An acetal acylation methodology for producing diversity of trihalomethyl-1,3-dielectrophiles and 1,2-azole derivatives

Article abstract of DOI:10.21577/0103-5053.20190160

A series of functionalized 1,1,1-trihalo-4-methoxy-3-alken-2-ones [CX₃C(O)CR¹=CROMe, where X = F or Cl; R = n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-tridecyl, (CH₂)₂CH=C(Me)₂, (CH₂)₂Ph, (CH₂)₂-(4-HOC₆H₄), (CH₂)₂-(4-MeOC₆H₄), (CH₂)₂CO₂Me, (CH₂)₃CO₂Me, CH(SMe)CH₃, CH₂(2-MeOC₆H₄), and R¹ = H, and R = H and R¹ = n-decyl] were synthesized from respective alkyl methyl ketones or aldehyde via acetal acylation using trifluoroacetic anhydride and trichloroacetyl chloride. 1,1,1-Trihalo-4-methoxy-3-alken-2-ones with acid-compatible substituents were easily hydrolyzed to respective trihalomethyl-1,3-diketones. The 1,1,1-trihalo-4-methoxy-3-alken-2-ones and/or respective trihalomethyl-1,3-diketones were reacted regiospecifically with hydroxylamine hydrochloride, leading to isoxazole derivatives, and with hydrazines, leading to respective 1H-pyrazole derivatives. The structures of all compounds were assigned based on nuclear magnetic resonance (NMR) and mass spectrometric data. This method represents an efficient pathway for the regioselective trihaloacetylation of asymmetrically substituted alkyl methyl ketones and highly self-condensing aldehydes. Moreover, this approach allows the introduction of biologically recognizable moieties, such as those from levulinic acid, sulcatone (prenyl), benzylacetone, anisylacetone, and raspberry ketone, as synthetic molecular targets.

Full text of DOI:10.21577/0103-5053.20190160

http://dx.doi.org/10.21577/0103-5053.20190160
J. Braz. Chem. Soc., Vol. 00, No. 00, 1-21, 2019
Printed in Brazil - ©2019 Sociedade Brasileira de Química
Article
An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-
1,3-dielectrophiles and 1,2-Azole Derivatives
Valéria D. O. Bareño,a Daiane S. Santos,a Leandro M. Frigo,b Debora L. de Mello,b
Juliana L. Malavolta,b Rogerio F. Blanco,b Lucas Pizzuti,c Darlene C. Floresa and
Alex F. C. Flores *,a
aEscola de Química e Alimentos, Universidade Federal do Rio Grande,
96203-900 Rio Grande-RS, Brazil
bDepartamento de Química, Universidade Federal de Santa Maria,
97105-900 Santa Maria-RS, Brazil
cFaculdade de Ciências Exatas e Tecnologia, Universidade Federal da Grande Dourados,
79804-970 Dourados-MS, Brazil
A series of functionalized 1,1,1-trihalo-4-methoxy-3-alken-2-ones [CX3C(O)CR1=CROMe,
where X = F or Cl; R = n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-tridecyl, (CH2)2CH=C(Me)2,
(CH2)2Ph, (CH2)2-(4-HOC6H4), (CH2)2-(4-MeOC6H4), (CH2)2CO2Me, (CH2)3CO2Me, CH(SMe)CH3,
CH2(2-MeOC6H4), and R1 = H, and R = H and R1 = n-decyl] were synthesized from respective alkyl
methyl ketones or aldehyde via acetal acylation using trifluoroacetic anhydride and trichloroacetyl
chloride. 1,1,1-Trihalo-4-methoxy-3-alken-2-ones with acid-compatible substituents were easily
hydrolyzed to respective trihalomethyl-1,3-diketones. The 1,1,1-trihalo-4-methoxy-3-alken-2-ones
and/or respective trihalomethyl-1,3-diketones were reacted regiospecifically with hydroxylamine
hydrochloride, leading to isoxazole derivatives, and with hydrazines, leading to respective
1H-pyrazole derivatives. The structures of all compounds were assigned based on nuclear magnetic
resonance (NMR) and mass spectrometric data. This method represents an efficient pathway
for the regioselective trihaloacetylation of asymmetrically substituted alkyl methyl ketones and
highly self-condensing aldehydes. Moreover, this approach allows the introduction of biologically
recognizable moieties, such as those from levulinic acid, sulcatone (prenyl), benzylacetone,
anisylacetone, and raspberry ketone, as synthetic molecular targets.
Keywords: organic chemistry: methodology and reactions, trihalomethyl-1,3-diketones,
nitrogen heterocycles, trihalomethylazoles, 1H-pyrazolecarboxylates
Introduction
receiving considerable attention as chelating reagents for
transition metals as well as lanthanides and actinides.12-17
Metal-organic chemical vapor deposition (MOCVD)
from volatile fluorinated β-diketonate precursors is
widely used to produce nanostructure and luminescent
materials used in microelectronics based on transition
metals.18-20 They are the most employed precursors for
fluorinate N-heterocycles such as pyrazoles,21 isoxazoles,22
pyrimidines,23 and quinolones.24 Claisen condensation,
the most used method to obtain these precursors, is very
efficient when using symmetrical ketones or ketones with
only one enolizable site.25-28 Figure 1 shows some of the
more commonly used trifluoromethyl-1,3-diketones in
metal coordination studies and heterocyclic synthesis.
The deprotonation of asymmetrical ketones results
1,1,1-Trihalo-4-alkoxy-3-alken-2-ones have been
used as important regioselective heterocycle precursors.1,2
These compounds can be used to prepare a wide variety
of trihalomethyl-substituted heterocyclic systems and
other useful compounds.3,4 Perfluoroacylation, including
trifluoroacetylation reactions, of the acetone and
asymmetrically substituted, one-enolizable-site ketones
with esters is of fundamental importance in organic
synthesis.5-7 1,3-Diketones products have long been widely
employed as effective chelating reagents and heterocyclic
precursors.8-11 Fluorinated 1,3-diketones are currently
*e-mail: alex.fcf.furg@gmail.com

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An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives J. Braz. Chem. Soc.
in a less-substituted enolate by irreversible kinetic
control, whereas those reactions under thermodynamic
control usually yield the more substituted product.
In more favorable cases, one regioisomer can greatly
predominate the equilibrium mixture, but often the
equilibrium constant is not sufficiently high to achieve
an acceptable regioselectivity. Furthermore, even if one
prepares a regiodefined enolate, problems may occur with
proton-transfer isomerization.29,30 On the other hand, the
trichloromethyl group has attracted the attention of new
material researchers in different fields of chemistry. For
example, in the course of screening fungal extracts for new
metabolites that induce morphological and physiological
differentiation in human HL-60 cells, Becker and Anke31
isolated and characterized pinicoloform, attributed as
(2Z, 5Z, 7E)-1,1,1-trichloro-2-hydroxy-2,5,7-undecatrien-
4-one, from fermentations of Risinicium pinicola (Figure 2).
Synthetic compounds containing a trichloromethyl
group have demonstrated high relevance as biological
agents and synthetic intermediates; among them, apcin
derivatives (Figure 2) have the ability to block mitotic exit,
inducing tumor cell death.32 Penclomedine, 3,5-dichloro-
2,4-dimethoxy-6-trichloromethyl pyridine (Figure 2) is
presently in clinical trials by the United States National
Institutes of Health for treating patients with unspecified
solid tumors and lymphoma.33
Furthermore, some specimens of sponge
(Dysidea herbacea) contain 5,5,5-trichloroleucine
derivatives, including dysidenin, barbamide, herbacic
acid, and herbamide (Figure 2). Interest in natural products
that contain the trichloromethyl group found in sponges
has been stimulated by biosynthetic observations that the
pro-S methyl group of leucine, or an unidentified leucine
derivative, is the origin of the trichloromethyl group in
a compound produced by the marine cyanobacterium
Lyngbya majuscule. This is important in the context that two
independent groups have provided evidence that another
cyanobacterium, the symbiotic Oscillatoria spongeliae,
which lives in association with D. herbacea, is the source
of chlorinated metabolites extracted from D. herbacea.34,35
Figure 1. Trifluoromethyl containing β-diketones broadly used as metal ligands.
Figure 2. Natural and synthetic trichloromethyl-substituted substances.

Vol. 00, No. 00, 2019
Bareño et al.
3
The trichloromethyl group also has attracted attention
in crystallographic studies, as well, due to potential
sigma effects on chlorine halogen bonding.36 Therefore,
the acylation process of acetals is important, particularly
for trichloromethyl derivatives, because of the wide
scope of the method and consequent diversification of
1,3-dielectrophilic precursors. To the best of our knowledge,
acylation of acetals is the only method to date that has been
useful to systematically obtain trichloromethyl-substituted
1,3-dielectrophiles.37,38
activation energy intermediary, favored by steric factors.
Although theoretically there is a higher concentration of
thermodynamic enol ether, its acylation requires a higher
activation energy, probably due to steric hindrance from
the substituent on the β-carbon. Our results demonstrate
that the presence of the substituents in the enol ether
precursor makes it difficult to form the C–C bond to obtain
the enolone push-pull system; thus, experimentally, we
can control the regioselectivity by controlling the reaction
temperature of trihaloacetylation.38
Using this method, it was possible to obtain a large and
diversified series of 1,3-dielectrophiles, as 1,1,1-trialo-
4-methoxy-3-alken-2-ones 2,3a-n. In the process of
acylating the dimethoxy acetal from raspberry ketone (1i),
the hydroxyl substituent of the aromatic ring competed
for the acylating agent, making it necessary to increase
the quantity of this reagent for complete C-acylation
of the enol ether; the proper stoichiometry was 1:3.5
between dimethoxy ketal 2i and trifluoroacetic anhydride.
The synthesis and reactivity of the acetal precursor is
key to the successful application of this method; for
example, the presence of only one α-halogen substituent
in the starting ketone facilitates the formation of the
ketal precursor, but dramatically reduces its reactivity
for enol ether formation. Thus, even when reacting the
1-chloro-2,2-dimethoxypropane and 1,1,1-trifluoro-
2,2-dimethoxypropane with trichloroacetyl chloride
for 24 h at toluene reflux temperature, it does not form
any detectable amount of trichloroacetylation product,
indicating that intermediate reactive enol ethers do not
form during the process (Scheme 2). In addition, no
acylated products were obtained in the acetal acylation
reaction starting from dimethoxy acetals derived from
2-acetylpyrrol, 2-acetylpyridine, 3-acetylpyridine,
Results and Discussion
Acetal acylation methodology
Acetal synthesis was conducted using an adaptation
of the Wohl method.37 Ketones 1a-j were reacted with
one mol-equivalent of trimethyl orthoformate under
p-toluenesulfonic acid catalysis; after 8 to 24 h, the acid
was neutralized with K2CO3. For levulinic acid (1m) and
5-oxohexanoic acid (1n), reacting one mol-equivalent of
trimethyl orthoformate led to methyl 4-oxopentanoate and
methyl 5-oxohexanoate, respectively, demonstrating that
esterification occurred before the ketalization. To perform
esterification and ketalization, 2.5 mol-equivalents of
trimethyl orthoformate were added and the mixture was
maintained without stirring for 48 h. Distilled acetals 2a-n
were reacted with two mol-equivalents of trifluoroacetyl
anhydride or trichloroacetyl chloride in a pyridine/
o
CHCl3 mixture at –5 to 10 C, leading to kinetic enol
ether, an unsubstituted enol, via O-acylation (Scheme 1).
According to the literature and our own experience,
this enol ether derived from asymmetrically substituted
dimethoxy acetals is readily acylated, through the lower
Scheme 1. Successful acetal acylation method.

4
An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives J. Braz. Chem. Soc.
Scheme 2. Limitations of the acetal acylation method.
and 4-acetylpyridine. Furthermore, the reaction of
hydroxybutanone and trimethyl orthoformate produced
2-methoxy-2-methyloxirane (2q), which was unreactive in
trichloroacylation medium under toluene reflux (Scheme 2).
This demonstrates the complementarity between the
acylation methods for some substrates since, for example,
the 1,1,1-trifluoro-4-(pyridinyl)-butan-2,4-dione derivatives
are easily obtained following the Claisen method.39,40
The acylation of acetals is particularly important in the
case of trichloromethyl-substituted derivatives because
of the scarce information available in the literature on
the diversification of methods for the production of
1,3-dielectrophilic precursors containing this group. That
is why we have concentrated our efforts on these in this
study and have previously disclosed some individual results
now discussed in this report.38,41 Therefore, if the ketal
precursor is formed and isolated in sufficient amounts,
it is also possible to vary the trihaloacetylating agent, as
demonstrated using chlorodifluoroacetic anhydride for the
acylation of methyl 4,4-dimethoxypentanoate (Scheme 3).
ester.42,43 In this case, acetal acylation with trihaloacetylating
agents is also an attractive alternative. Obtaining acetals from
aldehydes is preferred over obtaining them from ketones.
In addition, for steric reasons in the acylated product,44,45 it
allows the use of triethyl orthoformate instead of the more
expensive trimethyl orthoformate. Therefore, we reacted
lauric aldehyde and triethyl orthoformate under tosylic acid
(TsOH) catalysis to obtain 1,1-diethoxydodecane. This
aldehyde-derived precursor was reacted with two molar
equivalents of trifluoroacetic anhydride in chloroform-
o
pyridine solution at 50 C. After 24 h under stirring, the
consumption of all precursor acetal was observed and the
reaction was quenched. The product obtained was attributed
as 3-(ethoxymethylene)-1,1,1-trifluorotridecan-2-one. In
addition, with this precursor, acylation was performed
with chlorodifluoroacetic anhydride in chloroform-pyridine
solution, leading to 1-chloro-3-(ethoxymethylene)-
1,1-difluorotridecan-2-one (Scheme 4).
As discussed above, the results obtained from
1,1-diethoxydodecane demonstrate that the substituent in
the β-carbon in the enol ether system made the acylation
process difficult, leading to a longer reaction time (24-36 h)
and making it necessary to heat the solution after adding
all the acylating agent. Experimentally, when using volatile
trifluoroacetic anhydride as the acylating agent, it is
necessary for the cooled reflux system to be very efficient
and closed. From a mechanistic point of view, this indicates
difficulty forming the C–C bond by steric-electronic
factors. This was probably due to the alkyl substituent at
the α-carbonyl carbon, which may have complicated the
ideal geometric alignment between the electronic push-pull
π orbital system in the enol ether and the acylating agent,
thereby increasing the activation energy required to achieve
the transition state for the acylated ether enol product.44
Scheme 3. Synthesis of methyl 7-chloro-7,7-difluoro-4-methoxy-6-oxo-
4-heptenoate (5m).
On the other hand, Claisen condensation of aldehyde
precursors has not been reported in the literature as far as
we have been able to confirm; in fact, auto-condensation
between aldehydes in basic medium, or aldol condensation,
competes with and is preferential over acylation with an

Vol. 00, No. 00, 2019
Bareño et al.
5
Scheme 4. Acetal acylation applied to 1,1-diethoxydodecane.
Hydrolysis of 1,1,1-trihalo-4-methoxyalk-3-en-2-ones
of complete conversion to the respective trihalomethyl-
β-diketones. As previously reported for 1,1,1-trichloro-
4-methoxyalk-3-en-2-ones 4a-f,38 one-pot acylation and
hydrolysis in acid medium only produced a mixture of
1,1,1-trichloro-4-methoxyalk-3-en-2-one and the respective
trichloromethyl-β-diketone in different proportions
depending on the precursor.
Keeping in mind the possibility of diversifying
trihalomethyl-β-diketones via the hydrolysis of 4-alkoxy-
1,1,1-trihaloalk-3-en-2-ones,46 presenting an alternative
to the acylation of enolates with perfluorinated esters,
we proceeded in two ways to obtain the respective
trihalomethyl-1,3-diketones from the hydrolysis of the
series of new 1,1,1-trihalo-4-methoxyalk-3-en-2-ones.
First, we conducted one-pot reactions to acylate the
acetals and isolate 4-alkoxy-1,1,1-trihaloalk-3-en-2-one,
which was then reacted with sulfuric acid solution; acetal
acylation was continued and then subsequent hydrolysis
of 1,1,1-trihalo-4-methoxyalk-3-en-2-one with sulfuric
acid solution was carried out (Scheme 5). Hydrolysis was
performed in 1 to 3 mol L-1 sulfuric acid solution for 2 h
Attempts to hydrolyze the isolated 1,1,1-trifluoro(chloro)-
4-methoxyalk-3-en-2-ones 3,4a-g were not successful
even under conditions using acetonitrile to homogenize
the reaction medium. Table 1 shows the reaction media
used in the attempt to obtain the 1,1,1-trifluoro(chloro)
undecan-2,4-dione derivatives 5,6a from 1,1,1-trihalo-
4-methoxyundec-3-en-2-ones 3,4a. These reaction media
worked well for phenethyl-like derivatives 3,4h-j and for
the derivatives substituted with the thiomethyl group 3,4k.
For strongly acid-sensitive functional groups containing
1,1,1-trihalo-4-methoxyalk-3-en-2-ones (3,4g,m,n),
this process was not successful, forming in general,
polymeric products without reproducibility. It is worth
mentioning that one-pot hydrolysis of methyl 8,8,8-trifluoro-
5-methoxy-7-oxooct-5-enoate (3n) obtained 3-(4-oxo-
2,6-bis(trifluoromethyl)-4H-pyran-3-yl) propanoic acid,
derived from condensation between the hydrolyzed product,
8,8,8-trifluoro-5,7-dioxooctanoic acid, and the methyl
trifluoroacetate present in the reaction medium (Scheme 6).47
o
with stirring under a temperature between 25 to 100 C.
Diketones 5h-k were obtained as yellow to reddish oil
(see Experimental section). The results demonstrated the
viability of acid hydrolysis of 1,1,1-trihalo-4-methoxyalk-
3-en-2-ones with small alkyl chains to obtain the respective
trihalomethyl-β-diketones; however, for 1,1,1-trihalo-
4-methoxyalk-3-en-2-ones obtained from fatty ketone
precursors, this process does not work well. The low
solubility of 1,1,1-trihalo-4-methoxyalk-3-en-2-ones 3,4a-f
in aqueous acid medium probably explains the difficulty
Scheme 5. Hydrolysis of 1,1,1-trifluoro-4-methoxyalk-3-en-2-ones.

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An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives J. Braz. Chem. Soc.
Table 1. Hydrolysis methodologies tested for production of 1,1,1-trifluoro(chloro)undecan-2,4-dione derivatives and 1,1,1-trifluoro(chloro)-6-phenylhexan-
2,4-dione
entry
1a
2
Precursor
3ab
3ab
3a
Methodology
Product
Yield / %
20 mL 1 mol L-1 H2SO4, 25 to 100 oC
3a
–
–
20 mL 1 mol L-1 H2SO4, CH3CN, 100 oC
20 mL 1 mol L-1 H2SO4, 25% (m/v) PyH+CF3CO2–, 100 oC
20 mL 5 mol L-1 H2SO4, 25% (m/v) PyH+CF3CO2–, 100 oC
20 mL 1 mol L-1 H2SO4, 25 to 100 oC
3a
3a
4a
5
3a
–
3a
3a + 5a (2:1)
87
92
–
4ab
4ab
4a
4a + 6a (2:1)
6
20 mL 1 mol L-1 H2SO4, CH3CN, 100 oC
20 mL 5 mol L-1 H2SO4, 25% (m/v) PyH+CF3CO2–, 100 oC
20 mL 1 mol L-1 H2SO4, 25 to 100 oC
4a
7a
8
4a + 6a (1:1)
–
3h
5h
5h
6h
95
92
95
9
3h
20 mL 1 mol L-1 H2SO4, CH3CN, 100 oC
20 mL 1 mol L-1 H2SO4, 25 to 100 oC
10
4h
aOne-pot procedure; bafter isolation of oily precursor 3a or 4a.
Trichloromethyl-substituted derivative 4 also showed a
set of characteristic signals for the nuclei of the constituent
atoms of the enone entity, in addition to the characteristic
signals for each substituent coming from the precursor
methyl ketones. In these compounds, the 1H NMR spectra
showed common characteristics including singlet signals
from vinylic H-3 (H-5 for ester 4m, and H-6 for ester
4n) at high-field d 5.9 to 6.0 ppm and the methoxy group
at d 3.8-4.0 ppm; both were more deshielded than the
respective trifluoromethyl-substituted derivatives, and the
other signals were due to the alkyl from the starting ketone.
Further support for acylated products was provided by the
13C NMR spectra. Pattern 4g showed high-field signals
from carbonyl C-2 and enol ether C-4 at d 179.9 and
183.3 ppm, respectively. There was a signal from vinylic
C-3 at d 90.2 ppm, a short signal from CCl3 at d 98.0 ppm,
an intense signal from the methoxy group at d 56.2 ppm,
signals from methylenes at d 35.3 and 25.7 ppm, and
signals at d 132.8, 122.5, 25.6, and 17.6 ppm from the
other carbons in the substituent chain (see Supplementary
Information (SI) section).
Scheme 6. Condensation during hydrolysis.
1H, 13C, and 19F nuclear magnetic resonance (NMR)
attribution
The molecular structures of the alkoxy alkenones
were characterized based on NMR spectroscopy and mass
spectrometry (MS) data. The electron impact ionization
(EI) MS or exact mass recorded by high-resolution
measurements as well as the signal pattern of NMR
spectra confirmed the products obtained. In the case of
trifluoroacylated ketones, the 1,1,1-trifluoro-4-methoxyalk-
1
3-en-2-ones 3a-n, the H NMR spectra showed common
characteristics including singlet signals from vinylic H-3
(H-5 for ester 3m, and H-6 for ester 3n) at d 5.6 to 5.7 ppm
and the methoxy group at d 3.78-3.79 ppm; other signals
were due to alkyl from the starting ketone. The 13C NMR
spectra included signals from methoxyenone carbons C-1
to C-4 (C-4 to C-7 to ester 3m, and C-5 to C-8 to ester
3n), and a signal from the methoxy group. C-1 and C-2
appeared as quartets at d 116-117 ppm with 1JCF 292 Hz, and
d 178-179 ppm with 2JCF 34 Hz, respectively; C-3 appeared
at d 91-92 ppm; and C-4 appeared at d 182 to 185 ppm, with
spectra obtained for 1,1,1-trifluoro-4-methoxy-8-methyl
non-3,7-dien-2-one (3g) (Figure 3). The 19F NMR data were
compatible with already observed chemical shift values
for α,β-unsaturated trifluoromethyl ketones or enolized
trifluoromethyl-β-diketones ranging from –78 to –76 ppm
to trifluoromethyl substituted series 3 and 5.48
1
The H NMR spectra for 3-(ethoxymethylene)-
1,1,1-trihalotridecan-2-one showed characteristic signals of
the enone system, including a signal from vinylic hydrogen
at d 7.5 to 8.0 ppm, one from the ethoxy group at d 1.39
(t, JHH 6.8 Hz) and 4.2 ppm (q, JHH 6.8 Hz), and the pattern
signal set of a ten-carbon fatty chain (see SI section).
13C NMR data indicated that the enone C-2 was the more
deshielded signal at d 179.7 ppm with 2JCF 34 Hz; the signal
4
from C-4 at d 164.2 ppm was a quartet with JCF 5 Hz;
and the signals from CF3 and C-3 appeared at d 117.0 and
117.1 ppm, respectively, forming an interesting set, a large
quartet with JCF 291 Hz and an intense signal almost in the
middle (see SI section).

Vol. 00, No. 00, 2019
Bareño et al.
7
Figure 3. 13C{H} NMR spectra from mixture 4a + 6a.

8
An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives J. Braz. Chem. Soc.
For the series of 6-aryl-1,1,1-trifluorohexan-2,4-diones
for 6h, together with methylene multiplets at 2.71 and
2.98 ppm and phenyl hydrogens as a broad multiplet
at 7.18-7.30 ppm, demonstrating the presence of an
enone (keto-enol) form in CDCl3 solution. The 1H NMR
spectrum from 6k showed that this hydrolyzed product
exists in an enone form as well as in a diketo form when in
CDCl3 solution. The signal from vinylic H-3 was a singlet
at d 6.28 ppm, and doublet signals at d 4.28 and 4.43 ppm
were attributed to diastereotopic methylene between the
two carbonyls of the diketo form, with a geminal coupling
constant of JHH 16.4 Hz. Besides the two quartets from
H-5 at d 3.39 and 3.51 ppm with JHH 7.0 Hz, at a 3:1 ratio
between the enone and keto forms, the spectrum showed
two singlet signals from the thiomethyl group and two
doublets from the terminal CH3.
5h-j obtained from acid hydrolysis of the 6-aryl-
1,1,1-trifluoro-4-methoxyhex-3-en-2-ones 3h-j, in which
the substituents were not susceptible to the acid medium
1
used, the spectrum pattern for H NMR showed, as the
most remarkable characteristic, the disappearance of the
signal due to the methoxy group. The H-3 signal was
slightly deshielded to 5.9 ppm, and the enolic OH was not
clearly observed due to fast exchange with residual water
in the CDCl3. The 13C NMR spectra presented very evident
differences in chemical shifts, C–F coupling constants, and
multiplicity of the signals from the enone system carbons.
For example, the signal for C-2 in enone 3h appeared at
3
d 178.9 ppm with JCF 33 Hz, whereas in the diketone
5h the signal for C-2 was shielded by 4 ppm appearing
2
at d 174.8 ppm with JCF 36 Hz. The C-4 in enone 3h
Here we also present the 13C{1H} spectrum of the 4a / 6a
mixture to demonstrate that, in the trichloroacetylated
derivatives 4 and 6, a different trend was observed for
the chemical shifts of the carbon nuclei when comparing
enone and diketone trifluoroacetylated derivatives, 3 and
5, respectively. The signal for C-2 in enone 4a appeared at
d 179.8 ppm without hydrogen coupling, whereas in the
diketone 6a the signal for C-2 was deshielded by 5 ppm
appearing at d 185.3 ppm with 2JCH 3 Hz. The C-4 in enone
4a appeared at d 183.9 ppm while the C-4 in the diketone
6a was deshielded by 6 ppm at d 190.6 ppm. The signals
for CCl3 carbon appeared at d 98 and 94.8 ppm for enone
and diketone, respectively. C-3 signals included a doublet
at 89.6 ppm with JCH 158 Hz for enone 4a and a doublet
appeared at d 184.4 ppm while the C-4 in the diketone 5h
was deshielded by 12 ppm at d 196.5 ppm.
The signals for CF3 carbon appeared at d 117.1 ppm for
both enone and diketone, nevertheless the JCF values differed
by 10 Hz, with 292 Hz for CF3 in enone 3h and 282 Hz in
diketone 5h.Also important was the chemical shift variance
and coupling constant 3JCF of C-3 in the diketone product
relative to enone, as it appeared at 91.7 ppm without CF
coupling for 3h and was deshielded at d 96.2 ppm with
3JCF 2 Hz for diketone 5h. The trifluoromethyl-β-diketones
showed a remarkable preference for keto-enol forms in
CDCl3, with the intramolecular hydrogen bond.
When R = alkyl groups, as the series synthesized
here, the dynamic equilibrium constant between forms
A and B (Figure 4) is near unity.6 However, considering
the correlation between CF coupling constants and
alkene configuration described by Bégué et al.45 for
trifluoromethylated vinyl compounds, we can conclude
that the keto-enol form preferred is A, because we
observed a 3JCF around 2.0 Hz for isolated product 5. The
methoxy group in enone 3 fixed the resonant push-pull
system and caused the adoption of a geometry that does
not favor coupling between C-3 and the F atoms of the
trifluoromethyl group.
3
of triplets at 92.1 ppm with JCH 170 Hz and JCH 3 Hz in
diketone 6a (Figure 3).
[3 + 2] Cyclocondensation of 1,1,1-trihalo-4-methoxyalk-
3-en-2-ones and their respective trihalomethyl-β-diketones
and hydroxilamine
The experimental procedure for these cyclocondensation
reactions is very simple and allows the use of green
solvents to an extent. Our experiments showed that the
reaction between hydroxylamine hydrochloride and
1,1,1-trihalomethyl-4-alkoxy-3-alken-2-ones 3 or 4, leading
to 5-hydroxy-5-trihalomethyl-4,5-dihydroisoxazoles 8 or 9,
can be catalyzed by bases or acids. The reaction medium
pH is around 7-8 starting from a mixture with equimolar
amounts of NaOH and hydroxylamine hydrochloride
and dielectrophile precursor (8 or 9) in water, methanol,
or ethanol, reacting under neutral conditions. The
mixture pH is around 1-2 in water, methanol, or ethanol,
when starting from a mixture of only hydroxylamine
hydrochloride and dielectrophile precursor, without
adding other promoters. All of these reaction media led to
Figure 4. Keto-enol tautomeric forms for diketones 5h-k.
1
For trichloromethyl-β-diketones, the H NMR
spectrum showed signals from H-3 as a singlet at 6.0 ppm

Vol. 00, No. 00, 2019
Bareño et al.
9
the same products, namely, 5-hydroxy-5-trihalomethyl-
4,5-dihydroisoxazole 8 or 9, and at very similar yields.
Similar results were obtained when the dielectrophilic
precursor in cyclocondensation with hydroxylamine was
a trihalomethyl-β-diketone 5 or 6. Caution must be taken
not to add NaOH to the trichloromethyl-β-diketone, which
causes the haloform reaction.49
prove that, during the process of cyclocondensation, there
is an intermediate that allows the closure of the hemicetal
entity in the C-5 by Re or Si faces (Figure 5).
The 1H NMR spectrum of 9g displayed dihydroisoxazole
H-4 diasterotopic hydrogens as an AB system, with
doublets at d 3.2 and 3.63 ppm and a geminal coupling
2
constant at J 18.8 Hz. The H-4 that is cis to CCl3 was
The cyclization of trifluoromethyl-1,3-dielectrophiles
3h-l or trichloromethyl-1,3-dielectrophilic precursors
4a-h, 4k-n with hydroxylamine hydrochloride
attributed to the downfield doublet d 3.63 ppm, whereas
4-H, which is cis to the hydroxyl group, was attributed to
the upfield doublet d 3.20 ppm. For the 2a-f series, the
other 1H NMR signals were characteristic of the saturated
fatty chain at 3-position of the isoxazole ring, with a
triplet from α-methylene at d 2.41 ppm, a quintet from
β-methylene at d 1.60 ppm, a broad signal from internal
methylenes at d 1.35 ppm, and a triplet from the terminal
methyl at d 0.80 ppm. The 13C NMR spectra of 5-hydroxy-
5-trichloromethyl-4,5-dihydroisoxazoles displayed C-3,
C-4, and C-5 signals at approximately d 160, 46, and
110.4 ppm, respectively. The CCl3 carbon displayed a
characteristic small signal at approximately d 101 ppm, and
the saturated fatty substituent gave rise to a set of signals
at a high field, between d 14 and 32 ppm.
o
proceeded smoothly in EtOH at 50 C for 4-8 h.
Because ethanol functions with the entire set of
trihalomethyl-1,3-dielectrophiles studied in this work,
it was chosen as the solvent, although cyclization of
1,1,1-trichloromethyl-4-methoxy-3-alken-2-ones to
the isoxazoles has already been done in water.50 After
completion of the reaction, the solvent was evaporated,
and solid residues were purified by recrystallization from
hexane. White solids with a fibrous texture were obtained
in isolated yields of 85-90% and attributed as 5-hydroxy-
5-trifluoromethyl-4,5-dihydroisoxazoles 8g,h,k-m or
5-hydroxy-5-trichloromethyl-4,5-dihydroisoxazoles
9a-c,f-h,k,m (Scheme 7), which were fully characterized
by NMR spectroscopy and electrospray ionization (ESI)
high-resolution mass spectrometry (HRMS).
The details of the spectroscopic data for
5-hydroxy-3-(4-methyl-3-pentenyl)-5-trichloromethyl-
4,5-dihydroisoxazol (9g) are shown in the Experimental
section.
The 1H NMR spectrum of 5-hydroxy-5-trifluoromethyl-
4,5-dihydroisoxazole 8l exhibited only one set of signals:
the characteristic two doublets at d 3.0 and 3.22 ppm with
The compounds 9a-c,e,f were dehydrated in 98%
H2SO4 to produce trichloromethyl-substituted isoxazoles
11a-c,e,f (Scheme 7). Aromatization occurred smoothly
2
germinal JHH 18.4 Hz for the diastereotopic hydrogens
o
at the 4-position of the isoxazole ring. In addition,
there were signals from the hydrogens of the methoxy
group as a singlet at d 3.86 ppm, from the methylene
in the benzyl entity as a singlet at d 3.77 ppm, and
from aromatic ring between 6.91 and 7.32 ppm (see SI
section). However, the 4,5-dihydroisoxazoles 8k,9k were
a mixture of disteroisomers, because we started from
3-thiomethyl-2-butanone as a racemate. For example, the
1H NMR spectrum for 9k displayed two sets of signals for
diastereotopic H-4 with large variation in chemical shifts,
four doublets at d 3.37, 3.99, 3.78 and 3.88 ppm. These data
at 25 C, and white needle compounds (9) readily
dissolved in concentrated sulfuric acid, forming slightly
yellowish solutions. These were maintained under stirring
for a further 2 h. Then the reaction was treated with
ice water and extracted twice with ethyl acetate. The
solvent was evaporated to obtain yellowish oil residues
at excellent yields (> 90%); these were assigned as
5-trichloromethylisoxazole 11. The compound was also
characterized by its 1H / 13C NMR spectra, which displayed
a characteristic singlet signal at around d 6.47 ppm;
furthermore, the signals for isoxazole carbons C-3, C-4,
Scheme 7. Cyclocondensation to trihalomethylisoxazole derivatives.

10
An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives J. Braz. Chem. Soc.
Figure 5. 1H and 13C (acetone-d6) NMR spectra of two diatereoisomeric pair mixtures of isoxazole 9k.
and C-5 in compound 11 appeared at d 164, 103, and
168 ppm, respectively.
The dehydration reaction of 5-trichloromethyl-
4,5-dihydroisoxazoles in acidic media is a second-order

Vol. 00, No. 00, 2019
Bareño et al.
11
elimination reaction [E2 (E1-like)], in which the stability
of the activated complex depends on the participation of
the electron pair of the neighboring oxygen atom (O-1)
in the isoxazole ring and on the electron-donating effects
of the group attached to the C-5 of the isoxazole ring.51
Attempts to conduct the reaction until complete conversion
of the trichloromethyl group into the carboxyl acid-ester
were unsuccessful. For example, a reaction between 4c and
NH2OH.HCl in EtOH and a 30% sulfuric acid solution under
reflux for 8 to 20 h produced a mixture of products consisting
of a 53% majority of 5-trichloromethyl-5-hydroxy-
4,5-dihydroisoxazole (9c), 20% 5-trichloromethylisoxazole
(11c), 21% 3-trichloromethylisoxazole (12c), and 6%
isoxazole-5-carboxylic acid (13c) (Scheme 8, Figure 6).
[CCC + NN] cyclocondensation of alkenones 3-6 and
hydrazine for 1H-pyrazole derivatives was also simple,
allowing the use of ecofriendly ethanol. The reaction
between hydrazine hydrochloride and 1,1,1-trifluoromethyl-
4-alkoxy-3-alken-2-ones 3h,j, leading to tautomeric
5(3)-trifluoromethyl-1H-pyrazoles 12h,j, occurred
smoothly and efficiently. The reaction medium pH was
around 3.5 to 4.0 starting from a mixture with equimolar
amounts of hydrazine hydrochloride and precursors 3h,j
in ethanol, reacting in a slightly acidic medium. The
mixture pH was around 5-6 in ethanol, when starting
from β-diketone precursor 5h,j without adding other
promoters (Scheme 9). Both precursors 3 and 5 led to the
same product, 5(3)-trifluoromethyl-1H-pyrazoles 12h,j,
in very similar quantitative yields. The 1H-pyrazoles were
1
[3 + 2] Cyclocondensation of 1,1,1-trihalo-4-methoxyalk-3-
en-2-ones and their respective trihalomethyl-β-diketones
with hydrazine and hydrazides
identified by H, 13C and 19F NMR spectroscopy and by
1
MS. The H NMR spectrum of the 5(3)-trifluoromethyl-
3(5)-(2-phenylethyl)-1H-pyrazole (12h) displayed an
aromatic H4 at d 6.3 ppm, signals from the ethylene spacer
as a coalescent multiplet at d 2.99 ppm, and signals from
aromatic hydrogens as multiplets at d 7.17 and 7.29 ppm.
The 13C NMR data also conformed to the structure of 12h,
with signals from pyrazole cycle C3 at d 144.7 ppm, C5
at d 143.0 ppm with 2JCF 38 Hz, and C4 at 102.2 ppm with
3JCF 1.5 Hz, along with signals from a phenyl ring at d 139.9,
128.7, 128.3, and 126.6 ppm, a remarkable quartet from CF3
at 121.3 ppm with JCF 268 Hz, and signals from an ethylene
spacer at d 35.0 and 27.1 ppm. Finally, the 19F NMR spectra
showed a singlet signal at d –62 to –62.1 ppm, which
is typical for trifluoromethyl group in the predominant
tautomer 3-trifluoromethyl-5-phenylethyl-1H-pyrazole.52
The reaction between 4h or 6h and NH2NH2.HCl
in alcohol solvent, ethanol, or 2-methoxyethanol, was
conducted at the reflux temperature of the solvent for
The experimental procedure for 1H-pyrazole derivative
cyclocondensation is also simple, allowing the use of
ecofriendly ethanol. The reaction between hydrazine
hydrochloride and 1,1,1-trifluoromethyl-4-alkoxy-
3-alken-2-ones 3h,j, leading to 5(3)-trifluoromethyl-
1H-pyrazoles 12h,j, occurred smoothly and efficiently.
The reaction medium pH was around 3.0 to 3.5 starting
from a mixture with equimolar amounts of hydrazine
hydrochloride and dielectrophile precursors 3h,j in ethanol,
reacting in a slightly acidic medium. The mixture pH was
around 5-6 in ethanol, when starting from β-diketone
dielectrophile precursor 5h,j without adding other
promoters. Both precursors 3 and 5 led to the same product,
5(3)-trifluoromethyl-1H-pyrazoles 12h,j, in very similar
quantitative yields.
Scheme 8. Cyclocondensation with NH2OH in EtOH / H2SO4 solution.

12
An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives J. Braz. Chem. Soc.
Figure 6. 1H NMR spectrum of a mixture obtained from a reaction between 4c and NH2OH.HCl in 30% H2SO4.
5-10 h. Then the solvent was distilled off and the solid
residue was characterized by NMR as alkyl 3-phenethyl-
1H-pyrazole 5-carboxylate (Scheme 9). The [3 + 2]
cyclocondensation performed in an alcohol solvent
according to a previously described method led to the
intermediate aromatic 5(3)-trichloromethyl-1H-pyrazole;
thereafter, the trichloromethyl group was hydrolyzed,
leading to 1H-pyrazole-5(3)-carboxylates.38,41

Vol. 00, No. 00, 2019
Bareño et al.
13
Scheme 9. Cyclocondensation to trifluoromethyl-1H-pyrazole derivatives.
The 1H-pyrazole-5(3)-carboxylates were identified by
shifts are expressed in ppm and coupling constants in Hz.
The following NMR abbreviations were used: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet,
dd = doublet of doublet. Melting points were determined
using open capillaries on a Fisatom 431 apparatus and are
uncorrected. HRMS analyses: the compounds were dissolved
in acetonitrile (Merck, West Point, USA) and deionized water
(50% (v/v) with 0.1% formic acid. The dissolved compounds
were injected individually into the ESI source using a syringe
pump (Harvard Apparatus) at a flow rate of 150 μL min-1.
ESI(+)-MS and tandem ESI(+)-MS/MS data were acquired
using a hybrid high-resolution and high-accuracy (5 μL L-1)
microTof (quadrupole time of flight (QTOF)) MS (Bruker
Scientific). Conditions: cone voltages were set to +3500
and +40 V, respectively, with a de-solvation temperature
1H and C NMR spectroscopy and by MS. The H NMR
spectrum of the 3(5)-(2-phenylethyl)-1H-pyrazole-
5(3)-carboxylates (15,16h) displayed an aromatic H4 at
d6.6 ppm, signals from the ethylene spacer between pyrazole
and phenyl rings as multiplets at d 2.95 and 3.15 ppm, and
signals from aromatic hydrogens as multiplets at d 7.12
and 7.25 ppm, in addition to the characteristic signals of
the alkyl substituent from alcohol. The 13C NMR data also
confirmed the structure of 3(5)-(2-phenylethyl)-1H-pyrazole-
5(3)-carboxylates (15,16h); signals from the pyrazole
cycle at d 149, 138, and 107-108 ppm; from a phenyl ring
at d 139-140, 128, and 126 ppm; from carboxyl ester at d
156-157 ppm; and from the ethylene spacer at d 34-35 and
27-28 ppm.
13
1
o
of 100 C. For ESI (+)-MS/MS, the energy (between 5
Conclusions
and 40 eV) for collision-induced dissociation (CID) was
optimized for each component. Diagnostic ions were
identified by comparing the measurements to theoretical
ESI(+)-MS/MS data. EI-MS were registered in an HP 5973
MSD connected to an HP 6890 GC and interfaced with a
Pentium PC. The GC was equipped with a split-splitless
injector and an auto-sampler cross-linked HP-5 capillary
column (30 m, 0.32 mm internal diameter), and helium was
used as the carrier gas.
We demonstrate the wide scope of the acetal acylation
method for production of 1,3-dielectrophiles with diverse
functionalized substituents, including prenyl. This method
allows the formation of C-C bonds through acylation in a
mild acidic medium, allowing precursors with groups that
are vulnerable to attack by bases. The 1,3-dielectrophilic
products (4-alkoxy-1,1,1-trihaloalk-3-en-2-ones or
1,1,1-trihaloalkan-2,4-diones) are important precursors in
the preparation of 1,2-azole heterocycles, and herein we
report isoxazoles and 1H-pyrazoles with prenyl, phenethyl,
and substituted phenethyl entities, and a series with neutral
amphiphilic molecular structures.
Acetal acylation methodology
1,1,1-Trihalo-4-methoxy-3-alken-2-ones
To a stirred solution of dimethoxy acetal derived
from precursor ketones 1a-n (30 mmol) and pyridine
(60 mmol, 4.8 g) in CHCl3 (30 mL) kept at 0 oC, a solution
of trichloroacetyl chloride (60 mmol, 6.8 mL) in CHCl3
Experimental
Unless indicated otherwise, all common reagents were
used as obtained from commercial suppliers without further
purification. Yields listed are of isolated compounds. H,
13C, and 19F NMR spectra were acquired on a Bruker
DPX 200, Bruker DPX 400, or Ascend 400 spectrometer
at 300 K, using 5 mm sample tubes, and with a digital
resolution of 0.01 ppm. CDCl3 was used as a solvent with
tetramethylsilane (TMS) as the internal standard. Chemical
o
(20 mL) was added dropwise at –5 C. The mixture was
stirred for 8-12 h at room temperature (25-30 oC).After the
mixture was quenched with a 2 M HCl solution (30 mL),
the organic layer was separated and dried with Na2SO4,
the solvent was evaporated, and the residue was distilled
to remove methyl trichloroacetate. The products 2a-g were
obtained as black oil with high purity.
1

14
An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives J. Braz. Chem. Soc.
1,1,1-Trifluoro-4-methoxyundec-3-en-2-one (3a)
Yield 88%, reddish oil; IR (film) νmax / cm-1 3089,
2926, 2908, 1592, 1568, 1493, 1455, 1255, 1081; 1H NMR
(400 MHz, CDCl3) d 5.6 (1H, s, H3), 3.78 (3H, s, OMe),
2.79 (2H, t, J 7.8), 1.56 (2H, m, J 7.7), 1.32-1.27 (8H, br
m, (CH2)4), 0.88 (3H, t, J 6.7, CH3); 13C NMR (100 MHz,
CDCl3) d 185.5 (C4), 178.4 (C2, q, JCF 34), 116.7 (C1, q,
JCF 292), 91.0 (C3), 56.4 (OMe), 33.9, 31.6, 29.3, 28.9,
26.8, 22.5 (CH2), 13.9 (CH3); HRMS (ESI) m/z, calcd. for
C12H20F3O2 [M + H]+: 253.1415, found: 253.1437; anal.
calcd. for C12H19F3O2: C 57.13, H 7.59, found: C 57.21,
H 7.65.
1,1,1-Trifluoro-4-methoxypentadec-3-en-2-one (3e)
Yield 91%, reddish oil; IR (film) νmax / cm-1 3094,
2931, 2885, 1590, 1575, 1495, 1462, 1249, 1085; 1H NMR
(400 MHz, CDCl3) d 5.64 (1H, s, H3), 3.80 (3H, s, OMe),
2.80 (2H, t, J 7.8), 1.57 (2H, m, J 7.7), 1.36-1.27 (16H, br
m, (CH2)8), 0.89 (3H, t, J 7.0, CH3); 13C NMR (100 MHz,
CDCl3) d 185.4 (C4), 178.4 (C2, q, JCF 33), 116.8 (C1, q,
JCF 292), 91.0 (C3), 56.4 (OMe), 33.8, 31.9, 29.5, 29.4,
29.3, 29.2, 28.9, 26.9, 22.6 (CH2), 13.9 (CH3); HRMS
(ESI) m/z, calcd. for C16H28F3O2 [M + H]+: 309.2041, found:
309.2073; anal. calcd. for C16H27F3O2: C 62.32, H 8.83,
found: C 62.30, H 8.89.
1,1,1-Trifluoro-4-methoxydodec-3-en-2-one (3b)
Yield 90%, reddish oil; IR (film) νmax / cm-1 3090,
2930, 2895, 1595, 1568, 1495, 1455, 1255, 1081; 1H NMR
(400 MHz, CDCl3) d 5.63 (1H, s, H3), 3.80 (3H, s, OMe),
2.80 (2H, t, J 7.8), 1.58 (2H, m, J 7.7), 1.37-1.27 (10H, br
m, (CH2)5), 0.89 (3H, t, J 6.7, CH3); 13C NMR (100 MHz,
CDCl3) d 185.5 (C4), 178.4 (C2, q, JCF 33), 116.7 (C1, q,
JCF 292), 91.0 (C3), 56.4 (OMe), 33.8, 31.7, 29.3, 29.2, 29.1,
26.8, 22.6 (CH2), 13.9 (CH3); HRMS (ESI) m/z, calcd. for
C13H22F3O2 [M + H]+: 267.1572, found: 267.1607; anal.
calcd. for C13H21F3O2: C 58.63, H 7.95, found: C 58.55,
H 8.05.
1,1,1-Trifluoro-4-methoxyheptadec-3-en-2-one (3f)
Yield 92%, reddish oil; IR (film) νmax / cm-1 3090,
2919, 2885, 1595, 1571, 1493, 1460, 1255, 1079; 1H NMR
(400 MHz, CDCl3) d 5.64 (1H, s, H3), 3.80 (3H, s, OMe),
2.80 (2H, t, J 7.8), 1.57 (2H, m, J 7.7), 1.38-1.28 (20H, br
m, (CH2)10), 0.89 (3H, t, J 7.0); 13C NMR (100 MHz, CDCl3)
d 185.4 (C4), 178.4 (C2, q, JCF 33), 116.8 (C1, q, JCF 292),
91.0 (C3), 56.4 (OMe), 33.9, 31.9, 29.64, 29.61, 29.5, 29.4,
29.38, 29.31, 29.2, 27.0, 22.7 (CH2), 14.0 (3H, t, J 7.0,
CH3); HRMS (ESI) m/z, calcd. for C18H32F3O2 [M + H]+:
337.2354, found: 337.2369; anal. calcd. for C18H32F3O2:
C 64.26, H 9.29, found: C 64.35, H 9.42.
1,1,1-Trifluoro-4-methoxytridec-3-en-2-one (3c)
1,1,1-Trifluoro-4-methoxy-8-methylnon-3,7-dien-2-one (3g)
Yield 95%, reddish oil; IR (film) νmax / cm-1 3089,
2932, 2895, 1592, 1568, 1512, 1493, 1456, 1265, 1085;
1H NMR (400 MHz, CDCl3) d 5.62 (1H, s, H3), 5.12
(1H, t, J 7.6, H7), 3.78 (3H, s, OMe), 2.82 (2H, t, J 7.8),
2.24 (2H, q, J 7.7), 1.68 (3H, s, CH3), 1.61 (3H, s, CH3);
13C NMR (100 MHz, CDCl3) d 184.6 (C4), 178.4 (C2, q,
JCF 34), 133.1 (C8), 122.3 (C7), 116.7 (C1, q, JCF 292), 91.1
(C3), 56.4 (OMe), 33.9 (C5), 25.5 (CH3), 25.3 (C6), 17.4
(CH3); HRMS (ESI) m/z, calcd. for C11H16F3O2 [M + H]+:
237.1102, found: 237.1127; anal. calcd. for C11H15F3O2:
C 55.93, H 6.40, found: C 56.08, H, 6.58.
Yield 89%, reddish oil; IR (film) νmax / cm-1 3089,
2932, 2889, 1592, 1571, 1493, 1457, 1258, 1086; 1H NMR
(400 MHz, CDCl3) d 5.63 (1H, s, H3), 3.78 (3H, s, OMe),
2.80 (2H, t, J 7.7), 1.56 (2H, m, J 7.7), 1.37-1.27 (12H, br
m, (CH2)6), 0.88 (3H, t, J 6.7, CH3); 13C NMR (100 MHz,
CDCl3) d 185.7 (C4), 178.4 (C2, q, JCF 33), 116.8 (C1, q,
JCF 292), 91.0 (C3), 56.7 (OMe), 33.8, 31.8, 29.4, 29.3,
29.2, 28.9, 26.9, 22.6 (CH2), 13.9 (CH3); HRMS (ESI)
m/z, calcd. for C14H24F3O2 [M + H]+: 281.1728, found:
281.1762; anal. calcd. for C14H23F3O2: C 59.98, H 8.27,
found: C 60.07, H 8.38.
1,1,1-Trifluoro-4-methoxytetradec-3-en-2-one (3d)
Yield 90%, reddish oil; IR (film) νmax / cm-1 3095,
2932, 2881, 1591, 1570, 1493, 1465, 1258, 1085; 1H NMR
(400 MHz, CDCl3) d 5.64 (1H, s, H3), 3.78 (3H, s, OMe),
2.79 (2H, t, J 7.8), 1.56 (2H, m, J 7.6), 1.36-1.27 (16H, br
m, (CH2)8), 0.88 (3H, t, J 7.0, CH3); 13C NMR (100 MHz,
CDCl3) d 185.4 (C4), 178.4 (C2, q, JCF 33), 116.8 (C1, q,
JCF 292), 91.0 (C3), 56.5 (OMe), 33.8, 31.9, 29.5, 29.4,
29.3, 29.2, 28.9, 26.9, 22.6 (CH2), 13.9 (CH3); HRMS
(ESI) m/z, calcd. for C15H26F3O2 [M + H]+: 295.1885, found:
295.1914; anal. calcd. for C15H25F3O2: C 61.21, H, 8.56,
found: C 61.27, H 8.66.
1,1,1-Trifluoro-4-methoxy-6-phenylhex-3-en-2-one (3h)
Yield 95%, reddish oil; IR (film) νmax / cm-1 3090, 3075,
2940, 2910, 1595, 1587, 1560, 1495, 1465, 1265, 1103,
1090; 1H NMR (400 MHz, CDCl3) d 7.35-7.23 (5H, m, Ph),
5.71 (1H, s, H3), 3.80 (3H, s, OMe), 3.14 (2H, m, CH2),
2.91 (2H, m, CH2); 13C NMR (100 MHz, CDCl3) d 184.4
(C4), 178.9 (C2, q, JCF 33), 140.8, 128.8, 126.6 (Ph), 117.1
(C1, q, JCF 292), 91.7 (C3), 56.9 (OMe), 36.4 (CH2), 33.3
(CH2); HRMS (ESI) m/z, calcd. for C13H14F3O2 [M + H]+:
259.0946, found: 259.1006; anal. calcd. for C13H13F3O2:
C 60.46, H 5.07, found: C 60.45, H, 5.17.

Vol. 00, No. 00, 2019
Bareño et al.
15
1,1,1-Trifluoro-4-methoxy-6-(4-hydroxyphenyl)hex-3-en-
2-one (3i)
q, JCF 33), 157.6, 132.6, 129.6, 115.2 (Ph), 116.7 (C1, q,
JCF 292), 91.4 (C3), 56.6 (OMe), 36.3 (CH2), 32.1 (CH2);
19F NMR (376 MHz, CDCl3) d –78.1 (CF3); HRMS (ESI)
m/z, calcd. for C13H14F3O3 [M + H]+: 275.0895, found:
275.0916; anal. calcd. for C13H13F3O3: C 56.94, H 4.78,
found: C 57.10, H 4.85.
Yield 93%, reddish oil; IR (film) νmax / cm-1 3350, 3070,
2930, 2887, 1592, 1570, 1495, 1450, 1245, 1105, 1090;
1H NMR (400 MHz, CDCl3) d 7.14 (2H, d, J 8.5, Ph), 6.78
(2H, d, J 8.5, Ph), 5.67 (1H, s, H3), 3.80 (3H, s, OMe), 3.07
(2H, m, CH2), 2.80 (2H, m, CH2); 13C NMR (100 MHz,
CDCl3) d 184.3 (C4), 178.6 (C2, q, JCF 33), 154.8, 132.6,
129.6, 115.2 (Ph), 116.7 (C1, q, JCF 292), 91.4 (C3), 56.6
(OMe), 36.3 (CH2), 32.1 (CH2); HRMS (ESI) m/z, calcd.
for C13H14F3O3 [M + H]+: 275.0895, found: 275.0904; anal.
calcd. for C13H13F3O3: C 56.94, H 4.78, found: C 57.10,
H, 4.85.
Methyl 7,7,7-trifluoro-4-methoxy-6-oxohept-4-enoate (3m)
Yield 90%, yellowish oil; IR (film) νmax / cm-1 3090,
3045, 2936, 2885, 1690, 1592, 1570, 1495, 1460, 1270,
1
1120, 1085; H NMR (400 MHz, CDCl3) d 5.73 (1H, s,
H5), 3.83 (3H, s, OMe), 3.67 (3H, s, OMe), 3.16 (2H, m,
CH2), 2.59 (2H, m, CH2); 13C NMR (100 MHz, CDCl3)
d 182.3 (C4), 178.3 (C6, q, JCF 33), 172.2 (C1), 116.8
(C7, q, JCF 292), 91.3 (C5), 56.6 (OMe), 51.4 (OMe), 29.8
(CH2), 29.0 (CH2); 19F NMR (376 MHz, CDCl3) d –78.1
(CF3); HRMS (ESI) m/z, calcd. for C9H12F3O4 [M + H]+:
241.0688, found: 241.0747; anal. calcd. for C9H11F3O4:
C 45.01, H 4.62, found: C 45.20, H 4.70.
1,1,1-Trifluoro-4-methoxy-6-(4-methoxyphenyl)hex-3-en-
2-one (3j)
Yield 95%, reddish oil; IR (film) νmax / cm-1 3089,
2926, 2878, 1592, 1568, 1493, 1455, 1255, 1081; 1H NMR
(400 MHz, CDCl3) d 7.21 (2H, d, J 8.6, Ph), 6.78 (2H, d,
J 8.6, Ph), 5.70 (1H, s, H3), 3.82 (3H, s, OMe), 3.80 (3H,
s, OMe), 3.10 (2H, m, CH2), 2.85 (2H, m, CH2); 13C NMR
(100 MHz, CDCl3) d 184.2 (C4), 178.5 (C2, q, JCF 33),
158.1, 132.5, 129.4, 113.8 (Ph), 116.7 (C1, q, JCF 292), 91.3
(C3), 56.5 (OMe), 55.2 (OMe), 36.3 (CH2), 32.1 (CH2);
19F NMR (376 MHz, CDCl3) d –78.1 (CF3); HRMS (ESI)
m/z, calcd. for C14H16F3O3 [M + H]+: 289.1052, found:
289.1077; anal. calcd. for C14H15F3O2: C 58.33, H 5.25,
found: C 58.35, H 5.30.
Methyl 8,8,8-trifluoro-5-methoxy-7-oxooct-5-enoate (3n)
Yield 91%, yellow oil; IR (film) νmax / cm-1 3090, 3045,
2940, 2885, 1688, 1595, 1570, 1495, 1480, 1267, 1115, 1080;
1H NMR (400 MHz, CDCl3) d 5.66 (1H, s, H3), 3.80 (3H,
s, OMe), 3.68 (3H, s, OMe), 2.86 (2H, m, CH2), 2.38 (2H,
t, CH2), 1.91 (2H, m, CH2); 13C NMR (100 MHz, CDCl3)
d 182.3 (C5), 178.4 (C7, q, JCF 33), 172.4 (C1), 116.8 (C8, q,
JCF 292), 91.3 (C6), 56.6 (OMe), 51.3 (OMe), 29.9 (C4), 29.2
(C2), 19.1 (C3); 19F NMR (376 MHz, CDCl3) d –78.0 (3F,
s, CF3); HRMS (ESI) m/z, calcd. for C10H13F3O4 [M + H]+:
255.0844, found: 255.0898; anal. calcd. for C11H15F3O2:
C 47.25, H 5.15, found: C 47.47, H 5.30.
1,1,1-Trifluoro-4-methoxy-5-(methylthio)hex-3-en-2-one
(3k)
Yield 95%, yellow oil; IR (film) νmax / cm-1 3085, 2950,
2895, 2870, 1592, 1575, 1495, 1455, 1255, 1107, 1090;
1H NMR (400 MHz, CDCl3) d 5.58 (1H, s, H3), 4.95 (1H,
q, J 7.0, H5), 3.78 (3H, s, OMe), 2.04 (3H, s, SCH3), 1.35
(3H, d, CH3); 13C NMR (100 MHz, CDCl3) d 182.8 (C4),
178.1 (C2, q, JCF 34), 117.4 (C1, q, JCF 295), 90.6 (C3),
56.8 (OMe), 39.2 (C5), 16.8 (C6), 14.1 (SCH3); 19F NMR
(376 MHz, CDCl3) d –78.1 (CF3); HRMS (ESI) m/z, calcd.
for C8H12F3O2S [M + H]+: 229.0510, found: 229.0538; anal.
calcd. for C8H11F3O2S: C 42.10, H 4.86, found: C 42.17,
H 4.78.
Methyl 7-chloro-7,7-difluoro-4-methoxy-6-oxohept-4-enoate
(7m)
Yield 90%, yellowish oil; IR (film) νmax / cm-1 3087,
3046, 2943, 2882, 1687, 1591, 1570, 1496, 1458, 1270,
1
1120, 1085; H NMR (400 MHz, CDCl3) d 5.71 (1H, s,
H5), 3.82 (3H, s, OMe), 3.69 (3H, s, OMe), 3.16 (2H, m,
CH2), 2.59 (2H, m, CH2); 13C NMR (100 MHz, CDCl3)
d 182.1 (C4), 179.6 (C6, t, JCF 27), 172.3 (C1), 120.6 (C7,
t, JCF 306), 90.5 (C5), 56.7 (OMe), 51.4 (OMe), 29.9 (CH2),
29.0 (CH2); 19F NMR (376 MHz, CDCl3) d –65.0 (2F, s,
CClF2); HRMS (ESI) m/z, calcd. for C9H12ClF2O4 [M + H]+:
257.0392, found: 257.0435; anal. calcd. for C9H11ClF2O4:
C 42.12, H 4.32, found: C 42.17, H 4.30.
1,1,1-Trifluoro-4-methoxy-5-(2-methoxyphenyl)pent-3-en-
2-one (3l)
Yield 93%, yellowish oil; IR (film) νmax / cm-1 3090,
3080, 2946, 2910, 2885, 1596, 1570, 1495, 1460, 1258,
1102, 1091; 1H NMR (400 MHz, CDCl3) d 7.22 (1H, m,
Ph), 7.06 (1H, m, Ph), 6.85 (2H, m, Ph), 5.74 (1H, s, H3),
4.22 (2H, s, H5), 3.77 (3H, s, OMe), 3.65 (3H, s, OMe);
13C NMR (100 MHz, CDCl3) d 182.4 (C4), 178.5 (C2,
1,1,1-Trichloro-4-methoxy-8-methylnon-3,7-dien-2-one (4g)
Yield 95%, reddish oil; IR (film) νmax / cm-1 3092,
3075, 2926, 2883, 1592, 1580, 1495, 1458, 1265, 1118,
1091; 1H NMR (400 MHz, CDCl3) d 5.62 (1H, s, H3), 5.12

16
An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives J. Braz. Chem. Soc.
(1H, t, J 7.6, H7), 3.78 (3H, s, OMe), 2.82 (2H, t, J 7.8),
2.24 (2H, q, J 7.7), 1.68 (3H, s, CH3), 1.61 (3H, s, CH3);
13C NMR (100 MHz, CDCl3) d 184.6 (C4), 178.4 (C2, q,
JCF 34), 133.1 (C8), 122.3 (C7), 116.7 (C1, q, JCF 292), 91.1
(C3), 56.4 (OMe), 33.9 (C5), 25.5 (CH3), 25.3 (C6), 17.4
(CH3); HRMS (ESI) m/z, calcd. for C11H16Cl3O2 [M + H]+:
285.0216, 287.0286, found: 285.0234, 287.0278; anal. calcd.
for C11H15Cl3O2: C 46.26, H 5.29, found: C 46.30, H 5.43.
4.8 g) in CHCl3 (30 mL) kept at 0 oC, a solution of acylating
reagent (60 mmol: 8.4 mL trifluoroacetic anhydride,
10.5 mL chlorodifluoroacetic anhydride or 6.8 mL
trichloroacetyl chloride) in CHCl3 (20 mL) was added
o
dropwise at –5 to 10 C. Then the mixture was stirred
o
for 12-24 h under reflux (60 C). After the mixture was
quenched with a 2 M HCl solution (20 mL), the organic
layer was separated and washed twice with water and dried
with Na2SO4. The solvent was evaporated, and the residue
was distilled to remove methyl trihaloacetate byproducts.
The products 3v, 4v, and 7v were obtained as reddish to
black oil with high purity.
1,1,1-Trichloro-4-methoxy-6-phenylhex-3-en-2-one (4h)
Yield 95%, reddish oil; IR (film) νmax / cm-1 3093, 2945,
2889, 1592, 1572, 1493, 1453, 1261, 1107, 1081; 1H NMR
(400 MHz, CDCl3) d 7.35-7.23 (5H, m, Ph), 5.71 (1H, s,
H3), 3.80 (3H, s, OMe), 3.14 (2H, m, CH2), 2.91 (2H, m,
CH2); 13C NMR (100 MHz, CDCl3) d 184.4 (C4), 178.9 (C2,
q, JCF 33), 140.8, 128.8, 126.6 (Ph), 117.1 (C1, q, JCF 292),
91.7 (C3), 56.9 (OMe), 36.4 (CH2), 33.3 (CH2); HRMS
(ESI) m/z, calcd. for C13H14Cl3O2 [M + H]+: 307.0059,
309.0030, found: 307.0107, 309.0081; anal. calcd. for
C13H13Cl3O2: C 50.76, H 4.26, found: C 50.60, H 4.30.
3-(Ethoxymethylene)-1,1,1-trifluorotridecan-2-one (3v)
Yield 90%, reddish oil; IR (film) νmax / cm-1 2995,
2926, 2878, 1765, 1587, 1495, 1460, 1245, 1181; 1H NMR
(400 MHz, CDCl3) d 7.51 (1H, s, H14), 4.20 (2H, q,
J 6.9, OCH2), 2.32 (2H, t, J 7.5, H4), 1.39 (3H, t, J 6.8,
CH3), 1.30-1.24 (16H, m, CH2), 0.88 (3H, t, J 6.5, H13);
13C NMR (100 MHz, CDCl3) d 179.7 (C2, q, JCF 34), 164.2
(C14, q, JCF 5.0), 117.1 (C3), 117.0 (C1, q, JCF 291), 71.5
(OCH2), 31.9, 29.55, 29.5, 29.3, 29.29, 29.2, 27.9, 22.8,
22.6 (CH2), 15.1 (CH3), 13.9 (CH3); 19F NMR (376 MHz,
CDCl3) d –78.3 (CF3); HRMS (ESI) m/z, calcd. for
C16H28F3O2 [M + H]+: 309.2041, found: 309.2102; anal.
calcd. for C16H27F3O2: C 62.32, H 8.83, found: C 62.55,
H 8.80.
1,1,1-Trichloro-4-methoxy-5-(methylthio)hex-3-en-2-one
(4k)
Yield 95%, yellow oil; IR (film) νmax / cm-1 3089, 2926,
1
2878, 1592, 1568, 1493, 1455, 1255, 1081; H NMR
(400 MHz, CDCl3) d 5.58 (1H, s, H3), 4.95 (1H, q, J 7.0,
H5), 3.78 (3H, s, OMe), 2.04 (3H, s, SCH3), 1.35 (3H, d,
CH3); 13C NMR (100 MHz, CDCl3) d 182.8 (C4), 178.1
(C2, q, JCF 34), 117.4 (C1, q, JCF 295), 90.6 (C3), 56.8
(OMe), 39.2 (C5), 16.8 (C6), 14.1 (SCH3); HRMS (ESI)
m/z, calcd. for C8H11Cl3O2S [M + H]+: 276.9624, 278.9594,
found: 276.9686, 278.9658; anal. calcd. for C8H11Cl3O2S:
C 34.62, H 3.99, found: C 34.55, H 4.00.
1,1,1-Trichloro-3-(ethoxymethylene)tridecan-2-one (4v)
Yield 91%, black oil; IR (film) νmax / cm-1 2995, 2923,
1
2875, 1749, 1586, 1495, 1460, 1254, 1145; H NMR
(400 MHz, CDCl3) d 7.99 (1H, s, H14), 4.18 (2H, q, J 7.2,
OCH2), 2.39 (2H, t, J 7.6, H4), 1.40 (3H, t, J 7.2, CH3),
1.30-1.27 (16H, m, CH2), 0.90 (3H, t, J 6.8, H13); 13C NMR
(100 MHz, CDCl3) d 181.1 (C2), 163.5 (C14), 112.5 (C3),
96.7 (C1), 70.9 (OCH2), 31.8, 29.55, 29.5, 29.38, 29.35,
29.3, 28.1, 24.7, 22.6 (CH2), 15.4 (CH3), 14.0 (CH3); HRMS
(ESI) m/z, calcd. for C16H28Cl3O2 [M + H]+: 357.1155,
359.1125, found: 357.1205, 359.1173; anal. calcd. for
C16H27Cl3O2: C 53.72, H 7.61, found: C 53.60, H 7.60.
Methyl 7,7,7-trichloro-4-methoxy-6-oxohept-4-enoate (4m)
Yield 90%, yellowish oil; IR (film) νmax / cm-1 3089,
2935, 2880, 1728, 1595, 1570, 1490, 1470, 1265, 1120,
1085; 1H NMR (400 MHz, CDCl3) d 5.73 (1H, s, H5), 3.83
(3H, s, OMe), 3.67 (3H, s, OMe), 3.16 (2H, m, CH2), 2.59
(2H, m, CH2); 13C NMR (100 MHz, CDCl3) d 182.3 (C4),
178.3 (C6, q, JCF 33), 172.2 (C1), 116.8 (C7, q, JCF 292),
91.3 (C5), 56.6 (OMe), 51.4 (OMe), 29.8 (CH2), 29.0
(CH2); HRMS (ESI) m/z, calcd. for C9H12Cl3O4 [M + H]+:
288.9801, 290.9772, found: 288.9863, 290.9835; anal.
calcd. for C9H11F3O4: C 64.07, H 7.59, found: C 45.27,
H 2.68.
1-Chloro-3-(ethoxymethylene)-1,1-difluorotridecan-2-one
(7v)
Yield 90%, reddish oil; IR (film) νmax / cm-1 2995,
2930, 2878, 1758, 1586, 1495, 1460, 1250, 1150; 1H NMR
(400 MHz, CDCl3) d 7.63 (1H, s, H14), 4.18 (2H, q, J 7.0,
OCH2), 2.34 (2H, t, J 7.4, H4), 1.40 (3H, t, J 7.2, CH3),
1.30-1.27 (16H, m, CH2), 0.90 (3H, t, J 7.0, H13); 13C NMR
(100 MHz, CDCl3) d 180.9 (C2, t, JCF 34), 163.8 (C14, t,
JCF 6.3), 120.8 (C1, t, JCF 305), 115.6 (C3), 71.3 (OCH2),
31.8, 29.57, 29.5, 29.35, 29.3, 29.2, 27.9, 23.2, 22.6
3-(Ethoxymethylene)-1,1,1-trihalotridecan-2-ones
To a stirred solution of diethoxy acetal derived from
precursor aldehyde 2v (30 mmol) and pyridine (60 mmol,

Vol. 00, No. 00, 2019
Bareño et al.
17
(CH2), 15.3 (CH3), 14.0 (CH3); HRMS (ESI) m/z, calcd.
for C16H28ClF2O2 [M + H]+: 325.1746, found: 325.1793;
anal. calcd. for C16H27F2ClO2: C 59.16, H 8.38, found:
C 59.20, H 8.25.
HRMS (ESI) m/z, calcd. for C12H10F3O3 [M – 1]–: 259.0588,
found: 259.0649.
1,1,1-Trifluoro-6-(4-methoxyphenyl)hexan-2,4-dione (5j)
Yield 92%, reddish oil; IR (film) νmax / cm-1 3415, 3350,
3075, 2930, 2886, 1590, 1570, 1493, 1455, 1255, 1110.
1,1,1-Trihaloalkan-2,4-diones from hydrolysis of 1,1,1-trihalo-
4-methoxy-3-alken-2-ones
1
1085; H NMR (400 MHz, CDCl3) d 7.13 (2H, m, Ar),
6.88 (2H, m,Ar), 5.91 (1H, s, H3), 3.81 (3H, s, OMe), 2.95
(2H, m, CH2), 2.75 (2H, m, CH2); 13C NMR (100 MHz,
CDCl3) d 196.5 (C4), 175.0 (q, JCF 36, C2), 158.3, 131.6,
129.2, 113.8 (Ar), 117.0 (q, JCF 281, C1), 96.1 (q, JCF 2,
C3), 55.2 (OMe), 40.5 (CH2), 30.4 (CH2); 19F NMR
(376 MHz, CDCl3) d –76.5 (CF3); HRMS (ESI) m/z, calcd.
for C13H12F3O3 [M – 1]–: 273.0744, found: 273.0806.
To a solution of the isolated 1,1,1-trihalo-4-methoxy-
3-alken-2-one 3h-k or 4h,k (15 mmol) in 25 mL
chloroform, a mixture of 50 mL 3 mol L-1 H2SO4 was added
and stirred at reflux for 4 to 8 h. Then the organic layer was
separated and washed with deionized water (3 × 15 mL).
The organic layer was dried (anhydrous Na2SO4) and
evaporated in a rotary evaporator under vacuum to get the
respective 1,1,1-trihaloalkan-2,4-diones 5h-k and 6h,k in
quantitative yields (> 90%).
1,1,1-Trifluoro-5-(methylthio)hexan-2,4-dione (5k)
Yield 90%, yellow oil; IR (film) νmax / cm-1 3480, 3415,
3350, 3085, 2950, 2895, 2870, 1710, 1592, 1575, 1495,
1455, 1255, 1107, 1090; 1H NMR (400 MHz, CDCl3) d 6.08
(1H, s, H3), 3.31 (1H, q, J 7.2, H5), 1.98 (3H, s, SCH3),
1.39 (3H, d, J 7.2, CH3); 13C NMR (100 MHz, CDCl3)
d 198.6 (C4), 178.1 (q, JCF 36, C2), 117.6 (q, JCF 280, C1),
95.6 (q, JCF 2.0, C3), 46.3 (C5), 15.2 (C6), 12.9 (SCH3);
HRMS (ESI) m/z, calcd. for C7H8F3O2S [M – 1]–: 213.0203,
found: 213.0258.
One-pot procedure
A solution of acylating agent (trifluoromethyl anhydride
or trichloroacetyl chloride, 60 mmol) in chloroform
(20 mL) was added dropwise to a stirred solution of
dimethoxy-acetals, pyridine (5.2 mL, 60 mmol). The
o
mixture was stirred for 8 h at 0-25 C, quenched with a
3 mol L-1 H2SO4 solution (50 mL), and then stirred at reflux
for 4 to 8 h (85 oC). The organic layer was dried (anhydrous
Na2SO4), the solvent was evaporated, and products were
obtained in quantitative yields (> 90%).
3-(4-Oxo-2,6-bis(trifluoromethyl)-4H-pyran-3-yl) propanoic
acid, a 4-pyranone derivative obtained from 3n (Scheme 6)
Yield 17%, white needles; m.p. 118-120 oC; 1H NMR
(400 MHz, CDCl3) d 2.60 (m, H3, 2H); 2.94 (m, H2, 2H),
6.83 (s, 1H, H6); 13C NMR (100 MHz, CDCl3) d 177.4 (q,
4JCF 2.0, C4’), 176.7 (C1), 152.1 (q, 2JCF 40, C2’), 149.4 (q,
2JCF 38, C6’), 129.4 (C3’), 118.8 (q, JCF 276, CF3), 117.7 (q,
JCF 274, CF3), 114.0 (C5’), 31.5 (C2), 19.1(q, 4JCF 2.0, C3).
1,1,1-Trifluoro-6-phenylhexan-2,4-dione (5h)
Yield 95%, reddish oil; IR (film) νmax / cm-1 3412, 3375,
3064, 2940, 2910, 1777, 1774, 1650, 1570, 1515, 1305,
1265, 1103, 1090; 1H NMR (400 MHz, CDCl3) d 7.35 (m,
2H, Ph), 7.27 (m, 3H, Ph), 5.93 (s, 1H, H3), 3.03 (t, 2H,
CH2), 2.81 (m, 2H, CH2); 13C NMR (100 MHz, CDCl3)
d 196.5 (C4), 174.8 (q, JCF 36, C2), 139.6, 128.7, 128.2,
126.6 (Ph), 117.1 (q, JCF 282, C1), 96.2 (q, JCF 2, C3), 36.4
(CH2), 33.3 (CH2); 19F NMR (376 MHz, CDCl3) d –76.5
(CF3); HRMS (ESI) m/z, calcd. for C12H10F3O2– [M – 1]–:
243.0638, found: 243.0706.
1,1,1-Trichloro-6-phenylhexan-2,4-dione (6h)
Yield 89%, brown oil; IR (film) νmax / cm-1 3510, 3480,
3450, 3090, 2940, 2910, 1690, 1595, 1560, 1495, 1465,
780, 750; 1H NMR (400 MHz, CDCl3) d 7.29 (2H, m, Ph),
7.20 (3H, m, Ph), 6.07 (1H, s, H3), 2.97 (2H, m, CH2),
2.91 (2H, m, CH2); 13C NMR (100 MHz, CDCl3) d 188.8
(C4), 185.4 (C2), 139.6, 128.6, 128.2, 126.5 (Ph), 94.6
(C1), 92.8 (C3), 38.4 (CH2), 32.1 (CH2); HRMS (ESI)
m/z, calcd. for C12H12Cl3O2 [M + H]+: 292.9903, 294.9873,
found: 292.9968, 294.9930; anal. calcd. for C12H11Cl3O2:
C 49.09, H 3.78, found: C 49.45, H 3.80.
1,1,1-Trifluoro-6-(4-hydroxyphenyl)hexan-2,4-dione (5i)
Yield 85%, reddish oil; IR (film) νmax / cm-1 3415, 3380,
3350, 3070, 2930, 2886, 1590, 1570, 1495, 1450, 1245,
1105, 1090; 1H NMR (400 MHz, CDCl3) d 7.09 (2H, m,
Ar), 6.79 (2H, m, Ar), 5.90 (1H, s, H3), 2.93 (2H, m, CH2),
2.74 (2H, m, CH2); 13C NMR (100 MHz, CDCl3) d 196.5
(C4), 175.0 (q, JCF 36, C2), 154.3, 129.3, 115.6 (Ar), 115.5
(Ph), 117.0 (q, JCF 281, C1), 91.4 (q, J 2, C3), 40.5 (CH2),
30.4 (CH2); 19F NMR (376 MHz, CDCl3) d –76.7 (CF3);
1,1,1-Trichloro-5-(methylthio)hexan-2,4-dione (6k)
Yield 95%, yellow oil; IR (film) νmax / cm-1 3510, 3480,
2940, 2910, 2870, 1710, 1690, 1680, 1592, 1575, 1495,
1455, 780, 750; 1H NMR (400 MHz, CDCl3) d 6.28 (1H, s,

18
An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives J. Braz. Chem. Soc.
H3 enol), 4.35 (q, 2H, J 7.0, H3 keto), 3.51 (1H, q, J 7.0, H5,
keto), 3.38 (1H, q, J 7.0, H5 enol) 2.14 (3H, s, SCH3 enol),
1.95 (3H, s, SCH3 keto), 1.51 (3H, d, J 7.0, CH3 enol), 1.43
(3H, d, J 7.0, CH3 keto); 13C NMR (100 MHz, CDCl3) d enol
189.7 (C4), 184.5 (C2), 94.3 (C1), 91.5 (C3), 44.9 (C5),
16.7 (C6), 14.2 (SCH3); d keto 194.5 (C4), 186.1 (C2), 95.8
(C1), 47.8 (C3), 46.9 (C5), 16.5 (C6), 13.5 (SCH3); HRMS
(ESI) m/z, calcd. for C7H10Cl3O2S [M + H]+: 262.9467,
264.9438, found: 262.9528, 264.9492; anal. calcd. for
C7H9Cl3O2S: C 31.90, H 3.44, found: C 31.79, H 3.58.
5-Hydroxy-3-(2-methoxybenzyl)-5-trifluoromethyl-
4,5-dihydroisoxazole (8l)
Yield 91%, white needles; m.p. 131-132 oC; 1H NMR
(400 MHz, CDCl3) d 7.31 (dd, 1H, JHH 8.0, 1.6, Ar), 7.19
(dd, 1H, JHH 7.6, 1.6, Ar), 6.95 (td, 1H, JHH 7.5, 1.0, Ar),
6.92 (d, 1H, JHH 8.0, Ar), 3.86 (s, 3H, OCH3), 3.77 (s, 2H,
CH2), 3.22 (d, 1H, JHH 18, H4), 3.01 (d, 1H, JHH 18, H4);
13C NMR (100 MHz, CDCl3) d 159.1 (Ar), 157.2 (C3);
130.5 (Ar); 128.9 (Ar) 123.0 (Ar), 122.0 (q, JHH 284,
CF3), 121.0 (Ar), 110.0 (Ar), 102.6 (q, JHH 34, C5), 55.3
(OCH3), 44.6 (C4), 27.9 (CH2); HRMS (ESI) m/z, calcd.
for C12H13F3NO3 [M + H]+: 276.0848, found: 276.0883;
anal. calcd. for C12H12F3NO3: C 52.37, H 4.39, found:
C 52.50, H 4.35.
5-Trihalomethyl-4,5-dihydroisoxazoles (8,9)
General procedure
Trifluoromethyl-substituted precursors 3h,k,l,n or
5h,k (6.0 mmol) or trichloromethyl-substituted precursors
4a-c, 4f-h, 4k,n, or 6h,k (6.0 mmol) and hydroxylamine
hydrochloride (6.1 mmol, 0.45 g) were efficiently stirred
The data for isoxazole derivative 8m obtained in this
work are precisely in agreement with those previously
described by Flores et al.41
o
in 5 mL ethanol, under slight heating, 40-45 C, for
5-Trichloromethyl-3-heptyl-4,5-dihydroisoxazole (9a)
o
1
30-120 min. Then solvent was evaporated and solid
residue was assigned as 4,5-dihydroisoxazole derivatives
8h,k,l,n and 9a-c, 9f-h, and 9k,n in good to quantitative
yields.
Yield 90%, white needles; m.p. 83-84 C; H NMR
(400 MHz, CDCl3) d 0.81 (t, 3H, CH3), 1.25 (m, 8H,
‑CH2–), 1.51 (m, 2H, β-CH2), 2.32 (t, 2H, J 7.6, α-CH2),
3.12 (d, 1H, J 18.4, H-4), 3.55 (d, 1H, J 18.4, H-4);
13C NMR (100 MHz, CDCl3) d 160.6 (C3), 46.1 (C4), 110.5
(C5), 101.1 (CCl3), 31.2, 28.6. 27.5, 26.1, 22.3 (‑CH2–),
13.9 (CH3); Fourier transform MS (FTMS) calcd. for
C10H16Cl3NO2: 287.0247 g mol-1; found: 288.0307 g mol-1.
The NMR spectroscopic data for the complete
series of the 3-alkyl-5-hydroxy-5-trichloromethyl-
4,5-dihydroisoxazoles 9b-f are shown in the SI section.
5-Hydroxy-5-trifluoromethyl-3-(2-phenylethyl)-
4,5-dihydroisoxazole (8h)
o
1
Yield 95%, white solid; m.p. 87-88 C; H NMR
(400 MHz, CDCl3) d 7.34 (2H, m, Ph), 7.25 (m, 3H, Ph),
3.25 (1H, d, JHH 18, H4), 3.01 (1H, d, JHH 18, H4), 2.96
(t, 2H, JHH 8.0, CH2), 2.74 (t, 2H, JHH 8.0, CH2); 13C NMR
(100 MHz, CDCl3) d 158.9 (C3), 139.8, 128.7, 128.2, 126.6
(Ph), 122.0 (q, JCF 284, CF3), 102.6 (q, JCF 34, C5), 45.2
(C4), 32.4, (CH2), 29.1 (CH2); HRMS (ESI) m/z, calcd. for
C12H13F3NO2 [M + H]+: 260.0898, found: 260.0956; anal.
calcd. for C12H12F3NO2: C 55.60, H 4.67, found: C 55.50,
H 4.78.
5-Hydroxy-3-(4-methylpent-3-en-1-yl)-5-trichloromethyl-
4,5-dihydroisoxazol (9g)
Yield 91%, white needles; m.p. 118-119 oC; 1H NMR
(400 MHz, CDCl3) d 1.63 (s, 3H, CH3), 1.70 (s, 3H, CH3),
2.30 (m, 2H, CH2), 2.45 (m, 2H, CH2), 3.17 (d, 1H, JHH 18.4,
H4), 3.61 (d, 1H, JHH 18.4, H4), 5,11 (tt, 1H, JHH 7.2, 1.6,
CH); 13C NMR (100 MHz, CDCl3) d 160.1 (C3), 133.6
((CH3)2); 122.0 (CH); 110.4 (C5) 101.1, (CCl3); 46.1 (C4),
27.7 (CH2), 25.5 (CH3), 24.9 (CH2), 17.7 (CH3); MS (EI,
70 eV) m/z (%) 289 (M+ + 4, 9), 287 (M+ + 2, 26), 285 (M+,
30), 206 (62), 178 (21), 143 (23), 117 (28); anal. calcd. for
C10H14Cl3NO2 (286.58 g mol-1): C 41.91, H 4.92, N 4.89,
found: C 41.9, H 4.85, N 4.9.
5-Hydroxy-5-trifluoromethyl-3-(1-(thiomethyl)ethyl)-4,5-
dihydroisoxazole (8k)
o
1
Yield 93%, white needles; m.p. 70-75 C; H NMR
(400 MHz, CDCl3) d 3.72 (q, 1H, JHH 7.2, CH), 3.54 (d,
1H, JHH 18, H4), 3.44 (d, 1H, JHH 18, H4), 3.29 (d, 1H,
JHH 18, H4), 3.21 (d, 1H, JHH 18, H4), 2.05 (s, 3H, CH3),
2.03 (s, 3H, CH3), 1.49 (d, 3H, JHH 7.2, CH3), 1.48 (d,
3H, JHH 7.2, CH3); 13C NMR (100 MHz, CDCl3) d 160.7,
160.6 (C3), 121.9 (q, JHH 282, CF3), 41.4, 41.1 (C4), 37.6,
37.4 (CH), 17.6, 17.2 (CH3), 13.6, 13.3 (CH3); 19F NMR
(376 MHz, CDCl3) d –82.6, –83.0; HRMS (ESI) m/z,
calcd. for C7H11F3NO2S [M + H]+: 230.0463, found:
230.0511; anal. calcd. for C7H10F3NO2S: C 36.68, H 4.40,
found: C 36.50, H 4.45.
5-Hydroxy-5-trichloromethyl-3-(2-phenylethyl)-
4,5-dihydroisoxazole (9h)
o
1
Yield 93%, white solid; m.p. 131-132 C; H NMR
(400 MHz, CDCl3) d 7.30 (2H, m, Ph), 7.24 (m, 3H, Ph),
3.55 (1H, d, JHH 18.4, H4), 3.13 (1H, d, JHH 18.4, H4),
2.95 (t, 2H, JHH 8.0, CH2), 2.74 (m, 2H, CH2); 13C NMR

Vol. 00, No. 00, 2019
Bareño et al.
19
(100 MHz, CDCl3) d 159.6 (C3), 139.8, 128.6, 128.2, 126.5
(Ph), 110.5 (C5), 100.9 (CCl3), 46.1 (C4), 32.4, (CH2), 29.3
(CH2); HRMS (ESI) m/z, calcd. for C12H13Cl3NO2 [M + H]+:
260.0898, found: 308.0074, 310.0027; anal. calcd. for
C12H12Cl3NO2: C 46.71, H 3.92, found: C 46.89, H 3.80.
d 7.32-7.15 (5H, m, Ph), 6.32 (1H, s, H4), 3.01 (2H, m, CH2),
2.96 (2H, m, CH2); 13C NMR (100 MHz, CDCl3) d 144.7
(C3), 143.0 (q, JCF 38, C5) 139.9, 128.7, 128.3, 126.6 (Ph),
121.3(q, JCF 268, C5), 102.2 (q, JCF 1.5, C4), 35.0 (CH2), 27.1
(CH2); HRMS (ESI) m/z, calcd. for C12H12F3N2 [M + H]+:
241.0953, found: 241.0965; anal. calcd. for C12H12F3N2:
C 60.00, H 4.62, found: C 59.95, H 4.60.
5-Hydroxy-5-trifluoromethyl-3-(1-(thiomethyl)ethyl)-
4,5-dihydroisoxazole (9k)
o
1
Yield 88%, white needles; m.p. 70-75 C; H NMR
(400 MHz, CDCl3) d 3.85 (d, 1H, JHH 18, H4), 3.76 (d, 1H,
JHH 18.4, H4), 3.68 (q, 1H, JHH 7.4, CH), 3.37 (d, 1H, JHH 18,
H4), 3.29 (d, 1H, JHH 18.4, H4), 2.05 (s, 6H, 2 × CH3), 1.48
(d, 3H, JHH 7.2, CH3); 13C NMR (100 MHz, CDCl3) d 161.05,
161.03 (C3), 110.6 (C5), 100.9, 100.8 (CCl3), 42.6, 42.1 (C4),
38.0, 37.7 (CH), 17.7, 17.3 (CH3), 14.0, 13.2 (CH3); HRMS
(ESI) m/z, calcd. for C7H11Cl3NO2S [M + H]+: 276.9498,
278.9468, found: 276.9541, 278.9522; anal. calcd. for
C7H10Cl3NO2S: C 30.18, H 3.62, found: C 30.20, H 3.70.
5(3)-Trifluoromethyl-3(5)-(2-(4-methoxyphenyl)ethyl)-
1H-pyrazole (12j)
Yield 85%, yellowish oil; 1H NMR (400 MHz, CDCl3)
d 7.09 (2H, d, JHH 8.0, Ar), 6.85 (2H, d, JHH 8.0, Ar),
6.34 (1H, s, H4), 3.81 (3H, s, OCH3), 3.0 (2H, m, CH2),
2.93 (2H, m, CH2); 13C NMR (100 MHz, CDCl3) d 158.3
(Ar), 145.4 (C3), 142.4 (q, JCF 38, C5) 131.9, 129.2 (Ar),
121.1(q, JCF 268, C5), 114.0 (Ar), 102.4 (q, JCF 1.8, C4),
55.2 (OCH3), 34.1, (CH2), 27.4 (CH2); 19F NMR (376 MHz,
CDCl3) d –62.07; HRMS (ESI) m/z, calcd. for C13H14F3N2O
[M + H]+: 271.1058, found: 271.1118; anal. calcd. for
C13H13F3N2O: C 57.78, H 4.85, found: C 57.65, H 4.80.
5-Trichloromethylisoxazoles
Compounds 9a-c and 9e,f (3.5 mmol) were efficiently
stirred with 98% H2SO4 (2.0 mL) for 5 h. Then cooled
water was added and the insoluble residue was filtered and
washed with water and a saturated solution of NaHCO3,
producing 5-trichloromethylisoxazole derivatives 11a-c,
and 9e,f in good yields (Table 1).
1H-Pyrazole-5-carboxylates
A mixture of precursors 4h or 6h (10 mmol) and
NH2NH2.HCl (11 mmol, 0.76 g) in 5 mL alcohol (EtOH
or 2-methoxyethanol (2ME)) was stirred under reflux
for 8 h. The solvent was evaporated, the solid residue
was dissolved in CH2Cl2 (20 mL) and washed with water
(15 mL) twice, and then the organic layer was dried
with Na2SO4. After evaporating the solvent, the residues
were obtained as white solids, attributed as 1H-pyrazole
carboxylates 13h and 14h. Here we use these models to
demonstrate the versatility of trichloromethyl-substituted
precursors in molecular diversification during the synthesis
of 1H-pyrazole carboxylates:
5-Trichloromethyl-3-undecylisoxazole (11e)
1
Yield 90%, yellow oil; H NMR (400 MHz, CDCl3)
d 0.98 (t, 3H, J 7.8, Me), 1.75 (sx, 2H, J 7.8, –CH2–), 2.7
(t, 2H, J 7.8, –CH2–), 6.88 (s, 1H, H4); 13C NMR (50 MHz,
CDCl3) d 165.3 (C3), 104.7 (C4), 168.7 (C5), 85.6 (CCl3),
28.3 (–CH2–), 21.8 (–CH2–), 13.8 (Me); HRMS (ESI) m/z,
calcd. for C15H24Cl3NO [M + H]+: 340.1002, 342.0972,
found: 340.0986, 342.0957.
Ethyl 3(5)-(2-phenylethyl)-1H-pyrazole-5(3)-carboxylate
(13h)
Complete identification data for all isolated
5-trichloromethylisoxazoles are available in the SI section.
o
1
Yield 90%, white solid; m.p. 216 C; H NMR
(400 MHz, CDCl3) d 7.23-7.12 (5H, m, Ph), 6.64 (1H,
s, H4), 4.35 (2H, q, JHH 6.8, CH2), 3.15 (2H, m, CH2),
3.00 (2H, m, CH2), 1.33 (3H, t, JHH 6.8, CH3); 13C NMR
(100 MHz, CDCl3) d 157.0 (CO2Et), 149.5 (C3), 138.9
(Ph), 137.8 (C5), 128.3, 128.1, 126.3 (Ph), 108.1 (C4), 62.6
(OCH2), 33.8 (CH2), 26.8 (CH2), 13.6 (CH3); MS (70 eV)
m/z (%) 211 (M+ + 1, 10), 210 (M+, 60); anal. calcd. for
C11H18N2O2: C 62.83, H 8.63, found: C 62.7, H 8.7.
1H-Pyrazole derivatives
Trifluoromethyl-1H-pyrazoles
A solution of hydrazine hydrochloride (21 mmol) and
6-aryl-1,1,1-trifluoro-4-methoxyhex-3-en-2-one (3h or 3j,
20 mmol) in ethanol (10 mL) was stirred at reflux for 12 h.
Ethanol was evaporated and a brownish solid residue was
recrystallized from hexane, obtaining 1H-pyrazole products
12h,j in very good yields (> 80%).
2-Methoxyethyl 3(5)-(2-phenylethyl)-1H-pyrazole-
5(3)-carboxylate (14h)
Yield 93%, white solid; m.p. 130-131 C; H NMR
(400 MHz, CDCl3) d 6.49 (s, 1H, H4), 3.77 (s, 3H, OMe),
o
1
5(3)-Trifluoromethyl-3(5)-(2-phenylethyl)-1H-pyrazole (12h)
Yield 88%, yellowish oil; 1H NMR (400 MHz, CDCl3)

20
An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-1,3-dielectrophiles and 1,2-Azole Derivatives J. Braz. Chem. Soc.
2.61 (t, 2H, H6), 1.52 (qu, 2H, H7), 1.18 (m, 8H, –(CH2)4–),
0.77 (t, 3H, Me); 13C NMR (100 MHz, CDCl3) d 162.3
(CO2Me), 147.3 (C3), 141.4 (C5), 106.1 (C4), 51.7 (OMe),
31.6, 28.97, 28.93, 28.8, 25.6, 22.5 (CH2), 13.9 (Me); MS
(70 eV) m/z (%) 225 (M+ + 1, 10), 224 (M+, 58); anal. calcd.
for C12H20N2O2: C 64.26, H 8.99, found: C 64.5, H 8.9.
14. Nakamura, K.; Hasegawa,Y.; Kawai, H.;Yasuda, N.; Kanehisa,
N.; Kai, Y.; Nagamura, T.; Yanagida, S.; Wada, Y.; J. Phys.
Chem. A 2007, 111, 3029.
15. Rogachev, A. Yu.; Mironov, A. V.; Nemukhin, A. V.; J. Mol.
Struct. 2007, 831, 46.
16. Xiang, N-.J.; Leung, L. M.; So, S-.K.; Gong, M-.L.;
Spectrochim. Acta, Part A 2006, 65, 907.
Supplementary Information
17. Bazhin, D. N.; Kudyakova, Y. S.; Bogomyakov, A. S.;
Slepukhin, P. A.; Kim, G. A.; Burgart, Y. V.; Saloutin, V. I.;
Inorg. Chem. Front. 2019, 6, 40.
Supplementary information (1H, 13C and representative
19F NMR spectra, and MS of the synthesized compounds) is
available free of charge at http://jbcs.sbq.org.br as PDF file.
18. Turgambaeva, A. E.; Krisyuk, V. V.; Baidina, I. A.; Korolkov,
I. V.; Ilyin, I.Yu.; Urkasym kyzy, S.; Igumenov, I. K.; J. Struct.
Chem. 2017, 58, 1530.
Acknowledgments
19. Zharkova, G. I.; Baidina, I.A.; Turgambaeva,A. E.; Romanenko,
G. V.; Igumenov, I. K.; Polyhedron 2012, 40, 40.
20. Krisyuk, V. V.; Kyzy, S. U.; Rybalova, T. V.; Baidina, I. A.;
Korolkov, D. L.; Chizhov, D. L.; Bazhin, D. N.; Kudyakova,
Y. S.; J. Coord. Chem. 2018, 71, 2194.
Financial support from Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq)
and Fundação de Amparo à Pesquisa do Estado do Rio
Grande do Sul (FAPERGS) is acknowledged. V. D. O.
Bareño, D. S. Santos, and D. L. de Mello thank CAPES
for fellowships.
21. Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes,
A.; Chem. Rev. 2011, 111, 6984.
22. Kumar, V.; Kaur, K.; J. Fluorine Chem. 2015, 180, 55.
23. Emelina, E. E.; Petrov, A. A.; Stanislav, I. S.; Nelyubina,Y. V.;
Antipin, M. Yu.; J. Fluorine Chem. 2009, 130, 861.
24. Tireli, M.; Maracic, S.; Lukin, S.; Kulcsár, M. J.; Zilic, D.;
Cetina, M.; Halasz, I.; Malic, S.; Uzarevic, K.; Beilstein J. Org.
Chem. 2017, 13, 2352.
References
1. Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G.;
Tetrahedron 2007, 63, 7753.
25. Bazhin, D. N.; Chizhov, D. L.; Röschenthaler, G-.V.;
Kudyakova, Y. S.; Burgart, Y. V.; Slepukhin, P. A.; Saloutin, V.
I.; Charushin, V. N.; Tetrahedron Lett. 2014, 55, 5714.
26. Grünebaum, M.; Buchheit,A.; Gunther, C.; Wiemhöfer, H-.D.;
Tetrahedron Lett. 2016, 57, 1555.
2. Rulev, A. Yu.; Romanov, A. R.; RSC Adv. 2016, 6, 1984.
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. Nenajdenko, V. G.; Balenkova, E. S.; ARKIVOC 2011, 2011,
246.
27. Safrygin,A.V.; Irgashev, R.A.; Slepukhin, P.A.; Röschenthaler,
G-.V.; Sosnovskikh, V. Y.; Tetrahedron 2015, 71, 8535.
28. Irgashev, R.A.; Sosnovskikh,V.Ya.; Kalinovich, N.; Kazakova,
O.; Röschenthaler G-.V.; Tetrahedron Lett. 2009, 50, 4903.
29. Kende,A. S.; Blacklock, T. J.; Tetrahedron Lett. 1980, 21, 3119.
30. Mander, L.; Sethi, S. P.; Tetrahedron Lett. 1983, 24, 5425.
31. Becker, U.; Anke, T.; Z. Naturforsch., C: J. Biosci. 1994, 49,
772.
5. Olivier, J-.H.; Camerel, F.; Ziessel, R.; Chem. - Eur. J. 2011,
17, 9113.
6. Sloop, J. C.; Bumgardner, C. L. Washington, G.; Loehle, W. D.;
Sankar, S. S.; Lewis, A. B.; J. Fluorine Chem. 2006, 127, 780.
7. Yang, Y.; Zhang, M.; Zhu, Y.; Zhang, L.; Xie, Q.; Song, L.;
Deng, H.; Chin. J. Chem. 2013, 31, 950.
8. Bhakite, E. A.; Abdel-Rahman, A. E.; Al-Taifi, E. A.; Arabian
J. Chem. 2014, 7, 936.
32. Sackton, K. L.; Dimova, N.; Zeng, X.; Tian, W.; Zhang, M.;
Sackton, T. B.; Meaders, J.; Pfaff, K. L.; Sigoillot, F.; Yu, H.;
Luo, X.; King, R. W.; Nature 2014, 514, 646.
9. Chauvin, A-.S.; Gumy, F.; Matsubayashi, I.; Hasegawa, H.;
Bünzli, J-.C. G.; Eur. J. Inorg. Chem. 2006, 473.
10. Pace,A.; Buscemi, S.;Vivona, N.; Org. Prep. Proced. Int. 2007,
39, 1.
33. Tiwari, A.; Riordan, J. M.; Waud, W. R.; Struck, R. F.; J. Med.
Chem. 2002, 45, 1079.
34. MacMillan, J. B.; Molinski, T. F.; J. Nat. Prod. 2000, 63,
155.
11. Kudyakova, Yu. S.; Bazhin, D. N.; Goryaeva, M. V.; Burgart,
Ya. V.; Saloutin, V. I.; Russ. Chem. Rev. 2014, 83, 120.
12. DelaRosa, M. J.; Banger, K. K.; Higashiya, S.; Ngo, S. C.; Hunt,
D. H.; Bousman, K. S.; Toscano, P. J.; Welch, J. T.; J. Fluorine
Chem. 2003, 123, 109.
35. Sitachitta, N.; Rossi, J.; Roberts, M. A.; Gerwick, W. H.;
Fletcher, M. D.; Willis, C. L.; J. Am. Chem. Soc. 1998, 120,
7131.
36. Rybarczyk-Pirek, A. J.; Checinska, L.; Małecka, M.;
Wojtulewski, S.; Cryst. Growth Des. 2013, 13, 3913.
13. Khamidullina, L. A.; Obydennov, K. L.; Slepukhin, P. A.;
Puzyrev, I. S.; J. Mol. Struct. 2016, 1125, 550.

Vol. 00, No. 00, 2019
Bareño et al.
21
37. Flores, A. F. C.; Martins, M. J.; Frigo, L. M., Machado, P.;
Campos, P. T.; Malavolta, J. L. Synth. Commun. 2012, 42, 727.
38. Flores, A. F. C.; Blanco, R. F.; Souto, A. A.; Malavolta, J. L.;
Flores, D. C.; J. Braz. Chem. Soc. 2013, 24, 2059.
39. Singh, S. P.; Kumar, D.; Jones, B. G.; Threadgill, M. D.; J.
Fluorine Chem. 1999, 94, 199.
46. Flores, A. F. C.; Brondani, S.; Zanatta, N.; Rosa, A.; Martins,
M. A. P.; Tetrahedron Lett. 2002, 43, 8701.
47. Yachevskii, D. S.; Chizhov, D. L.; Pashkevich, K. I.; Charushin,
V. N.; ARKIVOC 2004, 2004, 71.
48. Sloop, J. C.; Rep. Org. Chem. 2013, 3, 1.
49. El Kaim, L.; Gaultier, L., Grimaud, L.; Vieu, E.; Tetrahedron
Lett. 2004, 45, 8047.
40. Montoya,V.; Pons, J.; García-Antón, J.; Solans, X.; Font-Bardia,
M.; Ros, J.; J. Fluorine Chem. 2007, 128, 1007.
41. Flores, A. F. C.; Piovesan, L. A.; Pizzuti, L.; Flores, D. C.;
Malavolta, J. L.; Martins, M. A. P.; J. Heterocycl. Chem. 2014,
51, 733.
50. Flores, A. F. C.; Piovesan, L. A.; Souto, A. A.; Pereira, M. A.;
Martins, M.A. P.; Balliano, T. L.; Silva, G. S.; Synth. Commun.
2013, 43, 2326.
51. Kumar, V.;Aggarwal, R.; Singh, S. P.; J. Fluorine Chem. 2006,
127, 880.
42. Vrbková, E.;Vyskocilová, E.; Cervený, L.; React. Kinet., Mech.
Catal. 2017, 121, 307.
52. Sloop, J. C.; Bumgardner, C. L.; Loehle, W. D.; J. Fluorine
Chem. 2002, 118, 135.
43. Zuo, C.; Li, C.; Ge, T.; Guo, X.; Zhang, S.; Can. J. Chem. Eng.
2017, 95, 2104.
44. Moriguchi, T.; Endo, T.; Takata, T.; J. Org. Chem. 1995, 60,
3523.
Submitted: March 29, 2019
Published online: July 15, 2019
45. Bégué, J-.P.; Bonnet-Delpon, D.; Mesureur, D.; Ourévitch, M.;
Magn. Reson. Chem. 1991, 29, 675.
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