α,β-Disubstituted CF3-Enones as a Trifluoromethyl Building Block: Regioselective Preparation of Totally Substituted 3-CF3-Pyrazoles

Article abstract of DOI:10.1021/acs.joc.0c02516

An efficient pathway toward a novel class of trifluoromethyl building blocks was elaborated. The reaction of α-CF3-enamines with arylaldehydes resulted in direct synthesis of α,β-diaryl-CF3-enones isolated in up to 93% yield as E-isomers. The possible reaction mechanism was proposed using the Zimmerman-Traxler model. The reaction of α,β-diaryl-CF3-enones with hydrazines opens a novel pathway to trifluoromethylated pyrazolines. Oxidation of pyrazolines with DDQ opened access to totally regioselective preparation of 3-CF3-pyrazoles isolated in high yield. Using this strategy, 4-arylated derivatives of known drugs Celebrex, Mavacoxib, and SC-560 can be synthesized.

Full text of DOI:10.1021/acs.joc.0c02516

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Article
α,β-Disubstituted CF3‑Enones as a Trifluoromethyl Building Block:
Regioselective Preparation of Totally Substituted 3‑CF3‑Pyrazoles
Vasiliy M. Muzalevskiy, Zoia A. Sizova, Vasiliy V. Panyushkin, Vyacheslav A. Chertkov,
Victor N. Khrustalev, and Valentine G. Nenajdenko*
Cite This: J. Org. Chem. 2021, 86, 2385−2405
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ABSTRACT: An efficient pathway toward a novel class of
trifluoromethyl building blocks was elaborated. The reaction of
α-CF3-enamines with arylaldehydes resulted in direct synthesis of
α,β-diaryl-CF3-enones isolated in up to 93% yield as E-isomers.
The possible reaction mechanism was proposed using the
Zimmerman−Traxler model. The reaction of α,β-diaryl-CF3-
enones with hydrazines opens a novel pathway to trifluoromethy-
lated pyrazolines. Oxidation of pyrazolines with DDQ opened
access to totally regioselective preparation of 3-CF3-pyrazoles
isolated in high yield. Using this strategy, 4-arylated derivatives of
known drugs Celebrex, Mavacoxib, and SC-560 can be synthesized.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Several years ago, the catalytic olefination reaction (COR) was
elaborated in our group. COR is a copper-catalyzed trans-
formation of hydrazones of carbonyl compounds into
haloalkenes by treatment with polyhalogenalkanes (PHA) in
the presence of base.19 Using CF3-substituted freons as
fluorine-containing PHA, β-fluoro-, β-chloro-, and β-bromo-
β-trifluoromethylstyrenes can be synthesized stereoselectively
by this method.20 These alkenes appeared to be very valuable
building blocks for the synthesis of various fluorinated
compounds by the reaction with nucleophiles and hetero-
cyclizations.21−25 We envisioned that α-CF3-β-aryl enamines,
easily obtained from these alkenes, could be used as key
building blocks to synthesize α,β-diaryl-CF3-enones by the
reaction with aldehydes. To start our investigation, a set of
enamines 2 with both electron-withdrawing and electron-
donating substituents in the aryl fragment was prepared from
chloro- and bromo-substituted CF3-styrenes 1.23 The reaction
gave the corresponding enamines 2 in up to 90% yield.
Unpredictable double substitution was observed in the case of
4-fluorophenyl derived styrene 1h to formenamine 2h with an
additional pyrrolidine moiety in the para-position of the aryl
ring. In the case of styrene 1i with a CO2Me group, additional
transformation of the ester group to amide functionality was
Organofluorine chemistry is one of the most attention
consuming areas of a modern organic chemistry. This results
from the many roles of fluorinated compounds in our everyday
life.1 These compounds can be found among construction
materials, key components of compositions for LCD, agro-
chemicals,2 and pharmaceuticals.3 It was recently estimated
that up to 20% (more than 300 compounds) of currently used
drugs4 contain at least one fluorine atom.5 The last two years
revealed even higher shares of fluoropharmaceuticals among
small-molecule drugs (45% in 2018,6 41% in 20197). Methods
of direct fluorination of organic molecules may suffer from low
selectivity to cause a formation of mixtures of fluorinated
compounds. Because of that, strategies based on application of
fluorinated building blocks are much more flexible and
convenient approaches to fluorinated compounds with fluorine
in desired positions.
Some of the most valuable representatives of such building
blocks are α,β-unsaturated CF3-ketones. A great potential of
these ketones was shown for the synthesis of various
organofluorine compounds, including carbo- and hetero-
cycles.8 Various approaches to the synthesis of α,β-unsaturated
CF3-ketones can be found in the literature.9−17 However, to
the best of our knowledge, only a couple of works reported
synthesis of α,β-diaryl-CF3-enones.18 Only four ketones of this
class have been described. This article reports a novel effective
pathway to the α,β-diaryl-CF3-enones based on the reaction of
α-CF3-enamines with aldehydes and regioselective synthesis of
3-CF3-pyrazole derivatives.
Received: October 22, 2020
Published: January 11, 2021
https://dx.doi.org/10.1021/acs.joc.0c02516
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achieved by keeping the reaction mixture for 7 days, while
enamine 2i with a CO2Me group can be isolated overnight
(Scheme 1).
ketone. Addition of strong acids such as PTSA, methanesul-
fonic acid, or HCl in methanol led to significant tarring of the
reaction mixture or to complete hydrolysis of starting enamine
to the corresponding ketone. Application of less acidic acetic
acid appeared to be a nice shot to provide suitable conditions
for the transformation. Thus, maintaining the reaction of
enamine 2a with benzaldehyde in acetic acid at 80−90 °C led
to desired CF3-enone 4a in 68% yield (Scheme 2, 4a).
Having found optimal reaction conditions, a number of
aldehydes were investigated. It was found that the reaction is
very general. Aryl aldehydes with both electron-donating and
electron-withdrawing substituents, sterically hindered alde-
hydes (1-naphtaldehyde, 2-bromobenzaldehyde, and 2,6-
dichlorobenzaldehyde), and bis-aldehydes (terephtaldehyde)
were successfully involved in the reaction with enamine 1a to
form the corresponding enones 4b−l in up to 93% yield.
Heterocyclic derivatives can be prepared as well. For example,
2-thiophenyl- (4m) and 4-pyridyl (4n) substituted ketones
were isolated in 76−77% yield. The only exclusion was
aliphatic isobutyraldehyde, giving no traces of the correspond-
ing ketone after several hours of heating.
Scheme 1. Synthesis of Starting α-CF3-β-Arylenamines 2
Next, the reaction of other enamines 2 with variety of
substituted benzaldehydes was studied. To our delight, the
reaction was found to be general, and almost no restrictions
Enamine 2a was used as a model substrate for optimization
of the reaction conditions with benzaldehyde. The reaction in
ethanol and toluene upon heating did not provide the desired
Scheme 2. Synthesis of α,β-Diaryl-CF3-enones
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were found. Enamines with both electron-withdrawing and
electron-donating substituents in the aryl fragment reacted
with the set of benzaldehydes to give the corresponding
ketones in good to high yields. It was shown that target CF3-
enones with various combinations of electron-withdrawing and
electron-donating substituents can be prepared very efficiently.
It should be noted that the synthesis of ketones 4 can be
performed easily in multigram scale without yield drop. Thus,
ketones 4b and 4s were prepared in the amount of 6.9 and 7.2
g, respectively (Scheme 2).
Scheme 3. Possible Mechanism of the Transformation 2
into 4
A very important feature of the method is almost 100%
stereoselectivity. E-Isomer with cis-oriented aryl substituents is
formed predominantly or exclusively. The admixture of Z-
isomers was in the range 1−4%, and in some cases, no
formation of minor Z-isomers was observed. Only in the case
of 4f, about 10% of Z-isomer was formed. Both isomers were
isolated in pure form, and their configuration was determined
by NMR (Figure 1).
with Zimmerman−Traxler model.28,29 We suggested formation
of six-membered Zimmerman−Traxler-like transition states
TS1 or TS2 for the reaction of enamine and protonated
aldehyde (Scheme 4). Transition state TS2 is disfavored due
to 1,3-diaxial interactions between bulky aryl group of
aldehyde (Ar2) and CF3 group of enamine. In contrast, TS1
has lower energy due to equatorial orientation of Ar2. As a
result, E-isomeric ketones 4 are formed selectively.
Having in hand new family of trifluoromethyl building
blocks 4, we investigated their synthetic utility. Trifluorome-
thylated pyrazoles are probably the most important type of
CF3-substituted heterocycles because many compounds of this
class exhibited pronounced biological activity and have found
applications as current drugs and agrochemicals2−4 (Figure 2).
A whole constellation of methods for the synthesis of pyrazoles
by the reactions of CF3-enones and ynones with various
nucleophiles and dipolarophiles has been published.30
Especially important is the regioselective synthesis of
trifluoromethylated pyrazoles because many current drugs
have a CF3 group installed at position 3.
We proposed that reaction of ketones 4 with hydrazines can
open direct access to trifluoromethylated pyrazole derivatives.
First, the reaction of ketone 4o with hydrazine hydrate 6a in
EtOH was studied. It was found that pyrazolidine 7a is formed
in 88% yield (crude material) at room temperature.
This compound eliminates water slowly at standing or very
rapidly at heating under acidic catalysis (MeSO3H) in CHCl3
to give regioselective pyrazoline 8a with conjugated with
phenyl double CN bond in 65% yield (Scheme 5). In
addition, the corresponding pyrazole 9a was isolated in 11%
yield as a result of aromatization of 8a (oxygen in air is a
possible oxidant).
Next, the reaction with aryl hydrazines was studied. We
performed a series of experiments of model ketone 4o with
both phenylhydrazine 6b and its hydrochloride in various
solvents (Scheme 6, Table 1).
Figure 1. NMR elucidation of the configuration of E- and Z-isomers
of ketone 4f.
The NMR elucidation of the configuration of E- and Z-
isomers of ketone 4f is based on values of vicinal spin−spin
coupling constants 13C−H between the olefinic proton with
the carbonyl of trifluoroacetyl and ipso-carbon C1 measured for
the both isomers via proton-coupled 13C NMR spectra (see
Experimental Details in Supporting Information). These values
allow an unambiguous assignment for the cis- and trans-
coupling pathways. Trans-coupling is noticeably greater than
cis in both compounds, which coincides well with the reference
data available.26,27
Next, efforts were undertaken to propose a possible
mechanism of the reaction to explain observed stereo-
selectivity. We focused our attention on the fact that the
formation of the corresponding benzyl trifluoromethylketones
was detected by 1H or 19F NMR. Thus, analysis of the reaction
mixtures after 0.5−1h of heating revealed absence of starting
enamine 2, while ketones 4 and benzyltrifluoromethylketones
5 were in comparable amounts. Moreover, concentration of
these ketones 5 decreased equally to the increase of
concentration of 4. To test the possibility of direct formation
of 4 from benzyltrifluoromethylketone 5a, we heated ketone 5a
with benzaldehyde in AcOH. However, formation of 4o was
not observed. Nevertheless, addition of 1 equiv of pyrrolidine
to this reaction mixture resulted in the appearance of 4o. The
most reasonable explanation of this fact is formation of ketone
4o by the reaction of enamine with benzaldehyde. The
presence of 5 in the reaction mixture can be explained by
reverse hydrolysis of enamine 2 (Scheme 3).
The composition of the reaction mixture and the yields of
1
the products were determined by H and/or 19F NMR. It was
found that the reaction is 100% regioselective in all solvents. 3-
CF3 derivatives of pyrazolidine 7b, pyrazoline 8b, and pyrazole
9b were formed as main products, while the formation of the
corresponding hydrazone was not observed at all. At room
temperature, pyrazolidine 7b was the main product of the
reaction (Table 1, entry 1). Heating of the reaction mixture
with pTSA (in CF3CH2OH and DMSO, Table 1, entries 5 and
6) or heating in EtOH resulted in formation of pyrazoline 8b
in up to 77% isolated yield (Table 1, entry 2). Reaction with
phenylhydrazine hydrochloride proceeded very slowly at room
temperature (3 weeks in EtOH, Table 1, entry 6). Upon
heating, the reaction was accomplished in 15 h to give a
mixture of diastereomeric pyrazolines 8b and 8b′ in 70% total
yield (Table 1, entry 9). Treatment of the reaction mixture
Another fact that should be explained is the stereoselectivity
of the reaction. At first glance, less sterically hindered Z-isomer
bearing trans-arranged aryl groups should be the major product
of the reaction. However, experiment shows the opposite
result. The observed stereochemistry is in a good agreement
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Scheme 4. Possible Reaction Mechanism of the Reaction of Enamines 2 with Arylaldehydes
Figure 2. Examples of biologically active fluorinated pyrazoles.
∼50% conversion after 11 h of heating to give low yields of
pyrazoline 8b. As a result, heating of ketone 4b with aryl
hydrazine (not hydrochloride) should be used for the
preparation of pyrazoline 8b (Table 1, entry 11).
Scheme 5. Reaction of 4o with Hydrazine Hydrate
The formation of 8b proceeds with 100% regioselectively to
give the 3-CF3 isomer only. The configuration of 8b and 8b′
can be established unambiguously by NMR using comparison
with literature data. 4,5-cis-Disubstituted pyrazolines exhibit
with DBU permits isomerization of 8b′ into thermodynami-
cally stable 8b with trans-configuration (Table 1, entry 8). It is
interesting to note that admixture of pyrazole 9b was formed in
both of the last cases. Similarly, heating of 4o with
phenylhydrazine hydrochloride in AcOH led to a mixture of
pyrazolines 8b, 8b′, and pyrazole 9b (Table 1, entry 10). The
reaction of 4o with phenylhydrazine in AcOH revealed only
3
larger J(HH) coupling constants (10−14 Hz) than trans-
isomers (3−10 Hz).31 These data are in perfect agreement
with observed coupling values of cis-pyrazoline 8b′ (11.9 Hz)
and trans-pyrazoline 8b (6.5 Hz). Finally, both regio- and
stereochemistry of the reaction was confirmed by X-ray
Scheme 6. Reaction of Ketone 4o with Phenylhydrazine
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Table 1. Reaction of Ketone 4o with Phenylhydrazine and Its Hydrochloride in Various Conditions
a
a
a
entry
solvent
EtOH
conditions
7b, %
8b + 8b′, %
9b, %
1
6b, rt, 48 h
69
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
CF3CH2OH
DMSO
EtOH
EtOH
EtOH
6b, rt, 48 h, then pTSA, 80 °C, 2 h
6b, rt, 48 h, then 80 °C, 2 h
6b, 80 °C, 3 h
6b, rt, 48 h, then pTSA, 80 °C, 2 h
6b, rt, 14 h, then pTSA, 80 °C, 4 h
6b·HCl, rt, 21 d
6b·HCl, rt, 21 d, then DBU, 1 d
6b·HCl, 80 °C, 15 h
6b·HCl, 80 °C, 15 h
77(b)
67(b)
69(b), 62
40(b)
39(b)
3
3
1
6
1
28
31
10
19
b
c
b
b
32(b) + 33(b′)
60(b)
36(b) + 34(b′)
26(b) + 28(b′)
d
10
11
AcOH
AcOH
e
e
6b, 80 °C, 11 h
6(b)
3
a
b
c
d
e
Determined by 19F NMR. Isolated yield. Conversion 87%. Conversion 86%. Conversion 57%.
Figure 3. Structure elucidation for 8b and 8b′. The atoms in 8b are represented as anisotropic displacement ellipsoids at the 50% probability level.
analysis for pyrazoline 8b with trans-orientation of phenyl
groups at C-4 and C-5 (Figure 3).
Next, oxidative aromatization of pyrazolines 8 was
investigated to obtain the corresponding 3-CF3-pyrazoles 9.
A number of systems were tested such as O2−Pd/C in
refluxing toluene or acetic acid, MnO2 in toluene, FeCl3 in
MeNO2, and DDQ in toluene. The last system allows
performing the desired transformation most efficiently. Target
3-CF3-pyrazoles 9 can be prepared in up to 86% yield (method
A, Scheme 10).
Nevertheless, we decided also to elaborate synthetically
more attractive one-pot procedure. It was observed that the
reaction of 4o with hydrochloride of phenylhydrazine 6b led to
the mixture of pyrazoline 8b and pyrazole 9b (Table 1, entries
7−9). We examined possibility of oxidation of 8b to obtain
pure pyrazole 9b without isolation of pyrazoline 8b. As a result,
one-pot two step procedure for synthesis of pyrazoles 9 was
elaborated (method B, Scheme 10) to open direct access to
pyrazoles from ketones 4. In this case much better total yields
were observed (up to 97%). The procedure includes heating of
4 with hydrochloride of aryl hydrazine, subsequent evaporation
of solvent, and treatment with DDQ in toluene. The approach
has a wide synthetic scope, allowing use of ketones 4 and
hydrazines 6 with electron-donating as well as electron-
withdrawing groups. Ketones with bulky ortho-substituted aryl
groups were also successfully used in the reaction to give the
corresponding pyrazoles 9 in high yield. The reaction tolerates
various functional groups, such as cyano-, nitro, sulfonylamino
groups, which is an advantage of the method.
On the basis of Table 1 data and our previous investigations,
we proposed that the possible reaction mechanism includes
formation of hemiaminal E as a key intermediate. Its
cyclization affords pyrazolidine 7b, which eliminates water to
give pyrazoline 8b (Scheme 7). Formation of the trans-isomer
of 8b is more favorable thermodynamically than the cis-isomer
8b′ due to steric reasons.
Scheme 7. Possible Mechanism of Regioselective
Heterocyclization
With the optimal conditions in hand, we performed a series
of reactions of ketones 4 with hydrazines 6 (Scheme 8) to
prepare the corresponding pyrazolines. Both aryl hydrazines
with electron-donating and electron-withdrawing groups as
well ethyl hydrazine were used. In most cases, the yields of
prepared pyrazolines are in the range of 50−60%.
In some cases, the reaction can be stopped on the stage of
formation of pyrazolidines. According to 19F NMR, heating for
2−4 h permits preparation of 7c and d isolated in good yield
(Scheme 9). Subsequent elimination of water by heating with
catalytic amounts of pTSA in toluene gives pyrazolines 8 very
cleanly.
We decided to use this approach for the synthesis of some
derivatives of Celebrex, Mavacoxib, and SC-560 (see Figure 2)
with an additional substituent at the position C-4 of pyrazole.
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Scheme 8. Synthesis of 3-CF3-Pyrazolines 8
Celebrex, Mavacoxib, and SC-560, with additional groups at C-
4 was elaborated.
Scheme 9. Formation of Intermediate Pyrazolidines 7
EXPERIMENTAL SECTION
■
1
General Remarks. H, 13C, and 19F NMR spectra were recorded
on a Bruker AVANCE 400 MHz spectrometer in CD3CN, DMSO-d6,
and CDCl3 at 400, 100, and 376 MHz, respectively. Chemical shifts
(δ) in ppm are reported with the use of the residual CHD2CN,
1
DMSO-d5, and chloroform signals (1.94, 2.54, and 7.25 for H and
1.30, 39.5, and 77.0 for 13C) as internal reference. The 19F chemical
shifts were referenced to C6F6 (−162.9 ppm). Structural assignments
of Z-4f and E-4f were made with additional information from gCOSY,
gHSQC, and gHMBC experiments. 2D correlation NMR experiments
gCOSY, gHSQC, and gHMBC were recorded on a Bruker AV-600
spectrometer (for parameters, see ref 32). The coupling constants (J)
are given in Hertz (Hz). ESI-MS spectra were measured with an
Orbitrap Elite instrument. X-ray diffraction data for 8b were collected
on a three-circle Bruker D8 QUEST PHOTON-III CCD diffrac-
tometer (λMo Kα radiation, graphite monochromator, φ and ω scan
mode) and corrected for absorption using the SADABS program.33
Compound 8b was recrystallized from heptane solution as colorless
crystals suitable for the single-crystal X-ray diffraction study. The data
were indexed and integrated using the SAINT program.34 For details,
see Table 1. The structure was solved by intrinsic phasing
modification of direct methods35 and refined by a full-matrix least-
squares technique on F2 with anisotropic displacement parameters for
all nonhydrogen atoms. The hydrogen atoms were placed in
calculated positions and refined within the riding model with fixed
isotropic displacement parameters [Uiso(H) = 1.2Ueq(C)]. All
calculations were carried out using the SHELXTL program.36
Crystallographic data for 8b have been deposited with the Cambridge
The corresponding tetra-substituted pyrazoles 9 were prepared
in up to 92% yield directly using a one-pot procedure (Figure
4). The prepared products are highly attractive compounds for
further biological studies.
In conclusion, we developed a general and efficient pathway
toward α,β-diaryl-substituted CF3-enones 3 based on the
reaction of α-CF3-β-aryl enamines 2 with arylaldehydes. The
reaction proceeds highly stereoselectively to form preferentially
E-isomers of 3 in up to 93% yield. The stereoselectivity of the
reaction was explained using the Zimmerman−Traxler model.
It was shown that the reaction of 3 with aryl hydrazines led
with 100% regioselectively to CF3-substituted pyrazole
derivatives. The approach permits the preparation of
pyrazolidines, pyrazolines, and pyrazoles depending on the
reaction conditions. All proposed procedures have a broad
synthetic scope, allowing synthesis of target products with
independent combinations of electron-withdrawing and
electron-donating groups. The synthesis of derivatives of
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Scheme 10. Synthesis of 3-CF3-Pyrazoles 8
Figure 4. Synthesis of 3-CF3-pyrazole derived drug analogues (for conditions A and B, see Scheme 10).
Crystallographic Data Center, CCDC 2040062. Copies of this
information may be obtained free of charge from the Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223
336033; e-mail: deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk).
TLC analysis was performed on Merck 60 F254 plates. Column
chromatography was performed on silica gel. Melting points were
determined on an Electrothermal 9100 apparatus. All reagents were of
reagent grade and were used as such or were distilled prior to use.
Starting α-CF3-β-aryl enamines 2 were synthesized using previously
reported procedures23 by the reaction of β-halogeno-β-trifluorome-
thylstyrenes with 2.2 equiv of lithium pyrrolidide (generated by the
reaction of pyrrolidine and n-BuLi, 2a, b, c, h) in THF (method A) or
by the reaction with 10 equiv of pyrrolidine in neat (2d, e, f, g, i, j,
method B). For the synthetic procedures and characterization data of
compounds 2a−e, g, i, see ref 23 (for structures and yields, see the
Supporting Information). For characterization data of side product 5a,
see ref 37. The NMR data of 4a and 4o are in agreement with those in
the literature.18a
(97:3). For the mixture of isomers: Z-isomer: 1H NMR (CDCl3,
3
3
400.1 MHz): δ 7.38 (d, 2H, J = 8.8 Hz), 6.53 (d, 2H, J = 8.8 Hz),
6.29 (s, 1H), 3.31−3.34 (m, 4H), 3.07−3.11 (m, 4H), 1.98−2.06 (m,
4H), 1.82−1.90 (m, 4H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
2
1
147.0, 130.7, 129.8 (q, JCF = 27.5 Hz), 123.3 (q, JCF = 280.0 Hz),
122.0, 117.3 (q, 3JCF = 6.1 Hz), 111.0, 49.5, 47.5, 25.5, 25.3. 19F NMR
1
(CDCl3, 376.5 MHz): δ −64.7 (s, 3F). E-isomer: H NMR (CDCl3,
3
3
400.1 MHz): δ 7.11 (d, 2H, J = 8.6 Hz), 6.51 (d, 2H, J = 8.6 Hz),
5.79 (s, 1H), 3.28−3.31 (m, 4H), 3.13−3.16 (m, 4H), 1.92−1.95 (m,
4H). Other signals are overlapped with those of the major isomer.
13C{1H} NMR (CDCl3, 100.6 MHz): δ 130.9, 130.5 (q, JCF = 29.4
2
Hz), 110.9, 49.8, 45.0, 24.42, 24.36. Other signals are overlapped with
those of the major isomer or cannot be seen in the spectrum due to
the low concentration of minor isomer. 19F NMR (CDCl3, 376.5
MHz): δ −59.8 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
+
C17H22F3N2 : 311.1730; found: 311.1723.
1-[(1Z)-3,3,3-Trifluoro-1-(4-trifluoromethylphenyl)prop-1-
en-2yl]pyrrolidine (2f). Obtained from (Z)-1-(2-bromo-3,3,3-
trifluoroprop-1-en-1-yl)-4-(trifluoromethyl)benzene 1f (3.962 g,
12.420 mmol) by method B. Purified by column chromatography
using gradient elution by hexane/CH2Cl2 mixtures (4:1 followed by
1-[(1Z)-2-(4-(Pyrrolidin-1-yl)-phenyl)-1-(trifluoromethyl)-
vinil]pyrrolidine (2h). Obtained from (Z)-1-(2-chloro-3,3,3-tri-
fluoroprop-1-en-1-yl)-4-fluorobenzene 1h (5.78 g, 18 mmol) by
method A. Purified by column chromatography using gradient elution
by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Slightly beige
solid, yield 4.035 g (72%), mp 57−58 °C. Mixture of Z/E isomers
1
2:1). Colorless oil, yield 3.257 g (85%). H NMR (CDCl3, 400.1
MHz): δ 7.54 (d, 2H, 3J = 8.3 Hz), 7.30 (d, 2H, 3J = 8.3 Hz), 6.07 (s,
1H), 3.04−3.08 (m, 4H), 1.80−1.87 (m, 4H). 13C{1H} NMR
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4
2
(CDCl3, 100.6 MHz): δ 139.7 (d, JCF = 1.3 Hz), 135.3 (q, JCF
=
Hz), 159.9, 144.2 (q, 4JCF = 2.8 Hz), 136.6, 134.8, 132.5, 132.2, 131.0,
128.8, 125.2, 116.8 (q, JCF = 292.1 Hz), 114.6, 55.2. 19F NMR
2
3
1
28.4 Hz), 129.1, 127.8 (q, JCF = 32.4 Hz), 124.6 (q, JCF = 3.7 Hz),
124.2 (q, 1JCF = 271.6 Hz), 122.0 (q, 1JCF = 278.6 Hz), 105.9 (q, 3JCF
(CDCl3, 376.5 MHz): δ −70.8 (s, 3F). For admixture of Z-isomer:
= 6.1 Hz), 50.6 (q, JCF = 1.7 Hz), 25.5. 19F NMR (CDCl3, 376.5
19F NMR (CDCl3, 376.5 MHz): δ −75.8 (s, 3F). HRMS (ESI-TOF):
4
+
m/z [M + Na]+ Calcd for C17H12ClF3NaO2+: 363.0370; found:
MHz): δ −65.8 (s, 3F), −63.5 (s, 3F). HRMS (ESI-TOF): m/z [M]
Calcd for C14H13F6N: 309.0947; found: 309.0943; m/z [M + H]+
Calcd for C14H13F6N+: 310.1025; found: 310.1020.
363.0363; [M+K]+ Calcd for C17H12ClF3KO2 : 379.0110; found:
379.0101.
(Z)-Pyrrolidin-1-yl-[4-(3,3,3-trifluoro-2-(pyrrolidin-1-yl)-
prop-1-en-1-yl)phenyl]metanone (2j). Obtained from methyl
(Z)-4-(2-bromo-3,3,3-trifluoroprop-1-en-1-yl)benzoate 1j (3.092 g,
10 mmol) method B. Yellow oil, yield 2.970 g (88%). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Mixture of Z/E isomers (76:24). For
(3E)-1,1,1-Trifluoro-4-(4-fluorophenyl)-3-(4-methoxy-
phenyl)but-3-en-2-one (4c). Obtained from enamine 2a (0.830 g,
3.060 mmol) and 4-fluorobenzaldehyde (0.390 g, 3.177 mmol).
Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Orange oil, yield
1
0.845 g (85%). Mixture of E- and Z-isomers 96:4. For E-isomer: H
1
the mixture of isomers: Z-isomer: H NMR (CDCl3, 400.1 MHz): δ
NMR (CDCl3, 400.1 MHz): δ 7.76 (s, 1H), 7.06−7.14 (m, 4H), 6.96
3
3
(d, 2H, 3J = 8.8 Hz), 6.90 (t, 2H, 3J = 8.7 Hz), 3.85 (s, 3H). 13C{1H}
7.45 (d, 2H, J = 8.3 Hz), 7.24 (d, 2H, J = 8.3 Hz), 6.07 (s, 1H),
3.61−3.65 (m, 2H), 3.43−3.46 (m, 2H), 3.03−3.06 (m, 4H), 1.75−
2.02 (m, 8H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 169.2, 137.3,
134.5, 134.2 (q, 2JCF = 28.3 Hz), 128.5, 126.50, 122.0 (q, 1JCF = 278.8
2
NMR (CDCl3, 100.6 MHz): δ 181.5 (q, JCF = 33.3 Hz), 163.7 (d,
1JCF = 254.1 Hz), 159.8, 144.5 (q, 4JCF = 2.5 Hz), 134.1 (d, 4JCF = 2.0
Hz), 133.6 (d, 3JCF = 8.6 Hz), 131.0, 130.0 (d, 4JCF = 3.3 Hz), 125.3,
3
4
116.9 (q, 1JCF = 292.3 Hz), 115.7 (d, 2JCF = 21.7 Hz), 114.6, 55.2. 19
F
Hz), 107.5 (q, JCF = 6.1 Hz), 50.2 (q, JCF = 1.3 Hz), 49.4, 46.02,
26.2, 25.3, 24.2. 19F NMR (CDCl3, 376.5 MHz): δ −65.8 (s, 3F). E-
isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.41 (d, 2H, 3J = 8.2 Hz),
4
NMR (CDCl3, 376.5 MHz): δ −70.7 (d, J = 0.9 Hz, 3F), −108.72,
−108.94 (m, 1F). For admixture of Z-isomer: 1H NMR (CDCl3,
400.1 MHz): δ 7.25−7.30 (m, 4H), 3.83 (s, 3H). Other signals are
overlapped with those of the major isomer. 19F NMR (CDCl3, 376.5
MHz): δ −75.8 (s, 3F), −112.37, −112.49 (m, 1F). HRMS (ESI-
3
7.18 (d, 2H, J = 8.2 Hz), 5.59 (s, 1H), 3.19−3.22 (m, 4H). Other
signals are overlapped with those of the major isomer. 13C{1H} NMR
2
(CDCl3, 100.6 MHz): δ 169.4, 138.3, 135.3 (q, JCF = 30.1 Hz),
3
1
+
TOF): m/z [M + H]+ Calcd for C17H13F4O2 : 325.0846; found:
134.3, 128.6 (q, JCF = 2.3 Hz), 126.47, 121.8 (q, JCF = 277.9 Hz),
3
4
105.6 (q, JCF = 3.1 Hz), 49.2 (q, JCF = 1.9 Hz), 45.98, 24.5. Other
signals are overlapped with those of the major isomer or cannot be
seen in the spectrum due to the low concentration of minor isomer.
19F NMR (CDCl3, 376.5 MHz): δ −59.7 (s, 3F). HRMS (ESI-TOF):
325.0842.
(3E)-1,1,1-Trifluoro-3-(4-methoxyphenyl)4-(4-methyl-
phenyl)but-3-en-2-one (4d). Obtained from enamine 2a (0.913 g,
3.370 mmol) and 4-methylbenzaldehyde (0.466 g, 3.883 mmol).
Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Orange crystals,
yield 1.004 g (93%), mp 74−76°C. Mixture of E- and Z-isomers 96:4.
m/z [M + H]+ Calcd for C18H22F3N2O+: 339.1679; found: 339.1681;
[M + Na]+ Calcd for C18H21F3N2NaO+: 361.1498; found: 361.1496.
Synthesis of α,β-Diaryl-CF3-enones by the Reactions of α-CF3-β-
Aryl Enamines with Aromatic Aldehydes (General Procedure). One-
necked 50 mL round-bottom flask (or 12 mL vial) was charged with
enamine (5 mmol), aromatic aldehyde (5.75 mmol, 1.15 equiv), and
glacial acetic acid (15 or 5 mL for reaction in vial). Reaction mixture
was kept at 80−90 °C (hot plate stirrer) under stirring (for 4−10 h
until consumption of the aldehyde and corresponding benzyl ketone
formed by hydrolysis of enamine (1H NMR control). Volatiles were
evaporated in vacuo, and the residue was dissolved in CH2Cl2 (50
mL), washed with water (2 × 20 mL), and dried over Na2SO4.
Volatiles were evaporated in vacuo, and the residue was purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1) or pure CH2Cl2 (for 4n) as eluents.
(3E)-1,1,1-Trifluoro-3-(4-methoxyphenyl)-4-phenylbut-3-
en-2-one (4a). Obtained from enamine 2a (0.813 g, 3 mmol) and
benzaldehyde (0.333 g, 3.14 mmol). Purified by column chromatog-
raphy using gradient elution by hexane/CH2Cl2 mixtures (3:1
followed by 1:1). Light yellow solid, yield 0.620 g (68%), mp 58−
1
For E-isomer: H NMR (CDCl3, 400.1 MHz): δ 7.81 (s, 1H), 7.12
3
3
(d, 2H, J = 8.5 Hz), 7.00−7.06 (m, 4H), 6.97 (d, 2H, J = 8.4 Hz),
3.86 (s, 3H), 2.31 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
2
4
181.5 (q, JCF = 33.0 Hz), 159.7, 146.2 (q, JCF = 2.6 Hz), 141.5,
1
133.4, 131.6, 131.0, 130.97, 129.3, 117.0 (q, JCF = 292.4 Hz), 114.5,
55.1, 21.4. 19F NMR (CDCl3, 376.5 MHz): δ −70.5 (d, 3F, J = 1.0
4
1
Hz). For admixture of Z-isomer: H NMR (CDCl3, 400.1 MHz): δ
3
7.27 (d, 2H, J = 8.9 Hz), 7.13 (s, 1H), 3.83 (s, 3H), 2.35 (s, 3H).
Other signals are overlapped with those of the major isomer. 13C{1H}
2
NMR (CDCl3, 100.6 MHz): δ 189.5 (q, JCF = 36.0 Hz), 160.2,
139.3, 135.0, 134.8, 129.5, 128.2, 127.8, 115.5 (q, JCF = 294.1 Hz),
1
114.4, 55.3, 21.3. Other signals are overlapped with those of the major
isomer. 19F NMR (CDCl3, 376.5 MHz): δ −75.7 (s, 3F). HRMS
+
(ESI-TOF): m/z [M + H]+ Calcd for C18H16F3O2 : 321.1097; found:
321.1098.
(3E)-1,1,1-Trifluoro-3,4-bis(4-methoxyphenyl)but-3-en-2-
one (4e). Obtained from enamine 2a (0.542 g, 2 mmol) and 4-
methoxybenzaldehyde (0.302 g, 2.22 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Light yellow solid, yield 0.461 g (69%).
1
60°C. Mixture of E- and Z-isomers 95:5. For E-isomer: H NMR
(CDCl3,400.1 MHz): δ 7.81 (s, 1H), 7.27−7.31 (m, 1H), 7.20−7.23
(m, 2H), 7.08−7.12 (m, 4H), 6.94 (d, 2H, 3J = 8.8 Hz, 2H), 3.85 (s,
2
3H, CH3). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 181.7 (q, JCF
=
1
Mixture of E- and Z-isomers 96:4. For E-isomer: H NMR (CDCl3,
4
400.1 MHz): δ 7.79 (s, 1H), 7.12 (d, 2H, 3J = 8.8 Hz), 7.07(d, 2H, 3J
33.4 Hz), 159.8, 145.9 (q, JCF = 2.8 Hz), 134.4, 133.7, 131.5, 131.0,
130.6, 128.5, 125.6, 116.9 (q, 1JCF = 292.3 Hz), 114.5, 55.2. 19F NMR
3
3
= 8.8 Hz), 6.97 (d, 2H, J = 8.8 Hz), 6.74 (d, 2H, J = 9.0 Hz), 3.86
1
(s, 3H), 3.77(s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 181.3
(q, JCF = 32.7 Hz), 161.7, 159.7, 146.1 (q, JCF = 2.7 Hz), 133.7,
(CDCl3,376.5 MHz): δ −70.7. For admixture of Z-isomer: H NMR
2
4
(400.1 MHz, CDCl3): δ 7.25−7.44 (m, 7H), 7.18 (s, 1H), 3.84 (s,
3H). Other signals are overlapped with those of the major isomer. 19F
NMR (CDCl3, 376.5 MHz): δ −75.8 (s, 3F). HRMS (ESI-TOF): m/
1
132.0, 131.0, 126.4, 126.2, 117.1 (q, JCF = 292.4 Hz), 114.6, 114.0,
55.3. 19F NMR (CDCl3, 376.5 MHz): δ −70.4 (s, 3F). For admixture
of Z-isomer: 19F NMR (CDCl3, 376.5 MHz): δ −75.6 (s, 3F). HRMS
+
z [M + H]+ Calcd for C17H14F3O2 : 307.0940; found: 307.0933.
+
(ESI-TOF): m/z [M + H]+ Calcd for C18H16F3O3 : 337.1046; found:
(E)-4-(4-Chlorophenyl)-1,1,1-trifluoro-3-(4-metoxyphenyl)-
but-3-en-2-one (4b). Obtained from enamine 2a (7.574 g, 27.920
mmol) and 4-chlorobenzaldehyde (4.514 g, 32.110 mmol). Purified
by column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Brown crystals, yield 6.85 g (72%),
mp 75−76°C. IR (v, cm−1): 1589, 1607 (CC); 1693 (CO).
337.1053.
(E)-1,1,1-Trifluoro-3-(4-methoxyphenyl)-4-(4-nitrophenyl)-
but-3-en-2-one (E-4f). Obtained from enamine 2a (0.549 g, 2.000
mmol) and 4-nitrobenzaldehyde (0.317 g, 1.05 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Yield 0.540 g (77%). Mixture of E-
and Z-isomers 90:10. The isomers were separated by column
chromatography. For pure E-isomer: Yellow solid, yield 0.486 g
1
Mixture of E- and Z-isomers 98:2. For E-isomer: H NMR (CDCl3,
400.1 MHz): δ 7.72 (s, 1H), 7.19 (d, 2H, 3J = 8.6 Hz), 7.08 (d, 2H, 3J
3
= 8.7 Hz), 7.03 (d, 2H, 3J = 8.6 Hz), 6.94 (d, 2H, J = 8.7 Hz), 3.85
(s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 181.5 (q, 2JCF = 33.5
(69.3%), mp 45−47°C. H NMR (CDCl3, 400.1 MHz): δ 8.03 (d,
1
2392
https://dx.doi.org/10.1021/acs.joc.0c02516
J. Org. Chem. 2021, 86, 2385−2405

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
2H, 3J = 8.8 Hz), 7.74 (s, 1H), 7.25 (d, 2H, 3J = 8.8 Hz), 7.06 (d, 2H,
viscous oil, yield 0.691 g (91%). Mixture of E- and Z-isomers 99:1.
1
3
3J = 8.8 Hz), 6.92 (d, 2H, J = 8.8 Hz), 3.82 (s, 3H). 13C{1H} NMR
For E-isomer: H NMR (CDCl3, 400.1 MHz): δ 7.65 (s, 1H), 7.22
3
3
3
(CDCl3, 100.6 MHz): δ 181.7 (q, 2JCF = 34.1 Hz), 160.3, 148.0, 141.8
(pseudo-d, 2H, J = 7.7 Hz), 7.14 (dd, 1H, J = 8.8 Hz, J = 7.0 Hz),
3
3
4
6.99 (d, 2H, J = 8.5 Hz), 6.73 (d, 2H, J = 8.5 Hz), 3.74 (s, 3H).
(q, JCF = 2.8 Hz), 140.1, 137.7, 131.7, 131.0, 124.2, 123.5, 114.7,
13C{1H} NMR (CDCl3, 100.6 MHz): δ 181.4 (q, JCF = 34.5 Hz),
2
1
116.6 (q, JCF = 292.1 Hz), 55.2. 19F NMR (CDCl3, 376.5 MHz): δ
4
−71.2 (s, 3F). HRMS (ESI-TOF): m/z [M + NH4]+ Calcd for
159.8, 139.6 (q, JCF = 3.3 Hz), 139.4, 133.6, 132.8, 130.6, 130.0,
127.9, 124.7, 116.5 (q, JCF = 292.3 Hz), 113.3, 54.9. 19F NMR
1
+
C17H16F3N2O4 : 369.1057; found: 369.1051; [M + CH3OH + Na]+
+
(CDCl3, 376.5 MHz): δ −71.5 (s, 3F). For admixture of Z-isomer:
Calcd for C18H16F3NNaO5 : 406.0873; found: 406.0858.
−73.8 (s, 3F). HRMS (ESI-TOF): m/z [M + Na]+ Calcd for
(Z)-1,1,1-Trifluoro-3-(4-methoxyphenyl)-4-(4-nitrophenyl)-
but-3-en-2-one (Z-4f). Obtained as an admixture to E-isomer 4f.
Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). For pure Z-isomer:
+
C17H11Cl2F3NaO2 : 396.9980, 398.9952; found: 396.9996, 398.9969.
(3E)-1,1,1-Trifluoro-3-(4-methoxyphenyl)-4-(3,4,5-trimeth-
oxyphenyl)but-3-en-2-one (4j). Obtained from enamine 2a (0.542
g, 2 mmol) and 3,4,5-trimethoxybenzaldehyde (0.442 g, 2.255 mmol).
Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Yellow powder,
yield 0.650 g (82%), mp108−110 °C. Mixture of E- and Z-isomers
1
Red solid, yield 0.054 g (7.7%), mp 108−110°C. H NMR (CDCl3,
3
3
400.1 MHz): δ 8.20 (d, 2H, J = 8.6 Hz), 7.42 (d, 2H, J = 8.6 Hz),
7.30 (d, 2H, 3J = 8.6 Hz), 7.16 (s, 1H), 6.96 (d, 2H, 3J = 8.6 Hz), 3.84
(s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 188.4 (q, 2JCF = 36.9
Hz), 161.0, 147.6, 141.8 (q, 4JCF = 1.8 Hz), 141.0, 139.4, 131.2, 129.3,
128.3, 126.4, 124.1, 115.3 (q, 1JCF = 293.2 Hz), 114.8, 55.4. 19F NMR
(CDCl3, 376.5 MHz): δ −75.9 (s, 3F). HRMS (ESI-TOF): m/z [M +
1
96:4. For E-isomer: H NMR (CDCl3, 400.1 MHz): δ 7.71 (s, 1H),
7.12 (d, 2H, 3J = 8.8 Hz), 6.96 (d, 2H, 3J = 8.8 Hz), 6.35 (s, 2H), 3.80
(s, 3H), 3.77 (s, 3H), 3.54 (s, 6H). 13C{1H} NMR (CDCl3, 100.6
MHz): δ 181.1 (q, 2JCF = 33.1 Hz), 159.7, 152.5, 146.0 (q, 4JCF = 2.5
+
Na]+ Calcd for C17H12F3NNaO4 : 374.0611; found: 374.0600;
1
Hz), 140.2, 133.2, 131.1, 128.7, 125.9, 116.9 (q, JCF = 292.4 Hz),
(E)-Methyl 4-(4,4,4-trifluoro-2-(4-methoxyphenyl)3-oxobut-
1-en-1-yl)benzoate (4g). Obtained from enamine 2a (0.542 g, 2
mmol) and methyl 4-formylbenzoate (0.376 g, 2.29 mmol). Purified
by column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Orange yellow viscous oil, yield 0.575
g (79%). Mixture of E- and Z-isomers 89:11. For E-isomer: 1H NMR
(CDCl3, 400.1 MHz): δ 7.84 (d, 2H,3J = 8.4 Hz), 7.77 (s, 1H), 7.15
114.5, 119.0, 60.7, 55.5, 55.1. 19F NMR (CDCl3, 376.5 MHz): δ
−70.6 (s, 3F). For admixture of Z-isomer: −75.5 (s, 3F). HRMS
+
(ESI-TOF): m/z [M + H]+ Calcd for C20H20F3O5 : 397.1257; found:
397.1258.
(3E,3′E)-4,4′-(1,4-Phenylen)bis(1,1,1-trifluoro-3-(4-meth-
oxyphenyl)but-3-en-2-one) (4k). Obtained from enamine 2a
(0.542 g, 2 mmol) and terephthalaldehyde (0.139 g, 1.037 mmol).
Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Orange crystals,,
yield 0.417 g (78%), mp 139−141°C. Mixture of E,E- and E,Z-
isomers 97:3. For E,E-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.65
3
(d, 2H, 3J = 8.4 Hz), 7.06 (d, 2H, 3J = 8.8 Hz), 6.90 (d, 2H, J = 8.8
Hz), 3.83 (s, 3H), 3.78 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz):
2
4
δ 181.5 (q, JCF = 33.7 Hz), 166.0, 159.9, 143.8 (q, JCF = 2.7 Hz),
1
137.9, 136.1, 131.0, 130.9, 129.3, 124.8, 116.6 (q, JCF = 292.3 Hz),
114.4, 54.9, 52.0. 19F NMR (CDCl3, 376.5 MHz): δ −70.8 (s, 3F).
For Z-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.99 (d, 2H, 3J = 8.2
Hz), 7.30 (d, 2H,3J = 8.2 Hz), 7.26 (d, 2H, 3J = 8.9 Hz), 7.14 (s, 1H),
6.90 (d, 2H, 3J = 8.9 Hz), 3.87 (s, 3H), 3.78 (s, 3H). 13C{1H} NMR
4
3
(pseudo-d, 2H, J = 0.8 Hz), 7.04 (d, 4H, J = 8.8 Hz), 6.94 (s, 4H),
6.91 (d, 4H,3J = 8.8 Hz), 3.84 (s, 6H). 13C{1H} NMR (CDCl3, 100.6
MHz): δ 181.6 (q, JCF = 33.7 Hz), 160.0, 144.1 (q, JCF = 2.8 Hz),
2
4
1
2
135.7, 135.6, 131.2, 131.0, 125.1, 116.8 (q, JCF = 292.2 Hz) 114.5,
(CDCl3, 100.6 MHz): δ 188.8 (q, JCF = 36.2 Hz), 166.2, 160.5,
55.2. 19F NMR (CDCl3, 376.5 MHz): δ −70.9 (d, 6F, J = 0.8 Hz).
4
139.0, 137.5, 132.8, 130.1, 129.9, 128.3, 128.1, 126.8, 115.3 (q, 1JCF
=
For admixture of E,Z-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.76
(s, 1H), 7.24−7.27 (m, 2H), 7.08−7.13 (m, 6H), 3.85 (s, 3H), 3.82
(s, 3H). Other signals are overlapped with those of the major isomer.
293.4 Hz), 114.5, 55.1, 52.02. Other signals are overlapped with those
of the major isomer. 19F NMR (CDCl3, 376.5 MHz): δ −75.9 (s, 3F).
+
HRMS (ESI-TOF): m/z [M + H]+ Calcd for C19H16F3O4 : 365.0995;
13C{1H} NMR (CDCl3, 100.6 MHz): δ 189.1 (q, JCF = 36.0 Hz),
2
found: 365.0993. HRMS (ESI-TOF): m/z [M + NH4]+ Calcd for
4
C19H13F3O4N+: 382.1261; found: 382.1259.
160.6, 159.9, 144.5 (q, JCF = 2.7 Hz), 137.1, 136.7, 135.1, 134.3,
133.0, 131.8, 129.0, 128.5, 128.2, 127.1, 125.3, 116.8 (q, 1JCF = 292.4
(3E)-4-(2-Bromophenyl)-1,1,1-trifluoro-3-(4-methoxy-
phenyl)but-3-en-2-one (4h). Obtained from enamine 2a (0.542 g,
2 mmol) and 2-bromobenzaldehyde (0.389 g, 2.103 mmol). Purified
by column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Light brown oil, yield 0.567 g (74%).
Hz), 115.4 (q, 1JCF = 293.4 Hz), 114.6, 55.3. 19F NMR (CDCl3, 376.5
4
MHz): δ −70.8 (d, 3F, J = 0.8 Hz), −75.9 (s, 3F). HRMS (ESI-
TOF): m/z [M + NH4]+ Calcd for C28H24F6O4N+: 552.1604; found:
552.1588.
1
Mixture of E- and Z-isomers 96:4. For E-isomer: H NMR (CDCl3,
(3E)-1,1,1-Trifluoro-3-(4-methoxyphenyl)4-(naphthalen-1-
yl)but-3-en-2-one (4l). Obtained from enamine 2a (0.542 g, 2
mmol) and 1-naphthaldehyde (0.338 g, 2.167 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Yellow oil, yield 0.569 g (80%).
400.1 MHz): δ 8.01 (s, 1H), 7.60 (dd, 1H, 3J = 8.0 Hz, 3J = 1.1 Hz),
3.79 (s, 3H), 7.11 (td, 1H, 3J = 7.7 Hz, 3J = 1.6 Hz), 7.05 (d, 2H, 3J =
8.8 Hz), 7.00 (td, 1H, 3J = 7.8 Hz, 3J = 0.8 Hz), 6.85 (d, 2H, 3J = 8.8
Hz), 6.82 (dd, 1H, 3J = 7.9 Hz, 3J = 1.5 Hz). 13C{1H} NMR (CDCl3,
1
2
4
Mixture of E- and Z-isomers 96:4. For E-isomer: H NMR (CDCl3,
100.6 MHz): δ 181.8 (q, JCF = 33.8 Hz), 159.8, 144.2 (q, JCF = 3.0
400.1 MHz): δ 8.60 (s, 1H), 8.14 (d, 1H, 3J = 8.4 Hz), 7.90 (d, 1H, 3J
Hz), 135.9, 134.5, 132.9, 131.39, 131.37, 130.9, 126.9, 125.7, 124.5,
3
1
116.7 (q, JCF = 292.3 Hz), 114.1, 55.1. 19F NMR (CDCl3, 376.5
= 7.9 Hz), 7.81 (d, 1H, J = 8.2 Hz), 7.63−7.69 (m, 1H), 7.56−7.63
3
MHz): δ −71.1 (s, 3F). For Z-isomer: 1H NMR (CDCl3, 400.1
MHz): δ 7.62 (dd, 1H, 3J = 7.8 Hz, 3J = 1.3 Hz), 7.35 (d, 2H, 3J = 8.9
Hz), 7.31 (s, 1H), 7.26−7.30 (m, 1H), 7.18−7.23 (m, 2H), 6.96 (d,
2H, 3J = 8.9 Hz), 3.84 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz):
(m, 1H), 7.24 (t, 1H, J = 7.7 Hz), 7.08−7.17 (m, 3H), 6.80−6.88
(m, 2H), 3.78 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 181.7
2
4
(q, JCF = 33.4 Hz), 159.5, 143.4 (q, JCF = 1.9 Hz), 136.3, 133.3,
131.8, 131.4, 130.9, 130.2, 128.8, 128.7, 127.1, 126.3, 125.2, 124.9,
1
123.3, 117.0 (q, JCF = 292.5 Hz), 113.9, 54.9. 19F NMR (CDCl3,
2
δ 188.5 (q, JCF = 35.8 Hz), 160.5, 137.5, 135.2, 133.8, 130.3, 130.1,
4
1
1
376.5 MHz): δ −70.5 (d, 3F, J = 0.9 Hz). For Z-isomer: H NMR
128.4, 127.6, 127.0, 124.1, 115.2 (q, JCF = 293.1 Hz), 114.5, 55.3.
Other signals are overlapped with those of the major isomer. 19F
NMR (CDCl3, 376.5 MHz): δ −76.2 (s, 3F). HRMS (ESI-TOF): m/
z [M + NH4]+ Calcd for C17H16BrF3O2N+: 402.0311; found:
402.0313.
(CDCl3, 400.1 MHz): δ 8.03−8.11 (m, 1H), 7.42−7.48 (m, 3H),
3
7.35−7.42 (m, 1H), 7.03 (d, 2H, J = 8.2 Hz), 3.87 (s, 3H). Other
signals are overlapped with those of the major isomer. 13C{1H} NMR
2
(CDCl3, 100.6 MHz): δ 189.4 (q, JCF = 36.1 Hz), 160.4, 138.1,
133.0, 132.6, 131.5, 129.8, 128.6, 128.4, 127.9, 127.3, 126.7, 126.4,
125.2, 124.4, 115.3 (q, 1JCF = 293.3 Hz), 114.4, 55.2. Other signals are
overlapped with those of the major isomer. 19F NMR (CDCl3, 376.5
MHz): δ −75.7 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
(3E)-4-(2,6-Dichlorophenyl)-1,1,1-trifluoro-3-(4-methoxyl-
phenyl)-but-3-en-2-one (4i). Obtained from enamine 2a (0.549 g,
2.025 mmol) and 2,6-dichlorobenzaldehyde (0.399 g, 2.28 mmol).
Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Yellow orange
+
C21H16F3O2 : 357.1097; found: 357.1097.
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(3E)-1,1,1-Trifluoro-3-(4-methoxyphenyl)4-(thiophen-2-yl)-
but-3-en-2-one (4m). Obtained from enamine 2a (0.542 g, 2
mmol) and thiophene-2-carbaldehyde (0.249 g, 2.223 mmol).
Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Yellow crystals,
yield 0.481 g (77%), mp 71−73°C. Mixture of E- and Z-isomers 99:1.
(3:1 followed by 1:1). Yellow viscous oil, yield 1.162 g (79%).
Mixture of E- and Z-isomers 97:3. For pure E-isomer: 1H NMR
(CDCl3, 400.1 MHz): δ 7.80 (s, 1H), 7.40−7.47 (m, 3H), 7.15−7.22
(m, 2H), 7.02−7.09 (m, 2H), 6.85−6.92 (m, 2H). 13C{1H} NMR
(CDCl3, 100.6 MHz): δ 181.2 (q, 2JCF = 33.6), 163.8 (d, 1JCF = 254.2
Hz), 144.7 (q, 4JCF = 2.8 Hz), 134.4 (d, 4JCF = 1.7 Hz), 133.7 (d, 3JCF
1
1
For E-isomer: H NMR (CDCl3, 400.1 MHz): δ 8.16 (s, 1H), 7.39
= 8.7 Hz), 133.5, 129.8, 129.7, 129.2, 128.8, 116.8 (q, JCF = 292.2
(dd, 2H, 3J = 13.4 Hz, 3J = 4.2 Hz), 7.16 (d, 2H, 3J = 8.6 Hz), 7.06 (d,
2
Hz), 115.8 (d, JCF = 21.9 Hz). 19F NMR (CDCl3, 376.5 MHz): δ
3
3
2H, J = 8.6 Hz), 7.01 (t, 1H, J = 4.4 Hz), 3.87 (s, 3H). 13C{1H}
−70.8 (s, 3F), −108.63, −108.70 (m, 1F). For admixture of Z-isomer:
−75.9 (s, 3F), −111.99, −112.09 (m, 1F). HRMS (ESI-TOF): m/z
[M + H]+ Calcd for C16H11F4O+: 295.0741; found: 295.0743.
(3E)-1,1,1-Trifluoro-3-phenyl-4-(4-methylphenyl)-but-3-en-
2-one (4r). Obtained from enamine 2b (0.723 g, 3 mmol) and 4-
methylbenzaldehyde (0.396 g, 3.3 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Yellow viscous oil, yield 0.709 g (81%).
Mixture of E- and Z-isomers 98:2. For pure E-isomer: 1H NMR
(CDCl3, 400.1 MHz): δ 7.83 (s, 1H), 7.40−7.45 (m, 3H), 7.16−7.22
(m, 2H, Ph), 7.01 (d, 2H, 3J = 8.3 Hz), 6.95 (d, 2H, 3J = 8.3 Hz), 2.29
(s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 181.2 (q, 2JCF = 36.1
Hz), 146.4 (q, 4JCF = 2.0 Hz), 141.7, 134.0, 133.8, 131.7, 130.8, 129.8,
NMR (CDCl3, 100.6 MHz): δ 180.1 (q, 2JCF = 33.3 Hz), 160.4, 139.4
4
(q, JCF = 2.5 Hz), 138.1, 136.6, 134.1, 131.4, 130.7, 127.0, 124.7,
116.9 (q, JCF = 292.2 Hz), 114.9, 55.0. 19F NMR (CDCl3, 376.5
1
MHz): δ −71.1 (d, 3F, 4J = 0.4 Hz). For Z-isomer: 1H NMR (CDCl3,
400.1 MHz): δ 7.42−7.43 (m, 1H), 7.24−7.26 (m, 2H), 7.23 (d, 1H,
3J = 3.6 Hz), 7.19 (s, 1H), 6.93 (d, 2H, J = 8.8 Hz), 3.83 (s, 3H).
3
Other signals are overlapped with those of the major isomer. 19F
NMR (CDCl3, 376.5 MHz): δ −74.8 (3F, CF3). HRMS (ESI-TOF):
m/z [M + H]+ Calcd for C15H12F3O2S+: 313.0505; found: 313.0499.
(3E)-1,1,1-Trifluoro-3-(4-methoxyphenyl)4-(pyridin-4-yl)-
but-3-en-2-one (4n). Obtained from enamine 2a (0.542 g, 2 mmol)
and isonicotinaldehyde (0.237 g, 2.115 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1 and 0:1). Orange viscous oil, yield 0.467 g
1
129.3, 129.1, 128.6, 127.0 (q, JCF = 292.5 Hz), 21.4. 19F NMR
(CDCl3, 376.5 MHz): δ −70.6 (s, 3F). For admixture of Z-isomer: 1H
NMR (CDCl3, 400.1 MHz): δ7.07 (d, 2H, 3J = 8.6 Hz), 2.37 (s, 3H).
19F NMR (CDCl3, 376.5 MHz): δ −75.8 (s, 3F). Other signals are
1
(76%). Mixture of E- and Z-isomers 96:4. For E-isomer: H NMR
(CDCl3, 400.1 MHz): δ 8.36−8.46 (m, 2H), 7.60 (s, 1H), 6.98−7.05
(m, 2H), 6.84−6.93 (m, 4H), 3.75 (s, 3H). 13C{1H} NMR (CDCl3,
overlapped with those of the major isomer. HRMS (ESI-TOF): m/z
[M + H]+ Calcd for C17H14F3O+: 291.0991; found: 291.0988.
(3E)-3-(4-Chlorophenyl)-1,1,1-trifluoro-4-phenylbut-3-en-2-
one (4s). Obtained from enamine 2c (7.733 g, 28.050 mmol) and
benzaldehyde (3.423 g, 32.260 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Yellow crystals, yield 7.146 g (82%), mp 72−
73°C. IR (υ, cm−1): 1573, 1596, 1619 (CC); 1704 (CO).
4
100.6 MHz): δ 181.4 (q, 2JCF = 34.5 Hz), 160.1, 149.7, 141.6(q, JCF
1
= 2.7 Hz), 141.0, 138.1, 130.7, 124.2, 124.0, 116.4 (q, JCF = 292.2
Hz), 114.4, 54.9. 19F NMR (CDCl3, 376.5 MHz): δ −71.4 (s, 3F).
For Z-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 8.50−8.55 (m, 2H),
7.06−7.10 (m, 3H), 6.73−6.78 (m, 4H), 3.70 (s, 3H). 13C NMR
(CDCl3, 100.6 MHz): δ 148.9, 141.9, 139.3, 131.0, 123.7, 114.5, 54.8.
Other signals are overlapped with those of the major isomer. 19F
NMR (CDCl3, 376.5 MHz): δ −76.0 (s, 3F). HRMS (ESI-TOF): m/
1
Mixture of E- and Z-isomers 99:1. For E-isomer: H NMR (CDCl3,
+
z [M + H]+ Calcd for C16H13F3NO2 : 308.0893; found: 308.0893.
400.1 MHz): δ 7.88 (s, 1H), 7.41 (d, 2H, 3J = 8.6 Hz), 7.30−7.35 (m,
(E)-1,1,1-Trifluoro-3,4-diphenylbut-3-en-2-one (4o). Ob-
tained from enamine 2b (2.42 g, 10.041 mmol) and benzaldehyde
(1.11 g, 10.472 mmol). Purified by column chromatography using
gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1).
Yellow oil, yield 2.073 g (75%). IR (υ, cm−1): 1579, 1602, 1619 (C
C); 1708 (CO). Mixture of E- and Z-isomers 97:3. For E-isomer:
1H NMR (CDCl3, 400.1 MHz): δ 7.88 (s, 1H), 7.42−7.48 (m, 3H),
7.29−7.33 (m, 1H), 7.19−7.26 (m, 4H), 7.08−7.12 (m, 2H).
3
1H), 7.23−7.27 (m, 2H), 7.14 (d, 2H, J = 8.6 Hz), 7.10−7.13 (m,
2
2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 181.0 (q, JCF = 33.9),
4
146.7 (q, JCF = 3.0 Hz), 134.8, 133.5, 133.2, 132.1, 131.5, 131.3,
1
131.0, 129.4, 128.6, 116.8 (q, JCF = 291.9 Hz). 19F NMR (CDCl3,
376.5 MHz): δ −70.3 (s, 3F). For admixture of Z-isomer: 19F NMR
(CDCl3, 376.5 MHz): δ −75.5 (s, 3F). HRMS (ESI-TOF): m/z [M +
Na]+ Calcd for C16H10ClF3ONa+: 333.0264; found: 333.0257.
(3E)-3-(4-Chlorophenyl)-1,1,1-Trifluoro-4-(4-nitrophenyl)-
but-3-en-2-one (4t). Obtained from enamine 2c (1.378 g, 5.000
mmol) and 4-nitrobenzaldehyde (0.869 g, 5.750 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Brown crystals, yield 1.298 g (73%),
2
13C{1H} NMR (CDCl3, 100.6 MHz): δ 181.3 (q, JCF = 33.8 Hz),
4
146.1 (q, JCF = 2.8 Hz), 134.7, 133.7, 133.5, 131.5, 130.8, 129.7,
1
129.0, 128.7, 128.5, 116.9 (q, JCF = 292.3 Hz). 19F NMR (CDCl3,
1
376.5 MHz): δ −70.7 (s, 3F). For admixture of Z-isomer: H NMR
(CDCl3, 400.1 MHz): δ 7.35−7.40 (m, 3H). 19F NMR (CDCl3, 376.5
MHz): δ −75.9 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
C16H12F3O+: 277.0835; found: 277.0831.
1
mp 70−71°C. Mixture of E- and Z-isomers 99:1. For E-isomer: H
NMR (CDCl3, 400.1 MHz): δ 8.11 (d, 2H, 3J = 8.7 Hz), 7.88 (s, 1H),
7.44 (d, 2H, 3J = 8.3 Hz), 7.29 (d, 2H, 3J = 8.7 Hz), 7.14 (d, 2H, 3J =
8.3 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.9 (q, 2JCF = 34.7
Hz), 148.2, 142.8 (q, 4JCF = 2.9 Hz), 139.4, 136.8, 135.7, 131.7, 131.1,
(3E)-4-(4-Chlorophenyl)-1,1,1-trifluoro-3-phenylbut-3-en-2-
one (4p). Obtained from enamine 2b (2.892 g, 12 mmol) and 4-
chlorobenzaldehyde (1.81 g, 12.87 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Yellow solid, yield 3.153 g (85%), mp 54−
1
130.8, 129.6, 123.7, 116.5 (q, JCF = 291.9 Hz). 19F NMR (CDCl3,
376.5 MHz): δ −70.0 (s, 3F). For admixture of Z-isomer: 19F NMR
(CDCl3, 376.5 MHz): δ −74.8 (s, 3F). HRMS (ESI-TOF): m/z [M
+MeOH + Na]+ Calcd for (C16H9ClF3NO3) CH3OH Na+: 410.0377;
found: 410.0371.
1
56°C. Mixture of E- and Z-isomers 94:6. For E-isomer: H NMR
(CDCl3, 400.1 MHz): δ 7.77 (s, 1H), 7.41−7.44 (m, 3H), 7.15−7.18
3
(m, 4H), 6.98 (d, 2H, J = 8.7 Hz). 13C{1H} NMR (CDCl3, 100.6
MHz): δ 181.2 (q, 2JCF = 33.7), 144.5 (q, 4JCF = 2.5 Hz), 136.8, 135.2,
133.3, 132.6, 132.0, 129.6, 129.2, 128.9, 128.8, 116.8 (q, 1JCF = 292.1
Hz). 19F NMR (CDCl3, 376.5 MHz): δ −70.8 (s, 3F). For admixture
(E)-3-(4-Chlorophenyl)-1,1,1-trifluoro-4-(p-tolyl)but-3-en-2-
one (4u). Obtained from enamine 2c (1.290 g, 4.680 mmol) and 4-
methylbenzaldehyde (0.646 g, 5.380 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Yellow crystals, yield 0.972 g (64%), mp 68−
1
of Z-isomer: H NMR (CDCl3, 400.1 MHz): δ 7.32−7.37 (m, 3H),
7.23 (d, 2H, 3J = 8.5 Hz). Other signals are overlapped with those of
the major isomer. 19F NMR (CDCl3, 376.5 MHz): δ −75.8 (s, 3F).
HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H11ClF3O+:
311.0445; found: 311.0442.
1
70°C. IR (υ, cm−1): 1569, 1610 (CC); 1695 (CO). H NMR
(CDCl3, 400.1 MHz): δ 7.85 (s, 1H), 7.41 (d, 2H, 3J = 8.4 Hz), 7.13
3
(d, 2H, 3J = 8.4 Hz), 7.05 (d, 2H, J = 8.1 Hz), 6.99 (d, 2H, 3J = 8.1
Hz), 2.32 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.9 (q,
(3E)-1,1,1-Trifluoro-3-phenyl-4-(4-fluorophenyl)-but-3-en-
2-one (4q). Obtained from enamine 2b (1.205 g, 5.0 mmol) and 4-
fluorobenzaldehyde (0.690 g, 5.565 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
4
2JCF = 33.9 Hz), 146.9 (q, JCF = 1.9 Hz), 142.0, 134.7, 132.6, 132.5,
131.6, 131.3, 130.5, 129.5, 129.4, 116.9 (q, 1JCF = 292.3 Hz), 21.5. 19
F
NMR (CDCl3, 376.5 MHz): δ −69.5 (s, 3F). Anal. Calcd for
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Article
C17H12ClF3O*(1/3)CH2Cl2: C, 58.97; H, 3.62. Found: C, 58.93; H,
3.62.
mmol) and 4-fluorobenzaldehyde (0.706 g, 5.674 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Yellow crystals, yield 1.120 g (67%),
mp 128−130°C. Mixture of E- and Z-isomers 98:2. For E-isomer: 1H
NMR (CDCl3, 400.1 MHz): δ 8.29 (d, 2H, 3J = 8.8 Hz), 7.91 (s, 1H),
7.39 (d, 2H, 3J = 8.8 Hz), 7.06 (dd, 2H, 3J = 8.7 Hz, 3J = 5.4 Hz), 6.94
(t, 2H, 3J = 8.7 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.2 (q,
2JCF = 34.4 Hz), 164.1 (d, 1JCF = 255.8 Hz), 148.0, 146.3 (q, 4JCF = 2.9
Hz), 140.5, 133.7 (d, 3JCF = 8.9 Hz), 132.2 (d, 4JCF = 1.9 Hz), 131.2,
128.9 (d, 4JCF = 3.4 Hz), 124.3, 116.6 (q, 1JCF = 291.8 Hz), 116.2 (d,
2JCF = 21.9 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −70.6 (d, 3F, 4J =
1.1 Hz), −106.94, −107.01 (m, 1F). For admixture of Z-isomer: 19F
NMR (CDCl3, 376.5 MHz): δ −75.9 (s, 3F). HRMS (ESI-TOF): m/
(3E)-1,1,1-Trifluoro-4-phenyl-3-(4-(trifluoromethyl)phenyl)-
but-3-en-2-one (4v). Obtained from enamine 2f (0.772 g, 2.498
mmol) and 4-trifluoromethylbenzaldehyde (0.290 g, 2.736 mmol).
Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Yellow crystals,
yield 0.568 g (66%), mp 64−65°C. IR (υ, cm−1): 1577, 1618 (C
1
C); 1703 (CO). H NMR (CDCl3, 400.1 MHz): δ 7.93 (s, 1H),
3
7.69 (d, 2H, J = 7.8 Hz), 7.31−7.37 (m, 3H), 7.22−7.26 (m, 2H),
3
7.06 (d, 2H, J = 7.8 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
2
4
180.8 (q, JCF = 33.9 Hz), 147.2 (q, JCF = 2.8 Hz), 137.6, 133.4,
2
133.0, 131.5, 131.2, 130.9 (q, JCF = 32.7 Hz), 130.5, 128.7, 126.0,
1
1
123.9 (q, JCF = 272.2 Hz), 116.8 (q, JCF = 292.0 Hz). 19F NMR
(CDCl3, 376.5 MHz): δ −63.5 (s, 3F), −70.2 (s, 3F). HRMS (ESI-
TOF): m/z [M − H]− Calcd for C17H9F6O−: 343.0563; found:
343.0565.
+
z [M + H]+ Calcd for C16H10F4NO3 : 340.0591; found: 340.0599.
(3E)-1,1,1-Trifluoro-3-(4-nitrophenyl)-4-(p-tolyl)but-3-en-2-
one (4aa). Obtained from enamine 2d (1.415 g, 4.942 mmol) and 4-
methylbenzaldehyde (0.689 g, 5.684 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Yellow crystals, yield 0.978 g (59%), mp 120−
(3E)-1,1,1-Trifluoro-3-(4-nitrophenyl)-4-phenylbut-3-en-2-
one (4w). Obtained from enamine 2d (1.433 g, 5.007 mmol) and
benzaldehyde (0.617 g, 5.815 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). White crystals, yield 0.947 g (59%), mp 109−
1
123°C. Mixture of E- and Z-isomers 99:1. For E-isomer: H NMR
(CDCl3, 400.1 MHz): δ 8.28 (d, 2H, 3J = 8.8 Hz), 7.93 (s, 1H), 7.38
3
(d, 2H, 3J = 8.8 Hz), 7.05 (d, 2H, J = 8.2 Hz), 6.93 (d, 2H, 3J = 8.2
1
Hz), 2.31 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.2 (q,
2JCF = 33.9 Hz), 148.0 (q, 4JCF = 2.8 Hz), 147.8, 142.6, 141.1, 131.59,
110°C. Mixture of E- and Z-isomers 99:1. For pure E-isomer: H
NMR (CDCl3, 400.1 MHz): δ 8.28 (d, 2H, 3J = 8.8 Hz), 7.96 (s, 1H),
7.38 (d, 2H, 3J = 8.8 Hz), 7.34 (pseudo-d, 1H, 3J = 7.5 Hz), 7.22−7.27
(pseudo-t, 2H), 7.05 (pseudo-d, 2H, 3J = 7.5 Hz). 13C{1H} NMR
1
131.56, 131.2, 129.9, 129.6, 124.1, 116.7 (q, JCF = 291.9 Hz), 21.5.
4
19F NMR (CDCl3, 376.5 MHz): δ −70.4 (d, 3F, J = 1.3 Hz). For
2
(CDCl3, 100.6 MHz): δ 180.4 (q, JCF = 34.5 Hz), 147.9, 147.8 (q,
admixture of Z-isomer: −75.8 (s, 3F). HRMS (ESI-TOF): m/z [M +
Na]+ Calcd for C17H12F3NO3Na+: 358.0661; found: 358.0668.
(3E)-1,1,1-Trifluoro-3-(3-nitrophenyl)-4-phenylbut-3-en-2-
one (4ab). Obtained from enamine 2e (1.431 g, 5.000 mmol) and
benzaldehyde (0.610 g, 5.75 mmol). Purified by column chromatog-
raphy using gradient elution by hexane/CH2Cl2 mixtures (3:1
followed by 1:1). Yellow oil, yield 0.883 g (55%). IR (υ, cm−1):
4JCF = 2.9 Hz), 140.8, 132.61, 132.58, 131.5, 131.4, 131.2, 128.9,
124.2, 116.7 (q, 1JCF = 291.7 Hz). 19F NMR (CDCl3, 376.5 MHz): δ
1
−70.6 (s, 3F). For admixture of Z-isomer: H NMR (CDCl3, 400.1
MHz): δ 7.54 (d, 2H, 3J = 7.7 Hz), 7.43 (s, 1H). 13C NMR (CDCl3,
100.6 MHz): δ 129.1, 127.6, 124.3. 19F NMR (CDCl3, 376.5 MHz): δ
−76.0 (s, 3F). Other signals are overlapped with those of the major
+
1
isomer. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H11F3NO3 :
1352, 1527 (NO2); 1571, 1608 (CC); 1699 (CO). H NMR
322.0686; found: 322.0695.
(CDCl3, 400.1 MHz): δ 8.29 (ddd, 1H, 3J = 8.2 Hz, 4J = 2.3 Hz, 4J =
1.1 Hz), 8.08 (pseudo-t, 1H, 4J ∼ 1.9 Hz), 7.97 (s, 1H), 7.61 (t, 1H, 3J
= 7.9 Hz), 7.49−7.55 (m, 1H), 7.31−7.37 (m, 1H), 7.21−7.25 (m,
2H), 7.01−7.07 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
(3E)-1,1,1-Trifluoro-4-(4-methoxyphenyl)-3-(4-nitrophenyl)-
but-3-en-2-one (4x). Obtained from enamine 2d (1.180 g, 4.128
mmol) and 4-methoxybenzaldehyde (0.628 g, 4.618 mmol). Purified
by column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Pale yellow crystals, yield 0.844 g
(57%), mp 137−138°C. Mixture of E- and Z-isomers 98:2. For E-
isomer: 1H NMR (CDCl3, 400.1 MHz): δ 8.30 (d, 2H, 3J = 8.8 Hz),
7.90 (s, 1H), 7.40 (d, 2H, 3J = 8.8 Hz), 7.00 (d, 2H, 3J = 8.8 Hz), 6.75
2
4
180.5 (q, JCF = 33.6 Hz), 148.6, 147.9 (q, JCF = 2.6 Hz), 136.3,
135.5, 132.6, 132.3, 131.43, 131.38, 130.1, 128.8, 125.2, 123.7, 116.7
(q, 1J = 291.9 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −70.5 (s, 3F).
+
HRMS (ESI-TOF): m/z [M + NH4]+ Calcd for C16H14F3N2O3+:
339.0951; found: 339.0949; [M + Na]+ Calcd for C16H10F3NNaO3 :
344.0505; found: 344.0503.
3
(d, 2H, J = 9.0 Hz), 3.79 (s, 3H). 13C{1H} NMR (CDCl3, 100.6
MHz): δ 180.0 (q, 2JCF = 33.8 Hz), 162.4, 147.8, 147.6 (q, 4JCF = 2.8
(3E)-4-(4-Chlorophenyl)-1,1,1-trifluoro-3-(3-nitrophenyl)-
but-3-en-2-one (4ac). Obtained from enamine 2e (1.431 g, 5.000
mmol) and 4-chlorobenzaldehyde (0.808 g, 5.750 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Yellow crystals, yield 0.965 g (54%),
mp 117−118°C. IR (υ, cm−1): 1352, 1535 (NO2); 1587, 1602 (C
C); 1693 (CO). Mixture of E- and Z-isomers 99:1. For E-isomer:
1H NMR (CDCl3, 400.1 MHz): δ 8.30 (ddd, 1H, 3J = 8.3 Hz, 4J = 2.3
1
Hz), 141.5, 133.9, 131.3, 130.0, 125.2, 124.2, 116.8 (q, JCF = 292.0
Hz), 114.4, 55.4. 19F NMR (CDCl3, 376.5 MHz): δ −70.3 (d, 3F, 4J =
1.1 Hz). For admixture of Z-isomer: 1H NMR (CDCl3, 400.1 MHz):
3
3
δ 8.26 (d, 2H, J = 9.0 Hz), 7.51 (d, 2H, J = 9.0 Hz), 7.36 (s, 1H),
7.29 (d, 2H, 3J = 8.6 Hz), 6.92 (d, 2H, 3J = 8.8 Hz), 3.85 (s, 3H). 19
F
NMR (CDCl3, 376.5 MHz): δ −75.8 (s, 3F). HRMS (ESI-TOF): m/
+
z [M + H]+ Calcd for C17H13F3NO4 : 352.0791; found: 352.0796.
Hz, 4J = 1.1 Hz), 8.07 (pseudo-t, 1H, 4J ∼ 1.9 Hz), 7.90 (s, 1H), 7.63
(3E)-4-(4-Chlorophenyl)-1,1,1-trifluoro-3-(4-nitrophenyl)-
but-3-en-2-one (4y). Obtained from enamine 2d (1.439 g, 5.029
mmol) and 4-chlorobenzaldehyde (0.850 g, 5.798 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Beige crystals, yield 1.107 g (62%),
mp 135−137°C. Mixture of E- and Z-isomers 96:4. For E-isomer: 1H
NMR (CDCl3, 400.1 MHz): δ 8.28 (d, 2H, 3J = 8.8 Hz), 7.89 (s, 1H),
7.37 (d, 2H, 3J = 8.8 Hz), 7.22 (d, 2H, 3J = 8.6 Hz), 6.98 (d, 2H, 3J =
8.6 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.2 (q, 2JCF = 34.4
Hz), 148.0, 146.1 (q, 4JCF = 2.8 Hz), 140.3, 137.7, 133.0, 132.5, 131.2,
3
3
(t, 1H, J = 8.0 Hz), 7.48−7.52 (m, 1H), 7.21 (d, 2H, J = 8.6 Hz),
6.98 (d, 2H, J = 8.6 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
3
2
4
180.3 (q, JCF = 34.3 Hz), 148.6, 146.3 (q, JCF = 2.4 Hz), 137.7,
136.2, 135.1, 132.6, 132.5, 131.0, 130.2, 129.2, 125.1, 123.8, 116.7 (q,
1JCF = 291.6 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −70.6 (s, 3F).
For admixture of Z-isomer: −75.8 (s, 3F). HRMS (ESI-TOF): m/z
−
[M − H]− Calcd for C16H8ClF3NO3 : 354.0150; found: 354.0145.
(3E)-1,1,1-Trifluoro-4-(4-fluorophenyl)-3-(3-nitrophenyl)-
but-3-en-2-one (4ad). Obtained from enamine 2e (1.432 g, 5
mmol) and 4-fluorobenzaldehyde (0.690 g, 5.565 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Yellow viscous oil, yield 1.002 g
1
131.1, 129.2, 124.3, 116.6 (q, JCF = 291.7 Hz). 19F NMR (CDCl3,
1
376.5 MHz): δ −70.7 (s, 3F). For admixture of Z-isomer: H NMR
3
(CDCl3, 400.1 MHz): δ 7.53 (d, 2H, J = 8.8 Hz). Other signals are
1
overlapped with those of the major isomer. 19F NMR (CDCl3, 376.5
(59%). Mixture of E- and Z-isomers 95:5. For E-isomer: H NMR
(CDCl3, 400.1 MHz): δ 8.28 (ddd, 1H, 3J = 8.2 Hz, 4J = 2.3 Hz, 4J =
1.1 Hz), 8.07 (d, 1H, 4J = 1.8 Hz), 7.93 (s, 1H), 7.63 (t, 1H, 3J = 7.9
MHz): δ −75.9 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
+
C16H10ClF3NO3 : 356.0296; found: 356.0310.
3
Hz), 7.50−7.56 (m, 1H), 7.04−7.11 (m, 2H), 6.91 (t, 2H, J = 8.6
(3E)-1,1,1-Trifluoro-4-(4-fluorophenyl)-3-(4-nitrophenyl)-
but-3-en-2-one (4z). Obtained from enamine 2d (1.412 g, 4.934
2
Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.3 (q, JCF = 34.3
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1
4
Hz), 164.1 (d, JCF = 255.5 Hz), 148.6, 146.5 (q, JCF = 2.9 Hz),
136.3, 135.2, 133.7 (d, 3JCF = 8.9 Hz), 131.9 (d, 4JCF1 = 1.8 Hz), 130.2,
(3E)-3-(2-Bromphenyl)-1,1,1-trifluoro-4-phenylbut-3-en-2-
one (4ah). Obtained from enamine 2g (1.600 g, 5 mmol) and
benzaldehyde (0.610 g, 5.750 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Yellow oil, yield 1.271 g (72%). IR (υ, cm−1):
1571, 1597, 1614 (CC); 1701 (CO). Mixture of E- and Z-
4
128.9 (d, JCF = 3.5 Hz), 125.1, 123.7, 116.7 (q, JCF = 291.7 Hz),
116.2 (d, JCF = 22.0 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −70.4
2
(d, 3F, 4J = 0.8 Hz), −107.04, −107.16 (m, 1F). For admixture of Z-
1
isomer: H NMR (CDCl3, 400.1 MHz): δ 8.21−8.25 (m, 1H), 7.39
1
3
3
isomers 98:2. For E-isomer: H NMR (CDCl3, 400.1 MHz): δ 7.99
(s, 1H), 7.33 (dd, 2H, J = 8.5 Hz, J = 5.2 Hz). Other signals are
overlapped with those of the major isomer. 19F NMR (CDCl3, 376.5
MHz): δ −75.7 (s, 3F), −110.32, −110.43 (m, 1F). HRMS (ESI-
(s, 1H), 7.74 (dd, 1H, 3J = 7.8 Hz, 4J = 1.3 Hz), 7.30−7.41 (m, 3H),
3
4
7.24−7.29 (m, 2H), 7.19 (dd, 1H, J = 7.3 Hz, J = 1.9 Hz), 7.10−
7.15 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.3 (q, 2JCF
= 33.9 Hz), 146.7 (q, JCF = 2.8 Hz), 135.3, 133.9, 133.09, 133.05,
131.4, 131.13, 131.11, 130.4, 128.7, 128.1, 124.2, 116.7 (q, JCF
+
TOF): m/z [M + H]+ Calcd for C16H10F4NO3 : 340.0591; found:
4
340.0588.
1
=
Methyl-4-[(1E)-3,3,3-Trifluoro-2-oxo-1-(phenylmethylyden)-
propyl]benzoate (4ae). Obtained from enamine 2i (1.496 g, 5.000
mmol) and benzaldehyde (0.610 g, 5.750 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). White crystals, yield 1.053 g (63%), mp 107−
102°C. IR (υ, cm−1): 1574, 1597, 1612 (CC); 1691 (CO); 1724
(COOMe). Mixture of E- and Z-isomers 99:1. For E-isomer: 1H
NMR (CDCl3, 400.1 MHz): δ 8.09 (d, 2H, 3J = 8.5 Hz), 7.89 (s, 1H),
292.2 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −71.2(s, 3F). For
admixture of Z-isomer: 19F NMR (CDCl3, 376.5 MHz): δ −74.5 (s,
3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H1179BrF3O+:
354.9940; found: 354.9930; Calcd for C16H1181BrF3O+: 356.9920;
found: 356.9909; m/z [M + NH4]+ Calcd for C16H1479BrF3NO+:
372.0205; found: 372.0192; Calcd for C16H1481BrF3NO+: 374.0185;
found: 374.0171; m/z [M + Na]+ Calcd for C16H1079BrF3NaO+:
376.9759; found: 376.9747; Calcd for C16H1081BrF3NaO+: 378.9739;
found: 378.9724.
3
7.27−7.33 (m, 3H), 7.20 (pseudo-t, 2H, J = 7.7 Hz), 7.03−7.06 (m,
2H), 3.94 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.8 (q,
2JCF = 34.0 Hz), 166.6, 146.8 (q, JCF = 2.2 Hz), 138.6, 133.8, 133.1,
4
(3E)-3-(2-Bromphenyl)-1,1,1-trifluoro-4-(4-nitrophenyl)but-
3-en-2-one (4ai). Obtained from enamine 2g (1.600 g, 5.000 mmol)
and 4-nitrobenzaldehyde (0.869 g, 5.750 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl21 mixtures
(3:1 followed by 1:1). Yellow oil, yield 1.240 g (62%). H NMR
1
131.5, 131.1, 130.4, 130.2, 130.1, 128.6, 116.7 (q, JCF = 292.0 Hz),
52.3. 19F NMR (CDCl3, 376.5 MHz): δ −70.7 (s, 3F). For admixture
of Z-isomer: 19F NMR (CDCl3, 376.5 MHz): δ −76.0 (s, 3F). HRMS
+
(ESI-TOF): m/z [M + H]+ Calcd for C18H14F3O3 : 335.0890; found:
3
335.0890; [M + NH4]+ Calcd for C18H17F3NO3+: 352.1155; found:
+
(CDCl3, 400.1 MHz): δ 8.08 (d, 2H, J = 8.8 Hz), 7.92 (s, 1H),
3
352.1152; [M + Na]+ Calcd for C18H13F3NaO3 : 357.0709; found:
7.67−7.75 (m, 1H), 7.31−7.41 (m, 2H), 7.25 (d, 2H, J = 8.8 Hz),
7.07−7.14 (m, 1H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.2 (q,
+
357.0710; [M+K]+ Calcd for C18H13F3KO3 : 373.0448; found:
4
2JCF = 35.0 Hz), 148.2, 143.1 (q, JCF = 2.9 Hz), 139.3, 137.2, 134.1,
373.0448.
1
133.3, 131.33, 131.25, 131.0, 128.3, 123.9, 123.7, 116.4 (q, JCF
=
Methyl-4-[(1E)-1-(4-chlorophenyl)-4,4,4-trifluoro-3-oxobut-
1-en-1-yl]benzoate (4af). Obtained from enamine 2i (1.496 g,
5.000 mmol) and 4-chlorobenzaldehyde (0.808 g, 5.750 mmol).
Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Yellow crystals,
yield 1.269 g (69%), mp 81−82°C. IR (υ, cm−1): 1587, 1606, 1616
(CC); 1687 (CO); 1730 (CO2Me). Mixture of E- and Z-isomers
291.9 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −70.5 (s, 3F). HRMS
(ESI-TOF): m/z [M + Na]+ Calcd for C16H9BrF3NO3Na+: 421.9610,
423.9590; found: 421.9608, 423.9590.
(3E)-1,1,1-Trifluoro-4-phenyl-3-(4-(pyrrolidin-1-yl)phenyl)-
but-3-en-2-one (4aj). Obtained from enamine 2h (1.322 g, 4
mmol) and benzaldehyde (0.490 g, 4.623 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Red powder, yield 1.334 g (87%), mp 102−
1
96:4. For pure E-isomer: H NMR (CDCl3, 400.1 MHz): δ 8.10 (d,
2H, 3J = 8.1 Hz), 7.82 (s, 1H), 7.26 (d, 2H, 3J = 8.1 Hz), 7.17 (d, 2H,
3
1
3J = 8.6 Hz), 6.97 (d, 2H, J = 8.6 Hz), 3.94 (s, 3H). 13C{1H} NMR
104°C. Mixture of E- and Z-isomers 97:3. For E-isomer: H NMR
2
(CDCl3, 400.1 MHz): δ 7.73 (s, 1H), 7.21−7.33 (m, 5H), 7.04 (d,
(CDCl3, 100.6 MHz): δ 180.6 (q, JCF = 34.0 Hz), 166.4, 145.1 (q,
3
3
4JCF = 2.0 Hz), 138.2, 137.2, 132.5, 130.3, 129.9, 129.2, 129.0, 126.7,
2H, J = 8.7 Hz), 6.60 (d, 2H, J = 8.7 Hz), 3.32−3.37 (m, 4H),
2.01−2.09 (m, 4H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 182.4 (q,
116.7 (q, JCF = 292.2 Hz), 52.2. 19F NMR (CDCl3, 376.5 MHz): δ
1
2JCF = 32.8 Hz), 147.8, 144.5 (q, JCF = 2.8 Hz), 135.3, 134.3, 131.4,
4
1
−70.8 (s, 3F). For admixture of Z-isomer: H NMR (CDCl3, 400.1
1
MHz): δ 7.42 (d, 2H, J = 8.4 Hz), 7.36 (d, 2H, J = 8.4 Hz). 19F
3
3
130.7, 130.1, 128.4, 119.6, 117.0 (q, JCF = 292.8 Hz), 111.8, 47.5,
25.4. 19F NMR (CDCl3, 376.5 MHz): δ −70.8 (d, 3F, J = 0.9 Hz).
5
NMR (CDCl3, 376.5 MHz): δ −75.9 (s, 3F). HRMS (ESI-TOF): m/
−
z [M − H]− Calcd for C18H11ClF3O3 : 367.0354; found: 367.0344;
For admixture of Z-isomer: −75.9 (s, 3F). HRMS (ESI-TOF): m/z
[M + H]+ Calcd for C20H19F3NO+: 346.1413; found: 346.1404.
Synthesis of Pyrazolinols (7) and Pyrazolines (8) (General
Procedure). A 12 mL vial with a screw cap was charged with
corresponding hydrazine (1.2 mmol, 1.2 equiv, for hydrazine hydrate,
ethylhydrazine, and phenylhydrazine) and EtOH (4 mL) to form a
clear solution (for other hydrazines, the solution was prepared by
mixing of 4 mL of EtOH, 1.2 mmol of arylhydrazine hydrochloride,
and 1.19 mmol of NaOH). To the solution obtained was added
corresponding ketone 4 (1 mmol), and the reaction mixture was
heated at 80 °C (hot plate stirrer) under stirring for 2−4 (for
synthesis of 7) or 8−16 h (for synthesis of 8). In both cases, the
reaction completion was monitored by TLC or 19F NMR. Volatiles
were evaporated in vacuo, and the residue was purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1) or CH2Cl2 followed by CH2Cl2:MeOH (30:1;
for compound 8p) as eluents.
4,5-Diphenyl-3-(trifluoromethyl)pyrazolidin-3-ole (7a). Ob-
tained from ketone 4o (0.193 g, 0.699 mmol) and hydrazine hydrate
(0.072 g, 1.44 mmol). Purified by column chromatography using
gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1).
Colorless oil, yield 0.190 g (88%). 1H NMR (CDCl3, 400.1 MHz): δ
7.41−7.26 (m, 10H), 4.70 (d, 1H, 3J = 11.0 Hz), 4.40 (br.s, 3H), 3.79
(d, 1H, 3J = 11.0 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 136.2,
[M + CH3OH-H]− Calcd for C19H15ClF3O4 : 399.0616; found:
−
399.0600.
(3E)-1,1,1-Trifluoro-4-phenyl-3-(4-(pyrrolidine-1carbonyl)-
phenyl)but-3-en-2-one (4ag). Obtained from enamine 2j (4.896 g,
5 mmol) and benzaldehyde (0.585 g, 5.519 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Yellow viscous oil, yield 1.221 g
(63%). Mixture of E- and Z-isomers 95:5. For E-isomer: H NMR
(CDCl3, 400.1 MHz): δ 7.85 (s, 1H), 7.57 (d, 2H, J = 7.9 Hz),
1
3
3
7.25−7.31 (m, 1H), 7.16−7.24 (m, 4H), 7.07 (d, 2H, J = 7.9 Hz),
3
3
3.64 (t, 2H, J = 6.9 Hz), 3.43 (t, 2H, J = 6.5 Hz), 1.82−1.98 (m,
4H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.9 (q, JCF = 33.5
2
Hz), 168.9, 146.6 (q, 4JCF = 2.7 Hz), 137.2, 135.2, 133.7, 133.0, 131.4,
130.9, 129.7, 128.5, 127.8, 116.7 (q, 1JCF = 292.4 Hz), 49.5, 46.2, 26.3,
24.3. 19F NMR (CDCl3, 376.5 MHz): δ −70.6 (d, 3F, J = 1.0 Hz).
4
For Z-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.53 (d, 2H, 3J = 8.2
3
Hz), 7.46 (d, 2H, J = 8.2 Hz), 7.33−7.4 (m, 3H). Other signals are
overlapped with those of the major isomer. 13C{1H} NMR (CDCl3,
100.6 MHz): δ 168.6, 138.4, 134.5, 134.2, 129.4, 128.8, 128.6, 127.6,
127.3, 126.6, 49.4, 46.1, 26.2. Other signals are overlapped with those
of the major isomer. 19F NMR (CDCl3, 376.5 MHz): δ −75.9 (s, 3F).
+
HRMS (ESI-TOF): m/z [M + H]+ Calcd for C21H19F3NO2 :
374.1362; found: 374.1372
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133.4, 130.0, 128.7, 128.5, 128.2, 127.9, 127.0, 124.8 (q, 1JCF = 285.9
1-(4-Fluorophenyl)-4,5-diphenyl-3-(trifluoromethyl)-4,5-di-
hydro-1H-pyrazole (8d). Obtained from ketone 4o (0.087 g, 0.315
mmol) and (4-fluorophenyl)hydrazine hydrochloride (0.062 g, 0.380
mmol). Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale yellow solid,
yield 0.064 g (53%), mp 96−98°C. 1H NMR (CDCl3, 400.1 MHz): δ
7.42−7.31 (m, 6H), 7.21−7.14 (m, 4H), 7.03−6.98 (m, 2H), 6.94−
2
Hz, CF3), 92.8 (q, JCF = 29.3 Hz, C-CF3), 69.1, 59.3. 19F NMR
(CDCl3, 376.5 MHz): δ −82.5. HRMS (ESI-TOF): m/z [M + H]+
Calcd for C16H16F3N2O+: 309.1209; found: 309.1210.
1,4,5-Triphenyl-3-(trifluoromethyl)pyrazolidin-3-ol (7b).
Obtained from ketone 4o (0.069 g, 0.25 mmol) and phenylhydrazine
(0.031 g, 0.287 mmol). This compound was not isolated. Only the
most characteristic signals are reported from 1H and 19F NMR spectra
3
3
6.87 (m, 2H), 5.19 (d, 1H, J = 6.9 Hz), 4.28 (dq, 1H, J = 6.9 Hz,
4JCF = 1.3 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 157.9 (d, 1JCF
1
of the reaction mixture. H NMR (CDCl3, 400.1 MHz): δ 4.95 (d,
4
2
3
3
1H, J = 10.3 Hz), 3.54 (d, 1H, J = 10.3 Hz). 19F NMR (CDCl3,
= 240.1 Hz), 139.7, 139.3 (d, JCF = 2.2 Hz), 138.4, 138.3 (q, JCF
=
36.1 Hz, C-CF3), 129.6, 129.3, 128.5, 128.3, 127.5, 125.4, 121.0 (q,
1JCF = 270.5 Hz, CF3), 115.7 (d, 2JCF = 22.7 Hz,), 115.4 (d, 3JCF = 7.6
Hz), 75.9, 61.2. 19F NMR (CDCl3, 376.5 MHz): δ −63.8 (s, 3F,
CF3), −124.21, −124.28 (m, 1F, 4−F-C6H4). HRMS (ESI-TOF): m/
376.5 MHz): δ −80.3.
5-(4-Chlorophenyl)-4-(4-metoxyphenyl)-1-phenyl-3-
(trifluoromethyl)pyrazolidine-3-ole (7c). Obtained from ketone
4b (1.131 g, 3.320 mmol) and phenylhydrazine (0.430 g, 3.980
mmol). Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Yellow oil, yield
+
z [M + H]+ Calcd for C22H17F4N2 : 385.1322; found: 385.1314.
1-(4-Cyanophenyl)-4,5-diphenyl-3-(trifluoromethyl)-4,5-di-
hydro-1H-pyrazole (8e). Obtained from ketone 4o (0.118 g, 0.428
mmol) and (4-cyanophenyl)hydrazine hydrochloride (0.087 g, 0.514
mmol). Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). White powder, yield
0.079 g (47%), mp 60−62°C. 1H NMR (CDCl3, 400.1 MHz): δ 7.46
0.700 g (47%). IR (υ, cm−1): 3380 (OH), 3050 (NH). H NMR
1
3
(CDCl3, 400.1 MHz): δ 7.37 (d, 2H, J = 8.5 Hz), 7.34−7.27 (m,
4H), 7.21 (d, 2H, 3J = 8.5 Hz), 7.07 (d, 2H, J = 8.1 Hz), 7.00−6.92
3
3
(m, 3H), 5.45 (br.s, 1H), 5.03 (d, 1H, J = 10.3 Hz), 3.85 (s, 3H),
2.97 (br.s, 1H), 3.63 (d, 1H, J = 10.3 Hz). 13C{1H} NMR (CDCl3,
3
3
(d, 2H, J = 8.9 Hz), 7.42−7.35 (m, 6H), 7.16−7.11 (m, 4H), 7.07
100.6 MHz): δ 159.3, 152.1, 139.5, 133.3, 131.1, 128.9, 128.8, 127.0,
(d, 2H, 3J = 8.9 Hz), 5.24 (d, 1H, 3J = 5.7 Hz), 4.27 (dq, 1H, 3J = 5.7
1
124.5, 123.0 (q, JCF = 289.0 Hz, CF3), 119.9, 114.0, 113.8, 89.7 (q,
4
Hz, JHF = 1.1 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 145.6,
2JCF = 29.5 Hz, C-CF3), 72.8, 62.2, 55.0. Anal. Calcd for
2
141.5 (q, JCF = 36.9 Hz, C-CF3), 138.6, 137.7, 133.4, 129.8, 129.5,
C23H20ClF3N2O2: C, 61.54; H, 4.49. Found: C, 61.60; H, 4.46.
5-(4-Chlorophenyl)-4-(3-nitrophenyl)-1-phenyl-3-
(trifluoromethyl)pyrazolidine-3-ole (7d). Obtained from ketone
4ac (0.356 g, 1.000 mmol) and phenylhydrazine (0.130 g, 1.200
mmol). Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Yellow oil, yield
1
128.8, 128.6, 127.2, 125.1, 120.5 (q, JCF = 271.3 Hz, CF3), 119.4,
114.1, 103.4, 74.6, 61.2. 19F NMR (CDCl3, 376.5 MHz): δ −64.3.
+
HRMS (ESI-TOF): m/z [M + H]+ Calcd for C23H17F3N3 : 392.1369;
found: 392.1361.
4-(4-Chlorophenyl)-1,5-diphenyl-3-(trifluoromethyl)-4,5-di-
hydro-1H-pyrazole (8f). Obtained from ketone 4s (0.307 g, 0.990
mmol) and phenylhydrazine (0.130 g, 1.200 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Yellow crystals, yield 0.255 g (64%),
mp 100−101°C. IR (υ, cm−1): 1583, 1600 (CN). 1H NMR
(CDCl3, 400.1 MHz): δ 7.42−7.30 (m, 5H), 7.23−7.15 (m, 4H),
7.10 (d, 2H, 3J = 8.4 Hz), 7.07−7.02 (m, 2H), 6.91 (pseudo-t, 1H, 3J =
0.240 g (52%). IR (υ, cm−1): 1360, 1542 (NO2); 3079 (NH). H
1
NMR (CDCl3, 400.1 MHz): δ 8.34 (pseudo-t, 1H,4J = 1.9 Hz), 8.22
(ddd, 1H, 3J = 8.2 Hz, 4J = 2.2 Hz, 4J = 1.0 Hz), 7.66 (pseudo-d, 1H, 3J
= 7.8 Hz), 7.51 (pseudo-t, 1H, 3J = 8.0 Hz), 7.30−7.22 (m, 4H), 7.13
(d, 2H, 3J = 8.6 Hz), 7.00−6.88 (m, 3H), 5.48 (br.s, 1H), 4.98 (d, 1H,
3J = 10.3 Hz), 3.69 (d, 1H, J = 10.3 Hz), 2.89 (br.s, 1H). 13C{1H}
3
3
3
7.3 Hz), 5.18 (d, 1H, J = 6.7 Hz), 4.23 (dq, 1H, J = 6.7 Hz, 4JHF
=
NMR (CDCl3, 100.6 MHz): δ 151.8, 148.2, 138.6, 136.4, 135.0,
1
1.3 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 142.7, 139.6, 137.7
134.0, 129.3, 128.9, 127.0, 124.9, 123.3, 122.7 (q, JCF = 286.0 Hz,
CF3), 120.5, 114.0, 89.9 (q, JCF = 30.2 Hz, C-CF3), 73.3, 62.3. 19F
2
2
(q, JCF = 36.5 Hz, C-CF3), 137.1, 134.3, 129.6, 129.5, 129.1, 128.8,
128.5, 125.3, 121.4, 121.0 (q, 1JCF = 270.5 Hz, CF3), 114.3, 75.4, 60.3.
19F NMR (CDCl3, 376.5 MHz): δ −63.9. HRMS (ESI-TOF): m/z
NMR (CDCl3, 376.5 MHz): δ −80.0. Anal. Calcd for
C22H17ClF3N3O3: C, 56.97; H, 3.69. Found: C, 57.04; H, 3.66.
1,4,5-Triphenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyra-
zole (8b). Obtained from ketone 4o (0.085 g, 0.308 mmol) and
phenylhydrazine (0.109 g, 0.370 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Pale brown solid, yield 0.070 g (62%), mp
+
[M + H]+ Calcd for C22H17ClF3N2 : 401.1027; found: 401.1023.
4-(4-Chlorophenyl)-1-(4-metoxyphenyl)-5-phenyl-3-(tri-
fluoromethyl)-4,5-dihydro-1H-pyrazole (8g). Obtained from
ketone 4s (0.205 g, 0.660 mmol) and (4-metoxyphenyl)hydrazine
(0.138 g, 0.790 mmol). Purified by column chromatography using
gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1).
Yellow crystals, yield 0.150 g (53%), mp 125−126°C. IR (υ, cm−1):
1
102−104°C. H NMR (CDCl3, 400.1 MHz): δ 7.42−7.31 (m, 6H),
7.25−7.16 (m, 6H), 7.09−7.07 (m, 2H), 6.94−6.88 (m, 1H), 5.25 (d,
1H, 3J = 6.5 Hz), 4.27 (dq, 1H, 3J = 6.5 Hz, 4JHF = 1.4 Hz). 13C{1H}
1
1582, 1603 (CN). H NMR (CDCl3, 400.1 MHz): δ 7.42−7.31
2
(m, 5H), 7.23−7.16 (m, 2H), 7.12 (d, 2H, 3J = 8.5 Hz), 7.02 (d, 2H,
3J = 9.1 Hz), 6.79 (d, 2H, 3J = 9.1 Hz), 5.14 (d, 1H, 3J = 7.5 Hz), 4.27
NMR (CDCl3, 100.6 MHz): δ 142.8, 140.0, 138.6, 138.2 (q, JCF
=
36.3 Hz, C-CF3), 129.5, 129.3, 129.1, 128.3, 128.2, 127.4, 125.3,
121.12, 121.06 (q, 1JCF = 270.5 Hz, CF3), 114.2, 75.3, 61.0. 19F NMR
(CDCl3, 376.5 MHz): δ −63.8. HRMS (ESI-TOF): m/z [M + H]+
3
4
(dq, 1H, J = 7.5 Hz, JHF = 1.4 Hz), 3.73 (s, 3H). 13C{1H} NMR
2
(CDCl3, 100.6 MHz): δ 154.7, 139.7, 137.1, 136.9, 136.8 (q, JCF
=
+
Calcd for C22H18F3N2 : 367.1417; found: 367.1417.
36.2 Hz, C-CF3), 134.2, 129.5, 129.4, 129.0, 128.4, 125.5, 121.1 (q,
1JCF = 270.4 Hz, CF3), 115.8, 114.5, 76.4, 60.4, 55.4. 19F NMR
1-(4-Metoxyphenyl)-4,5-diphenyl-3-(trifluoromethyl)-4,5-
dihydro-1H-pyrazole (8c). Obtained from ketone 4o (0.089 g,
0.321 mmol) and (4-metoxyphenyl)hydrazine hydrochloride (0.067
g, 0.385 mmol). Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale
(CDCl3, 376.5 MHz): δ −63.3. HRMS (ESI-TOF): m/z [M + H]+
Calcd for C23H19ClF3N2O+: 431.1133; found: 431.1120.
4-(4-Chlorophenyl)-1-(4-methylphenyl)-5-phenyl-3-(tri-
fluoromethyl)-4,5-dihydro-1H-pyrazole (8h). Obtained from
ketone 4s (0.320 g, 1.030 mmol) and (4-methylphenyl)hydrazine
hydrochloride (0.197 g, 1.240 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Yellow crystals, yield 0.213 g (50%), mp 127−
1
yellow oil, yield 0.058 g (46%). H NMR (CDCl3, 400.1 MHz): δ
3
7.40−7.30 (m, 6H), 7.20−7.15 (m, 4H), 7.00 (d, 2H, J = 9.1 Hz),
6.77 (d, 2H, 3J = 9.1 Hz), 5.16 (d, 1H, 3J = 7.3 Hz), 4.25 (dq, 1H, 3J =
4
7.3 Hz, JHF = 1.4 Hz), 3.73 (s, 3H). 13C{1H} NMR (CDCl3, 100.6
MHz): δ 154.5, 140.1, 138.7, 137.3 (q, 2JCF = 36.1 Hz, C-CF3), 137.0,
1
128°C. IR (υ, cm−1): 1578, 1599 (CN). H NMR (CDCl3, 400.1
1
129.4, 129.2, 128.3, 128.1, 127.6, 125.5, 121.2 (q, JCF = 270.4 Hz,
MHz): δ 7.43−7.36 (m, 5H), 7.24−7.19 (m, 2H), 7.17−7.12 (m,
CF3), 115.6, 114.4, 76.2, 61.0, 55.5. 19F NMR (CDCl3, 376.5 MHz):
δ −63.6. HRMS (ESI-TOF): m/z [M] Calcd for C23H19F3N2O:
396.1444; found: 396.1448; [M + H]+ Calcd for C23H20F3N2O+:
397.1522; found: 397.1525.
3
2H), 7.08−7.04 (m, 2H), 7.04−6.99 (m, 2H), 5.21 (d, 1H, J = 6.9
Hz), 4.28 (dq, 1H, 3J = 6.9 Hz, 4JHF = 1.3 Hz), 2.29 (s, 3H). 13C{1H}
2
NMR (CDCl3, 100.6 MHz): δ 140.5, 139.8, 137.2, 137.1 (q, JCF
=
36.5 Hz, C-CF3), 134.2, 130.8, 129.7, 129.6, 129.53, 129.48, 128.9,
2397
https://dx.doi.org/10.1021/acs.joc.0c02516
J. Org. Chem. 2021, 86, 2385−2405

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
3
128.4, 125.4, 121.1 (q, 1JCF = 270.2 Hz, CF3), 114.3, 113.6, 75.7, 60.3,
20.5. 19F NMR (CDCl3, 376.5 MHz): δ −63.2. Anal. Calcd for
C23H18ClF3N2: C, 66.59; H, 4.37; N, 6.75. Found: C, 66.37; H, 4.26;
N, 6.60.
62−64°C. H NMR (CDCl3, 400.1 MHz): δ 8.25 (d, 2H, J = 8.7
3
Hz), 7.42−7.34 (m, 5H), 7.24−7.19 (m, 4H), 7.08 (pseudo-d, 2H, J
3
= 7.8 Hz), 6.95−6.92 (m, 1H), 5.26 (d, 1H, J = 6.6 Hz), 4.40 (dq,
1H, 3J = 6.6 Hz, 4JHF = 1.2 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz):
δ 147.8, 145.4, 142.3, 139.1, 136.6 (q, 2JCF = 36.9 Hz, C-CF3), 129.7,
4-(4-Chlorophenyl)-1-(4-fluorophenyl)-5-phenyl-3-(trifluor-
omethyl)-4,5-dihydro-1H-pyrazole (8i). Obtained from ketone 4s
(0.308 g, 0.990 mmol) and (4-fluorophenyl)hydrazine hydrochloride
(0.195 g, 1.200 mmol). Purified by column chromatography using
gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1).
Yellow crystals, yield 0.200 g (48%), mp 124−125°C. IR (υ, cm−1):
1
129.2, 128.8, 128.5, 125.3, 124.6, 121.7, 120.9 (q, JCF = 270.4 Hz,
CF3), 114.3, 75.3, 60.3. 19F NMR (CDCl3, 376.5 MHz): δ −63.7.
+
HRMS (ESI-TOF): [M + H]+ Calcd for C22H17F3N3O2 : 412.1267;
found: 412.1260.
5-(4-Methoxyphenyl)-4-(4-nitrophenyl)-1-phenyl-3-(tri-
fluoromethyl)-4,5-dihydro-1H-pyrazole (8o). Obtained from
ketone 4x (0.099 g, 0.282 mmol) and phenylhydrazine (0.037 g,
0.340 mmol). Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Yellow
brown powder, yield 0.072 g (58%), mp 153−155°C. 1H NMR
1
1590, 1610 (CN). H NMR (CDCl3, 400.1 MHz): δ 7.45−7.33
3
(m, 5H), 7.24−7.18 (m, 2H), 7.14 (d, 2H, J = 7.2 Hz), 7.08−7.01
(m, 2H), 6.97−6.87 (m, 2H), 5.18 (d, 1H, 3J = 7.2 Hz), 4.31 (dq, 1H,
4
3J = 7.2 Hz, JHF = 1.0 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
158.0 (d, 1JCF = 240.3 Hz, CF), 139.4, 139.2 (d, 4JCF = 1.8 Hz), 137.8
3
3
2
(CDCl3, 400.1 MHz): δ 8.25 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J =
8.8 Hz), 7.23−7.19 (m, 2H), 7.10−7.05 (m, 4H), 6.94−6.91 (m, 1H),
6.89 (d, 2H, 3J = 8.8 Hz), 5.18 (d, 1H, 3J = 6.7 Hz), 4.35 (dq, 1H, 3J =
(q, JCF = 36.5 Hz, C-CF3), 136.8, 134.3, 129.6, 129.5, 128.9, 128.6,
1
2
125.4, 121.0 (q, JCF = 270.3 Hz, CF3), 115.7 (d, JCF = 33.2 Hz),
115.6 (d, 3JCF = 2.6 Hz), 76.0, 60.5. 19F NMR (CDCl3, 376.5 MHz):
δ −63.4 (s, 3F, CF3), −123.32, −123.47 (m, 1F, 4-FC6H4). Anal.
Calcd for C22H15ClF4N2: C, 63.09; H, 3.61; N, 6.69. Found: C, 63.25;
H, 3.67; N, 6.54.
6.7 Hz, JHF = 1.3 Hz), 3.79 (s, 3H). 13C{1H} NMR (CDCl3, 100.6
4
MHz): δ 159.8, 147.8, 145.5, 142.3, 136.6 (q, 2JCF = 37.0 Hz, C-CF3),
1
131.1, 129.2, 128.5, 126.6, 124.6, 121.7, 120.9 (q, JCF = 270.5 Hz,
CF3), 115.0, 114.4, 75.0, 60.5, 55.3. 19F NMR (CDCl3, 376.5 MHz):
1,4-Bis(4-chlorophenyl)-5-phenyl-3-(trifluoromethyl)-4,5-
dihydro-1H-pyrazole (8j). Obtained from ketone 4s (0.311 g, 1.000
mmol) and (4-chlorophenyl)hydrazine hydrochloride (0.215 g, 1.200
mmol). Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Yellow crystals, yield
0.283 g (65%), mp 118−119°C. IR (υ, cm−1): 1576, 1598 (CN).
1H NMR (CDCl3, 400.1 MHz): δ 7.44−7.31 (m, 5H), 7.18−7.13 (m,
+
δ −60.6. HRMS (ESI-TOF): [M + H]+ Calcd for C23H19F3N3O3 :
442.1373; found: 442.1360.
4-(4-Phenyl-5-(p-tolyl)-3-(trifluoromethyl)-4,5-dihydro-1H-
pyrazol-1-yl)-benzensulfonamide (8p). Obtained from ketone 4r
(1.005 g, 3.470 mmol) and 4-hydrazinylbenzenesulfonamide hydro-
chloride (0.933 g, 4.016 mmol). Purified by column chromatography
using gradient elution by CH2Cl2:MeOH mixtures (1:0 followed by
30:1). Pale brown solid, yield 1.143 g (72%), mp 97−99°C. 1H NMR
4H), 7.10 (d, 2H, 3J = 8.5 Hz), 6.98 (d, 2H, 3J = 9.0 Hz), 5.16 (d, 1H,
3J = 6.7 Hz), 4.27 (d, 1H, 3J = 6.7 Hz). 13C{1H} NMR (CDCl3, 100.6
3
2
(CDCl3, 400.1 MHz): δ 7.72 (d, 2H, J = 8.9 Hz), 7.42−7.33 (m,
MHz): δ 141.3, 139.1, 138.4 (q, J = 36.5 Hz, C-CF3), 136.7, 134.4,
3H), 7.21−7.13 (m, 4H), 7.11 (d, 2H, 3J = 8.9 Hz), 7.05 (d, 2H, 3J =
8.0 Hz), 5.26 (d, 1H, 3J = 5.6 Hz), 5.08 (s, 2H), 4.30 (d, 1H, 3J = 5.6
Hz), 2.34 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 145.8,
129.7, 129.6, 129.1, 128.8, 128.7, 126.5, 125.3, 120.8 (q, 1JCF = 270.9
Hz, CF3), 115.5, 75.5, 60.5. 19F NMR (CDCl3, 376.5 MHz): δ −63.4.
Anal. Calcd for C22H15Cl2F3N2: C, 60.71; H, 3.47; N, 6.44. Found: C,
60.64; H, 3.50; N, 6.28.
2
141.2 (q, JCF = 36.7 Hz, C-CF3), 138.6, 137.9, 135.8, 133.1, 130.4,
1
129.4, 128.5, 128.0, 127.2, 125.0, 120.6 (q, JCF = 271.3 Hz, CF3),
5-(4-Chlorophenyl)-1,4-bis(4-methoxyphenyl)-3-(trifluoro-
methyl)-4,5-dihydro-1H-pyrazole (8l). Obtained from ketone 4b
(0.170 g, 0.5 mmol) and (4-metoxyphenyl)hydrazine hydrochloride
(0.105 g, 0.6 mmol). Purified by column chromatography using
gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1).
Yellow-orange oil, yield 0.130 g (56%). 1H NMR (CDCl3, 400.1
MHz): δ 7.33 (d, 2H, 3J = 8.4 Hz), 7.12 (d, 2H, 3J = 8.4 Hz), 7.07 (d,
2H, 3J = 8.7 Hz), 6.97 (d, 2H, 3J = 9.1 Hz), 6.90 (d, 2H, 3J = 8.7 Hz),
6.78 (d, 2H, 3J = 9.1 Hz), 5.08 (d, 1H, 3J = 7.8 Hz), 4.17 (dq, 1H, 3J =
113.7, 74.5, 61.1, 21.1. 19F NMR (CDCl3, 376.5 MHz): δ −64.2.
HRMS (ESI-TOF): m/z [M + H]+ Calcd for C23H21F3N3O2S+:
460.1301; found: 460.1286; [M + NH4]+ Calcd for C23H24F3N4O2S+:
477.1567; found: 477.1550; [M
+
Na]+ Calcd for
C23H20F3N3NaO2S+: 482.1121; found: 482.1110; [M+K]+ Calcd for
C23H20F3KN3O2S+: 498.0860; found: 498.0848.
4-(4-Chlorophenyl)-1-ethyl-5-phenyl-3-(trifluoromethyl)-
4,5-dihydro-1H-pyrazole (8q). Obtained from ketone 4s (0.323 g,
1.040 mmol) and ethylhydrazine (0.075 g, 1.250 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Yellow oil, yield 0.210 g (57%). IR (υ,
4
7.8 Hz, JHF = 1.4 Hz), 3.81 (s, 3H), 3.73 (s, 3H). 13C{1H} NMR
(CDCl3, 100.6 MHz): δ 159.5, 154.7, 138.6, 137.8 (q, 2JCF = 36.1 Hz,
1
C-CF3), 137.0, 134.1, 130.2, 129.6, 128.7, 127.0, 121.1 (q, JCF
=
cm−1): 1595 (CN). H NMR (CDCl3, 400.1 MHz): δ 7.37−7.18
1
270.4 Hz, CF3), 115.7, 114.6, 114.5, 75.9, 60.4, 55.5, 55.2. 19F NMR
(CDCl3, 376.5 MHz): δ −63.7. HRMS (ESI-TOF): m/z [M + H]+
(m, 7H), 7.13−7.06 (m, 2H), 4.52−4.40 (m, 1H), 4.26−4.16 (m,
1H), 3.30−3.20 (m, 1H), 3.14−3.04 (m, 1H), 1.31−1.22 (m, 3H).
+
Calcd for C24H21ClF3N2O2 : 461.1238; found: 461.1240.
13C{1H} NMR (CDCl3, 100.6 MHz): δ 138.2, 137.1 (q, JCF = 35.5
2
4-(4-Nitrophenyl)-1,5-diphenyl-3-(trifluoromethyl)-4,5-di-
hydro-1H-pyrazole (8m). Obtained from ketone 4f (0.110 g, 0.313
mmol) and phenylhydrazine (0.041 g, 0.380 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Yellow powder, yield 0.058 g (57%),
Hz, C-CF3), 136.0, 133.8, 129.8, 129.0, 128.9, 128.5, 127.1, 120.8 (q,
1JCF = 270.8 Hz, CF3), 80.2, 60.3, 46.9, 12.1. 19F NMR (CDCl3, 376.5
MHz): δ −63.9. Anal. Calcd for C18H16ClF3N2: C, 61.28; H, 4.57.
Found: C, 61.25; H, 4.53.
1
mp 66−68°C. H NMR (CDCl3, 400.1 MHz): δ 3.82 (s, 3H), 4.20
Synthesis of 3,4-Diphenyl-5-(trifluoromethyl)-4,5-dihydro-
1H-pyrazole (8a) by Dehydration of 7a. A 4 mL vial with a screw
cap was charged with pyrazolidinol 7a (0.190 g, 0.617 mmol), CHCl3
(1.5 mL), and MeSO3H (0.010 g, 0.104 mmol), and the reaction
mixture was heated at 60−70 °C with stirring for 2 h (hot plate
stirrer). Volatiles were evaporated in vacuo, and the residue was
purified by column chromatography using CH2Cl2 followed by
CH2Cl2:MeOH (30:1) as eluents. Evaporation of the solvents
afforded pyrazoline 8a (yellow oil, 0.116 g (65%)) and pyrazole 9a
(white powder, 0.020 g (11%). For characterization data of 9a, see
below in the part concerning synthesis of other compounds 9. Yellow
oil, yield 0.116 g (65%). 1H NMR (CDCl3, 400.1 MHz): δ 7.62−7.56
3
4
3
(dq, 1H, J = 7.1 Hz, JHF = 1.2 Hz), 5.29 (d, 1H, J = 7.1 Hz), 6.92
(d, 2H, 3J = 8.7 Hz), 6.96−6.92 (m, 1H), 7.00 (pseudo-d, 2H, 3J = 7.8
Hz), 7.09 (d, 2H, 3J = 8.7 Hz), 7.25−7.20 (m, 2H), 7.37 (d, 2H, 3J =
8.7 Hz), 8.23 (d, 2H, J = 8.7 Hz). 13C{1H} NMR (CDCl3, 100.6
3
MHz): δ 159.8, 147.9, 146.9, 142.5, 138.9 (q, 2JCF = 36.3 Hz, C-CF3),
1
129.5, 129.3, 128.7, 126.4, 124.9, 121.7, 120.9 (q, JCF = 270.9 Hz,
CF3), 114.8, 114.2, 74.8, 60.2, 55.3. 19F NMR (CDCl3, 376.5 MHz):
δ −63.9. HRMS (ESI-TOF): [M + H]+ Calcd for C23H19F3N3O3 :
+
442.1373; found: 442.1366.
4-(4-Nitrophenyl)-1,5-diphenyl-3-(trifluoromethyl)-4,5-di-
hydro-1H-pyrazole (8n). Obtained from ketone 4w (0.158 g, 0.492
mmol) and phenylhydrazine (0.064 g, 0.593 mmol). Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Yellow solid, yield 0.115 g (56%), mp
3
(m, 2H), 7.38−7.24 (m, 8H), 6.09 (br s, 1H), 4.73 (d, 1H, J = 5.0
Hz), 4.20−4.12 (m, 1H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
152.9, 138.6, 130.8, 129.4, 129.0, 128.4, 127.9, 127.5, 126.7, 125.0 (q,
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1JCF = 281.0 Hz, CF3), 69.1 (q, 2JCF = 29.3 Hz, C-CF3), 53.0 (q, 3JCF
=
CH2Cl2:MeOH (30:1; for compounds 9a, v, ac, ad, ae, and af) as
eluents.
3
1.7 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −78.8 (d, JHF = 7.8).
+
HRMS (ESI-TOF): m/z [M + H]+ Calcd for C16H14F3N2 : 291.1104;
4,5-Diphenyl-3-(trifluoromethyl)-1H-pyrazole (9a). Obtained
from ketone 4o (0.078 g, 0.283 mmol) and hydrazine dihydrochloride
(0.036 g, 0.345 mmol) by procedure B. Purified by column
chromatography using gradient elution by CH2Cl2:MeOH mixtures
(1:0 followed by 30:1). White powder, yield 0.024 g (29%), mp 183−
found: 291.1097.
Synthesis of Pyrazolines 8 by Dehydratation of Pyrazolidinols 7
(General Procedure). A one-necked 50 mL round-bottom flask was
charged with corresponding pyrazolidinol 7 (0.5 mmol), toluene (5
mL), and catalytic amounts of p-TsOH (0.010 g, 0.05 mmol, ∼0.1
equiv). The reaction mixture was heated under reflux (hot plate
stirrer) for 4−6 h (TLC control). Volatiles were evaporated in vacuo,
and the residue was purified by column chromatography using
gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1) as
eluents.
1
185 °C. H NMR (CDCl3, 400.1 MHz): δ 11.79 (br s, 1H, NH),
7.38−7.28 (m, 10H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 142.4
3
2
(q, JCF = 0.7 Hz), 141.2 (q, JCF = 34.6 Hz, C-CF3), 130.3, 130.2,
1
129.1, 128.9, 128.4, 128.0, 127.9, 127.5, 121.4 (q, JCF = 270.0 Hz,
CF3), 118.3. 19F NMR (CDCl3, 376.5 MHz): δ −60.9 (s, 3F). HRMS
+
(ESI-TOF): m/z [M + H]+ Calcd for C16H12F3N2 : 289.0947; found:
5-(4-Chlorophenyl)-4-(4-metoxyphenyl)-1-phenyl-3-(tri-
fluoromethyl)-4,5-dihydro-1H-pyrazole (8k). Obtained from
pyrazolidinol 7c (0.224 g, 0.500 mmol). Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Yellow oil, yield 0.200 g (93%). Alternatively
obtained from ketone 4b (0.170 g, 0.499 mmol) and phenylhydrazine
(0.066 g, 0.611 mmol), yield 0.103 g (48%). IR (υ, cm−1): 1583, 1602
(CN). 1H NMR (CDCl3, 400.1 MHz): δ 7.33 (d, 2H, 3J = 8.4 Hz),
289.0952.
1,4,5-Triphenyl-3-(trifluoromethyl)-1H-pyrazole (9b). Ob-
tained from pyrazoline 8b (0.311 g, 0.850 mmol) by procedure A
or from ketone 4o (0.100 g, 0.362 mmol) and phenylhydrazine
hydrochloride (0.063 g, 0.435 mmol) by procedure B. Purified by
column chromatography using gradient elution by hexane/CH2Cl2
mixtures (3:1 followed by 1:1). Pale beige powder, yield 0.266 (86%,
A), 0.128 g (97%, B), mp 174−176°C. 1H NMR (CDCl3, 400.1
3
3
7.24−7.17 (m, 2H), 7.11 (d, 2H, J = 8.4 Hz), 7.06 (d, 2H, J = 8.6
MHz): δ 7.36−7.26 (m, 8H), 7.25−7.14 (m, 5H), 7.04−6.96 (m,
3
2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 142.4, 140.8 (q, JCF
=
2
Hz), 7.02 (pseudo-d, 2H, J = 7.9 Hz), 6.94−6.85 (m, 3H), 5.14 (d,
3
3
4
1H, J = 6.9 Hz), 4.16 (dq, 1H, J = 6.9 Hz, JHF = 0.9 Hz), 3.81 (s,
3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 159.6, 142.8, 138.7 (q,
2JCF = 36.2 Hz, C-CF3), 138.5, 134.1, 130.2, 129.7, 129.2, 128.6,
36.1 Hz, C-CF3), 139.2, 130.4, 130.3, 129.0, 128.7, 128.5, 128.4,
128.2, 128.1, 127.5, 125.4, 121.6 (q, 1JCF = 270.2 Hz, CF3), 121.1. 19
F
NMR (CDCl3, 376.5 MHz): δ −60.7 (s, 3F). HRMS (ESI-TOF): m/
126.8, 121.4, 121.0 (q, 1JCF = 270.9 Hz, CF3), 114.7, 114.2, 74.9, 60.4,
55.3. 19F NMR (CDCl3, 376.5 MHz): δ −63.9. HRMS (ESI-TOF):
m/z [M + H]+ Calcd for C23H19ClF3N2O+: 431.1133; found:
431.1121.
+
z [M + H]+ Calcd for C22H16F3N2 : 365.1260; found: 365.1258; [M
+ Na]+ Calcd for C22H15F3N2Na+: 387.1080; found: 387.1074.
1-(4-Chlorophenyl)-4,5-diphenyl-3-(trifluoromethyl)-1H-
pyrazole (9c). Obtained from ketone 4o (0.136 g, 0.491 mmol) and
phenylhydrazine hydrochloride (0.085 g, 0.584 mmol) by procedure
B. Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale brown powder,
yield 0.143 g (73%), mp 168−170°C. 1H NMR (CDCl3, 400.1
5-(4-Chlorophenyl)-4-(3-nitrophenyl)-1-phenyl-3-(trifluoro-
methyl)-4,5-dihydro-1H-pyrazole (8r). Obtained from pyrazolidi-
nol 7d (0.042 g, 0.090 mmol). Purified by column chromatography
using gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by
1:1). Yellow crystals, yield 0.036 g (90%), mp 75−76°C. IR (υ,
MHz): δ 7.33−7.26 (m, 6H), 7.24−7.16 (m, 6H), 7.03−6.96 (m,
1
cm−1): 1352, 1533 (NO2); 1577, 1597 (CN). H NMR (CDCl3,
2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 142.4, 141.1 (q, JCF
=
2
400.1 MHz): δ 8.26−8.23 (m, 1H), 8.06 (s, 1H), 7.61 (t, 1H, 3J = 7.8
36.5 Hz, C-CF3), 137.7, 134.0, 130.2, 130.1, 129.1, 129.0, 128.6,
3
3
128.3, 128.1, 127.6, 126.5, 121.5 (q, 1JCF = 270.5 Hz, CF3), 121.4. 19
F
Hz), 7.51 (d, 1H, J = 7.8 Hz), 7.38 (d, 2H, J = 8.4 Hz), 7.27−7.20
(m, 2H), 7.14 (d, 2H, 3J = 8.4 Hz), 7.05 (pseudo-d, 2H, 3J = 8.5 Hz),
NMR (CDCl3, 376.5 MHz): δ −60.8 (s, 3F). HRMS (ESI-TOF): m/
3
3
+
z [M + H]+ Calcd for C22H15ClF3N2 : 399.0870, 401.0842; found:
6.99−6.93 (m, 1H), 5.24 (d, 1H, J = 6.7 Hz,) 4.37 (d, 1H, J = 6.7
Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 148.8, 142.1, 140.1,
399.0864, 401.0840.
2
137.5, 136.8 (q, JCF = 37.2 Hz, C-CF3), 134.7, 133.5, 130.6, 130.0,
1-(4-Methoxyphenyl)-4,5-diphenyl-3-(trifluoromethyl)-1H-
pyrazole (9d). Obtained from ketone 4o (0.124 g, 0.449 mmol) and
(4-methoxyphenyl)hydrazine hydrochloride (0.095 g, 0.543 mmol)
by procedure B. Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale
brown powder, yield 0.157 g (88%), mp 198−200°C. 1H NMR
(CDCl3, 400.1 MHz): δ 7.29−7.16 (m, 10H), 7.01−6.99 (m, 2H),
6.83 (d, 2H, 3J = 9.0 Hz), 3.78 (s, 3H). 13C{1H} NMR (CDCl3, 100.6
1
129.3, 126.8, 123.5, 122.5, 122.0, 120.8 (q, JCF = 270.4 Hz, CF3),
114.5, 74.8, 60.3. 19F NMR (CDCl3, 376.5 MHz): δ −63.4. Anal.
Calcd for C22H15ClF3N3O2: C, 59.27; H, 3.39. Found: C, 59.31; H,
3.40.
Synthesis of Pyrazoles 9 by Oxidation of Pyrazolines 8 (General
Procedure A). One-necked 50 mL round-bottom flask was charged
with pyrazoline 8 (1 mmol), toluene (15 mL), and DDQ (5 mmol, 5
equiv). The reaction mixture was heated under reflux (hot plate
stirrer) for 8−10 h (TLC control). Volatiles were evaporated in vacuo,
and the residue was purified by column chromatography using
appropriate hexane/CH2Cl2 mixtures or CH2Cl2 as eluents.
One Pot Synthesis of Pyrazoles 9 from Ketones 4 (General
Procedure B). A 4 mL vial with a screw cap was charged with
corresponding ketone 4 (0.5 mmol), hydrochloride of arylhydrazine
(0.6 mmol, 1.2 equiv), and EtOH (2 mL), and the reaction mixture
was heated at 80−90 °C (hot plate stirrer) under stirring for 8−16 h
(TLC or 19F NMR control). The screw cap was removed, and the
volatiles were evaporated by heating at 80−90 °C (hot plate stirrer)
on open air for approximately 0.5−1 h. Next, the vial was charged
with DDQ (1.5 mmol, 3 equiv) and toluene (2 mL), and the reaction
mixture was heated at 120 °C (hot plate stirrer) under stirring for 8−
16 h (TLC or 19F NMR control). Next, the reaction was quenched by
addition of K2CO3 (0.2 mL, 10% solution in water) and stirred for 1 h
at 80 °C (hot plate stirrer). The obtained dark green-brown-black
mass was transferred to the chromatographic column with silica gel,
and the product was isolated by column chromatography using
gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1; for
compounds 9b−u, w−z, aa, and ab), or CH2Cl2 followed by
MHz): δ 159.2, 142.3, 140.3 (q, 2JCF = 35.9 Hz, C-CF3), 132.3, 130.5,
1
130.29, 130.27, 128.6, 128.4, 128.1, 127.5, 126.8, 121.6 (q, JCF
=
270.0 Hz, CF3), 120.7, 114.1, 55.4. 19F NMR (CDCl3, 376.5 MHz): δ
−60.5 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
C23H18F3N2O+: 395.1366; found: 395.1365.
1-(4-Fluorophenyl)-4,5-diphenyl-3-(trifluoromethyl)-1H-
pyrazole (9e). Obtained from ketone 4o (0.125 g, 0.452 mmol) and
(4-fluorophenyl)hydrazine hydrochloride (0.088 g, 0.542 mmol) by
procedure B. Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale beige
1
powder, yield 0.161 g (93%), mp 155−157°C. H NMR (CDCl3,
400.1 MHz): δ 7.32−7.19 (m, 10H), 7.05−6.99 (m, 4H). 13C{1H}
1
NMR (CDCl3, 100.6 MHz): δ 161.9 (d, JCF = 249.0 Hz), 142.5,
2
4
140.8 (q, JCF = 36.1 Hz, C-CF3), 135.3 (d, JCF = 3.3 Hz), 130.23,
3
130.21, 128.9, 128.5, 128.3, 128.1, 127.6, 127.2 (d, JCF = 8.8 Hz),
121.5 (q, 1JCF = 270.2 Hz, CF3), 121.1, 115.9 (d, 2JCF = 23.0 Hz). 19
F
NMR (CDCl3, 376.5 MHz): δ −113.8, −113.7 (m, 1F, Ar−F), −60.7
(s, 3F, CF3). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
+
C22H15F4N2 : 383.1166; found: 383.1167.
1-(4-Cyanoxyphenyl)-4,5-diphenyl-3-(trifluoromethyl)-1H-
pyrazole (9f). Obtained from ketone 4o (0.162 g, 0.585 mmol) and
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(4-cyanophenyl)hydrazine hydrochloride (0.121 g, 0.714 mmol) by
procedure B. Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale
brown powder, yield 0.189 g (83%), mp 173−175°C. 1H NMR
yellow-green solid, yield 0.197 g (93%), mp 65−66°C. 1H NMR
3 4
(CDCl3, 400.1 MHz): δ 7.57 (dd, 1H, J = 8.0 Hz, J = 1.0 Hz),
7.40−7.32 (m, 6H), 7.28 (td, 1H, 3J = 7.6 Hz, 4J = 1.2 Hz), 7.24−7.15
(m, 4H), 7.08−7.05 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
3
3
2
(CDCl3, 400.1 MHz): δ 7.62 (d, 2H, J = 8.9 Hz), 7.44 (d, 2H, J =
142.6, 141.0 (q, JCF = 36.5 Hz, C-CF3), 139.0, 132.7, 132.5, 131.8,
8.9 Hz), 7.36−7.21 (m, 8H), 7.07−7.04 (m, 2H). 13C{1H} NMR
129.8, 129.6, 129.0, 128.8, 128.4, 128.3, 128.2, 127.0, 125.6, 125.3,
1
121.3 (q, JCF = 270.4 Hz, CF3), 120.1. 19F NMR (CDCl3, 376.5
2
(CDCl3, 100.6 MHz): δ 142.5, 142.3, 141.9 (q, JCF = 36.5 Hz, C-
MHz): δ −62.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
CF3), 132.9, 130.1, 129.6, 129.3, 128.8, 128.1, 127.9, 127.8, 125.3,
C22H15[79]BrF3N2+: 443.0365; found: 443.0357. Calcd for
1
122.1, 121.2 (q, JCF = 270.4 Hz, CF3), 117.8, 111.6. 19F NMR
+
C22H15[81]BrF3N2 : 445.0346; found: 445.0340.
(CDCl3, 376.5 MHz): δ −61.0 (s, 3F). HRMS (ESI-TOF): m/z [M +
+
H]+ Calcd for C23H15F3N3 : 390.1213; found: 390.1204.
5-(4-Chlorophenyl)-1,4-diphenyl-3-(trifluoromethyl)-1H-
pyrazole (9l). Obtained from ketone 4p (0.134 g, 0.433 mmol) and
phenylhydrazine hydrochloride (0.077 g, 0.528 mmol) by procedure
B. Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale yellow-green
4-(4-Chlorophenyl)-1-(4-metoxyphenyl)-5-phenyl-3-(tri-
fluoromethyl)-1H-pyrazole (9g). Obtained from pyrazoline 8g
(0.082 g, 0.190 mmol) by procedure A. Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). White crystals, yield 0.071 g (89%), mp 141−
1
powder, yield 0.149 g (86%), mp 159−161°C. H NMR (CDCl3,
1
400.1 MHz): δ 7.41−7.31 (m, 8H), 7.26−7.23 (m, 2H), 7.19 (d, 2H,
3J = 8.4 Hz), 6.96 (d, 2H, 3J = 8.4 Hz). 13C{1H} NMR (CDCl3, 100.6
MHz): δ 141.1, 140.9 (q, 2JCF = 36.1 Hz, C-CF3), 138.9, 134.9, 131.5,
130.2, 130.0, 129.1, 128.8, 128.4, 128.3, 127.7, 126.9, 125.4, 121.5 (q,
1JCF = 270.2 Hz, CF3), 121.3. 19F NMR (CDCl3, 376.5 MHz): δ
−60.7 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
142°C. H NMR (CDCl3, 400.1 MHz): δ 7.31−7.18 (m, 7H), 7.15
3
3
(d, 2H, J = 8.4 Hz), 7.04−6.96 (m, 2H), 6.84 (d, 2H, J = 9.0 Hz),
3.80 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 159.3, 142.4,
140.2 (q, JCF = 36.1 Hz, C-CF3), 133.6, 132.1, 131.5, 130.2, 129.1,
2
1
128.8, 128.5, 128.4, 128.3, 126.7, 119.4, 121.5 (q, JCF = 270.2 Hz,
CF3), 114.1, 55.4. 19F NMR (CDCl3, 376.5 MHz): δ −60.5 (s, 3F).
HRMS (ESI-TOF): m/z [M + H]+ Calcd for C23H17ClF3N2O+:
429.0976, 431.0948; found: 429.0984, 431.0963.
+
C22H15ClF3N2 : 399.0870; found: 399.0865.
1,5-Bis(4-chlorophenyl)-4-phenyl-3-(trifluoromethyl)-1H-
pyrazole (9m). Obtained from ketone 4p (0.136 g, 0.439 mmol) and
(4-chlorophenyl)hydrazine hydrochloride (0.095 g, 0.0531 mmol) by
procedure B. Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale
yellow-green powder, yield 0.173 g (92%), mp 150−152°C. 1H NMR
(CDCl3, 400.1 MHz): δ 7.37−7.31 (m, 5H), 7.29−7.21 (m, 6H),
4-(4-Chlorophenyl)-1-(4-fluorophenyl)-5-phenyl-3-(trifluor-
omethyl)-1H-pyrazole (9h). Obtained from pyrazoline 8i (0.142 g,
0.340 mmol)by procedure A. Purified by column chromatography
using gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by
1
1:1). White crystals, yield 0.070 g (49%), mp 180−181°C. H NMR
(CDCl3, 400.1 MHz): δ 7.42−7.19 (m, 7H), 7.18−7.11 (m, 2H),
7.10−6.95 (m, 4H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 162.1 (d,
1JCF = 249.2 Hz, CF), 142.6, 140.8 (q, 2JCF = 36.1 Hz, C-CF3), 135.1
3
6.97 (d, 2H, J = 8.6 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
2
141.1, 141.2 (q, JCF = 36.3 Hz, C-CF3), 137.4, 135.2, 134.3, 131.4,
4
(d, JCF = 3.0 Hz,), 133.8, 131.5, 130.2, 129.1, 128.7, 128.5, 128.0,
130.1, 129.8, 129.3, 129.0, 128.3, 127.8, 126.6, 126.5, 121.6, 121.3 (q,
127.2 (d, 3JCF = 8.8 Hz), 121.4 (q, 1JCF = 270.2 Hz, CF3), 119.9, 116.0
(d, 2JCF = 23.2 Hz). 19F NMR (CDCl3, 376.5 MHz): δ −60.7 (s, 3F,
CF3), −113.60, −113.54 (m, 1F, 4-FC6H4). HRMS (ESI-TOF): m/z
1JCF = 270.4 Hz, CF3). 19F NMR (CDCl3, 376.5 MHz): δ −60.8 (s,
+
3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C22H14Cl2F3N2 :
433.0481, 435.0452; found: 433.0473, 435.0458.
+
[M + H]+ Calcd for C22H14ClF4N2 : 417.0776, 419.0747; found:
4-(4-Nitrophenyl)-1,5-diphenyl-3-(trifluoromethyl)-1H-pyr-
azole (9n). Obtained from pyrazoline 8n (0.069 g, 0.168 mmol) by
procedure A. Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale
yellow powder, yield 0.052 g (76%), mp 147−148°C. 1H NMR
417.0775, 419.0761.
1,4-Bis(4-chlorophenyl)-5-phenyl-3-(trifluoromethyl)-1H-
pyrazole (9i). Obtained from pyrazoline 8j (0.061 g, 0.140 mmol) by
procedure A. Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). White
3
(CDCl3, 400.1 MHz): δ 8.14 (d, 2H, J = 8.9 Hz), 7.38−7.21 (m,
1
10H), 7.00−6.98 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
crystals, yield 0.040 g (68%), mp 152−154°C. H NMR (CDCl3,
400.1 MHz): δ 7.19−7.33 (m, 9H), 7.12 (d, 2H, 3J = 8.4 Hz), 7.03−
2
147.1, 142.9, 140.5 (q, JCF = 36.7 Hz, C-CF3), 138.7, 137.6, 131.1,
6.95 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 142.5, 141.0
130.2, 129.4, 129.1, 128.8, 128.6, 127.7, 125.3, 123.4, 121.3 (q, 1JCF
=
2
270.2 Hz, CF3), 118.8. 19F NMR (CDCl3, 376.5 MHz): δ −60.5 (s,
(q, JCF = 35.8 Hz, C-CF3), 137.5, 134.2, 133.8, 131.5, 130.2, 129.2,
1
+
3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for C22H15F3N3O2 :
128.8, 128.7, 128.5, 128.0, 126.4, 121.7 (q, JCF = 270.9 Hz, CF3),
120.1. 19F NMR (CDCl3, 376.5 MHz): δ −60.8 (s, 3F). HRMS (ESI-
410.1111; found: 410.1099.
+
TOF): m/z [M + H]+ Calcd for C22H14Cl2F3N2 : 433.0481,
5-(4-Methoxyphenyl)-4-(4-nitrophenyl)-1-phenyl-3-(tri-
fluoromethyl)-1H-pyrazole (9o). Obtained from pyrazoline 8o
(0.072 g, 0.163 mmol) by procedure A. Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Yellow-brown solid, yield 0.062 g (87%), mp
435.0452; found: 433.0489, 435.0462.
1,5-Diphenyl-3-(trifluoromethyl)-4-(4-(trifluoromethyl)-
phenyl)-1H-pyrazole (9j). Obtained from ketone 4v (0.106 g, 0.308
mmol) and phenylhydrazine hydrochloride (0.054 g, 0.372 mmol) by
procedure B. Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale beige
1
3
120−122°C. H NMR (CDCl3, 400.1 MHz): δ 8.15 (d, 2H, J = 8.8
3
Hz), 7.37 (d, 2H, J = 8.8 Hz), 7.33−7.36 (m, 3H), 7.26−7.31 (m,
1
3
3
powder, yield 0.109 g (82%), mp 146−148°C. H NMR (CDCl3,
2H), 6.89 (d, 2H, J = 8.8 Hz), 6.74 (d, 2H, J = 8.8 Hz), 3.75 (s,
400.1 MHz): δ 7.54 (d, 2H, 3J = 8.1 Hz), 7.34−7.20 (m, 10H), 7.00−
6.98 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 142.7, 140.7
3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 160.1, 147.1, 142.9,
2
140.4 (q, JCF = 36.5 Hz, C-CF3), 138.8, 137.8, 131.5, 131.1, 129.1,
2
4
1
(q, JCF = 36.5 Hz, C-CF3), 138.9, 134.3 (q, JCF = 1.1 Hz), 130.6,
128.5, 125.4, 123.5, 121.3 (q, JCF = 270.0 Hz, CF3), 119.6, 118.4,
2
114.3, 55.2. 19F NMR (CDCl3, 376.5 MHz): δ −60.6 (s, 3F). HRMS
130.2, 129.6 (q, JCF = 32.6 Hz, C-CF3), 129.1, 129.0, 128.7, 128.4,
3
1
+
(ESI-TOF): m/z [M + H]+ Calcd for C23H17F3N3O3 : 440.1217;
128.0, 125.4, 125.1 (q, JCF = 3.7 Hz), 121.42 (q, JCF = 270.2 Hz,
CF3), 121.37 (q, JCF = 272.0 Hz, CF3), 119.6. 19F NMR (CDCl3,
1
found: 440.1206.
376.5 MHz): δ −63.8 (s, 3F, CF3), −60.6 (s, 3F, CF3). HRMS (ESI-
4-(4-Methoxyphenyl)-1,5-diphenyl-3-(trifluoromethyl)-1H-
pyrazole (9p). Obtained from ketone 4a (0.147 g, 0.480 mmol) and
phenylhydrazine hydrochloride (0.084 g, 0.581 mmol) by procedure
B. Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale yellow powder,
yield 0.149 g (86%), mp 159−161°C. 1H NMR (CDCl3, 400.1
MHz): δ 7.34−7.14 (m, 10H), 7.04−7.01 (m, 2H), 6.83 (d, 2H, 3J =
9.0 Hz), 3.76 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 158.9,
+
TOF): m/z [M + H]+ Calcd for C23H15F6N2 : 433.1134; found:
433.1141.
4-(2-Bromophenyl)-1,5-diphenyl-3-(trifluoromethyl)-1H-
pyrazole (9k). Obtained from ketone 4ah (0.170 g, 0.479 mmol)
and phenylhydrazine hydrochloride (0.083 g, 0.572 mmol) by
procedure B. Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale
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2
3
142.2, 140.7 (q, JCF = 35.6 Hz, C-CF3), 139.1, 131.3, 130.2, 128.9,
8.9 Hz), 6.71 (d, 2H, J = 8.9 Hz), 3.78 (s, 3H, MeO), 3.78 (s, 3H,
MeO), 3.73 (s, 3H, MeO). 13C{1H} NMR (CDCl3, 100.6 MHz): δ
128.61, 128.58, 128.4, 128.1, 125.3, 122.4, 121.6 (q, 1JCF = 270.0 Hz,
CF3), 120.7 (q, 4JCF = 1.1 Hz), 113.6, 55.0. 19F NMR (CDCl3, 376.5
MHz): δ −60.7 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
C23H18F3N2O+: 395.1366; found: 395.1365.
2
159.5, 159.1, 158.8, 140.3 (q, JCF = 35.6 Hz, C-CF3), 132.4, 131.6,
1
131.4, 126.8, 122.9, 121.7 (q, JCF = 270.2 Hz, CF3), 120.8, 120.0,
114.0, 113.8, 113.6, 55.4 (MeO), 55.0 (2 MeO). 19F NMR (CDCl3,
5-(4-Chlorophenyl)-4-(4-metoxyphenyl)-1-phenyl-3-(tri-
fluoromethyl)-1H-pyrazole (9q). Obtained from pyrazoline 8k
(0.211 g, 0.490 mmol) by procedure A. Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Yellow crystals, yield 0.173 g (82%), mp 154−
155°C. 1H NMR (CDCl3, 400.1 MHz): δ 7.38−7.32 (m, 3H), 7.29−
376.5 MHz): δ −60.6 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+
+
Calcd for C25H22F3N2O3 : 455.1577; found: 455.1565.
1,4-Bis(4-(4-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-
1H-pyrazol-5-yl)benzene (9v). Obtained from ketone 4a (0.130 g,
0.243 mmol) and phenylhydrazine hydrochloride (0.085 g, 0.586
mmol) by procedure B. Purified by column chromatography using
gradient elution by CH2Cl2:MeOH mixtures (1:0 followed by 30:1).
3
3
7.25 (m, 2H), 7.17 (d, 2H, J = 8.5 Hz), 7.11 (d, 2H, J = 8.7 Hz),
1
3
3
Pale beige powder, yield 0.085 g (49%), mp 270−272°C. H NMR
6.92 (d, 2H, J = 8.7 Hz), 6.84 (d, 2H, J = 8.6 Hz), 3.80 (s, 3H).
13C{1H} NMR (CDCl3, 100.6 MHz): δ 159.1, 141.0, 140.9 (q, 2JCF
=
(DMSO-d6,400.1 MHz): δ 7.37−6.83 (m, 22H), 3.76 (s, 6H).
13C{1H} NMR (DMSO-d6,100.6 MHz): δ 159.1, 142.3, 141.4 (q, 2JCF
= 37.6 Hz, C-CF3), 138.8, 131.3, 130.9, 129.3, 129.2, 128.7, 125.5,
36.1 Hz, C-CF3), 138.9, 134.8, 131.5, 131.3, 129.1, 128.8, 128.4,
1
127.1, 125.4, 122.1, 121.5 (q, JCF = 270.2 Hz, CF3), 120.9, 113.7,
122.0 (q, JCF = 269.7 Hz, CF3), 121.9, 120.9, 113.9, 55.2. 19F NMR
1
55.1. 19F NMR (CDCl3, 376.5 MHz): δ −60.8 (s, 3F). HRMS (ESI-
TOF): m/z [M + H]+ Calcd for C23H17ClF3N2O+: 429.0976; found:
429.0975; [M+K]+ Calcd for C23H16ClF3KN2O+: 467.0535; found:
467.0532.
(DMSO-d6,376.5 MHz): δ −59.9 (s, 3F). HRMS (ESI-TOF): m/z
+
[M + H]+ Calcd for C40H29F6N4O2 : 711.2189; found: 711.2197.
1,5-Diphenyl-4-(4-(pyrrolidin-1-yl)phenyl)-3-(trifluorometh-
yl)-1H-pyrazole (9w). Obtained from ketone 4ak (0.106 g, 0.294
mmol) and phenylhydrazine hydrochloride (0.052 g, 0.359 mmol) by
procedure B. Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Brown
5-(2,6-Dichlorophenyl)-4-(4-methoxyphenyl)-1-phenyl-3-
(trifluoromethyl)-1H-pyrazole (9r). Obtained from ketone 4i
(0.135 g, 0.360 mmol) and phenylhydrazine hydrochloride (0.064
g, 0.439 mmol) by procedure B. Purified by column chromatography
using gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by
1
solid, yield 0.065 g (51%), mp 98−100°C. H NMR (CDCl3, 400.1
3
1
MHz): δ 7.35−7.19 (m, 8H), 7.08−7.04 (m, 4H), 6.49 (d, 2H, J =
1:1). White powder, yield 0.070 g (42%), mp 153−155°C. H NMR
9.0 Hz), 3.30−3.27 (m, 4H), 2.03−1.96 (m, 4H). 13C{1H} NMR
(CDCl3, 400.1 MHz): δ 7.39−7.35 (m, 2H), 7.33−7.30 (m, 3H),
2
7.26−7.17 (m, 5H), 6.80 (d, 2H, 3J = 8.8 Hz), 3.75 (s, 3H). 13C{1H}
(CDCl3, 100.6 MHz): δ 141.9, 140.8 (q, JCF = 35.8 Hz, C-CF3),
2
139.3, 131.1, 130.4, 129.0, 128.9, 128.5, 128.4, 128.0, 125.44, 125.40
(q, 4JCF = 1.3 Hz), 121.8 (q, 1JCF = 270.3 Hz, CF3), 119.8, 111.5, 25.4.
19F NMR (CDCl3, 376.5 MHz): δ −60.8 (s, 3F). HRMS (ESI-TOF):
NMR (CDCl3, 100.6 MHz): δ 159.1, 140.6 (q, JCF = 35.6 Hz, C-
CF3), 138.9, 137.4, 136.8, 131.6, 130.4, 128.9, 128.6, 128.0, 127.9,
4
1
124.4, 122.4 (q, JCF = 1.1 Hz), 122.0, 121.6 (q, JCF = 270.2 Hz,
CF3), 113.5, 55.0. 19F NMR (CDCl3, 376.5 MHz): δ −60.6 (s, 3F).
HRMS (ESI-TOF): m/z [M + H]+ Calcd for C23H16Cl2F3N2O+:
463.0586, 465.0558; found: 463.0573, 465.0547.
+
m/z [M + H]+ Calcd for C26H23F3N3 : 434.1839; found: 434.1827.
4-(4-Methoxyphenyl)-1-phenyl-5-(thiophen-2-yl)-3-(tri-
fluoromethyl)-1H-pyrazole (9x). Obtained from ketone 4m (0.102
g, 0.327 mmol) and phenylhydrazine hydrochloride (0.057 g, 0.393
mmol) by procedure B. Purified by column chromatography using
gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1).
White solid, yield 0.119 g (91%), mp 134−135°C. 1H NMR (CDCl3,
4-(4-Methoxyphenyl)-5-(4-nitrophenyl)-1-phenyl-3-(tri-
fluoromethyl)-1H-pyrazole (9s). Obtained from ketone 4f (0.098
g, 0.279 mmol) and phenylhydrazine hydrochloride (0.049 g, 0.338
mmol) by procedure B. Purified by column chromatography using
gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1).
3
400.1 MHz): δ 7.39 (m, 5H), 7.26−7.23 (m, 3H), 6.89 (d, 2H, J =
1
9.0 Hz), 6.86 (dd, 1H, 3J = 5.1 Hz, 3J = 3.7 Hz), 6.71 (dd, 1H, 3J = 3.7
Hz, 4J = 1.2 Hz), 3.80 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz):
δ 159.3, 140.8 (q, 2JCF = 35.9 Hz, C-CF3), 139.0, 136.4, 131.5, 129.9,
129.0, 128.7, 128.6, 128.2, 127.0, 125.8, 122.8, 121.48, 121.44 (q, 1JCF
= 270.4 Hz, CF3), 113.6, 55.1. 19F NMR (CDCl3, 376.5 MHz): δ
−61.0 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
C21H16F3N2OS+: 401.0930; found: 401.0930.
Pale yellow-beige solid, yield 0.078 g (64%), mp 175−177°C. H
3
NMR (CDCl3, 400.1 MHz): δ 8.04 (d, 2H, J = 8.9 Hz), 7.39−7.36
(m, 3H), 7.28−7.24 (m, 2H), 7.16 (d, 2H, 3J = 8.9 Hz), 7.10 (d, 2H,
3J = 8.7 Hz), 6.85 (d, 2H, J = 8.7 Hz), 3.80 (s, 3H). 13C{1H} NMR
3
2
(CDCl3, 100.6 MHz): δ 159.4, 147.5, 141.3 (q, JCF = 36.1 Hz, C-
CF3), 139.8, 138.6, 135.1, 131.3, 131.1, 129.4, 128.9, 125.5, 123.6,
121.9, 121.4, 121.3 (q, JCF = 270.3 Hz, CF3), 114.0, 55.2. 19F NMR
1
4-(4-Chlorophenyl)-1-ethyl-5-phenyl-3-(trifluoromethyl)-
1H-pyrazole (9y). Obtained from pyrazoline 8q (0.092 g, 0.260
mmol) by procedure A. Purified by column chromatography using
gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1).
(CDCl3, 376.5 MHz): δ −60.9 (s, 3F). HRMS (ESI-TOF): m/z [M +
+
H]+ Calcd for C23H17F3N3O3 : 440.1217; found: 440.1206.
4,5-Bis(4-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-1H-
pyrazole (9t). Obtained from ketone 4e (0.123 g, 0.366 mmol) and
phenylhydrazine hydrochloride (0.064 g, 0.439 mmol) by procedure
B. Purified by column chromatography using gradient elution by
hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Pale beige solid, yield
1
Yellow oil, yield 0.030 g (33%). H NMR (CDCl3, 400.1 MHz): δ
3
7.41−7.35 (m, 3H), 7.21−7.16 (m, 4H), 7.06 (d, 2H, J = 8.4 Hz),
3
3
4.14 (q, 2H, J = 7.3 Hz), 1.40 (t, 3H, J = 7.3 Hz). 13C{1H} NMR
2
1
(CDCl3, 100.6 MHz): δ 142.6, 138.8 (q, JCF = 36.3 Hz, C-CF3),
0.141 g (91%), mp 181−183°C. H NMR (CDCl3, 400.1 MHz): δ
133.3, 131.3, 130.1, 129.30, 129.25, 128.9, 128.5, 128.3, 121.6 (q, 1JCF
= 269.6 Hz, CF3), 118.8, 45.4, 15.6. 19F NMR (CDCl3, 376.5 MHz):
δ −60.3 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
3
3
7.35−7.28 (m, 5H), 7.15 (d, 2H, J = 8.9 Hz), 6.92 (d, 2H, J = 8.9
3
3
Hz), 6.83 (d, 2H, J = 8.9 Hz), 6.72 (d, 2H, J = 8.9 Hz), 3.78 (s,
3H), 3.73 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 159.6,
+
2
C18H15ClF3N2 : 351.0870; found: 351.0878.
158.9, 142.1, 140.6 (q, JCF = 35.8 Hz, C-CF3), 139.3, 131.5, 131.4,
1
5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-phenyl-3-(tri-
fluoromethyl)-1H-pyrazole (9z). Obtained from ketone 4p (0.138
g, 0.445 mmol) and (4-methoxyphenyl)hydrazine hydrochloride
(0.095 g, 0.543 mmol) by procedure B. Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Pale beige powder, yield 0.176 g (92%), mp
128.9, 128.0, 125.4, 122.7, 121.7 (q, JCF = 270.9 Hz, CF3), 120.7,
113.9, 113.6, 55.0 (2 MeO). 19F NMR (CDCl3, 376.5 MHz): δ −60.7
(s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
+
C24H20F3N2O2 : 425.1471; found: 425.1470.
1,4,5-Tris(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyra-
zole (9u). Obtained from ketone 4e (0.087 g, 0.259 mmol) and (4-
methoxyphenyl)hydrazine hydrochloride (0.055 g, 0.318 mmol) by
procedure B. Purified by column chromatography using gradient
elution by hexane/CH2Cl2 mixtures (3:1 followed by 1:1). Light
brown solid, yield 0.100 g (85%), mp 125−127°C. 1H NMR (CDCl3,
1
154−156°C. H NMR (CDCl3, 400.1 MHz): δ 7.36−7.09 (m, 9H),
3
3
6.94 (d, 2H, J = 8.3 Hz), 6.86 (d, 2H, J = 8.7 Hz), 3.79 (s, 3H).
13C{1H} NMR (CDCl3, 100.6 MHz): δ 159.4, 141.1, 140.4 (q, 2JCF
=
36.3 Hz, C-CF3), 134.8, 131.9, 131.5, 130.2, 128.7, 128.2, 127.7,
3
3
1
400.1 MHz): δ 7.20 (d, 2H, J = 9.0 Hz), 7.13 (d, 2H, J = 8.9 Hz),
127.0, 126.8, 121.5 (q, JCF = 270.0 Hz, CF3), 120.9, 114.2, 55.4
6.91 (d, 2H, 3J = 8.9 Hz), 6.83 (d, 2H, 3J = 9.0 Hz), 6.82 (d, 2H, 3J =
(MeO). 19F NMR (CDCl3, 376.5 MHz): δ −60.6 (s, 3F). HRMS
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(ESI-TOF): m/z [M + H]+ Calcd for C23H17ClF3N2O+: 429.0976;
found: 429.0983.
212°C. 1H NMR (CD3CN, 400.1 MHz) δ 7.87 (d, 2H, 3J = 8.7 Hz),
3
7.47 (d, 2H, J = 8.7 Hz), 7.35−7.32 (m, 3H), 7.29−7.25 (m, 2H),
3
5-(4-Chlorophenyl)-1,4-bis(4-methoxyphenyl)-3-(trifluoro-
methyl)-1H-pyrazole (9aa). Obtained from ketone 4b (0.118 g,
0.346 mmol) and (4-methoxyphenyl)hydrazine hydrochloride (0.073
g, 0.417 mmol) by procedure B. Purified by column chromatography
using gradient elution by hexane/CH2Cl2 mixtures (3:1 followed by
7.20−7.15 (m, 2H), 7.02 (pseudo-t, 2H, J = 8.9 Hz), 5.80 (s, 2H).
13C{1H} NMR (CD3CN, 100.6 MHz): δ 163.9 (d, 1JCF = 248.0 Hz),
143.8, 143.2, 142.7, 141.4 (q, 2JCF = 35.7 Hz, C-CF3), 133.7 (d, 3JCF
=
8.7 Hz), 131.2, 130.9, 129.1, 128.9, 128.0, 126.6, 125.5 (d, 4JCF = 3.3
1
2
Hz), 122.7, 122.6 (q, JCF = 269.4 Hz, CF3), 116.5 (d, JCF = 22.1
Hz). 19F NMR (CD3CN, 376.5 MHz) δ −111.4 (br s, 1F, Ar−F),
−59.0 (s, 3F, CF3). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
C22H16F4N3O2S+: 462.0894; found: 462.0886.
1
1:1). Pale brown powder, yield 0.124 g (78%), mp 128−130°C. H
NMR (CDCl3, 400.1 MHz): δ 7.18 (d, 2H, 3J = 9.0 Hz), 7.16 (d, 2H,
3J = 8.7 Hz), 7.11 (d, 2H, 3J = 8.6 Hz), 6.92 (d, 2H, 3J = 8.6 Hz), 6.85
(d, 2H, 3J = 8.7 Hz), 6.83 (d, 2H, 3J = 9.0 Hz), 3.80 (s, 3H), 3.79 (s,
3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 159.4, 159.1, 141.0,
4-(5-(4-Fluorophenyl)-4-(4-methoxyphenyl)-3-(trifluoro-
methyl)-1H-pyrazol-1-yl)benzenesulfonamide (9af). Obtained
from ketone 4c (0.167 g, 0.514 mmol) and 4-sulfonamidophenylhy-
drazine hydrochloride (0.136 g, 0.608 mmol) by procedure B. Purified
by column chromatography using gradient elution by CH2Cl2:MeOH
mixtures (1:0 followed by 30:1). Light gray powder, yield 0.193 g
2
140.6 (q, JCF = 35.9 Hz, C-CF3), 134.7, 132.0, 131.5, 131.3, 128.8,
127.2, 126.8, 122.3, 121.6 (q, 1JCF = 270.2 Hz, CF3), 120.6 (q, 4JCF
=
1.1 Hz), 114.2, 113.7, 55.5, 55.1. 19F NMR (CDCl3, 376.5 MHz): δ
−60.7 (s, 3F). HRMS (ESI-TOF): m/z [M + H]+ Calcd for
1
+
(76%), mp 197−199°C. H NMR (CD3CN, 400.1 MHz) δ 7.86 (d,
C24H19ClF3N2O2 : 459.1082; found: 459.1081.
2H, 3J = 8.8 Hz), 7.45 (d, 2H, 3J = 8.8 Hz), 7.20−7.16 (m, 4H), 7.03
5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-(4-nitrophen-
yl)-3-(trifluoromethyl)-1H-pyrazole (9ab). Obtained from ketone
4y (0.103 g, 0.289 mmol) and (4-methoxyphenyl)hydrazine hydro-
chloride (0.062 g, 0.354 mmol) by procedure B. Purified by column
chromatography using gradient elution by hexane/CH2Cl2 mixtures
(3:1 followed by 1:1). Beige solid, yield 0.047 g (34%), mp 138−
3
3
(pseudo-t, 2H, J = 8.9 Hz), 6.88 (d, 2H, J = 8.8 Hz), 5.80 (s, 2H),
3.77 (s, 3H). 13C{1H} NMR (CD3CN, 100.6 MHz): δ 163.9 (d, 1JCF
= 247.9 Hz), 160.3, 143.7, 143.1, 142.7, 141.9 (q, JCF = 35.4 Hz, C-
2
3
4
CF3), 133.7 (d, JCF = 8.7 Hz), 132.4, 128.0, 126.6, 125.6, (d, JCF
=
3.7 Hz), 122.8, 122.7 (q, 1JCF = 269.4 Hz, CF3), 122.4, 116.5 (d, 2JCF
= 22.1 Hz), 114.5. 19F NMR (CD3CN, 376.5 MHz) δ −111.44−
111.36 (m, 1F, Ar−F), −58.9 (s, 3F, CF3). HRMS (ESI-TOF): m/z
[M + H]+ Calcd for C23H18F4N3O3S+: 492.1000; found: 492.0990.
1
3
140°C. H NMR (CDCl3, 400.1 MHz): δ 8.16 (d, 2H, J = 9.0 Hz),
7.36 (d, 2H, 3J = 8.8 Hz), 7.21 (d, 2H, 3J = 8.7 Hz), 7.18 (d, 2H, 3J =
9.0 Hz), 6.90 (d, 2H, 3J = 8.7 Hz), 6.86 (d, 2H, 3J = 9.0 Hz), 3.81 (s,
3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 159.7, 147.2, 141.7,
140.3 (q, 2JCF = 35.9 Hz, C-CF3), 137.3, 135.6, 131.44, 131.41, 131.1,
ASSOCIATED CONTENT
■
1
129.2, 126.8, 126.2, 123.6, 121.2 (q, JCF = 270.2 Hz, CF3), 118.7,
sı
* Supporting Information
114.3, 55.5. 19F NMR (CDCl3, 376.5 MHz): δ −60.5 (s, 3F). HRMS
+
(ESI-TOF): m/z [M + H]+ Calcd for C23H16ClF3N3O3 : 474.0827;
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02516.
found: 474.0834.
4-[5-(4-Methylphenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyr-
azol-1-yl]benzenesulfonamide (9ac). Obtained from pyrazoline
8p (0.040 g, 0.088 mmol) by procedure A or from ketone 4r (0.103 g,
0.357 mmol) and 4-sulfonamidophenylhydrazine hydrochloride
(0.104 g, 0.464 mmol) by procedure B. Purified by column
chromatography using gradient elution by CH2Cl2:MeOH mixtures
(1:0 followed by 30:1). Pale beige powder, yield 0.026 (65%, A),
0.092 g (56%, B), mp 168−170°C. 1H NMR (CDCl3, 400.1 MHz) δ
7.85 (d, 2H, J = 8.8 Hz), 7.42 (d, 2H, J = 8.8 Hz), 7.29−7.28 (m,
3H), 7.20−7.18 (m, 2H), 7.03 (d, 2H, 3J = 8.0 Hz), 6.89 (d, 2H, 3J =
8.0 Hz), 5.34 (s, 2H), 2.28 (s, 3H). 13C{1H} NMR (CDCl3, 100.6
MHz): δ 142.8, 142.4, 141.7 (q, 2JCF = 36.1 Hz, C-CF3), 141.1, 139.4,
130.2, 130.0, 129.8, 129.6, 128.9, 128.2, 127.7, 127.3, 125.4, 124.8,
121.7, 121.3 (q, 1JCF = 270.4 Hz, CF3), 21.3. 19F NMR (CDCl3, 376.5
MHz) δ −61.0 (s, 3F). The NMR data are in agreement with those in
the literature.2 HRMS (ESI-TOF): m/z [M + H]+ Calcd for
C23H19F3N3O2S+: 458.1145; found: 458.1135.
Structures of CF3-enamines 2, copies of all NMR
spectra, and X-ray data (PDF)
Accession Codes
CCDC 2040062 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
3
3
AUTHOR INFORMATION
■
Corresponding Author
Valentine G. Nenajdenko − Department of Chemistry, M. V.
Lomonosov Moscow State University, Moscow 119991,
Russia; orcid.org/0000-0001-9162-5169;
Email: nenajdenko@org.chem.msu.ru
4-(4-(4-Methoxyphenyl)-5-(p-tolyl)-3-(trifluoromethyl)-1H-
pyrazol-1-yl)benzenesulfonamide (9ad). Obtained from ketone
4d (0.166 g, 0.521 mmol) and 4-sulfonamidophenylhydrazine
hydrochloride (0.138 g, 0.617 mmol) by procedure B. Purified by
column chromatography using gradient elution by CH2Cl2:MeOH
mixtures (1:0 followed by 30:1). Burgundy crystals, yield 0.225 g
Authors
Vasiliy M. Muzalevskiy − Department of Chemistry, M. V.
Lomonosov Moscow State University, Moscow 119991,
Russia
Zoia A. Sizova − Department of Chemistry, M. V. Lomonosov
Moscow State University, Moscow 119991, Russia
Vasiliy V. Panyushkin − Department of Chemistry, M. V.
Lomonosov Moscow State University, Moscow 119991,
Russia
Vyacheslav A. Chertkov − Department of Chemistry, M. V.
Lomonosov Moscow State University, Moscow 119991,
Russia
Victor N. Khrustalev − Peoples’ Friendship University of
Russia, Moscow 117198, Russia; N. D. Zelinsky Institute of
Organic Chemistry of RAS, Moscow 119991, Russia;
orcid.org/0000-0001-8806-2975
1
(89%), mp 115−118°C. H NMR (CDCl3, 400.1 MHz) δ 7.82 (d,
2H, 3J = 8.5 Hz), 7.39 (d, 2H, 3J = 8.5 Hz), 7.12 (d, 2H, 3J = 8.7 Hz),
7.03 (d, 2H, 3J = 8.1 Hz), 6.90 (d, 2H, 3J = 8.1 Hz), 6.82 (d, 2H, 3J =
8.7 Hz), 5.56 (s, 2H), 3.77 (s, 3H), 2.27 (s, 3H). 13C{1H} NMR
(CDCl3, 100.6 MHz): δ 159.0, 142.7, 142.2, 141.6 (q, 2JCF = 36.1 Hz,
C-CF3), 141.1, 139.3, 131.2, 130.0, 129.5, 127.2, 125.4, 124.8, 121.9,
121.32, 121.31 (q, 1JCF = 270.5 Hz, CF3), 113.6, 55.0, 21.2. 19F NMR
(CDCl3, 376.5 MHz) δ −61.1 (s, 3F). HRMS (ESI-TOF): m/z [M +
H]+ Calcd for C24H21F3N3O3S+: 488.1250; found: 488.1246.
4-[5-(4-Fluorophenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyr-
azol-1-yl]benzenesulfonamide (9ae). Obtained from ketone 4q
(0.217 g, 0.738 mmol) and 4-sulfonamidophenylhydrazine hydro-
chloride (0.214 g, 0.955 mmol) by procedure B. Purified by column
chromatography using gradient elution by CH2Cl2:MeOH mixtures
(1:0 followed by 30:1). White powder, yield 0.253 (74%), mp 210−
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The many roles for fluorine in medicinal chemistry. J. Med. Chem.
2008, 51, 4359−4369. (f) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu,
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W.; Acena, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next generation
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02516
of fluorine containing pharmaceuticals, compounds currently in phase
II-III clinical trials of major pharmaceutical companies: new structural
trends and therapeutic areas. Chem. Rev. 2016, 116, 422−518.
Notes
The authors declare no competing financial interest.
́
́
(g) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.;
̃
ACKNOWLEDGMENTS
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in
pharmaceutical industry: fluorine-containing drugs introduced to the
market in the last decade (2001−2011). Chem. Rev. 2014, 114, 2432−
2506. (h) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. Data-mining for
sulfur and fluorine: an evaluation of pharmaceuticals to reveal
opportunities for drug design and discovery. J. Med. Chem. 2014, 57,
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(5) Inoue, M.; Sumii, Y.; Shibata, N. Contribution of Organofluorine
Compounds to Pharmaceuticals. ACS Omega 2020, 5, 10633−10640.
(6) De la Torre, B. G.; Albericio, F. The Pharmaceutical Industry in
2018. An Analysis of FDA Drug Approvals from the Perspective of
Molecules. Molecules 2019, 24, 809.
■
This work was supported by the Russian Science Foundation
(Grant 18-13-00136). The authors acknowledge partial
support in measuring of NMR from M.V. Lomonosov Moscow
State University Program of Development. The authors
acknowledge Thermo Fisher Scientific Inc., MS Analytica
(Moscow, Russia), and personally Prof. A. Makarov for
providing mass spectrometry equipment for this work. This
work was supported in part by the RUDN University Strategic
Academic Leadership Program.
(7) De la Torre, B. G.; Albericio, F. The Pharmaceutical Industry in
2019. An Analysis of FDA Drug Approvals from the Perspective of
Molecules. Molecules 2020, 25, 745.
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