New 4-fluoroalkyl substituted N-phenylpyrazoles: Synthesis promoted by DAST and multinuclear NMR analysis

Article abstract of DOI:10.1016/j.jfluchem.2015.05.010

This paper reports a synthetic and NMR spectroscopic studies of two new series of 4-fluorinated 1,3,5-substituted 1H-pyrazoles. Firstly, an efficient synthesis of new series of 3-aryl-4-(di)fluoromethyl-1H-1-phenylpyrazoles, where [aryl = Ph, 4-NO₂

Full text of DOI:10.1016/j.jfluchem.2015.05.010

Accepted Manuscript
Title: New 4-fluoroalkyl substituted N-phenylpyrazoles:
Synthesis promoted by DAST and multinuclear NMR analysis
Author: Helio G. Bonacorso Everton P. Pittaluga Liliane M.F.
Porte Andrizia F. Junges Francieli M. Libero Nilo Zanatta
Marcos A.P. Martins
PII:
S0022-1139(15)00136-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.05.010
FLUOR 8568
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
16-4-2015
14-5-2015
16-5-2015
Pleasecitethisarticleas:H.G. Bonacorso, E.P. Pittaluga, L.M.F. Porte, A.F. Junges, F.M.
Libero, N. Zanatta, M.A.P. Martins, New 4-fluoroalkyl substituted N-phenylpyrazoles:
Synthesis promoted by DAST and multinuclear NMR analysis, Journal of Fluorine
Chemistry (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.05.010
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Graphical Abstract
R
R
CH3
H
N
F
F
Ph
N
F
H
H
R
H
DAST
DAST
N
N
POCl3 in DMF
(Vilsmeier-Haack reagent)
N
N
Ph
Ph
Page 1 of 24

HIGHLIGHTS
>DAST in fluorination reactions of 4-(formyl) and 4-(hydroxymethyl) 3-aryl-1H-1-
phenylpyrazoles.
>Mono- and difluoromethyl groups insertion at C4 position of phenylpyrazoles.
>New 3-aryl-4-(di)fluoromethyl-1H-1-phenylpyrazoles are synthesized.
>Fluorinated compounds 1H, 13C and 19F spin-spin coupling NMR spectra assignments
are presented and discussed.
>New 19F NMR assignments for the fluoromethyl groups at C4 position of
phenylpyrazoles.
Page 2 of 24

Graphical Abstract Synopsis
Fluorination reactions using DAST and the synthesis of a new series of six 3-aryl-4-
1
13
19
(di)fluoromethyl-1H-1-phenylpyrazoles and their H, C and F spin-spin coupling NMR spectra
assignments, at 41 - 73% yields, is reported.
Page 3 of 24

New 4-fluoroalkyl substituted N-phenylpyrazoles: Synthesis
promoted by DAST and multinuclear NMR analysis
Helio G. Bonacorso*, Everton P. Pittaluga, Liliane M. F. Porte, Andrizia F. Junges,
Francieli M. Libero, Nilo Zanatta and Marcos A. P. Martins
Núcleo de Química de Heterociclos – NUQUIMHE, Departamento de Química, Universidade Federal de
Santa Maria - 97105-900 – Santa Maria, RS – Brazil
_______________________________________
*Corresponding Author. Fax +55 55 3220 8031
E-mail address: helio.bonacorso@ufsm.br (H.G. Bonacorso).
Page 4 of 24

Abstract
This paper reports a synthetic and NMR spectroscopic studies of two new series
of 4-fluorinated 1,3,5-substituted 1H-pyrazoles. Firstly, an efficient synthesis of new
series of 3-aryl-4-(di)fluoromethyl-1H-1-phenylpyrazoles, where [aryl = Ph, 4-
NO2C6H4, 4-CH3OC6H4] is described, from fluorination reactions of 4-(formyl)- and 4-
(hydroxymethyl)-1H-1-phenylpyrazoles in dichloromethane as solvent at room
temperature, employing diethylaminosulfur trifluoride (DAST) as fluorinating agent in
41 to 73 % yield. The 4-formyl-pyrazoles are obtained in 54 – 58 % yield by Vilsmeier-
Haack reaction using a mixture of POCl3/DMF with arylhydrazones, which were
derived from the respective aryl methyl ketones and phenylhydrazine. The 4-
hydroxymethyl-pyrazole precursors were easily obtained from the reduction of 4-
formyl-pyrazoles by sodium borohydride (NaBH4) in 52 – 87 % yield. Subsequently,
the present work also discusses the 1H, 13C and 19F NMR spectroscopic data.
Keywords – DAST; Fluorination reactions; Vilsmeier-Haack reaction; phenylpyrazoles.
Page 5 of 24

1. Introduction
Fluorine atoms strategically placed into organic molecules often have a positive
influence on the biological properties of active compounds and some of the best selling
prescription drugs and agrochemicals contain fluoroalkyl functional groups [1,2]. The
chemical and biological importance of alkyl-F groups incorporated into more complex
organic compounds is already well discussed in literature [3,4]. The CHF2 group can act
as a bioisostere designed as a thiol, hydroxamic acid, hydroxyl or amide mimic. In the
same way, the CH2F group can act as a useful bioisostere of a methyl, hydroxymethyl or
methoxymethyl group. The fluorine atom can also prevent metabolic oxidation due to
its electron-withdrawing effect [5].
Pyrazoles bearing fluorocarbon substituents are becoming increasingly prevalent
as synthetic targets and building blocks within the fine chemicals sector [6,7]. Many
examples of bioactive fluorinated pyrazoles have emerged in recent years, and among
these, the fungicide Bixafen® is a particularly noteworthy example [8]. Moreover, the
phenylpyrazole structure is the scaffold of common worldwide over-the-counter
antipyretic and analgesic [9,10] Dipyrone® and the insecticide Fipronil® [11].
For this reason, fluorinated building blocks and fluorinating reagents are
important for selective preparation of specific fluoro-compounds. Generally, the
synthesis of 3(5)-fluoroalkyl-substituted-pyrazoles is achieved from fluorinated building
blocks such as 1,3-diketones, vinyl ketones, β-keto esters, perfluoro acetylenes and
hydrazines or hydrazide through cyclocondensation reactions, but in most cases leading
to mixture of regioisomers [8].
For the past two decades, our research group has introduced trifluoromethyl
groups into 3- and 5-pyrazoles positions through the cyclocondensation reaction of 4-
alkoxy-1,1,1-trifluoroalk-3-en-2-ones and different hydrazines and their derivatives [12-
Page 6 of 24

15], screening their biological activities [16-21]. Nonetheless, the trifluoromethylated
building blocks approach shows limitation in scope range leading to few possibilities
for the trifluoromethyl group insertion. Moreover, this synthetic strategy do not have
allowed to synthesize difluoromethyl or fluoromethyl substituted heterocycles.
On the other hand, nucleophilic fluorination reactions of organic compounds
using fluorinating reagents like Olah’s reagent, Deoxofluor, Xtalfluor and DAST, are
one of the most widely used methodologies in the field of fluorine chemistry. DAST
(diethylaminosulfur trifluoride) has proven to be a very popular reagent due to its ease
of handling and versatility. It has regularly been employed in selective fluorination of
alcohol, carbohydrates, ketones, sulfides, epoxides, thioethers and cyanohydrins
[22,23].
We have observed a lack in literature about the fluoroalkyl substitution at the C-
4 position of pyrazoles and the data about the NMR spectroscopic analysis, in this
paper, we aim to report the synthesis of new series of 3-aryl-4-(di)fluoromethyl-1H-1-
phenylpyrazoles through fluorination with DAST reacting with the formyl and
1
hydroxymethyl groups. Moreover, this paper discusses the H, 13C and 19F NMR
spectral assignments as well as highlights the main chemical shifts and coupling
constants of new fluorinated compounds.
2. Results and discussion
The initial goal of this work was to achieve the fluoromethyl groups substitution
at the C4 position of trifluoromethylated-pyrazoles and screening NMR studies about
the new polyfluorinated compounds. Therefore, we first carried out formylation
reactions on 3- and 5-trifluoromethyl-1H-1-phenylpyrazoles [24,25] employing two
different Vilsmeyer-Haack reagents: (i) POCl3 in DMF [26,27] or (ii) oxalyl chloride in
Page 7 of 24

DMF [27], but no reaction took place in any case (Figure 1). We assigned the non-
formation of the desired products to the great deactivation effect induced by the CF3
group.
O
H
CF3
R
H
CH3
H
N
N
N
R1
i or ii
F3C
i or ii
H3C
N
x
N
x
N
5-(trifluoromethyl)pyrazole
3-(trifluoromethyl)pyrazole
i = POCl3, DMF; ii = (COCl)2, DMF; (R, R1 = CH3 andCF3)
Fig. 1. Formylation reactions of 3- and 5-trifluormethyl-1H-1-phenylpyrazoles.
Once we could not obtain the 4-formyl-5(3)-trifluoromethyl-pyrazoles we
worked on different approach to prepare formylated pyrazoles, which led us to 3-aryl-4-
formyl-1H-1-phenylpyrazoles (1a-c). For this study, we have selected N-
phenylpyrazoles due to their undisputed pharmacological importance, two aryl groups
attached to the C-3 position containing substituents with extreme opposite electronic
effects (R = p-OMe and p-NO2) and one non-substituted aryl group without electronic
effect (R = H) as a reference for a synthetic and spectroscopic comparative study.
Compounds 1a-c were successfully synthesized from the condensation of aryl
methyl ketones, phenylhydrazine followed by a subsequent one-step Vilsmeier-Haack
reaction [26,27] of the respective arylhydrazones with POCl3/DMF, involving the
formylation of the methyl group followed by the self cyclization and then hydrolysis in
basic medium (see Experimental Section) (Scheme 1). Products 1a-c were obtained as
yellow to orange solids in comparable literature yields of 54 – 58 % [26,27].
Page 8 of 24

R
O
H
O
N
CH3
H
NH2
H
N
POCl3, DMF
0 - 90°C, 3 h
CH3
N
N
54- 58 %
H
N
R
R
1
a
b
c
H
NO2 OMe
R
1a-c
Scheme 1. Synthesis of 3-aryl-4-formyl-1H-1-phenylpyrazoles (1a-c).
Compounds 1a-c show the formyl group as one suitable site for direct
fluorination with DAST. Therefore, we proceeded with the conversion of the carbonyl
function to the corresponding difluoromethyl substituent which furnished compounds 3-
aryl-4-difluoromethyl-1H-1-phenylpyrazoles (2a-c) (Scheme 2) with 2 equivalents of
DAST following literature method [29]. Products 2a-c were isolated through
chromatography purification (2a) or simple filtration (2b-c) to obtain air-stable solids of
pallid brown color in 56 – 73 % yields.
R
R
F
O
F
H
H
6
DAST, DCM,
3
4
0 - 25 °C, 24 h
5
2
1
N
N
56 - 73 %
N
N
1a-c
2a-c
1,2
a
b
c
R
H
NO2 OMe
Scheme 2. Synthesis of 3-aryl-4-difluoromethyl-1H-1-phenylpyrazoles (2a-c).
Besides the deshielding effect in chemical shift range of NMR spectroscopy,
fluorine frequently brings up changes in multiplicity of neighbor carbon and hydrogen
atoms. The mono and difluoroalkyl groups exhibit a wide range of chemical shifts
1
13
19
possibilities in H, C and especially in F NMR (from -277 to +40 ppm). It can also
be seen that spin-spin coupling constants between fluorine and hydrogen as well as
between carbon and fluorine are quite predictable and thus useful in detailed structure
characterization [30].
Page 9 of 24

The NMR literature data is limited in relation to CH2F and CHF2 groups
attached to pyrazole rings even for the most common substituted 3 and 5 positions [31-
34]. In general, mono and difluoromethyl groups do not show great variation of
chemical shifts in aromatic pyrazole ring independent of their positions in the
heterocycle [35,36].
Figure 2a illustrates experimental results obtained in this work for the 1H and 13C
NMR data of CHF2 group (C6) of 3-(4-nitrophenyl)-4-difluoromethyl-1H-1-
phenylpyrazole (2b), observing the spin-spin coupling as typical triplet with coupling
constants of 55.2 and 233.5 Hz, and chemical shifts of 6.88 and 110.6 ppm, respectively
1
in H and 13C NMR spectra. In addition, Figure 2b shows a doublet in -106.2 ppm with
coupling constant of 55.2 Hz in 19F NMR spectra in the characteristic signal for the
CHF2 group.
Fig. 2. (a) 1H, 13C, (b) 19F NMR experimental signals for CHF2 group of compound 2b.
The complete experimental data of the NMR study about the CHF2 group and its
influence on pyrazole atoms of compounds 2 as well as the similar data found in the
literature for this group is resumed in Table 1. The chemical shifts range for hydrogen
of C6 in 1H NMR was found to be between 6.78 – 6.88 ppm and the coupling constants
13
of triplets had a variation of 55.2 to 55.5 Hz as expected for CHF2 group. In the C
NMR was found a range of 110.6 – 111.3 ppm and J = 234.5 Hz for the same group.
19
Furthermore, the F NMR show a doublet with chemical shift in range of -105.9 to -
106.2 ppm and coupling constants of 55.1 to 55.2 Hz for compounds 2b and 2c. Only
Page 10 of 24

for compound 2a it was observed a second spin-spin coupling with J = 3.4 Hz, probably
due to the coupling of the hydrogen of C5 and the CHF2 group. All compounds spectra
are illustrated in the Supporting Information and are in accordance with available data
in literature [31,35,36].
Moreover, it was also noticed that the hydrogen of C5 do not couple with CHF2
1
group in H NMR, but on the contrary, the C3 of all compounds (except for compound
2c), the C4 and C5 show coupling constants in a range of 3J = 4.1 – 5.1, 2J = 25.3 – 26.2
3
13
and J = 4.5 – 6.3 Hz, respectively in C NMR spectra. Additionally, the C3, C4 and
C5 chemical shifts range are 148.5 – 151.2, 115.8 – 116.7 and 127.3 – 128.3 ppm,
respectively.
Table 1. Experimental 1H, 13C and 19F NMR multiplicity,a chemical shiftsb and coupling
constantsc data of compounds 2 in CDCl3.d
F
F
6
H
4
5
3
N1
2
a
b
c
R
N
R
H
NO2 OMe
2a-c
C3
C4
13C
C5
C6
13C
13C
1H
13C
1H
19F
t, 151.2,
t, 116.7,
t, 128.3,
t, 6.78,
J = 55.4
t, 110.6,
J = 234.5
dd, -105.9,
J = 55.2, 3.4
s, 8.15
3J = 5.1
2J = 26.2
3J = 6.3
2a
t, 148.5,
t, 116.7,
t, 128.3,
t, 6.88,
J = 55.2
t, 110.6,
J = 234.5
d, -106.2,
J = 55.2
s, 8.27
s, 8.20
-
3J = 4.1
2J = 26.2
3J = 6.3
2b
2c
t, 115.8,
t, 127.3,
t, 6.84,
J = 55.5
t, 111.3,
J = 233.5
d, -106.0,
J = 55.1
s, 150.9
2J = 25.3
3J = 4.5
t, 6.63 – 7.56
J = 53.4 – 54.2
t, 108.5 – 112.2
J = 230.0 – 235.5
Lit.e
-
-
-
s, -110.9
aMultiplicity data: s = singlet, t = triplet; bChemical shifts in ppm;
cCoupling constants in relation to the two fluorine atoms: nJ = Hz;
dData order in the table: multiplicity/chemical shift/coupling constant;
eLiterature range data of multiplicities, chemical shifts and coupling constants found for CHF2 group in 3, 4 or 5 position of
pyrazole rings in CDCl3.
In addition to the fluorination reaction, the 4-formyl group can undergo a
reduction leading to the hydroxymethyl group, which is also suitable for direct
fluorination with DAST. Thus, a new series of 3-aryl-4-hydroxymethyl-1H-1-
phenylpyrazoles (3a-c) was synthetized from compounds 1a-c utilizing 1.2 equivalent
Page 11 of 24

of NaBH4 as carbonyl reducing agent [37,38] (Scheme 3). Compounds 3a-c were
isolated by simple extraction to obtain white or orange solids in 52 – 87 % [37].
R
R
O
H
HO
NaBH4, DCM, EtOH
0 - 25°C, 1 h
N
N
52 - 87 %
N
N
1a-c
3a-c
1,3
R
a
H
b
c
NO2 OMe
Scheme 3. Synthesis of 3-aryl-4-hydroxymethyl-1H-1-phenylpyrazoles (3a-c).
Hereafter, for the fluorination reactions of compounds 3a-c we have applied the
standard methodology with DAST. Hence, the 3-aryl-4-fluoromethyl-1H-1-
phenylpyrazoles (4a-c) were obtained through substitution of the hydroxyl moiety for a
fluorine atom (Scheme 4). Products 4a-c were isolated by extraction and purified on
chromatographic column resulting in white air-stable solids in 41 – 56 % yields. One
observation is worth of attention in relation to compounds 4a-c: they are air-stable only
as dry solids; when they are dissolved in organic solvent, like deuterated chloroform
used for NMR analysis or hexane and ethyl acetate for the chromatography purification,
a slow decomposition reaction is observed. Thereby, the chromatographic purification
and the NMR analysis must be carried out in the shortest period as possible.
R
R
HO
F
6
DAST, DCM,
3
4
0 - 25 °C, 24 h
41 - 56 %
5
2
1
N
N
N
N
3a-c
4a-c
3,4
R
a
H
b
c
NO2 OMe
Scheme 4. Synthesis of 3-aryl-4-fluoromethyl-1H-1-phenylpyrazoles (4a-c).
In Figure 3 is depicted the coupling constants observed for compound 3-(4-
nitrophenyl)-4-fluoromethyl-1H-1-phenylpyrazole (4b). The expected doublets for the
Page 12 of 24

spin-spin coupling between the hydrogen and carbon atoms with the fluorine atom of
1
13
the CH2F group (C6) show constants of J = 49.4 Hz and J = 159.2 Hz in H and C
19
NMR, respectively (Figure 3a). Additionally, the F NMR spectra shows a triplet for
the CH2F group with a chemical shift of -194.3 ppm with J = 49.4 Hz (Figure 3b).
Fig. 3. (a) 1H, 13C, (b) 19F NMR experimental signals for CH2F group of compound 4b.
Table 2 summarizes the experimental results of NMR study of pyrazole
members in relation to CH2F group attached to the C-4 position and similar data found
in literature for this group. Except for C3 of compound 4b, all hydrogen and carbon
atoms are influenced by the single fluorine atom. The hydrogen of C5 shows a coupling
3
1
constants range of J = 3.1 – 3.2 Hz and chemical shifts from 8.07 to 8.13 ppm, in H
NMR. Moreover, the C3, C4 and C5 show coupling constants in a range of 3J = 1.9, 2J
13
= 20.9 and 3J = 4.6 – 4.8 Hz, respectively in C NMR. In addition, the C3, C4 and C5
chemical range were 148.5 – 151.2, 115.8 – 116.7 and 127.3 – 128.3 ppm, respectively.
1
The chemical shift range for hydrogen of C6 in H NMR was found to be
between 5.41 – 5.46 ppm and the coupling constants of doublets had a variation from
49.4 to 49.6 Hz as expected for CH2F group. C6 in the 13C NMR was found to be
between 74.9 – 75.9 ppm with J = 161.6 – 162.9 Hz. Furthermore, the 19F NMR shows
triplets with chemical shift range of -193.0 to -194.3 ppm for compounds 4b and 4c
with J = 49.4 Hz. Only for compound 4a the coupling constants observed were a triple
of doublets, probably due to the coupling of the hydrogen of C5 and the CH2F group,
Page 13 of 24

with coupling constants of 49.5 and 3.7 Hz for the chemical shift of -193.6 ppm. All
these experimental values are in accordance with available data in literature [31].
1
Table 2. Experimental H, 13C and 19F NMR multiplicity,a chemical shiftsb and
coupling constantsc data of compounds 4 in CDCl3.d
F
6
4
3
5
N1
2
a
b
c
R
N
R
H
NO2 OMe
4a-c
C3
13C
C4
C5
C6
13C
d, 75.6,
13C
1H
d, 8.11, d, 129.4,
3J = 3.1 3J = 4.8
13C
1H
d, 5.46,
J = 49.5
19F
d, 152.8,
d, 116.1,
td, -193.6,
J = 49.5, 3.7
4a
4b
3J = 1.9
2J = 20.9
J = 162.3
d, 116.7,
d, 8.13, d, 130.5,
3J = 3.2 3J = 5.1
d, 5.46,
J = 49.4
d, 74.9,
J = 162.9
t, -194.3,
J = 49.4
s, 150.4
2J = 21.3
d, 152.8,
d, 115.7,
d, 8.07, d, 129.4,
d, 5.41,
J = 49.6
d, 75.9,
J = 161.6
t, -193.0,
J = 49.4
4c
3J = 1.9
2J = 20.9
3J = 3.2
3J = 4.6
d, 5.40 – 5.67
J = 48.2 – 49.0
d, 73.8 – 74.2
J = 162.0 – 163.0
Lit.e
-
-
-
-
-
aMultiplicity data: s = singlet, d = doublet; bChemical shifts in ppm;
cCoupling constants in relation to the fluorine atom: nJ = Hz;
dData order in the table: multiplicity/chemical shift/coupling constant;
eLiterature range data of multiplicities, chemical shifts and coupling constants found for CH2F group in 3, 4 or 5 position of pyrazole
rings in CDCl3.
3. Conclusion
In this work, we have continued our investigation on fluorination reactions in
azo-heterocycles employing the nucleophilic fluorinating reagent DAST. The 4-formyl-
1H-pyrazoles 1a-c and their 4-hydroxymethyl derivatives 3a-c reacted smoothly with
DAST to provide new series of 4-mono and 4-difluoromethyl substituted pyrazoles 2a-c
and 4a-c through simple and convenient procedure and work-ups.
1
In summary, the H, 13C and 19F NMR spectra characterizing fluorinated
compounds 2 and 4 were analyzed. The analysis of JH,F and JC,F coupling constants and
the respective multiplicities allows for the unambiguous assignment of the NMR signals
1
originating from H, 13C and 19F nuclei. The chemical shifts and coupling constants
Page 14 of 24

data obtained can be used as reference values for interpreting NMR spectra of other
derivatives of fluorinated 1,3,5-substituted 1H-pyrazoles, once these values are rarely
1
found in literature. Assignments of H, 13C and 19F signals are consistent with the
limited results available in literature for 3- and 5-fluoromethyl substituted pyrazoles
[31-33, 35-37].
4. Experimental
4.1. Analytical equipments and procedures
Unless otherwise indicated, all common reagents and solvents were used as obtained
from commercial suppliers, without further purification. The melting points were
determined using coverslips on a Microquímica MQAPF–302 apparatus and are
uncorrected. 1H and 13C NMR spectra were acquired on a Bruker DPX 400 spectrometer
13
19
(1H at 400.13 MHz and C at 100.32 MHz) and F NMR spectra were acquired on a
Bruker DPX 600 (19F at 376.3 MHz) spectrometer, using 5 mm sample tubes, 298 K,
and a digital resolution of ±0.01 ppm, in CDCl3, with TMS as the internal reference (1H
13
and C). The CHN elemental analyses were performed on a Perkin–Elmer 2400 CHN
elemental analyzer (University of São Paulo, Brazil) and the high resolution mass
spectrometry was performed using an Agilent-QTOF 6530 spectrometer (Santa Maria
Federal University, Brazil) and Bruker Daltonics MicrOTOF (University of São Paulo,
Brazil).
4.2.
Synthesis
Reagent DAST was purchased from Sigma-Aldrich Brazil. The arylhydrazones
and 3-aryl-4-formyl-1H-1-phenylpyrazoles (1a-c) were synthesized according to
literature procedures [26,27].
Page 15 of 24

4.2.1. Typical procedure for synthesis of compounds 3-aryl-4-formyl-1H-1-
phenylpyrazoles (1a-c).
POCl3 (30 mmol) was added dropwise at 0 °C to 5 ml of dry DMF. The mixture was
allowed to stand for 20 min at 0 °C, after which 10 mmol of arylhydrazone in 5 mL of
dry DMF was added and uniform gas evolution was observed. The mixture was stirred
for 3 h at 90 °C, cooled down and treated with 30% aqueous K2CO3 until the
effervescence stopped. Then the reaction mixture was extracted with CH2Cl2 (3 x 10
mL) and the combined extracts were dried with anhydrous Na2SO4, filtered and
evaporated under reduced pressure to obtain the corresponding compounds 1a-c which
were isolated as white (1a, 1c) or pallid orange solids (1b) recrystallized from diethyl
ether [26,27].
4.2.2. Typical procedure for synthesis of compounds 3-aryl-4-hydroxymethyl-1H-1-
phenylpyrazoles (3a-c)
The reduction reactions of 3-aryl-4-formyl-1H-1-phenylpyrazoles (1a-c) (1 mmol) were
conducted in anhydrous EtOH and CH2Cl2 (for better solubilization), at 0 °C, where
small portions of sodium borohydride (1.2 mmol) were added to the solution. After the
addition, the reaction mixture was stirred at 25 °C for 1 h. Then the solvents were
evaporated under reduced pressure. The residue was dissolved in 20 mL H2O/CH2Cl2
(1:1), stirred for 1 h and extracted with CH2Cl2 (3 x 10 mL). The combined extracts
were dried with anhydrous Na2SO4, filtered and evaporated under reduced pressure to
obtain the corresponding compounds 3a-c which were isolated as white (3a, 3c) or
orange solids (3b) recrystallized from diethyl ether. Only compound 3a is already
described and its analytical data were also compared with the available literature [38].
Page 16 of 24

4.2.2.1.
4-Hydroxymethyl-1H-1,3-diphenylpyrazole (3a): white solid, yield 52%,
mp 73 – 75 °C. 1H NMR (400.13 MHz, DMSO-d6): δ 8.50 (s, 1H), 7.90 (d, 4H), 7.53 –
7.46 (m, 4H), 5.18 (s, 1H), 4,59 (s, 2H).
13C NMR (100.61 MHz, DMSO-d6): δ 151.8, 140.0; 133.5; 138,7; 130.0; 129.0;
128.3, 127.8, 126.5, 118.5, 129.1, 122.5, 54.6.
HRMS Calcd. for C16H14N2O: 251.1179. Found: 251.1151.
4.2.2.2.
4-Hydroxymethyl-3-(4-nitrophenyl)-1H-1-phenylpyrazole (3b): orange
solid, yield 87%, mp 143 – 144 °C. 1H NMR (400.13 MHz, DMSO-d6): δ 8.58 (s, 1H),
8.33 (d, J = 8.3, 2H), 8.20 (d, J = 8.5, 2H), 7.92 (d, J = 8.0, 2H), 7.55 (t, J = 8.0, 2H),
7.36 (t, J = 7.3, 1H), 5.36 (t, J = 4.9, 1H), 4.64 (d, J = 4.9, 2H).
13C NMR (100.61 MHz, DMSO-d6): δ 148.5, 147.1, 139.9, 139.7, 130.0, 128.4,
127.0, 124.2, 118.8, 129.8, 123.4, 54.4.
Anal. Calcd. for C16H13N3O3 (295.10): C, 65.08; H, 4.44; N, 14.23. Found: C,
64.78; H, 4.48; N, 14.17.
4.2.2.3.
4-Hydroxymethyl-3-(4-methoxyphenyl)-1H-1-phenylpyrazole (3c): white
solid, yield 60%, mp 125 – 127 °C. 1H NMR (400.13 MHz, DMSO-d6): δ 8.45 (s, 1H),
7.89 – 7.84 (m, 4H), 7.50 (t, J = 7.8, 2H), 7.29 (t, J = 7.6, 1H), 7.04 (d, J = 8.8, 2H),
5.18 (s, 1H), 4.56 (d, J = 2.4, 2H), 3.81 (s, 3H).
13C NMR (100.61 MHz, DMSO-d6): δ 159.6, 150.7, 140.0, 129.9, 129.1, 126.3,
126.0, 118.4, 114.4, 128.9, 121.9, 55.6, 54.6.
Anal. Calcd. for C17H16N2O2 (280.12): C, 72.84; H, 5.75; N, 9.99. Found: C,
72.79; H, 5.51; N, 10.01.
Page 17 of 24

4.2.3. Typical procedure for the fluorination reactions with DAST: Synthesis of
compounds 2 and 4.
To a solution of 3-aryl-4-formyl(4-hydroxymethyl)-1H-1-phenylpyrazole (1a-c, 3a-c) (1
mmol) in anhydrous CH2Cl2, under ice bath, was added dropwise a solution of DAST
(2 mmol) in anhydrous CH2Cl2. After the addition, the reaction mixture was stirred at
room temperature for 24 h and a saturated aqueous solution of NaHCO3 was added to
the mixture and then extracted with CH2Cl2 (2 x 15 mL). The organic layer was washed
with aqueous solution of NaHCO3 and with distilled water (1 x 20mL). The organic
layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure.
The products 2a and 4a-c were purified on chromatography column using silicagel 60
and n-hexane:ethyl acetate (95:5) as eluent. The solid compounds 2b-c were purified by
simple filtration and washing with diethyl ether.
4.2.3.1.
4-Difluoromethyl-1H-1,3-diphenylpyrazole (2a): white solid, yield 45%,
1
mp 97 – 98 °C. H NMR (400.13 MHz, CDCl3): δ 8.15 (s, 1H), 7.75 (d, J = 7.1, 2H),
7.71 (d, 2H, J = 8.5), 7.45 – 7.36 (m, 5H), 7.28 (t, 1H, J = 7.5), 6.78 (t, 1H, J = 55.4).
3
13C NMR (100.61 MHz, CDCl3): δ 151.2 (t, J = 5.1), 147.8, 139.1, 138.1,
3
2
129.7, 128.6, 128.3, 128.3 (t, J = 6.3), 127.8, 119.5, 116.7 (t, J = 26.2), 110.6 (t, J =
234.5).
19F NMR (376.3 MHz, CDCl3): δ -105.9 (dd, J = 55.2, J = 3.4).
Anal. Calcd. for C16H12F2N2 (270.10): C, 71.10; H, 4.48; N, 10.36. Found: C,
70.84; H, 4.52; N, 10.11.
4.2.3.2.
4-Difluoromethyl-3-(4-nitrophenyl)-1H-1-phenylpyrazole (2b): white
solid, yield 67%, mp 108 – 109 °C. 1H NMR (400.13 MHz, CDCl3): δ 8.35 (d, J = 8.5,
Page 18 of 24

2H), 8.27 (s, 1H), 8.02 (d, 2H, J = 8.5), 7.79 (d, 1H, J = 8.0), 7.54 (t, 2H, J = 7.5), 7.42
(t, 1H, J = 7.0), 6.88 (t, 1H, J = 55.2).
3
13C NMR (100.61 MHz, CDCl3): δ 148.5 (t, J = 4.1), 147.8, 139.1, 138.1,
3
2
129.7, 128.6, 128.3 (t, J = 6.3), 127.8, 123.9, 119.5, 116.7 (t, J = 26.3), 110.7 (t, J =
234.5).
19F NMR (376.3 MHz, CDCl3): δ -106.2 (d, J = 55.2).
HRMS Calcd. for C16H11F3N3O2: 316.2816. Found: 316.2811.
4.2.3.3.
4-Difluoromethyl-3-(4-methoxyphenyl)-1H-1-phenylpyrazole
(2c):
1
yellow solid, yield 54%, mp 111 – 112 °C H NMR (400.13 MHz, CDCl3): δ 8.20 (s,
1H), 7.78 – 7.75 (m, 4H), 7.49 (t, 2H, J = 8.3), 7.34 (t, 1H, J = 7.3), 7.04 (d, 2H, J =
8.8), 6.84 (t, 1H, J = 55.5), 3.87 (s, 3H).
13C NMR (100.61 MHz, CDCl3): δ 160.1, 150.9, 139.5, 129.4, 129.2, 127.3 (t,
3J = 4.5), 127.0, 124.5, 119.2, 115.8 (t, 2J = 25.3), 114.2, 111.3 (t, J = 233.5), 55.2.
19F NMR (376.3 MHz, CDCl3): δ -106.0 (d, J = 55.1).
Anal. Calcd. for C17H14F2N2O (300.11): C, 67.99; H, 4.70; N, 9.33. Found: C,
67.70; H, 4.74; N, 9.11.
4.2.3.4.
4-Fluoromethyl-1H-1,3-diphenylpyrazole (4a): white solid, yield 41%,
mp 71 – 72 °C. 1H NMR (400.13 MHz, CDCl3): δ 8.11 (d, J = 3.1, 1H, H-5), 7.86 (d, J
= 7.4, 2H, Ar), 7.79 (d, 2H, J = 8.1, Ar), 7.50 (t, 4H, J = 7.4, Ar), 7.45 – 7.42 (m, 1H,
Ar), 5.46 (d, 2H, J = 49.5, CH2-F).
3
13C NMR (100.61 MHz, CDCl3): δ 152.8 (d, J = 1.9, C3), 139.8, 132.3, 129.4,
128.7, 128.4; 126.8; 119.2 (10C, Ar), 127.9 (d, 4J = 1.6, 2C, Ar) 129.4 (d, 3J = 4.8, C5),
116.1 (d, 2J = 20.9, C4), 75.6 (d, J = 162.3, CH2F).
Page 19 of 24

19F NMR (376.3 MHz, CDCl3): δ -193.6 (td, J = 49.5, J = 3.7, CHF2).
HRMS Calcd. for C16H13FN2: 253.1141. Found: 253.1140.
4.2.3.5.
4-Fluoromethyl-3-(4-nitrophenyl)-1H-1-phenylpyrazole (4b): yellow
1
solid, yield 43%, mp 143-144 °C. H NMR (400.13 MHz, CDCl3): δ 8.32 (d, J = 8.5,
2H, Ar), 8.13 (d, J = 3.2, 1H, H-5), 8.04 (d, 2H, J = 8.5, Ar), 7.76 (d, 2H, J = 8.0, Ar),
7.51 (t, 2H, J = 7.5, Ar), 7.37 (t, 1H, J = 7.0, Ar), 5.46 (d, 2H, J = 49.4, CH2-F).
13C NMR (100.61 MHz, DMSO-d6): δ 150.4 (C3), 147.6; 139.4; 138.7; 129.6;
127.5; 124.0; 119.4 (10C, Ar), 130.5 (d, 3J = 5.1, C5), 128.4 (d, 5J= 2.5, 2C, Ar), 116.7
(d, 2J = 21.3, C4), 74.9 (d, J = 162.9, CH2F).
19F NMR (376.3 MHz, CDCl3): δ -194.3 (t, J = 49.4, CHF2).
HRMS Calcd. for C16H12FN3O2: 298.0986. Found: 298.0951.
4.2.3.6.
4-Fluoromethyl-3-(4-methoxyphenyl)-1H-1-phenylpyrazole (4c): yellow
1
solid, yield 56%, mp 150-151 °C. H NMR (400.13 MHz, CDCl3): δ 8.07 (d, J = 3.2,
1H, H-5), 7.76 (t, J = 7.6, 4H, Ar), 7.47 (t, 2H, J = 7.5, Ar), 7.30 (t, 1H, J = 7.0, Ar),
6.99 (d, 2H, J = 8.0, Ar), 5.41 (d, 2H, J = 49.6, CH2-F), 3,86 (s, 3H, OCH3).
3
13C NMR (100.61 MHz, CDCl3): δ 159.9 (Ar), 152.8 (d, J = 1.9, C3), 139.8,
129.2, 126.7, 124.9; 119.2; 114.2 (12C, Ar), 129.4 (d, 3J = 4.6, C5), 129.3 (d, 4J = 2.1,
2C, Ar), 115.7 (d, 2J = 20.9, C4), 75.9 (d, J = 161.6, CH2F), 55.3 (OCH3).
19F NMR (376.3 MHz, CDCl3): δ -193.0 (t, J = 49.4, CHF2).
HRMS Calcd. for C17H15FN2O: 283.1241. Found: 283.1221.
Acknowledgements
Page 20 of 24

The authors thank the Coordination for Improvement of Higher Education Personnel
(CAPES) for fellowships, and the National Council for Scientific and Technological
Development (CNPq) and the Rio Grande do Sul Foundation for Support of Research
(FAPERGS) for financial support (Process numbers 303.013/2011-7, 470.788/2010.0-
CNPq/Universal, and 12/0982-1/FAPERGS/PqG).
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