Mild and Regioselective Synthesis of 3-CF3-Pyrazoles by the AgOTf-Catalysed Reaction of CF3-Ynones with Hydrazines

Article abstract of DOI:10.1002/ejoc.201800208

Gold- and silver-catalysed reactions of trifluoromethylated ynones with aryl (alkyl) hydrazines were investigated. The use of (THD-Dipp)AuOTf and AgOTf resulted in quick heterocyclization reactions to selectively give 3-CF₃-pyrazoles. AgOTf was found to be the catalyst of choice, and various 3-CF₃-pyrazoles were formed in up to 99 % isolated yield with high regioselectivity. The reaction has a broad scope: 3-CF₃-pyrazoles with alkyl and aryl substituents as well as different functional groups can be prepared by this approach. The known pyrazole drugs Celebrex and SC-560 were efficiently prepared to demonstrate the utility of the method. Mechanistic investigations revealed that the reaction involves the formation of a hemiaminal as a key intermediate.

Full text of DOI:10.1002/ejoc.201800208

A Journal of
Accepted Article
Title: Mild and regioselective synthesis of 3-CF3-pyrazoles via AgOTf
catalyzed reaction of CF3-ynones with hydrazines
Authors: Valentine G. Nenajdenko, Maxim Topchiy, Vasiliy
Muzalevskiy, Andrey Asachenko, Mikhail Nechaev,
Vyacheslav Chertkov, and Daria Zharkova
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800208
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800208
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European Journal of Organic Chemistry
Table of contents
CF3
Ar
CF3
1 mol % AgOTf
Ar
N N
CHCl3, 1h
O
R
+
up to 99 %
24 examples
RNHNH2
Efficient synthesis of 3-CF3-pyrazoles was elaborated via silver catalyzed reaction of
trifluoromethylated ynones with aryl (alkyl) hydrazines. Very quick heterocyclization (within 1h at
rt) using AgOTf as a catalyst (1 mol %) provided highly regioselectively various 3-CF3-pyrazoles
in up to 99% isolated yield. Known pyrazole drugs Celebrex® and SC-560 were effectively
prepared to demonstrate utility of the method. The mechanism of the reaction was investigated
to reveal that reaction proceeds through the formation of hemiaminal as a key intermediate.
Key words: pyrazole, fluorine, regioselectivity, silver, catalysis
Mild and regioselective synthesis of 3-CF3-pyrazoles via AgOTf catalyzed reaction of CF3-
ynones with hydrazines
Maxim A. Topchiy,a Daria A. Zharkova,a,b Andrey F. Asachenko,a Vasiliy M. Muzalevskiy,b
Vyacheslav A. Chertkov,b Valentine G. Nenajdenko*b and Mikhail S. Nechaeva,b
aA. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, Lenynsky
Prospect 29, Moscow, Russian Federation
bDepartment of Chemistry, Moscow State University Leninskie Gory, Moscow 119992, Russia,
Fax: (+)7-495-9328846, E-mail: nenajdenko@org.chem.msu.ru
Abstract
Gold and silver catalyzed reaction of trifluoromethylated ynones with aryl (alkyl)
hydrazines was investigated. Application of (THD-Dipp)AuOTf and AgOTf resulted in quick
heterocyclization to form selectively 3-CF3-pyrazoles. AgOTf was found to be a catalyst of
choice to provide highly regioselective synthesis of various 3-CF3-pyrazoles in up to 99%
isolated yield. The reaction has broad scope, 3-CF3-pyrazoles, having alkyl- and aryl
1
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10.1002/ejoc.201800208
European Journal of Organic Chemistry
substituents, as well as different functional groups can be prepared by this approach. Known
pyrazole drugs Celebrex® and SC-560 were effectively prepared to demonstrate utility of the
method. The possible reaction mechanism was investigated to reveal that reaction proceeds
through the formation of hemiaminal as a key intermediate.
Pyrazoles are of great interest for the synthetic organic chemistry as important building
blocks.[1] These heterocycles can be found in the structure of many compounds of biological
interest.[2] Trifluoromethylated pyrazoles are especially important molecules for drug discovery,
they have demonstrated various types of biological activity and found the application as
medicines. For example Celecoxib (Celebrex®) is a selective potent COX-2 inhibitor, which is
currently used as non steroid anti-inflammatory drug having more than 2 billion dollars sales
worldwide.[3] Moreover, some CF3-substituted pyrazoles are important agrochemicals (Fig. 1).
Fig 1. Some biologically active pyrazoles.
Traditional approach to trifluoromethylated pyrazoles is a condensation of 1,3-diketones
with hydrazines.[4] This method has high efficiency in terms of the target heterocycles yields.
Unfortunately, the reaction is not regioselective in the case of the use of asymmetrical 1,3-
diketones with monosubstituted hydrazines, affording as a rule a mixture of hardly separable
regioisomers.[5a] Although a progress was achieved in this field[5b], more effective approach to
the trifluoromethylated pyrazoles is reactions of hydrazines with acetylenic ketones or enones
having leaving group in β-position.[6] Recently, novel convenient pathways towards 3- and 5-
CF3-pyrazoles based on the solvent-switchable[7] or copper catalyzed reactions of CF3-ynones
and alkyl- and arylhydrazines were reported.[8] In this work we publish mild and regioselective
synthesis of 3-CF3-pyrazoles via AgOTf catalyzed reaction of CF3-ynones with hydrazines.
However, our first idea was to use gold catalysis for this reaction.
2
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10.1002/ejoc.201800208
European Journal of Organic Chemistry
It is well known, that gold (I) species are efficient catalysts of inter- and intramolecular
hydroamination of alkynes.[9] Thus, we have previously shown[10] that utilization of the seven-
membered-ring carbine, bearing bulky Dipp groups, in combination with weakly coordinating
anions such as triflate results in extremely active catalytic systems for intramolecular
hydroamination of 2-ethynylanilines and intermolecular hydrohydrazination of alkynes leading to
the indoles and hydrazones correspondingly under unprecedentedly mild conditions.
In continuation of our investigation of (THD-Dipp)AuOTf chemistry[9f,10], we envisioned,
that utilization of (THD-Dipp)AuOTf would allow to perform regioselective transformation of CF3-
ynones into CF3-pyrazoles by the reaction with hydrazines. To start our investigation, a model
reaction of ynone 1a with phenylhydrazine 2a was investigated in various solvents at 60-80 °C
(Scheme 1). The preliminary set of experiments demonstrated that [(THD-Dipp)AuOTf]
promotes efficiently an addition of phenylhydrazine to CF3-ynone 1a in all solvents studied
(Table 1, entries 1–8). It was found that selectivity of the reaction proved to be highly sensitive
to the choice of solvent. The highest yield and selectivity in the reaction of phenylhydrazine with
1a were obtained when CHCl3 was used as a solvent (Table 1, entry 2). These conditions
provided very high yield (98 %) and nice selectivity of heterocyclization to give regioisomeric
pyrazoles in 98 to 2 ratio. Similar selectivity was observed when 1,4-dioxane was used,
however total yield was slightly lower. Other solvents were found less useful in terms of the
reaction regioselectivity.
Table 1. Influence of solvents on the (THD-Dipp)AuOTf catalyzed reaction of 1a with PhNHNH2
2a.
Total
yield
, %
Ratio
#
Solvent
T, oC
t, min
3a
4a
solvent
free
1
60
120
99
91
9
2
3
4
CHCl3
MesH
THF
60
80
60
120
240
120
98
41
94
98
83
46
2
17
54
1,4-
dioxane
5
60
120
85
98
2
3
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European Journal of Organic Chemistry
6
7
8
PhCN
MeCN
EtOH
80
60
60
240
120
120
36
97
93
20
39
90
80
61
10
Next, the nature of a catalyst was studied. As we have previously shown[10] the nature of
counter anion plays a significant role in the catalysis by gold-carbene complexes. In the case of
the reaction of phenylhydrazine with CF3-ynone similar situation was observed. Thus, [(THD-
Dipp)AuCl] revealed lower selectivity to give almost ten fold higher amount of minor 5-CF3-
pyrazole in the mixture of regioisomers. At the same time, [(THD-Dipp)AuCl] activated by AgOTf
(Table 2, entry 2) showed almost the same results to (THD-Dipp)AuOTf (Table 2, entry 1). To
exclude possible influence of Ag+ catalysis in (THD-Dipp)AuCl+AgOTf system (Table 2, entry 3),
reaction with AgOTf was performed (Table 2, entry 4). To our surprise, AgOTf was appeared to
be even more effective than (THD-Dipp)AuOTf (Table 1, entry 1). Moreover, use of AgOTf
allowed performing of the reaction at room temperature in quantitative yield and high
regioselectivity to reach ratio of isomers 99.5/0.5 (Table 2, entry 5). Other tested silver salts did
not lead to the changing of the leader (Table 2, entries 6-9). High activity showed by AgOTf
allowed reducing the reaction time to 1 h at rt (Table 1, entry 10). Cu(OTf)2 demonstrated good
effectiveness as well, but lower yield was observed (Table 2, entry 10). It should be noted, that
all investigated catalysts directed reaction course to preferable formation of 3-CF3-pyrazole 3a.
In comparison, catalyst free reaction is low selective to form mixture of target isomeric pyrazoles
in 66 to 28 ratio (Table 2, entry 12). Thus, we found highly efficient catalytic system (AgOTf-
CHCl3) to prepare selectively 3-CF3-substituted pyrazole 3a at rt within 1h. A fraction of isomeric
5-CF3-pyrazole 4a is ≤ 0.5 % and target product 3a can be easily purified by column
chromatography to be isolated in pure form.
Table 2. Influence of the catalyst on the reaction of ynone 1a with phenylhydrazine 2a.
Time, Yield, %
h
Ratio
3a
#
Catalyst
T, oC
4a
2
1
2
3
4
5
6
(THD-Dipp)AuOTf
(THD-Dipp)AuCl
60
60
60
60
rt
2
2
98
80
99
99
99
98
98
60
40
(THD-Dipp)AuCl+AgOTf
2
96.5 3.5
99.5 0.5
99.5 0.5
99.4 0.6
AgOTf
AgOTf
AgOAc
2
12
12
rt
4
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10.1002/ejoc.201800208
European Journal of Organic Chemistry
7
8
AgOTs
AgNO3
rt
rt
rt
rt
rt
rt
12
12
12
1
97
96
97
99
78
94a
99
1
99.5 0.5
96.1 3.9
99.5 0.5
99.2 0.8
9
AgF
10
11
12
AgOTf
Cu(OTf)2
no catalyst
12
24
66
28
a – Literature data. Formation of the corresponding hydrazone in 4 % yield was also observed[7].
To determine the scope of this new catalytic protocol the reaction of phenylhydrazine with
various CF3-ynones (Scheme 1) was investigated. It was found that phenylhydrazine reacts with
all CF3-ynones 2a highly regioselectively to give 3-CF3-pyrazoles 3 in almost quantitative yields.
Only in the case of most sterically hindered CF3-ynone, containing naphthalene ring, the yield
dropped slightly below 90 %. In all cases studied a fraction of isomeric 5-CF3-pyrazoles was
below 0.5-1%.
CF3
Ar
Ar
Ph
CF3
1 mol % AgOTf
O
1
+
N N
CHCl3, 1h
87-99 %
PhNHNH2
3
2a
CF3
CF3
CF3
Ph
Br
Cl
N
N
N
N
N
N
Ph
3b, 99%
3a, 99%
3c, 97%
Ph
Ph
O
CF3
CF3
O
CF3
O
N
N
N
N
N
N
3d, 94% Ph
3e, 99%
Ph
3f, 97% Ph
CF3
CF3
CF3
n-C6H13
N
N
N
O
N
N
Ph
N
3i, 98%
Ph
3g, 98%
3h, 87%
Ph
Scheme 1. Scope of ynones
Next, the influence of the hydrazine component nature was tested in the reaction with
phenyl CF3-ynone 1a. Arylhydrazines with both electron-withdrawing and electron-donating
substituents at the aromatic ring were successfully involved into the transformation to give
pyrazoles in high to quantitative yields (Scheme 2). Reaction was found to be tolerant to
different functional groups (CO2H, NO2, CN, CF3) and ortho-substituents (3n, 3q). Alkyl
hydrazines (Et, t-Bu), Boc- and tosylhydrazine can be also used in the reaction with CF3-ynone
1a to afford regioselectively 3-CF3-pyrazoles 3r-3u in 89-98 % yields.
5
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10.1002/ejoc.201800208
European Journal of Organic Chemistry
CF3
O
Ph
1a
Ph
Ar
CF3
1 mol % AgOTf
+
N N
CHCl3, 1h
89-99 %
ArNHNH2
3
2
CF3
CF3
CF3
CF3
CF3
CF3
Ph
Cl
Ph
Ph
Ph
Ph
Ph
C6F5
N
N
N
N
N
N
N
N
N
N
N
N
Cl
3l, 93%
F3C
3j, 99%
CF3
3k, 95%
3n, 99%
CF3
3o, 98%
3m, 89%
HO2C
N
Br
CF3
N
CF3
CF3
Ph
Ph
CF3
CF3
Ph
O
Ph
Ph
Ph
Ph
N
N
N
N N
N
N
N
N
O
N
N
N
S
O
NO2
O
3s, 89%
3t, 94%
3v, 98%
O2N
3u, 96%
O
3q, 89%
3p, 92%
3r, 99%
NC
Scheme 2. Scope of hydrazines
We decided to demonstrate utility of the method for the synthesis of practically important
molecules. Using elaborated approach, Celebrex® as well as perspective anti-cancer drug SC-
560 were effectively prepared in high yields using appropriate combinations of ynone and
hydrazine (Scheme 3).
Ar1
Ar2
CF3
CF3
1 mol % AgOTf
CHCl3, 1 h
Ar2NHNH2
Ar1
+
N N
1
O
2
Cl
3
CF3
N
N
CF3
N
N
O
89 %
Celebrex
S
O
H2N
93%
O
SC-560
Scheme 3. Novel AgOTf catalyzed synthesis of SC-560 and Celebrex
Previously we have studied in details and confirmed by NMR the mechanism for the
formation of 3-CF3-pyrazoles 3 in the reaction of CF3-ynones with hydrazines (Scheme 4).7 At
first step fast reversible formation of hemiaminal 5 takes place, which structure was carefully
confirmed. Next, intramolecular cyclization of 5 leads to pyrazolinol 6, which rapidly eliminates
water to give final 3-CF3-pyrazole 3 (Scheme 4). We also demonstrated, that hydrazone 7,
which is formed in the reaction as an admixture, does not transform into 3-CF3-pyrazole 3 in the
reaction conditions. Moreover, cyclization of 7 can occur under action of strong inorganic
(NaOH, KOH) or organic (DBU) bases. It has been also reported that acetylenic hydrazones
can be transformed into pyrazoles under transition metals11 catalysis. In frames of previously
confirmed mechanism for non-catalyzed reaction we proposed mechanism for Ag+ catalysed
synthesis of 3-CF3 pyrazoles by the reaction of hydrazines with CF3-ynones. After formation of
6
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10.1002/ejoc.201800208
European Journal of Organic Chemistry
intermediate 5 the triple bond makes more nucleophilic. Subsequent formation of complex with
silver 8 facilitates heterocylization. Finally, protonation of silver substituted pyrazoline
intermediate 9 makes catalytic cycle complete (“heminal pathway”, Scheme 4).
Scheme 4. Possible pathways of the reaction of CF3-ynones 1 with hydrazines 2.
Similarly to the mechanism reported for the copper catalyzed reaction of CF3-ynones with
hydrazines[8], alternative scheme of heterocyclization can be written in terms of formation of
hydrazone 7 and its silver promoted cyclization (“hydrazone pathway”, Scheme 4). To confirm
the real mechanism of the reaction we decided to prepare hydrazone 7a and check possibility of
AgOTf catalyzed cyclization of 7a into 3a. For this purpose, NMR monitoring was used. In
contrast with real observations (the reaction of ynone with hydrazines is complete within 1h), it
was turned out, that heterocyclization of 7a proceeds very slowly. Thus, in the case of 0.3 mol
% of AgOTf loading, conversion of hydrazone is only 15 % during 24 h. Increasing of catalyst
load to 7 mol % gives about 50 % conversion within 24 h (for details see SI). Full conversion
during 24h is observed if 20 mol % of AgOTf was used. We tested also several other silver,
copper and gold salts for the cyclization of 7 into 3. It was found that AuCl·Me2S, AgNO3,
Cu(OAc)2·2H2O are almost inactive for such cyclization of hydrazone 7a to give very small
conversion (3-7 %) of 7a within 48-72h. Cu(OTf)2 does not catalyze cyclization of 7a at all.
Cyclization of electron-deficient hydrazone 7b derived from 2,4-dinitrophenyl hydrazine does not
take place even under action of AgOTf. In contrast, the reaction of CF3-ynone 1a with
phenylhydrazine proceeds in few minutes at catalysis with 1 % of AgOTf (Table 1). So, we can
conclude, that investigated reaction does not involve hydrazone 7 as a reactive intermediate, in
contrast to the previously published data.[8]
7
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European Journal of Organic Chemistry
Ph
Ar
CF3
catalyst
Ph
CF3
N
N NH
CHCl3, r.t.
N
7
Ar
3
Ar=Ph, a; 2,4-diNO2C6H3, b
Table 3. Influence of the catalyst on the cyclization of hydrazones 7.
Catalyst,
mol %
0.3
7
Conversion
of 7, %a
Yield
of 3, %a
#
Catalyst
Ar
Time, h
1
2
3
4
AgOTf
AgOTf
AgOTf
AgOTf
Ph
24
24
24
72
72
72
48
48
48
15
50
100
0
15
50
96b
0
Ph
Ph
2,4-diNO2C6H3
Ph
20
10
5 Cu(OAc)2·2H2O
10
3
3
6 Cu(OAc)2·2H2O 2,4-diNO2C6H3
10
0
0
7
8
9
Cu(OTf)2
AuCl·Me2S
AgNO3
Ph
Ph
Ph
10
0
0
10
7
7
10
6
6
a – NMR data; b- isolated yield.
Next, we investigated the possibility of hemiaminal 5 to be a key intermediate of the
reaction. For that purpose solutions of phenylhydrazine and CF3-ynone 1a were mixed in CDCl3,
left for few minutes to form hemiaminal 5, (the signal of 5 appeared at ~ –83 ppm which is in
agreement with previously published 19F NMR data for this molecule7). Next, AgOTf was added
19
and F NMR monitoring was carried out. It was found that addition of 1 mol % of AgOTf led to
instantaneous cyclization of hemiaminal 7 into 3-CF3-pyrazol 3a just after the mixing of the
reagents. Similarly, reaction catalyzed with 0.4 mol % has finished before the first 19F NMR
were managed to measure. Decreasing of AgOTf load to 0.2 mol % allowed to slow down the
transformation and to perform 19F NMR monitoring. Thus, in the beginning of monitoring (20 min
after mixing of ketone 1a and hydrazine), the main compounds in the mixture were ketone 1a
(~46%) hemiaminal 5 (~46%) and pyrazole 3a (~4%). After addition of AgOTf consumption of
both 1a and 5a were observed along with increasing of pyrazole 3a amount (Figure 2).
8
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10.1002/ejoc.201800208
European Journal of Organic Chemistry
Figure 2. 19F NMR monitoring of AgOTf induced transformation.
Monitoring was maintained for 3h to revealed almost full transformation of ketone 1a and
hemiaminal 5a (for details of kinetic parameters see SI). At the end of monitoring the main
product was pyrazole 3a (77 % yield by NMR). It should be noted, due to the low amount of
AgOTf (0.2 mol %) non catalyzed reaction makes noticeable contribution to cause formation of
5-CF3-pyrazol 4a (8 %) and hydrazone 7a (10 %). Moreover, 0.1 mol % of AgOTf does not show
influence on the reaction course to give products ratio same to non-catalyzed reaction (4a 36 %,
3a 57 %, 7a 5 %, compare with Table 2, entry 12. See also SI). The loss of AgOTf activity at low
concentration can be explained by formation of inactive silver species resulting from reactions
with traces admixtures in solvent (e.g., AgCl by the reaction with HCl in chloroform) or reactants.
Conclusions
It was found that (THD-Dipp)AuOTf and AgOTf can catalyze effectively the reaction of
trifluoromethylated ynones with aryl (alkyl) hydrazines to form selectively 3-CF3-pyrazoles in up
to 99% yields in few minutes. The admixture of minor 5-CF3-pyrazole is less than 0.5% and can
be easily eliminated by column chromatography. The broad synthetic potential of the reaction
was demonstrated by the synthesis of various pyrazoles, having alkyl- and aryl substituents, as
well as different functional groups. Using this method known pyrazole drugs Celebrex® and SC-
560 were effectively prepared. The investigation of reaction mechanism showed, that reaction
proceeds through the formation of hemiaminal as a key intermediate. The role of Ag+ is in a
formation of complex with hemiaminal to facilitate its cyclization.
9
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10.1002/ejoc.201800208
European Journal of Organic Chemistry
Experimental part
General Remarks: NMR spectra were recorded at 600.2 and 400.1 (1H), 150.9 and
100.6 (13C), 376.3 (19F) MHz respectively from solutions in CDCl3. Chemical shifts (δ) in ppm
1
13
are reported with the use of the residual chloroform signals (7.26 for H and 77.16 for C) as
internal references.[12] The 19F chemical shifts were referenced to C6F6 (-162.9). Coupling
constants J are given in Hertz as positive values regardless of their real individual signs. The
coupling constants (J) are given in Hertz (Hz). The multiplicity of the signals is indicated as ‘‘s”,
‘‘d”, “t” or ‘‘m” for singlet, doublet, triplet or multiplet, respectively. The abbreviation ‘‘br” is given
for broadened signals. The silica gel used for flash chromatography was 230–400 mesh. 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. CF3-Ynones 1 and
hydrazones 7 were prepared as reported previously. [7] The NMR data of all compounds are in
agreement with previously reported: 3a-l, 3n-t, SC-560 and Celebrex[7]; 3m[8a]; 3v[13] (for NMR
data see SI file).
General procedure for the preparation of CF3-pyrazoles
A screw cap vial equipped with magnetic stir bar was charged with 2.5 mg (1 mol %) of AgOTf,
1 mmol of corresponding CF3-ynone and 0.5 ml of dry CHCl3. The reaction mixture was stirred
for 5 min, and then the solution of 1 mmol of substituted hydrazine in 0.5 ml of dry CHCl3 was
added. The reaction mixture was allowed to stir at room temperature for 1 h and filtered through
1 cm pad of silica gel and washed with CHCl3 for several times. The filtrate was concentrated to
give a crude product, which was purified by flash chromatography (eluent –
hexane/dichloromethane 5:1 or pure dichloromethane).
1,5-Diphenyl-3-(trifluoromethyl)-1H-pyrazole (3a). White solid (284 mg, 99 % yield),
m.p. 86-87 °C (lit. data[7]: m.p. 85-87°C).
1-Phenyl-5-p-tolyl-3-(trifluoromethyl)-1H-pyrazole (3b). Colorless oil (299 mg, 99 %
yield).
5-(4-Chlorophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole (3c). White solid (311
mg, 97 % yield), m.p. 78-79 °C (lit. data[14]: m.p. 80 °C).
5-(4-Bromophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole (3d). Light yellow solid
(345 mg, 94 % yield), m.p. 104-105 °C (lit. data[7]: m.p. 104-106 °C).
5-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole
(3e). Beige solid (343 mg, 99 % yield), m.p. 122-123 °C (lit. data[7]: m.p. 122-124 °C).
10
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10.1002/ejoc.201800208
European Journal of Organic Chemistry
5-(4-Methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole (3f). Light yellow oil
(309 mg, 97 % yield).
5-(4-tert-Butylphenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole (3g). Light yellow
needles (337 mg, 98 % yield), m.p. 106-107 °C (lit. data[7]: m.p. 107-108 °C).
5-(4-Methoxynaphthalen-1-yl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole (3h). Light
brown solid (321 mg, 87 % yield), m.p. 90-91 °C (lit. data[7]: m.p. 91-93 °C).
5-Hexyl-1-phenyl-3-trifluoromethyl-1H-pyrazole (3i). Light yellow oil (289 mg, 98%
yield).
5-Phenyl-1-p-tolyl-3-(trifluoromethyl)-1H-pyrazole (3j). Light yellow solid (300 mg, 99
% yield), m.p. 86-87 °C (lit. data[7]: m.p. 86-88 °C).
1-(4-Bromophenyl)-5-phenyl-3-(trifluoromethyl)-1H-pyrazole (3k). Light yellow solid
(349 mg, 95 % yield), m.p. 72-73 °C (lit. data[7]: m.p. 73-74 °C).
1-(Perfluorophenyl)-5-phenyl-3-(trifluoromethyl)-1H-pyrazole (3l). White solid (352
mg, 93 % yield), m.p. 79-80 °C (lit. data[7]: m.p. 79-81 °C).
4-(5-Phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoic acid (3m). Light yellow solid
(297 mg, 89 % yield), m.p. 154-155 °C (lit. data[8a]: m.p. 79-81 °C).
5-Phenyl-3-(trifluoromethyl)-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole (3n). Light
yellow solid (353 mg, 99 % yield), m.p. 66-67 °C (lit. data[7]: m.p. 66-68 °C).
1-(2,6-Dichlorophenyl)-5-phenyl-3-(trifluoromethyl)-1H-pyrazole (3o). White solid
(350 mg, 98 % yield), m.p. 63-64 °C (lit. data[7]: m.p. 62-64 °C).
4-(5-Phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (3p). Light yellow solid
(288 mg, 92 % yield), m.p. 89-90 °C (lit. data[7]: m.p. 88-90 °C).
1-(4-Methoxyphenyl)-5-phenyl-3-(trifluoromethyl)-1H-pyrazole (3q). Beige solid (284
mg, 89 % yield), m.p. 76-78 °C (lit. data[7]: m.p. 78-79 °C).
1-(2,4-Dinitrophenyl)-5-phenyl-3-(trifluoromethyl)-1H-pyrazole (3r). Light yellow oil
(375 mg, 99 % yield).
1-Ethyl-5-phenyl-3-trifluoromethyl-1H-pyrazole (3s). Light yellow oil (212 mg, 89%
yield).
1-tert-Butyl-3-(trifluoromethyl)-5-phenyl-1H-pyrazole (3t). Colorless solid (253 mg,
94% yield), m.p. 92-94 °C (Lit. data:[7] m.p. 92-94 °C).
5-Phenyl-1-tosyl-3-(trifluoromethyl)-1H-pyrazole (3u). White solid (353 mg, 96 %
yield), m.p. 103-104 °C. 1H NMR (600 MHz, CDCl3) δ 7.64 – 7.61 (m, 2H), 7.53 – 7.49 (m, 1H),
7.47 – 7.43 (m, 2H), 7.39 – 7.35 (m, 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.51 (s, 1H), 2.42 (s, 3H). 13C
NMR (151 MHz, CDCl3) δ 148.9, 146.6, 145.4, 134.1, 130.2, 130.2, 130.1, 128.6, 128.3, 128.1,
11
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10.1002/ejoc.201800208
European Journal of Organic Chemistry
19
120.4 (q, J = 270.7 Hz), 108.7, 21.9. F NMR (376.3 MHz, CDCl3):  -64.3. HRMS (ESI-TOF):
m/z [M+H]+ Calcd for C17H14F3N2O2S+: 367.0723; found: 367.0724.
tert-Butyl 5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-carboxylate (3v). Colorless
needles (307 mg, 98 % yield), m.p. 76-78 °C.
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(Celebrex). Pale yellow powder, m.p. 160-161 °C (Lit. data:[7] m.p. 160-161 °C) (340 mg, 89%
yield).
5-(4-Chlorophenyl)-3-(trifluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazole (SC-560).
Yellow oil (326 mg, 93% yield).
Acknowledgements
This work was supported by the Russian Science Foundation (RSF) grant number 17-73-
20023. 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 to Prof. A.Makarov for providing
mass spectrometry equipment for this work.
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