ANRORC rearrangement in tetrahydro-2H-chromenones. Synthesis and structural assignment by NMR, MS, X-ray and DFT calculations of 2-[3(5)-trifluoromethyl- 1H-pyrazol-4-yl)arylmethyl]cyclohexenones and derivatives

Article abstract of DOI:10.1016/j.jfluchem.2013.03.014

This paper describes firstly the synthesis of a new series of 3-hydroxy-2-[(3(5)-(methyl/phenyl)-5(3)-(trifluoromethyl)-1H-pyrazol-4-yl) arylmethyl]-cyclohex-2-en-1-ones (2), where aryl = C₆H₅, 4-NO₂C₆H₄, 4-OCH₃C₆H ₄, from an ANRORC ring transformation reaction of 3-acyl-4-aryl-2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H) -ones (1), where acyl = acetyl and benzoyl, in the presence of hydrazine hydrate, at 63-90% yields. In subsequent steps, an oxidative aromatization reaction from 2 was done in an iodine/methanol medium for the preparation of 3(5)-trifluoromethyl-5(3)-methyl-4-[(2,6-dimethoxyphenyl)-(4- methoxyphenylmethyl)]-1H-pyrazole (3) at 72% yields. Also, the alkylation reaction using benzyl chloride easily converted a pyrazole like 2 to its N-benzyl derivative (4), at 69% yield. Finally, the structural assignment of compounds 2-4 was deduced by mass spectrometry, X-ray crystal diffraction and density functional theory (DFT) calculations, which clearly and unambiguously furnished values very close to those determined from ¹H, ¹³C and ¹⁹F NMR data.

Full text of DOI:10.1016/j.jfluchem.2013.03.014

Journal of Fluorine Chemistry 151 (2013) 38–44
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
ANRORC rearrangement in tetrahydro-2H-chromenones. Synthesis
and structural assignment by NMR, MS, X-ray and DFT calculations of
2-[3(5)-trifluoromethyl-1H-pyrazol-4-yl)arylmethyl]cyclohexenones
and derivatives
Helio G. Bonacorso 1, , Jussara Navarini, Liliane M.F. Porte, Everton P. Pittaluga,
*
Andrizia F. Junges, Alexandre R. Meyer, Marcos A.P. Martins, Nilo Zanatta
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:
This paper describes firstly the synthesis of a new series of 3-hydroxy-2-[(3(5)-(methyl/phenyl)-5(3)-
(trifluoromethyl)-1H-pyrazol-4-yl)arylmethyl]-cyclohex-2-en-1-ones (2), where aryl = C6H5, 4-
NO2C6H4, 4-OCH3C6H4, from an ANRORC ring transformation reaction of 3-acyl-4-aryl-2-(trifluor-
omethyl)-2-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-ones (1), where acyl = acetyl and benzoyl,
in the presence of hydrazine hydrate, at 63–90% yields. In subsequent steps, an oxidative aromatization
reaction from 2 was done in an iodine/methanol medium for the preparation of 3(5)-trifluoromethyl-
5(3)-methyl-4-[(2,6-dimethoxyphenyl)-(4-methoxyphenylmethyl)]-1H-pyrazole (3) at 72% yields. Also,
the alkylation reaction using benzyl chloride easily converted a pyrazole like 2 to its N-benzyl derivative
(4), at 69% yield. Finally, the structural assignment of compounds 2–4 was deduced by mass
spectrometry, X-ray crystal diffraction and density functional theory (DFT) calculations, which clearly
and unambiguously furnished values very close to those determined from 1H, 13C and 19F NMR data.
ß 2013 Elsevier B.V. All rights reserved.
Received 5 February 2013
Received in revised form 12 March 2013
Accepted 14 March 2013
Available online 25 March 2013
Keywords:
Chromenones
Pyrazoles
ANRORC reactions
Cyclohexenones
DFT calculations
1. Introduction
among others [2]. Hence, their synthesis holds a special place and
considerable efforts are devoted to the development of efficient
The understanding of the chemical rearrangement of heterocy-
clic scaffolds into new molecules is an interesting research area
because the correct assemblies can provide significant contribu-
tions to medicinal chemistry conducting to more complex and
poly-substituted structures in good yields and few reaction steps.
Additionally, the insertion of fluorine atoms, especially the
trifluoromethyl group, imparts a variety of properties to certain
medicines, including enhanced binding interactions, metabolic
stability, changes in physical properties, and selective reactivities
[1].
methods to achieve this.
On the other hand, development in the area of pyrazole
synthesis is continuously growing due to their applications in the
pharmaceutical and agrochemical industry [3]. In general,
conventional approaches for the synthesis of pyrazoles involve
the construction of two C–N bonds by the condensation of
hydrazines with 1,3-dielectrophilic derivatives [4]. Also, the
ANRORC rearrangement that consists of an initial Attack of
Nucleophiles followed by Ring-Opening and Ring-Closure repre-
sents a useful tool in the hands of the synthetic heterocyclic
chemist for achieving the ring transformation for various pyrazole
systems [5–12].
In the context of our research on fluorinated heterocycles, we
recently reported the synthesis of chromenones (1) [13] and their
transformation to 2-fluoro-2H-chromenones (I) by chemoselective
fluorination with DAST [14], and then to chromanes (II) as the
product of an aromatization reaction with alcohol/iodine [15]; and,
also, the resulting product (III) from the reduction reactions using
NaBH4 (Fig. 1) [16]. Although the degenerated ring transformation
SN(ANRORC) is well established and described in the literature for
the reaction of some benzopyran-4-ones (chromanes) [6–10] with
Chromenes are an important group of heterocyclic compounds.
Their structure is present in numerous natural products and they
have biological and pharmacological activities, including as a
spasmolytic, diuretic, antiviral, antitumoral, and antianaphylactic,
* Corresponding author. Fax: +55 55 3220 8031.
E-mail address: heliogb@base.ufsm.br (H.G. Bonacorso).
1
This paper is dedicated to the more than 100 young students of the Federal
University of Santa Maria that lost their lives by the Kiss nightclub fire on January
27, 2013.
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.03.014

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 151 (2013) 38–44
39
O
O
OR1
R
+
+
ArCHO
F3C
O
O
[Ref. 13]
OR1 Ar
O
O
Ar
O
Ar
O
R1OH/I2
[Ref. 15]
R
DAST
[Ref. 14]
R
OH
CF3
R
OH
CF3
F
CF3
O
I
O
1
O
II
[Ref. 16]
NaBH4
O
H
Ar
O
R
H
CF3
O
III
HO
Fig. 1. Synthesis and chemical transformations of tetrahydro-2H-chromenones (1).
hydrazines to give substituted pyrazole tautomers or mixtures of
1,3- and 1,5-isomers, the specific rearrangement for 3-acyl-4-aryl-
2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2H-chromen-
5(6H)-ones (1) has not yet been studied.
According to the ANRORC reaction results in chromenones 1a–f,
we proposed a reasonable mechanism for this reaction, as shown in
Fig. 2. The closure ring step of the corresponding ANRORC
mechanism for the preparation of pyrazoles 2a–f can be proposed
from the conversion of some 1,3-dicarbonyl compounds into
With this in mind, we wish now to report the use of the well-
known SN(ANRORC) degenerate ring transformation approach as a
valuable method for obtaining a series of 4-functionalized 3(5)-
trifluoromethyl-1H-pyrazoles (2) from the tetrahydro-2H-chro-
menones (1), which would be very difficult to obtain by other
procedures. A partial aromatization employing methanol/I2 and an
N-alkylation reaction using benzyl chloride of 3(5),4-substituted-
5(3)-trifluoromethyl-1H-pyrazoles is also subsequently presented.
Finally, the results of monocrystal X-ray diffraction measurements
of one pyrazole from series 2 will be presented. And in order to
structurally assign the N-benzylpyrazole 4 as either a 1,3- or 1,5-
isomer, mass spectrometry analysis and theoretical calculations
using the DFT method are employed.
pyrazoles by
a [3 + 2] cyclocondensation reaction with the
hydrazines and derivatives thereof, as reported previously
elsewhere [17]. However, in the present case, the first step
reaction (addition of nucleophile) should be preceded by the
removal of the hydroxyl group attached to the C-2 of the
chromenones 1a–f. Consequently, the first step of the reaction
mechanism would be an initial removal of the most acidic proton
of the chromenones 1 by the hydrazine hydrate. Thus, this first
action simultaneously promotes the pyran ring opening and the
generation of two 1,3-dicarbonyl compounds linked to each other
by a methylaryl unit (intermediate I). A subsequent nucleophilic
attack of the hydrazine on the more reactive carbonyl carbon (due
to the presence of the CF3) yields the intermediate II, which
furnishes the enamino ketone III by dehydration. Finally, an
intramolecular cyclocondensation reaction yields a 2-pyrazoline
(IV), which undergoes a second dehydration to furnish the desired
series of 3-hydroxy-2-[(3(5)-(methyl/phenyl)-5(3)-(trifluoro-
methyl)-1H-pyrazol-4-yl)arylmethyl]cyclohex-2-en-1-ones (2),
that is, the new 2,3,4-substituted pyrazole rings.
2. Results and discussion
The 2-trifluoromethyl-2H-chromenones 1a–f were readily
prepared using a multicomponent reaction (MCR) methodology
from 4-methoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalken-3-
en-2-ones, aryl aldehydes and 1,3-cyclohexanedione in the
presence of a catalytic amount of triethylamine, as described by
us previously [13].
As we reported previously [14], chromenones 1 undergo partial
aromatization from the reaction with iodine and methanol, which
The structure of chromenones 1 offers two masked 1,3-
dieletrophile building fragments composed of (O1–C2–C3–
(C55O)R) and (O1–C8a–C4a–C555O), which could react with
different dinucleophiles and lead to numerous heterocycles –
hydrazine in the present case. The synthesis of 2a–f was done from
the reaction of 1a–f with hydrazine hydrate at a 1:1 molar ratio,
using ethanol as the reaction solvent and under reflux for 16 h
(Scheme 1). The products were obtained as red solids from
recrystallization of a solvent mixture of ethanol:ethyl acetate (1:1
v/v), and as a racemic mixture of enantiomers due to the presence
of one asymmetric carbon, which according to the proposed
mechanism (Fig. 2) cannot change its configuration. Also, due to
the fast NH proton exchange, both enantiomers from the
compounds of 2 were identified by NMR as a mixture of tautomers.
O
Ar
O
HO
Ar
O
HO
Ar
O
i
R
R
R
OH
CF3
63 - 90 %
O
N
NH
F3C
F3C
N
H
N
1a-f
2a-f
1,2
Ar
R
a
b
c
d
e
f
Ph Ph 4-NO2C6H4 4-NO2C6H4 4-OCH3C6H4 4-OCH3C6H4
CH3 Ph CH3 Ph CH3 Ph
Scheme 1. Synthesis of 3(5),4-substituted-3(5)-trifluoromethyl-1H-pyrazoles.
Reagents and conditions: (i) NH2NH2ꢀH2O, ethanol, reflux, 16 h.

40
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 151 (2013) 38–44
O
Ar
O
O
R
O
O
O
OH
CF3
O
OH
O
OH
+
_
H
H
CF3
CF3
CF3
CF3
Ar
Ar
Ar
Ar
HO
O
NH
NH2
NH
NH2
H
O
OH
H2N NH2
O
OH
OH
O
O
1a-f
R
R
H2N NH2
R
I
R
II
-H2O
O
OH
CF3
O
OH
O
OH
CF3
O
OH
CF3
O
OH
CF3
-H2O
CF3
Ar
Ar
Ar
Ar
Ar
HO
R
N
NH2
N
N
O
NH
HN NH2
O
R
R
N
H
N
H
N
R
R
2a-f
(Tautomers)
III
IV
Fig. 2. Proposed mechanism for the ANRORC rearrangement in chromenones (1).
also leads to the chromanes (Fig. 1 structure II). Thus, we decided
to apply the reported methodology, since the pyrazoles of 2 show
resemblance to the chromenones of 1, that is, in the 2-hydroxy-2H-
chromenones of 1 and in the pyrazoles of 2, there is a similar cyclic
and preserved moiety (–O–C55C–C55O). Consequently, the synthe-
sis of 3(5)-trifluoromethyl-5(3)-methyl-4-[(2,6-dimethoxyphe-
nyl)-(4-methoxyphenylmethyl)]-1H-pyrazole 3e was conducted
according to the literature [14]. We performed the reaction by
using pyrazole 2e and iodine at a 1:2 molar ratio in methanol under
reflux for 2 h. For this reaction time, it was not possible to obtain
compound 3e, and only the starting material was recovered.
However, when the reaction was performed increasing the
reaction time from 2 h to 8 h, the products 3e was obtained as a
yellow solid in 6 h and at an optimal 72% yield (Scheme 2).
Since the compounds 2a–f were obtained as NH-tautomers, we
decided to investigate a possible derivatization by employing an
alkylation reaction using benzyl chloride as the alkylating reagent
in order to study the chemical behavior for both tautomers. This
reaction should furnish one or two isomers, namely, 1,3- and/or
1,5-isomers. Both are related to the benzyl and the CF3 substituents
attached to the specific positions of the pyrazole ring. The
alkylation reaction was performed using 2-[(3(5)-trifluoro-
methyl-5(3)-methyl-1H-pyrazol-4-yl)phenylmethyl]-3-hydroxy-
cyclohex-2-en-1-one (2a) in the presence of a strong base (NaH)
and benzyl chloride in DMF as solvent. After 24 h at room
temperature, we isolated (by easy purification) the product 4a as
yellow oil at 69% yield (Scheme 2). The subsequent NMR and DFT
calculation studies revealed that the alkylation reaction was
regioselective and it furnished 4a exclusively as a pure 1,3-
regioisomer.
Before any structural analysis by NMR, it is important to note
that compounds 2a–f could present two simultaneous tautomer-
ism processes involving rapid site proton exchange of the55N–NH
(pyrazole ring) and of the O55C–C55C–OH/O55C–CH2–C55O (1,3-
cyclohexanodione) moieties, but pyrazole 3e can shows only two
tautomers due to the 55N–NH. On the contrary, the N-benzyl
substituted pyrazole 4 showed only the ketoenol form (O55C–C55C–
OH fragment) for the 1,3-cyclohexanodione ring at the unique
isolated isomer (1,3-isomer).
Subsequently, a complete analysis of the NMR spectra of the
new pyrazoles 2a–f, 3 and 4 was achieved also by comparison with
reported chemical shifts for pyrazoles [26].
Pyrazoles 2 and 3 were characterized by 1H NMR and the
spectra showed broad singlet signals in the range of
d 12.66–
13.55 ppm related to the NH, and in the range of 5.61–5.88 ppm
d
for the CH group linked to the C-4 of the pyrazole rings (2–4).
Although the spectra were registered in DMSO-d6, the signals
related to the OH groups were not observed for compounds 2 and 4.
As a general characteristic for 13C NMR, the CF3 carbons
resonated as quartets near
CF3 carbons also resonated as quartets but near
near 34 Hz. The C-4 carbons presented signals as singlets near
d
122 ppm with 1JCF near 269 Hz. The C–
139 ppm with 2JCF
d
d
HO
O
H3CO
OCH3
CH3
H3CO
OCH3
CH3
CH3
i
72 %
N
H3CO
F3C
2e
N
NH
H3CO
N
H
H3CO
F3C
F3C
N
H
N
3e
(tautomers)
O
OH
CF3
HO
O
HO
O
CH3
CH3
ii
or
69 %
N
N
N
F3C
H3C
N
F3C
N
N
H
4a (R,S)
(1,3 - isomer)
4a'(R,S) (not isolable)
2a
(1,5 - isomer)
Scheme 2. Aromatization and N-alkylation reaction of 3,4-substituted-3(5)-trifluoromethyl-1H-pyrazoles. Reagents and conditions: (i) I2 (2 equiv.), MeOH, reflux, 6 h; (ii)
BnCl, NaH, DMF, r.t., 24 h.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 151 (2013) 38–44
41
Fig. 3. ORTEP of 2-[(3-trifluoromethyl-5-methyl-1H-pyrazol-4-yl)phenylmethyl]-3-hydroxycyclohex-2-en-1-one (2a).
116 ppm. For compound 3, a 4-[(2,6-dimethoxyphenyl)-(4-meth-
oxyphenylmethyl)]-substituted 1H-pyrazole, the C-4 resonated
effect from the two carbocyclic substituents attached to the
asymmetric carbon attached to C-4 of the pyrazole ring, the
trifluoromethyl group occupies a preferential position closer to the
cyclohexenedione ring. Due to the 1H and 13C NMR similarities
with 2a data, we suggest that for other pyrazoles (2b, 2d, 2f), where
R and Ar are substituents with a stronger steric effect, because
R = phenyl, and Ar = 4-NO2C6H4 and 4-OMeC6H4, the preferential
spatial relationship also remains similar.
In order to clarify whether the N-benzylation reaction of the
pyrazole 2a conducted for the 1,3- or the 1,5-pyrazole isomer, a CI
(positive mode) mass spectrum of pyrazole 4a was recorded and
investigated (Fig. 4). The spectrum was then characterized by some
prominent fragment ions. The presence of a signal at m/z 469 refers
to a typical characteristic of this spectrometric technique [M+29]
and the signal at m/z 441 [C25H23F3N2O2]+ (43%) corresponds to the
appearance of the molecular ion [M+1]. In agreement to the
literature data [18a], the signal at m/z 421 [C25H20F3N2O+] (29%)
can refer to a simple loss of H3O (H2O + H). The appearance of
another signal at m/z 329 (47%) refers to the characteristic
fragmentation of a typical 1,3-substituted-pyrazole, where a loss of
CF3CN results in a [M–CF3CN] fragment, which is a fundamental
characteristic for a 1,3-pyrazole isomer [18b]. The fragment ion (m/
z 329) can further undergo a loss of benzyl, to furnish a fragment
around
attached to the C-4 presented signals for tertiary CH in the range of
31.3–35.3 ppm. The C55O, C55C–OH, and55C–OH carbons of the 3-
hydroxy-cyclohex-2-en-1-one moiety resonated as singlets in the
range of 184.5–197.6 ppm, 172.1–184.9 ppm, and 113.8–
d 5 ppm further downfield at d 120.8 ppm. The substituent
d
d
d
d
117 ppm, respectively. It is interesting to note that due to the rapid
site proton exchange at the O55C–C55C–OH fragment, the ketoenol
carbons appeared only as broad singlets of compounds 2a,b, 2d, 2f,
and 4 and did not show signals for 2c and 2e.
Finally, 19F NMR has been found to be a simple and efficient
method for assigning the trifluoromethyl group position at
pyrazole 4. This compound exhibited a typical signal for a 3-
(CF3)-pyrazole isomer near
d 58.85 ppm, in contrast to the more
downfield resonance of similar 5-(CF3)-pyrazole isomers, which
present signals near
d – 54.0 ppm [26]. Consequently, the 1,3- and
1,5-isomer of 4 could be easily distinguished by their 19F NMR
spectrum.
In addition, to determine the molecular structure of the
pyrazoles of 2, an X-ray monocrystal diffraction measurement of
compound 2a was performed and the results evaluated (Fig. 3). The
crystallographic data showed that because of the possible steric
O
O
CF3
NH
H3C
N
H3C
N
m/z 241
m/z 421
O
OH
CF3
N
H3C
4a
m/z 440
N
O
N
NH
H3C
H3C
m/z 57
m/z 329
Fig. 4. Prominent fragment ions of compound 4a.

42
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 151 (2013) 38–44
Table 1
230 pm, respectively. These distances are highly consistent with a
H-F intramolecular bridge [20] stabilizing the molecule and
enabling the isolation of only the structure assigned as 4a.
Relative energies of isomersa for compounds 4a and 4a0 at B3LYP/cc-pVDZ level of
theory.
Entry
Enantiomers
1,3-Isomer (4a)
1,5-Isomer (4a0)
(OH. . .CF3)
(OH. . .CH3)
(OH. . .CF3)
(OH. . .CH3)
3. Conclusion
1
2
R
S
0.36
0.00
3.85
1.53
5.27
3.75
3.91
3.04
In this work we developed a simple and convenient new one-
pot procedure to obtain novel 2,3,4-trisubstituted-1H-pyrazoles
(2) by a ring rearrangement ANRORC type reaction of specific
chromenones with hydrazine. The chemical structure of a racemic
mixture of pyrazole tautomers 2a–f was verified by an oxidative
process and in addition by an alkylation reaction, which furnished
pyrazoles 3e and 4a, respectively, both at good yields. To
demonstrate the importance of the analytical methods in organic
synthesis, the structure of compounds 2–4 was determined with
the aid and simultaneous application of 1H, 13C and 19F NMR, X-ray
crystal diffraction, mass spectrometry, and DFT calculation
techniques. The preferential geometry, including a conclusion
about the configuration and isomerism of tetra-substituted
pyrazoles 4, could only be demonstrated by employing a DFT
calculation.
a
D
E (kcal/mol) related to the stablest 1,3(S) isomer.
+
ion [C16H19NO] at m/z 241 (100%) – this was also found in the
mass spectrum as the more stable fragment. Moreover, the
formation and presence of a fragment ion [C3H6N]+ at m/z 57
(36%) proves the existence of a stable aziridinium ion, which
should also result from an initial CF3CN loss. Thus, these results
suggest that the CF3 group is definitively linked to the 3-position of
the pyrazole ring and not to the 5-position. Other complementary
MS fragments from this compound are given in the experimental
part.
With the aim of determining the stablest structure from all
possible isomers for the compounds of 4, we simulated all
structural possibilities for obtaining the stablest isomer (1,3 or 1,5),
the R and S configurations for the substituent attached to C-4, and
the position of the hydroxy group (cyclohexendione) related to the
CF3 or CH3 group. All geometries were verified as minima on the
potential energy by calculating the Hessian matrices using
harmonic frequency calculations. The theoretical calculations
were done using the Gaussian 09 package of programs [19] and
the density functional theory calculations were performed for the
possible isomers in compounds 4a and 4a0 at the B3LYP/cc-pVDZ
level of theory.
4. Experimental
4.1. Analytical equipment’s and procedures
Unless otherwise indicated, all common reagents and
solvents were used as obtained from commercial suppliers,
without further purification. The melting points were deter-
´
The DFT calculations presented in Table 1 clearly show that
isomer 1,3 (column 1) is stabler than isomer 1,5 (column 2), in
addition to showing that the S enantiomer (entry 2) is more stable
than the R enantiomer (entry 1). The theoretical calculations also
revealed that the hydroxyl group stabilizes the molecular
geometries nearer the CF3 than the CH3 group (Fig. 5). Therefore,
we concluded that isomer 1,3 with the S configuration for the
group attached to the C-4 of the pyrazole ring, which presents the
OH substituent near the CF3 group, is the stablest structure.
Distances for the hydroxyl oxygen and the hydrogen atom to the
fluorine atoms of the CF3 substituent were found to be 310 pm and
mined using coverslips on a Microquımica MQAPF–302 appara-
tus and are uncorrected. 1H, 13C and 19F NMR spectra were
acquired on a Bruker DPX 200 spectrometer (1H at 200.13 MHz)
and Bruker DPX 400 (13C at 100.32 MHz and 19F at 376.3 MHz)
spectrometer, using 5 mm sample tubes, 298 K, and a digital
resolution of ꢁ0.01 ppm, in DMSO-d6 or CDCl3, with TMS as the
internal reference (1H and 13C) or hexafluorobenzene as the
external reference (19F). 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, cross-linked HP-5 capillary column (30 m, 0.32 mm
internal diameter), and helium was used as the carrier gas. Mass
spectra were registered in an Agilent 6460 Triple Quad LC/MS
connected to a 1200 series LC and equipped with a solvent degasser,
binary pump, column oven, and auto-sampler. The CHN elemental
analyses were performed on a Perkin–Elmer 2400 CHN elemental
analyzer (University of Sa˜o 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 Sa˜o Paulo, Brazil). The diffrac-
tion measurements were done by graphite-monochromatized Mo
˚
Ka radiation with l = 0.71073 A on
a Bruker SMART CCD
diffractometer [21]. The structure of 2a was solved with direct
methods using the SHELXS-97 program [22], and refined on F2 by
full-matrix least-squares using the SHELXL-97 package [23]. The
absorption correction was done by Gaussian methods [24].
Anisotropic displacement parameters for non-hydrogen 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 [25].
Fig. 5. Molecular structure of (S)-2-[(1-benzyl-5-trifluoromethyl-3-methyl-1H-
pyrazol-4-yl)phenylmethyl]-3-hydroxycyclohex-2-en-1-one (4a) from DFT
calculations.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 151 (2013) 38–44
43
4.2. Synthesis
HRMS Calc. for C18H16F3N3O4: 396.1179. Found: 396.1177.
Compounds 1a–f were obtained from a multi-component
4.2.1.4. 3-Hydroxy-2-[(5(3)-(trifluoromethyl)-3(5)-phenyl-1H-pyra-
reaction (MCR) involving 1,3-cyclohexanedione, aryl aldehydes,
zol-4-yl)-4-nitrophenylmethyl]cyclohex-2-en-1-one (2d): red solid,
yield 85%, mp. 170–172 8C. 1H NMR (DMSO-d6):
d = 13.55 (s, 1H,
4-(alkyl/aryl/heteroaryl)substituted
4-methoxy-1,1,1-trifluor-
oalk-3-en-2-ones and triethylamine [13].
NH), 7.89 (d, J = 8 Hz, 2H, Ph), 7.24–7.17 (m, 7H, Ph), 5.77 (s, 1H,
CH), 2.20–2.02 (m, 4H, H40, H60), 1.69–1.64 (m, 2H, H50).
4.2.1. General procedure for the synthesis of 3-hydroxy-2-[(3(5)-
(methyl/phenyl)-5(3)-(trifluoromethyl)-1H-pyrazol-4-
13C NMR (DMSO-d6): = 197.6 (C10), 184.9 (C30), 151.3, 145.2
d
(Ph), 142.7 (C3/C5), 138.9 (q, J = 34 Hz, C5/C3), 129.5, 129.4, 127.7,
127.1, 122.0 (Ph), 122.0 (q, J = 269 Hz, CF3), 116.7 (C4), 114.6 (C20),
35.3 (CH), 33.1 (C40 e C60), 19.7 (C50).
yl)arylmethyl]cyclohex-2-en-1-ones (2a–f)
Hydrazine monohydrate (2 mmol, 100 mg) was added at room
temperature to a solution of 3-acyl-2-trifluoromethyl-2H-chro-
menones 1a–f (1 mmol) stirred in ethanol (10–15 mL). The
mixture was then boiled under reflux for 16 h. The solvent was
slowly evaporated under reduced pressure. The resulting red solid
product was dried in a desiccator under reduced pressure over
P2O5 and this furnished pyrazoles 2a–f at 63–90% yields without
purification at a high degree of purity according to HRMS analysis
data.
MS (ESI) m/z [(M+H)+, 458.2].
HRMS Calc. for C23H18F3N3O4: 458.1279. Found: 458.1281.
4.2.1.5. 3-Hydroxy-2-[(5(3)-(trifluoromethyl)-3(5)-methyl-1H-pyra-
zol-4-yl)-4-methoxyphenylmethyl]cyclohex-2-en-1-one (2e): yellow
solid, yield 63%, mp. 127–129 8C. 1H NMR (DMSO-d6):
d = 12.75 (s,
NH, 1H), 6.95 (d, J = 8 Hz, 2H, Ph), 6.79 (d, J = 8 Hz, 2H, Ph), 5.61 (s,
1H, CH), 3.70 (s, 3H, OCH3), 2.41–2.28 (m, 4H, H40, H60), 1.85–1.80
(m, 2H, H50), 1.54 (s, 3H, CH3).
R
R
O
O
Ar
13C NMR (DMSO-d6):
d = 157.2 (Ph), 139.7 (C3/C5), 138.8 (q,
Ar
1'
1'
6'
5'
6'
5'
2'
N
HN
2'
HN
N
J = 34 Hz, C5/C3), 133.6, 128.9 (Ph), 122.4 (q, J = 269 Hz, CF3), 117.6
(C4), 115.4 (C20), 113.0 (Ph), 54.8 (OCH3), 33.0 (C40), 32.9 (C60), 32.8
(CH), 20.3 (C50), 10.4 (CH3).
3'
3'
4'
4'
CF3
CF3
HO
HO
MS (EI, 70 eV): m/z (%) 380 (100), 340 (100), 309 (50), 269 (75).
HRMS Calc. for C19H19F3N2O3: 381.1394. Found: 381.1389.
4.2.1.6. 3-Hydroxy-2-[(5(3)-(trifluoromethyl)-3(5)-phenyl-1H-pyra-
4.2.1.1. 3-Hydroxy-2-[(3(5)-methyl-5(3)-(trifluoromethyl)-1H-pyra-
zol-4-yl)-4-methoxyphenylmethyl]cyclohex-2-en-1-one (2f): yellow
zol-4-yl)phenylmethyl]cyclohex-2-en-1-one (2a): yellow solid, yield
solid, yield 72%, mp. 120–122 8C. 1H NMR (DMSO-d6):
d = 12.81 (s,
78%, mp. 234–236 8C. 1H NMR (DMSO-d6):
d = 12.66 (s, 1H, NH),
NH, 1H), 7.20 (m, 5H, Ph), 6.82 (d, J = 8 Hz, 2H, Ph), 6.47 (d, J = 8 Hz,
2H, Ph), 5.61 (s, 1H, CH), 3.60 (s, 3H, OCH3), 2.10–2.02 (m, 4H, H40,
H60), 1.70–1.63 (m, 2H, H50).
7.22 (t, J = 7 Hz, 2H, Ph), 7.12 (t, J = 7 Hz, 1H, Ph), 7.04 (d, J = 8 Hz,
2H, Ph), 5.69 (s, 1H, CH), 2.38–2.25 (m, 4H, H40, H60), 1.86–1.79 (m,
2H, H50), 1.55 (s, 3H, CH3).
13C NMR (DMSO-d6):
d
= 184.5 (C10, C30), 156.8 (Ph), 142.4 (C3/
13C NMR (DMSO-d6):
d
= 195.7 (C10), 172.6 (C30), 141.6 (Ph),
C5), 138.7 (q, J = 34 Hz, C5/C3), 134.2, 130.1, 129.4, 129.3, 127.2,
126.9, 126.2 (Ph), 122.2 (q, J = 269 Hz, CF3), 115.3 (C4), 113.8 (C20),
112.3 (Ph), 54.7 (OCH3), 34.3 (CH), 34.3 (C40 e C60), 20.0 (C60).
MS (ESI) m/z (%) 442 (71), 402 (100), 371 (26), 331 (31), 229
(21).
139.6 (C3/C5), 138.9 (q, J = 30 Hz, C5/C3), 127.9, 127.5, 123.7 (Ph),
122.3 (q, J = 269 Hz, CF3), 116.9 (C4), 115.0 (C20), 36.4 (C60), 33.6
(CH), 29.4 (C40), 20.2 (C50), 10.3 (CH3).
MS (EI, 70 eV): m/z (%) 350 (100), 310 (80), 279 (30), 226 (35),
199 (15).
HRMS Calc. for C24H21F3N2O3: 443.1579. Found: 443.1574.
HRMS Calc. for C18H17F3N2O2: 351.1279. Found: 351.1275.
4.2.2. Synthesis of 3(5)-trifluoromethyl-5(3)-methyl-4-[(2,6-
4.2.1.2. 3-Hydroxy-2-[(5(3)-(trifluoromethyl)-3(5)-phenyl-1H-pyra-
dimethoxyphenyl)-(4-methoxyphenylmethyl)]-1H-pyrazole (3e)
zol-4-yl)phenylmethyl]cyclohex-2-en-1-one (2b): yellow solid, yield
A
mixture of 3-hydroxy-2-[(5(3)-(trifluoromethyl)-3(5)-
80%, mp. 136–137 8C. 1H NMR (DMSO-d6):
d = 13.26 (s, 1H, NH),
methyl-1H-pyrazol-4-yl)-4-methoxyphenylmethyl]cyclohex-
2-en-1-one (2e) (0.198 g, 0.5 mmol) and iodine (0.126 g,
1 mmol) stirred in methanol (5 mL) was boiled under reflux
for 6 h. The solvent was evaporated under pressure and the
residue was taken up into dichloromethane (15 mL). The organic
solution was sequentially washed with saturated aqueous
sodium thiosulfate, sodium bicarbonate, and brine and then
dried over Na2SO4. The mixture was filtered and the solvent
evaporated under reduced pressure. The resulting solid product
was dried in a desiccator under reduced pressure over P2O5 and
furnished 3e (72%) without purification as a yellow solid (mp.
109–111 8C) and at a high degree of purity according to CHN
elemental analysis data.
7.19–7.12 (m, 5H, Ph), 6.93–6.88 (m, 5H, Ph), 5.67 (s, 1H, CH), 2.18–
2.01 (m, 4H, H60 e H40), 1.69–1.60 (m, 2H, H50).
13C NMR (DMSO-d6): = 193.5 (C10), 172.1 (C30), 147.2 (C3/C5),
d
142.3 (Ph), 139.0 (q, J = 34 Hz, C5/C3), 129.8, 129.2, 128.2, 127.0,
126.8, 124.8 (Ph), 122.1 (q, J = 269 Hz, CF3), 117.9 (C4), 115.0 (C20),
35.9 (C60), 35.0 (CH), 29.6 (C40), 20.4 (C50).
MS (ESI) m/z [(M+H)+, 413.2].
HRMS Calc. for C23H19F3N2O2: 413.1479. Found: 413.1476.
4.2.1.3. 3-Hydroxy-2-[(5(3)-(trifluoromethyl)-3(5)-methyl-1H-pyra-
zol-4-yl)-4-nitrophenylmethyl]cyclohex-2-en-1-one (2c): red solid,
yield 90%, mp. 164–166 8C. 1H NMR (DMSO-d6):
d = 13.01 (s, NH,
1H NMR (DMSO-d6):
d = 7.21 (t, J = 8 Hz, 1H, Ph), 6.91 (d,
1H), 8.01 (d, J = 8 Hz, 2H, Ph), 7.29 (d, J = 8 Hz, 2H, Ph), 5.80 (s, CH,
1H), 2.43–2.29 (m, 4H, H40, H60), 1.92–1.79 (m, 2H, H50), 1.17 (s, 3H,
CH3).
J = 8 Hz, 2H, Ph), 6.79 (d, J = 8 Hz, 2H, Ph), 6.65 (d, J = 8 Hz, 2H, Ph),
6.13 (s, 1H, CH), 3.70 (s, 3H, OCH3), 3.58 (s, 6H, OCH3), 1.61 (s, 3H,
CH3).
13C NMR (DMSO-d6):
d = 151.1, 145.5 (Ph), 139.3 (C3/C5), 139.2
13C NMR (DMSO-d6):
d = 157.8, 157.2 (Ph), 139.6 (C3/C5, Pz),
(q, J = 34 Hz, C5/C3), 129.0, 122.9 (Ph), 122.3 (q, J = 269 Hz, CF3),
115.6 (C4), 114.0 (C20), 34.0 (CH), 34.0 (C40, C60), 20.3 (C50), 10.6
(CH3).
138.9 (q, J = 34 Hz, C5/C3, Pz), 133.1, 128.9, 128.0 (Ph), 122.2 (q,
J = 269 Hz, CF3), 120.8 (C4, Pz), 117.0, 113.12, 104.7 (Ph), 55.4
(OCH3), 54.7 (OCH3), 33.8 (CH), 10.0 (CH3).
MS (EI, 70 eV): m/z (%) 396 (32), 378 (92), 349 (75), 326 (100),
201 (42).
MS (EI, 70 eV): m/z (%) 406 (100), 366 (75), 337 (87).

44
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 151 (2013) 38–44
[2] M. Rueping, E. Merino, M. Bolte, Org. Biomol. Chem. 10 (2012) 6201.
Anal. Calc. for C21H21F3N2O3 (406.15): C, 62.06; H, 5.21; N, 6.89.
[3] (a) S. Manfredini, R. Bazzanini, P.G. Baraldi, M. Guarneri, D. Simoni, M.E. Mar-
ongiu, A. Pani, E. Tramontano, P. La Colla, J. Med. Chem. 35 (917) (1992);
(b) M.E.Y. Francisco, H.H. Seltzman, A.F. Gilliam, R.A. Mitchell, S.L. Rider, R.G.
Pertwee, L.A. Stevenson, B.F. Thomas, J. Med. Chem. 45 (2708) (2002);
(c) T.D. Penning, J.J. Talley, S.R. Bertenshaw, J.S. Carter, P.W. Collins, S. Docter, M.J.
Graneto, L.F. Lee, J.W. Malecha, J.M. Miyashiro, R.S. Rogers, D.J. Rogier, S.S. Yu, G.D.
Anderson, E.G. Burton, J.N. Cogburn, S.A. Gregory, C.M. Koboldt, W.E. Perkins, K.
Seibert, A.W. Veenhuizen, Y.Y. Zhang, P.C. Isakson, J. Med. Chem. 40 (1347) (1997);
(d) R. Mulder, K. Wellinga, J.J. Van Daalen, Naturwissenschaften 62 (1975) 531.
[4] P. Liu, Y.-M. Pan, Y.-L. Xu, H.-S. Wang, Org. Biomol. Chem. 10 (2012) 4696.
[5] A.P. Piccionello, A. Pace, S. Buscemi, N. Vivona, ARKIVOC vi (2009) 235.
[6] V.Y. Sosnovskikh, M.A. Barabanov, B.I. Usachev, Russ. Chem. Int. Ed. 52 (2003)
1758.
[7] V.Y. Sosnovskikh, M.A. Barabanov, A.Y. Sizov, Russ. Chem. Int. Ed. 51 (2002) 1280.
[8] C.D. Gabbut, T.F.L. Hargrove, B.M. Heron, D. Jones, C. Poyner, E. Yildiz, P.N. Horton,
M.B. Hurtshouse, Tetrahedron 62 (2006) 10945.
[9] E. Budzisc, M. Malecka, B. Nawrot, Tetrahedron 60 (2004) 1749.
[10] G. Palazzino, G. Filachioni, J. Heterocycl. Chem. 25 (1988) 1367.
[11] A. Rykowski, E. Wolinska, D. Branowska, H.C. Van der Plas, ARKIVOC iii (2004) 74.
[12] H.G. Bonacorso, A.D. Wastowski, N. Zanatta, M.A.P. Martins, Synth. Commun. 30
(2000) 1457.
[13] H.G. Bonacorso, J. Navarini, C.W. Wiethan, G.P. Bortolotto, G.R. Paim, S. Cavinatto,
M.A.P. Martins, N. Zanatta, M.S.B. Caro, J. Fluorine Chem. 132 (2011) 160.
[14] H.G. Bonacorso, L.M.F. Porte, J. Navarini, G.R. Paim, F.M. Luz, L.M. Oliveira, C.W.
Wiethan, M.A.P. Martins, N. Zanatta, Tetrahedron Lett. 52 (2011) 3333.
[15] H.G. Bonacorso, J. Navarini, C.W. Wiethan, A.F. Junges, S. Cavinatto, R. Andrighetto,
M.A.P. Martins, N. Zanatta, J. Fluorine Chem. 142 (2012) 90.
[16] H.G. Bonacorso, J. Navarini, F.M. Luz, C.W. Whietan, A.F. Junges, S. Cavinatto,
M.A.P. Martins, N. Zanatta, J. Fluorine Chem. 146 (2013) 53.
[17] J. Elguero, in: A.R. Katritzky, C.W. Rees, E.F.V. Scriven (Eds.), Comprehensive
Heterocyclic Chemistry II: Pyrazoles, vol. 3, Pergamon Press, Oxford, 1996
, pp. 1–75.
[18] (a) L. Corda, G. Delogu, D. Favretto, E. Maccioni, G. Podda, L. Santana, C. Tomaselli,
P. Traldi, E. Uriarte, Rapid Commun. Mass Spectrom. 12 (2041) (1998);
(b) W.C.M.M. Luijten, J.V. Thuijl, Org. Mass Spectrom. 14 (1979) 577.
[19] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G.
Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
H. Nakai, T. Vreven Jr., J.A. Montgomery, J.E. Peralta, F. Ogliaro, M. Bearpark, J.J.
Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega,
J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W.
Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador,
Found: C, 61.97, H, 5.15, N, 6.91.
4.2.3. Synthesis of 2-[(1-benzyl-5-trifluoromethyl-3-methyl-1H-
pyrazol-4-yl)phenylmethyl]-3-hydroxycyclohex-2-en-1-one (4a)
To
a solution of 2-[(3(5)-trifluoromethyl-5(3)-methyl-1H-
pyrazol-4-yl)phenylmethyl]-3-hydroxycyclohex-2-en-1-one (2a)
(0.5 mmol, 175 mg), and sodium hydride (0.9 mmol, 21 mg) stirred
with anhydrous DMF (10 mL), pure benzyl chloride (0.55 mmol,
69 mg) was added at room temperature. After the addition process,
the mixture was stirred for a further 24 h at room temperature.
After this time, chloroform (15 mL) was added to the reaction and
the organic layer was washed with distilled water (3 ꢂ 10 mL).
Then, the organic layer was dried over Na2SO4, filtered, and the
solvent was evaporated under reduced pressure. The resulting
brown oil was boiled in chloroform (10 mL) in the presence of
active charcoal and filtered hot. After a second solvent evaporation
under reduced pressure, the alkylated product 4a (yellow oil) was
isolated at 69% yield without purification and at a high degree of
purity according to the CHN elemental analysis data.
CH3
O
Ar
1'
6'
5'
2'
N
N
3'
4'
CF3
HO
4a (R,S)
1H NMR (CDCl3):
d = 7.98 (s, 1H, OH), 7.24–6.97 (m, 10H, Ph),
5.88 (s, 1H, CH), 5.01 (m, 2H, CH2), 2.68–2.63 (m, 2H, H60), 2.34 (bs,
2H, H40), 2.01–1.98 (m, 2H, H50), 1.35 (s, 3H, CH3).
13C NMR (CDCl3):
d
= 197.2 (C10), 172.5 (C30), 150.6 (Ph), 150.6
(Ph), 140.6 (C3), 139.5 (q, J = 34 Hz, C5), 135.6, 128.4, 128.3, 128.1,
127.7, 126.9, 125.8 (Ph), 122.3 (q, J = 269 Hz, CF3), 117.2 (C20),
114.4 (C4), 69.6 (CH2Ph), 36.5 (C60), 34.6 (C40), 31.3 (CH), 24.9 (C50),
10.4 (CH3).
¨
J.J. Dannenberg, S. Dapprich, A.D. Daniels, O. Farkas, J.B. Foresman, J.V. Ortiz, J.
MS (CI+): m/z (%) 441 (M+1) (43); 421 (29); 329 (47); 241 (100);
211 (85); 221 (85); 91 (71); 69 (10); 57 (36).
Anal. Calc. for C25H23F3N2O2 (440.17): C, 68.17; H, 5.26; N, 6.36.
Found: C, 68.30, H, 5.25, N, 6.05.
Cioslowski, D.J. Fox, Gaussian 09 Revision A.1, Gaussian Inc., Wallingford, CT,
2009.
[20] J. Steiner, Angew. Chem. Int. Ed. 41 (2002) 48.
[21] Bruker, APEX2 (Version 2.1), COSMO (Version 1.56), BIS (Version 2.0.1.9), SAINT
(Version 7.3A) and SADABS (Version 2004/1), XPREP 9Version 2005/4), Bruker
AXS Inc., Madison, Wisconsin, USA, 2006.
[22] G.M. Sheldrick, SHELXS-97, Program for Crystal Structure Solution, University of
Go¨ttingen, Germany, 1997.
Acknowledgements
[23] G.M. Sheldrick, SHELXL-97, Program for Crystal Structure Refinement, University
of Go¨ttingen, Germany, 1997.
[24] P. Coppens, L. Leiserowitz, D. Rabinovich, Acta Crystallogr. 18 (1965) 1035.
[25] L.J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565.
[26] (a) M.D. Threadgill, A.K. Heer, B.G. Jones, J. Fluorine Chem. 65 (21) (1993);
(b) S.P. Sing, J.K. Kapoor, D. Kumar, M.D. Threadgill, J. Fluorine Chem. 83 (73)
(1997);
The authors thank the Coordination for Improvement of Higher
Education Personnel (CAPES) for fellowships, and the National
Council for Scientific and Technological Development (CNPq) for
financial support (Process numbers 303.013/2011-7 and 470.788/
2010-0-Universal).
(c) J. Diab, A. Laurent, I. Le Dre´an, J. Fluorine Chem. 84 (145) (1997);
(d) S.P. Sing, D. Kumar, B.G. Jones, M.D. Threadgill, J. Fluorine Chem. 94 (199)
(1999);
References
(e) S. Fustero, R. Roma´n, J.F. Sanz-Cervera, A. Simo´n-Fuentes, A.C. Cun˜at, S.
´
Villanova, M. Murgıa, J. Org. Chem. 73 (2008) 3523.
[1] (a) V.G. Nenajdenko, E.S. Balenkova, ARKIVOC i (2011) 246;
(b) W.K. Hangmann, J. Med. Chem. 51 (2008) 4359.