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

http://dx.doi.org/10.21577/0103-5053.20190160

J. Braz. Chem. Soc., Vol. 00, No. 00, 1-21, 2019

Article

An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl-

1,3-dielectrophiles and 1,2-Azole Derivatives

Valéria D. O. Bareño,^aDaiane S. Santos,^aLeandro M. Frigo,^bDebora L. de Mello,^b

Juliana L. Malavolta,^bRogerio F. Blanco,^bLucas Pizzuti,^cDarlene C. Flores^aand

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.^18-20They are the most employed precursors for

ﬂuorinate N-heterocycles such as pyrazoles,²¹isoxazoles,²²

pyrimidines,²³and quinolones.²⁴Claisen condensation,

the most used method to obtain these precursors, is very

efﬁcient when using symmetrical ketones or ketones with

only one enolizable site.^25-28Figure 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.^3,4Perﬂuoroacylation, including

trifluoroacetylation reactions, of the acetone and

asymmetrically substituted, one-enolizable-site ketones

with esters is of fundamental importance in organic

synthesis.^5-71,3-Diketones products have long been widely

employed as effective chelating reagents and heterocyclic

precursors.^8-11Fluorinated 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.^29,30On 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.³²Penclomedine, 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.³⁶Therefore,

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.³⁷Ketones 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

CHCl₃mixture 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.^38,41Therefore, 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.^42,43In 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,^44,45it

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

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Bareño et al.

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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,³⁸one-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,⁴⁶presenting 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^-1sulfuric 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.

6

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

1^a

2

Precursor

3a^b

3a

Methodology

Product

Yield / %

20 mL 1 mol L^-1H₂SO₄, 25 to 100 ^oC

3a

–

20 mL 1 mol L^-1H₂SO₄, CH₃CN, 100 ^oC

20 mL 1 mol L^-1H₂SO₄, 25% (m/v) PyH⁺CF₃CO₂^–, 100 ^oC

20 mL 5 mol L^-1H₂SO₄, 25% (m/v) PyH⁺CF₃CO₂^–, 100 ^oC

20 mL 1 mol L^-1H₂SO₄, 25 to 100 ^oC

3a

3^a

4^a

5

3a

–

3a

3a + 5a (2:1)

87

92

–

4a^b

4a

4a + 6a (2:1)

6

20 mL 1 mol L^-1H₂SO₄, CH₃CN, 100 ^oC

20 mL 5 mol L^-1H₂SO₄, 25% (m/v) PyH⁺CF₃CO₂^–, 100 ^oC

20 mL 1 mol L^-1H₂SO₄, 25 to 100 ^oC

4a

7^a

8

4a + 6a (1:1)

–

3h

5h

6h

95

92

95

9

3h

20 mL 1 mol L^-1H₂SO₄, CH₃CN, 100 ^oC

20 mL 1 mol L^-1H₂SO₄, 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 CCl₃at 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 ¹J_CF292 Hz, and

d 178-179 ppm with ²J_CF34 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, J_HH6.8 Hz) and 4.2 ppm (q, J_HH6.8 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 ²J_CF34 Hz; the signal

4

from C-4 at d 164.2 ppm was a quartet with J_CF5 Hz;

and the signals from CF₃and C-3 appeared at d 117.0 and

117.1 ppm, respectively, forming an interesting set, a large

quartet with J_CF291 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.

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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.

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 CDCl₃solution. 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

CDCl₃solution. 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 J_HH16.4 Hz. Besides the two quartets from

H-5 at d 3.39 and 3.51 ppm with J_HH7.0 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 J_CF33 Hz, whereas in the diketone

5h the signal for C-2 was shielded by 4 ppm appearing

2

at d 174.8 ppm with J_CF36 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 ²J_CH3 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 CCl₃carbon appeared at d 98 and 94.8 ppm for enone

and diketone, respectively. C-3 signals included a doublet

at 89.6 ppm with J_CH158 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 CF₃carbon appeared at d 117.1 ppm for

both enone and diketone, nevertheless the J_CFvalues differed

by 10 Hz, with 292 Hz for CF₃in enone 3h and 282 Hz in

diketone 5h.Also important was the chemical shift variance

and coupling constant ³J_CFof 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

³J_CF2 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.⁶However, considering

the correlation between CF coupling constants and

alkene configuration described by Bégué et al.⁴⁵for

triﬂuoromethylated vinyl compounds, we can conclude

that the keto-enol form preferred is A, because we

observed a ³J_CFaround 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 J_CH170 Hz and J_CH3 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 CCl₃was

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 CCl₃carbon 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.⁵⁰After

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%

H₂SO₄to produce trichloromethyl-substituted isoxazoles

11a-c,e,f (Scheme 7). Aromatization occurred smoothly

2

germinal J_HH18.4 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 ²J_CF38 Hz, and C4 at 102.2 ppm with

³J_CF1.5 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 J_CF268 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 / H₂SO₄solution.

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. CDCl₃was 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) ν_max/ cm^-13089,

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, J_CF34), 116.7 (C1, q,

J_CF292), 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) ν_max/ cm^-13094,

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, J_CF33), 116.8 (C1, q,

J_CF292), 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) ν_max/ cm^-13090,

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, J_CF33), 116.7 (C1, q,

J_CF292), 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) ν_max/ cm^-13090,

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, J_CF33), 116.8 (C1, q, J_CF292),

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) ν_max/ cm^-13089,

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,

J_CF34), 133.1 (C8), 122.3 (C7), 116.7 (C1, q, J_CF292), 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) ν_max/ cm^-13089,

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, J_CF33), 116.8 (C1, q,

J_CF292), 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) ν_max/ cm^-13095,

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, J_CF33), 116.8 (C1, q,

J_CF292), 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) ν_max/ cm^-13090, 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, J_CF33), 140.8, 128.8, 126.6 (Ph), 117.1

(C1, q, J_CF292), 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, J_CF33), 157.6, 132.6, 129.6, 115.2 (Ph), 116.7 (C1, q,

J_CF292), 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) ν_max/ cm^-13350, 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, J_CF33), 154.8, 132.6,

129.6, 115.2 (Ph), 116.7 (C1, q, J_CF292), 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) ν_max/ cm^-13090,

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, J_CF33), 172.2 (C1), 116.8

(C7, q, J_CF292), 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) ν_max/ cm^-13089,

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, J_CF33),

158.1, 132.5, 129.4, 113.8 (Ph), 116.7 (C1, q, J_CF292), 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) ν_max/ cm^-13090, 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, J_CF33), 172.4 (C1), 116.8 (C8, q,

J_CF292), 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) ν_max/ cm^-13085, 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, J_CF34), 117.4 (C1, q, J_CF295), 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) ν_max/ cm^-13087,

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, J_CF27), 172.3 (C1), 120.6 (C7,

t, J_CF306), 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) ν_max/ cm^-13090,

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) ν_max/ cm^-13092,

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,

J_CF34), 133.1 (C8), 122.3 (C7), 116.7 (C1, q, J_CF292), 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) ν_max/ cm^-13093, 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, J_CF33), 140.8, 128.8, 126.6 (Ph), 117.1 (C1, q, J_CF292),

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) ν_max/ cm^-12995,

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, J_CF34), 164.2

(C14, q, J_CF5.0), 117.1 (C3), 117.0 (C1, q, J_CF291), 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) ν_max/ cm^-13089, 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, J_CF34), 117.4 (C1, q, J_CF295), 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) ν_max/ cm^-12995, 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) ν_max/ cm^-13089,

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, J_CF33), 172.2 (C1), 116.8 (C7, q, J_CF292),

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) ν_max/ cm^-12995,

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, J_CF34), 163.8 (C14, t,

J_CF6.3), 120.8 (C1, t, J_CF305), 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) ν_max/ cm^-13415, 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, J_CF36, C2), 158.3, 131.6,

129.2, 113.8 (Ar), 117.0 (q, J_CF281, C1), 96.1 (q, J_CF2,

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^-1H₂SO₄was 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) ν_max/ cm^-13480, 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, J_CF36, C2), 117.6 (q, J_CF280, C1),

95.6 (q, J_CF2.0, 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^-1H₂SO₄solution (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,

⁴J_CF2.0, C4’), 176.7 (C1), 152.1 (q, ²J_CF40, C2’), 149.4 (q,

²J_CF38, C6’), 129.4 (C3’), 118.8 (q, J_CF276, CF₃), 117.7 (q,

J_CF274, CF₃), 114.0 (C5’), 31.5 (C2), 19.1(q, ⁴J_CF2.0, C3).

1,1,1-Triﬂuoro-6-phenylhexan-2,4-dione (5h)

Yield 95%, reddish oil; IR (ﬁlm) ν_max/ cm^-13412, 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, J_CF36, C2), 139.6, 128.7, 128.2,

126.6 (Ph), 117.1 (q, J_CF282, C1), 96.2 (q, J_CF2, 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) ν_max/ cm^-13510, 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) ν_max/ cm^-13415, 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, J_CF36, C2), 154.3, 129.3, 115.6 (Ar), 115.5

(Ph), 117.0 (q, J_CF281, 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) ν_max/ cm^-13510, 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, SCH₃enol),

1.95 (3H, s, SCH₃keto), 1.51 (3H, d, J 7.0, CH₃enol), 1.43

(3H, d, J 7.0, CH₃keto); 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, J_HH8.0, 1.6, Ar), 7.19

(dd, 1H, J_HH7.6, 1.6, Ar), 6.95 (td, 1H, J_HH7.5, 1.0, Ar),

6.92 (d, 1H, J_HH8.0, Ar), 3.86 (s, 3H, OCH₃), 3.77 (s, 2H,

CH₂), 3.22 (d, 1H, J_HH18, H4), 3.01 (d, 1H, J_HH18, 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, J_HH284,

CF₃), 121.0 (Ar), 110.0 (Ar), 102.6 (q, J_HH34, 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, J_HH18, H4), 3.01 (1H, d, J_HH18, H4), 2.96

(t, 2H, J_HH8.0, CH₂), 2.74 (t, 2H, J_HH8.0, CH₂); ¹³C NMR

(100 MHz, CDCl₃) d 158.9 (C3), 139.8, 128.7, 128.2, 126.6

(Ph), 122.0 (q, J_CF284, CF₃), 102.6 (q, J_CF34, 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, J_HH18.4,

H4), 3.61 (d, 1H, J_HH18.4, H4), 5,11 (tt, 1H, J_HH7.2, 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, J_HH7.2, CH), 3.54 (d,

1H, J_HH18, H4), 3.44 (d, 1H, J_HH18, H4), 3.29 (d, 1H,

J_HH18, H4), 3.21 (d, 1H, J_HH18, H4), 2.05 (s, 3H, CH₃),

2.03 (s, 3H, CH₃), 1.49 (d, 3H, J_HH7.2, CH₃), 1.48 (d,

3H, J_HH7.2, CH₃); ¹³C NMR (100 MHz, CDCl₃) d 160.7,

160.6 (C3), 121.9 (q, J_HH282, 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, J_HH18.4, H4), 3.13 (1H, d, J_HH18.4, H4),

2.95 (t, 2H, J_HH8.0, 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, J_CF38, C5) 139.9, 128.7, 128.3, 126.6 (Ph),

121.3(q, J_CF268, C5), 102.2 (q, J_CF1.5, 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, J_HH18, H4), 3.76 (d, 1H,

J_HH18.4, H4), 3.68 (q, 1H, J_HH7.4, CH), 3.37 (d, 1H, J_HH18,

H4), 3.29 (d, 1H, J_HH18.4, H4), 2.05 (s, 6H, 2 × CH₃), 1.48

(d, 3H, J_HH7.2, 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, J_HH8.0, Ar), 6.85 (2H, d, J_HH8.0, 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, J_CF38, C5) 131.9, 129.2 (Ar),

121.1(q, J_CF268, C5), 114.0 (Ar), 102.4 (q, J_CF1.8, 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

NH₂NH_2.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, J_HH6.8, CH₂), 3.15 (2H, m, CH₂),

3.00 (2H, m, CH₂), 1.33 (3H, t, J_HH6.8, 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.

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

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