Sequential one-pot three-step synthesis of polysubstituted 4-(5-(trifluoromethyl)-1: H -pyrazol-4-yl)-1 H -1,2,3-triazole systems

Article abstract of DOI:10.1039/c7ra07960e

This work reports a successful one-pot three-step protocol for the synthesis of a new series of 15 examples of polysubstituted 4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazoles, in which sequential Sonogashira cross-coupling, desilylation, and a

Full text of DOI:10.1039/c7ra07960e

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Sequential one-pot three-step synthesis of
polysubstituted 4-(5-(trifluoromethyl)-1H-pyrazol-
4-yl)-1H-1,2,3-triazole systems†
Cite this: RSC Adv., 2017, 7, 43957
a
*
Helio G. Bonacorso,
Gean M. Dal Forno,a Carson Wiethan,a Alex Ketzer,a
Nilo Zanatta,a Clarissa P. Frizzo,a Marcos A. P. Martins
and Mark Stradiotto
a
b
This work reports a successful one-pot three-step protocol for the synthesis of a new series of 15 examples
of polysubstituted 4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazoles, in which sequential
Sonogashira cross-coupling, desilylation, and a copper(I)-catalyzed azide–alkyne cycloaddition reaction
(CuAAC) with an overall yield of up to 72% were used. The presence of a trifluoromethyl substituent
attached to the pyrazole moiety made the Sonogashira cross-coupling reaction challenging. Additionally,
the selection of the ancillary ligand XPhos was essential and indispensable for the desired heterocyclic
construction.
Received 19th July 2017
Accepted 6th September 2017
DOI: 10.1039/c7ra07960e
rsc.li/rsc-advances
numerous challenges encountered in pharmaceutical candidate
optimization.1
Introduction
Given our shared interest in the synthesis of uorinated
nitrogenous heterocycles with potential pharmacological
application,4 in a recent publication we disclosed cross-
coupling reactions involving 4-halo-5-triuoromethyl-1H-pyr-
azoles, in order to achieve the related tetrasubstituted struc-
tures.5 Despite such success, cross-coupling reactions of this
type involving organometallic reagents derived from nitrogen-
containing heterocycles continue to represent a signicant
challenge.
Due to their broad spectrum of biological properties, ve-
membered nitrogen heterocycles with triuoromethyl moie-
ties represent sought-aer motifs in many elds of medicinal
chemistry, biology, materials science, and agriculture.1 Several
triuoromethylated azole cores are present in many of the
prescribed and/or protable drugs commercialized in the U.S.
pharmaceutical market. As an example, sitagliptin is an anti-
diabetic drug that was the eenth most prescribed drug
overall in 2015, generating $ 2.8 billion; while celecoxib – which
is a nonsteroidal anti-inammatory drug – generated $ 2.2
billion in the U.S. market in the same year (Fig. 1).2
Notably, 20–30% of approved drugs, and about 40% of the
new compounds entering phase III trials, possess at least one
uorine atom in their structure.2 This trend is mainly due to the
nature of the uorine atom, which furnishes specic physico
chemical properties such as: the introduction of uorine groups
to aromatic compounds, which increases the lipophilicity and
metabolic stability of the molecule in vivo; and stronger elec-
trostatic interaction with the receptors that bind the
compounds more tightly in the active sites of the enzymes.3 The
increasing use of uorine atoms in active pharmaceutical
ingredients parallels advances in understanding of physico-
chemical attributes, and it gives an enhanced appreciation of
how these unique properties can be exploited to address the
Given the established anticancer,7 antimycobacterial,8 CB1
receptor ligand,9,10 antibacterial,11 and nematicidal12,13 proper-
ties of heterocyclic systems containing pyrazole-1,2,3-triazole
a
´
´
´
Nucleo de Quımica de Heterociclos – NUQUIMHE, Departamento de Quımica,
Universidade Federal de Santa Maria, 97105-900 Santa Maria, Brazil. E-mail: helio.
bonacorso@ufsm.br
bDepartment of Chemistry, Dalhousie University, Halifax, NS, B3H 4R2 Canada
† Electronic supplementary information (ESI) available: Copies of NMR spectra.
See DOI: 10.1039/c7ra07960e
Fig. 1 Some fluorinated azoles and pyrazolyl-1,2,3-triazoles with
biological activity.
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Scheme
1 Sequential one-pot, three-step synthesis of 4-(5-(tri-
fluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazoles.
scaffolds (Fig. 1), we were encouraged to develop an efficient
and useful protocol for obtaining 4-(pyrazol-4-yl)-1H-1,2,3-tri-
azole systems, seeking to avoid some limitations associated
with coupling reactions involving triuoromethyl-substituted
pyrazole precursors.5,6
Scheme
3a–d.
2
Synthesis of 4-bromo-5-(trifluoromethyl)-1H-pyrazoles
Thus, we envisioned the possibility of performing Sonoga-
shira coupling and copper(I)-catalyzed azide–alkyne cycloaddi-
tion (CuAAC) in a one-pot fashion. The Pd(0) catalyzed cross-
coupling reaction of 4-bromo-5-triuoromethyl-1H-pyrazole
with ethynyltrimethylsilane (TMSA) would furnish the alkyne-
containing TMSA-5-triuoromethyl-1H-pyrazoles, which, aer
in situ uorine deprotection, would give terminal alkyne inter-
mediates. The Cu(I)-catalyzed reaction (CuAAC) is a click reac-
tion, in which the reaction involving an azide and the terminal
4-ethynyl-5-triuoromethyl-1H-pyrazoles would give direct
access to 4-(5-(triuoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-tri-
methoxyphenyl)pyrazole, the formation of another non-
separable mixture of monobrominated products (both rings)
and the starting pyrazole was observed. However, when we
applied the same reaction conditions to the 3-(4-uorophenyl)
pyrazole, the formation of the desired monobrominated pyr-
azole 3c was observed as a single product in 92% yield. The
structurally simple 4-bromo-1-phenylpyrazole 3d was prepared
in 38% yield, from the bromination reaction of 4-ethoxy-1,1,1-
triuorobut-3-en-2-one 1d via a cyclocondensation reaction
involving the brominated enone 1e and phenylhydrazine, in
accordance with a procedure described in the literature.16,17
With the starting materials 3a–d in hand, we turned our
attention towards targeting an expedient protocol for the
Sonogashira cross-coupling reaction between trimethylsilyla-
cetylene (TMSA) and 4-bromo-5-triuoromethyl-1H-pyrazole 3a
– see Table 1. The presence of a triuoromethyl group makes
these substrates less reactive, and, consequently, Pd-catalyzed
alkyne coupling transformations become a challenge that has
to be overcome. However, according to the literature, for the
activation of less reactive substrates, the simple PPh3 or other
triarylphosphines have proven to be ineffective.18 In keeping
with this trend, poor results were obtained in an initial test
involving the reaction between 3a and TMSA, following
a procedure similar to that in the literature,19 but using: 3 mol%
Pd(OAc)2, 6 mol% PPh3, and 6 mol% CuI aꢀs the catalyst; Et3N as
azoles, in
Selected examples in the literature detail the synthesis of a 4-
(1H-pyrazol-4-yl)-1H-1,2,3-triazole by similar approach;
a one-pot sequential metal-catalyzed reaction.
a
however, this pyrazolyl-triazole did not have a triuoromethyl
group in the pyrazole core.14 The presence of an electron-
withdrawing group like CF3 would make the Sonogashira
cross-coupling difficult, and hinder the synthesis of the
compounds proposed herein.
In this work we disclose the Sonogashira cross-coupling,
desilylation, and CuAAC in a sequential one-pot three-step
reaction – which is summarized in Scheme 1 – for the
synthesis of a new series of 15 examples of a polysubstituted 4-
(5-(triuoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazole system.
Results and discussion
We commenced our investigations by targeting an expedient the base; and DMF as the solvent, at 100 C in an argon atmo-
route for the synthesis of 4-bromo-5-(triuoromethyl)-1H-pyr- sphere. As expected, this reaction provided a conversion rate of
azoles 3a–d, for use as starting materials for the proposed study only 18% for 4a.
(Scheme 2). Compounds 2a–c were prepared by the cyclo-
To address this difficulty, a screening involving several
condensation reaction of 1,1,1-triuoro-4-methoxy-alken-2-ones highly effective, bulky electron-rich dialkylbiarylphosphine
(1a–c) and phenylhydrazine, following procedures found in the ligands (L1–L5) – with Pd(OAc)2 as the catalyst, Et3N as the base,
literature.15 The starting materials 3a–d were obtained by the and MeCN as the solvent, at 110 ꢀC in an argon atmosphere
subsequent bromination reaction of 2a–c with NBS, following (Table 1, entries 1–5) – was performed. These ligands have been
a procedure that we described previously.5 Seeking to increase used in a variety of transformations especially in Pd-catalyzed
the scope of this reaction, we also tried to expand this bromi- carbon–carbon, carbon–nitrogen, and carbon–oxygen bond-
nation methodology to aryl substituents attached to the 3- forming processes – for the synthesis of pharmaceuticals,
position of the pyrazole ring. When we used the same reaction natural products, polymers, and new materials.20
condition for a 3-(furan-2-yl)pyrazole, the formation of a non-
Among the ve different phosphine ligands tested, the best
separable mixture of dibrominated (both rings) and mono- conversion was found with 3 mol% of Pd(OAc)2 and 6 mol% of
brominated products was observed via GC. For the 1-(4- XPhos (L4) – see Table 1, entry 5. Xphos was previously reported
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as tetrabutylammonium uoride (TBAF), uorine salts,23 or
silver salts24 – to give terminal alkynes. We chose CsF as the
reagent for deprotecting TMSA-5-triuoromethyl-1H-pyrazole 4a
in order to generate the terminal alkyne 5a, which subsequently
reacted with 1.5 equivalents of benzyl azide and 10 mol% of CuI
to furnish the 4-(5-(triuoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-
triazole 6a (Table 2).
Table 1 Optimization of the Sonogashira coupling of 4-bromo-3-
methyl-5-(trifluoromethyl)-1H-pyrazolea
Entry
Solvent
Ligand
T (ꢀC)
Conversionb [%]
In optimizing the temperature we observed that when the
reaction was conducted at 25 ꢀC, only the 4-ethynyl-5-tri-
uoromethyl-1H-pyrazole 5a was isolated (Table 2, entry 1).
However, with an increase in temperature, the formation of the
desired product was observed (Table 2, entries 2–4). When the
reaction was conducted at 100 ꢀC, decomposition of the product
and a lower yield than that obtained at 80 ꢀC was observed. The
use of 3 equiv. of CsF was necessary to obtain an optimal yield
(Table 2, entry 5). The worst yield resulted when we tried to
substitute the use of pre-formed benzyl azide with the in situ
formation of benzyl azide, by adding equimolar quantities of
benzyl chloride and NaN3 to the reaction (Table 2, entry 6).
Given the optimized reaction conditions (Table 2, entry 5),
the scope for the synthesis of 4-(5-(triuoromethyl)-1H-pyrazol-
4-yl)-1H-1,2,3-triazoles was explored – the results are shown in
Table 3. We investigated the scope of the azide in this reaction
by exploring the reactivity of different benzyl, alkyl, and aryl
azides. The best results were obtained for the benzyl azides,
while the worst results were noted for the alkyl and aryl azides.
1
2
3
4
5
6
7
8
MeCN
MeCN
MeCN
MeCN
MeCN
THF
DMF
DMF
DMF
DMF
CyJohnPhos (L1)
JohnPhos (L2)
tBuXPhos (L5)
SPhos (L3)
XPhos (L4)
XPhos (L4)
XPhos (L4)
XPhos (L4)
XPhos (L4)
XPhos (L4)
110
110
110
110
110
65
100
25
50
28
33
19
77
94
31
98 (83)d
32
81
89
9
10c
100
a
Reaction conditions: pyrazole 3a (0.5 mmol), TMSA (0.75 mmol), Et3N
b
(1.5 mmol), and solvent (2 mL). Conversion determined by GC.
c
d
1.5 mol% of Pd(OAc)2 and 3 mol% of ligand were used. Isolated
yield aer column chromatography.
Table 2 One-pot, three-step optimization: Sonogashira coupling,
TMS desilylation, and CuAACa
like an active ligand in copper-free Sonogashira coupling reac-
tion with various aryl chlorides and tosylates in the presence of
PdCl2(CH3CN)2;18 or aryl(heteroaryl) halides in combination
with precatalyst in continuous-ow21 or by copper-free Sono-
gashira coupling of aryl chlorides on charcoal,22 or by Negishi
cross-coupling reaction of triuoromethylated 1H-pyrazoles.5
In light of a previous report stating that copper suppresses
the desired transformation,18 we chose a copper-free version,
which, under such conditions, is also known as the Heck
alkynylation.
We next focused on studying the effect of solvent on the
reaction, including transformations in THF at 65 ꢀC and DMF at
100 ꢀC (Table 1, entries 6–7). The best conversion was observed
when the reaction was conducted in DMF at 100 ꢀC. The effects
of lowering the reaction temperature were also investigated. We
observed that a reduction in reaction temperature from 100 ꢀC
to 25 ꢀC and 50 ꢀC signicantly decreased the conversion
observed, from 98% to 32% and 81%, respectively (Table 1,
Entry
CsF (eq.)
T (ꢀC)
t (h)
Yieldb [%]
1
2
3
4
5
6c
7
8
9
2
2
2
2
3
3
3
3
3
25
50
80
100
80
80
100
80
24
24
24
24
24
24
24
16
24
0d
40
58
45
72
64
61
64
63
ꢀ
entries 8–9), which indicates that 100 C was probably close to
the optimal temperature for this reaction. Finally, the effects of
lowering the catalyst concentration to 3 mol% of XPhos and
1.5 mol% of Pd(OAc)2 resulted in low conversion (Table 1,
entry 10).
60
a
Aer establishing the best reaction condition for Sonoga-
Reaction conditions: pyrazole 3a (0.5 mmol), Pd(OAc)2 (3 mol%),
shira coupling (Table 1, entry 7), we next turned our attention to XPhos (6 mol%), TMSA (0.75 mmol), Et3N (1.5 mmol), DMF (2 mL),
b
CuI (10 mol%), and PhCH2N3 (0.75 mmol). Isolated yields aer
optimizing the sequential desilylation-CuAAC cycloaddition in
a one-pot fashion. It has previously been reported that TMS
c
column chromatography. Benzyl chloride (0.75 mmol) and NaN3
(0.75 mmol) were used instead of benzyl azide. d 5a was isolated.
acetylenes can be deprotected by using several reagents – such
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Table
Paper
3
Sequential one-pot three-step synthesis of 4-(5-(tri-
We also utilized uorinated azides, such as 1-azido-4-
uorobenzene and 2-(azidomethyl)-1,3-diuorobenzene, given
the biological potential that these compounds may have.
Compound 6i feature the (2,6-diuorobenzyl)-1,2,3-triazole
fragment, that is present in the anticonvulsant Runamide,
a drug which is used in combination with other medication and
therapy to treat Lennox–Gastaut syndrome and various other
seizure disorders.25 All the new products were fully character-
ized on the basis of GC-MS and 1H/13C NMR spectroscopic data,
as well as elemental analysis or high-resolution mass spectro-
metric data. For the nal compounds 6a–o, the 13C{1H} NMR
spectra recorded in CDCl3 displayed a through-space 13C–19F
spin–spin coupling between the uorine atoms of the CF3 group
and the C-5 carbon of the triazole. The signal for the hydroge-
nated C-5 carbon of the triazole was observed in the range of
121.1–123.8 ppm, as a broad singlet or a quartet with a JCF
between 2–4 Hz. The 19F NMR spectra were recorded for
representative compounds. The CF3 signals appeared as
a singlet, in average at ꢁ55.3 ppm because are very little inu-
enced by both electronic and steric effects. Notably, the average
yield obtained for 6a–o (51%) corresponds to an 80% yield
across each of the three synthetic steps involved in our one-pot
protocol (Sonogashira cross-coupling, desilylation, and cop-
per(I)-catalyzed azide–alkyne cycloaddition).
fluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazolesa,b
Conclusions
In summary, we successfully developed a new one-pot, three-
step protocol for the synthesis of a series of 15 examples of
polysubstituted 4-(5-(triuoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-
triazoles, by employing
a sequential Sonogashira cross-
coupling, desilylation, and copper(I)-catalyzed azide–alkyne
cycloaddition (CuAAC). The presence of a triuoromethyl group
in the pyrazole core made Sonogashira cross-coupling a chal-
lenge, and the selection of ancillary ligand XPhos was indis-
pensable for the desired heterocyclic transformation in search
of new bioactive molecules. The new useful method applied
successful to pyrazoles in this work creates the possibility also
for other azoles containing electron-withdrawing groups.
Experimental section
General considerations
Unless otherwise indicated, all reagents and solvents used were
obtained from commercial suppliers and were used without
further purication. The THF was puried by reuxing over Na/
benzophenone, followed by distillation. The DMF and MeCN
˚
were puried and stored over activated 4 A molecular sieves.
Column chromatography was performed on silica gel (230–400
mesh). The melting points were determined using glass capil-
lary tubes in the Electrothermal MEL-TEMP 3.0 apparatus, with
uncorrected values. 1H and 13C spectra were acquired on
a Bruker DPX 400 (1H at 400 MHz and 13C at 100 MHz) or
a Bruker Avance III HD 600 (1H at 600 MHz and 13C at 150 MHz),
with 5 mm sample tubes, 298 K, and digital resolution of
a
Reaction conditions: pyrazole 3a–d (0.5 mmol), Pd(OAc)2 (3 mol%),
XPhos (6 mol%), TMSA (0.75 mmol), Et3N (1.5 mmol), DMF (2 mL),
CsF (1.5 mmol), CuI (10 mol%), and R1N3 (0.75 mmol). Isolated
b
yields aer column chromatography.
0.01 ppm, in CDCl3 and using TMS as an internal reference. 19
F
NMR spectra of selected compounds were registered on
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a Bruker Avance III 600 spectrometer (at 565 MHz), in CDCl3 ask, equipped with a rubber septum and a stirrer bar, was
and using uorobenzene as external reference with the chem- charged with the pyrazole (2a–c, 5 mmol) and NBS (12.5 mmol,
ical shis reported according to the CFCl3 standard. The CHN 2.22 g for 2a; 15 mmol, 2.67 g for 2b–c). The system was evac-
elemental analyses were performed on a Perkin-Elmer 2400 uated and backlled with argon (operation performed three
˜
CHN elemental analyzer (University of Sao Paulo, SP, Brazil). times in total). Anhydrous DMF (15 mL) was added, and the
Gas chromatography was done using an Agilent Technologies mixture was stirred at 80 ꢀC for 2 h. Upon cooling to room
6890N Network GC system, autosampler 7683 series, injector temperature, the crude reaction mixture was puried via
7683B series, detector 5975 B inert XL EI/CI MSD. High- column chromatography (without prior removal of the DMF), by
resolution mass spectra (HRMS) were obtained for all using 2% ethyl acetate in hexane solution as eluent.
compounds using an LTQ Orbitrap Discovery mass spectrom-
eter (Thermo Fisher Scientic).
4-Bromo-3-methyl-1-phenyl-5-(triuoromethyl)-1H-pyrazole
(3a). Physical aspect: yellow oil. Yield: 1.43 g, 94%. NMR: 1H
ꢀ
(400 MHz, CDCl3, 25 C) d ¼ 7.48–7.44 (m, 3H), 7.43–7.39 (m,
13
1
ꢀ
2H), 2.34 (s, 3H). C{ H} (100 MHz, CDCl3, 25 C) d ¼ 149.3,
General procedure for the synthesis of 3-substituted-1-phenyl-
5-(triuoromethyl)-1H-pyrazoles (2a–c)
139.6, 130.4 (q, 2JC–F ¼ 38), 129.6, 129.2, 126.0, 119.5 (q, 1JC–F
¼
271), 97.7, 12.2. Agrees with data previously reported in the
literature.5
The pyrazoles were prepared by following the procedures
described in the literature.5,15 A solution of phenylhydrazine
(5.5 mmol, 0.59 g) in ethanol (20 mL) was added dropwise – via
a pipette over the course of 5 min – into a 100 mL round bottom
ask containing a magnetic stir bar and a solution of the cor-
responding enone 1a–c (5 mmol) in ethanol (50 mL), which was
kept at 0 ꢀC under magnetic stirring. The system was subse-
quently le to warm to room temperature over a 1 h period. A
reux condenser was then affixed to the reaction ask, and the
ask was submerged in an oil bath, set to 78 ꢀC, that was
continually stirred for 24 h. The solvent was removed in a rotary
evaporator under reduced pressure, and the residual crude
pyrazoles 2a–c were puried via column chromatography, by
using 5% ethyl acetate in hexane solution as eluent.
4-Bromo-1,3-diphenyl-5-(triuoromethyl)-1H-pyrazole (3b).
Physical aspect: white solid. Yield: 1.70 g, 93%. Melting point:
98–100 ꢀC. NMR: 1H (400 MHz, CDCl3, 25 ꢀC) d ¼ 7.89–7.87 (m,
2H), 7.51–7.48 (m, 5H), 7.48–7.42 (m, 3H). 3C{1H} (100 MHz,
CDCl3, 25 ꢀC) d ¼ 150.8, 139.7, 131.5 (q, 2JC–F ¼ 38), 130.7, 129.9,
1
129.3, 129.2, 129.0, 128.5, 126.2, 119.5 (q, JC–F ¼ 271), 95.7.
Agrees with data previously reported in the literature.5
4-Bromo-3-(4-uorophenyl)-1-phenyl-5-(triuoromethyl)-1H-
pyrazole (3c). Physical aspect: white solid. Yield: 1.69 g, 92%.
1
ꢀ
ꢀ
Melting point: 94–97 C. NMR: H (400 MHz, CDCl3, 25 C) d ¼
7.89–7.85 (m, 2H), 7.52–7.46 (m, 5H), 7.17–7.13 (m, 2H). 13C{1H}
(100 MHz, CDCl3, 25 ꢀC) d ¼ 163.4 (d, J ¼ 249), 150.0, 139.6, 131.6
(q, 2JC–F ¼ 38), 130.4 (d, J ¼ 8), 130.0, 129.3, 126.9 (d, J ¼ 3), 126.2,
119.4 (q, 1JC–F ¼ 271), 115.7 (d, J ¼ 22), 95.6. GC-MS (EI, 70 eV): m/z
(%) 384 (M+, 100), 304 (31), 77 (33). Elemental analysis: C16H9BrF4N2
requires: C 49.89; H 2.36; N 7.27. Found: C 50.15; H 2.38; N 7.25.
3-Methyl-1-phenyl-5-(triuoromethyl)-1H-pyrazole
(2a).
Physical aspect: yellow oil. Yield: 1.07 g, 95%. NMR: 1H (400
MHz, CDCl3, 25 ꢀC) d ¼ 7.48–7.41 (m, 5H), 6.59 (s, 1H), 2.35 (s,
3H). 13C{1H} (100 MHz, CDCl3, 25 ꢀC) d ¼ 148.9, 139.1, 132.9 (q,
1
2JC–F ¼ 39), 129.0, 198.9, 125.5, 119.8 (q, JC–F ¼ 269), 108.5 (q,
3JC–F ¼ 2), 13.2. Agrees with data previously reported in the
General procedure for the synthesis of 4-bromo-1-phenyl-5-
(triuoromethyl)-1H-pyrazole (3d)
literature.5
1,3-Diphenyl-5-(triuoromethyl)-1H-pyrazole (2b). Physical This procedure was adapted from the literature.16 A phenyl-
aspect: yellow solid. Yield: 1.32 g, 92%. Melting point: 52–54 ꢀC. hydrazine (5.2 mmol, 0.56 g) was slowly added to a stirred
NMR: 1H (400 MHz, CDCl3, 25 ꢀC) d ¼ 7.91–7.88 (m, 2H), 7.60– solution of the enone 1e (5.0 mmol, 1.23 g) in AcOH (15 mL),
7.57 (m, 2H), 7.55–7.50 (m, 3H), 7.48–7.44 (m, 2H), 7.42–7.37 and this was then stirred at 25 ꢀC for 24 h. The reaction was then
(m, 1H), 7.14 (s, 1H). 13C{1H} (100 MHz, CDCl3, 25 ꢀC) d ¼ 151.7, poured into water and extracted with AcOEt (3 ꢂ 20 mL). The
2
139.3, 134.0 (q, JC–F ¼ 39), 131.8, 129.4, 129.2, 128.9, 128.8, combined organic extracts were washed with a solution of
1
126.0, 125.8, 119.9 (q, JC–F ¼ 269), 106.2. Agrees with data NaHCO3 and water, then dried with Na2SO4 and ltered, and
previously reported in the literature.5
the solvent was then removed in a rotary evaporator under
3-(4-Fluorophenyl)-1-phenyl-5-(triuoromethyl)-1H-pyrazole reduced pressure. The residual crude pyrazole was puried via
(2c). Physical aspect: yellow solid. Yield: 1.31 g, 86%. Melting column chromatography by using 5% ethyl acetate in hexane
point: 57–60 ꢀC. NMR: 1H (400 MHz, CDCl3, 25 ꢀC) d ¼ 7.85–7.80 solution as eluent.
(m, 2H), 7.56–7.47 (m, 5H), 7.14–7.08 (m, 2H), 7.05 (s, 1H). 13C
4-Bromo-1-phenyl-5-(triuoromethyl)-1H-pyrazole
(3d).
{1H} (100 MHz, CDCl3, 25 ꢀC) d ¼ 163.2 (d, J ¼ 248), 134.1, 150.8, Physical aspect: yellow oil. Yield: 0.99 g, 34%. NMR: 1H (400
139.2, 134.1 (q, 2JC–F ¼ 38), 129.5, 129.3, 128.1 (d, J ¼ 3), 127.7 (d, MHz, CDCl3, 25 C) d ¼ 7.71 (s, 1H), 7.50–7.46 (m, 3H), 7.43–
ꢀ
1
J ¼ 8), 119.8 (q, JC–F ¼ 269), 115.9 (d, J ¼ 22), 106.0 (d, J ¼ 2). 7.39 (m, 2H). 13C{1H} (100 MHz, CDCl3, 25 ꢀC) d ¼ 141.9, 139.5,
2
1
Agrees with data previously reported in the literature.26
129.9 (q, JC–F ¼ 38), 129.9, 129.3, 126.1, 119.6 (q, JC–F ¼ 271),
97.0. Agrees with data previously reported in the literature.16
General procedure for the synthesis of 4-bromo-1-phenyl-5-
(triuoromethyl)-1H-pyrazoles (3a–c)
General procedure for the synthesis of azides
Pyrazoles 3a–c were prepared by following the procedures The alkyl azides and 1-azido-4-uorobenzene were prepared by
described in the literature.5 An oven-dried 25 mL round bottom following the procedures described in the literature.27
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atmosphere. The round bottom ask was sealed, and the
mixture was stirred at 100 ꢀC for 24 h. Aer cooling to room
temperature, the system was opened, and CsF (1.5 mmol, 0.227
g), CuI (10 mol%, 10.0 mg), and organic azide (0.75 mmol) were
added. The mixture was then stirred at 80 ꢀC for 24 h. The crude
reaction mixture was then cooled to room temperature, ltered
through a silica pad with ethyl acetate (80 mL), and the ltrate
was concentrated under reduced pressure. Purication by ash
column chromatography furnished the desired product.
Alkyl azides. In a round bottom ask, alkyl chloride or alkyl
bromide (10 mmol) was dissolved in DMSO (15 mL), and NaN3
(12 mmol) was added slowly. The reaction was stirred overnight
at room temperature until the raw materials were consumed.
The mixture was poured into water and extracted with Et2O (3 ꢂ
20 mL). The combined organic extracts were washed with water
(3 ꢂ 20 mL) and then brine (20 mL), then they were dried with
Na2SO4, ltered, and concentrated in vacuo in order to furnish
the azide without further purication.
1-Benzyl-4-(3-methyl-1-phenyl-5-(triuoromethyl)-1H-pyr-
azol-4-yl)-1H-1,2,3-triazole (6a). Eluted with 25% EtOAc/
hexanes. Physical aspect: white solid. Yield: 138 mg, 72%.
1-Azido-4-uorobenzene. In a round bottom ask, 4-uo-
roaniline (4 mmol) was dissolved in 10% aqueous HCl (10 mL).
NaNO2 (4 mmol) was added dropwise to the solution at 0 C,
and this was then stirred for 10 min, and then NaN3 (5 mmol)
was added portionwise. The solution was allowed 2 h – while
being stirred – to warm to room temperature. The reaction was
diluted with H2O, extracted with Et2O, washed with water and
then brine, and the combined organic layers were dried with
Na2SO4 and concentrated in vacuo to furnish the product
without further purication.
ꢀ
1
ꢀ
ꢀ
Melting point: 152–154 C. NMR: H (400 MHz, CDCl3, 25 C)
d ¼ 7.57 (s, 1H), 7.49–7.41 (m, 5H), 7.38–7.35 (m, 3H), 7.30–7.28
(m, 2H), 5.59 (s, 2H), 2.42 (s, 3H). 13C{1H} (100 MHz, CDCl3, 25
2
ꢀC) d ¼ 149.4, 139.6, 138.3, 134.7, 129.5 (q, JC–F ¼ 38), 129.3,
129.2, 129.1, 128.8, 127.9, 126.0, 122.9 (q, J ¼ 3), 120.1 (q, 1JC–F
¼
271), 113.2, 54.2, 12.82. 19F (565 MHz, CDCl3, 25 ꢀC): d ¼ ꢁ55.4.
GC-MS (EI, 70 eV): m/z (%) 383 (M+, 15), 355 (61), 286 (100), 264
(77), 91 (64), 77 (38). Elemental analysis: C20H16F3N5 requires: C
62.66; H 4.21; N 18.27. Found: C 62.53; H 4.33; N 18.14.
1-Benzyl-4-(1,3-diphenyl-5-(triuoromethyl)-1H-pyrazol-4-yl)-
1H-1,2,3-triazole (6b). Eluted with 15% EtOAc/hexanes. Physical
General procedure for the synthesis of 3-methyl-1-phenyl-5-
(triuoromethyl)-4-((trimethylsilyl)ethynyl)-1H-pyrazole (4a)
An oven-dried 5 mL round bottom ask, equipped with a rubber
septum and a stirrer bar, was charged with the 4-bromo-3-
methyl-1-phenyl-5-(triuoromethyl)-1H-pyrazole 3a (0.5 mmol,
152.5 mg), Pd(OAc)2 (3 mol%, 3.35 mg), and ligand (L1–L5,
6 mol%). The system was evacuated and backlled with argon
(operation performed three times), then Et3N (1.5 mmol, 0.21
mL), TMSA (0.75 mmol, 0.11 mL), and dry solvent (2 mL) were
added successively in an argon atmosphere. The round bottom
ask was sealed and the mixture was stirred at the indicated
temperature for 24 h. The crude reaction mixture was then
cooled to room temperature, ltered through a silica pad with
ethyl acetate (60 mL), and the ltrate was concentrated under
reduced pressure and the pyrazole 4a was puried via column
chromatography, using 2% ethyl acetate in hexane solution as
eluent.
aspect: white solid. Yield: 147 mg, 66%. Melting point: 214–
1
ꢀ
ꢀ
215 C. NMR: H (600 MHz, CDCl3, 25 C) d ¼ 7.55 (d, J ¼ 5.9,
2H), 7.51–7.48 (m, 5H), 7.40 (s, 1H), 7.36–7.33 (m, 3H), 7.31–7.25
(m, 3H), 7.19 (d, J ¼ 6.5, 2H), 5.58 (s, 2H). 13C{1H} (150 MHz,
CDCl3, 25 ꢀC) d ¼ 151.6, 139.4, 137.9, 134.7, 131.9 (q, 2JC–F ¼ 38),
131.3, 129.6, 129.1, 129.1, 128.7, 128.5, 128.3, 128.3, 127.6,
1
126.1, 123.7, 119.7 (q, JC–F ¼ 271), 112.1, 54.2. 19F (565 MHz,
+
ꢀ
CDCl3, 25 C): d ¼ ꢁ55.3. GC-MS (EI, 70 eV): m/z (%) 445 (M ,
25), 416 (85), 348 (55), 321 (57), 91 (100), 77 (54). Elemental
analysis: C25H18F3N5 requires: C, 67.41; H, 4.07; N, 15.72.
Found: C, 67.23; H, 4.17; N, 15.34.
1-Benzyl-4-(3-(4-uorophenyl)-1-phenyl-5-(triuoromethyl)-
1H-pyrazol-4-yl)-1H-1,2,3-triazole (6c). Eluted with 15% EtOAc/
hexanes. Physical aspect: white solid. Yield: 104 mg, 45%.
1
ꢀ
ꢀ
Melting point: 227–229 C. NMR: H (400 MHz, CDCl3, 25 C)
d ¼ 7.53–7.46 (m, 7H), 7.40 (s, 1H), 7.38–7.33 (m, 3H), 7.24–7.17
(m, 3H), 6.94 (t, J ¼ 8.7, 2H), 5.58 (s, 2H). 13C{1H} (100 MHz,
3-Methyl-1-phenyl-5-(triuoromethyl)-4-((trimethylsilyl)
ethynyl)-1H-pyrazole (4a). Physical aspect: brown oil. Yield:
1
ꢀ
134 mg, 83%. NMR: H (400 MHz, CDCl3, 25 C) d ¼ 7.47–7.44
(m, 3H), 7.42–7.40 (m, 2H), 2.38 (s, 3H), 0.26 (s, 9H). 13C{1H}
(100 MHz, CDCl3, 25 ꢀC) d ¼ 152.5, 139.2, 133.5 (q, 2JC–F ¼ 38),
ꢀ
CDCl3, 25 C) d ¼ 163.1 (d, J ¼ 248), 150.9, 139.4, 137.9, 134.7,
132.0 (q, 2JC–F ¼ 37), 130.2 (d, J ¼ 9), 129.8, 129.3, 129.0, 127.8,
127.6 (d, J ¼ 3), 126.2, 123.8, 119.7 (q, 1JC–F ¼ 271), 115.5 (d, J ¼
23), 112.0, 54.3. 19F (565 MHz, CDCl3, 25 ꢀC): d ¼ ꢁ55.3, ꢁ113.0.
GC-MS (EI, 70 eV): m/z (%) 463 (M+, 13), 435 (32), 366 (49), 344
(30), 91 (100), 77 (41). HRMS (ESI-TOF): C25H17F4N5 (M + H)
requires 464.1493/found: 464.1515.
1
129.5, 129.2, 126.1, 119.6 (q, JC–F ¼ 271), 106.39, 102.05, 93.1,
12.2, ꢁ0.1. GC-MS (EI, 70 eV): m/z (%) 322 (M+, 62), 307 (100),
287 (30), 77 (27). HRMS (ESI-TOF): C16H18F3N2Si (M + H)
requires 323.1186/found: 323.1190.
1-Benzyl-4-(1-phenyl-5-(triuoromethyl)-1H-pyrazol-4-yl)-1H-
1,2,3-triazole (6d). Eluted with 20% EtOAc/hexanes. Physical
aspect: white solid. Yield: 124 mg, 67%. Melting point: 135–
General procedure for the synthesis of 4-(5-(triuoromethyl)-
1H-pyrazol-4-yl)-1H-1,2,3-triazoles (6a–o)
An oven-dried 5 mL round bottom ask, equipped with a rubber 137 ꢀC. NMR: 1H (600 MHz, CDCl3, 25 ꢀC) d ¼ 8.19 (s, 1H), 7.61
septum and a stirrer bar, was charged with the 4-bromopyr- (s, 1H), 7.50–7.45 (m, 5H), 7.41–7.35 (m, 3H), 7.30 (d, J ¼ 6.8,
13
1
ꢀ
azoles (3a–d, 0.5 mmol), Pd(OAc)2 (3 mol%, 3.35 mg), and 2H), 5.60 (s, 2H). C{ H} (150 MHz, CDCl3, 25 C) d ¼ 140.4,
XPhos (6 mol%, 14.3 mg). The system was evacuated and 139.6, 138.3, 134.6, 129.6, 129.3, 129.2, 129.0, 128.1, 127.8 (q,
backlled with argon (operation performed three times), and 2JC–F ¼ 38), 126.1, 122.0 (q, J ¼ 4), 120.27 (q, 1JC–F ¼ 270), 115.5,
then Et3N (1.5 mmol, 0.21 mL), TMSA (0.75 mmol, 0.11 mL), 54.4, 19F (565 MHz, CDCl3, 25 ꢀC): d ¼ ꢁ55.3. GC-MS (EI, 70 eV):
and DMF (2 mL) were added successively in an argon m/z (%) 369 (M+, 17), 340 (50), 272 (89), 250 (100), 91 (75), 77
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(41). Elemental analysis: C19H14F3N5 requires: C, 61.79; H, 3.82; 2JC–F ¼ 38), 129.3, 129.1, 126.0, 123.1, 120.0 (q, 1JC–F ¼ 271), 113.0,
N, 18.96. Found: C, 61.90; H, 3.91; N, 18.60.
111.9 (dd, J ¼ 19, 6), 110.7 (t, J ¼ 19), 41.5 (t, J ¼ 4), 12.8. GC-MS (EI,
1-(4-Methoxybenzyl)-4-(3-methyl-1-phenyl-5-(triuoromethyl)- 70 eV): m/z (%) 419 (M+, 5), 391 (34), 322 (100), 264 (66), 127 (165),
1H-pyrazol-4-yl)-1H-1,2,3-triazole (6e). Eluted with 25% EtOAc/ 77 (53). HRMS (ESI-TOF): C20H15F5N5 (M + H) requires 420.1242/
hexanes. Physical aspect: white solid. Yield: 147 mg, 71%. found: 420.1268.
Melting point: 136–138 ꢀC. NMR: 1H (400 MHz, CDCl3, 25 ꢀC) d ¼
1-(4-Fluorophenyl)-4-(3-methyl-1-phenyl-5-(triuoromethyl)-
7.51 (s, 1H), 7.48–7.43 (m, 5H), 7.26 (d, J ¼ 8.7, 2H), 6.92 (d, J ¼ 1H-pyrazol-4-yl)-1H-1,2,3-triazole (6j). Eluted with 15% EtOAc/
8.7, 2H), 5.54 (s, 2H), 3.81 (s, 3H), 2.41 (s, 3H). 13C{1H} (100 MHz, hexanes. Physical aspect: white solid. Yield: 66 mg, 35%.
2
1
CDCl3, 25 ꢀC) d ¼ 160.1, 149.5, 139.6, 138.3, 129.7, 129.6 (q, JC–F Melting point: 177–180 C. NMR: H (400 MHz, CDCl3, 25 C)
ꢀ
ꢀ
¼ 38), 129.4, 129.1, 126.6, 126.1, 122.7 (q, J ¼ 3), 120.1 (q, 1JC–F
¼
d ¼ 8.01 (s, 1H), 7.80–7.77 (m, 2H), 7.51–7.47 (m, 5H), 7.27–7.23
271), 114.7, 113.2, 55.5, 53.9, 12.9. GC-MS (EI, 70 eV): m/z (%) 413 (m, 2H), 2.50 (s, 3H). 13C{1H} (100 MHz, CDCl3, 25 ꢀC) d ¼ 162.7
(M+, 23), 385 (48), 316 (72), 264 (94), 121 (100), 77 (43). HRMS (d, J ¼ 249), 149.6, 139.6, 138.9, 133.3, 129.8 (q, JC–F ¼ 38),
2
(ESI-TOF): C21H19F3N5O (M + H) requires 414.1536/found: 129.5, 129.2, 126.1, 122.7 (d, J ¼ 9), 121.1 (q, J ¼ 3), 120.1 (q, 1JC–F
414.1552.
¼ 271), 117.0 (d, J ¼ 23.3), 112.7, 13.0. GC-MS (EI, 70 eV): m/z (%)
4-(1,3-Diphenyl-5-(triuoromethyl)-1H-pyrazol-4-yl)-1-(4- 387 (M+, <1), 359 (100), 290 (65), 95 (20), 77 (41). HRMS (ESI-
methoxybenzyl)-1H-1,2,3-triazole (6f). Eluted with 15% EtOAc/ TOF): C19H14F4N5 (M + H) requires 388.1180/found: 388.1201.
hexanes. Physical aspect: white solid. Yield: 122 mg, 55%.
Melting point: 192–194 C. NMR: H (400 MHz, CDCl3, 25 C) orophenyl)-1H-1,2,3-triazole (6k). Eluted with 15% EtOAc/
4-(1,3-Diphenyl-5-(triuoromethyl)-1H-pyrazol-4-yl)-1-(4-u-
1
ꢀ
ꢀ
d ¼ 7.58–7.47 (m, 7H), 7.36 (s, 1H), 7.29–7.23 (m, 3H), 7.15 (d, J hexanes. Physical aspect: white solid. Yield: 74 mg, 33%.
1
¼ 8.6, 2H), 6.87 (d, J ¼ 8.6, 2H), 5.50 (s, 2H), 3.79 (s, 3H). 13C{1H} Melting point: 222–224 C. NMR: H (400 MHz, CDCl3, 25 C)
(100 MHz, CDCl3, 25 ꢀC) d ¼ 160.0, 151.7, 139.5, 137.8, 131.9 (q, d ¼ 7.88 (s, 1H), 7.75–7.72 (m, 2H), 7.60–7.52 (m, 7H), 7.35–7.32
2JC–F ¼ 37), 131.5, 129.6, 129.3, 129.2, 128.6, 128.4, 128.3, 126.8, (m, 3H), 7.25–7.20 (m, 2H). 13C{1H} (100 MHz, CDCl3, 25 ꢀC) d ¼
ꢀ
ꢀ
126.2, 123.6, 119.8 (q, JC–F ¼ 271), 114.6, 112.3, 55.4, 53.8. 162.6 (d, J ¼ 249), 151.9, 139.5, 138.5, 133.2, 132.0 (q, 2JC–F ¼ 37),
1
HRMS (ESI-TOF): C26H21F3N5O (M + H) requires 476.1693/ 131.4, 129.8, 129.3, 128.8, 128.6, 128.5, 126.2, 122.6 (d, J ¼ 9),
1
found: 476.1699.
121.7, 120.1 (q, JC–F ¼ 271), 117.0 (d, J ¼ 23), 111.6. 19F (565
4-(3-(4-Fluorophenyl)-1-phenyl-5-(triuoromethyl)-1H- MHz, CDCl3, 25 ꢀC): d ¼ ꢁ55.1, ꢁ111.8. GC-MS (EI, 70 eV): m/z
pyrazol-4-yl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole (6g). Eluted (%) 449 (M+, <1), 421 (100), 352 (38), 95 (18), 77 (45). HRMS (ESI-
with 15% EtOAc/hexanes. Physical aspect: white solid. Yield: TOF): C24H16F4N5 (M + H) requires 450.1336/found: 450.1354.
95 mg, 39%. Melting point: 197–200 ꢀC. NMR: 1H (400 MHz,
1-(4-Fluorophenyl)-4-(1-phenyl-5-(triuoromethyl)-1H-pyr-
ꢀ
CDCl3, 25 C) d ¼ 7.54–7.46 (m, 7H), 7.37 (s, 1H), 7.18–7.16 (d, azol-4-yl)-1H-1,2,3-triazole (6l). Eluted with 15% EtOAc/hexanes.
2H), 6.97–6.88 (m, 4H), 5.52 (s, 2H), 3.81 (s, 3H). 13C{1H} (100 Physical aspect: white solid. Yield: 51 mg, 29%. Melting point:
1
MHz, CDCl3, 25 C) d ¼ 163.1 (d, J ¼ 248), 160.1, 150.9, 139.4, 157–159 ꢀC. NMR: H (600 MHz, CDCl3, 25 ꢀC) d ¼ 8.27 (s, 1H),
137.7, 132.0 (q, 2JC–F ¼ 37), 130.2 (d, J ¼ 8), 129.7, 129.4, 129.4, 8.07 (d, J ¼ 1), 7.79–7.76 (m, 2H), 7.53–7.50 (m, 5H), 7.27–7.25
127.6 (d, J ¼ 3), 126.6, 126.2, 123.6, 119.7 (q, 1JC–F ¼ 271), 115.5 (m, 2H). 13C{1H} (150 MHz, CDCl3, 25 ꢀC) d ¼ 162.7 (d, J ¼ 249),
ꢀ
(d, J ¼ 22), 114.6, 112.1, 55.5, 53.9. GC-MS (EI, 70 eV): m/z (%) 140.4, 139.5, 138.8, 133.3 (d, J ¼ 3), 129.8, 129.3, 128.0 (q, 2JC–F
¼
493 (M+, 15), 469 (52), 333 (55), 281 (40), 207 (100), 121 (79), 77 39), 126.1, 122.8 (d, J ¼ 9), 120.3 (q, 1JC–F ¼ 271), 120.2 (q, J ¼ 4),
(30). HRMS (ESI-TOF): C26H20F4N5O (M + H) requires 494.1598/ 117.0 (q, J ¼ 23), 115.0. GC-MS (EI, 70 eV): m/z (%) 373 (M+, <1),
found: 494.1601.
345 (100), 276 (3), 128 (17), 77 (26). HRMS (ESI-TOF):
1-(4-Methoxybenzyl)-4-(1-phenyl-5-(triuoromethyl)-1H-pyr-
azol-4-yl)-1H-1,2,3-triazole (6h). Eluted with 20% EtOAc/
C
18H12F4N5 (M + H) requires 374.1023/found: 374.1045.
4-(3-Methyl-1-phenyl-5-(triuoromethyl)-1H-pyrazol-4-yl)-1-
hexanes. Physical aspect: white solid. Yield: 129 mg, 64%. octyl-1H-1,2,3-triazole (6m). Eluted with 15% EtOAc/hexanes.
1
ꢀ
ꢀ
Melting point: 127–129 C. NMR: H (400 MHz, CDCl3, 25 C) Physical aspect: white solid. Yield: 109 mg, 54%. Melting
1
d ¼ 8.17 (s, 1H), 7.56 (s, 1H), 7.49–7.42 (m, 5H), 7.26 (d, J ¼ 8.5, point: 95–97 C. NMR: H (400 MHz, CDCl3, 25 ꢀC) d ¼ 7.60 (s,
2H), 6.91 (d, J ¼ 8.6, 2H), 5.52 (s, 2H), 3.81 (s, 3H). 13C{1H} (100 1H), 7.54–7.43 (m, 5H), 4.42 (t, J ¼ 7.2, 2H), 2.44 (s, 3H), 2.02–
MHz, CDCl3, 25 ꢀC) d ¼ 160.2, 140.4, 139.7, 138.2, 129.7, 129.6, 1.93 (m, 2H), 1.40–1.22 (m, 10H), 0.88 (t, J ¼ 6.7, 3H). 13C{1H}
129.2, 127.7 (q, 2JC–F ¼ 37), 126.6, 126.2, 121.8 (q, J ¼ 4), 120.2 (q, (100 MHz, CDCl3, 25 ꢀC) d ¼ 149.6, 139.8, 137.9, 129.4, 129.4 (q,
1JC–F ¼ 270), 115.6, 114.7, 55.5, 54.0. GC-MS (EI, 70 eV): m/z (%) 2JC–F ¼ 37), 129.2, 126.2, 122.8 (q, J ¼ 2), 121.6 (q, 1JC–F ¼ 270),
399 (M+, 24), 370 (25), 302 (61), 250 (68), 121 (100), 77 (35). 113.4, 50.6, 31.8, 30.4, 29.2, 29.1, 26.6, 22.7, 14.1, 13.0. 19F (565
HRMS (ESI-TOF): C20H17F3N5O (M + H) requires 400.1380/ MHz, CDCl3, 25 ꢀC): d ¼ ꢁ55.4. GC-MS (EI, 70 eV): m/z (%) 391
ꢀ
found: 400.1393.
(M+, 22), 279 (100), 251 (62), 238 (48), 77 (31). HRMS (ESI-TOF):
1-(2,6-Diuorobenzyl)-4-(3-methyl-1-phenyl-5-(triuoromethyl)-
1H-pyrazol-4-yl)-1H-1,2,3-triazole (6i). Eluted with 25% EtOAc/
C
21H27F3N5 (M + H) requires 406.2213/found: 406.2238.
4-(1,3-Diphenyl-5-(triuoromethyl)-1H-pyrazol-4-yl)-1-octyl-
hexanes. Physical aspect: white solid. Yield: 146 mg, 69%. 1H-1,2,3-triazole (6n). Eluted with 15% EtOAc/hexanes. Physical
Melting point: 167–169 ꢀC. NMR: 1H (400 MHz, CDCl3, 25 ꢀC) d ¼ aspect: white solid. Yield: 72 mg, 31%. Melting point: 165–
7.72 (s, 1H), 7.54–7.42 (m, 5H), 7.41–7.34 (m, 1H), 6.98 (t, J ¼ 7.9, 166 ꢀC. NMR: 1H (400 MHz, CDCl3, 25 ꢀC) d ¼ 7.58–7.56 (m, 2H),
2H), 5.70 (s, 2H), 2.42 (s, 3H). 13C{1H} (100 MHz, CDCl3, 25 ꢀC) d ¼ 7.54–7.50 (m, 5H), 7.44 (s, 1H), 7.32–7.27 (m, 3H), 4.39 (t, J ¼ 7.1,
161.4 (dd, J ¼ 251, 7), 149.4, 139.5, 138.1, 131.6 (t, J ¼ 10), 129.5 (q, 2H), 1.95–1.86 (m, 2H), 1.38–1.20 (m, 10H), 0.88 (t, J ¼ 6.8, 3H).
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13
1
ꢀ
C{ H} (100 MHz, CDCl3, 25 C) d ¼ 151.7, 139.5, 137.4, 131.9
C. F. Mello, M. A. Rubin, J. Ferreira and H. G. Bonacorso,
Life Sci., 2008, 83, 739; (f) P. D. Sauzem, P. Machado,
M. A. Rubin, G. da S. Sant'Anna, H. B. Faber, A. H. de Souza,
C. F. Mello, P. Beck, R. A. Burrow, H. G. Bonacorso, N. Zanatta
and M. A. P. Martins, Eur. J. Med. Chem., 2008, 43, 1247; (g)
W. Cunico, C. A. Cechinel, H. G. Bonacorso, M. A. P. Martins,
N. Zanatta, M. V. N. de Souza, I. O. Freitas, R. P. P. Soares and
A. U. Krettlia, Bioorg. Med. Chem. Lett., 2006, 16, 649.
5 C. Wiethan, W. C. Rosa, H. G. Bonacorso and M. Stradiotto,
Org. Biomol. Chem., 2016, 14, 2352.
6 K. M. Clapham, A. S. Batsanov, M. R. Bryce and B. Tarbitb,
Org. Biomol. Chem., 2009, 7, 2155.
7 T. S. Reddy, H. Kulhari, V. G. Reddy, A. V. S. Rao, V. Bansal,
A. Kamal and R. Shukla, Org. Biomol. Chem., 2015, 13, 10136.
8 N. R. Emmadi, C. Bingi, S. S. Kotapalli, R. Ummanni,
J. B. Nanubolu and K. Atmakur, Bioorg. Med. Chem. Lett.,
2015, 25, 2918.
2
(q, JC–F ¼ 37), 131.5, 129.6, 129.2, 128.6, 128.4, 128.4, 126.2,
1
123.5, 119.8 (q, JC–F ¼ 271), 112.3, 50.5, 31.7, 30.3, 29.1, 29.0,
26.4, 22.7, 14.1. GC-MS (EI, 70 eV): m/z (%) 467 (M+, 30), 439 (22),
355 (100), 326 (55), 313 (82), 77 (50). HRMS (ESI-TOF):
C
26H29F3N5 (M + H) requires 468.2370/found: 468.2379.
1-Octyl-4-(1-phenyl-5-(triuoromethyl)-1H-pyrazol-4-yl)-1H-
1,2,3-triazole (6o). Eluted with 15% EtOAc/hexanes. Physical
aspect: white solid. Yield: 68 mg, 35%. Melting point: 57–59 ꢀC.
NMR: 1H (400 MHz, CDCl3, 25 ꢀC) d ¼ 8.21 (s, 1H), 7.66 (s, 1H),
7.58–7.40 (m, 5H), 4.40 (t, J ¼ 7.1, 2H), 2.01–1.89 (m, 2H), 1.42–
1.19 (m, 10H), 0.88 (t, J ¼ 6.8, 3H). 13C{1H} (100 MHz, CDCl3, 25
2
ꢀC) d ¼ 140.4, 139.7, 137.8, 129.6, 129.2, 127.8 (q, JC–F ¼ 38),
1
126.2, 121.9 (q, J ¼ 4), 120.4 (q, JC–F ¼ 271), 115.7, 50.6, 31.8,
30.4, 29.1, 29.0, 26.6, 22.7, 14.1. GC-MS (EI, 70 eV): m/z (%) 391
(M+, 22), 279 (100), 251 (62), 238 (48), 77 (31). HRMS (ESI-TOF):
C
20H25F3N5 (M + H) requires 392.2057/found: 392.2070.
9 R. Distinto, C. Zanato, S. Montanari, M. G. Cascio, P. Lazzari,
R. Pertwee and M. Zanda, J. Fluorine Chem., 2014, 167, 184.
10 C. Zanato, M. G. Cascio, P. Lazzari, R. Pertwee, A. Testa and
M. Zanda, Synthesis, 2015, 47, 817.
Conflicts of interest
There are no conicts to declare.
11 N. Nayak, J. Ramprasad, U. Dalimba, P. Yogeeswari,
D. Sriram, H. S. S. Kumar, S. K. Peethambar and R. Achur,
Res. Chem. Intermed., 2016, 42, 3721.
Acknowledgements
The authors thank: the Coordination for Improvement of 12 X. Chen, Y. Xiao, G. Wang, Z. Li and X. Xu, Res. Chem.
Higher Education Personnel (CAPES) for the fellowships, and
Intermed., 2016, 42, 5495.
the National Council for Scientic and Technological Develop- 13 M. Maue, A. Decor, J. J. Hahn, W. Hallenbach, R. Fischer,
¨
H. G. Schwarz, U. Gorgens, K. Ilg, K. Raming and
ment (CNPq) for the nancial support (Process numbers
¨
306.883/2015-5 and 402.075/2016-1-CNPq/Universal).
J. Kobberling, Int. Pat., WO 2015193218A1, 2015.
14 E. Merkul, F. Klukas, D. Dorsch, U. Gradler, H. E. Greiner
and T. J. J. Muller, Org. Biomol. Chem., 2011, 9, 5129.
15 (a) M. Hojo, R. Masuda, Y. Kokuryo, H. Shioda and S. Matsuo,
Chem. Lett., 1976, 5, 499; (b) M. Hojo, R. Masuda and E. Okada,
Synthesis, 1986, 1013; (c) G. M. Siqueira, A. F. C. Flores, G. Clar,
N. Zanatta and M. A. P. Martins, Quim. Nova, 1994, 17, 24; (d)
H. G. Bonacorso, M. A. P. Martins, S. R. T. Bittencourt,
R. V. Lourega, N. Zanatta and A. F. C. Flores, J. Fluorine
Chem., 1999, 99, 177.
Notes and references
1 V. Nenajdenko, Fluorine in Heterocyclic Chemistry Vol. 1:5-
Membered Heterocycles and Macrocycles, Springer-Verlag,
Heidelberg, 2014.
2 Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Acena,
V. A. Soloshonok, K. Izawa and H. Liu, Chem. Rev., 2016,
116, 422.
˜
3 C. D. Murphy and G. Sandford, Expert Opin. Drug Metab. 16 V. G. Nenajdenko, A. L. Reznichenko and E. S. Balenkova,
Toxicol., 2015, 11, 589. Russ. Chem. Bull., 2006, 55, 172.
4 (a) H. G. Bonacorso, W. C. Rosa, S. M. Oliveira, I. Brusco, 17 I. I. Gerus, L. M. Kacharova and S. I. Vdovenko, Synthesis,
E. S. Brum, M. B. Rodrigues, C. P. Frizzo and N. Zanatta,
2001, 431.
Bioorg. Med. Chem. Lett., 2017, 27, 1551; (b) M. M. Lobo, 18 D. Gelman and S. L. Buchwald, Angew. Chem., Int. Ed., 2003,
S. M. Oliveira, I. Brusco, P. Machado, L. F. S. M. Timmers,
42, 5993.
O. N. de Souza, M. A. P. Martins, H. G. Bonacorso, 19 R. W. Burli, W. R. K. Esmieu, C. J. Lock, K. F. Malagu,
J. M. dos Santos, B. Canova, T. V. F. da Silva and A. P. Owens and W. E. Harte, Int. Pat., WO2014066836A1, 2014.
N. Zanatta, Eur. J. Med. Chem., 2015, 102, 143; (c) 20 R. Martin and S. L. Buchwald, Acc. Chem. Res., 2008, 41, 1461.
S. M. Oliveira, C. R. Silva, A. P. Wentz, G. R. Paim, 21 W. Shu and S. L. Buchwald, Chem. Sci., 2011, 2, 2321.
M. S. Correa, H. G. Bonacorso, A. S. Prudente, M. F. Otuki 22 A. Komaromi and Z. Novak, Chem. Commun., 2008, 4968.
and J. Ferreira, Pharmacol., Biochem. Behav., 2014, 124, 396; 23 F. Friscourt and G.-J. Boons, Org. Lett., 2010, 12, 4936.
(d) G. Trevisan, M. F. Rossato, C. I. B. Walker, 24 V. Aucagne and D. A. Leigh, Org. Lett., 2006, 8, 4505.
S. M. Oliveira, F. Rosa, R. Tonello, C. R. Silva, P. Machado, 25 S. Hakimian, A. Cheng-Hakimian, G. D. Anderson and
A. A. Boligon, M. A. P. Martins, N. Zanatta,
H. G. Bonacorso, M. L. Athayde, M. A. Rubin, J. B. Calixto 26 T. N. Ngo, S. A. Ejaz, T. Q. Hung, T. T. Dang, J. Iqbal, J. Lecka,
and J. Ferreira, Neuropharmacology, 2013, 73, 261; (e) J. Sevigny and P. Langer, Org. Biomol. Chem., 2015, 13, 8277.
J. Milano, M. F. Rossato, S. M. Oliveira, C. Drewes, 27 K. Yamamoto, T. Bruun, J. Y. Kim, L. Zhang and M. Lautens,
J. W. Miller, Expert Opin. Pharmacother., 2007, 8, 1931.
P. Machado, P. Beck, N. Zanatta, M. A. P. Martins,
Org. Lett., 2016, 18, 2644.
43964 | RSC Adv., 2017, 7, 43957–43964
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