Synthesis of 3-amino-4-fluoropyrazoles

Article abstract of DOI:10.1021/jo2000989

Fluorinated pyrazoles bearing additional functional groups that allow further functionalization are of considerable interest as building blocks in medicinal chemistry. The developed synthetic strategy for new 3-amino-4-fluoropyrazoles consists of a monofluorination of β-methylthio- β-enaminoketones using 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2] octane bis(tetrafluoroborate) (Selectfluor) toward the corresponding monofluorinated enaminoketones, followed by condensation with different hydrazines.

Full text of DOI:10.1021/jo2000989

NOTE
pubs.acs.org/joc
Synthesis of 3-Amino-4-fluoropyrazoles
||
Riccardo Surmont,†,§ Guido Verniest,†, Mathias De Schrijver,† Jan Willem Thuring,‡ Peter ten Holte,‡
Frederik Deroose,‡ and Norbert De Kimpe*,†
†Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Gent, Belgium
‡Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
S Supporting Information
b
ABSTRACT: Fluorinated pyrazoles bearing additional functional groups that
allow further functionalization are of considerable interest as building blocks in
medicinal chemistry. The developed synthetic strategy for new 3-amino-4-fluor-
opyrazoles consists of a monofluorination of β-methylthio-β-enaminoketones
using 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-
borate) (Selectfluor) toward the corresponding monofluorinated enaminoketones,
followed by condensation with different hydrazines.
n the search for new bioactive compounds, the introduction of
fluorine atoms into organic structures has proven to be a
photochemical decomposition of diazonium tetrafluoroborates.25
3,5-Diamino-4-fluoropyrazoles were synthesized via reaction of
3-amino-3-chloro-2-fluoroacrylimidoyl chloride and phenylhy-
drazine.26 Another strategymakes use of N-alkyl imidatesprepared
from methyl 2-cyano-2-fluoroacetate, in condensation reactions
with trichlorophenylhydrazine to give 3-amino-4-fluoro-5-hydro-
xypyrazoles in low yields.27 It is clear that no straightforward
method for synthesizing functionalized 3-amino-4-fluoropyrazoles
is available, although 3-amino-4-fluoropyrazoles make up a class of
compounds with considerable potential as building blocks in
medicinal chemistry. Recently, an efficient synthesis of 3-amino-
4-fluoro-5-phenylpyrazole, via the condensation of benzoylfluor-
oacetonitrile with hydrazine, has been described.28 However, the
starting benzoylfluoroacetonitrile is not easily prepared because of
the problematic selective monofluorination of benzoylacetonitrile.
To overcome the undesired difluorination of the starting sub-
strates, other synthetic strategies toward 3-amino-4-fluoropyra-
zoles have been developed starting from β-methylthio-β-
enaminoketones instead of β-ketonitriles.
An important general procedure for the synthesis of 3-ami-
nopyrazoles involves the cyclocondensation of β-methylthio-β-
enaminoketones 2 with hydrazines. These substituted β-enam-
inoketones are useful 1,3-dielectrophiles and have demonstrated
their potential in the synthesis of amino-substituted five- and six-
member heterocycles.29,30 Furthermore, the condensation of
these N,S-acetals with unsymmetrical hydrazines such as phe-
nylhydrazine can result in 5-amino-1-arylpyrazoles in a highly
regiocontrolled fashion.31 The use of fluorinated β-methylthio-
β-enaminoketones 4 for the synthesis of fluorinated aminopyr-
azoles offers interesting perspectives. It should be noted that
fluorinated β-methylthio-β-enaminoketones have not been
I
valuable tool for changing the physical and chemical properties of
the compound without major steric implications.1,2 In that
respect, there is a growing demand for synthetic methods for
the preparation of selectively fluorinated heterocyclic compounds
for use in pharmaceutical and agrochemical industry.3 Pyrazoles,
which can be considered as bioisosteres of pyrroles,4 are widely
used as pharmaceuticals and agrochemicals.5ꢀ7 Consequently,
fluorinated pyrazoles are of specific interest because the introduc-
tion of a fluorine atom can drastically affect the biological proper-
ties of members of this class of heterocycles. Unfortunately,
in contrast to chlorinated, brominated, or trifluoroalkylated
pyrazoles,8,9 the synthesis of ring-fluorinated pyrazoles has been
more problematic and less well studied.10ꢀ14 Fluoropyrazoles
have been synthesized via direct electrophilic fluorination of the
pyrazole ring, but this strategy generally proceeds with low
yields.10 Cyclocondensation reactions of fluorinated β-dicarbo-
nyl compounds or R,β-unsaturated carbonyl compounds with
hydrazines are more generally applicable and give better yields of
the corresponding fluoropyrazoles.11ꢀ14 Because of the estab-
lished activity of the bicyclic aminopyrazoles Zaleplon, Sildenafil,
and Allopurinol, there has been a revival of the interest in the
particular class of pyrazoles bearing an amino substituent.15ꢀ19
More specifically, 3-amino-4-fluoropyrazoles have been used,
albeit to a limited extend, to synthesize bioactive compounds with
potential for treating eating disorders,20 diabetes,21 and inflammatory
diseases.22 Substituted 3-amino-4-fluoropyrazoles have also been used
as gastric acid inhibitors,23 insecticides, and acaricides.24 Unfortu-
nately, only limited synthetic pathways for synthesizing 3-amino-4-
fluoropyrazoles are available. Some ring-fluorinated 3-aminopyrazoles
have been synthesized following a rather inefficient direct fluorination
approach using N-fluorodibenzenesulfonimide (NFSI),20 1-chloro-
methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluorobo-
rate) (Selectfluor),21 or trifluoromethylhypofluorite23 and via the
Received: February 8, 2011
Published: April 18, 2011
r
2011 American Chemical Society
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NOTE
Scheme 1. Synthesis of R-Fluorinated Ketones 4aꢀg
some polarized N,S-ketals are known to occur as tautomeric
mixtures of enamine and imine forms,41 compounds 2aꢀg were
isolated as single enamine isomers. In no case were the methy-
lene protons at C-2 of the β-ketoimidate forms detected by 1H or
13C NMR spectroscopy. The fact that only one geometric form
of the enamine was isolated is demonstrated by the sharp signals
of the vinylic proton at C-2 and of the thiomethyl moiety in 1H
NMR spectra and is in accordance with literature data of related
N,S-ketals.41 The enamine double bond of compounds 2aꢀg was
shown to adopt an E configuration (the thiomethyl and carbonyl
groups at opposite sides of the enamine double bond) because of
hydrogen bonding of the enamine NH proton with the carbonyl
group. This is demonstrated by the significant downfield shift
1
1
of the NH proton in H NMR spectra (recording H NMR
data using extended X-sweep parameters revealed the presence of
broadened signals at 13.2ꢀ14.0 ppm) and the presence of stretching
vibrations of the NH group at 3000ꢀ3300 cmꢀ1 and stretching
vibrations of the carbonyl groups below 1600 cmꢀ1 in infrared
spectra. Both IR and 1H NMR data are characteristic of enaminoke-
tones displaying strong internal H-bonds.35,39,46 Furthermore, NOE
experiments showed a strong correlation through space between the
vinylic proton at C-2 of 2c and the SMe moiety (see the Supporting
Information), which proves the assigned E stereochemistry.
For derivatives 2aꢀe [R1 = aryl, R2 = aryl; or R2 = Ph,
R1 = CH(OMe)2], the reaction between ketones 1 and aromatic
isothiocyanates was performed in the presence of sodium hydride as a
base and iodomethane to give R-oxoketene N,S-acetals 2aꢀe in
good yields. N-Benzyl derivative 2f was prepared in 69% yield from
S,S-acetal 3a via a described thioacetal exchange reaction using
benzylamine.37 Finally, 4-(methylthio)-4-(phenylamino)but-3-en-2-
one 2g was also prepared by treating 4,4-bis(methylthio)but-3-en-2-
one 3b with aniline in the presence of n-BuLi in THF.38ꢀ46
described so far except for some very specific 2-fluoro-2-(1,3-
thiazolylidene)ethanones.32ꢀ34
3-(Methylthio)-1-phenyl-3-(phenylamino)prop-2-en-1-one
2a is easily available from acetophenone 1a via deprotonation
with sodium hydride and reaction with phenyl isothiocyanate,
followed by quenching with iodomethane (Scheme 1).35 How-
ever, when the same reaction was evaluated using R-fluoroace-
tophenone, no fluorinated R-oxoketene N,S-acetal 4a was
formed, most probably because of the reduced nucleophilicity
of the fluorinated enolate derived from fluoroacetophenone.
Also, the enamine derived from R-fluoroacetophenone and
pyrrolidine36 did not react with phenyl isothiocyanate to give
the desired compound 4a. In a next attempt to synthesize
fluorinated β-methylthio-β-enaminoketones 4, the electrophilic
fluorination of β-enaminoketones 2 was investigated. 3-
(Methylthio)-1-phenyl-3-(phenylamino)prop-2-en-1-one 2a was
treated with 1.0 equiv of 1-(chloromethyl)-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor)
in acetonitrile at 0 °C, which nicely resulted in a clean mono-
fluorination toward 4a within 0.5 h with minor formation of
difluorinated product 5 (<5%) (Scheme 1). When using a slight
excessofSelectfluor oruponaddition of Selectfluor in one portion,
an increase of the amount of difluorinated product 5 was
observed, which was difficult to separate from the monofluori-
nated product 4a via flash chromatography. The fluorination
reaction of 2a toward 4a using NFSI led to substantial amounts of
methyl 2,2-difluoro-3-oxo-N,3-diphenylpropanethioimidate 5,
besides the desired monofluorinated compound 4a. For analy-
tical purposes, the difluorinated reaction product 5 was easily
obtained in 55% yield by reaction of 2a with 2 equiv of NFSI at
room temperature. A variety of R-oxoketene N,S-acetal deriva-
tives 2aꢀg were synthesized using the procedure described
above or via literature procedures (Scheme 1).37ꢀ45 Although
The selective monofluorination of the prepared β-methylthio-
β-enaminoketones 2 toward fluorinated compounds 4 pro-
ceeded smoothly with minor formation of difluorinated thioimi-
dates, except for the N-benzyl derivative 2f. In the latter case, the
crude reaction mixture after fluorination of 2f contained starting
material, monofluorinated N,S-acetal 4f, and difluorinated thioi-
1
midate in a ratio of 18:66:16 (calculated via H NMR). The
obtained compounds were not separated, but the mixture was
used directly for further transformations. The 1H and 13C NMR
spectra of compounds 4aꢀg clearly show the presence of an
enamine tautomer, as evidenced by the downfield NH shift in
1H NMR, the upfield shift of the enamine SMe group as com-
pared to the imine tautomers, and the presence of a quaternary
C-2 in the 13C NMR spectrum (C-2 occurs as a doublet due to
coupling with fluorine). Although the enamine tautomers of
compounds 4aꢀg are believed to display a Z stereochemistry
because of internal hydrogen bonding analogous to the corre-
sponding nonfluorinated oxoketene N,S-acetals 2aꢀg, this could
not be verified by NOE NMR experiments. It should be noted
that the 1H NMR spectra of 4aꢀg are rather complex because the
N,S-acetals exist as three isomers: the enamino form, the (E)-
imino form, and the (Z)-imino form, which cannot be isolated as
single compounds. The imine tautomers of 4aꢀg clearly exist as
mixtures of E and Z isomers (with respect to the CdN double
bond), which is demonstrated by the presence of two vinylic
CHF protons and two separated thioimidate SMe groups in both
1H and 13C NMR spectra. It can be postulated that the 1H NMR
signals of the vinylic CHF protons of the Z isomers of the imine
forms of compounds 4aꢀg show a slightly more upfield shift
compared to those of the corresponding E isomers, because of
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NOTE
Scheme 2. Synthesis of 3-Amino-4-fluoropyrazoles 6aꢀg
HOAc. The reaction nicely resulted in 3-amino-4-fluoro-5-phenyl-
1H-pyrazole 7 in 94% yield. When phenylhydrazine and methyl-
hydrazine were used in the cyclocondensation reaction with
compound 4b, a catalytic amount of acetic acid and prolonged
reaction times (24 h) were needed to complete the reaction
(Scheme 3). While the reaction of 4b with phenylhydrazine
resulted in only one pyrazole, 9, the reaction of 4b with methylhy-
drazine yielded a 1:1 mixture of 5-amino-1-methylpyrazole 8 and
3-amino-1-methylpyrazole 10. In an attempt to synthesize 5-ami-
no-1,4-diphenylpyrazole 11, pyrazole 9 was treated with cerium
ammonium nitrate (CAN) in aqueous acetonitrile. Surprisingly,
after reaction for 1 h at0 °C, the intermediate benzoquinone imine
appeared to be quite stable toward hydrolysis. Unfortunately,
more stringent hydrolytic conditions using 0.5 or 3 M HCl or TFA
in dichloromethane, DMF, or acetonitrile all gave rise to complex
reaction mixtures and did not lead to the isolation of pyrazole 11.
In conclusion, it can be stated that a new entry toward
3-amino-4-fluoropyrazoles was developed. These compounds
are of considerable interest as building blocks in medicinal chem-
istry. The developed strategy consists of an efficient chemoselective
monofluorination of β-methylthio-β-enaminoketones using
Selectfluor toward the corresponding new monofluorinated
enaminoketones, followed by condensation with different hy-
drazines to afford new 3-amino-4-fluoropyrazoles in good yields.
and 7
Scheme 3. Synthesis of 1-Substituted Fluoropyrazoles 8ꢀ10
’ EXPERIMENTAL SECTION
1H NMR (300 MHz), 13C NMR (75 MHz), and 19F NMR (282
MHz) spectra were recorded in CDCl3 unless specified otherwise, using
tetramethylsilane (TMS, δ = 0 ppm) as an internal reference for proton
spectra. Carbon spectra were referenced to the solvent. 19F NMR spectra
were recorded using CDCl3 as a lock solvent. Peak assignments were
13
performed with the use of 1Hꢀ C HSQC 2D-NMR. IR spectra were
obtained using an ATR infrared spectrometer. Mass spectra were
recorded (70 eV) using either GCꢀMS coupling or a direct inlet system.
LCꢀMS data were obtained via an electrospray (ES, 4000 V) mass
spectrometer. Elemental analysis of new compounds was performed
using a CHN elemental analyzer (tin combustion capsules were used for
both solids and sticky oils).
(Z)-(4-Fluorophenyl)-3-[(4-methoxyphenyl)amino]-3-(meth-
ylsulfanyl)prop-2-en-1-one 2e. To an ice-cooled solution of 4.14 g
(30 mmol, 1 equiv) of 40-fluoroacetophenone 1e in 40 mL of DMF
was added 1.44 g (36 mmol, 1.2 equiv) of sodium hydride. Subsequently,
a solution of 4.96 g (30 mmol, 1 equiv) of 4-methoxyphenyl isothio-
cyanate in 20 mL of DMF was added dropwise. The reaction mixture was
stirred at room temperature for 45 min. The solution was cooled to 0 °C;
4.26 g (30 mmol, 1 equiv) of iodomethane was added, and the reaction
mixture was stirred at room temperature for 45 min. The solution was
poured into 100 mL of water (0ꢀ5 °C) and extracted with 150 mL of
Et2O. The organic layers were washed with 100 mL of brine and dried
over MgSO4. After filtration and evaporation, the residue was purified by
chromatography (4:1 hexane/EtOAc; Rf = 0.21) to afford 9.47 g of (4-
fluorophenyl)-3-[(4-methoxyphenyl)amino]-3-(methylsulfanyl)prop-
2-en-1-one 2e (26.1 mmol, 88% yield). Analogous compounds 2aꢀd, 2f,
and 2g were prepared according to literature procedures.35ꢀ45 2e: mp
97ꢀ98 °C (1:1 hexane/Et2O); 1H NMR (CDCl3) δ 2.40 (3H, s, Me),
3.80 (3H, s, Me), 5.78 (1H, s, CH), 6.89 (2H, d, J = 8.8 Hz, 2 ꢁ CH),
7.09 (2H, t, J = 8.8 Hz, 2 ꢁ CH), 7.22 (2H, d, J = 8.8 Hz, 2 ꢁ CH), 7.91
(2H, dd, J = 8.8 Hz, 5.5 Hz, 2 ꢁ CH); 19F NMR (CDCl3) δ ꢀ109.4 (1F,
tt, J = 8.8, 5.5 Hz, CF); 13C NMR (CDCl3) δ 14.5 (Me), 55.3 (Me), 87.3
(CH), 114.1 (2 ꢁ CH), 115.1 (d, J = 21.9 Hz, 2 ꢁ CH), 127.2 (2 ꢁ
CH), 129.1 (d, J = 9.2 Hz, 2 ꢁ CH), 130.6 (C), 136.4 (C), 158.3 (C),
164.3 (d, J = 250.4 Hz, C), 168.7 (C), 184.3 (C); IR (ATR) ν 3074,
the influence of the free electron pair at the nitrogen atom of the
CdN group.47 Depending on the substitution pattern, the E:Z
isomer ratio of the imine forms of 4aꢀg ranges from 40:60 to
70:30, while the enamine/imine ratio shifts from 32:68 to 41:59
(calculated from 1H NMR data).
In a next step, the desired 3-amino-4-fluoro-1H-pyrazoles 6aꢀg
were efficiently synthesized by heating monofluorinated β-enam-
inoketones 4aꢀg and hydrazine hydrate in 2-propanol for 2 h
(Scheme 2). The obtained 1H-pyrazoles 6aꢀg, showing a diverse
substitution pattern, were easily purified by flash chromatography
and recrystallization. To evaluate the possibility of removing the
N-benzyl protecting group of pyrazole 6f without losing the
fluorine substituent at the pyrazole core, we treated compound
6f with hydrogen over Pd-C in ethyl acetate in the presence of
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NOTE
1596, 1557, 1530 cmꢀ1; MS (ESþ) m/z (%) 318 (M þ Hþ, 100). Anal.
Calcd for C17H16FNO2S: C, 64.33; H, 5.08; N, 4.41. Found: C, 64.70;
H, 5.39; N, 4.55.
J = 8.3 Hz, 6 ꢁ CHar), 6.88 (2H, d, J = 8.3 Hz, 2 ꢁ CHar), 7.21 (2H, d, J =
8.3 Hz, 2 ꢁ CHar), 7.39ꢀ7.52 (7H, m, 7 ꢁ CHar), 7.58 (2H, d, J = 7.7
Hz, 2 ꢁ CHar), 7.71 (2H, d, J = 7.7 Hz, 2 ꢁ CHar), 7.88 (2H, d, J = 7.7
Hz, 2 ꢁ CHar), 8.06 (2H, d, J = 7.7 Hz, 2 ꢁ CHar), 11.77 [1H, s(broad),
NH]; 19F NMR (CDCl3) δ ꢀ158.5 (1F, s, CF), ꢀ181.4 (1F, d, J = 47.4
Hz, CF), ꢀ183.4 (1F, d, J = 48.3 Hz, CF); 13C NMR (CDCl3) δ 12.8
(SMe), 14.3 (d, 5.8 Hz, SMe), 16.5 (d, J = 9.2 Hz, SMe), 55.3 and 55.4
(9H, s, 3 ꢁ MeO), 88.1 (d, J = 192.7 Hz, CHF), 94.6 (d, J = 192.7 Hz),
114.0 (2 ꢁ CHar), 114.2 (2 ꢁ CHar), 114.5 (2 ꢁ CHar), 120.7 (2 ꢁ CHar),
121.1 (2 ꢁ CHar), 125.8 (2 ꢁ CHar), 128.0 (2 ꢁ CHar), 128.6
(6 ꢁ CHar), 128.7 (2 ꢁ CHar), 129.1 (2 ꢁ CHar), 131.3 (CHar), 131.8
(Car), 133.7 (Car), 133.8 (CHar), 133.9 (Car), 134.1 (CHar), 137.3 (d,
J =5.8Hz, Car), 141.6 (d, J=5.8 Hz, Car), 142.0 [s(broad), Car], 143.3 (d, J=
199.6 Hz, CF), 152.4 (d, J = 27.7 Hz, NCS), 156.7 (OCar), 157.0 (OCar),
157.5 (OCar), 160.9 (d, J = 23.1 Hz, CdN), 162.1 (d, J = 21.9 Hz, CdN),
182.0 (d, J=25.4Hz, CdO), 191.3 (d, J=21.9Hz, CdO), 191.8 (d, J= 19.6
Methyl 2,2-Difluoro-3-oxo-N,3-diphenylpropanethioimi-
date 5. To a stirred solution of 2.34 g (7.43 mmol, 2 equiv) of NFSI
in50mLofacetonitrile undera N2 atmosphere wasadded dropwise1.00 g
(3.72 mmol, 1 equiv) of 3-(methylsulfanyl)-1-phenyl-3-(phenylamino)-
prop-2-en-1-one 2a at 0 °C. Stirring was continued for 15 h at room
temperature. Subsequently, the mixture was filtered and filtrate was
poured into 50 mL of water. The aqueous phase was extracted with
50 mL of diethyl ether and dried over MgSO4. After filtration and
evaporation, the oil was purified by silica gel chromatography (4:1
hexane/EtOAc; Rf = 0.43), yielding 0.62 g of methyl 2,2-difluoro-3-oxo-
N,3-diphenylpropanethioimidate 5 (2.05 mmol, 55% yield) as a yellow
oil: 1H NMR (CDCl3) δ 2.60 (3H, s, SCH3), 6.75 (2H, d, J = 7.3 Hz, 2
ꢁ CHar), 7.11 (1H, t, J = 7.3 Hz, CHar), 7.29 (2H, d, J = 7.3 Hz, 2 ꢁ
CHar), 7.49 (2H, d, J = 7.3 Hz, 2 ꢁ CHar), 7.61 (1H, tt, J = 7.3, 1.7 Hz,
CHar), 8.04 (2H, d, J = 7.3 Hz, 2 ꢁ CHar); 19F NMR (CDCl3) δ ꢀ98.3
(2F, s, CF2); 13C NMR (CDCl3) δ 14.0 (SCH3), 114.4 (t, J = 257.9 Hz,
CF2), 118.8 (2 ꢁ CHar), 125.3 (CHar), 128.3 (2 ꢁ CHar), 128.7 (2 ꢁ
CHar), 129.9 (2 ꢁ CHar), 132.2 (Car), 133.8 (CHar), 147.1 (Car), 159.9
(t, J = 32.9 Hz, CdN), 186.4 (t, J = 27.7 Hz, CdO); IR (ATR) ν 3416,
1711, 1593, 1484 cmꢀ1; MS (ESþ) m/z (%) 306 (M þ Hþ, 100).
2-Fluoro-3-(methylsulfanyl)-1-phenyl-3-(phenylamino)-
prop-2-en-1-one (enamine, 33%) and Methyl 2-Fluoro-3-
oxo-N,3-diphenylpropanethioimidate (imines, 67%) 4a. To
a solution of 1.00 g (3.72 mmol, 1 equiv) of 3-(methylthio)-1-phenyl-
3-(phenylamino)prop-2-en-1-one 2a in 25 mL of acetonitrile was
added in portions 1.31 g (3.72 mmol, 1 equiv) of Selectfluor was under
a N2 atmosphere at 0 °C. The mixture was stirred for 30 min at 0 °C.
Subsequently, the reaction mixture was poured into 50 mL of water
(0 °C) and 50 mL of dichloromethane. After separation of the organic
layer, the aqueous phase was extracted with 2 ꢁ 20 mL of dichlor-
omethane. The combined organic phases were dried with MgSO4.
Filtration of the drying agents and evaporation of the solvents in vacuo
yielded almost pure monofluorinated compound 4a. Further purifica-
tion was performed by silica gel chromatography (4:1 hexane/EtOAc;
Rf = 0.34) yielding 0.78 g (2.72 mmol, 73% yield) of 4a as a yellow oil:
1H NMR (CDCl3) δ 2.28 (3H, d, J = 1.7 Hz, SMe), 2.48 (6H, s, 2 ꢁ
SMe), 6.22 (1H, d, J = 45.1 Hz, CHF), 6.38 (1H, d, J = 46.8 Hz, CHF),
6.74 (2H, s, 2 ꢁ CHar), 6.84 (2H, s, 2 ꢁ CHar), 7.10 (2H, t, J = 7.2 Hz,
2 ꢁ CHar), 7.18 (1H, t, J = 7.2 Hz, CHar), 7.26ꢀ7.39 (8H, m, 8 ꢁ
CHar), 7.40ꢀ7.53 (7H, m, 7 ꢁ CHar), 7.59 (2H, s, 2 ꢁ CHar), 7.89
(2H, d, J = 7.2 Hz, 2 ꢁ CHar), 8.01ꢀ8.17 (4H, m, 4 ꢁ CHar), 11.59
(1H, s, NH); 19F NMR (CDCl3) δ ꢀ155.5 (1F, s, CF), ꢀ181.5 (1F, d,
J = 47.4 Hz, CF), ꢀ183.9 (1F, d, J = 47.4 Hz, CF); 13C NMR (CDCl3)
δ 12.8 (SMe), 14.2 (SMe), 16.2 (d, J = 8.1 Hz, SMe), 88.2 (d, J = 195.0
Hz, CHF), 94.5 (d, J = 195.0 Hz, CHF), 118.8 (2 ꢁ CHar), 119.8 (2 ꢁ
CHar), 123.3 (2 ꢁ CHar), 124.4 (CHar), 124.7 (CHar), 125.1 (CHar),
128.3, 128.5, 128.8, 128.9, 129.0, 129.2, 129.3 (18 ꢁ CHar), 131.7
(CHar), 134.0 (2 ꢁ CHar), 137.1 (3 ꢁ Car), 139.1 (NCar), 143.6 (d, J =
225.0 Hz, CF), 148.7 (2 ꢁ NCar), 150.6 (d, J = 27.7 Hz, NCS), 162.2
(2 ꢁ CdN), 182.6 (d, J = 25.4 Hz, CdO), 191.4 (2 ꢁ CdO); IR
(ATR) ν 3347, 3190, 1703, 1595, 1542, 1497, 1487, 1448 cmꢀ1; MS
(ESþ) m/z (%) 288 (M þ Hþ, 100).
Hz, CdO); IR (ATR) ν 3382, 1697, 1601, 1499, 1464, 1453, 1441 cmꢀ1
;
MS(ESþ) m/z(%) 318(Mþ Hþ, 100). Anal. Calcd for C17H16FNO2S: C,
64.33; H, 5.08; N, 4.41. Found: C, 63.98; H, 4.89; N, 4.15.
2-Fluoro-1-(furan-2-yl)-3-(methylsulfanyl)-3-(phenylamino)-
prop-2-en-1-one (enamine, 40%) and Methyl (1Z)-2-Fluoro-
3-(furan-2-yl)-3-oxo-N-phenylpropanethioimidate (imines,
60%) 4c. Flash chromatography (9:1 hexane/EtOAc; Rf = 0.10) was
used: 93% yield; yellow oil; 1H NMR (CDCl3) δ 2.27 (3H, d, J = 1.7 Hz,
SMe), 2.46 [6H, s(broad), 2 ꢁ SMe], 6.01 (1H, d, J = 48.47 Hz, CHF),
6.20 (1H, d, J = 46.2 Hz, CHF), 6.56 (3H, dd, J = 3.3, 1.7 Hz, 3 ꢁ
CHfuran), 6.78 [2H, s(broad), 2 ꢁ CHar], 6.86 [2H, s(broad), 2 ꢁ
CHar], 7.09 (2H, t, J = 7.2 Hz, 2 ꢁ CHar), 7.17 (1H, t, J = 7.2 Hz, CHar),
7.25ꢀ7.38 (11H, m, 8 ꢁ CHar and 3 ꢁ CHfuran), 7.63 [2H, s(broad), 2
ꢁ OCHfuran], 7.67 (1H, s, OCHfuran), 11.40 [1H, s(broad), NH]; 19
F
NMR (CDCl3) δ ꢀ158.5 (1F, s, CF), ꢀ184.1 (1F, d, J = 44.7 Hz, CF),
ꢀ186.4 (1F, d, J = 44.7 Hz, CF); 13C NMR (CDCl3) δ 12.8 (SMe), 14.1
(SMe), 16.2 (d, J = 8.1 Hz, SMe), 88.1 (d, J = 191.5 Hz, CHF), 93.1 (d,
J = 197.3 Hz, CHF), 112.0 (CH), 112.1 (CH), 112.6 (CH), 118.4 (d, J =
17.3 Hz, CH), 118.9 (2 ꢁ CH), 119.7 (2 ꢁ CH), 120.5 (CH), 121.1
(CH), 123.4 (2 ꢁ CH), 124.2 (CH), 124.7 (CH), 125.1 (CH), 129.0
and 129.1 (3 ꢁ 2 ꢁ CH), 139.0 (NCar), 142.6 (d, J = 225.0 Hz, CF),
146.3 (OCH), 147.6 (OCH), 147.9 (OCH), 148.8 (2 ꢁ NCar), 149.4
and 150.0 and 150.1 (3 ꢁ C), 150.0 (d, J = 27.7 Hz, NCS), 161.6 (d, J =
21.9 Hz, 2 ꢁ CdN), 169.8 (d, J = 25.4 Hz, CdO), 179.6 and 180.2 (m, 2
ꢁ CdO); IR (ATR) ν 3135, 1697, 1590, 1567, 1541, 1484, 1459,
1414 cmꢀ1; MS (ESþ) m/z (%) 278 (M þ Hþ, 100).
3-Fluoro-1,1-dimethoxy-4-(methylsulfanyl)-4-(phenylamino)-
but-3-en-2-one (enamine, 32%) and Methyl 2-Fluoro-4,4-
dimethoxy-3-oxo-N-phenylbutanethioimidate (imines, 68%)
4d. Silica gel chromatography (7:3 hexane/EtOAc; Rf = 0.32) was used:
73% yield; yellow oil; 1H NMR (CDCl3) δ 2.20 (3H, d, J = 2.8 Hz, SMe),
2.41ꢀ2.45 (6H, m, 2 ꢁ SMe), 3.19ꢀ3.31 (3H, m, MeO), 3.36 (6H, s, 2 ꢁ
MeO), 3.42 (6H, s, 2 ꢁ MeO), 3.44 (3H, s, MeO), 4.66 (1H, s, OCHO),
4.86 (1H, s, OCHO), 5.07 (1H, d, J = 3.3 Hz, OCHO), 5.75 (1H, d, J =
47.3 Hz, CHF), 6.04 (1H, d, J = 49.0 Hz, CHF), 6.75ꢀ6.83 (4H, m, 2 ꢁ 2
ꢁ CHar), 7.02ꢀ7.10 (2H, m, 2 ꢁ CHar), 7.11ꢀ7.19 (3H, m, 3 ꢁ CHar),
7.23ꢀ7.31 (6H, m, 3 ꢁ 2 ꢁ CHar), 11.15 [1H, s(broad), NH]; 19F NMR
(CDCl3) δ ꢀ167.3 (1F, s, CF), ꢀ187.9 (1F, d, J = 46.0 Hz, CF), ꢀ189.9
(1F, d, J = 48.7 Hz, CF); 13C NMR (CDCl3) δ 12.4 (SMe), 13.9 (SMe),
16.0 (d, J = 10.4 Hz, SMe), 53.5 (2 ꢁ MeO), 54.0 (2 ꢁ MeO), 54.2 (2 ꢁ
MeO), 88.0 (d, J = 191.5 Hz, CHF), 91.2 (d, J = 191.5 Hz, CHF), 98.8
(OCHO), 101.9 (2 ꢁ OCHO), 118.8 (CHar), 119.0 (CHar), 119.6
(CHar), 123.4 (3 ꢁ CHar), 124.8 (CHar), 125.4 (2 ꢁ CHar), 128.7 (3 ꢁ
CHar), 128.9 (3 ꢁ CHar), 138.3 (NCar), 142.1 (d, J = 221.5 Hz, CF),
148.3 (2 ꢁ NCar), 151.6 (d, J = 26.5 Hz, NCS), 162.2 (d, J = 20.8 Hz, 2 ꢁ
CdN), 181.9 (d, J = 25.4 Hz, CdO), 196.7 (d, J = 17.3 Hz, 2 ꢁ CdO);
IR (ATR) ν 3060, 1608, 1592, 1556, 1485 cmꢀ1; MS (ESþ) m/z (%) 286
(M þ Hþ, 100).
2-Fluoro-3-[(4-methoxyphenyl)amino]-3-(methylsulfanyl)-
1-phenylprop-2-en-1-one (enamine, 41%) and Methyl
2-Fluoro-N-(4-methoxyphenyl)-3-oxo-3-phenylpropanethioi-
midate (imines, 59%) 4b. Silica gel chromatography (9:1 hexane/
EtOAc; Rf = 0.13) was used: 91% yield; mp 106ꢀ107 °C (1:1 hexane/
1
Et2O); yellow crystals; H NMR (CDCl3) δ 2.31 (3H, d, J = 2.2 Hz,
SMe), 2.43 (3H, s, SMe), 2.53 (3H, s, SMe), 3.77 [6H, s(broad), 2 ꢁ
MeO], 3.81 (3H, s, MeO), 6.27 (1H, d, J = 47.4 Hz, CHF), 6.37 (1H, d,
J = 48.3 Hz, CHF), 6.73 (2H, d, J = 8.3 Hz, 2 ꢁ CHar), 6.83 (6H, d,
4108
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NOTE
3-Fluoro-4-(methylsulfanyl)-4-(phenylamino)but-3-en-2-
one (enamine, 40%) and Methyl 2-Fluoro-3-oxo-N-phenyl-
butanethioimidate (imines, 60%) 4g. Silica gel chromatography
(9:1 hexane/EtOAc; Rf = 0.31) was used: 63% yield; yellow oil; 1H NMR
(CDCl3) δ 2.14 (3H, d, J = 1.7 Hz, SMe), 2.17 (3H, s, CH3CO), 2.22
(3H, d, J = 4.4 Hz, CH3CO), 2.33 (3H, s, CH3CO), 2.38 (6H, s, 2 ꢁ
SMe), 5.41 (1H, d, J = 47.7 Hz, CHF), 5.53 (1H, d, J = 47.2 Hz, CHF),
6.82 (4H, d, J = 7.7 Hz, 2 ꢁ 2 ꢁ CHar), 7.09 (3H, t, J = 7.7 Hz, 3 ꢁ
CHar), 7.18 (2H, d, J = 7.7 Hz, 2 ꢁ CHar), 7.27 (6H, t, J = 7.7 Hz, 3 ꢁ 2
ꢁ CHar), 10.65 (1H, s, NH); 19F NMR (CDCl3) δ ꢀ156.0 (1F, s, CF),
ꢀ181.9 (1F, d, J = 47.2 Hz, CF), ꢀ182.6 (1F, d, J = 47.7 Hz, CF); 13C
NMR (CDCl3) δ 12.3 (SMe), 13.7 (SMe), 15.6 (d, J = 8.1 Hz, SMe),
25.0 (CH3CO), 26.0 (CH3), 90.1 (d, J = 195.0 Hz, CHF), 94.2 (d, J =
197.0 Hz, CHF), 119.6 (4 ꢁ CHar), 122.9 (2 ꢁ CHar), 124.9 (3 ꢁ
CHar), 128.8 (6 ꢁ CHar), 139.2 (Car), 143.4 (d, J = 222.7 Hz, CF), 146.3
(d, J = 27.7 Hz, NCS), 148.6 (2 ꢁ Car), 161.1 (d, J = 20.8 Hz, 2 ꢁ
CdN), 189.3 (d, J = 31.2 Hz, CdO), 201.4 (d, J = 26.5 Hz, 2 ꢁ CdO);
IR (ATR) ν 3451, 3199, 1731, 1611, 1592, 1560, 1496, 1484 cmꢀ1; MS
(ESþ) m/z (%) 226 (M þ Hþ, 100).
m/z (%) 244 (M þ Hþ, 100). Anal. Calcd for C13H10FN3O: C, 64.19;
H, 4.14; N, 17.28. Found: C, 63.92; H, 3.92; N, 17.12.
5-(Dimethoxymethyl)-4-fluoro-3-(phenylamino)-1H-pyr-
azole 6d. Silica gel chromatography (7:3 hexane/EtOAc; Rf = 0.12)
was used: 73% yield; mp 78ꢀ79 °C (1:1 hexane/Et2O); white crystals;
1H NMR (acetone-d6) δ 3.35 (6H, s, 2 ꢁ OMe), 5.60 (1H, s, CH), 6.76
(1H, t, J = 7.7 Hz, CHar), 7.18 (2H, t, J = 7.7 Hz, 2 ꢁ CHar), 7.30 (2H, d,
J = 7.7 Hz, 2 ꢁ CHar), 7.38 [1H, s(broad), NH], 11.36 [1H, s(broad),
NH]; 19F NMR (acetone-d6) δ ꢀ183.1 (1F, s, CF); 13C NMR
(acetone-d6) δ 52.5 (2 ꢁ OMe), 96.6 (d, J = 2.3 Hz, CH), 115.1 (2
ꢁ CHar), 119.2 (CHar), 126.1 (d, J = 19.6 Hz, NCq), 128.9 (2 ꢁ CHar),
136.7 (d, J = 244.6 Hz, CF), 138.0 (d, J = 9.2 Hz, NCqN), 144.1 (NCar);
IR (ATR) ν 3401, 1597, 1569 cmꢀ1; MS (ESꢀ) m/z (%) 250 (M ꢀ
Hþ, 100). Anal. Calcd for C12H14FN3O2: C, 57.36; H, 5.62; N, 16.72.
Found: C, 57.52; H, 5.68; N, 16.66.
4-Fluoro-5-(4-fluorophenyl)-3-(4-methoxyphenylamino)-
1H-pyrazole 6e. Silica gel chromatography (7:3 hexane/EtOAc;
Rf = 0.10) was used: 68% yield (two steps); mp 170ꢀ171 °C (Et2O);
1H NMR (acetone-d6) δ 3.71 (3H, s, OCH3), 6.82 (2H, d, J = 8.8 Hz, 2
ꢁ CHar), 7.26 (2H, t, J = 8.8 Hz, 2 ꢁ CHar), 7.32 (2H, d, J = 8.8 Hz, 2 ꢁ
CHar), 7.80 (2H, dd, J = 8.8, 5.5 Hz, 2 ꢁ CHar), 11.40 [1H, s(broad),
NH]; 19F NMR (acetone-d6) δ ꢀ114.4 [1F, s(broad), CarF], ꢀ184.3
(1F, s, CF); 13C NMR (acetone-d6) δ 54.9 (OCH3), 114.3 (2 ꢁ CHar),
115.9 (CHar), 116.2 (CHar), 116.8 (2 ꢁ CHar), 125.1 [s(broad), NCq],
127.3 (d, J = 8.1 Hz, CHar and Car), 127.4 (d, J = 8.1 Hz, CHar), 136.3 (d,
J = 243.5 Hz, CF), 137.5 (NCar), 139.0 [s(broad), NCqN], 153.5
(OCar), 162.5 (d, J = 245.8 Hz, CF); IR (ATR) ν 3440, 1625, 1604,
1580, 1506 cmꢀ1; MS (ESþ) m/z (%) 302 (M þ Hþ, 100). Anal. Calcd
for C16H13F2N3O: C, 63.78; H, 4.35; N, 13.95. Found: C, 63.52; H,
4.17; N, 13.73.
3-(Benzylamino)-4-fluoro-5-phenyl-1H-pyrazole 6f. Silica
gel chromatography (3:2 hexane/EtOAc; Rf = 0.27) was used: 57%
yield (two steps); mp 138ꢀ139 °C (1:1 hexane/Et2O); 1H NMR
(acetone-d6) δ 4.46 (2H, s, CH2), 5.09 [1H, s(broad), NH], 7.20 (1H, t,
J = 7.5 Hz, CHar), 7.29 (2H, t, J = 7.5 Hz, 2 ꢁ CHar), 7.33 (1H, t, J = 7.5
Hz, CHar), 7.44 (2H, d, J = 7.5 Hz, 2 ꢁ CHar), 7.45 (2H, t, J = 7.5 Hz, 2
ꢁ CHar), 7.71 (2H, d, J = 7.5 Hz, 2 ꢁ CHar), 11.21 [1H, s(broad), NH],
19F NMR (acetone-d6) δ ꢀ188.2 (1F, s, CF); 13C NMR (acetone-d6) δ
47.6 (CH2), 125.0 and 125.1 (2 ꢁ CHar), 126.7 (CHar), 127.7 (2 ꢁ
CHar), 128.0 (CHar and Car), 128.2 (2 ꢁ CHar), 128.8 [s(broad), NCq],
129.0 (2 ꢁ CHar), 135.0 (d, J = 241.4 Hz, CF), 141.0 (Car), 144.2
[s(broad), NCqN]; IR (ATR) ν 3350, 1584 cmꢀ1; MS (ESþ) m/z (%)
268 (M þ Hþ, 100). Anal. Calcd for C16H14FN3: C, 71.89; H, 5.28; N,
15.72. Found: C, 71.51; H, 5.07; N, 15.37.
4-Fluoro-5-methyl-3-(phenylamino)-1H-pyrazole 6g. Silica
gel chromatography (7:3 hexane/EtOAc; Rf1= 0.15) was used: 82%
yield; mp 132ꢀ133 °C (1:1 hexane/Et2O); H NMR (acetone-d6) δ
2.21 (3H, d, J = 1.1 Hz, CH3), 6.76 (1H, t, J = 7.7 Hz, CHar), 7.18 (2H, t,
J = 7.7 Hz, 2 ꢁ CHar), 7.29 (2H, d, J = 7.7 Hz, 2 ꢁ CHar), 7.37 [1H,
s(broad), NH], 11.21 [1H, s(broad), NH]; 19F NMR (acetone-d6) δ
ꢀ187.9 (1F, s, CF); 13C NMR (acetone-d6) δ 7.4 (CH3), 115.0 (2 ꢁ
CHar), 118.9 (CHar), 125.0 [s(broad), NCq], 128.9 (2 ꢁ CHar), 137.6
(d, J = 237.7 Hz, CF), 138.1 [s(broad), NCqN], 144.4 (NCar); IR
(ATR) ν 3332, 1618, 1602, 1551 cmꢀ1; MS (ESþ) m/z (%) 192 (M þ
Hþ, 100). Anal. Calcd for C10H10FN3: C, 62.82; H, 5.27; N, 21.98.
Found: C, 62.56; H, 5.07; N, 21.52.
4-Fluoro-5-phenyl-3-(phenylamino)-1H-pyrazole 6a. To a
solution of 2-fluoro-3-(methylthio)-1-phenyl-3-(phenylamino)prop-2-
en-1-one 4a (0.70 g, 2.44 mmol) in 2-propanol (25 mL) was added 0.10
g of hydrazine (80% in water, 2.44 mmol, 1 equiv), and the mixture was
heated at reflux temperature for 2 h. The solvent was evaporated in
vacuo, and the obtained oil was purified by silica gel chromatography
(7:3 hexane/EtOAc; Rf = 0.17) yielding 0.50 g of 4-fluoro-5-phenyl-3-
phenylamino-1H-pyrazole 6a (1.98 mmol, 81% yield) after recrystalliza-
1
tion from a 1:1 hexane/Et2O mixture: mp 181ꢀ182 °C; H NMR
(acetone-d6) δ 6.80 (1H, t, J = 7.4 Hz, CHar), 7.22 (2H, t, J = 7.7 Hz, 2 ꢁ
CHar), 7.37 (2H, d, J = 7.4 Hz, 2 ꢁ CHar), 7.38 (1H, t, J = 7.7 Hz, CHar),
7.49 (2H, t, J = 7.4 Hz, 2 ꢁ CHar), 7.53 [1H, s(broad), NH], 7.79 (2H,
d, J = 7.7 Hz, 2 ꢁ CHar), 11.87 [1H, s(broad), NH]; 19F NMR
(acetone-d6) δ ꢀ182.6 (1F, s, CF); 13C NMR (acetone-d6) δ 115.2
(2 ꢁ CHar), 119.1 (CHar), 125.2 and 125.3 (2 ꢁ CHar), 128.4 (CHar,
Car, NCq), 128.9 (2 ꢁ CHar), 129.1 (2 ꢁ CHar), 137.0 (d, J = 244.6 Hz,
CF), 138.5 [s(broad), NCqN], 144.1 (NCar); IR (ATR) δ 3435, 1601,
1574 cmꢀ1; MS (ESþ) m/z (%) 254 (M þ Hþ, 100). Anal. Calcd for
C15H12FN3: C, 71.13; H, 4.78; N, 16.59. Found: C, 71.38; H, 4.39;
N, 16.55.
4-Fluoro-3-(4-methoxyphenylamino)-5-phenyl-1H-pyrazole
6b. Silica gel chromatography (7:3 hexane/EtOAc; Rf = 0.20) was used:
88% yield; mp 139ꢀ140 °C (1:1 hexane/Et2O); 1H NMR (acetone-d6)
δ 3.72 (3H, s, OCH3), 6.82 (2H, d, J = 8.5 Hz, 2 ꢁ CHar), 7.27 [1H,
s(broad), NH], 7.30ꢀ7.34 (1H, m, CHar), 7.35ꢀ7.41 (2H, m, 2 ꢁ CHar),
7.49 (2H, t, J= 7.7 Hz, 2 ꢁ CHar), 7.76 (2H, d, J = 7.7 Hz, 2ꢁ CHar), 11.60
[1H, s(broad), NH], 19F NMR (acetone-d6) δ ꢀ184.0 (1F, s, CF); 13
C
NMR (acetone-d6) δ 55.7 (OCH3), 115.0 (2 ꢁ CHar), 117.6 (2 ꢁ CHar),
125.9 and 126.0 (2 ꢁ CHar), 129.1 (CHar, Car, NCq), 129.9 (2 ꢁ CHar),
137.2 (d, J = 244.6 Hz, CF), 138.2 (NCar), 140.2 [s(broad), NCqN], 154.2
(OCar); IR (ATR) ν 3441, 1610, 1575, 1505, 1442 cmꢀ1; MS (ESþ) m/z
(%) 284 (M þ Hþ, 100). Anal. Calcd for C16H14FN3O: C, 67.83; H, 4.98;
N, 14.83. Found: C, 67.60; H, 4.79; N, 14.52.
4-Fluoro-5-(furan-2-yl)-3-(phenylamino)-1H-pyrazole 6c.
Silica gel chromatography (7:3 hexane/EtOAc; Rf = 0.17) was used:
70% yield; mp 148ꢀ149 °C (1:1 hexane/Et2O); 1H NMR (acetone-d6)
δ 6.57 (1H, dd, J = 3.5, 1.5 Hz, CHfuran), 6.76 (1H, d, J = 3.5 Hz,
CHfuran), 6.81 (1H, t, J = 7.7 Hz, CHar), 7.22 (2H, t, J = 7.7 Hz, 2 ꢁ
CHar), 7.35 (2H, d, J = 7.7 Hz, 2 ꢁ CHar), 7.57 [1H, s(broad), NH], 7.62
(1H, d, J = 1.5 Hz, OCHfuran), 11.98 [1H, s(broad), NH]; 19F NMR
(acetone-d6) δ ꢀ181.7 (1F, s, CF); 13C NMR (acetone-d6) δ 107.6 (d,
J = 3.5 Hz, CHfuran), 111.8 (CHfuran), 115.3 (2 ꢁ CHar), 119.4 (CHar),
121.7 [s(broad), NCq], 129.0 (2 ꢁ CHar), 135.7 (d, J = 246.9 Hz, CF),
138.1 [s(broad), NCqN], 142.9 (OCHfuran), 143.0 (OCfuran), 144.0
(NCar); IR (ATR) ν 3432, 1664, 1602, 1572, 1551 cmꢀ1; MS (ESþ)
3-Amino-4-fluoro-5-phenyl-1H-pyrazole 7. To a solution of
25 mg (0.09 mmol, 1 equiv) of 3-(benzylamino)-4-fluoro-5-phenyl-1H-
pyrazole 6f in 1 mL of MeOH were added 17 mg (0.28 mmol, 3 equiv) of
acetic acid and 10 mg (40 wt %) of Pd-C. The mixture was stirred under a
H2 atmosphere (2.5 bar) at room temperature for 30 h. The mixture was
filtered, and the solvent was evaporated to afford 16 mg of 3-aminopyr-
azole 7 (0.09 mmol, 94% yield): mp 96ꢀ97 °C (1:1 hexane/Et2O); 1H
NMR (CDCl3) δ 7.36 (1H, t, J = 7.4 Hz, CHar), 7.44 (2H, t, J = 7.4 Hz,
4109
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The Journal of Organic Chemistry
NOTE
2 ꢁ CHar), 7.60 (2H, d, J = 7.4 Hz, 2 ꢁ CHar); 19F NMR (CDCl3)
δ ꢀ186.0 (1F, s, CF); 13C NMR (CDCl3) δ 125.2 and 125.3 (2 ꢁ
CHar), 127.8 (d, J = 4.6 Hz, NCq), 128.4 (CHar), 128.6 (Car), 129.0 (2 ꢁ
CHar), 135.3 (d, J = 243.5 Hz, CF), 141.9 (d, J = 11.5 Hz, NCqN); IR
(ATR) ν 3404, 1662, 1600, 1550 cmꢀ1; MS (ESþ) m/z (%) 178 (M þ
Hþ, 100). Anal. Calcd for C9H8FN3: C, 61.01; H, 4.55; N, 23.72. Found:
C, 59.89; H, 4.51; N, 23.68.
(5) Clemens, L. Heterocycles 2007, 71, 1467.
(6) Fustero, S.; Romꢀan, R.; Sanz-Cervera, J. F.; Simꢀon-Fuentes, A.;
Cu~nat, A. C.; Villanova, S.; Murguía, M. J. Org. Chem. 2008, 73, 3523 and
references cited therein.
(7) Fustero, S.; Romꢀan, R.; Sanz-Cervera, J. F.; Simꢀon-Fuentes, A.;
Bueno, J.; Villanova, S. J. Org. Chem. 2008, 73, 8545.
(8) Fustero, S.; Simꢀon-Fuentes, A.; Sanz-Cervera, J. F. Org. Prep.
Proced. Int. 2009, 41, 253 and references cited therein.
(9) Pace, A.; Buscemi, S.; Vivona, N. Org. Prep. Proced. Int. 2007,
39, 1 and references cited therein.
(10) For an example, see: Skinner, P. J.; Cherrier, M. C.; Webb, P. J.;
Shin, Y. J.; Gharbaoui, T.; Lindstrom, A.; Hong, V.; Tamura, S. Y.; Dang,
H. T.; Pride, C. C.; Chen, R.; Richman, J. G.; Connolly, D. T.; Semple, G.
Bioorg. Med. Chem. Lett. 2007, 17, 5620.
(11) Molines, H.; Wakselman, C. J. Org. Chem. 1989, 54, 5618.
(12) Sloop, J. C.; Bumgardner, C. L. J. Fluorine Chem. 2002, 118, 135.
(13) Ishihara, T.; Okada, Y.; Kuroboshi, M.; Shinozaki, T.; Ando, T.
Chem. Lett. 1995, 239.
(14) Zhang, Q.; Lu, L. Tetrahedron Lett. 2000, 41, 8545.
(15) Elmaati, T. M. A.; El-Taweel, F. M. J. Heterocycl. Chem. 2004,
41, 109.
(16) Anwara, H. F.; Elnagdic, M. H. ARKIVOC 2009, i, 198.
(17) Tang, J.; Shewchuk, L. M.; Sato, H.; Hasegawa, M.; Washio, Y.;
Nishigaki, N. Bioorg. Med. Chem. Lett. 2003, 13, 2985.
(18) Teng, M.; Zhu, J.; Johnson, M. D.; Chen, P.; Kornmann, J.;
Chen, E.; Blasina, A.; Register, J.; Anderes, K.; Rogers, C.; Deng, Y.;
Ninkovic, S.; Grant, S.; Hu, Q.; Lundgren, K.; Peng, Z.; Kania, R. S.
J. Med. Chem. 2007, 50, 5253.
4-Fluoro-5-(4-methoxyphenylamino)-1,3-diphenyl-1H-
pyrazole 9. A solution of 5.77 g (18.20 mmol, 1 equiv) of compound 4b
and 2.16 g (20 mmol, 1.1 equiv) of phenylhydrazine in 150 mL of EtOH
and AcOH (0.6 mL) was heated at reflux temperature for 24 h. The sol-
vent was removed under reduced pressure to give the crude product that
was purified by column chromatography (9:1 hexane/EtOAc; Rf = 0.17)
to yield 4.97 g (13.83 mmol, 76% yield) of pyrazole 9: 1H NMR (CDCl3)
δ 3.76 (3H, s, OCH3), 5.27 [1H, s(broad), NH], 6.72 (2H, d, J = 8.8 Hz, 2
ꢁ CHar), 6.82 (2H, d, J = 8.8 Hz, 2 ꢁ CHar), 7.35 (1H, t, J = 7.7 Hz,
CHar), 7.42 (3H, t, J = 7.7 Hz, 3 ꢁ CHar), 7.49 (2H, t, J = 7.7 Hz, 2 ꢁ
CHar), 7.63 (2H, t, J = 7.7 Hz, 2 ꢁ CHar), 8.03 (2H, d, J = 7.7 Hz, 2 ꢁ
CHar); 19F NMR (CDCl3) δ ꢀ171.2 (1F, s, CF); 13C NMR (CDCl3)
δ 55.5 (OCH3), 114.8 (2 ꢁ CHar), 115.6 (2 ꢁ CHar), 123.1 (2 ꢁ CHar),
125.9 (d, J = 4.6 Hz, 2 ꢁ CHar), 127.4 (CHar), 127.7 (Car), 128.2 (CHar),
128.6 (2 ꢁ CHar), 129.1 (2 ꢁ CHar), 130.8 (d, J = 4.6 Hz, NCq), 137.3
(NCar), 137.6 (d, J = 4.6 Hz, NCqN), 138.6 (NCar), 141.2 (d, J = 251.5
Hz, CF), 153.8 (OCar); IR (ATR) ν 3374, 1622, 1596, 1509 cmꢀ1; MS
(ESþ) m/z (%) 360 (M þ Hþ, 100). Anal. Calcd for C22H18FN3O: C,
73.52; H, 5.05; N, 11.69. Found: C, 73.72; H, 4.83; N, 12.00.
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Supporting Information. Copies of H NMR and 13C
S
b
NMR spectra of all isolated new compounds (2e, 4aꢀd, 4g, 5, 6aꢀg,
and 7ꢀ10) and 1H NOE NMR spectrum of 2c. This material is
available free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail:norbert.dekimpe@UGent.be.
Notes
§Aspirant of the Research Foundation-Flanders (FWO,
Vlaanderen, Belgium).
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Present Addresses
Department of Chemistry, Faculty of Sciences and Bio-engi-
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’ ACKNOWLEDGMENT
We are indebted to the Research Foundation-Flanders, Ghent
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ment, a Division of Janssen Pharmaceutica NV, for financial
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