Cyanoacetylazoles and salicylic aldehydes promoting the synthesis of new trifluoromethyl-substituted azolecarbonyl-2H-chromen-2-ones through the Knoevenagel condensation reaction

Article abstract of DOI:10.1016/j.jfluchem.2015.08.005

The results of the chemical behavior of three substituted cyanoacetylazoles and some salicylic aldehydes used to obtain new trifluoromethylated azolecarbonyl-2H-chromen-2-ones through Knoevenagel condensation reactions, are reported. First, a new series of four 3-(5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1H-pyrazole-1-carbonyl)-2-imino-2H-chromenes were efficiently synthesized, in yields of 50-78%, using 0.4 M NaOH/EtOH as the catalyst. They were then subjected to an acid hydrolysis reaction, which produced the respective trifluoromethyl-substituted pyrazolinecarbonyl coumarins in good yields (80-91%). In order to study the influence of the CF₃ substituent, reactions involving 1-cyanoacetyl-3,5-dimethyl-5-hydroxy-4,5-dihydro-1H-pyrazole were also performed, but they did not provide the desired coumarins. On the other hand, attempts to synthesize some pyrrolecarbonyl coumarins not containing trifluoromethyl groups, but using the same methodology, directly resulted in a new series of five 3-(1-methyl-1H-pyrrol-2-carbonyl)-2H-chromen-2-ones in good yields (40-60%).

Full text of DOI:10.1016/j.jfluchem.2015.08.005

Journal of Fluorine Chemistry 178 (2015) 296–305
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Cyanoacetylazoles and salicylic aldehydes promoting the synthesis of
new trifluoromethyl-substituted azolecarbonyl-2H-chromen-2-ones
through the Knoevenagel condensation reaction
*
´
Helio G. Bonacorso , Melissa B. Rodrigues, Wilian C. Rosa, Letıcia B. Silva, Clarissa P. Frizzo,
Nilo Zanatta, Marcos A.P. Martins
Nu´cleo de Quı´mica de Heterociclos, NUQUIMHE, Departamento de Quı´mica, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
A R T I C L E I N F O
A B S T R A C T
Article history:
The results of the chemical behavior of three substituted cyanoacetylazoles and some salicylic aldehydes
used to obtain new trifluoromethylated azolecarbonyl-2H-chromen-2-ones through Knoevenagel
condensation reactions, are reported. First, a new series of four 3-(5-hydroxy-3-methyl-5-trifluor-
omethyl-4,5-dihydro-1H-pyrazole-1-carbonyl)-2-imino-2H-chromenes were efficiently synthesized, in
yields of 50–78%, using 0.4 M NaOH/EtOH as the catalyst. They were then subjected to an acid hydrolysis
reaction, which produced the respective trifluoromethyl-substituted pyrazolinecarbonyl coumarins in
good yields (80–91%). In order to study the influence of the CF3 substituent, reactions involving 1-
cyanoacetyl-3,5-dimethyl-5-hydroxy-4,5-dihydro-1H-pyrazole were also performed, but they did not
provide the desired coumarins. On the other hand, attempts to synthesize some pyrrolecarbonyl
coumarins not containing trifluoromethyl groups, but using the same methodology, directly resulted in a
new series of five 3-(1-methyl-1H-pyrrol-2-carbonyl)-2H-chromen-2-ones in good yields (40–60%).
ß 2015 Elsevier B.V. All rights reserved.
Received 27 May 2015
Received in revised form 3 August 2015
Accepted 6 August 2015
Available online 10 August 2015
Keywords:
Knoevenagel condensation
Trifluoromethyl group
Coumarins
Pyrazolines
Pyrroles
1. Introduction
ring, giving them more flexibility to adapt well to various
applications [17,32–34].
2H-Chromen-2-one derivatives (coumarins or benzo [b] pyr-
ones) are found in several plant species in nature. Coumarins are a
class of secondary metabolites widely distributed in the plant
kingdom and can also be found in fungi and bacteria [1]. These
kinds of compounds have a large range of applications in the food,
cosmetic and perfume industries, as well as a major role in
technological advances. Coumarins have been studied by many
research groups and reported as biological agents with anticoagu-
lant, antibacterial, antifungal, antibiotic, anti-inflammatory, anti-
depressant, and antimalarial activities, among other things [2–6].
Coumarins are part of an important class of fluorescent and laser
dyes and are used for synthesizing brighteners and fluorescent
labels, as well as in probes for measuring physiological [7–9],
organic nonlinear optical materials, and they are widely used in the
emission layers of organic light-emitting diodes (OLED) [10–31].
Their photophysical and spectroscopic properties can be easily
modified by the introduction of substituents into the coumarin
Different substituted coumarin derivatives can be obtained by
several synthetic methods. In the field of synthetic organic
chemistry, salicylic aldehydes have been used as substrates in
organic synthesis in order to obtain coumarins. Despite all the
interesting uses of coumarins, a brief review of the literature has
shown that the synthesis of more complex heterocyclic com-
pounds (e.g., those containing
a benzo [b] pyrone moiety
associated to a pyrazole or a pyrrole nucleus and both linked to
a carbonyl function) has been little explored, but coumarin
systems directly related to pyrazoles and pyrroles without a
carbonyl spacer are commonly found in the literature [18,35,36].
On the other hand, a very important substituent in medicinal
chemistry is the trifluoromethyl group [37], due to its stereoelec-
tronic properties and increase in molecular lipophilicity [38–45].
Thus, the introduction of trifluoromethyl groups into bioactive
molecules has become very important in pharmaceutical studies
[46–48], stimulating work directed towards the elaboration of
synthetic methodology for compounds containing these groups.
Due to all these factors, organofluorine chemistry has been
vigorously developing over the past two decades [49–57]. Our
research group and a few others around the world have been
*
Corresponding author. fax: +55 55 3220 8031.
studying the synthetic potential of b-alkoxyvinyl trifluoromethyl
E-mail address: helio.bonacorso@ufsm.br (H.G. Bonacorso).
http://dx.doi.org/10.1016/j.jfluchem.2015.08.005
0022-1139/ß 2015 Elsevier B.V. All rights reserved.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 178 (2015) 296–305
297
ketones for obtaining new trifluoromethylated heterocycles, as
well as other molecules that could provide chemical derivatiza-
tions, thus leading to substances, or the substances structural
analogues, with proven applications [54–57].
[77,78], with it being necessary to introduce small experimental
modifications; for example, the use of methanol as the reaction
solvent, under reflux for 16 h and further purification by extraction
with ethyl acetate (see experimental section).
Among the various classes of known heterocycles, pyrazoles
and their derivatives possess a diversity of functional groups and
they have attracted a great deal of interest because of their wide
range of pharmacological properties [58–63]. In recent years we
have performed the syntheses of some tosylpyrazoles containing
the CF3 group. The syntheses showed good results for pathological
pain in comparison with the drug Celecoxib [64]. Also, in 2006 the
biological activities of pyrazoles containing the CF3 group were
explored [65]. A series of pyrazolyl-quinolines were synthesized
and biological assays showed antimalarial activity stronger than
chloroquine, which is one of the drugs commonly prescribed for
malaria. Taking into consideration recently developed works, we
confirm the importance of the study of new pyrazoles containing
the CF3 group due to their wide range of pharmacological
properties [66,67,45,68,69].
On the other hand, it is also reported in the literature some
computational and experimental approaches that can estimate the
permeability and solubility of organic compounds. One such
approach would be the study reported as the Lipinski rules of five
[70]. This rule predicts that the bad absorption or permeation is
more likely when the compounds have more than five H-bonds
donors, ten H-bonds acceptors, the molecular weight of the
compounds is higher than 500 g/mol and when a calculated log P
(ClogP) is greater than 5. This study has recently been applied to
many compounds containing the trifluoromethyl group to predict
the performance of these in the organism [71–73].
In this context, and aiming for the synthesis of new
trifluoromethyl-substituted molecules, we synthesized 1-cyanoa-
cetyl-5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1H-
pyrazole (3) – a trifluoromethylated heterocyclic molecule that has
a cyanoacetyl group attached to the N-1 – as well as a 2-
cyanoacetyl-1-methylpyrrole system (9), both of which were used
as precursors in reactions with salicylic aldehydes. The structural
chemical characteristics of these two cyanoacetylazoles (3 and 9)
allowed them to be studied in synthetic applications for the
obtainment of new iminochromene and coumarinic pyrazoline/
pyrrole substituent [74].
Thus, considering the biological importance and application of
coumarins, the known synthetic potential of the pyrazoline 3, the
importance of heterocycles containing the CF3 group, and the study
of the reactivity of these systems when compared to non
trifluoromethyl-substituted heterocycles, we wish to report here
Subsequently, when pure 4,5-dihydropyrazole (3) reacted with
some selected substituted salicylic aldehydes (4a–d), regiospeci-
fically and in a one-step reaction, pyrazolinyl-iminochromenes
(5a–d) were obtained through a typical Knoevenagel condensation
reaction, due to the existence of an active methylenic center in the
precursor 3 (Scheme 2).
Based on the methodology described in the literature [79], we
started the optimization of the reaction conditions using 4b as the
aldehyde precursor. In order to obtain the desired iminochromene
5b, different catalysts were tested. When piperidine or triethyla-
mine were used, the imino compounds were isolated at low yields.
However, when the reaction was done employing 0.4 M NaOH/
EtOH, the product 5b was obtained at better yields (78%). The
presence of 0.4 M NaOH/EtOH was the best methodology for
generating the active methylenic center, which is essential for
beginning the condensation reaction and providing the desired
pyrazolinyl-iminochromenes 5. We also tested different solvents,
such as ethanol and acetone, but ethanol was the most efficient
medium—it contributed to a significant increase in product yields.
Interestingly, the initial condensation reaction enabled the
isolation of the products, with the imino function being preserved
at position 2 of the coumarin ring. The conversion to the product
was followed by TLC, checking of the consumption of the starting
materials over time, and choosing the best reaction time that
would lead to a higher yield in a shorter amount of time. Thus, the
optimal conditions enabled the isolation of a new series of
pyrazolinyl-iminochromenes 5a-d.
The reactions were done at a molar ratio of 1:1, with ethanol as
the solvent, at 78 8C for 2 h, using drops of 0.4 M NaOH/EtOH as the
catalyst. After the reaction time, compounds 5a–d precipitated and
were isolated in yields of 50–78% by simple filtration and washing
with acetone/dichloromethane (Scheme 2). Compounds 5a–d
were obtained with small amounts of the carbonyl compounds
6a-d, which were easily discarded by washing with a mixture of
acetone and dichloromethane. Unfortunately, when we performed
the reaction with the cyanoacetylated precursor 3 and the 2-
hydroxy-4-methoxybenzaldehyde, which contains the electron-
donating group 4-OCH3, it was not possible to isolate the
corresponding product 5e. The electrophilicity is lower of this
aldehyde, which leads to the formation of a complex mixture with
difficult isolation and identification of the products by proton
NMR.
the synthesis of
a
new series of 3-(5-hydroxy-3-methyl-5-
It should also be noted that the compounds 5a–d (iminochro-
menes) had very low solubility in many common organic solvents
and were completely insoluble in water. Thus, the 5 series could
not be completely characterized by GC–MS or LC–MS, and the 1H
and 13C NMR spectra could only be recorded for compounds 5a–c,
with the limitation being due to the low solubility of compounds
5a–c. The compounds 5a–c were then identified by 1H NMR in a
highly diluted solution in DMSO-d6; however, only 5b and 5c could
be identified by 13C NMR. Contrastingly, the whole of series 5 had
its purity confirmed by satisfactory data from CHN elemental
trifluoromethyl-4,5-dihydro-1H-pyrazol-1-carbonyl)-2-imino-2H-
chromenes (5) and 3-(3-methyl-5-trifluoromethyl-5-hydroxy-4,5-
dihydro-1H-pyrazol-1-carbonyl)-2H-chromen-2-ones (6) obtained
from an initial Knoevenagel condensation reaction involving 1-
cyanoacetyl-5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-
1H-pyrazole (3) and substituted salicylic aldehydes (4) under
conventional heating. Subsequently, in order to establish
a
comparative study, we present the synthesis of 3-(1-methyl-1H-
pyrrol-2-carbonyl)-2H-chromenes (10) using 2-cyanoacetyl-1-
methylpyrrole (9) and the same substituted salicylic aldehydes
(4) as precursors.
2. Results and discussion
In order to achieve the first synthetic target of this work, it was
necessary to synthesize the precursor 1-cyanoacetyl-4,5-dihydro-
1H-pyrazole (3), which was obtained from the cyclocondensation
of cyanoacetic hydrazide (1) and 4-methoxy-1,1,1-trifluoropent-3-
en-2-one (2) [75,76], in accordance with the literature (Scheme 1)
Scheme 1. Cyclocondensation reaction involving cyanoacetic hydrazide (1) and 4-
methoxy-1,1,1-trifluoropent-3-en-2-one (2). Reagents and conditions: (i) MeOH,
reflux, 16 h.

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H.G. Bonacorso et al. / Journal of Fluorine Chemistry 178 (2015) 296–305
CH3
CH3
HO
F3C
O
N
HO
F3C
R1
N
N
H
R1
N
+
i
O
CN
HO
O
50-78%
HN
O
4a-d
3
5a-d
d
a
H
b
NO2
c
Br
4,5
R1
OCH3
Scheme 2. Knoevenagel condensation reaction involving 4,5-dihydropyrazole (3) and salicylic aldehydes (4). Reagents and conditions: (i) EtOH, 0.4 M NaOH/EtOH, reflux, 2 h.
analysis. All the coumarins of the 6 series showed good solubility in
various solvents and could be completely characterized by the
previously mentioned spectral methods.
aromatic ring (e.g., 4a) or aromatic aldehydes containing electron-
withdrawing groups are employed as the substituents at the same
position (e.g., 4b–c), higher yields are obtained.
Subsequently, and with the aim of trying to expand the reaction
scope, some reaction tests were performed to synthesize
pyrazolinyl-iminochromenes without the trifluoromethyl substit-
uent, in order compare the reactivity of the precursors and the
structure of the isolated products. The reaction tests were
Due to the presence of the imino group, compounds 5a–d
exhibited very low solubility in the majority of organic solvents. In
order to improve the solubility of these compounds and thus
obtain better resolution for NMR analysis, the imino function of
these molecules was converted into a carbonyl group, generating
the pyrazolinyl-coumarins (6a-d) in 80–91% yields. The synthesis
of 6 was done in ethanol, using 36% HCl as the catalyst for 1 h at
reflux, in accordance with the methodology reported by Bona-
corso et al. [80] in 2003 (Scheme 4). After the reaction time, the
reaction mixtures were refrigerated and the products were
isolated by precipitation and filtration, followed by washing with
cold ethanol.
Attempts to obtain the aromatic pyrazoles by dehydration
reactions of the pyrazolines 3, and compounds 5 and 6 were
performed according to the appropriated methodology described
in literature [81], but the cleavage of the amide bond occurred,
poor yields were registered and some non-identified byproducts
observed. So, as expected, compounds 3, 5 and 6 were resistant to
dehydration reactions.
performed using
droxy-3,5-dimethyl-4,5-dihydro-1H-pyrazole, and the same alde-
hydes (Scheme 3). Unfortunately, under the standard
a structural analogue, 1-cyanoacetyl-5-hy-
4
methodology optimized to obtain the compounds of 5, no reactions
were observed by TLC in any case—only the starting materials 4
were recovered. We believe that the absence of the trifluoromethyl
group, which was substituted by a methyl group at the pyrazoline
ring, clearly reduces the electron-withdrawing effect in relation to
the trifluoromethyl-substituted group that existed in the precursor
3. This electronic effect minimizes the electronic deficiency of the
carbonyl carbon that directly affects the acidity of the methylene
protons of the cyanoacetyl group. This reactivity test shows that
the CF3 group in pyrazole 3 is extremely important for the
cyclocondensation reaction being studied and decisive in the
formation of the coumarin when a Knoevenagel condensation is
involved.
On the other hand, the influence that the substituents attached
to the aldehyde moiety had on the yields for the synthesis of
compounds 5a-d was also verified. It was observed that the
electron-donating groups at the C-5 position in the aromatic
aldehydes (e.g., 4d) lead to lower yields, because these groups have
a direct influence on the reactivity of the aldehyde carbonyl group
present in this precursor. However, when either a non-substituted
According to the literature reports, reactions involving com-
pounds that contain a cyanoacetyl moiety and aldehydes (e.g., 3),
respectively, could generate two isomer intermediates in the Z and
E-styryl forms [82]. The intermediates formed can be worked
through the E-styryl intermediate (Scheme 4), since the interme-
diate E would be less sterically hindered and would have the cyano
group close to the hydroxyl group, thereby facilitating the
cyclization step of this reaction. Therefore, we propose
a
mechanism for condensation reactions involving the obtainment
Scheme 3. Knoevenagel condensation reaction involving 1-cyanoacetyl-5-hydroxy-3,5-dimethyl-4,5-dihydro-1H-pyrazole and salicylic aldehydes 4. Reagents and
conditions: (i) EtOH, 0.4 M NaOH/EtOH, reflux, 2 h.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 178 (2015) 296–305
299
Fig. 1. ORTEP obtained from the crystal structure of 3-(5-hydroxy-3-methyl-5-
trifluoromethyl-4,5-dihydro-1H-pyrazol-1-carbonyl)-6-nitro-2H-chromen-2-one
(6b) with atoms labeled (CCDC 1056179) [83]. Displacement ellipsoids are drawn at
the 50% probability level.
Scheme 4. New Coumarins
6 from hydrolysis reaction of pyrazolinyl-
iminochromenes 5. Reagents and conditions: (i) EtOH, 36% HCl, reflux, 1 h.
of pyrazolinyl- iminochromenes systems and their acid hydrolysis,
leading to coumarin systems, as shown in Scheme 5.
product structureand the presenceof the lactone carbonyl at the C-2
position. Also, the existence of the pyran and pyrazoline rings
(shown in the ORTEP) confirms the formation of the compound and
the relative position at which there are two rings, wherein the plane
of the pyrazoline ring is 62.48 from the plane of the coumarin ring.
In order to expand the scope of the products and prove the
feasibility of this synthesis for another heterocyclic system
attached to the coumarin moiety, reactions using the standard
methodology and involving 2-cyanoacetyl-1-methylpyrrole (9)
and salicylic aldehydes (4a–e) were performed in order to obtain
the pyrrolyl-coumarins (10a–e). The precursor 9 was synthetized
by a reaction involving refluxing of cyanoacetic acid and 1-
methylpyrrole in acetic anhydride for 1 h, in accordance with the
methodology described in the literature (Scheme 6) [84].
It was possible to directly obtain a series of pyrrolyl-coumarins
(10a–e) and only traces of pyrrolyl-iminochromene intermediate
derivatives, in accordance with Scheme 7.
Products 5 and 6 were identified by 1H and 13C NMR, elemental
analysis, and GC–MS. Also, through FT-IR analysis it was possible to
confirm the presence of the imino group (55NH) in compounds 5a–
d and the corresponding carbonyl group in compounds 6a–d, at
position 2 of the coumarin nucleus. The infrared analysis shows a
characteristic NH band in the region of
n
= 3000 cmꢀ1, which
characterizes the compounds 5a–d, and for compounds 6a–d it is
possible to verify the presence of the carbonyl group of the lactone
function due to the band in the region of
n .
= 1700 cmꢀ1
The analysis of the 1H NMR spectrum data for compounds 5 and
6 shows the signals of protons the aromatic and pyran rings in the
characteristic region at
d 7.00–8.20 ppm for these moieties, which
are important for proving the structures.
Through the crystal X-ray diffraction obtained for coumarin 6b
(Fig. 1), it was possible to confirm the structure and establish the
Scheme 5. Proposed mechanism for the Knoevenagel condensation reactions of the compounds 5 and 6.

300
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 178 (2015) 296–305
Scheme 6. Reagents and conditions: (i) acetic anhydride, reflux, 1 h.
Fig. 2. ORTEP obtained from the crystal structure of 6-bromo-3-(1-methyl-1H-
pyrrol-2-carbonyl)-2H-chromen-2-one (10c) with atoms labeled (CCDC 1056083)
[83]. Displacement ellipsoids are drawn at the 50% probability level.
Initially, we expected that the pyrrolyl-iminochromenes would
be the first products and that they would be similar to 5a–d, but
the reactivity of the cyanoacetylated pyrrole 9 proved to be very
different. The pyrrole precursor 9 has an active methylenic group
neighboring a ketone function, while the pyrazoline 3 has an
hydrazide function. This fact makes
b
-ketonitrile 9 more reactive
In order to evaluate the performance as new drugs in the
synthesized compounds, the parameters of Lipinski [70] were
applied to the thirteen chromenones (5a–d, 6a–d and 10a–e).
These parameters have the ability to estimate the activities of the
compounds in the organism by the evaluation of hydrogen donor
and receptor interactions and estimated lipophilicity by the use of
the partition coefficient calculations. Through the results obtained,
we could verify that the all studied compounds remain within the
established limits according the following data: (i) the molecular
weights were under 500: 253,07 ꢁ MW5,6,10 ꢁ 417,98; (ii) a limited
lipophilicity (expressed by Log P < 5): ꢀ1,36 ꢁ ClogP5,6,10 ꢁ 4,99
(calculated with ChemDrawTM Ultra, version 12.0); (iii) maximum
5 H-bond donors (expressed as the sum of OHs and NHs groups): the
values are 02 for compounds 5a–d, 01 for compounds 6a–d and
0(zero) for compounds 10a–e and (iv) a maximum 10 H-bond
acceptors (expressed as the sum of Os and Ns atoms): the values
remained within the range 04 to 09 atoms for the compounds 5, 6
and 10.
than 3 in the first step of the condensation reaction, despite not
having a trifluoromethyl group attached to the pyrrole ring of 9. To
ensure total conversion into pyrrolyl-coumarin compounds (10a–
e), after 2–3 h of reaction time, drops of 36% HCl were added and
the resulting solution was kept under reflux for one additional
hour. Compounds 10a–e were obtained by precipitation in
reaction solvent at a low temperature, as black or pale brown
solids in yields of 40–60%, according to the substituent in the
salicylic aldehydes (4a–e). Table 1 shows the yields and melting
points of the compounds belonging to the 5, 6, and 10 series.
The single-crystal X-ray diffraction obtained for compound 10c
confirms the presence of the lactone carbonyl at the C-2 position
and also the existence of the pyran and pyrrole rings, thus proving
the structure of the compound. The torsion angles measured for
10c show that the C-2, C-3, C-9, and C-10 carbons are located with a
588 dihedral angle between the planes of the pyrrole and pyran
ring (Fig. 2).
Scheme 7. Synthsis of coumarins 10 via Knoevenagel condensation reaction of cyanoacetylpyrrole 9 and salicylic aldehydes 4. Reagents and conditions: (i) EtOH, 0.4 M NaOH/
EtOH, reflux, 2-3 h. (ii) EtOH/36% HCl, reflux, 1 h.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 178 (2015) 296–305
301
Table 1
Yields and melting points of compounds 5, 6, and 10.
.
Compound
R1
R2
Molecular Weight (g/mol)
m.p. (8C)a
Yield (%)a
5a
H
H
C15H12F3N3O3 (339.08)
C15H11F3N2O4 (340.07)
C15H11NO3 (253.07)
208–211
212–214
162–163
203–205
218–219
200–203
228–231
230–231
222–224
213–216
(219–222)b
193–196
188–190
64
80
40
78
91
45
60
86
60
50
81
53
51
6a
H
H
10a
5b
H
H
NO2
NO2
NO2
Br
H
C15H11F3N4O5 (384.07)
C15H10F3N3O6 (385.05)
C15H10N2O5 (295.06)
C15H11BrF3N3O3 (416.99)
C15H10BrF3N2O4 (417.98)
C15H10BrNO3 (330.98)
C16H14F3N3O4 (369.09)
C16H13F3N2O5 (370.08)
C16H13NO4 (283.28)
6b
H
10b
5c
H
H
6c
Br
H
10c
5d
Br
H
OCH3
OCH3
OCH3
H
H
6d
H
10d
10e
H
OCH3
C16H13NO4 (283.28)
a
Data for isolated pure products.
b
Product decomposition by melting point.
3. Conclusions
analyses were performed on a Perkin-Elmer 2400 CHN elemental
analyzer (University of Sa˜o Paulo, Brazil). To obtain the infrared
spectrum of the samples, we used a Perkin Elmer FTIR Spectrum
100 spectrophotometer (Federal Technical University of Parana´,
Brazil). The diffraction measurements were done by graphite-
In summary, we presented the synthesis of a series of 3-(5-
hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1H-pyrazol-
1-carbonyl)-2-imino-2H-chromenes (5a–d), 3-(3-methyl-5-tri-
fluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-carbonyl)-
2H-chromen-2-ones (6a–d), and also a series of 3-(1-methyl-1H-
pyrrol-2-carbonyl)-2H-chromenes (10a–e) via a Knoevenagel
condensation reaction, which was derived from 4,5-dihydropyr-
azole (3) or 2-cyanoacetyl-1-methylpyrrole (9) and five selected
salicylic aldehydes (4a–e). The synthesis of four series of allyl
coumarins was attempted but only three series (5, 6, and 10) were
successfully obtained through the use of two different cyanoa-
cetylated azoles (starting materials), in which the methylene
group attached to a ketone or hydrazide function, as well as the
presence or absence of CF3 units, were decisive and demonstrate
the specific chemical behavior. Also, the influence of the
substituents presented in the salicylic aldehydes 4 used as
precursors, was observed. Finally, a quick and efficient synthesis
for the preparation of 13 new interesting carbonyl-spaced
azolecarbonyl coumarins in yields of up to 91%, under conven-
tional heating and in short reaction times, was reported.
˚
monochromatized Mo Ka radiation, with l = 0.71073 A, on a Bruker
SMART CCD diffractometer [85]. The structures of 6b and 10c were
solved by direct methods using the SHELXS-97 program [86], and
refined on F2 by full-matrix least-squares using the SHELXL-97
package [87]. The absorption correction was done by Gaussian
methods [88]. Anisotropic displacement parameters for non-hydro-
gen atoms were applied. The hydrogen atoms were placed at
˚
˚
calculated positions with 0.96 A (methyl CH3) and 0.93 A (aromatic
CH), using a riding model. The hydrogen isotropic thermal parameters
were kept at Uiso(H) = xUeq (carrier C atom), with x = 1.5 for the
methyl groups and x = 1.2 for the other groups. The valence angles C–
C–H and H–C–H of the methyl groups were set to 109.58, and the H
atoms were allowed to rotate around the C–C bond. The molecular
graph was prepared using ORTEP-3 for Windows [89].
4.2. Synthesis
4.2.1. General procedure for the synthesis of 1-cyanoacetyl-5-
hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1H-pyrazole (3)
To a flask containing cyanoacetohydrazide (1) (1.2 mmol,
0.119 g) and being magnetically stirred, methanol (10 mL) and
4-methoxy-1,1,1-trifluoropent-3-en-2-one (2) (1.2 mmol, 0.202 g)
were added at room temperature. The resulting mixture was
refluxed for 16 h. The reaction solvent was then removed in a
rotary evaporator and to the resulting oil, distilled water (10 mL)
was added and extracted with ethyl acetate (3 ꢃ 10 mL). The
organic layer was separated, dried with anhydrous sodium sulfate
(15 g), and the solvent was removed in a rotary evaporator under
reduced pressure. Compound 3 was isolated as a brown oil in a
yield of 95%; Literature [77] 80%.
4. Experimental
4.1. Analytical equipment and procedures
Unless otherwise indicated, all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. All melting points were determined using coverslips
´
on a Microquımica MQAPF-302 apparatus, and are uncorrected.
Mass spectra were registered in a HP 5973 MSD connected to a HP
6890 GC and interfaced by a Pentium PC. The GC was equipped
with a split-splitless injector, auto sampler, and cross-linked HP-5
capillary column (30 m, 0.32 mm internal diameter), and helium
was used as the carrier gas. The high-resolution mass spectrometry
(HRMS) spectra were obtained using an Agilent-QTOF 6530 spec-
trometer (LARP/UFSM). 1H and 13C NMR spectra were acquired on a
Bruker DPX 400 spectrometer and Bruker Avance III 600 MHz,
using 5 mm sample tubes, 298 K, digital resolution ofꢂ0.01 ppm, in
DMSO-d6, with TMS as internal reference. The CHN elemental
4.2.2. General procedure for the synthesis of 3-(5-hydroxy-3-methyl-
5-trifluoromethyl-4,5-dihydro-1H-pyrazol-1-carbonyl)-2-imino-2H-
chromenes (5a–d)
In a flask containing 4,5-dihydropyrazole (3) (1 mmol, 0.235 g),
ethanol (10 ml) and 0.4 M NaOH/EtOH (0.036 g or 0.075 mL) were

302
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 178 (2015) 296–305
added under magnetic stirring at room temperature. The
temperature of the mixture was elevated to 78 8C and maintained
in this condition under magnetic stirring for 15 min. Subsequently,
to each reaction, the corresponding salicylic aldehydes (4a–d)
(1 mmol) were added and the reactions were then refluxed for an
additional 2 h. During this period, the precipitation of the
respective compounds of 5 was observed. The resulting solids
were filtered under atmospheric pressure and washed with a
mixture of acetone and dichloromethane 1:1 (1 ꢃ 30 mL) at room
temperature. Finally, the solids were isolated in a pure form when
left under reduced pressure at room temperature for several hours.
4.2.3.1. 3-(5-Hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1H-
pyrazol-1-carbonyl)-2H-chromen-2-one (6a). yellow solid, yield
80%, mp. 212–214 8C. 1H NMR (400 MHz, DMSO-d6):
d 8.18 (s,
1H, H-4), 8.08 (s, 1H, OH), 7.81 (d, J = 8 Hz, 1H, H-5), 7.67 (t, J = 8 Hz,
1H, H-7), 7.43 (d, J = 8 Hz, 1H, H-8), 7.39 (t, J = 8 Hz, 1H, H-6), 3.48
(d, J = 19 Hz, 1H, H-13a), 3.14 (d, J = 19 Hz, 1H, H-13b), 1.92 (s, 3H,
CH3).
13C NMR (400 MHz, DMSO-d6):
d 162.4 (C-9), 157.2 (C-12),
155.3 (C-2), 153.9 (C-8a); 141.6 (C-4), 133.2 (C-7), 129.6 (C-6),
126.3 (C-4a), 125.3 (C-5), 123.6 (q, J = 286 Hz, CF3), 119.4 (C-3),
118.4 (C-8), 91.2 (q, J = 34 Hz, C-14), 48.3 (C-13), 15.5 (CH3).
MS, m/z (%), 340 (M+,1.4), 173 (100), 229 (14), 89 (17).
4.2.2.1. 3-(5-Hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1H-
pyrazol-1-carbonyl)-2-imino-2H-chromene (5a). red solid, yield
IR (KBr): n
= 3262 cmꢀ1(OH), 2972 cmꢀ1 (CH), 1698 cmꢀ1
(lactone C55O), 1662 cmꢀ1 (C55O amide)
64%, mp. 208–211 8C. 1H NMR (600 MHz, DMSO-d6):
d
8.27 (s,
Anal. Calc. for C15H11F3N2O4 (340.1): C, 52.95, H, 3.26, N, 8.23;
Found: C, 53.46, H, 3.31, N, 8.09.
1H, H-4); 8.15 (s, 1H, OH); 8.09 (d, J = 8 Hz, 1H, H-8); 7.43 (td,
J = 2 Hz, J = 7 Hz, 1H, H-6), 7.01 (d, J = 8 Hz, 1H, H-5); 6.96 (t,
J = 7 Hz, 1H, H-7); 3.54 (d, J = 19 Hz, 1H, H-13a); 3.13 (d, J = 19 Hz,
1H, H-13b); 2.04 (s, 3H, CH3).
Anal. Calc. for C15H12F3N3O3 (339.1): C, 53.10, H, 3.57, N,
12.39. Found: C, 52.95, H, 3.75, N, 11.92.
4.2.3.2. 3-(5-Hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1H-
pyrazol-1-carbonyl)-6-nitro-2H-chromen-2-one (6b). pale yellow
solid, yield 91%, mp. 218–219 8C. 1H NMR (400 MHz, DMSO-d6):
8.82 (d, J = 3 Hz, 1H, H-5), 8.46 (dd, J = 3 Hz, J = 9 Hz, 1H, H-7), 8.39
(s, 1H, H-4), 8.24 (s, 1H, OH), 7.67 (d, J = 9 Hz, 1H, H-8) 3.49 (d,
J = 19 Hz, 1H, H-13a), 3.21 (d, J = 19 Hz, 1H, H-13b), 1.93 (s, 3H,
CH3).
4.2.2.2. 3-(5-Hydroxy-3-methyl-5-trifluormethyl-4,5-dihydro-1H-
pyrazol-1-carbonyl)-6-nitro-2-imino-2H-chromene (5b). black sol-
id, yield 78%, mp. 203–205 8C. 1H NMR (400 MHz, DMSO-d6):
d
13C NMR (400 MHz, DMSO-d6):
d 161.5 (C-9), 157.4 (C-12),
8.96 (d, J = 3 Hz, 1H, H5); 8.27 (dd, J = 3 Hz, J = 9 Hz, 1H, H-7); 8.20
(s, 1H, H-4); 7.13 (d, J = 9 Hz, 1H, H-8); 3.54 (d, J = 19 Hz, 1H, H-
13a); 3.14 (d, J = 19 Hz, 1H, H-13b); 2.04 (s, 3H, CH3).
13C NMR (400 MHz, DMSO-d6): 161.5 (C-9); 157.5 (C-2); 156.3
(C-12); 155.8 (C-8a); 144.5 (C-6); 140.8 (C-7); 127.7 (C-4a); 125.6
(C-4); 123.3 (q, J = 286 Hz, CF3); 118.9 (C-8); 118.4 (C-5); 102.5 (C-
3); 91.4 (q, J = 34 Hz, C-14); 48.4 (C-13); 15.6 (CH3).
156.3 (C-2), 155.9 (C-8a); 144.3 (C-4), 140.8 (C-7), 127.9 (C-4a),
127.7 (C-6), 125.5 (C-5), 123.5 (J = 285 Hz, CF3), 118.8 (C-3), 118.3
(C-8), 91.1 (q, J = 34 Hz, C-14), 48.2 (C-13), 15.6 (CH3).
MS, m/z (%), 385 (M+,1.3), 218 (100), 172 (47), 274 (33).
IR (KBr):
n
= 1742 cmꢀ1 (C55O, lactone), 1674 cmꢀ1 (C55O,
amide), 1619 cmꢀ1 (C–C aromatic ring), 1345 cmꢀ1 (CN)
Anal. Calc. for C15H10F3N3O6 (385.1): C, 46.76, H, 2.62, N, 10.91,
Found: C, 46.68, H, 2.62, N, 10.91.
Anal. Calc. for C15H11F3N4O5 (384.1): C, 46.88, H, 2.89, N,
14.58. Found: C, 46.83, H, 2.89, N, 14.36.
4.2.3.3. 6-Bromo-3-(5-hydroxy-3-methyl-5-trifluoromethyl-4,5-
dihydro-1H-pyrazol-1-carbonyl)-2H-chromen-2-one (6c). pale yel-
low solid, yield 86%, mp 230–231 8C. 1H NMR (400 MHz, DMSO-
4.2.2.3. 6-Bromo-3-(5-hydroxy-3-methyl-5-trifluoromethyl-4,5-
dihydro-1H-pyrazol-1-carbonyl)-2-imino-2H-chromene
(5c). red
solid, yield 60%, mp. 228–231 8C. 1H NMR (600 MHz, DMSO-d6):
8.22 (s, 1H, OH); 8.19 (s, 1H, H-4); 8.17 (d, J = 2 Hz, 1H, H-5); 7.58
(dd, J = 2 Hz, J = 9 Hz, 1H, H-7); 6.90 (d, J = 9 Hz, 1H, H-8); 3.54 (d,
J = 19 Hz, 1H, H-13a); 3.14 (d, J = 19 Hz, 1H, H-13b); 2.05 (s, 3H,
CH3).
d6): d 8.16 (s, 2H, OH, H-4), 8.07 (d, J = 2 Hz, 1H, H-5), 7.82 (dd,
J = 2 Hz, J = 9 Hz, 1H, H-7), 7.43 (d, J = 9 Hz, 1H, H-8), 3.49 (d,
J = 19 Hz, 1H, H-13a), 3.14 (d, J = 19 Hz, 1H, H-13b), 1.92 (s, 3H,
CH3);
13C NMR (400 MHz, DMSO-d6):
d 161.9 (C-9), 156.8 (C-12),
13C NMR (600 MHz, DMSO-d6):
d
160.1 (C-9); 157.5 (C-2);
155.7 (C-2), 152.9 (C-8a); 140.4 (C-7), 135.6 (C-4), 131.6 (C-5),
127.3 (C-4a), 123.6 (q, J = 286 Hz, CF3); 120.2 (C-6), 119.0 (C-8),
116.9 (C-3), 91.1 (q, J = 34 Hz, C-14), 48.2 (C-13), 15.6 (CH3).
MS, m/z (%), 420 [(M++2) 1], 253 (100), 309 (19), 167 (15).
155.9 (C-12); 145.9 (C-8a); 136.8 (C-7); 130.3 (C-4a); 123 (q,
J = 286 Hz, CF3); 121.4 (C-6); 119.0 (C-4,C-5); 116.0 (C-10); 110.8
(C-8); 107.5 (C-3); 92.0 (q, J = 34 Hz, C-14); 48.1 (C-13); 15.7 (CH3).
Anal. Calc. for C15H11BrF3N3O3 (417): C, 43.08, H, 2.65, N,
10.05. Found: C, 42.95, H, 2.58, N, 9.66.
IR (KBr):
n
= 3350 cmꢀ1 (OH), 1734 cmꢀ1 (lactone C55O),
1657 cmꢀ1(C55O amide).
Anal. Calc. for C15H10BrF3N2O4 (418): C, 42.98, H, 2.40, N, 6.68;
Found: C, 42.81, H, 2.64, N, 6.38.
4.2.2.4. 6-Methoxy-3-(5-hydroxy-3-methyl-5-trifluoromethyl-4,5-
dihydro-1H-pyrazol-1-carbonyl)-2-imino-2H-chromene (5d). Yield
50%, red solid, mp. 213–216 8C. Anal. Calc. for C16H14F3N3O4
(369.1): C, 52.04, H, 3.82; N, 11.38. Found: C, 52.04; H, 3.82; N,
11.35.
4.2.3.4. 3-(5-Hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1H-
pyrazol-1-carbonyl)-6-methoxy-2H-chromen-2-one
(6d). yellow
solid, yield 82%, mp. 222–223 8C. 1H NMR (400 MHz, DMSO-d6):
8.08 (s, 1H, H-4); 7.73 (d, J = 9 Hz, 1H, H-8); 7.02 (d, J = 2 Hz, 1H, H-
5); 6.99 (dd, J = 3 Hz, J = 9 Hz, 1H, H-6); 3.89 (s, 3H, OCH3); 3.46 (d,
J = 19 Hz, 1H, H-13a); 3.13 (d, J = 19 Hz, 1H, H-13b); 1.90 (s, 3H,
CH3).
4.2.3. General procedure for the synthesis of 3-(3-methyl-5-
trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-carbonyl)-2H-
chromen-2-ones (6a–d)
To a magnetically stirred solution of the compounds 5a–d
(1 mmol) in ethanol (10 mL), 1.8 mL of 36% HCl was added. The
resulting mixture was subjected to a temperature of 78 8C for 1 h
under magnetic stirring. Subsequently, the solution was cooled
and precipitation of the product occurred. The solids were then
filtered under atmospheric pressure, washed with cold ethanol
(1 ꢃ 20 mL), and dried under reduced pressure, which led to
yellow solids as the pure products of 6.
13C NMR (400 MHz, DMSO-d6): 163.8 (C-9); 162.8 (C-2); 157.5
(C-12); 156.0 (C-6); 155.0 (C-8a); 142.2 (C-7); 130.8 (C-4); 123.7
(q, J = 286 Hz, CF3); 122.7 (C-4a); 113.4 (C-5); 112.0 (C-3); 101.2
(C-8); 91.2 (q, J = 34 Hz, C-14); 56.6 (OCH3); 48.4 (C-13); 15.6
(CH3).
MS, m/z (%), 370 [(M+ +1) 5]; 208 (100); 259 (10); 119 (12). Anal.
Calcd. for C16H14F3N2O4 (369.1): C, 51.90, H, 3.54, N, 7.57; Found: C,
52.18, H, 3.68, N, 7.46.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 178 (2015) 296–305
303
4.2.4. General procedure for the synthesis of 3-(1-methyl-1H-pyrrol-
2-carbonyl)-2H-chromenes (10a–e)
13C NMR (400 MHz, DMSO-d6):
d
180.2 (C-9); 158.5 (C-2); 156.2
(C-6); 148.5 (C-8a); 142.8 (C-7); 134.2 (C-5); 130.0 (C-10); 128.0
(C-3); 124.0 (C-12); 120.9 (C-14); 119.1 (C-4a); 117.7 (C-8); 111.2
(C-4); 109.1(C-13); 56.2 (OCH3); 37.3 (CH3).
To
a flask containing 2-cyanoacetyl-1-methylpyrrole (9)
(1 mmol, 0.148 g) and under magnetic stirring, ethanol (10 mL)
and 0.4 M NaOH/EtOH (0.036 g or 0.075 mL) were added at room
temperature. The temperature of the resulting mixture was
elevated to 78 8C and maintained in this condition under magnetic
stirring for 15 min. The corresponding salicylic aldehyde (4a–e)
was then added (1 mmol) and the reaction was refluxed for further
2 h. Subsequently, 1.8 mL of 36% HCl was added and the resulting
mixture was refluxed for 1 h. The products 10 precipitated from
the reaction mixture immediately after cooling. These products
were filtered under atmospheric pressure, washed with cold
ethanol (20 mL), and then dried under reduced pressure, which led
to brown solids as the pure products 10.
MS, m/z (%), 283 (M+,100); 203 (26); 108 (82); 80 (22);
HRMS (ESI): m/z Calcd. 284.0917 (M + H); Found 284.0916.
4.2.4.5. 3-(1-Methyl-1H-pyrrol-2-carbonyl)-7-methoxy-2H-chro-
men-2-one (10e). black solid, yield 51%, mp. 188–190 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.21 (s, 1H, H-4); 7.72 (d, J = 9 Hz, 1H, H-8);
7.30 (t, J = 2 Hz, 1H, H-13); 7.04 (d, J = 2 Hz, 1H, H-5); 6.99 (dd,
J = 2 Hz, J = 9 Hz, 1H, H-6); 6.87 (dd, J = 2 Hz, J = 4 Hz, 1H, H-12);
6.15 (dd, J = 2 Hz, J = 4 Hz, 1H, H-14); 3.95 (s, 3H, NCH3); 3.89 (s, 3H,
OCH3).
13C NMR (400 MHz, DMSO-d6):
d 180.5 (C-9); 163.9 (C-2); 158.7
(C-7); 156.3 (C-8a); 143.8 (C-4); 133.9 (C-10); 131.1 (C-5); 130.2
(C-3); 124.1 (C-4a); 123.7 (C-6); 113.3 (C-12); 112.1 (C-8); 109.0
(C-14); 101.0 (C-13); 56.6 (OCH3); 37.3 (CH3).
4.2.4.1. 3-(1-Methyl-1H-pyrrol-2-carbonyl-2H-chromen-2-one
(10a). brown solid, yield 40%, mp. 162–163 8C. 1H NMR (400 MHz,
DMSO-d6):
d
8.21 (s, 1H, H-4); 7.78 (dd, J = 1 Hz, J = 7 Hz, 1H, H-5);
MS, m/z (%), 283 (M+, 100); 203 (26); 108 (82); 80 (22);
HRMS (ESI): m/z Calcd. 284.0917 (M + H); Found 284.0944.
7.67 (td, J = 2 Hz, J = 8 Hz, 1H, H-7); 7.42 (d, J = 8 Hz, 1H, H-8); 7.37
(td, J = 1 Hz, J = 7 Hz, 1H, H-6); 7.27 (t, J = 2 Hz, 1H, H-13); 6.88 (dd,
J = 1 Hz, J = 2 Hz, 1H, H-12); 6.15 (dd, J = 2 Hz, 1H, H-14); 3.96 (s,
3H, NCH3).
Acknowledgments
13C NMR (400 MHz, DMSO-d6):
d 180.1 (C-9); 158.4 (C-2); 154.3
The authors thank the Coordination for Improvement of Higher
Education Personnel (CAPES) for the fellowships, as well as the
National Council for Scientific and Technological Development
(CNPq) and the Rio Grande do Sul Foundation for Research Support
(FAPERGS) for the financial support (Process numbers 303.013/
2011-7 and 470.788/2010.0-CNPq/Universal).
(C-8a); 142.9 (C-4); 134.1 (C-3); 133.3 (C-5); 130.2 (C-10); 129.8
(C-6); 127.9 (C-4a); 125.2 (C-12); 123.9 (C-14); 118.7 (C-8); 116.7
(C-7); 109.1 (C-13); 37.3 (CH3).
MS, m/z (%), 253 (M+, 55); 173(26); 108(100); 80(97); 53(89);
HRMS (ESI): m/z Calcd. 254.0812 (M + H); Found 254.0803.
4.2.4.2. 3-(1-Methyl-1H-pyrrol-2-carbonyl)-6-nitro-2H-chromen-2-
one (10b). brown solid, yield 45%, mp. 200–203 8C. 1H NMR
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d 8.80 (d, J = 3 Hz, 1H, H-5); 8.47 (dd,
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179.6 (C-9); 157.9 (C-2); 153.2
(C-8a); 141.6 (C-7) 135.5 (C-4); 134.4 (C-3); 131.7 (C-5); 129.9 (C-
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´
´ ˇ
ˇ
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ˇ
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