Design, synthesis, and structure of alkyl 1H-pyrazolecarboxylates from a raspberry ketone methyl ether

Article abstract of DOI:10.1007/s10593-020-02816-z

[Figure not available: see fulltext.] This paper reports a one-pot synthesis of 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-3-carboxylates via cyclocondensation of 1,1,1-trichloro-4-methoxy-6-(4-methoxyphenyl)hex-3-en-2-one with hydrazine hydrochloride in RO

Full text of DOI:10.1007/s10593-020-02816-z

DOI 10.1007/s10593-020-02816-z
Chemistry of Heterocyclic Compounds 2020, 56(10), 1314–1320
Design, synthesis, and structure of alkyl 1H-pyrazolecarboxylates
from a raspberry ketone methyl etherꢀ
Taís B. Goulart1 Adriana M. Neves1, Mayara S. P. Soares2, Francieli M. Stefanello2,
,
3 4 5 1
Patrick T. Campos , Sidnei Moura , Roberta Cargnelutti , Alex F. C. Flores *
1
School of Chemistry and Food, Federal University of Rio Grande,
Rio Grande 96203-900, RS, Brazil; e-mail: alex.fcf.furg@gmail.com
Laboratory of Biomarkers, Center for Chemical,
Pharmaceutical and Food Sciences, Federal University of Pelotas,
Capão do Leão 96010-900, RS, Brazil; e-mail: mspereirasoares@gmail.com
Laboratory of Synthetic, Structural and Computational Organic Chemistry,
Sulriograndense Federal Institute (IFSul),
Pelotas 96015-360, RS, Brazil; e-mail: patrickcampos@pelotas.ifsul.edu.br
Biotechnology Institute, University of Caxias do Sul,
Caxias do Sul 95070-560, RS, Brazil; e-mail: sidmoura@gmail.com
2
3
4
5
Chemistry Department, Federal University of Santa Maria,
Santa Maria 97105-900, RS, Brazil; e-mail: roberta.cargnelutti@ufsm.br
Published in Khimiya Geterotsiklicheskikh Soedinenii,
020, 56(10), 1314–1320
Submitted June 17, 2020
Accepted after revision September 30, 2020
2
O
OMe
+
, 65–180°C
O
2
0–24 h, 20–75%
OR
Cl C
3
or
N
N
MW, 85–160°C
OMe
MeO
3
5 min, 33–80%
NH2NH2·HCl
ROH
R = Me, Et, n-Pr, i-Pr, i-Bu, i-Am, hexadecyl
H
This paper reports a one-pot synthesis of 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-3-carboxylates via cyclocondensation of 1,1,1-tri-
chloro-4-methoxy-6-(4-methoxyphenyl)hex-3-en-2-one with hydrazine hydrochloride in ROH (R = Me, Et, n-Pr, i-Pr, i-Bu, i-Am,
hexadecyl) under conventional and microwave heating. Yields are comparable in both methods, but under MW heating the reaction
proceeds faster. The antioxidant activity of the compounds was measured using DPPH radical scavenging assay. It was observed, that the
increase of the alcohol chain length decreases the antioxidant potential of the raspberry ketone derived molecular system.
Keywords: 4-alkoxy-1,1,1-trichloroalk-3-en-2-ones, 1H-pyrazolecarboxylates, raspberry ketone, antioxidants, microwave irradiation.
1
H-Pyrazole is a very important structural motif,
define the molecular structure of the alkyl 1H-pyrazole-
carboxylate obtained. This methodology gives an opportu-
nity to regiospecifically and in very good yields produce a
series of 1H-pyrazolecarboxylates, which exist in a solution
attracting much attention in organic synthesis, medicinal
1
chemistry, and agrochemistry. Among 1H-pyrazoles,
3
- or 5-carboxylates have important applications as anti-
2
5,6
inflammatory and antioxidant agents. A versatile and
interesting synthetic methodology using 1,1,1-trichloro-
as a mixture of 1,3- and 1,5-tautomers (Fig. 1).
4
-methoxyalk-3-en-2-ones to produce 1H-pyrazolecarboxy-
lates has been developed as one-pot process, when both
C–C–C + N–N] cyclization and hydrolysis of the tri-
[
chloromethyl group to the carboxyl one occur. Using the
acetal acylation reaction, it is possible to design the
dielectrophilic 1,1,1-trichloro-4-methoxy-3-alken-2-one by
selecting the respective alkyl methyl ketone precursor.3
Followed by the cyclocondensation reaction with hydrazine
the choice of the alcohol as a solvent and reactant will
,4
Figure 1. Structures of 1,3- and 1,5-tautomers of 1H-pyrazole-5(3)-
carboxylates obtained from 1,1,1-trichloro-4-methoxyalk-3-en-2-ones.
0
009-3122/20/56(10)-1314©2020 Springer Science+Business Media, LLC
1314

Chemistry of Heterocyclic Compounds 2020, 56(10), 1314–1320
Scheme 1. Synthesis of 1,1,1-trichloro-4-methoxy-6-(4-methoxyphenyl)hex-3-en-2-one (3) and 1H-pyrazole-5(3)-carboxylates 4a–g
under conventional and microwave heating
Antioxidants are molecules that prevent cellular damage
by scavenging or regulating the generation and elimination
of reactive oxygen and nitrogen species (ROS and RNS,
respectively).7 Natural antioxidants include molecules
alcohols: MeOH, EtOH, n-PrOH, i-PrOH, i-BuOH, isoamyl
alcohol, and hexadecyl alcohol. These cyclocondensations
were carried out using conventional heating and under
microwave irradiation (Scheme 1). Initially, the [3+2] cyclo-
8
found in leaf, fruit, and root extracts, such as zingerone,
condensation between compound 3 and NH
2
NH ·HCl in
2
9
raspberry ketone (4-(4-hydroxyphenyl)butan-2-one), and
MeOH (2 ml) was conducted at reflux (65°C) for 20 h. The
completion of the reaction was controlled by TLC until the
total consumption of the precursor and the appearance of
only one product. Then MeOH was distilled off, and the
solid (grease) residue was worked up to give methyl
5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-3-carboxylate (4a)
in 75% yield.
their ethers.10 The search for new antioxidants as drug
candidates is an active field of medicinal chemistry.11,12
The goal of the present work was to obtain different
alkyl 1H-pyrazolecarboxylates containing 2-(4-methoxy-
phenyl)ethyl moiety as new molecular prototypes of the
compounds with already recognized antioxidant activity,
using conventional and microwave heating methods. The
use of focused microwave irradiation to decrease reaction
times and improve yields has already been demonstrated
This synthetic protocol between compound 3 and
NH
2
NH ·HCl was extended to cyclocondensations of the
2
series of other alcohols. For the reactions in EtOH,
n-PrOH, and i-PrOH, the mixture was heated at the boiling
point of the respective alcohol for 20–24 h, leading to
corresponding alkyl 1H-pyrazole-3-carboxylates 4b–d in
relatively poor yields (35–68%). Upon the cyclocondensa-
tions in i-BuOH, isoamyl alcohol, and hexadecyl alcohol,
the reaction mixture was kept at 110°C for 24 h, leading to
the respective alkyl 1H-pyrazole-3(5)-carboxylates 4e–g in
even worse yields (20–58%) (Scheme 1). Knowing that
microwave-assisted syntheses lead to better yields in
shorter reaction times, this methodology was applied in
order to decrease reaction time and improve the yields
of the alkyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
3-carboxylates. The optimum conditions for carrying out
microwave-assisted [3+2] cyclocondensation reactions
were ascertained by carrying out the reaction of 1,1,1-tri-
chloro-4-methoxy-6-(4-methoxyphenyl)hex-3-en-2-one (3)
1
1,13
for 1H-pyrazoles.
In addition, antioxidant activity of the
newly synthesized molecules by DPPH radical scavenging
1
4
test in vitro has been assessed. The transformation of the
trichloromethyl group bound to 1H-pyrazole has become a
priority for our research group due to the diversification of
trichloromethyl-substituted substrates together with the
possibility of the diversification of substituted hydrazines.4
Employing [3+2] cyclocondensation reaction and using
alternative synthetic methodologies such as microwave
irradiation,15 use of ionic liquids, solvent-free, it is
possible to obtain 1H-pyrazoles with interesting structural
characteristics and numerous application possibilities, such
16
17
4
,13,14
as the development of new biological mediators.
Synthesis of alkyl 1H-pyrazole-3-carboxylate precursors
was carried out in three steps. The first step involved the
large-scale production of 1-(3,3-dimethoxybutyl)-4-methoxy-
benzene (2) from 4-(4-methoxyphenyl)butan-2-one (raspberry
ketone methyl ether) (1) and trimethyl orthoformate;
compound 2 was obtained in quantitative 95% yield
18
with NH
2
NH ·HCl in i-BuOH (ε 15); a time of 35 min
2
was determined for the consumption of all the precursor 3,
and isobutyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
3-carboxylate (4e) obtained in slightly better yield (66%),
in comparance to conventional heating. This procedure was
extended to the reactions with other alcohols excluding
hexadecyl alcohol resulting in no rapid heating and
consequently no homogenization of the reaction medium.
This remained a solid hydrazine salt even after 1 h in the
microwave oven. This was overcome by the addition of
MeCN as a solvent, resulting in the desired transformation –
hexadecyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
3-carboxylate (4g) was obtained in a slightly better yield
(Scheme 1). Then the acylation with trichloroacetyl
chloride was applied to produce the dielectrophilic pre-
cursor of the target 1H-pyrazolecarboxylates in almost
quantitative 90% yield. Trichloroacetyl derivative 3 was
obtained with sufficient purity and used in the following
transformations without additional purification. Both steps
3
were performed based on the literature methods. Finally,
the last step was [3+2] cyclocondensation between
NH
2
NH ·HCl and 1,1,1-trichloro-4-methoxy-6-(4-methoxy-
2
phenyl)hex-3-en-2-one (3), carried out in a series of
1
315

Chemistry of Heterocyclic Compounds 2020, 56(10), 1314–1320
Figure 3. Representation of the bidentate 5-membered pseudoring
in the molecular packing of compound 4b.
Figure 4. Representation of molecules forming infinite chains
along the plane b, c in the crystal of compound 4b.
determined by different refinements of the structure
indicating lower indices of disagreement when compared to
this H(1) atom in the other nitrogen atom of the molecule.
This data is in accordance with the bond lengths found
for the heterocycle C–N bonds. The bond lengths found
for N(1)–C(5) and N(2)–C(3) were 1.349 and 1.331 Å,
respectively, indicating the best representation of the
structure, corroborating the assignment of the H(1) ring
position.19 Another finding in the molecule is that the
dihedral angle found for N(2)–C(3)–C(13)–O(1) was 8.47°
revealing that the heterocycle and carbonyl are almost in
the same plane indicating a possible electronic resonance
by transferring hydrogen atoms or electrons followed by
protons, mainly for its simplicity and efficiency.25
The results described in Table 3 showed that alkyl
5-(4-methoxyphenethyl)-1H-pyrazole-3-carboxylates 4a–g
display antioxidant activity. Methyl and ethyl derivatives
4a,b displayed highest activity at the 10 μM concentration,
however, antioxidant activity increases much less than the
activity of the standard ascorbic acid, with increased
concentration. All compounds in the series 4a–g follow the
same trend, while each unit of ascorbic acid concentration
corresponds to 2.0 to 2.59% inhibition of the absorption of
DPPH colored radicals (Table 2), increasing the concentra-
tion of the samples tested by forty times, 10 to 400 μM,
caused the activity per unit of concentration to decrease.
Overall, the antioxidant activity in the series of compounds
4a–g demonstrates the potential of 1H-pyrazole nitrogen or
benzyl carbon radical intermediates in reducing DPPH
radicals.
2
0
between the two fragments of the molecule.
The crystalline structure of compound 4b is stabilized by
hydrogen bonds forming infinite chains along a plane b, c,
heterocycle and carbonyl group are almost in the same
plane indicating a possible electronic resonance between
them. In this molecule, two strong hydrogen bonds were
found, with the N(1)H group being the proton donor in the
interactions with the N(2) pyrazole atom together with the
carboxyl O(1) atom acting as H-acceptors.2 The inter-
atomic distances found were 2.128 and 2.564 Å for H(1)···O(1)
and H(1)···N(2), respectively, and 2.928 and 3.199 Å,
smaller than the sum of Van der Waals radii of the atoms
involved21 for N(1)···O(1) and N(1)···N(2), respectively in
the interactions N(1)–H(1)···O(1) (Fig. 4).
To conclude, a methodology for the synthesis of alkyl
5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-3-carboxylates
was developed. The synthetic methodology we have found
is simple and efficient for obtaining diverse alkyl
1H-pyrazolecarboxylates using conventional heating and
microwave irradiation, including obtaining the fatty deriva-
tive – hexadecyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
0
Table 2. DPPH antioxidant activity of ascorbic acid
used as standard*
Considering the information about the antioxidant
2
2
activity of the raspberry ketone, its alkyl ether deriva-
tives,23 and also 1H-pyrazoles, we decided to study the
antioxidant activity of the new hybrid molecules containing
both ester function and 1H-pyrazole. This preliminary
study aims to evaluate the antioxidant activity of alkyl
2
Concentration, μM
Inhibition rate, %
2.0 ± 0.8
1
5
11.5 ± 0.5**
22.6 ± 0.7**
34.3 ± 1.9**
51.9 ± 1.4**
1
1
2
0
5
0
1
H-pyrazole-3-carboxylates 4a–g by comparing the
obtained data with ascorbic acid data (Table 2), a standard
antioxidant compound widely used in different therapeutic
applications. To study the antioxidant activity of the
synthesized compounds, the DPPH radical scavenging
*
Values are expressed as mean ± SE of percentage of inhibition by the
compound compared to the control in EtOH.
* p < 0.001 indicates significant difference when compared with control
sample.
2
4
assay was employed. This test is widely used to
investigate the antioxidant activity of synthetic compounds
*
1
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Chemistry of Heterocyclic Compounds 2020, 56(10), 1314–1320
Scheme 2. The proposed mechanism of [3+2] cyclocondensation leading to 1H-pyrazole-3-carboxylates 4a–g
(
41%), after 35 min (Scheme 1). The proposed mechanism
region, 6.81–6.82 and 7.08–7.11 ppm with JHH = 8.0 Hz.
6
of the transformation is described in Scheme 2.
The singlet at 6.56–6.63 ppm is typical for H-4 proton of
5
Regardless of the method used, alkyl 5-[2-(4-methoxy-
phenyl)ethyl]-1H-pyrazole-3-carboxylates 4a,b,e have shown
the best yields and did not require purification for
spectroscopic analysis. Compounds 4c,d,f,g required
recrystallization from hexane. However, considering the
need for the high purity of the products necessary for the
antioxidant activity analysis the entire series was recrystal-
lized from hexane. Yields are presented in Table 1. All
isolated alkyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
the
4-unsubstituted
1H-pyrazole-3(5)-carboxylates.
Signals were also observed that prove the presence of the
ester groups corresponding to each alcohol tested in this
work. The structures of compounds 4a–g were confirmed
by the presence of the aromatic 1H-pyrazole ring signals
around 147.5–148.5 ppm for C-3 atom, 106.7–109.7 ppm
for C-4 atom, 138.8–140.9 ppm for C-5 atom, and 158.7–
161.8 ppm for CO
R atom in 13C NMR spectra. Sets of
2
signals proving the presence of the 2-(4-methoxyphenyl)-
ethyl moiety and the respective alcohol fragment in each
product 4a–g were observed.
1
13
3
-carboxylates 4a–g were identified using H and C NMR
spectroscopy and HRMS. X-ray diffraction was used for
the identification of the single crystal of ethyl 5-[2-(4-meth-
oxyphenyl)ethyl]-1H-pyrazole-3-carboxylate (4b).
The single crystal of compound 4b was obtained by the
slow evaporation from hexane solution at room tempe-
rature. 1H-Pyrazole 4b crystallized in the monoclinic
The HRMS analyses confirm the formation of com-
pounds 4a–g since all showed an acceptable experimental
crystalline system and P2 /n space group with only one
1
+
1
molecular ion value [M+H] . The H NMR spectra for all
compounds 4a–g exhibit two multiplet signals assigned to
two methylene groups of the phenylethyl moiety, with
typical chemical shift values of 2.91–2.99 and 2.98–3.16 ppm,
and signals from 4-methoxyphenyl group, a singlet at
independent molecule in the asymmetric unit (Fig. 2). The
assignment of H(1) atom to N(1) atom (Fig. 3) was
3
.78 ppm and two doublets in the characteristic aromatic
Table 1. Yields of 1H-pyrazole-5(3)-carboxylates 4a–g
under conventional and MW heating
Yield*, %
Compound
R
Conventional heating
MW heating
4
a
Me
Et
75
68
48
35
58
20
31
80
74
55
43
66
33
40
4
b
4
c
n-Pr
4
d
i-Pr
4
e
i-Bu
4
f
i-Am
Hexadecyl
4
g
Figure 2. Projection of the molecular structure of compound 4b
showing the atomic numbering scheme.
*
Yield of compounds after crystallization from hexane.
1
317

Chemistry of Heterocyclic Compounds 2020, 56(10), 1314–1320
Table 3. Evaluation of DPPH radical scavenging activity of 1H-pyrazole-3-carboxylates 4a–g (inhibition rate, %)*
Concentration, μM
Compound
1
0
25
50
100
200
400
4
a
9.2 ±1.8**
14.4 ± 1.2***
0.8 ± 0.3
12.8 ± 2.5***
17.3 ± 0.6***
0.7 ± 0.3
4.3 ± 0.2
nd
11.1 ± 0.2***
17.1 ± 0.5***
2.2 ± 0.3
7.6 ± 0.2
nd
12.2 ± 0.4***
18 ± 0.9***
1.8 ± 0.3
13.6 ± 0.2***
20.1 ± 0.6***
3.3 ± 0.3
16.6 ± 1.3***
21.5 ± 0.1***
3.8 ± 0.1
4
b
4
c
4
d
4.4 ± 0.4
10.6 ± 1.3
5.6 ± 1.6
23.4 ± 1.2
28.2 ± 2.4
nd*4
3.7 ± 2.6
5.9 ± 0.1
4
e
2.7 ± 0.2*5
2.1 ± 0.5**
3.8 + 0.1
3.2 ± 0.1**
1.6 ± 0.1
2.5 ± 0.5**
0.9 ± 0.1
2.7 ± 0.1*5
3.6 ± 2.7
2.7 ± 0.9*5
1.7 ± 0.1
4
f
4
g
3.2 ± 0.4
*
*
*
*
*
Values are expressed as mean ± SE of percentage of inhibition by the compound compared to the control 60 μM DPPH solution in EtOH.
* p < 0.01, indicates significant difference when compared with control sample.
** p < 0.001, indicates significant difference when compared with control sample.
4
nd – not detectable.
5
p < 0.05, indicates significant difference when compared with control sample.
3
-carboxylate. When we compare conventional heating
were determined using a Fisatom 430D melting point
determiner with three capillary tubes, and thermometer up
to 360°C. Microwave reactions were performed using a
CEM Discover SP W/ActiVent microwave reactor model
no 909155, in a 5-ml vials with stirring option, using
Teflon caps, under completely sealed environment with
reactor specifications: voltage 180/240 V AC; max current
6.3 A; frequency 50/60 Hz; max microwave power 300 W.
The reaction temperature 85–160°C was reached in a ramp
time of 2–5 min and hold time was set for 35 min.
with microwave irradiation, it was observed that the latter
significantly reduces the reaction time from 20 h to 35 min,
although yields were only slightly higher after purification
by crystallization from hexane. In addition, the antioxidant
activity results in DPPH assay indicated that several of the
obtained compounds exhibit good antioxidant activity,
when compared to the activity of ascorbic acid.
Experimental
IR spectrum of compound 4b was obtained on a
Shimadzu IRPrestige-21 spectrophotometer. The analysis
was performed in the solid state, using the diffuse
reflectance technique, with readings in the region 4000–
Synthesis of 1H-pyrazole-3-carboxylates 4a–g (General
procedure). Conventional heating method. In a round-
bottom 25-ml flask, 1,1,1-trichloro-4-methoxy-6-(4-methoxy-
phenyl)hex-3-en-2-one (3) (2 mmol), hydrazine dihydro-
chloride (2.2 mmol), and alcohol (2 ml) were added. The
mixture was stirred at reflux temperature for 20–24 h. Then
solvent was evaporated under reduced pressure and the
–1
5
00 cm . Spectrum was treated using the ACD software
package, located at the School of Chemistry and Food at
1
the Federal University of Rio Grande (FURG). The H and
1
3
С NMR spectra (400 and 100 MHz, respectively), as well
solid residue was diluted with CH
distilled H O. The organic phase was neutralized with 10%
CaCO solution, washed with distilled H O, dried over
anhydrous Na
2
Cl
2
and washed with
1
13
1
13
as COSY, H– C HSQC, H– C HMBC spectra, were
acquired on a Bruker Ascend 400 spectrometer in CDCl
with TMS as internal standard. Atom numbering in the H
2
3
3
2
1
2
SO , and solvent was evaporated. Com-
4
13
and C NMR spectra assignments does not correspond to
the IUPAC nomenclature and is given in the
Supplementary information file for each compound. High-
resolution mass spectra were obtained on an Agilent 6460
Triple Quadrupole connected to a 1200 series LC and
equipped with a solvent degasser, binary pump, column
oven, auto-sampler. The Agilent QQQ 6460 tandem mass
spectrometer was operated in positive jet stream
electrospray ionization (ESI) mode. Nitrogen was used as the
nebulizer, turbo (heater) gas, curtain gas, and collision-
activated dissociation gas. The capillary voltage was set at
pounds 4c,d,f,g,h were recrystallized from hexane.
Microwave irradiation method. A compatible vessel in a
Discover SP reactor for microwave synthesis was filled
with 1,1,1-tricloro-4-methoxy-6-(4-methoxyphenyl)hex-3-en-
2-one (3) (2 mmol), hydrazine dihydrochloride (2.2 mmol),
and alcohol (2 ml). Alcohol itself was used as a solvent,
except for compound 4g, when MeCN (2 ml) was used
since the alcohol is solid compound. After the container
was sealed, the sample was irradiated with stirring in a
closed system for 35 min, the irradiation power was in the
range of 1–50 W, pressure between 0–100 psi, and the
reaction temperature 85–160°C. After completion, the
reaction mixture was subsequently cooled to 50°C with
compressed air. The reaction mixture was treated as
described for the conventional heating method. Compounds
4c,d,f,g were recrystallized from hexane.
+
3500 V, and the nozzle voltage was at +500 V. The ion
source gas temperature was 300°C with a flow rate of 5 l/
min. The jet stream sheath gas temperature was 250°C with a
flow rate of 11 l/min. All samples were infused into the ESI
source at a 5 ml/min flow rate. Data was acquired in
positive MS total ion scan mode (mass scan range m/z 50–
Methyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
3-carboxylate (4a). Yield 195 mg (75%, thermal), 209 mg
6
50) and in positive MS/MS product ion scan mode source at
1
the University of Caxias do Sul (UCS). The melting points
(80%, MW), amber grease. H NMR spectrum, δ, ppm
1
318

Chemistry of Heterocyclic Compounds 2020, 56(10), 1314–1320
(
J, Hz): 9.41 (1H, s, NH); 7.10 (2H, d, J = 8.5, H-2,6 Ar);
(C-4); 71.0 (C-14); 55.3 (C-12); 34.7 (C-6); 28.6 (C-15);
+
6
3
.81 (2H, d, J = 8.6, H-3,5 Ar); 6.63 (1H, s, H pyrazole);
.94 (3H, s, CO CH ); 3.78 (3H, s, OCH ); 3.16 (2H, t,
); 2.99 (2H, t, J = 7.6, 7-CH
27.9 (C-7); 19.2 (C-16,17). Found, m/z: 303.1701 [M+H] .
2
3
3
C
17
H
23
N
2
O . Calculated, m/z: 303.1709.
3
1
3
J = 7.6, 6-CH
2
2
). C NMR
Isopentyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
spectrum, δ, ppm: 159.6 (C-13); 158.3 (C-11); 148.5 (C-3);
38.8 (C-5); 131.7 (C-8); 129.5 (C-9); 114.1 (C-10); 107.9
C-4); 55.4 (C-12); 52.9 (C-14); 34.0 (C-6); 27.8 (C-7).
3-carboxylate (4f). Yield 63 mg (20%, thermal), 105 mg
1
1
(33%, MW), amber grease. H NMR spectrum, δ, ppm
(
(J, Hz): 7.09 (2H, d, J = 8.6, H-2,6 Ar); 6.81 (2H, d, J = 8.6,
H-3,5 Ar); 6.56 (1H, s, H pyrazole); 4.32 (2H, t, J = 6.9,
+
Found, m/z: 261.1246 [M+H] . C14
H
17
N
2
O
3
. Calculated, m/z:
2
61.1239.
OCH
2.94–2.90 (2H, m, 7-CH
1.67–1.60 (2H, quint, J = 6.8, CH
13
2
); 3.78 (3H, s, OCH
3
); 3.02–2.98 (2H, m, 6-CH
); 1.76–1.73 (1H, m, CH(CH
CH CH(CH
2
);
);
Ethyl
5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
2
3
)
2
3
-carboxylate (4b). Yield 187 mg (68%, thermal), 203 mg
2
2
3
)
2
); 0.95
–1
(
74%, MW), amber solid, mp 78–80°C. IR spectrum, ν, cm :
(6H, d, J = 4.0, CH
2
CH
2
CH(CH ) ). C NMR spectrum,
3
2
1
1
750 (C=O), 1500 (Ar), 1050 (C–O), 860 (Ar). H NMR
δ, ppm: 161.8 (C-13); 158.1 (C-11); 147.5 (C-3); 140.9
(C-5); 132.8 (C-8); 129.4 (C-9); 113.9 (C-10); 106.7 (C-4);
63.8 (C-14); 55.3 (C-12); 37.7 (C-15); 34.5 (C-6); 28.4 (C-7);
spectrum, δ, ppm (J, Hz): 7.08 (2H, d, J = 8.5, H-2,6 Ar);
6
4
.82 (d, J = 8.6, 2H, H-3,5 Ar); 6.60 (1H, s, H pyrazole);
.36 (2H, q, J = 7.1, CH CH ); 3.78 (3H, s, OCH ); 3.00
); 2.94 (2H, t, J = 7.1, 7-CH ); 1.36
). C NMR spectrum, δ, ppm:
+
2
3
3
25.7 (C-16); 22.6 (C-17,18). Found, m/z: 317.1875 [M+H] .
(
(
2H, t, J = 7.1, 6-CH
3H, t, J = 7.6, CH
2
2
C
18
H
25
N
2
O . Calculated, m/z: 317.1865.
3
1
3
2
CH
3
Hexadecyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
1
1
61.6 (C-13); 158.2 (C-11); 148.1 (C-3); 140.7 (C-5);
32.8 (C-8); 129.4 (C-9); 114.1 (C-10); 106.9 (C-4); 61.2
3-carboxylate (4g). Yield 146 mg (31%, thermal), 188 mg
1
(40%, MW), white solid, mp 78–80°C. H NMR spectrum,
(
C-14); 55.4 (C-12); 34.6 (C-6); 28.6 (C-7); 14.4 (C-15).
δ, ppm (J, Hz): 7.08 (2H, d, J = 8.6, H-2,6 Ar); 6.81 (2H, d,
J = 8.6, H-3,5 Ar); 6.59 (1H, s, H pyrazole); 4.28 (2H, t,
+
Found, m/z: 275.1387 [M+H] . C15
H N
19 2
O . Calculated, m/z:
3
2
75.1396.
J = 6.8, OCH
6-CH
m, 15-CH
17–30-CH
2
); 3.78 (3H, s, OCH
); 2.92–2.88 (2H, m, J = 7.5, 7-CH
); 1.39–1.35 (2H, m, 16-CH
3
); 3.01–2.96 (2H, m,
); 1.79–1.67 (2H,
); 1.25 (28H, s,
Propyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
2
2
3
-carboxylate (4c). Yield 139 mg (48%, thermal), 160 mg
2
2
1
13
(
55%, MW), brown solid, mp 80–82°C. H NMR spectrum,
2
); 0.88 (3H, t, J = 6.8, CH ). C NMR
3
δ, ppm (J, Hz): 7.08 (2H, d, J = 8.5, H-2,6 Ar); 6.81 (2H, d,
J = 8.5, H-3,5 Ar); 6.58 (1H, s, H pyrazole); 4.26 (2H, t,
spectrum, δ, ppm: 171.3 (C-13); 129.3 (C-9); 114.0 (C-10);
109.7 (C-4); 64.8 (C-14); 55.3 (C-12); 45.3 (C-15); 32.0 (C-6);
J = 6.8, OCH
-CH ); 2.93 (2H, t, J = 7.6, 7-CH
CH CH CH ); 0.99 (3H, t, J = 7.4, CH
spectrum, δ, ppm: 160.3 (C-13); 156.8 (C-11); 146.7 (C-3);
39.7 (C-5); 131.5 (C-8); 128.1 (C-9); 112.7 (C-10); 105.5
C-4); 65.3 (C-14); 54.0 (C-12); 33.3 (C-6); 27.2 (C-7);
2
); 3.78 (3H, s, OCH
3
); 2.95 (2H, q, J = 7.3,
29.5 (C-7); 22.8 (C-17,18); 14.2 (C-29). Found, m/z:
+
6
2
2
); 1.79–1.73 (2H, m,
471.3572 [M+H] . C29
H
47
N
2
O . Calculated, m/z: 471.3587.
3
1
3
2
2
3
2
CH
2
CH
3
). C NMR
Antioxidant activity of compounds 4a–g in DPPH
scavenging test. The antioxidant activity of compounds 4a–g
was measured using the DPPH radical scavenging test
1
2
5
(
according to a modified method by Brand-Williams et al.
+
2
0.8 (C-15); 13.9 (C-16). Found, m/z: 289.1559 [M+H] .
. Calculated, m/z: 289.1552.
Isopropyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
-carboxylate (4d). Yield 101 mg (35%, thermal), 124 mg
60 μM DPPH solution in EtOH (2 ml) was added to the
solution of the test compound (at 10, 25, 50, 100, 200, and
400 μM concentration) in EtOH (2 ml), and the mixture
was incubated in assay tubes and kept in the dark for
30 min. The decrease in absorbance was determined at
515 nm on a UV/Vis spectrophotometer Biospectro, com-
mercial synthetic ascorbic acid (1–20 μM) was used for
comparison.22 The results were expressed as a percentage
of reduction of the DPPH control in EtOH solution
(Table 3).
C
16
H
21
N
2
O
3
3
1
(
43%, MW), amber solid, mp 93–95°C. H NMR spectrum,
δ, ppm (J, Hz): 9.81 (1H, s, NH); 7.11 (2H, d, J = 8.6,
H-2,6 Ar); 6.82 (2H, d, J = 8.6, H-3,5 Ar); 6.63 (1H, s,
H pyrazole); 5.27–5.21 (1H, m, CH(CH
3
)
2
); 3.78 (3H, s,
OCH
-CH
δ, ppm: 164.6 (C-13); 158.2 (C-11); 148.4 (C-3); 139.1
C-5); 131.5 (C-8); 129.1 (C-9); 113.8 (C-10); 107.6 (C-4);
0.3 (C-14); 55.0 (C-12); 33.8 (C-6); 27.5 (C-7); 21.5
3
); 3.15 (2H, t, J = 7.7, 6-CH ); 2.98 (2H, t, J = 7.7,
); 1.38 (6H, d, J = 6.5, CH(CH ) ). C NMR spectrum,
2
13
7
2
3
2
Single crystal X-ray diffraction data of compound 4b
was obtained on a Bruker D8 QUEST diffractometer using
CuKα radiation (λ 1.54080 Å) with a KAPPA four-circle
goniometer equipped with a PHOTON II CPAD area
detector at the Federal University of Santa Maria. The
structure was solved by direct methods using SHELXT and
refined with SHELXL.26 All non-hydrogen atoms were
refined using anisotropic displacement parameters in
SHELXL. The hydrogen atom positions were calculated
starting from the idealised positions. Absorption cor-
rections were performed using multiscan methods. The
molecular structure was visualized using the Mercury27
program. Full crystallographic data of compound 4b was
deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 1965453).
(
7
+
(
C-15,16). Found, m/z: 289.1565 [M+H] . C16
H
21
N
2
O . Calcu-
3
lated, m/z: 289.1552.
Isobutyl 5-[2-(4-methoxyphenyl)ethyl]-1H-pyrazole-
3
-carboxylate (4e). Yield 166 mg (58%, thermal), 200 mg
1
(
66%, MW), beige solid, mp 108–110°C. H NMR spectrum,
δ, ppm (J, Hz): 7.09 (2H, d, J = 8.6, H-2,6 Ar); 6.82 (2H, d,
J = 8.6, H-3,5 Ar); 6.58 (1H, s, H pyrazole); 4.07 (2H, d,
J = 6.8, OCH
-CH ); 2.93–2.90 (2H, m, 7-CH
CH(CH ); 0.98 (6H, d, J = 8.0, CH
spectrum, δ, ppm: 161.8 (C-13); 158.2 (C-11); 148.0 (C-3);
40.7 (C-5); 132.9 (C-8); 129.4 (C-9); 114.0 (C-10); 106.8
2
); 3.78 (3H, s, OCH
3
); 3.01–2.97 (2H, m,
6
2
2
); 2.08–2.01 (1H, m,
1
3
3
)
2
2
CH(CH ) ). C NMR
3
2
1
1
319

Chemistry of Heterocyclic Compounds 2020, 56(10), 1314–1320
Supplementary information file containing H and 13C
1
11. Chanda, S.; Dave, R. Afr. J. Microbiol. Res. 2009, 3, 981.
1
1
1
2. Flores, A. F. C.; Martins, M. A. P.; Rosa, A.; Flores, D. C.;
NMR spectra, HRMS data of all synthesized compounds,
IR spectrum and X-ray data of compound 4b is available at
the journal website at http://link.springer.com/journal/10593.
Zanatta, N.; Bonacorso, H. G. Synth. Commun. 2002, 32,
1585.
3. Martins, M. A. P.; Cunico, W.; Pereira, C. M. P.; Sinhorin, A. P.;
Flores, A. F. C.; Bonacorso, H. G.; Zanatta, N. Curr. Org.
Synth. 2004, 1, 391.
4. Bellam, M.; Gundluru, M.; Sarva, S.; Chadive, S.; Natala, V. R.;
Tartte, V.; Cirandur, S. R. Chem. Heterocycl. Compd. 2017,
53, 173. [Khim. Geterotsikl. Soedin. 2017, 53, 173.]
The authors thank CNPq, Fundação de Apoio a Ciência
e Tecnologia do Rio Grande do Sul (FAPERGS), and
CAPES for the financial support and scholarships and
Centro Integrado de Análise CIA-(FURG) for technical
analysis.
15. Martins, M. A. P.; Pereira, C. M. P.; Beck, P.; Machado, P.;
Moura, S.; Teixeira, M. V. M.; Bonacorso, H. G.; Zanatta, N.
Tetrahedron Lett. 2003, 44, 6669.
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