCMSꢀ6120
diodematrix and massꢀselective detector, column: Poroshell 120 SBC18, 4.6 mm × 30 mm. Eluent, A, acetonitrile–water with 0.1%
of FA (99: 1); B, water with 0.1% of FA.
General procedure for fluorination with NFSI in the presence of n-BuLi or LDA. A 3ꢀneck roundꢀbottom flask was equipped
with a dropping funnel, thermometer, airꢀbubbles counter, and filled with argon. Then, the appropriate pyrazole (1 equiv), dry THF
were loaded to the flask, and the mixture was cooled to ꢀ65 °C. To the stirred solution nꢀBuLi or LDA (1.05 equiv) was added
dropwise. When addition was finished the mixture was stirred for 45 min at the same temperature. Then, it was cooled to ꢀ75 °C,
and a solution of NFSI (1.2 equiv) in THF was added dropwise. The mixture was stirred for 2 h at the same temperature. The
cooling bath was removed, and the mixture was stirred at rt for 12 h, diluted with a saturated solution of ammonium chloride, and
concentrated under reduced pressure. The residue was dissolved in MTBE, washed with a sodium bicarbonate solution (3 times).
The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure.
General procedure for halogenation with N-bromosuccinimide. A solution of the appropriate compound (1 equiv) in acetonitrile
was combined with NBS (1.05 equiv), and the resulting mixture was stirred for 14 h at rt. Then, it was concentrated, and the residue
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was dissolved in MTBE. The organic solution was washed with sodium bicarbonate, dried over sodium sulfate and concentrated to
get a pure product.
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5-Fluoro-1-phenyl-1H-pyrazole (1a): nꢀBuLi was used as the base, the compound was purified by column chromatography
1
(gradient, MTBE, 0ꢀ35%). Yield 3.3 g (65%), colorless oil. H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.7 Hz, 2H), 7.50 (s, 1H),
7.43 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 5.91 – 5.70 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 153.4 (d, J = 242.2 Hz), 139.6
(d, J = 11.0 Hz), 137.3, 129.3, 127.3, 121.4 (d, J = 4.1 Hz), 88.2 (d, J = 15.4 Hz). 19F NMR (376 MHz, CDCl3) δ ꢀ133.3. Anal.
Calcd for C9H7FN2: C, 66.66; H, 4.35; N, 17.27. Found: C, 66.52; H, 4.49; N, 17.39.
5-Fluoro-1-(o-tolyl)-1H-pyrazole (2a): nꢀBuLi was used as the base. Yield 3.1 g (61%), yellow oil. 1H NMR (500 MHz, CDCl3) δ
7.54 (d, J = 2.1 Hz, 1H), 7.46 – 7.05 (m, 4H), 5.86 (dd, J = 5.7, 1.8 Hz, 1H), 2.20 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 153.9 (d,
J = 276.5 Hz), 139.7 (d, J = 10.6 Hz), 135.4 (d, J = 7.6 Hz), 131.1, 129.5, 127.3, 126.6, 86.5 (d, J = 15.0 Hz), 17.4. 19F NMR (376
MHz, CDCl3) δ ꢀ134.7. Anal. Calcd for C10H9FN2: C, 68.17; H, 5.15; N, 15.90. Found: C, 68.05; H, 5.40; N, 15.68.
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5-Fluoro-1-(p-tolyl)-1H-pyrazole (3a): nꢀBuLi was used as the base. Yield 4.5 g (60%), yellow oil. H NMR (400 MHz, DMSOꢀ
d6) δ 7.64 – 7.61 (m, 1H), 7.50 (d, J = 7.0 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 6.20 (dd, J = 5.3, 1.8 Hz, 1H), 2.35 (s, 3H). 13C NMR
(126 MHz, DMSOꢀd6) δ 152.6 (d, J = 277.8 Hz), 139.6 (d, J = 11.3 Hz), 137.1, 134.2, 129.9, 121.5 (d, J = 3.6 Hz), 88.3 (d, J = 15.3
Hz), 20.5. 19F NMR (376 MHz, DMSOꢀd6) δ ꢀ134.4. MS (APCI) m/z [M+H]+ calculated for C10H10FN2: 177.1; found: 177 (M+H).
Anal. calcd. for C10H9FN2: C, 68.17; H, 5.15; N, 15.90. Found: C, 68.02; H, 5.30; F, N, 15.78.
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1-(4-Ethylphenyl)-5-fluoro-1H-pyrazole (4a): nꢀBuLi was used as the base. Yield 2.8 g (64%), yellow oil. H NMR (400 MHz,
CDCl3) δ 7.56 – 7.48 (m, 3H), 7.29 (d, J = 8.1 Hz, 2H), 5.89 (dd, J = 5.4, 1.7 Hz, 1H), 2.71 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.6 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 142.3 (d, J = 283.0 Hz), 139.6, 139.5, 128.6, 121.7 (d, J = 3.8 Hz), 119.4, 107.4, 88.1 (d, J =
15.4 Hz), 28.5, 15.6. 19F NMR (376 MHz, CDCl3) δ ꢀ133.7. MS (APCI) m/z [M+H]+ calculated for C11H12FN2: 191.1; found: 191
(M+H). Anal. calcd. for C11H11FN2: C, 69.46; H, 5.83; N, 14.73. Found: C, 69.63; H, 5.98; N, 14.59.
5-Fluoro-1-(4-fluorophenyl)-1H-pyrazole (5a): nꢀBuLi was used as the base, compound was purified by column chromatography
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(gradient, MTBE, 0ꢀ35%). Yield 2.3 g (63%), yellow oil. H NMR (400 MHz, CDCl3) δ 7.60 (ddd, J = 8.8, 4.6, 1.6 Hz, 2H), 7.51
(dd, J = 3.0, 2.0 Hz, 1H), 7.15 (dd, J = 9.0, 8.2 Hz, 2H), 5.90 (dd, J = 5.4, 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 161.6 (d, J =
247.3 Hz), 153.4 (d, J = 280.0 Hz), 139.8 (d, J = 11.0 Hz), 133.5, 123.5 (dd, J = 8.5, 4.0 Hz), 116.3 (d, J = 23.0 Hz), 88.3 (d, J =
15.3 Hz). 19F NMR (376 MHz, CDCl3) δ ꢀ114.6, ꢀ133.7. Anal. Calcd for C9H6F2N2: C, 60.00; H, 3.36; N, 15.55. Found: C, 60.25;
H, 3.62; N, 15.28.
1-(4-Bromophenyl)-5-fluoro-1H-pyrazole (6a): LDA was used as the base, compound was purified by column chromatography
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(gradient, MTBE, 0ꢀ35%). Yield 1.8 g (65%), orange oil. H NMR (400 MHz, DMSOꢀd6) δ 7.73 (d, J = 8.6 Hz, 2H), 7.68 (s, 1H),
7.60 (d, J = 8.0 Hz, 2H), 6.25 (d, J = 3.8 Hz, 1H). 13C NMR (101 MHz, DMSOꢀd6) δ 152.8 (d, J = 279.5 Hz), 140.4 (d, J = 11.2
Hz), 135.9, 132.5, 123.1 (d, J = 4.3 Hz), 120.1, 88.9 (d, J = 15.1 Hz). 19F NMR (376 MHz, DMSOꢀd6) δ ꢀ133.2. MS (APCI) m/z
[M+H]+ calculated for C9H7BrFN2: 242.1; found: 242 (M+H). Anal. calcd. for C9H6BrFN2: C, 44.84; H, 2.51; N, 11.62. Found: C,
44.69; H, 2.71; N, 11.48.
1-([1,1'-Biphenyl]-4-yl)-5-fluoro-1H-pyrazole (8a): nꢀBuLi was used as the base, compound was purified by column
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chromatography (gradient, MTBE, 0ꢀ35%). Yield 1.1 g (63%), yellow solid, mp 59ꢀ60 °C. H NMR (400 MHz, DMSOꢀd6) δ 7.85
(d, J = 8.4 Hz, 2H), 7.77 – 7.62 (m, 5H), 7.50 (t, J = 7.4 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 6.26 (d, J = 3.6 Hz, 1H). 13C NMR (126
MHz, DMSOꢀd6) δ 152.8 (d, J = 278.8 Hz), 140.1 (d, J = 11.3 Hz), 139.1, 138.9, 135.9, 129.0, 127.8, 127.7, 126.7, 121.7 (d, J =
3.9 Hz), 88.7 (d, J = 15.3 Hz). 19F NMR (376 MHz, DMSOꢀd6) δ ꢀ133.7. MS (APCI) m/z [M+H]+ calculated for C15H12FN2: 239.1;
found: 239 (M+H). Anal. calcd. for C15H11FN2: C, 75.62; H, 4.65; N, 11.76. Found: C, 75.88; H, 4.90; N, 11.51.
5-Fluoro-1,4-diphenyl-1H-pyrazole (9a): nꢀBuLi was used as the base, compound was purified by column chromatography
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(gradient, MTBE, 0ꢀ35%). Yield 1.2 g (61%), yellow solid, mp 57ꢀ58 °C. H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 3.0 Hz, 1H),
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7.70 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.29 (t,
J = 7.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 149.8 (d, J = 283.9 Hz), 138.1 (d, J = 9.5 Hz), 137.3, 129.8 (d, J = 5.0 Hz), 129.5,
129.1, 127.6, 127.0, 125.9 (d, J = 3.4 Hz), 121.6 (d, J = 4.1 Hz), 103.9 (d, J = 9.6 Hz). 19F NMR (376 MHz, CDCl3) δ ꢀ133.7. MS
(APCI) m/z [M+H]+ calculated for C15H12FN2: 239.1; found: 239 (M+H). Anal. calcd. for C15H11FN2: C, 75.62; H, 4.65; N, 11.76.
Found: C, 75.48; H, 4.76; N, 11.91.
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5-Fluoro-1-isopropyl-1H-pyrazole (10a): nꢀBuLi was used as the base, compound was purified by distillation (20 mmHg, 57ꢀ60
°C). Yield 2.1 g (51%), colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 5.59 (d, J = 1.5 Hz, 1H), 4.41 (m, 1H), 1.40 (d, J =
6.7 Hz, 6H), 13C NMR (101 MHz, CDCl3) δ 152.9 (d, J = 273.9 Hz), 137.8 (d, J = 11.0 Hz), 86.1 (d, J = 15.2 Hz), 49.4, 21.7. 19F
NMR (376 MHz, CDCl3) δ ꢀ138.0. Anal. Calcd for C6H9FN2: C, 56.24; H, 7.08; N, 21.86. Found: C, 56.34; H, 6.98; N, 21.74.
1-(Cyclopropylmethyl)-5-fluoro-1H-pyrazole (12a): nꢀBuLi was used as the base, compound was purified by column
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chromatography (gradient, MTBE, 0ꢀ30%). Yield 2.3 g (68%), colorless oil. H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 5.70 (d, J
= 4.6 Hz, 1H), 3.87 (d, J = 7.0 Hz, 2H), 1.37 – 1.03 (m, 1H), 0.58 (q, J = 5.1 Hz, 2H), 0.36 (d, J = 4.9 Hz, 2H). 13C NMR (100
MHz, CDCl3) δ 153.5 (d, J = 274.3 Hz), 137.9 (d, J = 10.9 Hz), 85.9 (d, J = 15.1 Hz), 52.0, 10.8, 3.5. 19F NMR (376 MHz, CDCl3)
δ ꢀ138.4. Anal. Calcd for C7H9FN2: C, 59.99; H, 6.47; N, 19.99. Found: C, 59.82; H, 6.31; N, 20.16.
5-fluoro-1-phenethyl-1H-pyrazole (13a): nꢀBuLi was used as the base, compound was purified by column chromatography
(gradient, MTBE, 0ꢀ30%). Yield 1.4 g (62%), colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.33 (m, 1H), 7.33 – 7.16 (m, 3H),
7.11 (d, J = 6.9 Hz, 2H), 5.63 (dd, J = 5.6, 1.9 Hz, 1H), 4.21 (t, J = 7.4 Hz, 2H), 3.12 (t, J = 7.4 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 153.8 (d, J = 274.9 Hz), 138.6 (d, J = 10.8 Hz), 137.7, 128.7, 128.6, 126.8, 86.0 (d, J = 14.9 Hz), 48.6, 36.0. 19F NMR
(376 MHz, CDCl3) δ ꢀ138.2. Anal. Calcd for C11H11FN2: C, 69.46; H, 5.83; N, 14.73. Found: C, C, 69.71; H, 5.69; N, 14.60.
5-Fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (14a): LDA was used as the base, after the general procedure compound was
obtained as the mixture of the desired product and the starting pyrazole in the ratio of 7:3 in 4.3 g (73%) yield. It was used in the
next step as the spectra data matched the reference (Kurihara, T.; Harusawa, S.; Matsuda, C.; Araki, L. Synthesis. 2006, 793).
5-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (15a): LDA was used as the base, compound was purified by column
chromatography (gradient, hexane/MTBE, 0ꢀ70%). Yield 3.8 g (55%), colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H),
5.73 (dd, J = 5.5, 1.8 Hz, 1H), 5.33 (s, 2H), 3.71 – 3.40 (m, 2H), 0.96 – 0.77 (m, 2H), ꢀ0.03 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
154.3 (d, J = 277.4 Hz), 139.3 (d, J = 10.6 Hz), 86.8 (d, J = 14.4 Hz), 75.6, 66.9, 17.7, ꢀ1.5. 19F NMR (376 MHz, CDCl3) δ ꢀ137.5.
Anal. Calcd for C9H17FN2OSi: C, 49.97; H, 7.92; N, 12.95. Found: C, 49.81; H, 7.78; N, 13.06.
3-Bromo-5-fluoro-1-methyl-1H-pyrazole (17a): LDA was used as the base, compound was purified by column chromatography
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(gradient, hexane/MTBE 0ꢀ35%). Yield 3.4 g (61%), yellow oil. H NMR (400 MHz, CDCl3) δ 5.69 (d, J = 5.9 Hz, 1H), 3.60 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 153.2 (d, J = 280.7 Hz), 124.0 (d, J = 13.9 Hz), 89.4 (d, J = 15.3 Hz), 34.1. 19F NMR (376
MHz, CDCl3) δ ꢀ131.2. Anal. Calcd for C4H4BrFN2: C, 26.84; H, 2.25; N, 15.65. Found: C, 26.72; H, 2.35; N, 15.81.
5-Fluoro-3-iodo-1-methyl-1H-pyrazole (18a): LDA was used as the base, compound was purified by column chromatography
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(gradient, hexane/MTBE 0ꢀ50%). Yield 4.6 g (63%), colorless crystals, mp 29ꢀ30 °C. H NMR (400 MHz, CDCl3) δ 5.86 (d, J =
6.0 Hz, 1H), 3.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.6 (d, J = 281.4 Hz), 95.1 (d, J = 14.3 Hz), 93.0 (d, J = 12.4 Hz), 34.4.
19F NMR (376 MHz, CDCl3) δ ꢀ132.9. Anal. Calcd for C4H4IFN2: C, 21.26; H, 1.78; N, 12.40. Found: C, 21.01; H, 1.97; N, 12.21.
1-(3-Bromo-2-fluorophenyl)-1H-pyrazole (7b): LDA was used as the base, compound was purified by column chromatography
(gradient, hexane/MTBE 0ꢀ35%). Yield 1.1 g (60%), colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.86 (t, J = 7.5 Hz,
1H), 7.74 (s, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.49 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 149.1, 141.3,
131.2, 130.9, 130.8, 125.6 (d, J = 4.6 Hz), 123.6, 110.5 (d, J = 20.4 Hz), 108.0. 19F NMR (376 MHz, CDCl3) δ ꢀ133.7. MS (APCI)
m/z [M+H]+ calculated for C9H7BrFN2: 242.1; found: 242 (M+H). Anal. calcd. for C9H6BrFN2: C, 44.84; H, 2.51; N, 11.62. Found:
C, 44.98; H, 2.68; N, 11.40.
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1-(tert-Butyl)-1H-pyrazole-5-carboxylic acid (19): nꢀBuLi was used as the base. Yield 0.9 g (75%), white solid, mp 140ꢀ141 °C.
1H NMR (500 MHz, DMSOꢀd6) δ 7.41 (d, J = 1.9 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H), 1.64 (s, 9H). 13C NMR (126 MHz, DMSOꢀd6)
δ 161.8, 135.4, 133.5, 113.5, 61.7, 29.3. MS (APCI) m/z [MꢀH]ꢀ calculated for C8H11N2O2: 167.1; found: 167 (MꢀH). Anal. calcd.
for C8H12N2O2: C, 57.13; H, 7.19; N, 16.66. Found: C, 57.01; H, 7.06; N, 16.85.
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5-Fluoropyrazole (20). Method A, SEM-protection. To a solution of 15a (1.2 g, 5.55 mmol, 1 equiv) in dry dichloromethane (5
mL) trifluoroacetic acid (8.5 mL, 111 mmol, 20 equiv) was added dropwise at ꢀ10 °C. The reaction mixture was stirred for 12 h at
rt, and then concentrated under reduced pressure. The residue was dissolved in dry ethanol (20 mL) and sodium acetate (2.3 g, 27.7
mmol, 5 equiv) was added. The reaction mixture was stirred for 12 h at rt and then concentrated. The residue was purified by
column chromatography (gradient, MTBE/acetonitrile, 0ꢀ30%) to get the desired compound in 100 mg (21%) yield. Method B,
DMSA-protection. To a solution of 14a (4.6 g, 23.8 mmol, 1 equiv) in dry dichloromethane (100 mL) trifluoroacetic acid (36.5
mL, 476 mmol, 20 equiv) was added dropwise at ꢀ10 °C. The reaction mixture was stirred for 12 h at rt, and then concentrated. The
residue was dissolved in water (20 mL) and basified with ammonia to pH 9. The compound was extracted with dichloromethane (3
× 50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column
chromatography (gradient, MTBE/acetonitrile, 0ꢀ30%) to get the desired compound in 1.1 g (54%) yield as yellow liquid. 1H NMR
(500 MHz, CDCl3) δ 11.77 (s, 1H), 7.42 (t, J = 2.1 Hz, 1H), 5.84 (dd, J = 5.8, 2.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 164.5 (d,
J = 243.0 Hz), 130.6, 89.1 (d, J = 24.1 Hz). 19F NMR (376 MHz, CDCl3) δ ꢀ134.0. Anal. Calcd for C3H3FN2: C, 41.87; H, 3.51; N,
32.55. Found: C, 41.70; H, 3.39; N, 32.74.
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5-Fluoro-1-methyl-1H-pyrazole-3-carboxylic acid (21). To a solution of 17a (1 equiv) in THF, Et3N (5 equiv) and cat.
Pd(dppf)Cl2×CH2Cl2 (0.1 equiv) were added in a steel autoclave. The resulted mixture was stirred with CO at 10ꢀ15 atm pressure at
rt for 18 h. The mixture was filtered through SiO2, treated with 10% aq. NaOH (2 equiv) and left stirred at rt overnight. The
solution was partially concentrated under reduced pressure and diluted with MTBE. The organic layer was separate, and the
aqueous layer was acidified with H3PO4 to pH 2. The desired acid was extracted with CH2Cl2, dried over Na2SO4, and concentrated
under reduced pressure to give 21 as a white solid, mp 153ꢀ154 °C, 5.6 g, (76% yield). 1H NMR (500 MHz, DMSOꢀd6) δ 12.90 (br
s, 1H), 6.38 (d, J = 5.8 Hz, 1H), 3.77 (s, 3H). 13C NMR (126 MHz, DMSOꢀd6) δ 162.6 (d, J = 2.2 Hz), 153.0 (d, J = 276.8 Hz),
141.2 (d, J = 10.2 Hz), 88.8 (d, J = 14.0 Hz), 34.7. 19F NMR (376 MHz, DMSOꢀd6) δ ꢀ133.6. MS (APCI) m/z [MꢀH]ꢀ calculated for
C5H4FN2O2: 143.1; found: 143 (MꢀH). Anal. calcd. for C5H5FN2O2: C, 41.67; H, 3.50; N, 19.44. Found: C, 41.79; H, 3.63; N,
19.26.
3-Bromo-4-chloro-5-fluoro-1-methyl-1H-pyrazole (22). A solution of 17a (1.05 g, 5.87 mmol, 1 equiv) in acetonitrile (50mL)
was combined with NCS (0.82 g, 6.16 mmol, 1.05 equiv), and the resulting mixture was stirred for 14 h at rt. The mixture was
concentrated, and the residue was dissolved in CH2Cl2. The organic solution was washed with sodium bicarbonate (3 × 30 mL),
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dried over sodium sulfate and concentrated to get a pure product as brown oil. Yield 1.15 g (93%). H NMR (500 MHz, CDCl3) δ
3.74 (d, J = 1.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 149.2 (d, J = 281.1 Hz), 124.5 (d, J = 8.7 Hz), 92.3 (d, J = 15.1 Hz), 35.5.
19F NMR (376 MHz, CDCl3) δ ꢀ131.3. MS (APEI) m/z [M] calculated for C4H3BrClFN2: 213. Found: 213 (M). Anal. calcd. for
C4H3BrClFN2: C, 22.51; H, 1.42, N, 13.13. Found: C, 22.30; H, 1.26, N, 13.36.
5-Fluoro-4-iodo-1-phenyl-1H-pyrazole (23). A solution of 1a (2 g, 12.33 mmol, 1 equiv) in acetonitrile (75 mL) was combined
with NIS (5.85 g, 25.9 mmol, 2.1 equiv), and the resulting mixture was stirred for 48 h at 60 °C. Then it was concentrated, and
residue was dissolved in dichloromethane. The organic solution was washed with sodium thiosulfate (3 times), sodium bicarbonate
(3 times), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (gradient,
hexane/MTBE, 0ꢀ35%) to get a pure product. Yield 2.2 g (63%), beige crystals, mp 166ꢀ167 °C, 1H NMR (500 MHz, DMSOꢀd6) δ
7.61 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 2.1 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ
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153.8 (d, J = 278.1 Hz), 143.6 (d, J = 7.9 Hz), 137.0, 129.5, 128.0, 121.4 (d, J = 3.9 Hz), 38.8 (d, J = 21.7 Hz). 19F NMR (376
MHz, CDCl3) δ ꢀ130.0. Anal. Calcd for C9H6FIN2: C, 37.53; H, 2.10; N, 9.72. Found: C, 37.30; H, 2.28; N, 9.61.
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5-Fluoro-1-phenyl-1H-pyrazole-4-sulfonyl chloride (24). To a solution of 27 (4.7 g, 19.5 mmol, 1 equiv) in 200 mL of Et2O was
added nꢀBuLi (8.2 mL, 20.47 mmol, 1.05 equiv) dropwise at ꢀ78 °C under argon. The mixture was stirred for 30 min, then was
added a fresh prepared solution of SO2 in Et2O at the same temperature, and left to warmꢀup to rt overnight. The resulted precipitate
was filtered, washed with ether and dried under reduced pressure to give a solid residue (4 g, 17.23 mmol, 1 equiv) which was
treated with NCS in dry acetonitrile. The mixture was stirred for 16 h, then it was concentrated under reduced pressure. The
resulted residue was dissolved in 100 mL of CH2Cl2 and washed with water (3 × 30 mL). The organic layer was dried over Na2SO4,
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filtered and concentrated. The desired compound was obtained as a yellow solid, mp 63ꢀ64 °C, 3.3 g (64%). H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.56 (t, J = 7.6 Hz, 2H), 7.51 (t, J = 7.2 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ 149.6 (d, J = 297.6 Hz), 138.3 (d, J = 5.3 Hz), 135.3, 130.0, 129.7, 122.4 (d, J = 3.5 Hz), 110.3 (d, J = 11.5 Hz). 19F NMR
(376 MHz, CDCl3) δ ꢀ119.0. MS (APEI) m/z [M] calculated for C9H6ClFN2O2S: 260. found: 260 (M). Anal. calcd. for
C9H6ClFN2O2S: C, 41.47; H, 2.32; Cl, 13.60; N, 10.75; S, 12.30. Found: C, 41.59; H, 2.52; Cl, 13.72; N, 10.60; S, 12.11.
1-(5-Fluoro-1-phenyl-1H-pyrazol-4-yl)ethanol (25). A 3ꢀneck roundꢀbottom flask was equipped with a dropping funnel,
thermometer, airꢀbubbles counter, and filled with argon. Then a starting bromide (9.66 mmol, 1 equiv) with dry THF (100 mL) was
loaded to the flask, and cooled to ꢀ75 °C. To the stirred solution nꢀBuLi (2.5 M in hexane, 4.1 mL, 10.1 mmol, 1.05 equiv) was
added dropwise. After 45 min at the same temperature acetaldehyde (2.2 mL, 38.6 mmol, 4 equiv) was added dropwise. Then the
cooling bath was removed, and mixture was stirred at rt for 12 h, diluted with a saturated solution of ammonium chloride, and
concentrated under reduced pressure. The residue was dissolved in water, and washed with MTBE (3 × 50 mL). The organic
solution was washed with water (3 × 30 mL), dried over sodium sulfate, and concentrated. The residue was purified by column
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chromatography (gradient, hexane/MTBE, 0ꢀ100%) to get a pure product. Yield 1.1 g (64%), yellow oil. H NMR (400 MHz,
CDCl3) δ 7.62 – 7.57 (m, 2H), 7.55 (d, J = 3.1 Hz, 1H), 7.45 (t, J = 7.9 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 4.91 (d, J = 6.4 Hz, 1H),
2.25 (s, 1H), 1.55 (d, J = 6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 149.8 (d, JCꢀF = 281.8 Hz), 138.1 (d, J = 9.9 Hz), 137.2 (d, J =
2.8 Hz), 129.4, 127.5, 121.5 (d, J = 4.0 Hz), 107.0 (d, J = 11.6 Hz), 60.9 (d, J = 3.4 Hz), 23.6. 19F NMR (376 MHz, CDCl3) δ ꢀ
134.1. Anal. Calcd for C11H11FN2O: C, 64.07; H, 5.38; N, 13.58. Found: C, 64.21; H, 5.53; N, 13.31.
1-(5-Fluoro-1-phenyl-1H-pyrazol-4-yl)ethanone (26). To a solution of the corresponding alcohol (5.82 mmol, 1 equiv) in dry
dichloromethane (75 mL) was added pyridinium chlorochromate (2 g, 8.73 mmol, 1.5 equiv). The resulting mixture was stirred for
16 h at rt, and then putted onto silica gel. The silica gel was washed with MTBE, and combined organic layers were concentrated.
The residue was purified by column chromatography (gradient, hexane/ MTBE, 0ꢀ100%) to get a pure product. Yield 0.9 g, (75%),
yellow crystals, mp 62ꢀ63 °C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 2.6 Hz, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 7.7 Hz,
2H), 7.40 (t, J = 7.3 Hz, 1H), 2.46 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 189.8 (d, J = 4.8 Hz), 152.6 (d, J = 292.6 Hz), 140.5 (d, J
= 8.2 Hz), 136.2, 129.6, 128.6, 122.1 (d, J = 3.9 Hz), 106.3 (d, J = 9.4 Hz), 28.7. 19F NMR (376 MHz, CDCl3) δ ꢀ123.9. Anal. Calcd
for C11H9FN2O: C, 64.70; H, 4.44; N, 13.72. Found: C, 64.60; H, 4.25; N, 13.89.
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4-Bromo-5-fluoro-1-phenyl-1H-pyrazole (27). Yield 9.7 g (93%), brown oil, H NMR (400 MHz, CDCl3) δ 7.65 – 7.54 (m, 2H),
7.50 (t, J = 7.0 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 150.4 (d, J = 279.4 Hz),
139.8 (d, J = 6.9 Hz), 136.9 (d, J = 2.7 Hz), 129.4, 127.8, 121.2 (d, J = 3.9 Hz), 75.5 (d, J = 18.3 Hz). 19F NMR (376 MHz, CDCl3)
δ ꢀ132.9 (d, J = 1.8 Hz). Anal. Calcd for C9H6BrFN2: C, 44.84; H, 2.51; N, 11.62. Found: C, 44.71; H, 2.62; N, 11.50.
5-Fluoro-1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (28). A 3ꢀneck roundꢀbottom flask was
equipped with a dropping funnel, thermometer, airꢀbubbles counter, and filled with argon. Then a starting bromide (9.66 mmol, 1
equiv) in dry THF (50 mL) was loaded to the flask, and cooled to ꢀ75 °C. To the stirred solution nꢀBuLi (2.5M in hexane, 4.1 mL,
10.1 mmol, 1.05 equiv) was added dropwise. After 45 min at the same temperature 2ꢀisopropoxyꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀ
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dioxaborolane (2 g, 11.6 mmol, 2.0 equiv) was added dropwise under stirring, and when addition was finished the mixture was
stirred for 20 min more at the same temperature. The cooling bath was removed, and mixture was stirred at rt for 12 h, diluted with
a saturated solution of ammonium chloride, and concentrated. The residue was dissolved in MTBE (100 mL), and washed with
water (3 × 50 mL), dried over sodium sulfate, and concentrated. The residue was reꢀcrystallized from hexane to get the pure
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product. Yield 2.1 g (73%), white crystals, mp 76ꢀ77 °C. H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 7.4
Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.27 (t, J = 7.1 Hz, 1H), 1.28 (s, 12H). 13C NMR (100 MHz, CDCl3) δ 157.9 (d, J = 287.4 Hz),
145.2 (d, J = 12.1 Hz), 136.9, 129.3, 127.5, 121.6 (d, J = 4.2 Hz), 83.6, 24.8. 19F NMR (376 MHz, CDCl3) δ ꢀ124.6. Anal. Calcd for
C15H18BrFN2O2: C, 62.53; H, 6.30; N, 9.72. Found: C, 62.71; H, 6.19; N, 9.56.
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5-Fluoro-4-nitro-1-phenyl-1H-pyrazole (29). A 3ꢀneck roundꢀbottom flask was equipped with a dropping funnel, thermometer,
and airꢀbubbles counter. Then it was loaded with acetic anhydride (15 mL), cooled to ꢀ15 °C, and fuming nitric acid (5.4 mL, 129.5
mmol, 2.1 equiv) was added dropwise. The resulting mixture was stirred for 20 min under cooling, and a solution of 1a (9.9 g, 61.7
mmol, 1 equiv) in acetic anhydride (10 mL) was added dropwise. The mixture was stirred for 4 h at ꢀ10 °C, 12 h at rt, and poured
onto the ice. The formed precipitate was collected by filtration and purified by column chromatography (silica gel, hexane, MTBE,
gradient, 0ꢀ50%). Yield 8.7 g (68%), yellow powder, mp 108ꢀ109 °C. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 1.6 Hz, 1H), 7.69
– 7.60 (m, 2H), 7.56 (t, J = 7.6 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 147.5 (d, J = 298.7 Hz), 136.0 (d, J
= 3.6 Hz), 135.6, 129.9, 129.6, 124.0, 122.3 (d, J = 3.6 Hz). 19F NMR (376 MHz, CDCl3) δ ꢀ121.4. Anal. Calcd for C9H6FN3O2: C,
52.18; H, 2.92; N, 20.28. Found: C, 52.35; H, 2.78; N, 20.15.
5-Fluoro-1-phenyl-1H-pyrazol-4-amine hydrochloride (30). To a solution of 29 (2 g, 9.65 mmol, 1 equiv) in THF (50 mL) was
added hydrochloric acid (1.2 mL, 9.65 mmol, 1 equiv), and Pd/C (5%, 1 g, 0.05 equiv). The resulting mixture was hydrogenated at
50 atm and monitored by TLC. The mixture was filtered, and filtrate was concentrated to get the desired compound in 1.9 g yield
1
(8.89 mmol, 92%), white crystals, mp 173ꢀ174 °C. H NMR (400 MHz, DMSOꢀd6) δ 10.63 (s, 3H), 7.85 (s, 1H), 7.63 (d, J = 7.9
Hz, 2H), 7.57 (t, J = 7.7 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H). 13C NMR (126 MHz, DMSOꢀd6) δ 146.0 (d, J = 281.9 Hz), 136.1, 135.1
(d, J = 7.1 Hz), 129.7, 128.3, 121.6 (d, J = 3.3 Hz), 96.7 (d, J = 12.0 Hz). 19F NMR (376 MHz, DMSOꢀd6) δ ꢀ134.7. Anal. Calcd for
C9H9ClFN3: C, 50.60; H, 4.25; N, 19.67. Found: C, 50.49; H, 4.41; N, 19.45.
5-Fluoro-1-phenyl-1H-pyrazole-4-carboxylic acid (31). A 3ꢀneck roundꢀbottom flask was equipped with a dropping funnel,
thermometer, airꢀbubbles counter, and filled with argon. Compound 27 (13 g, 54.1 mmol, 1 equiv) with dry THF (150 mL) was
loaded to the flask, and cooled to ꢀ75 °C. To the stirred solution nꢀBuLi (2.5 M in hexane, 23 mL, 56.8 mmol, 1.05 equiv) was
added dropwise. The mixture was stirred for 45 min at the same temperature, and crashed dry ice was added. The cooling bath was
removed, and mixture was stirred at rt for 12 h, then diluted with a saturated solution of ammonium chloride, and concentrated. The
residue was dissolved in water, and washed with MTBE (3 × 50 mL). The separated water layer was acidified with citric acid to pH
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4, and the formed precipitate was collected by filtration. Yield 8.7 g (75%), yellow powder, mp 166ꢀ167 °C. H NMR (500 MHz,
DMSOꢀd6) δ 12.96 (s, 1H), 8.02 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.48 (d, J = 7.4 Hz, 1H). 13
C
NMR (100 MHz, DMSOꢀd6) δ 162.1 (d, J = 5.0 Hz), 152.7 (d, J = 291.1 Hz), 141.6 (d, J = 7.1 Hz), 136.3, 130.1, 129.0, 122.8 (d, J
= 3.3 Hz), 98.2 (d, J = 8.4 Hz). 19F NMR (376 MHz, DMSOꢀd6) δ ꢀ124.3. Anal. Calcd for C10H7FN2O2: C, 58.26; H, 3.42; N, 13.59.
Found: C, 58.01; H, 3.54 N, 13.83.
4-Bromo-5-fluoro-1,3-dimethyl-1H-pyrazole (32). A 3ꢀneck roundꢀbottom flask was equipped with a dropping funnel,
thermometer, airꢀbubbles counter, and filled with argon. Compound 16 (10 g, 104 mmol, 1 equiv) with dry THF (200 mL) was
loaded to the flask, and cooled to ꢀ75 °C. To the stirred solution nꢀBuLi (2.5 M in hexane, 44 mL, 109.2 mmol, 1.05 equiv) was
added dropwise. The mixture was stirred for 30 min at the same temperature, and a solution of NFSI (39.4 g, 124.8 mmol, 1.2
equiv) in dry THF (50 mL) was added. The mixture was stirred at ꢀ75 °C for 2 h, and then left overnight at rt. The mixture was
diluted with dry CH3CN (200 mL) and NBS (20.4 g, 114.4 mmol, 1.1 equiv) was added at rt. The solution was stirred for 12 h at rt.
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Solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with sodium bicarbonate (3 × 75
mL), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (gradient,
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hexane/CH2Cl2, 0ꢀ50%) to give the desired product as yellow oil. H NMR (400 MHz, CDCl3) δ 3.62 (s, 3H), 2.10 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 151.0 (d, J = 274.6 Hz), 146.0 (d, J = 6.2 Hz), 73.3 (d, J = 16.8 Hz), 33.5, 13.0. 19F NMR (376 MHz,
CDCl3) δ ꢀ134.6. Anal. Calcd for C5H6BrFN2: C, 31.11; H, 3.13; N, 14.51. Found: C, C, 31.21; H, 3.30; N, 14.26.
5-Fluoro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (33). The reaction mixture after hydrolysis was acidified with phosphoric
acid to pH 2. Yield 6.9 g (81%), white solid, mp 211ꢀ212 °C. The spectra data matched the literature data (Ohtsuka, Y.; Uraguchi,
D.; Yamamoto, K.; Tokuhisa, K.; Yamakawa, T. Tetrahedron. 2012, 68, 2636).
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2-(4-Methylpentan-2-yl)aniline (34). Step 1: A flask was charged with 1ꢀ(2ꢀaminophenyl)ethanꢀ1ꢀone (26 g, 192.3 mmol, 1 equiv)
in THF (750 mL), and to the resulting mixture isobutyl magnesium bromide (355 mL, 2 M in diethyl ether, 3.7 equiv) was added
dropwise at ꢀ30 °C. When addition was finished, the mixture was stirred for 1 h at the same temperature. Then the cooling bath was
removed, and the mixture was stirred at rt for 12 h, diluted with a saturated solution of ammonium chloride and filtered. The filtrate
was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (250 mL). The solution was washed with water
(3 × 50 mL), dried over sodium sulfate, and concentrated to get 2ꢀ(1ꢀhydroxyꢀ1,3ꢀdimethylbutyl)aniline in 30.1 g. 81%, yield. Step
2: The above compound (10 g, 51.74 mmol, 1 equiv) was dissolved in toluene (250 mL), and pTSA (0.45 g, 0.05 equiv) was added.
The resulting solution was refluxed with DeanꢀStark trap till water evaluation finished, then it was cooled and washed with a
sodium bicarbonate solution (50 mL), dried over sodium sulfate, and concentrated to get a mixture of 2ꢀ(2ꢀAminophenyl)ꢀ4ꢀ
methylpentꢀ2ꢀen and 2ꢀ(4ꢀmethylpentꢀ1ꢀenꢀ2ꢀyl)aniline (4:1) in 8.9 g (98%) yield. Step 3: To a solution of above mixture (7 g, 40
mmol) in methanol (100 mL) Pd/C (5%, 4.25 g, 2 mmol) was added, and the mixture was hydrogenated for 24 h. The reaction was
controlled by TLC. The mixture was filtered, and the filtrate was concentrated to give the desired product in 6.9 g (97%) yield,
brown liquid. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 7.6 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.74 (d, J =
7.6 Hz, 1H), 3.67 (s, 2H), 2.90 (dd, J = 13.8, 6.9 Hz, 1H), 1.73 – 1.57 (m, 2H), 1.48 (dt, J = 13.5, 6.7 Hz, 1H), 1.30 (d, J = 6.8 Hz,
3H), 1.00 (dd, J = 12.1, 6.2 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 143.5, 132.0, 126.4, 126.2, 119.1, 116.1, 46.3, 30.4, 25.7, 23.1,
22.6, 20.8. Anal. Calcd for C12H19N: C, 81.30; H, 10.80; N, 7.90. Found: C, 81.52; H, 10.69; N, 7.77.
5-Fluoro-1,3-dimethyl-N-(2-(4-methylpentan-2-yl)phenyl)-1H-pyrazole-4-carboxamide, PenflufenTM. To a solution of 33 (300
mg, 1.9 mmol, 1 equiv) in dry DMF (20 mL) was added 1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide (380 mg, 2.0 mmol, 1.05
equiv) and hydroxybenzotriazole (280 mg, 2.1 mmol, 1.1 equiv). The resulting mixture was stirred for 30 min at rt, and 34 (336 mg,
1.9 mmol, 1 equiv) was added. The resulting mixture was stirred for 1 d at rt, and then diluted with water (200 mL). The formed
precipitate was collected by filtration and purified by column chromatography (gradient, hexane with MTBE, 20ꢀ100%) to get the
desired compound in 300 mg (50%) yield, beige crystals, mp 109ꢀ110 °C. 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.3 Hz, 1H),
7.28 (s, 1H), 7.19 (d, J = 3.8 Hz, 1H), 7.12 (s, 2H), 3.67 (s, 3H), 2.91 (dd, J = 13.8, 6.9 Hz, 1H), 2.41 (s, 3H), 1.46 (s, 2H), 1.35 (s,
1H), 1.15 (d, J = 6.8 Hz, 3H), 0.78 (d, J = 6.0 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 159.6, 151.4 (d, J = 291.1 Hz), 144.8, 139.7,
134.1, 126.4 (d, J = 14.3 Hz), 126.1, 125.0, 96.1 (d, J = 9.7 Hz), 46.8, 34.1, 31.0, 25.7, 22.9, 22.6, 21.7, 14.9. 19F NMR (376 MHz,
CDCl3) δ ꢀ128.3. Anal. Calcd for C18H24FN3O: C, 68.11; H, 7.62; N, 13.24. Found: C, 68.00; H, 7.48; N, 13.10.
Supporting Information
Experimental copies of NMR spectra and Xꢀray crystallography data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Authors
* Eꢀmail: Pavel.Mykhailiuk@gmail.com
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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Authors are very grateful to Dr. S. Shishkina for XꢀRay studies, and to Mrs. I. Sadkova for the help with the preparation of the
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manuscript.
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