Selective, Metal-Free Approach to 3- or 5-CF3-Pyrazoles: Solvent Switchable Reaction of CF3-Ynones with Hydrazines

Article abstract of DOI:10.1021/acs.joc.7b00774

A detailed study of the reaction of trifluoroacetylated acetylenes and aryl (alkyl) hydrazines was performed, aimed to the regioselective synthesis of 3- or 5-trifluoromethylated pyrazoles. It was found that the regioselectivity of reaction depends dramatically on the solvent nature. Highly polar protic solvents (hexafluoroisopropanol) favor the formation of 3-trifluoromethylpyrazoles. In contrast, when the reaction was performed in polar aprotic solvents (DMSO), the formation of their 5-CF₃-substituted isomers was preferentially observed. Alternatively, the regioselective assembly of 3-CF₃-substituted pyrazoles can be performed via two-step one-pot procedure. The reaction of trifluoromethylated ynones with aryl (alkyl) hydrazines in the presence of acidic catalysts leads to formation of the corresponding hydrazones. The latter can be smoothly transformed into 3-CF₃-pyrazoles by treatment with a base. This solvent-switchable procedure was used for the preparation of such important drugs as Celebrex and SC-560 as well as their isomers in gram scale. The possible reaction mechanism is discussed.

Full text of DOI:10.1021/acs.joc.7b00774

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Article
Selective, Metal-free Approach to 3- or 5-CF3-Pyrazoles.
Solvent Switchable Reaction of CF3-ynones with Hydrazines
Vasiliy M. Muzalevskiy, Alexander Yu. Rulev, Alexey R. Romanov, Evgeniy V. Kondrashov,
Igor A. Ushakov, Vyacheslav A. Chertkov, and Valentine Georgievich Nenajdenko
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 18 Jun 2017
Downloaded from http://pubs.acs.org on June 19, 2017
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Page 1 of 43
The Journal of Organic Chemistry
Selective, Metal-free Approach to 3- or 5-CF3-Pyrazoles. Solvent Switchable Reaction of CF3-ynones
with Hydrazines
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Vasiliy M. Muzalevskiy,a Alexander Yu. Rulev,*b Alexey R. Romanov,b Evgeniy V. Kondrashov,b Igor A.
Ushakov,b Vyacheslav A. Chertkov,a and Valentine G. Nenajdenko*a
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Department of Chemistry, Moscow State University Leninskie Gory, Moscow 119992, Russia, Fax: (+)7ꢀ
495ꢀ9328846, Eꢀmail: nenajdenko@org.chem.msu.ru
b
A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1, Favorsky
Str., Irkutsk 664033, Russia, Fax: +7 3952 419346, Eꢀmail: rulev@irioch.irk.ru
N NHR2
up to 100 %
24 examples
R1
DBU
CF3
H+
CF3
CF3
R2
O
R1
R1
R1
N
N
N
N
HFIP
DMSO
CF3
R2
+
R2NHNH2
up to 96 %
24 examples
up to 100 %
28 examples
Abstract
A detailed study of the reaction of trifluoroacetylated acetylenes and aryl(alkyl) hydrazines was performed
aimed to the regioselective synthesis of 3ꢀ or 5ꢀtrifluoromethylated pyrazoles. It was found that the
regioselectivity of reaction depends dramatically on the solvent nature. Highly polar protic solvents
(hexafluoroisopropanol) favor the formation of 3ꢀtrifluoromethylpyrazoles. In contrast, when the reaction
was performed in polar aprotic solvents (DMSO), the formation of their 5ꢀCF3ꢀsubstituted isomers was
preferentially observed. Alternatively, the regioselective assembly of 3ꢀCF3ꢀsubstituted pyrazoles can be
performed via two step oneꢀpot procedure. The reaction of trifluoromethylated ynones with
aryl(alkyl)hydrazines in the presence of acidic catalysts leads to formation of the corresponding hydrazones.
The latter can be smoothly transformed into 3ꢀCF3ꢀpyrazoles by treatment with a base. This solventꢀ
switchable procedure was used for the preparation of such important drugs as Celebrex and SCꢀ560 as well
as their isomers in gram scale. The possible reaction mechanism is discussed.
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Introduction
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Over the recent decade the chemistry of fluorinated heterocycles has enjoyed a lot of attention due to the
wide application of these derivatives as pharmaceuticals, agrochemicals and high utility for further design of
biologically active compounds.1 The pyrazole core is a privileged structural unit of modern drugs and
agrochemicals.2 A very important task in this field is to incorporate selectively the fluorineꢀcontaining groups
into proper place of this heterocyclic ring to discover new biologically active candidates for drug design.3
Thus, a lot of fluorinated pyrazoles exhibited the various type of biological activity and found the
applications as medicines and agrochemicals (Figure 1). Nevertheless, there is a significant demand for the
searching of new methods for the selective preparation of CF3ꢀsubstituted pyrazoles.4
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In the recent years many approaches towards trifluoromethylated pyrazoles were developed. The modern
metodologies for the synthesis of pyrazoles bearing fluorine or fluorineꢀcontaining functional group at
various position of this heterocyclic molecule were analysed very recently.4d Generally, CF3ꢀsubstituted
pyrazoles are obtained by a traditional method based on condensation of 1,3ꢀdiketones with hydrazines.1
However, despite the high yields of the target heterocycles this method suffers from a very important
drawback: when asymmetrical ketones were treated with monosubstituted hydrazines, a mixture of hardly
separable regioisomers was formed as a rule.5 In spite of significant progress in this field, the use of
acetylenic or βꢀfunctionally substituted unsaturated fluorineꢀcontaining ketones (as synthetic equivalents of
1,3ꢀdiketones) is more efficient approach affording the target heterocycles in good yield. Thus, a series of 3ꢀ
and 5ꢀpolyfluoroalkylpyrazoles were synthesized from βꢀfunctionally substituted enones and hydrazines.6
The synthesis of Nꢀunsubstituted CF3ꢀpyrazoles based on trifluoromethylated ynones and hydrazine hydrate
was also reported.7 The reaction with monosubstituted hydrazines a priori can give a mixture of isomeric
pyrazoles to be dependent on the reaction conditions and the structure of starting compounds. A search for
efficient methods for the selective formation of CF3ꢀpyrazoles is still a significant challenge of modern
organic synthesis. Very recently, the preferential formation of either 3ꢀ or 5ꢀCF3ꢀpyrazoles from ynones and
arylhydrazines was reported under the catalytic or catalystꢀfree conditions.8 Herein, we report the general and
highly efficient method for the selective preparation of 3ꢀ and 5ꢀtrifluoromethylpyrazoles based on the
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solventꢀswitchable reaction of CF3ꢀynones and alkylꢀ and arylhydrazines and the study of the reaction
mechanism.
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F
Cl
O
CF3
CN
S
7
8
9
H2N
Cl
F3C
F3C
F3C
N
N
N
N
N
N
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N
N
O
O
Cl
Fipronil
F3C
S
S
OMe
Celecoxib
NH2
NH2
SC-560
O
O
(Celebrex)
(Terminator, Frontline)
anticancer drug
Mavacoxib
nonsteroidal
nonsteroidal
insecticide
O
Cl
anti-inflammatory drug
anti-inflammatory drug
O
F
F3C
N
O
NMe2
H
CF3
HN
N
F
Br
N
N
N
N
O
N
S
N
N
F3C
Razaxaban
anticoagulant
Penthiopyrad
H2N
Fluazolate
herbicide
fungicide
O
N
Figure 1. Some examples of bioactive CF3ꢀpyrazoles.
Results and Discussion
To start our study, a model reaction of ynone 1a with phenylhydrazine 2a was investigated in various
solvents at room temperature (Scheme 1). Trifluoroacetylated acetylene 1a has highly polarized triple bond
activated for nucleophilic addition and highly electrophilic carbonyl group. Therefore, both 1,2ꢀ and 1,4ꢀ
addition of hydrazine can be expected to result in different regiochemistry of formed pyrazoles. The reaction
19
progress was monitored by F NMR. It was found that reaction is extremely sensitive to the solvent nature
and led almost in all cases to a mixture of five principal products in varying ratios: the target 5ꢀ and 3ꢀ
trifluoromethylpyrazoles 3a and 4a, pyrazoline 5a, hemiaminal 6a, and hydrazone 7a (Table 1). Structures of
1
13
19
all these compounds were determined unambiguously by H, C, and F NMR data (see SI). Moreover,
NMR data of 3a, 4a, 5a are in agreement with literature data.3,8
These preliminary results revealed the complicated nature of the reaction. However, the intermediates 5a, 6a,
and 7a can be regarded as precursors of pyrazoles 3a and 4a. Therefore, to achieve a full conversion we used
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heating of the reaction mixture with pꢀTSA (Table 1). After this treatment a much simpler picture of the
products ratio was observed: the reaction mixture contained 3a and 4a only.
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3
4
5
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7
8
Ph
Ph
1,4ꢀaddition
OH
CF3
N
CF3
N
ꢀH2O
N
N
O
9
Ph
Ph
5a
Ph
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3a
CF
3 14ꢀ48h, rt
solvent
1a
+
F3C
CF3
OH
Ph
PhNHNH2
2a
Ph
Ph
N
HN
ꢀH2O
N
1,2ꢀaddition
N
6a
Ph
4a
H
H
N N
Ph
Ph
CF3
7a
Scheme 1. Reaction of ynone 1a with phenylhydrazine 2a in different solvents.
Table 1. Composition of the reaction mixture by 19F NMR data.
Compound (19F NMR chemical shift, ppm)
Entry Solvent
3a (ꢀ58.5)
4a (ꢀ63.2)
3(3)
5a (ꢀ80.5)
6a (ꢀ82.5)
7a (ꢀ67.1)
0(0)
1
DMSO
DMF
0(97)a
84/97b(0)
13/0 (0)
2
2(97)
1(24)
0/8(87)
1(76)
28(70)
0
3(3)
95(0)
77/88(68)
57/79(0)
74(0)
42(0)
8/66
0(0)
0(0)
0(0)
5(5)
0(0)
3(3)
0
3
HMPA
THF
11
11/0(0)
30/0(0)
2/0(0)
0(0)
4
8(8)
5
MeCN
neat
24(24)
27(27)
8/30
11
6
7
Et3N
84/4
8
Me2N(CH2)2OH
CHCl3
PhMe
1
88
0
0
9
28
66
0
2/0
4
10
11
12
11(36)
2(26)
1(32)
62(62)
73(73)
68(68)
25(0)
24(0)
31(0)
4/0(0)
2/0(0)
0(0)
2(2)
1(1)
0(0)
Hexane
NH2CHO
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13
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tꢀBuOH
19
67
12
0
2
1
2
3
4
5
6
7
8
HO(CH2)2OH
MeOH
0(13)
0(20)
12
87(87)
80(80)
88
13(13)
0(0)
0(0)
0
0(0)
0(0)
0
20(0)
EtOH
0
0
0
0
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HFIP
2
98
0
0
AcOH
3
30
0
67
97
19
THF+BF3·Et2O
0
3
0
a
b
ꢀ yields obtained after heating of the reaction mixture with pꢀTSA are given in parentheses. ꢀ composition
of the reaction mixture after 14h / 48h.
It was found that the solvent nature influenced very significantly the products ratio and the reaction
selectivity. Thus, the reaction under solventꢀfree conditions as well as in polar aprotic solvents (DMSO,
DMF, HMPA, THF, MeCN) led mostly to pyrazoline 5a, which can be further converted into 5ꢀCF3ꢀpyrazole
3a by heating at 80°C in the presence of the catalytic amounts of pꢀTSA. The highest selectivity was
observed for the reaction in DMSO and DMF which afforded (97:3) a mixture of isomers 3a and 4a (Table 1,
entry 1). We have chosen DMSO as a nonꢀtoxic solvent for further research due to its simpler work up
procedures and NMR reaction control. More basic solvents such as Et3N and Me2N(CH2)2OH afforded
preferentially 5a. In contrast, the reaction in nonꢀpolar medium (hexane, toluene, CHCl3) and polar protic
solvents (fluorinated and nonꢀfluorinated alcohols) resulted in 3ꢀCF3ꢀisomer 4a preferentially. The best
regioselectivity was observed when hexafluoroisopropanol (HFIP) was used as the reaction media (Table 1,
entry 17). However, the corresponding hydrazone 7a was obtained mostly (AcOH) or exclusively (BF3·Et2O
in THF) when the reaction was catalyzed by Lewis or Brønsted acids. It is important to note that the formed
hydrazone 7a is stable under these conditions: heating of the obtained reaction mixture at 80 °C during 5ꢀ7 h
did not lead to the cyclization of hydrazone 7a into pyrazole 4a. It is also very interesting to point out that
hemiaminal 6a (initially formed in polar aprotic solvents) was transformed into pyrazole 4a and pyrazoline
5a instead of hydrazone 7a after standing of the reaction mixture at room temperature for 48 h. That means
that there is equilibrium between starting ketone 1a and hemiaminal 6a.
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According to these preliminary data, DMSO provided highly controlled formation of 5ꢀCF3ꢀpyrazole 3a,
whereas 3ꢀCF3ꢀpyrazole can be prepared selectively using HFIP as the reaction media. Thus, at the first stage
of the study, the possibility to control the regioselectivity of the reaction (formation of either 3ꢀCF3ꢀpyrazoles
or 5ꢀCF3ꢀpyrazoles) by a proper choice of the solvent was demonstrated.
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Having in hand the optimal reaction conditions for the selective formation of each isomer, the synthetic scope
of the reaction was studied. A number of ynones bearing both aryl and alkyl substituents at the triple bond
was treated with phenylhydrazine in DMSO for two days at room temperature followed by heating at 85°C
with pꢀTSA for 4h. As a result, a number of 5ꢀCF3 pyrazoles 3a-j was prepared in high isolated yields
(Scheme 2).
1) PhNHNH2
DMSO, rt, 48h
CF3
O
R
R
N
2) pꢀTSA, 20 mol%
N
CF3
Ph
1
85 °C, 4h
3 (83ꢀ92%)
CF3
N
CF3
X
N
Ph
O
O
N
N
3a-g
N
Ph
CF3
Ph
3h, 85%
3i, 88%
3a (X = H, 85%)
3b (X = Cl, 86%)
3c (X = Br, 83%)
3d (X = Me, 88%)
3e (X = tꢀBu, 92%)
O
N
N
3f (X = OMe, 92%)
3g (X = SMe, 86%)
CF3
Ph
nꢀC6H13
3j, 85%
N
Scheme 2. Scope of the reaction of ynones 1 with phenylhydrazine to form 5ꢀCF3ꢀpyrazoles 3.
The reaction of ketones 1a-j with phenylhydrazine in HFIP showed even better results to give isomeric 3ꢀ
CF3ꢀpyrazoles 4a-j in excellent yield and regioselectivity. It should be noted that the reaction in HFIP was
found to be highly sensitive to the temperature of the reagents mixing due to significant exothermicity of the
reaction. When the starting materials were mixed at room temperature, admixture of minor isomer 3 was
formed in 5ꢀ9% yield. However, simple precooling down to 7°C of the initial ketone solution minimized the
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share of the minor isomer to ~2% in all cases. Moreover, minor isomers are easily separable by column
1
2
3
4
chromatography or recrystallization (Scheme 3).
5
6
7
8
CF3
O
PhNHNH2
7 °C rt
HFIP, 24h
R
R
N
N
CF3
1
9
Ph
4 (91ꢀ100%)
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CF3
X
N
N
4a-g
Ph
4a (X = H, 98%)
4b (X = Cl, 99%)
4c (X = Br, 99%)
4d (X = Me, 94%)
4e (X = tꢀBu, 97%)
4f (X = OMe, 97%)
4g (X = SMe, 91%)
CF3
O
N
N
Ph
4h, 100%
O
O
CF3
CF3
nꢀC6H13
N
N
N
N
Ph
4j, 94%
Ph
4i, 99%
Scheme 3. Scope of the reaction of ynones 1 with phenylhydrazine to form 3ꢀCF3ꢀpyrazoles 4.
The configuration of isomeric pyrazoles 3j and 4j with aliphatic substituent was determined on the basis of
1
1
1
13
the concerted application of H – H 2D homonuclear experiment NOESY and H – C 2D heteronuclear
experiment HMBC (Figure 2). Thus, intensive cross peaks between the resonance signals of the C5CH2 group
and both ortho protons of the benzene ring and olefinic proton were observed in the spectrum of isomer 4j. In
contrast, the presence of intensive NOE peak between olefinic and methylene protons along with the absence
of any NOE between protons of the aromatic and alkyl groups was revealed in minor isomer 3j. Moreover,
the structure of two isomeric trifluoromethylated pyrazoles was additionally confirmed by 19F NMR
spectra.5,6f
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Figure 2. Main NOESY and HMBC correlations for pyrazoles 3j and 4j.
Next, the influence of hydrazine component on the reaction scope was examined. Aryl hydrazines bearing
both electronꢀdonating and electronꢀwithdrawing substituents in the aromatic ring were evaluated in the
reaction with ynone 1a. Similarly to phenylhydrazine 2a, hydrazines 2b-j reacted with ynone 1a in DMSO to
afford 5ꢀtrifluoromethylpyrazoles 3k-t in high yields and selectivity (Scheme 4). The reaction tolerates a
wide variety of substituents (orthoꢀisopropyl, 2,6ꢀdichloro, pentafluoro) and functional groups (CO2H,
SO2NH2, CN) in the aryl moiety of hydrazine. 5ꢀTrifluoromethylated pyrazole 3s was formed exclusively in
the case of the reaction with pentafluorophenylhydrazine 2e. As a rule, in all cases the corresponding 3ꢀ
substituted isomer 4 was formed as a minor admixture (in amounts less than 1ꢀ2%). It should be noted, that
the reaction with most electronꢀpoor 2,4ꢀdinitrophenylhydrazine 2j under the same conditions afforded a
mixture of pyrazole 3q (71%), the corresponding hydrazone 7b (7%) and pyrazole 4q (7%) (Scheme 4).
However, single recrystallization permits to obtain pure product 3q very easily. Surprisingly, the reaction
with tertꢀbutylhydrazine led to a mixture of pyrazoles 3v and 4x in 3:2 ratio and the reaction with
ethylhydrazine did not give 5ꢀCF3ꢀpyrazole 3u at all to form only 3ꢀCF3ꢀpyrazole 4w in 78% yield. Such
reversed selectivity can be explained by a higher nucleophilicity of nitrogen attached to the alkyl substituent
in contrast to the aryl hydrazines.
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1) RNHNH2
DMSO, rt, 48h
1
2
3
4
5
6
7
8
CF3
R
O
Ph
Ph
N
2) pꢀTSA, 20 mol%
N
CF3
85 °C, 4h
3 (71ꢀ96 %)
Ph
3k (X = 4ꢀBr, 86%)
3l (X = 4ꢀMe, 89%)
CF3
N
9
N
3m (X = 3ꢀCF3, 95%)
3n (X = 4ꢀCN, 89%)
3o (X = 3ꢀCO2H, 94%)
3p (X = 2ꢀiꢀPr, 84%)
3r (X = 4ꢀSO2NH2, 85%)
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X
N
3k-p,r
Ph
Ph
Ph
CF3
CF3
Cl
N
CF3
C6F5
N
N
N
N
O2N
Cl
3s, 91%
NO2
CF3
3q, 71%
Ph
3t, 96%
Ph
N
CF3
N
N
N
3u, 0%
+4w, 78%
3v, 59%
+4x, 37%
Scheme 4. Scope of the reaction of 1a with various hydrazines 2 to form 5ꢀCF3ꢀpyrazoles.
It was found that the reaction in HFIP was much more sensitive to the hydrazine structure. Thus, the reaction
of the aryl hydrazines bearing electron donating substituents in the phenyl ring led to 3ꢀCF3ꢀpyrazoles 4
highly regioselectively (Scheme 5). To our delight, the reaction with highly nucleophilic ethylhydrazine
afforded regioselectively 3ꢀCF3ꢀpyrazole 4w in spite of the fact that both nitrogens in starting hydrazine have
similar nucleophilicity. At the same time the reaction with more bulky tertꢀbutylhydrazine led to a mixture of
regiosomeric pyrazoles 3v and 4x in nearly 1:1 ratio. Increase of electron withdrawing properties of the
substituents in the aryl group of hydrazine resulted in raise of 5ꢀCF3ꢀpyrazole 3 fraction in the mixture of
CF3ꢀpyrazole products. Moreover, in the case of highly electronꢀpoor 2,4ꢀdinitrophenylꢀ, 4ꢀ
aminosulfonylphenylꢀ, and polyfluorophenylhydrazine the corresponding 5ꢀCF3ꢀisomers 3q,r,s became the
major reaction products (isolated yields 82, 63, and 94% correspondingly). The reaction with
pentafluorophenylꢀ and 2,4ꢀdinitrophenylhydrazines afforded also the corresponding hydrazones (9% and
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12%) and only 4% and 2% of pyrazoles 4q,s (Scheme 5). Therefore, this approach was found to be most
applicable for the selective preparation of 3ꢀCF3ꢀpyrazoles 4 with the highly nucleophilic aryl and alkyl
hydrazines. The reaction has the significant restrictions in terms of regioselectivity for less nucleophilic
hydrazines bearing EWGs.
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Since hydrazines bearing strongly electronꢀwithdrawing groups have shown poor selectivity in the reactions
with ynones 1, we decided to find an alternative possibility for the selective assembly of the target CF3ꢀ
pyrazoles having more electronꢀdeficient aryl ring at the nitrogen. This is an especially important problem
due to a number of current drugs and drug candidates (Celebrex and its analogues) having such substituents
at the position 1 of the pyrazole core.9
CF3
Ph
RNHNH2
O
Ph
F3C
+
Ph
N
N
7 °C → rt
HFIP, 24h
N
R
N
CF3
4
R
3
73ꢀ99 %
CF3
CF3
CF3
CF3
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
N
F3C
4k, 82%
+ 3k, 11%
Br
4m, 83%
+ 3m, 6%
4n, 69%
+ 3n, 22%
NC
4l, 92%
CF3
CF3
CF3
N
CF3
CF3
Ph
Ph
Ph
Ph
Ph
C6F5
N
N
N
N
N
N
N
N
N
NO2
4s, 2%
+ 3s, 94%
CO2H
4p, 90%
+ 3p, 5%
4o, 91%
+ 3o, 8%
O2N
H2NO2S
4q, 5%
+ 3q, 82%
4r, 34%
+ 3r, 63%
CF3
CF3
CF3
N
CF3
Ph
CF3
Ph
N
N
Ph
Ph
N
N
N
N
N
Ph
N
N
4x, 44%
+ 3v, 50%
4w, 95%
4t, 90%
O
Cl
4u, 73%
4v, 75%
Scheme 5. Scope of the reaction of 1a with various hydrazines to form 3ꢀCF3ꢀpyrazoles 4.
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We found that the problem can be solved very efficiently by the use of the acidic catalysts in the reaction of
ynones 1 with hydrazines 2. The selective formation of the corresponding hydrazones 7 was observed under
these particular conditions (Table 1). It has been reported that acetylenic hydrazones can be transformed into
pyrazoles by the treatment with a base4c,10 or by the transition metals11 catalysis. Taking into account these
data, we assumed that the similar cyclization can be used for the transformation of hydrazones 7 into the
target CF3ꢀpyrazoles.
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CF3
H
R'NHNH2—HCl 2
DMSO, rt, 24h
O
base, rt, 24h
N N
CF3
R
R
N
R
R'
N
CF3
1
R'
7
4 (66ꢀ99%)
base: A ꢀ NaOH, B ꢀ tꢀBuOK, C ꢀ DBU
CF3
CF3
CF3
CF3
Ph
Ph
Ph
N
N
N
X
N
N
N
CF3
N
N
nꢀC6H13
Ph
4a,b,f,g
N
N
HO2C
4o, 99% (C)
CF3
F3C
Ph
Y
4m, 72% (C)
4j, 79% (B)
4k,n,r
4a (X = H, A ꢀ 83%; C ꢀ 94%),
4b (X = Cl, A ꢀ 72%),
4f (X = OMe, B ꢀ 86%),
4g (X = SMe, B ꢀ 80%)
4k (Y = Br, C ꢀ 69%)
4n (Y = CN, C ꢀ 70%)
4r (Y = SO2NH2, C ꢀ 81%)
Ph
N
4s, 66% (C)
N
C6F5
CF3
Ph
CF3
C
CF3
Ph
F3C
CF3
F
Ph
3
CF3
N
N
N
N
N
N
N
N
N
Ph
Ph
Cl
N
N
N
N
NO2
N
Cl
Ph
Ph
O2N
4z, 67% (C)
4y, 83% (C)
4w, 45% (C)
4x, 49% (C)
4t, 90% (C)
4q, 87% (C)
in CHCl3
Scheme 6. Synthesis of 3ꢀCF3ꢀpyrazoles 4 via intermediate formation of hydrazones.
Hydrazones 7 were easily prepared in situ by the reaction of ketones 1 with aryl hydrazine hydrochlorides
2.HCl in DMSO at room temperature; their formation was confirmed by 19F NMR spectroscopy. Next,
different reaction conditions were examined for the cyclization of intermediate hydrazones. It was found that
this reaction proceeds efficiently in the presence of the strong inorganic (NaOH) or organic (tꢀBuOK, DBU)
bases to give the target pyrazoles 4 in high yield and excellent selectivity. Both the electronꢀrich and
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electronꢀpoor hydrazones were successfully involved in the reaction (Scheme 6). It was found that the scope
of such approach was wide enough to be applicable for the bulky substituents as well as the various
functional groups in the structure of both starting hydrazine and ynone. Alkyl hydrazines were also
successfully involved into the transformation to form only 3ꢀCF3ꢀpyrazoles 4w (ethyl) and 4x (tertꢀbutyl) in
good yields. The attempt to carry out the reaction with the most electronꢀpoor 2,4ꢀdinitrophenylhydrazine
resulted in severe tarring in DMSO. However, the treatment of hydrazone 7b with DBU in CHCl3 led to
pyrazole 4q in 87% yield. Hydrazone 7b was easily prepared by the reflux of ynone 1a with 2,4ꢀ
dinitrophenylhydrazine in 5M solution of HCl in MeOH.
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As a result, the additional solventꢀswitchable procedure for the assembly of CF3ꢀpyrazoles was elaborated.
Using this approach Celebrex and SC-560 as well as the corresponding regioisomers can be prepared very
efficiently (Scheme 7). The principle advantage of this approach is its flexibility and simplicity. Very
efficient switching of the reaction direction with total regiocontrol was provided by the sequence of the same
reagents added in a oneꢀpot (ynone 1d, hydrazine 2i, DMSO, DBU) procedure. For example, when DBU was
first added to the solution of hydrochloride of 4ꢀaminosulfonylphenylhydrazine 2i in DMSO followed by the
addition of ketone 1d, the 5ꢀtrifluoromethylated pyrazole 3w was formed selectively. Alternatively, Celebrex
can be synthesized by the reaction of hydrazine 2i as hydrochloride with ynone 1d to form intermediate
hydrazone. The subsequent addition of DBU resulted in cyclization into the target drug molecule. We
demonstrated that all these syntheses can be performed in gram scale without any restrictions.
We even were able to find two types of conditions for the selective synthesis of SC-560 and its isomer 4aa.
Since the electron rich 4ꢀmethoxyꢀ and 4ꢀchlorophenylhydrazines were used in this case, the reaction can be
performed either directly in HFIP or in DMSO via intermediate hydrazone formation. Both methods provided
very high yields of the target compounds. It is important to note that the preparation of regioisomeric
pyrazoles 3x and 3y is also possible. In this case, a oneꢀpot reaction in DMSO followed by heating with pꢀ
TSA resulted in 5ꢀtrifluoromethylated products 3x and 3y in 80% and 60% yields correspondingly. It should
be noted, that there is confusion with the structure of SC-560 in the literature. In some recent articles4a,4c,12
isomer 4aa (chlorine in the aryl adjacent to N(1) atom, methoxy group in the aryl adjacent to C(5) atom) is
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named as SC-560, which is not correct. The correct structure vice versa has chlorine in aryl adjacent to C(5)
1
2
3
4
atom and methoxy group in the aryl moiety adjacent to N(1) 8,13 (Scheme 7, Figure 1).
5
6
7
1) DBU, DMSO, 1 min
8
9
2) ketone 1d, rt, 24h
CF3
3) pꢀTSA, 3h, 85 °C
N
N
10
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. HCl
NHNH2
3w, 92%
SO2NH2
SO2NH2
2i
1) ketone 1d, rt, 24h
CF3
N
N
2) DBU, DMSO, rt, 24h
Celebrex, 86%
H2NO2S
X
1) ArNHNH2, DMSO, 24h
2) pꢀTSA, 3h, 85 °C
CF3
N
N
3x (X = OMe, R = Cl, 80%)
3y (X = Cl, R = OMe, 60%)
O
X
CF3
1b or 1f
X = Cl (1b), OMe (1f)
R
X
4aa (X = OMe, R = Cl, 100%) (i)
4aa (X = OMe, R = Cl, 89%) (ii)
SC-560 (X = Cl, R = OMe, 91%) (i)
SC-560 (X = Cl, R = OMe, 79%) (ii)
i or ii
Ar = 4ꢀOMeC6H4 or 4ꢀClC6H4
i: ArNHNH2, HFIP, rt, 24h
CF3
N
N
.
ii: 1) ArNHNH2 HCl, DMSO, rt, 24h
R
2) DBU, rt, 24h
Scheme 7. Synthesis of Celebrex, SC-560, and their regioisomers
19
A possible pathway for the selective formation of either pyrazoles 3 or 4 is shown in Scheme 8. F NMR
monitoring of the reaction of phenylhydrazine 2a with ketone 1a in HFIP revealed the fast consumption of
the starting substrate (80% after 2 min and full consumption after 30 min) accompanied by a parallel
formation of pyrazole 3a and minor amounts of isomeric pyrazole 4a (Figure 3). No intermediates were
observed in the course of the reaction: all these transformations proceeded very quickly.
To get a clue the reaction mechanistic scheme, we studied a slower reacting system such as ynone 1e with
phenylhydrazine 2a in CDCl3. It was found that the first step of the transformation is a nucleophilic addition
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of phenylhydrazine 2a to the carbonyl group of ynone 1, which led to the formation of hemiaminal
intermediate 6b (Figure 4). This step of the reaction sequence proceeded rapidly to give a 1:3 mixture (19F
NMR) of the starting ketone 1e with adduct 6b in one minute at rt. The structure of 6b was elucidated by
analysis of both NMR and IR spectra. Only two singlets of tertꢀbutyl group (the initial ynone 1 and new
compound in the ratio 1:3) were presented in the 1H NMR spectrum of the reaction mixture, while no signals
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of olefinic protons were observed. At the same time, in C NMR spectrum two new singlets of Csp atoms
(82.2 and 87.8 ppm) as well as new quartet of quaternary carbon center (82.6 ppm, J = 32 Hz) were detected.
The appearance of a new peak in the 19F NMR spectrum at ꢀ82.5 ppm is also in agreement with the proposed
structure. Finally, the IR spectrum of this mixture shows two strong bands in the C≡C stretching region: at
2201 cmꢀ1 for ketone 1e and 2240 cmꢀ1 as well as a band of the OH group at 3589 cmꢀ1 for intermediate 6b.
As the reaction proceeded, the intensity of the signal at ꢀ82.5 ppm decreased while the intensity of two new
signals of pyrazole 4e (ꢀ62.4 ppm) and pyrazoline 5b (ꢀ78.4 ppm) increased.
Figure 3. Monitoring of the reaction of ynone 1a with phenylhydrazine in HFIP.
19
The structure of 5b was assigned by the comparison of its F and 1H NMR spectra with those of pyrazoline
1
5a. The most characteristic signals in H NMR spectra are doublets of the AB system of the methylene
protons at 3.59 and 3.73 ppm (J = 17.8 Hz). Disappearance of these signals accompanied by the growing of
the minor pyrazole 3e signal value in 19F NMR spectrum (ꢀ57.9 ppm) also proved its structure as well as the
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last step of cascade transformation leading to isomer 3e. Additionally, the structures of two principle
intermediates 5b and 6b (Figure 4) were confirmed by 2D NMR experiments (1H – 13C HMBC and 1H – 15N
HMBC). Thus, for structure 6b correlations in 2D 1Hꢀ15N HMBC spectra allowed to assign the signals of Ho
aromatic protons of PhNH group (7.03 ppm) by the crossꢀpeak with the signal of nitrogen atom (PhNH)
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resonating at ꢀ291.7 ppm. The narrow singlet in H NMR spectra (4.52 ppm) belongs to the second NH
1
proton and has the coupling constant J(H,N) = 80 Hz with signal at ꢀ289.5 ppm and crossꢀpeak with signal
resonating at ꢀ291.7 ppm. Moreover, correlations of NH proton singlet with carbon signals at 82.6 and 87.8
ppm in 2D spectra Hꢀ13C HMBC, which allow the assigning signals in C NMR spectra. The chemical
1
13
15
shifts of nitrogen atoms in N NMR of structure 5b were assigned by the correlations with CH2 protons: ꢀ
47.4 ppm (C=N), ꢀ222.9 ppm (NPh). At the end of the monitoring only the signals of pyrazoles 3e (ꢀ57.9
ppm) and 4e (ꢀ62.4 ppm) were observed in the 19F NMR.
Figure 4. Structures of intermediates 5b and 6b.
The reaction of ynone 1a with phenylhydrazine in DMSOꢀd6 was also very fast. We observed no signals of
the starting ketone 1a even after 1ꢀ2 min from the beginning of the NMR monitoring (Figure 5). Surprisingly,
only hemiaminal 6a (ꢀ80.5 ppm) and pyrazolinol 5a (ꢀ78.8 ppm) were found in the reaction mixture.
Moreover, conversion of 6a into 5a was observed in the course of monitoring to give pyrazoline 5a as the
only product in about 10 h. The structure of hemiaminal 6a was confirmed by the formation of hydrazone 7a
after addition of MeSO3H and heating up to 80 °C for 2h of the reaction mixture, which was obtained by the
standing of 1a and phenylhydrazine for 10 min at rt. These manipulations led to a mixture of pyrazole 3a and
hydrazone 7a in the ratio equal to that of pyrazoline 5a and hemiaminal 6a (26:74).
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Figure 5. Monitoring of the reaction of 1a with phenylhydrazine in DMSOꢀd6.
The following scheme of the reaction can be proposed on the base of NMR monitoring data obtained
(Scheme 8). The hydrazine addition to the carbonyl group leads rapidly to hemiaminal 6 both in DMSO and
HFIP. Next, the fast intramolecular cyclization of 6 takes place in HFIP to form pyrazole 4 probably through
the intermediate formation of pyrazoline 8. In contrast, in DMSO hemiaminal 6 dissociates back to ketone 1
and hydrazine 2, and their slow recombination gives enone 9 which then rapidly undergoes the
intramolecular cyclization to pyrazoline 5. These conclusions are also in good agreement with nature of the
used solvents. Most probably, highly acidic HFIP activates carbonyl group of ketone by protonation of
14
oxygen (see, for example, and references herein). On the contrary, the aprotic and highly polar DMSO is
coordinated at highly polar carbonyl group to enhance its efficient steric bulkiness and to direct nucleophile
(aryl hydrazine) to the triple bond of ynone. On the other hand the proton source is necessary for
heterocyclization of 6 into pyrazole 4. In the absence of proton in DMSO the reverse reaction of hemiaminal
6 takes place.
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Scheme 8. Possible mechanism of the reaction.
To rationalize the reasons of the observed regioselectivity of the reaction by the nature of the solvent, the
quantum chemical modeling of the reaction of ketone 1a with phenylhydrazine 2a in HFIP and DMSO was
performed. The calculations were carried out using Gaussian 09 software by DFT B3LYP with 6ꢀ311+G**
basis.15 The solvent effect was investigated by the polarized continuum model (PCM model), a specific
solvation was accounted by including of HFIP molecule (in case of HFIP) and molecule of H2O (in case of
DMSO originated from dehydration step). As a reasonable preposition, we postulated that the initial attack of
hydrazine on the carbonyl group triggers the reaction sequence leading to the 3ꢀCF3ꢀpyrazole 4a. In contrast,
Michael addition of hydrazine to the triple bond of ynone initiates the process to give 5ꢀCF3ꢀpyrazole 3a
(Schemes 8, 9).
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Scheme 9. Probable reaction pathways in DMSO (ROH=H2O) and HFIP (ROH=HFIP).
Diagrams of the energy changes for the most important steps of the reaction are presented on Figure 6. In the
case of the reaction in DMSO, the calculations showed that the addition energy to the triple bond (TS1*H2O)
is 6.7 kcal/mol lower than the addition energy to the carbonyl group (TS3*H2O), which makes the addition
to the triple bond more preferential. As a result, the reaction in DMSO should lead to 5ꢀCF3ꢀpyrazole 3a. The
similar calculation for HFIP revealed no significant difference of the corresponding transition states for the
competitive processes (TS1*HFIP) and (TS3*HFIP), allowing the addition to carbonyl to take place.
Probably, using more accurate models for accounting of the solvent effect, better accordance of the
calculated and experimental data can be achieved. We made some additional calculations with participation
of one molecule DMSO for proton transfer instead of water. In this case the barrier of TS1 dropped from 11.2
to 8.3 kcal/mol. Also energies of adducts A and 9a were found to be ~3 kcal/mol lower. The obtained results
show that in HFIP the formation of pyrazole 4a is more favorable by 2.9 kcal/mol compared to formation of
3a. The opposite situation is observed in DMSO where pyrazole 3a is more stable by 2.5 kcal/mol.
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red - addition to carbonyl
blue - addition to acetylene
1
2
E(ZPE), kcal/mol
in DMSO
in HFIP
3
4
5
6
7
8
9
17.9
20
15
15.9
TS3*H2O
TS3*HFIP
9.3
TS2*H2O
11.2
8.3
10
5
7.9
TS1*H2O
5.9
8.2
A*H2O
TS2*HFIP
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A*HFIP
TS1*HFIP
0.0
0.0
-2.6
-3.2
CF3
O
6*HFIP
6*H2O
-5
-35
-40
Ph
+
-36.1
-38.3
PhNHNH2
9*H2O
+
9*HFIP
ROH
-45
-50
-55
-60
-65
START HERE
-57.1
-59.6
4*2H2O
-61.9
3*2H2O
-64.8
3*H2O*HFIP
4*H2O*HFIP
Figure 6. ꢁE(ZPE) (kcal/mol) by B3LYP/6ꢀ311+G(d,p) for the reaction in HFIP.
Conclusions
It was found that the reaction of trifluoromethylated ynones with aryl (alkyl) hydrazines can be directed
selectively either to 3ꢀCF3ꢀpyrazoles or 5ꢀCF3ꢀpyrazoles. The reaction route can be totally controlled by the
solvent nature. The activation of the carbonyl group by very polar protic solvents such as fluorinated alcohols
leads to formation of 3ꢀCF3ꢀsubstituted pyrazoles. In contrast, polar aprotic solvents (DMSO, DMF)
coordinate with the carbonyl group to enhance its efficient steric bulkiness and to direct nucleophile to the
triple bond of ynone. The acidic catalysis favors the formation of hydrazones, transformed easily into 3ꢀCF3ꢀ
substituted pyrazoles by the treatment with a base. As a result, this study provided an efficient tool for the
selective preparation of trifluoromethylated pyrazoles. The utility of the elaborated methods was confirmed
by the gram scale synthesis of known pyrazole drugs Celebrex and SCꢀ560 as well as the corresponding
regioisomeric molecules.
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Experimental Section
1
2
NMR spectra were recorded at 600.2 and 400.1 (1H,), 150.9 and 100.6 (13C), 40.6 (15N), 564.7, 376.3, and
3
4
5
6
282.4 (19F) MHz respectively from solutions in CDCl3 and DMSOꢀd6. Chemical shifts (δ) in ppm are
7
8
9
1
13
reported with the use of the residual chloroform (7.25 for H and 77.0 for C), dimethyl sulfoxide (2.49 for
1H and 39.5 for C) as internal references. The coupling constants (J) are given in Hertz (Hz). The N and
19F chemical shifts were referenced to CH3NO2 and CFCl3, respectively. The IR spectra were recorded with a
Bruker Vertex 70 FTꢀIR spectrometer and with a portable Varian 3100 diamond ATR/FTꢀIR spectrometer.
The films of solid products for IR spectra are prepared by vaporization of corresponding solutions. The
GC/MS analyses were performed with a Shimadzu GCMSꢀQP5050A instrument (EI, 70 eV). The silica gel
used for flash chromatography was 230–400 mesh. HRMS spectra were measured at MicroTof Bruker
Daltonics and Orbitrap Elite instrument. All reagents were of reagent grade and were either used as such or
distilled prior to use. All solvents were dried by standard procedures and freshly distilled prior to use.
Synthesis of CF3-ynones 1 (general procedure): Preheated 500 mL threeꢀnecked round bottom flask
equipped with thermometer, dropping funnel (with rubber septum) and argon inlet was purged with argon
and then charged with 200 mL of dry THF and 0.1 mol of corresponding terminal acetylene. Thus obtained
solution was cooled to ꢀ60°C and 0.11 mol of nꢀBuLi (44 mL, 2.5 M solution in hexane) was added
dropwise. The reaction mixture was allowed to warm up to ꢀ20 °C and then was cooled to ꢀ60 °C. Next,
CF3CO2Et was added slowly at temperature lower than ꢀ50 °C. The reaction mixture was allowed to warm up
to room temperature (15ꢀ20 °C) and then quenched with ~100 mL of 2M HCl at 0ꢀ20 °C. Organic layer was
separated and water phase was extracted with CH2Cl2 (3x30 mL). Combined extracts were washed with
water (50 mL), dried over Na2SO4 and volatiles were evaporated in vacuo. The residue was purified by
vacuum distillation, recrystallization or by passing through short silica gel pad using appropriate hexane–
CH2Cl2 mixtures as an eluent.
13
15
10
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13
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60
1,1,1-Trifluoro-4-phenylbut-3-yn-2-one (1a). Purified by vacuum distillation (b.p. = 76ꢀ79 °C / 10 Torr).
1
Colorless oil (17.42 g, 88% yield). H NMR (400.1 MHz, CDCl3):
δ 7.43ꢀ7.47 (m, 2H, Ph), 7.54ꢀ7.59 (m,
1H, Ph), 7.66ꢀ7.69 (m, 2H, Ph). The NMR data are in agreement with previously reported.16
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4-(4-Chlorophenyl)-1,1,1-trifluorobut-3-yn-2-one (1b). Purified by passing through short silica gel pad
1
2
3
4
1
(hexane–CH2Cl2 3:1). Pale yellow crystals, m.p. 40ꢀ42 °C (14.61 g, 62% yield). H NMR (400.0 MHz,
5
6
13
CDCl3)
δ
7.43 (d, JHH = 8.5 Hz, 2H), 7.61 (d, JHH = 8.5 Hz, 2H). C NMR (100.6 MHz, CDCl3):
δ
84.0,
7
8
9
98.9, 114.8 (q, JCF = 288.2 Hz, CF3), 116.5, 129.5, 135.1, 139.3, 167.0 (q, JCF = 42.4 Hz, C=O). The NMR
data are in agreement with previously reported.17
10
11
12
13
14
15
16
17
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19
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26
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59
60
4-(4-Bromophenyl)-1,1,1-trifluorobut-3-yn-2-one (1c). Purified by vacuum distillation (b.p. = 113ꢀ116 °C
/ 10 Torr). Colorless crystals, m.p. 44ꢀ46 °C (15.43 g, 56% yield). 1H NMR (400.1 MHz, CDCl3):
JHH = 8.4 Hz, 2H, Ar), 7.60 (d, JHH = 8.4 Hz, 2H, Ar). 13C NMR (100.6 MHz, CDCl3):
δ 7.53 (d,
δ
84.0, 98.9, 114.8 (q,
19
JCF = 288.6 Hz, CF3), 116.9, 127.8, 132.4, 135.1, 167.1 (q, JCF = 42.4 Hz, C=O). F NMR (376.3 MHz,
CDCl3):
δ
ꢀ77.8. IR (ν, cm–1): 1699 (C=O), 2197 (C≡C). HRMS (ESIꢀTOF): m/z [M+OH]– Calcd for
–
C10H5BrF3O2 : 292.9431; found: 292.9432.
1,1,1-Trifluoro-4-p-tolylbut-3-yn-2-one (1d). Purified by passing through short silica gel pad (hexane–
1
CH2Cl2 3:1). Yellow oil (15.96 g, 75% yield). H NMR (400.1 MHz, CDCl3)
δ
2.43 (s, 3H, CH3), 7.26 (d,
21.8, 83.5, 101.5,
13
JHH = 8.4 Hz, 2H, Ar), 7.57 (d, JHH = 8.4 Hz, 2H, Ar). C NMR (100.6 MHz, CDCl3):
δ
114.9 (q, JCF = 288.6 Hz, CF3), 115.0, 129.7, 134.0, 143.8, 167.1 (q, JCF = 42.0 Hz, C=O). 19F NMR (376.3
ꢀ78.7. IR (ν, cm–1): 1698 (C=O), 2195 (C≡C). The NMR data are in agreement with
MHz, CDCl3):
δ
previously reported.8
4-(4-tert-Butylphenyl)-1,1,1-trifluorobut-3-yn-2-one (1e). Purified by passing through short silica gel pad
1
(hexane–CH2Cl2 3:1). Pale yellow crystals, m.p. 48ꢀ50 °C (15.20 g, 60% yield). H NMR (400.1 MHz,
CDCl3):
δ
1.33 (s, 9H, tꢀBu), 7.46 (d, JHH = 8.3 Hz, 2H, Ar), 7.61 (d, JHH = 8.3 Hz, 2H, Ar). 13C NMR (100.6
30.9, 35.3, 83.5, 101.5, 114.9 (q, JCF = 288.0 Hz, CF3), 115.0, 126.1, 134.0, 156.7, 167.2 (q,
MHz, CDCl3):
δ
JCF = 41.0 Hz, C=O). The NMR data are in agreement with previously reported.16
1,1,1-Trifluoro-4-(4-methoxyphenyl)but-3-yn-2-one (1f). Purified by passing through short silica gel pad
(hexane–CH2Cl2 3:1). Yellow oil (15.78 g, 69% yield). 1H NMR (400.1 MHz, CDCl3):
δ 3.86 (s, 3H, OCH3),
6.93 (d, JHH = 8.9 Hz, 2H, Ar), 7.62 (d, JHH = 8.9 Hz, 2H, Ar). 13C NMR (100.6 MHz, CDCl3):
δ 55.5, 84.1,
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102.5, 109.6, 114.8, 115.0 (q, JCF = 288.2 Hz, CF3), 136.3, 163.2, 167.0 (q, JCF = 41.7 Hz, C=O). The NMR
data are in agreement with previously reported.16
1
2
3
4
5
6
1,1,1-Trifluoro-4-(4-(methylthio)phenyl)but-3-yn-2-one (1g). Purified by passing through short silica gel
7
8
9
pad (hexane–CH2Cl2 3:1). Brownꢀyellow crystals, m.p. 31ꢀ33 °C (9.81 g, 40% yield). 1H NMR (400.1 MHz,
10
11
12
13
14
15
16
17
18
19
20
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22
23
24
25
26
27
28
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48
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50
51
52
53
54
55
56
57
58
59
60
13
CDCl3):
δ
2.52 (s, 3H, SCH3), 7.24 (d, JHH = 8.4 Hz, 2H, Ar), 7.56 (d, JHH = 8.4 Hz, 2H, Ar). C NMR
(100.6 MHz, CDCl3):
δ
14.3, 84.2, 101.4, 113.2, 114.8 (q, JCF = 288.6 Hz, CF3), 125.1, 134.0, 146.4, 166.8
19
(q, JCF = 42.0 Hz, C=O). F NMR (376.3 MHz, CDCl3)
δ
ꢀ78.6. IR (ν, cmꢀ1): 1689 (C=O), 2180 (C≡C).
HRMS (ESIꢀTOF): m/z [M+OH]– Calcd for C11H8F3O2S– 261.0203; found: 261.0203.
1,1,1-Trifluoro-4-(1-methoxynaphthalen-4-yl)but-3-yn-2-one (1h). Purified by recrystallization from
1
hexane. Yellow crystals, m.p. 73ꢀ75 °C (18.57 g, 67% yield). H NMR (400.1 MHz, CDCl3):
δ 4.00 (s, 3H,
OCH3), 6.69 (d, 3JHH = 8.2 Hz, 1H, Ar), 7.51 (dt, 3JHH = 8.0 Hz, 4JHH = 0.8 Hz, 1H, Ar), 7.61 (dt, 3JHH = 8.0
Hz, 4JHH = 0.8 Hz, 1H, Ar), 7.78 (d, 3JHH = 8.2 Hz, 1H, Ar), 8.11 (d, 3JHH = 8.0 Hz, 1H, Ar), 8.24 (d, 3JHH
8.0 Hz, 1H, Ar). 13C NMR (100.6 MHz, CDCl3):
CF3), 122.8, 124.8, 125.1, 126.4, 128.8, 134.8, 137.3, 160.0, 166.7 (q, JCF = 41.6 Hz, C=O). 19F NMR (376.3
=
δ
55.8, 88.9, 101.9, 103.9, 107.0, 115.2 (q, JCF = 289.0 Hz,
MHz, CDCl3):
δ
ꢀ78.0. IR (ν, cm–1): 1678 (C=O), 2175 (C≡C). HRMS (ESIꢀTOF): m/z [M+H]+ Calcd for
+
C15H10F3O2 279.0627; found: 279.0624.
1,1,1-Trifluoro-4-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)but-3-yn-2-one (1i). Purified by recrystallization
1
from hexane. Pale yellow crystals, m.p. 83ꢀ85 °C (15.38 g, 60% yield). H NMR (400.1 MHz, CDCl3):
δ
13
4.24ꢀ4.31 (m, 4H, OCH2CH2O), 6.87 (d, JHH = 8.9 Hz, 1H, Ar), 7.13ꢀ7.18 (m, 2H, Ar). C NMR (100.6
MHz, CDCl3):
δ
64.0, 64.7, 83.4, 102.0, 110.2, 114.9 (q, JCF = 288.6 Hz, CF3), 118.2, 123.0, 128.4, 143.7,
ꢀ78.7. IR (ν, cm–1): 1687 (C=O),
148.2, 166.9 (q, JCF = 41.6 Hz, C=O). 19F NMR (376.3 MHz, CDCl3):
δ
2186 (C≡C). HRMS (ESIꢀTOF): m/z [M+Na]+ Calcd for C12H7F3O3Na+: 279.0239; found: 279.0235.
1,1,1-Trifluorodec-3-yn-2-one (1j). Purified by vacuum distillation (b.p. = 71ꢀ73 °C / 12 Torr). Colorless oil
1
(16.29 g, 79% yield). H NMR (400.1 MHz, CDCl3):
δ 0.89 (t, JHH = 6.7 Hz, 3H), 1.25ꢀ1.34 (m, 4H), 1.42
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(pent, JHH = 7.3 Hz, 2H), 1.63 (pent, JHH = 7.3 Hz, 2H), 2.49 (t, JHH = 7.1 Hz, 2H). The NMR data are in
agreement with previously reported.18
1
2
3
4
5
6
7
8
Reaction of ketone 1a with phenylhydrazine 2a in various solvents (general procedure): A 3 mL screw
neck vial was charged with corresponding solvent (1 mL), ketone 1a (99 mg, 0.5 mmol) and phenylhydrazine
2a (56 mg, 0.53 mmol), and maintained for appropriate time (see main text). Next, pꢀTSA (17 mg, 0.1 mmol)
9
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60
19
was added and reaction mixture was heated at 80 °C for 4 hours. Reaction progress was monitored by F
NMR. Probes for 19F NMR were prepared by diluting of aliquote with CDCl3. The yields and ratio of
19
products were determined by F NMR as well (with the use of C6F6 or 4ꢀchlorobenzotrifluoride as internal
standard) (see Table 1).
5-(Trifluoromethyl)-1,3-diphenyl-1H-pyrazole (3a). Pale brown powder, m.p. 55ꢀ57 °C (Lit. data:19 53ꢀ54
1
°C). H NMR (400.1 MHz, CDCl3):
δ 7.14 (s, 1H, CHpyr), 7.37ꢀ7.42 (m, 1H), 7.44ꢀ7.55 (m, 5H), 7.57ꢀ7.61
19
(m, 2H), 7.89ꢀ7.92 (m, 2H). F NMR (376.3 MHz, CDCl3):
δ ꢀ58.7. The NMR data are in agreement with
previously reported.19
3-(Trifluoromethyl)-1,5-diphenyl-1H-pyrazole (4a). Light yellow powder, m.p. 85ꢀ87 °C (Lit. data:20 86ꢀ
1
13
88 °C). H NMR (400 MHz, CDCl3)
δ
6.75 (s, 1H, C4H); 7.15ꢀ7.40 (m, 10H, Ph). C NMR (100.6 MHz,
CDCl3):
δ
105.7 (q, J = 2 Hz, C4), 121.5 (q, J = 269 Hz, CF3), 125.7, 128.6, 128.8, 129.0, 129.1, 129.3,
19
129.4, 139.4 (2 Ph), 143.4 (q, J = 38 Hz, C3), 144.9 (C5). F NMR (376.5 MHz, CDCl3):
δ ꢀ62.5. IR (KBr,
cm–1): ν 1154, 1165 (CꢀF), 1557, 1596, 1645 (C=C, C=N, Ph). The NMR data are in agreement with
previously reported.4c
5-(Trifluoromethyl)-4,5-dihydro-1,3-diphenyl-1H-pyrazol-5-ol (5a). This compound was not isolated and
NMR data were obtained from reaction mixture in DMSO. 1H NMR (400.1 MHz, DMSOꢀd6):
δ 3.57 (d, JHH
= 18.9 Hz, 1H), 3.87 (d, JHH = 18.9 Hz, 1H), 7.00 (td, JHH = 7.2 Hz, JHH = 1.1 Hz, 1H), 7.29 (td, JHH = 7.4
Hz, JHH = 1.6 Hz, 2H), 7.38ꢀ7.50 (m, 5H), 7.75 (dd, JHH = 8.1 Hz, JHH = 1.5 Hz, 2H), 8.22 (br s, 1H, OH). 13C
NMR (100.6 MHz, DMSOꢀd6):
δ
44.0, 93.1 (q, JCF = 31.7 Hz, CꢀCF3), 118.8, 121.1 (q, JCF = 290.8 Hz, CF3),
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122.0, 125.6, 128.3, 128.7, 129.1, 131.4, 142.5, 146.7. 19F NMR (376.3 MHz, DMSOꢀd6):
δ ꢀ78.8. The NMR
1
2
data are in agreement with previously reported.3
3
4
5
6
7
8
1,1,1-Trifluoro-4-phenyl-2-(2-phenylhydrazino)but-3-yn-2-ol (6a). This compound was not isolated and
NMR data were obtained from reaction mixture in Et3N. 1H NMR (400.1 MHz, CDCl3):
(s, 1H), 6.22ꢀ6.27 (m, 2H), 6.47ꢀ6.51 (m, 4H), 6.62ꢀ6.69 (m, 4H), 6.71ꢀ6.76 (m, 1H). 13C NMR (100.6 MHz,
δ
4.02 (s, 1H), 5.34
9
10
11
12
13
14
15
16
17
18
19
20
21
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41
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CDCl3):
δ 81.0 (q, JCF = 31.3 Hz, CꢀCF3), 82.7, 85.1, 112.2, 117.7, 120.4, 121.8 (q, JCF = 287.5 Hz, CF3),
127.1, 127.7, 127.8, 130.6, 149.0. 19F NMR (376.3 MHz, CDCl3):
δ
ꢀ82.6.
(E)-2-(1,1,1-trifluoro-4-phenylbut-3-yn-2-ylidene)-1-phenylhydrazine (7a). Pale yellowꢀgreen needles,
m.p. 99ꢀ101 °C (Lit. data:19 97ꢀ99 °C). 1H NMR (400.1 MHz, DMSOꢀd6):
δ
7.01 (td, JHH = 6.6 Hz, JHH = 2.0
13
Hz, 1H), 7.30ꢀ7.38 (m, 4H), 7.47ꢀ7.54 (m, 3H), 7.70ꢀ7.74 (m, 2H), 10.86 (br s, 1H, NH). C NMR (100.6
MHz, DMSOꢀd6):
δ
75.6, 104.2, 112.1 (q, JCF = 38.0 Hz, CꢀCF3), 114.6, 120.5, 121.1 (q, JCF = 270.9 Hz,
19
CF3), 122.5, 128.8, 129.2, 130.2, 132.0, 142.8. F NMR (376.3 MHz, DMSOꢀd6):
δ ꢀ64.9. HRMS (ESIꢀ
TOF): m/z [M+H]+ Calcd for C16H12F3N2 : 289.0947; found: 289.0948.
+
Synthesis of pyrazoles 3 by the reaction of ketones 1 with hydrazines 2 in DMSO (general procedure):
A 3 mL screw neck vial was charged with DMSO (2 mL), aryl hydrazine 2* (1.05 mmol), corresponding
ketone 1 (198 mg, 1 mmol), and maintained for 2 days at room temperature. Next, pꢀTSA (34 mg, 0.2 mmol)
was added and reaction mixture was heated at 80ꢀ85 °C for 4 hours. After that reaction mixture was poured
into ~0.1 M solution of HCl (50 mL), extracted with CH2Cl2 (3x20 mL). The combined organic phase was
washed with water (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel using appropriate mixtures of hexane and CH2Cl2 (2:1ꢀ1:1,
3a-3m, 3p, 3s, 3t, 3v, 3x, 3y), CH2Cl2 (3n, 3q), or mixture of CH2Cl2 and MeOH (30:1, 3o, 3r, 3w). Aryl
hydrazine was generated in situ by mixing of equivalent amounts of aryl hydrazine hydrochloride and DBU.
5-(Trifluoromethyl)-1,3-diphenyl-1H-pyrazole (3a). Pale brown powder (244 mg, 85% yield). The
characterization data (m.p. and NMR) are given in previous section.
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3-(4-Chlorophenyl)-5-(trifluoromethyl)-1-phenyl-1H-pyrazole (3b). Pale yellow crystals, m.p. 62ꢀ64 °C
1
2
3
4
1
(278 mg, 86% yield). H NMR (600.2 MHz, CDCl3):
δ
7.10 (s, 1H, CHpyr), 7.44 (d, JHH = 8.4 Hz, 2H, 4ꢀ
5
6
13
ClC6H4), 7.51ꢀ7.55 (m, 3H, Ph), 7.61 (d, JHH = 6.6 Hz, 2H, Ph), 7.84 (d, JHH = 8.4 Hz, 2H, 4ꢀClC6H4). C
7
8
9
NMR (150.9 MHz, CDCl3):
δ
105.9 (q, JCF = 2.2 Hz, CHpyr), 119.6 (q, JCF = 268.5 Hz, CF3), 125.5, 127.0,
10
11
12
13
14
15
16
17
18
19
20
21
22
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24
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27
28
29
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58
59
60
19
128.9, 129.0, 129.3, 130.2, 133.9 (q, JCF = 39.6 Hz, CꢀCF3), 134.4, 139.0, 150.4. F NMR (564.7 MHz,
CDCl3)
δ
ꢀ58.7. The NMR data are in agreement with previously reported.3
3-(4-Bromophenyl)-5-(trifluoromethyl)-1-phenyl-1H-pyrazole (3c). Light yellow needles, m.p. 62ꢀ64 °C
(305 mg, 83% yield). 1H NMR (400.1 MHz, CDCl3):
δ
7.08 (s, 1H, CHpyr), 7.48ꢀ7.52 (m, 3H), 7.54ꢀ7.58 (m,
105.9 (q, JCF = 2.2 Hz, CHpyr), 119.6 (q,
13
4H), 7.74 (d, JHH = 8.6 Hz, 2H). C NMR (100.6 MHz, CDCl3):
δ
JCF = 269.1 Hz, CF3), 122.7, 125.6, 127.3, 129.1, 129.3, 130.7, 131.9, 133.0 (q, JCF = 39.4 Hz, CꢀCF3), 139.0,
19
+
150.5. F NMR (282.4 MHz, CDCl3):
δ
ꢀ58.8. HRMS (ESIꢀTOF): m/z [M+H]+ Calcd for C16H11BrF3N2 :
367.0052; found: 367.0059.
5-(Trifluoromethyl)-1-phenyl-3-p-tolyl-1H-pyrazole (3d). Pale yellow crystals, m.p. 61ꢀ64 °C (266 mg,
1
88% yield). H NMR (400.1 MHz, CDCl3):
δ
2.43 (s, 3H, Me), 7.13 (s, 1H, CHpyr), 7.29 (d, JHH = 8.0 Hz,
13
2H, 4ꢀMeC6H4), 7.48ꢀ7.55 (m, 3H, Ph), 7.60ꢀ7.64 (m, 2H, Ph), 7.83 (d, JHH = 8.0 Hz, 2H, 4ꢀMeC6H4). C
NMR (100.6 MHz, CDCl3):
δ
21.1, 105.8 (q, JCF = 1.8 Hz, CHpyr), 119.8 (q, JCF = 269.4 Hz, CF3), 125.6,
19
125.7, 128.9, 129.0, 129.1, 129.4, 133.7, (q, JCF = 39.1 Hz, CꢀCF3), 138.5, 139.2, 151.7. F NMR (282.4
MHz, CDCl3): δ
ꢀ58.5. The NMR data are in agreement with previously reported.19
3-(4-tert-Butylphenyl)-5-(trifluoromethyl)-1-phenyl-1H-pyrazole (3e). Pale yellow oil (317 mg, 92%
1
yield). H NMR (600.2 MHz, CDCl3):
δ 1.45 (s, 9H, tꢀBu), 7.18 (s, 1H, CHpyr), 7.49ꢀ7.55 (m, 3H, Ph), 7.56
(d, JHH = 8.4 Hz, 2H, 4ꢀtꢀBuC6H4), 7.65 (d, JHH = 7.3 Hz, 2H, Ph), 7.91 (d, JHH = 8.4 Hz, 2H, 4ꢀtꢀBuC6H4).
13C NMR (150.9 MHz, CDCl3):
δ
31.2, 34.6, 105.9 (q, JCF = 2.2 Hz, CHpyr), 119.8 (q, JCF = 268.5 Hz, CF3),
19
125.5, 125.6, 125.7, 128.9, 129.0, 129.1, 133.6 (q, JCF = 38.5 Hz, CꢀCF3), 139.2, 151.6, 151.7. F NMR
(564.7 MHz, CDCl3):
δ
ꢀ58.5. 15N NMR (40.6 MHz, CDCl3):
δ ꢀ169.5, ꢀ68.6. HRMS (ESIꢀTOF): m/z
+
[M+H]+ Calcd for C20H20F3N2 : 345.1573; found: 345.1573.
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5-(Trifluoromethyl)-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole (3f). Pale brown crystals, m.p. 76ꢀ78 °C
1
2
3
4
1
(Lit. data:19 m.p. 77ꢀ78 °C) (293 mg, 92% yield). H NMR (600.2 MHz, CDCl3):
δ 3.86 (s, 3H, MeO), 7.03
5
6
7
8
(d, JHH = 8.8 Hz, 2H, 4ꢀMeOC6H4), 7.10 (s, 1H, CHpyr), 7.50ꢀ7.55 (m, 3H, Ph), 7.64 (d, JHH = 7.3 Hz, 2H,
Ph), 7.88 (d, JHH = 8.8 Hz, 2H, 4ꢀMeOC6H4). 13C NMR (150.9 MHz, CDCl3):
δ
55.0, 105.5 (q, JCF = 2.2 Hz,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CHpyr), 114.1, 119.7 (q, JCF = 268.5 Hz, CF3), 124.4, 125.6, 127.0, 129.0, 129.1, 133.6 (q, JCF = 38.5 Hz, Cꢀ
19
CF3), 139.2, 151.4, 160.0. F NMR (564.7 MHz, CDCl3):
δ ꢀ58.5. The NMR data are in agreement with
previously reported.19
5-(Trifluoromethyl)-3-(4-(methylthio)phenyl)-1-phenyl-1H-pyrazole (3g). Pale brown crystals, m.p. 83ꢀ
84 °C (287 mg, 86% yield). 1H NMR (600.2 MHz, CDCl3):
δ
2.50 (s, 3H, MeS), 7.10 (s, 1H, CHpyr), 7.33 (d,
JHH = 8.4 Hz, 2H, 4ꢀMeSC6H4), 7.48ꢀ7.52 (m, 3H, Ph), 7.59 (d, JHH = 7.3 Hz, 2H, Ph), 7.82 (d, JHH = 8.4 Hz,
13
2H, 4ꢀMeSC6H4). C NMR (150.9 MHz, CDCl3):
δ 15.3, 105.7 (q, JCF = 2.2 Hz, CHpyr), 119.6 (q, JCF =
269.6 Hz, CF3), 125.5, 126.0, 126.3, 128.3, 128.9, 129.1, 133.6 (q, JCF = 39.6 Hz, CꢀCF3), 139.1, 139.2,
19
151.0. F NMR (564.7 MHz, CDCl3):
δ
ꢀ58.6. HRMS (ESIꢀTOF): m/z [M+H]+ Calcd for C17H13F3N2S+:
335.0824; found: 335.0825.
5-(Trifluoromethyl)-3-(1-methoxynaphthalen-4-yl)-1-phenyl-1H-pyrazole (3h). Pale yellow oil (313 mg,
1
85% yield). H NMR (600.2 MHz, CDCl3):
δ 4.03 (s, 3H, MeO), 6.90 (d, JHH = 8.1 Hz, 1H), 7.19 (s, 1H,
CHpyr), 7.50ꢀ7.53 (m, 1H), 7.55ꢀ7.58 (m, 2H), 7.59ꢀ7.61 (m, 1H), 7.64ꢀ7.66 (m, 1H), 7.73ꢀ7.75 (m, 3H), 8.48
13
(d, JHH = 8.1 Hz, 1H), 8.66 (d, JHH = 8.4 Hz, 1H). C NMR (150.9 MHz, CDCl3):
δ 55.3, 103.3, 109.5 (q,
JCF = 2.2 Hz, CHpyr), 119.9 (q, JCF = 268.5 Hz, CF3), 121.9, 122.2, 125.2, 125.3, 125.6, 125.7, 127.1, 127.8,
129.0, 129.1, 131.9, 132.9 (q, JCF = 38.5 Hz, CꢀCF3), 139.2, 151.7, 156.0. 19F NMR (564.7 MHz, CDCl3):
δ ꢀ
58.2. HRMS (ESIꢀTOF): m/z [M+H]+ Calcd for C21H15F3N2O+: 369.1209; found: 369.1209.
5-(Trifluoromethyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-1-phenyl-1H-pyrazole (3i). Pale yellow oil
1
(305 mg, 88% yield). H NMR (600.2 MHz, CDCl3):
δ 4.25 (s, 4H, ꢀOCH2CH2Oꢀ), 6.94 (d, JHH = 8.2 Hz,
1H), 7.03 (s, 1H, CHpyr), 7.37 (dd, JHH = 8.2 Hz, JHH = 2.0 Hz, 1H), 7.43 (d, JHH = 2.0 Hz, 1H), 7.45ꢀ7.51 (m,
3H, Ph), 7.57 (d, JHH = 7.7 Hz, 2H, Ph). 13C NMR (150.9 MHz, CDCl3):
δ 64.2, 64.3, 105.7 (q, JCF = 2.2 Hz,
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CHpyr), 114.7, 117.5, 119.0, 119.7 (q, JCF = 269.6 Hz, CF3), 125.2, 125.5, 129.0, 129.1, 133.6 (q, JCF = 38.5
1
2
3
4
19
Hz, CꢀCF3), 139.1, 143.7, 144.1, 151.2. F NMR (564.7 MHz, CDCl3):
δ
ꢀ58.6; HRMS (ESIꢀTOF): m/z
5
6
+
[M+H+] Calcd for C18H13F3N2O2 : 347.1002; found: 347.0996.
7
8
9
1
5-(Trifluoromethyl)-3-hexyl-1-phenyl-1H-pyrazole (3j). Pale yellow oil (252 mg, 85% yield). H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(600.2 MHz, CDCl3):
δ 0.89 (t, JHH = 7.0 Hz, 3H), 1.30ꢀ1.35 (m, 4H), 1.38ꢀ1.43 (m, 2H), 1.71 (pent, JHH =
7.8 Hz, 2H), 2.70 (t, JHH = 7.8 Hz, 2H), 6.61 (s, 1H, CHpyr), 7.41 (pent, JHH = 7.2 Hz, 1H), 7.43 (t, JHH = 7.2
13
Hz, 2H), 7.48 (d, JHH = 7.2 Hz, 2H). C NMR (150.9 MHz, CDCl3):
δ 13.9, 22.5, 27.9, 28.9, 29.3, 31.5,
107.6 (q, JCF = 2.2 Hz, CHpyr), 119.9 (q, JCF = 268.5 Hz, CF3), 125.5, 128.8, 128.9, 132.8 (q, JCF = 39.6 Hz,
19
CꢀCF3), 139.2, 153.7. F NMR (564.7 MHz, CDCl3):
δ
ꢀ58.5. HRMS (ESIꢀTOF): m/z [M+H]+ Calcd for
+
C16H19F3N2 : 297.1573; found: 297.1574. The NMR data are in agreement with previously reported.21
1-(4-Bromophenyl)-5-(trifluoromethyl)-3-phenyl-1H-pyrazole (3k). Pale yellow needles, m.p. 62ꢀ64 °C
(316 mg, 86% yield). 1H NMR (600.2 MHz, CDCl3):
δ
7.13 (s, 1H, CHpyr), 7.38ꢀ7.42 (m, 1H, Ph), 7.43ꢀ7.48
13
(m, 4H, Ph), 7.64 (d, JHH = 8.6 Hz, 2H, 4ꢀBrC6H4), 7.89 (d, JHH = 8.6 Hz, 2H, 4ꢀBrC6H4). C NMR (150.9
MHz, CDCl3):
δ
106.4 (q, JCF = 2.2 Hz, CHpyr), 119.6 (q, JCF = 269.4 Hz, CF3), 123.1, 125.7, 127.0, 128.7,
19
128.8, 131.4, 132.2, 133.6 (q, JCF = 39.4 Hz, CꢀCF3), 138.1, 151.8. F NMR (564.7 MHz, CDCl3):
δ ꢀ58.6.
HRMS (ESIꢀTOF): m/z [M+H]+ Calcd for C16H10BrF3N2 : 367.0052; found: 367.0050.
+
5-(Trifluoromethyl)-3-phenyl-1-p-tolyl-1H-pyrazole (3l). Pale yellow crystals, m.p. 64ꢀ66 °C (269 mg,
1
89% yield). H NMR (600.2 MHz, CDCl3):
δ
2.47 (s, 3H, Me), 7.16 (s, 1H, CHpyr), 7.34 (d, JHH = 8.1 Hz,
13
2H, 4ꢀMeC6H4), 7.40ꢀ7.44 (m, 1H, Ph), 7.46ꢀ7.53 (m, 4H, Ph), 7.94 (d, JHH = 8.1 Hz, 2H, 4ꢀMeC6H4). C
NMR (150.9 MHz, CDCl3):
δ
21.0, 105.8 (q, JCF = 1.8 Hz, CHpyr), 119.8 (q, JCF = 269.1 Hz, CF3), 125.5,
19
125.7, 128.5, 128.7, 129.6, 131.8, 133.7 (q, JCF = 39.1 Hz, CꢀCF3), 136.7, 139.4, 151.4. F NMR (564.7
+
MHz, CDCl3):
δ
ꢀ58.7. HRMS (ESIꢀTOF): m/z [M+H]+ Calcd for C17H13F3N2 : 303.1104; found: 303.1108.
5-(Trifluoromethyl)-1-(3-(trifluoromethyl)phenyl)-3-phenyl-1H-pyrazole (3m). Pale yellow oil (338 mg,
1
95% yield). H NMR (400.1 MHz, CDCl3):
δ
7.17 (s, 1H, CHpyr), 7.39ꢀ7.43 (m, 1H), 7.47 (t, JHH = 7.5 Hz,
13
2H), 7.64 (t, JHH = 7.9 Hz, 1H), 7.78 (t, JHH = 9.0 Hz, 2H), 7.87ꢀ7.94 (m, 3H). C NMR (100.6 MHz,
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1
2
CDCl3):
δ 106.8 (q, JCF = 1.9 Hz, CHpyr), 119.7 (q, JCF = 269.1 Hz, CF3Pyr), 123.7 (q, JCF = 272.4 Hz, CF3Ar),
3
4
122.7 (q, JCF = 3.0 Hz), 123.4, 125.9, 128.6, 128.8, 128.9, 129.8, 131.3, 131.9 (q, JCF = 33.5 Hz, CꢀCF3),
5
6
7
8
19
134.0 (q, JCF = 39.4 Hz, CꢀCF3), 139.6, 152.3. F NMR (376.3 MHz, CDCl3):
δ ꢀ58.5 (3F, CF3Pyr), ꢀ63.8
+
(3F, CF3Ar). HRMS (ESIꢀTOF): m/z [M+H]+ Calcd for C17H10F6N2 : 357.0821; found: 357.0823.
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
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27
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48
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53
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58
59
60
4-(5-(Trifluoromethyl)-3-phenyl-1H-pyrazol-1-yl)benzonitrile (3n). White crystals, m.p. 85ꢀ86 °C (279
mg, 89% yield). 1H NMR (400.1 MHz, CDCl3):
δ
7.17 (s, 1H, CHpyr), 7.38ꢀ7.47 (m, 3H, Ph), 7.72 (d, JHH =
13
8.7 Hz, 2H, 4ꢀCNC6H4), 7.78 (d, JHH = 8.7 Hz, 2H, 4ꢀCNC6H4), 7.83ꢀ7.87 (m, 2H, Ph). C NMR (100.6
MHz, CDCl3):
δ 107.6 (q, JCF = 2.2 Hz, CHpyr), 112.7, 117.7, 119.5 (q, JCF = 269.4 Hz, CF3), 125.5, 125.8,
128.8, 129.1, 131.0, 133.1, 133.7 (q, JCF = 39.8 Hz, CꢀCF3), 142.4, 152.6. 19F NMR (376.3 MHz, CDCl3):
δ
ꢀ
+
58.2. IR (cm–1) ν 2254 (CN), 1460, 1170, 1125. HRMS (ESIꢀTOF): m/z [M+H]+ Calcd for C17H10F3N3 :
314.0900; found: 314.0902.
3-(5-(Trifluoromethyl)-3-phenyl-1H-pyrazol-1-yl)benzoic acid (3o). Pale brown powder, m.p. 138ꢀ140 °C
(312 mg, 94% yield). 1H NMR (400.1 MHz, CDCl3):
2H), 7.56ꢀ7.61 (m, 1H), 7.77 (d, JHH = 7.8 Hz, 1H), 7.84ꢀ7.88 (m, 2H), 8.21 (d, JHH = 7.8 Hz, 1H), 8.32 (s,
δ 7.13 (s, 1H, CHpyr), 7.34ꢀ7.39 (m, 1H), 7.41ꢀ7.45 (m,
1H), 11.94 (br s, 1H, CO2H). 13C NMR (100.6 MHz, CDCl3)
δ
106.4, 119.6 (q, JCF = 269.1 Hz, CF3), 125.8,
19
127.1, 128.7, 129.2, 130.0, 130.6, 131.3, 133.8 (q, JCF = 39.4 Hz, CꢀCF3), 139.2, 151.9, 169.1. F NMR
(376.3 MHz, CDCl3):
found: 355.0658.
δ
ꢀ58.6; HRMS (ESIꢀTOF): m/z [M+Na+] Calcd for C17H11F3N2O2Na+: 355.0665;
5-(Trifluoromethyl)-1-(2-isopropylphenyl)-3-phenyl-1H-pyrazole (3p). Pale yellow oil (277 mg, 84%
1
yield). H NMR (400.1 MHz, CDCl3):
δ
1.25 (br s, 6H, CH(CH3)2), 2.51ꢀ2.62 (m, 1H, CH(CH3)2), 7.15 (s,
13
1H, CHpyr), 7.31ꢀ7.35 (m, 1H), 7.37ꢀ7.42 (m, 2H), 7.45ꢀ7.56 (m, 4H), 7.90ꢀ7.94 (m, 2H). C NMR (100.6
MHz, CDCl3):
δ 22.7 (br. s.), 24.7 (br. s.), 28.2, 104.7 (q, JCF = 1.8 Hz, CHpyr), 119.6 (q, JCF = 269.1 Hz,
CF3), 125.5, 126.0, 126.6, 127.8, 128.5, 128.8, 130.6, 131.9, 134.8 (q, JCF = 38.7 Hz, CꢀCF3), 136.5, 147.0,
19
+
151.1. F NMR (376.3 MHz, CDCl3):
δ
ꢀ60.0. HRMS (ESIꢀTOF): m/z [M+H]+ Calcd for C19H17F3N2 :
331.1417; found: 331.1418.
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5-(Trifluoromethyl)-1-(2,4-dinitrophenyl)-3-phenyl-1H-pyrazole (3q). Yellow oil (268 mg, 71% yield).
1
2
1H NMR (400.1 MHz, CDCl3):
δ
7.22 (s, 1H, CHpyr), 7.37ꢀ7.45 (m, 3H, Ph), 7.74ꢀ7.77 (m, 2H, Ph), 7.89 (d,
3
4
5
6
13
JHH = 8.7 Hz, 1H), 8.62 (dd, JHH = 8.7 Hz, JHH = 2.4 Hz, 1H), 8.94 (d, JHH = 2.4 Hz, 1H). C NMR (100.6
7
8
9
MHz, CDCl3):
δ
107.6 (q, JCF = 1.9 Hz, CHpyr), 119.3 (q, JCF = 269.4 Hz, CF3), 121.3, 126.0, 127.8, 128.9,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
129.5, 130.4, 130.5, 135.0 (q, JCF = 39.8 Hz, CꢀCF3), 136.9, 146.0, 147.9, 154.2. F NMR (376.3 MHz,
CDCl3): δ
ꢀ59.4. The NMR data are in agreement with previously reported.22
4-[3-Phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (3r). White powder, m.p. 201ꢀ203
°C (Lit. data:23 m.p. 199ꢀ201 °C) (312 mg, 85% yield). H NMR (400.1 MHz, DMSOꢀd6):
δ 7.39ꢀ7.43 (m,
1
1H, Ph), 7.46ꢀ7.50 (m, 2H, Ph), 7.59 (s, 2H, NH2), 7.78 (s, 1H, CHpyr), 7.83 (d, JHH = 8.5 Hz, 2H, 4ꢀ
13
(SO2NH2)C6H4), 7.95 (d, JHH = 8.5 Hz, 2H, 4ꢀ(SO2NH2)C6H4), 8.04 (d, JHH = 8.8 Hz, 2H, Ph). C NMR
(100.6 MHz, DMSOꢀd6):
δ
107.7 (q, JCF = 1.9 Hz, CHpyr), 119.6 (q, JCF = 269.4 Hz, CF3), 125.7, 126.2,
19
127.0, 128.9, 129.0, 130.9, 132.9 (q, JCF = 38.7 Hz, CꢀCF3), 140.9, 144.9, 151.6. F NMR (376.3 MHz,
DMSOꢀd6): δ
ꢀ56.7. The NMR data are in agreement with previously reported.23
5-(Trifluoromethyl)-1-(perfluorophenyl)-3-phenyl-1H-pyrazole (3s). Colorless crystals, m.p. 85ꢀ87 °C
(344 mg, 91% yield). 1H NMR (400.1 MHz, CDCl3):
(m, 2H, Ph). 13C NMR (100.6 MHz, CDCl3):
106.5 (q, JCF = 1.8 Hz, CHpyr), 114.2 (td, JCF = 13.6 Hz, JCF =
δ
7.19 (s, 1H, CHpyr), 7.39ꢀ7.48 (m, 3H, Ph), 7.82ꢀ7.85
δ
4.4 Hz, C6F6), 119.1 (q, JCF = 269.4 Hz, CF3), 126.0, 128.9, 129.3, 130.8, 136.2 (q, JCF = 40.2 Hz, CꢀCF3),
137.6 (dtt, JCF = 252.8 Hz, JCF = 13.3 Hz, JCF = 2.4 Hz, C6F6), 143.0 (dt, JCF = 259.9 Hz, JCF = 13.3 Hz,
C6F6), 144.7 (ddt, JCF = 257.3 Hz, JCF = 11.4 Hz, JCF = 3.1 Hz, C6F6), 154.2. 19F NMR (376.3 MHz, CDCl3):
δ
ꢀ62.0 (s, 3F, CF3), ꢀ145.3...ꢀ145.4 (m, 2F, C6F6), ꢀ150.0...ꢀ150.1 (m, 1F, C6F6), ꢀ161.4...ꢀ161.2 (m, 2F,
C6F6). HRMS (ESIꢀTOF): m/z [M+H+] Calcd for C16H7F8N2 : 379.0476; found: 379.0476.
+
1-(2,6-Dichlorophenyl)-5-(trifluoromethyl)-3-phenyl-1H-pyrazole (3t). Pale yellow crystals, m.p. 94ꢀ96
1
°C (343 mg, 96% yield). H NMR (400.1 MHz, CDCl3):
δ
7.17 (s, 1H, CHpyr), 7.38ꢀ7.42 (m, 2H, Ph), 7.44ꢀ
105.5 (q, JCF = 1.8 Hz, CHpyr), 119.2
7.49 (m, 4H), 7.88ꢀ7.91 (m, 2H, Ph). 13C NMR (100.6 MHz, CDCl3):
δ
(q, JCF = 269.4 Hz, CF3), 126.0, 128.6, 128.8, 128.9, 131.5, 131.7, 134.8, 135.0 (q, JCF = 39.4 Hz, CꢀCF3),
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