2-aryl-6-polyfluoroalkyl-4-pyrones as promising rf-building-blocks: Synthesis and application for construction of fluorinated azaheterocycles

Article abstract of DOI:10.3390/molecules26154415

A convenient and general method for the direct synthesis of 2-aryl-6-(trifluoromethyl)-4-pyrones and 2-aryl-5-bromo-6-(trifluoromethyl)-4-pyrones has been developed on the basis of one-pot oxidative cyclization of (E)-6-aryl-1,1,1-trifluorohex-5-ene-2,4-diones via a bromination/dehy-drobromination approach. This strategy was also applied for the preparation of 2-phenyl-6-polyfluoroalkyl-4-pyrones and their 5-bromo derivatives. Conditions of chemoselective enediones bromination were found and the key intermediates of the cyclization of bromo-derivatives to 4-pyrones were characterized. Synthetic application of the prepared 4-pyrones has been demonstrated for the construction of biologically important CF3-bearing azaheterocycles, such as pyra-zoles, pyridones, and triazoles.

Full text of DOI:10.3390/molecules26154415

molecules
Article
2-Aryl-6-Polyfluoroalkyl-4-Pyrones as Promising
RF-Building-Blocks: Synthesis and Application for
Construction of Fluorinated Azaheterocycles
Sergey A. Usachev , Diana I. Nigamatova, Daria K. Mysik, Nikita A. Naumov, Dmitrii L. Obydennov
and Vyacheslav Y. Sosnovskikh *
Institute of Natural Sciences and Mathematics, Ural Federal University, 51 Lenina Ave.,
620000 Ekaterinburg, Russia; s.a.usachev@urfu.ru (S.A.U.); nigamatova.di@yandex.ru (D.I.N.);
mysik.darya@gmail.com (D.K.M.); niquezor@yandex.ru (N.A.N.); dobydennov@mail.ru (D.L.O.)
* Correspondence: vy.sosnovskikh@urfu.ru; Tel.: +7-343-3899597
Abstract: A convenient and general method for the direct synthesis of 2-aryl-6-(trifluoromethyl)-4-
pyrones and 2-aryl-5-bromo-6-(trifluoromethyl)-4-pyrones has been developed on the basis of one-pot
oxidative cyclization of (E)-6-aryl-1,1,1-trifluorohex-5-ene-2,4-diones via a bromination/dehydrobrom-
ination approach. This strategy was also applied for the preparation of 2-phenyl-6-polyfluoroalkyl-4-
pyrones and their 5-bromo derivatives. Conditions of chemoselective enediones bromination were
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
found and the key intermediates of the cyclization of bromo-derivatives to 4-pyrones were character-
ꢀꢁꢂꢃꢄꢅꢆ
ized. Synthetic application of the prepared 4-pyrones has been demonstrated for the construction of
biologically important CF3-bearing azaheterocycles, such as pyrazoles, pyridones, and triazoles.
D.I.; Mysik, D.K.; Naumov, N.A.;
Citation: Usachev, S.A.; Nigamatova,
Obydennov, D.L.; Sosnovskikh, V.Y.
Keywords: β-diketones; 4-pyrones; fluorinated heterocycles; regioselective bromination
2-Aryl-6-Polyfluoroalkyl-4-Pyrones as
Promising RF-Building-Blocks:
Synthesis and Application for
Construction of Fluorinated
1. Introduction
Azaheterocycles. Molecules 2021, 26,
4415. https://doi.org/10.3390/
4-Pyrone unit is an important heterocyclic motif, which is frequently present in nu-
molecules26154415
merous natural products that exhibit a wide range of important biological activities [
and medicines, such as phenoxan [ ] (Figure 1). Mainly, pyrones are of interest as useful
and versatile building-blocks for the synthesis of valuable molecules [ ], including phar-
1–5]
5
Academic Editor: Viktor
O. Iaroshenko
6–9
maceuticals [10] and pyranic fluorophores [11]. Pyrones as polyelectrophilic substrates and
cyclic enone are able to react regioselectively with nucleophiles to undergo ring-opening
transformations affording azaheterocycles [12–16]. The formation of the product is usually
very sensitive to the reaction conditions (acidity, solvent polarity, temperature) that allows
divergent syntheses on the basis of 4-pyrones [15,16].
Received: 28 June 2021
Accepted: 19 July 2021
Published: 21 July 2021
It is known that fluorine-bearing compounds are of considerable interest for medicinal
chemistry and agrochemistry [17]. The search for readily available and highly functional-
ized fluorinated building blocks for the construction of complex molecules is an important
task for the synthesis of new bioactive substances.
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with regard to jurisdictional claims in
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iations.
To date considerable attention has been focused on 4-pyrones bearing the electron-
withdrawing RF group, which demonstrate higher reactivity with high chemoselectivity
of processes compared to non-fluorinated analogs [17,18]. The ring-opening reactions of
2-RF-4-pyrones can be applied for the preparation of a wide range of trifluoromethylated
azaheterocycles, such as indoles, regioisomeric pyrazoles, pyridines, benzodiazepines
etc., [14,16–18].
Despite the promising synthetic utility of CF3-bearing 4-pyrones, they remain to
be hard-to-reach compounds [17,18]. The methods for the construction of 4-pyrones are
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
actively developed, and in the literature there are three general approaches for the synthesis
of 2-RF-4-pyrones based on (i) cyclization of tricarbonyl compounds or their derivatives
prepared via Claisen condensation [19–22], (ii) cycloadditions of ketenes [23–25], and
Molecules 2021, 26, 4415. https://doi.org/10.3390/molecules26154415
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 4415
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(iii) modification of substituted 2-RF-4-pyrones (usually for carboxylic acid derivatives) via
side-chain transformations [26] (Scheme 1). However, there are usually some limitations
connected with the narrow scope of obtained pyrones, variation of the nature of the
substituents in several positions of the pyrone ring, and preparation of 4-pyrones bearing
long-chain polyfluoroakyl substituents.
Figure 1. Some representative examples of biologically important arylated 4-pyrones.
Scheme 1. The main strategies in the synthesis of arylated 2-RF-4-pyrones [20,21,23].
Inspired by the chemistry of 2-CF3-chromones (benzopyrones) [27] and 2-CF3-4-
pyrones [18], we decided to find an approach for the construction of a range of novel
arylated 2-RF-4-pyrones as useful building-blocks for the preparation of fluorinated hete-
rocycles. The number of 2-aryl-6-(trifluoromethyl)-4-pyrones described in the literature
is limited by several examples [23–25], and there is also the publication regarding the
reaction of 2-phenyl-6-(trifluoromethyl)-4-pyrone and salicylic aldehyde with no mention
of its synthesis [28]. Thus, there is no general method for the synthesis of the fluorinated
2-aryl-4-pyrones at the moment.

Molecules 2021, 26, 4415
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Recently, methods for the preparation of pyrones based on the cyclization of acetylenyl-
1,3-diketones have been actively developed [29–33], which allows the switchable prepa-
ration of 4-pyrones or furanones. Similar approach is the use of dibromo derivatives,
which can react as synthetic equivalents of acetylenyl-1,3-diketones and undergo dehydro-
bromination reactions under basic conditions [34–37]. This method was applied for the
preparation of 2-aryl-4-pyrones bearing the methyl and carboethoxy substituents. However,
low selectivity of the bromination reaction of the starting enediones, difficult isolation of
intermediate products, low yields, and very high sensitivity to the nature of the substituents
strongly restrict its utilization.
The chemical properties of 6-aryl-1,1,1-trifluorohex-5-ene-2,4-diones remain unex-
plored, but they can be considered as a platform for the preparation of new fluorinated
compounds [38–41]. The presence of several functional groups (conjugated double bonds
and the diketone moiety) in their molecules makes them attractive and useful tools in or-
ganic synthesis. The introduction of the strong electron-withdrawing trifluoromethyl group
can lead to a change in the chemoselectivity of the bromination reaction of 6-aryl-1,1,1-
trifluorohex-5-ene-2,4-diones in comparison with non-fluorinated analogs and to changes
in the cyclization step due to the ability of this group to stabilize cyclic and hemiacetal
forms [17].
In the present work, we have developed a general method for the preparation of
2-aryl-6-polyfluoroalkyl-4-pyrones and their 3-bromo derivatives based on one-pot cycliza-
tion through the stage of bromination/dehydrobromination of enediones. The synthetic
potential of the pyrones was demonstrated on the example of regioselective reactions with
N-nucleophiles.
2. Results and Discussion
We started our research with the preparation of fluorinated enediones
2 based on the
condensation reaction of 4-aryl-3-buten-2-ones with ethyl polyfluoroalkanoates in the
1
presence of sodium hydride in diethyl ether at room temperature or lithium hydride in
benzene under reflux (Scheme 2, Table 1). Both methods were comparably effective, and
CF3-bearing products 2a
described in the literature, but they were prepared by other methods [38
approach was applied for the preparation of polyfluorinated enediones 2j–l in 43–51%.
–
i
were obtained in 51–92% yields. Compounds 2a
,f–h have been
–41]. Besides, this
Scheme 2. Synthesis of enediones 2 via Claisen condensation.
We first focused on the bromination of CF3-containing compounds 2a–i in order
to obtain active intermediates and to develop a general method for the construction of
pyrones based on enediones
2. Both the double bond and the diketone moiety in 6-aryl-
1,1,1-trifluorohex-5-ene-2,4-diones
2
can undergo an electrophilic attack of bromine. To
estimate the influence of conditions on conversion, the chemo- and stereoselectivity (see
detailed data in Supplementary Materials), the bromination reaction was examined for
compound 2b bearing the para-fluorophenyl substituent (Scheme 3, Table 2). It was shown
that the most active fragment is the double bond that leads to the initial formation of
dibromo derivative 3b, and no product of initial attack only at the methylene group of
the diketone moiety was found. At the same time, compounds
3 due to the absence of
conjugation were able to react with Br2 by the diketone moiety at a comparable rate with
the starting enediones 2 giving tribromo derivatives 4.

Molecules 2021, 26, 4415
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Table 1. The scope of prepared enediones 2.
◦
Enedione
Ar
RF
Yield, %
Mp, C
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
3-O2NC6H4
4-MeC6H4
4-MeOC6H4
4-Me2NC6H4
2-C4H3S
Ph
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
75
64
60
92
51 a
65
81
67
84
43
43
51
56–58
83–84
92–93
86–87
119–120
61–62
104–105
79–80
94–95
85–87
Liq.
2j
2k
2l
CF2H
H(CF2)2
H(CF2)4
Ph
Ph
Liq.
a
Lithium hydride in benzene under reflux.
Scheme 3. Reaction of enediones 2 with Br2.
Table 2. Selectivity of bromination of enediones 2 a.
2:3:4 Ratio b
№
Ar
Enedione
Br2 Equiv.
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-MeOC6H4
2-C4H3S
4-ClC6H4
3-O2NC6H4
Ph
2b
2b
2b
2b
2b
2b
2b
2b
2b
2g
2i
1.0
1.0
2.5
1.0
1.0
1.0
1.0
1.2
2.2
1.0
1.0
1.0
1.0
1.0
1.0
AcOH e
CH2Cl2
CH2Cl2
t-BuOMe
dioxane
CS2
C6H6
C6H6
C6H6
C6H6
74:(7 + 2 c):(16 + 1 c)
42:(37 + 2 c):19
0:7 c:93
17:(31 + 4 c):(39 + 9 c)
29:65:6
25:(65 + 2 c):(7 + 1 c)
12:78:10
0:(75 + 4 c):(19 + 2 c)
0:(46 + 10 c):(33 + 11 c)
3:75:22
9:(80 + 8 d):3
C6H6
C6H6
C6H6
C6H6
2c
62:(10 + 3 c):25
55:(14 + 2 c):(26 + 3 c)
62:24:14
2e
2a
2a
Ph
CH2Cl2
0:(86 + 2 c):12
a
A solution of Br2 was added to enedione
2
under cooling on an ice-bath. The reaction mixture was stirred at
room temperature for 15 h. Based on the 19F and 1H NMR spectra. Cyclized to dihydropyrone. A product of
dehydrobromination was spontaneously formed. Br2 was added at room temperature.
b
c
d
e
When 1 equiv. of bromine was used, incomplete conversion was usually observed,
accompanied by the formation of tribromo derivative 4b. Bromination in acetic acid gave
low conversion (26%) and predominant formation of the tribromo derivative (3b:4b = 9:17)
(entry 1). Carrying out the reaction in aprotic polar solvents CH2Cl2 and t-BuOMe made it
possible to increase the conversion to 58 and 83%, respectively, but the selectivity turned
out to be low (entries 2,4). The use of non-polar aprotic solvents (dioxane, CS2) led to
the improved 3b
carried out in benzene, the highest conversion (88%), the highest NMR yield of 3b, and
the good selectivity of the reaction were found (3b 4b = 78:10) (entry 7). A slight increase
:4b ratio and 71–75% conversion (entries 5,6). When the reaction was
:
in the amount of bromine (up to 1.2 equiv.) led to a decrease in selectivity (3b
although the starting compound 2b was not detected at all (entry 8).
:4b = 79:21),
Further investigation showed that the bromination reaction is very sensitive to the
nature of the substituents in the aromatic ring (Scheme 3, Table 2, and Table S1 in Supple-
mentary Materials). Thus, the reaction proceeded with the highest selectivity with one

Molecules 2021, 26, 4415
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equivalent of bromine in benzene for compounds bearing moderate and good
π
-donors
(4-MeO, 4-F or Ar = 2-Th) (entries 7,10,11). The introduction of electron-withdrawing
substituents (4-Cl, 3-NO2) into the aromatic ring decreased the selectivity of the transfor-
mation for compounds 2c,e due to incomplete conversion and the formation of tribromo
derivatives 4 as major products (entries 12,13). Even in the case of enedione 2a (Ar = Ph),
selectivity and conversion of bromination in benzene turned out to be poor (entry 14), how-
ever, the use of CH2Cl2 as a solvent improved the selectivity and the conversion (entry 15).
The introduction of the strong electron-donating substituent (4-Me2N) led to preferential
bromination at the aromatic ring rather than at the double bond followed by cyclization
because of basic properties of the substituent (Scheme S1 in Supplementary Materials).
It should be noted that, in all cases, compounds
3 were formed as a sole anti-dibromo
diastereoisomer according to the classical concept of electrophilic addition of bromine to
alkenes via the cyclic bromonium cation [42].
Further, we decided to develop a procedure for the bromination of both fragments
of enediones
The reaction of enedione 2b with an excess of bromine (2.2 equiv.) in benzene gave
products with low selectivity (3b 4b = 56:44) (Table 2, entry 9). Moreover, significant
2 simultaneously for the selective preparation of tribromo derivatives 4.
:
amounts of corresponding dihydropyrones were formed as a result of spontaneous acid-
catalyzed cyclization. One of the highest yields of compound 4b in reaction with 1 equiv.
of bromine was observed in dichloromethane (entry 2). The use of bromine (2.5 equiv.) in
this solvent led to the almost selective formation of tribromo derivative 4b as a mixture of
two diastereoisomers in a ratio of 80:20 (entry 3).
Although the reaction of enediones
2 with Br2 gave dibromo derivatives 3 or tribromo
derivatives as major products, we did not usually isolate them in pure form to avoid
4
additional losses because of their ability to cyclize and high reactivity. But for several cases,
these compounds were obtained as a single isomer by recrystallization. The reaction of
enediones 2a,g with one equivalent of bromine in acetic acid made it possible to obtain
dibromo derivatives 3a and 3g in 71 and 28% yields, respectively (Scheme 4).
Scheme 4. Preparative bromination of enediones 2.
The reaction of chloro-substituted enedione 2c with an excess of bromine (2.5 equiv.)
in CH2Cl2 led to tribromo derivative 4c (dr = 80:20) smoothly in 82% yield. Compound
4c in pure crystalline form prepared by recrystallization from hexane is stable and can be
stored for a long time without changes.
The structure of tribromo derivatives
4 was established on the basis of elemental
analysis data and 1H and 19F NMR spectra (Table S3 in Supplementary Materials). In the
1H NMR spectra of these compounds in CDCl3, two singlets of the diastereotopic OH
groups were observed at
the CF3 group at 79.7–79.9 ppm indicating its location at the saturated carbon atom.
For compounds and , the characteristic chemical shifts of the trifluoromethyl group
appeared at 84.5–85.0 and 86.0 ppm, respectively (Table S2 in Supplementary Materials).
δ
4.06–4.46 and 4.62–4.79 ppm. The 19F NMR spectra exhibit
δ
2
3
δ
At the next stage of our work, we studied the cyclization of dibromo derivatives 3a,g
in the presence of bases. The use of t-BuOK in THF or pyridine, DIPEA, DBU, NaHCO3 in
various solvents (acetone, ethanol, DMSO) at room temperature did not allow us to obtain
4-pyrone 5a in an acceptable yield. The most favorable conditions turned out to be stirring
with a 2.5-fold excess of triethylamine in acetone for three days (Scheme 5). In addition,
the isolation of the product, in this case, does not require chromatography, and pyrones

Molecules 2021, 26, 4415
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5a,g precipitated in pure form upon dilution with water in 51–54% yields. This approach
can be scaled up to 5 g of enedione 2a, and the yield of pyrone 5a was 36% in two stages.
Scheme 5. Cyclization of dibromo derivatives 3 to pyrones 5.
The cyclization mechanism of compounds
intermediate via two possible pathways. The first path comprises the elimination of
hydrogen bromide (E) and the production of bromoenone , which then undergoes an
intramolecular Michael reaction (1,4-AN). The second possibility is the direct intramolecular
nucleophilic substitution of bromine (SN). As mentioned above, the cyclic pyranic form
was observed in the bromination reaction mixtures (Table 2), whereas bromoenones were
detected by NMR spectroscopy on the treatment of the dibromo derivatives with pyridine
3 includes the formation of dihydropyran
B
A
B
A
3
at room temperature. The easy formation of 2-bromoenones from 2,3-dibromoketones is
also well presented in the literature [42]. Thus, it can be assumed that the first path is more
preferable in basic conditions. Intermediate A0 was isolated in pure form with the use
of column chromatography (56% yield) from enedione 2i via bromination (1 equiv.) and
subsequent monodehydrobromination by DIPEA at room temperature.
Tribromo derivatives 4 undergo cyclization under the action of triethylamine in ace-
tone at room temperature much slower, furthermore, the high basicity of the medium could
provide a possibility of side reactions associated with detrifluoroacetylation [41]. Therefore,
dehydrohalogenation of 4 was carried out by refluxing for 10 h in pyridine as a solvent and
a weaker base (Scheme 6). The cyclization of compound 4c gave pyrone 6c in 36% yield.
These results demonstrate that the cyclization step determines mainly total output of the
pyrones. Moreover, the difference in reaction rates of cyclization of tribromo derivatives
4
and dibromo derivatives 3 allowed the isolation of pyrones 5 in the presence of Et3N
in acetone selectively, even when the reaction mixtures of the brominated intermediates
were used.

Molecules 2021, 26, 4415
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Scheme 6. Cyclization of tribromo derivative 4c to pyrone 6c.
With the optimized conditions of the bromination and cyclization of intermediate
bromo derivatives in hand, we decided to develop a simple one-pot two-step preparative
method for the synthesis of 4-pyrones
5 and 6 based on oxidative cyclization of enediones
2. Considering that the reaction mixtures of bromination contain various bromine-bearing
forms (cyclic and acyclic), the overall efficiency and convenience of this two-step process
without intermediate purification can improve (Scheme 7, Table 3).
Scheme 7. One-pot preparation of pyrones 5 and 6 from enediones 2.
For the preparation of 4-pyrones 5 in the one-pot approach, enediones 2 were treated
with 1 equiv. of bromine in benzene (Method A) for compounds bearing electron-donating
substituents (F, Me, MeO) and in CH2Cl2 (Method B) for compounds bearing weak electron-
withdrawing substituents (Cl, Br) or H at the C-4 position. After bromination, the solvent
was evaporated, and the cyclization was carried out using Et3N (2.5 equiv.) in acetone, as a
result, pyrones 5 were obtained in 28–69% yields.
The preparation of 3-bromo-4-pyrones
6 with a one-pot method was possible only for
substrates bearing weak electron-donating (H, 4-Me, 4-F) and electron-withdrawing groups
(4-Cl, 3-NO2) in the benzene ring since aromatic bromination was unavoidable with an
excess of bromine in case of highly activated aryl substituents. At the first stage, enedione
2
was treated with 2.5 equiv. of bromine in CH2Cl2 and subsequent heating at 100 ◦C in
pyridine for 10 h led to the formation of pyrones 6 in 4–42% yields (Method C).

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Table 3. The scope of 4-pyrone synthesis via the one-pot oxidative cyclization of enediones 2.
Enedione
Ar
Pyrone
Method
Yield, %
2a
2b
2c
2d
2f
2g
2i
2a
2b
2c
2e
2f
Ph
5a
5b
5c
5d
5f
5g
5i
6a
6b
6c
6e
6f
B
A
B
B
B
A
A
C
C
C
C
C
48
69
62
65
28
65
62
23
28
34
4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-C4H3S
Ph
4-FC6H4
4-ClC6H4
3-O2NC6H4
4-MeC6H4
42
Method A: The mixture of enedione
2 (1.0 mmol) with bromine (1.0 mmol) in C6H6 was stirred at room tem-
perature. Cyclization was carried out in the presence of Et3N (2.5 equiv.) in acetone. Method B: The mixture of
enedione (1.0 mmol) with bromine (1.0 mmol) was stirred in CH2Cl2 at room temperature. Cyclization was
2
carried out in the presence of Et3N in acetone. Method C: The mixture of enedione 2 (1.0 mmol) with bromine
(2.5 mmol) in CH2Cl2 was stirred at room temperature. Cyclization was carried in pyridine at 100 ◦C for 10 h.
This one-pot approach was also applied for the preparation of phenyl-4-pyrones bear-
ing various polyfluoroalkyl substituent. No significant difference in reactivity was observed
depending on fluorine content or chain length of RF-moiety, and the cyclization of ene-
diones 2j–l in the presence of 1 equiv. of bromine (Method B) gave 4-pyrones 5j–l in 40–70%
yields (Scheme 8). The use of Method C led to 3-bromopyrones 6j–l in 24–33% yields.
Scheme 8. Synthesis of 2-aryl-6-polyfluoroalkyl-4-pyrones 6j–l.
The structure of 4-pyrones
data, HRMS and NMR spectra. In the 1H NMR spectra of compounds
istic doublets of H-3 and H-5 protons of the pyrone ring were observed at
with a coupling constant of 1.8–2.2 Hz. In the case of pyrones , the signal of the H-5 proton
5
and
6
was established on the basis of elemental analysis
in CDCl3, character-
6.63–6.88 ppm
5
δ
6
of the pyrone ring appeared as a singlet at δ 6.88–7.04 ppm (CDCl3).
The next step was to study the chemical properties of 2-aryl-6-(trifluoromethyl)-4-
pyrones with N-nucleophiles to obtain azaheterocycles (Scheme 9). The reaction of pyrone
◦
5a with ammonia in ethanol in an autoclave at 120 C for 10 h led to the formation of
pyridone
azide [43] in DMSO afforded triazole
5a regioselectively attacking with the amino group at the C-2 and C-4 positions to give
pyrazole . The structure of pyrazole was assigned based on NMR spectra according to
the literature data [16,34].
7
in 70% yield. The ring-opening transformation of pyrone 5a with sodium
8
in 55% yield. Phenylhydrazine reacted with pyrone
9
9

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Scheme 9. Reaction of pyrone 5a with N-nucleophiles for the synthesis of fluorinated azaheterocycles.
Thus, a convenient and general method for the synthesis of 2-aryl-6-polyfluoroalkyl-
4-pyrones and their bromo derivatives has been developed based on one-pot oxidative
cyclization of fluorinated enediones. The selectivity of monobromination of 6-aryl-1,1,1-
trifluorohex-5-ene-2,4-diones is connected with the predominant electrophilic attack on the
double bond and strongly depends on the solvent used and the nature of the substituent in
the aromatic ring, which determines the scope of obtained fluorinated 2-aryl-4-pyrones.
6-Aryl-1,1,1-trifluorohex-5-ene-2,4-diones bearing electron-withdrawing and weak electron-
donating substituents in the aromatic ring react with an excess of bromine leading to
tribromo derivatives as a result of bromination of the double bond and the diketone moiety.
Di- and tribromo derivatives in a basic medium selectively undergo cyclization to form
4-pyrones. The resulting 4-pyrones have proven to be useful building blocks and have
been utilized to synthesize CF3-bearing heterocycles, which are of further interest in terms
of potential biological activity.
3. Materials and Methods
NMR spectra were recorded on Bruker DRX-400 (1H: 400 MHz, 13C: 100 MHz, 19F:
376.5 MHz) and Bruker Avance III-500 (1H: 500 MHz, 13C: 126 MHz, 19F: 471 MHz) spec-
trometers in DMSO-d6 and CDCl3. The chemical shifts (δ) are reported in ppm relative to
the internal standard TMS (1H NMR), C6F6 (19F NMR), and residual signals of the solvents
(13C NMR). IR spectra were recorded on a Shimadzu IRSpirit-T spectrometer using an
attenuated total reflectance (ATR) unit (FTIR mode, ZnSe crystal), the absorbance maxima
(ν
) are reported in cm–1. Elemental analyses were performed on an automatic analyzer
PerkinElmer PE 2400. Melting points were determined using a Stuart SMP40 melting point
apparatus. Column chromatography was performed on silica gel (Merck 60, 70–230 mesh).
All solvents that were used were dried and distilled by standard procedures. Arylideneace-
tones
1 have been synthesized according to the procedure, previously described in the
literature [44].
3.1. Synthesis of Enediones 2a–l
General Procedure. A suspension of NaH (60% by weight in mineral oil) (240 mg,
6.0 mmol) in dry Et2O (5 mL) was cooled on an ice bath, then CF3CO2Et (0.86 g, 6.0 mmol)
and a solution of arylideneacetone 1 (4.0 mmol) in dry Et2O (3 mL) were successively
added under stirring. The reaction mixture was warmed to room temperature and stirred
for 20 h. Then 1M aqueous HCl (10 mL) was added, and the organic phase was separated
(if the precipitate of diketonate formed, it was filtered and treated with 1M aqueous HCl
(10 mL)). The aqueous phase was extracted with AcOEt (5 mL). The combined organics
were washed with H2O and dried over anhydrous Na2SO4, the solvents evaporated, and

Molecules 2021, 26, 4415
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the residue recrystallized from hexane with decantation of hot solution from insoluble tarry
by-products.
General procedure (with LiH) [38]. A solution of arylideneacetone 1 (4.0 mmol) in dry
C6H6 (1 mL) and CF3CO2Et (0.86 g, 6.0 mmol) were successively added to a suspension
of LiH (48 mg, 6.0 mmol) in dry C6H6 (4 mL) under stirring. The reaction mixture was
warmed until the reaction started and then was stirred at room temperature for 20 h.
After that, the reaction mixture was poured into a mixture of ice (4 g) and H2SO4 (1 mL),
extracted with chloroform (5 mL), and dried over MgSO4. The solvents were evaporated,
and the residue recrystallized from hexane with decantation of hot solution from insoluble
tarry by-products.
(E)-1,1,1-Trifluoro-6-phenylhex-5-ene-2,4-dione (2a). Yield 0.73 g (75%), colorless needles, mp
56–58 ◦C (lit. mp 58 ◦C [40], 61–61.5 ◦C [38]).1H NMR (400 MHz, CDCl3) enol form:
δ 6.04
(1H, s, 3-CH); 6.58 (1H, d, J = 15.9 Hz, 5-CH); 7.37–7.57 (3H, m, H Ph); 7.53–7.61 (2H, m,
H-2, H-6 Ph); 7.77 (1H, d, J = 15.9 Hz, 6-CH); 14.22 (1H, s, OH). The analytical data are in
consistence with the literature [38,40].
(E)-1,1,1-Trifluoro-6-(4-fluorophenyl)hex-5-ene-2,4-dione (2b). Yield 0.67 g (64%), yellow prisms,
◦
mp 83–84 C. IR (ATR)
enol form: 6.02 (1H, s, 3-CH); 6.50 (1H, d, J = 15.8 Hz, 5-CH); 7.12 (2H, t, J = 8.6 Hz,
JHF = 8.6 Hz, H-3, H-5 Ar); 7.57 (2H, dd, J = 8.7 Hz, J = 5.3 Hz, H-2, H-6 Ar); 7.73 (1H, d,
J = 15.8 Hz, 6-CH); 14.24 (1H, s, OH). 19F NMR (376 MHz, CDCl3)
53.9 (tt, JHF = 8.4 Hz,
HF = 5.4 Hz, F); 84.7 (s, CF3). 13C NMR (126 MHz, CDCl3) 95.6 (q, 3JCF = 1.4 Hz, C-3); 116.4
ν
1637, 1578, 1509, 1444, 1414. 1H NMR (500 MHz, CDCl3)
δ
δ
J
δ
(d, 2JCF = 22.0 Hz, C-3, C-5 Ar); 116.7 (q, 1JCF = 286.6 Hz, CF3); 120.8 (d, 6JCF = 2.4 Hz, C-5);
130.4 (s, C-1 Ar); 130.5 (d, 4JCF = 8.8 Hz, C-2, C-6 Ar); 142.3 (C-6); 164.3 (d, 1JCF = 253.2 Hz,
C-4 Ar); 180.5 (q, 2JCF = 36.1 Hz, C-2); 180.8 (C-4). HRMS (ESI) m/z [M + H]+. Calcd for
C12H9F4O2: 261.0539. Found: 261.0533.
(E)-6-(4-Chlorophenyl)-1,1,1-trifluorohex-5-ene-2,4-dione (2c). Yield 0.66 g (60%), yellow nee-
◦
1
dles, mp 92–93 C. IR (ATR)
(500 MHz, CDCl3) enol form:
d, J = 8.5 Hz, H Ar); 7.50 (2H, d, J = 8.5 Hz, H Ar); 7.71 (1H, d, J = 15.8 Hz, 6-CH); 14.17 (1H,
ν
3072, 3035, 1632, 1610, 1573, 1561, 1491, 1454, 1410. H NMR
δ
6.03 (1H, s, 3-CH); 6.54 (1H, d, J = 15.8 Hz, 5-CH); 7.40 (2H,
s, OH). 19F NMR (471 MHz, CDCl3) 84.6 (s, CF3). 13C NMR (126 MHz, CDCl3)
δ δ 95.80 (q,
3JCF = 1.4 Hz, C-3); 116.63 (q, 1JCF = 285.6 Hz, CF3); 121.5 (s, C-5); 129.4 (s, 2H); 129.6 (s,
2H); 132.7 (s, C Ar); 137.1 (s, C Ar); 142.1 (s, C-6); 180.4 (s, C-4); 180.8 (q, 2JCF = 36.1 Hz,
C-2). Anal. Calcd for C12H8ClF3O2: C 52.10; H 2.91. Found: C 51.93; H 2.94%.
(E)-6-(4-Bromophenyl)-1,1,1-trifluorohex-5-ene-2,4-dione (2d). Yield 1.18 g (92%), white crystals,
1
mp 86–87 ◦C. IR (ATR)
enol form:
ν
1632, 1609, 1582, 1487, 1454, 1406. H NMR (400 MHz, CDCl3)
δ
6.03 (1H, s, 3-CH); 6.56 (1H, d, 3J = 15.9 Hz, 5-CH); 7.43 (2H, d, 3J = 8.4 Hz, H
Ar); 7.56 (2H, d, 3J = 8.4 Hz, H Ar); 7.69 (1H, d, 3J = 15.9 Hz, 6-CH); 14.15 (1H, s, OH). 19
F
NMR (376 MHz, CDCl3) δ δ 95.8 (unresolved
84.7 (s, CF3). 13C NMR (101 MHz, CDCl3)
q, C-3); 116.7 (q, 1JCF = 285.5 Hz, CF3); 121.6 (C-5); 125.5 (C Ar); 129.8 (2C Ar); 132.4 (2C
Ar); 133.1 (C Ar); 142.1 (C-6); 180.4 (C-4); 180.8 (q, 2JCF = 36.2 Hz, C-2). Anal. Calcd for
C12H8BrF3O2: C 44.89; H 2.51. Found: C 45.03; H 2.57%.
(E)-1,1,1-Trifluoro-6-(3-nitrophenyl)hex-5-ene-2,4-dione (2e). Yield 0.59 g (51%), white scales,
1
mp 118–119 ◦C. IR (ATR)
enol form:
ν
1644, 1610, 1577, 1523, 1477, 1429. H NMR (400 MHz, CDCl3)
δ
6.10 (1H, s, 3-CH); 6.70 (1H, d, 3J = 15.9 Hz, 5-CH); 7.63 (1H, t, 3J = 8.0 Hz, H-5
Ar); 7.79 (1H, d, 3J = 15.9 Hz, 6-CH); 7.86 (1H, dt, 3J = 7.7 Hz, 4J = 1.0 Hz, H-6 Ar); 8.27 (1H,
ddd, 3J = 8.5 Hz, 4J = 2.1 Hz, 4J = 0.8 Hz, H-4 Ar); 8.44 (1H, t, 4J = 1.8 Hz, H-2 Ar); 13.96
(1H, s, OH). 19F NMR (376 MHz, CDCl3) 84.5 (s, CF3). HRMS (ESI) m/z [M – H]–. Calcd
δ
for C12H7F3NO4: 286.0327. Found: 286.0331.
(E)-1,1,1-Trifluoro-6-(p-tolyl)hex-5-ene-2,4-dione (2f). Yield 0.67 g (65%), yellow needles, mp
1
61–62 ◦C. IR (ATR)
ν
3031, 2956, 2926, 2360, 1652, 1594, 1575, 1516, 1447, 1416. H NMR
(400 MHz, CDCl3) enol form:
δ 2.40 (3H, s, Me); 6.01 (1H, s, 3-CH); 6.53 (1H, d, J = 15.8 Hz,
5-CH); 7.23 (2H, d, J = 8.0 Hz, H-3, H-5 Ar); 7.47 (2H, d, J = 8.1 Hz, H-2, H-6 Ar); 7.75 (1H,

Molecules 2021, 26, 4415
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d, J = 15.8 Hz, 6-CH); 14.30 (1H, s, OH). 19F NMR (376 MHz, CDCl3)
NMR (101 MHz, CDCl3)
δ
84.7 (s, CF3). 13C
δ
21.6 (CH3); 95.4 (q, 3JCF = 1.5 Hz, C-3); 116.8 (q, 1JCF = 285.3 Hz,
CF3); 120.0 (C-5); 128.6 (2C Ar); 129.9 (2C Ar); 131.5 (C Ar); 141.9 (C Ar); 143.90 (C-6); 180.1
(q, 2JCF = 36.0 Hz, C-2); 181.5 (C-4). Anal. Calcd for C13H11F3O2: C 60.94; H 4.33. Found: C
60.96; H 4.47%. The analytical data are in consistence with the literature [41].
(E)-1,1,1-Trifluoro-6-(4-methoxyphenyl)hex-5-ene-2,4-dione (2g). Yield 0.88 g (81%), yellow
needles, mp 100–101 ◦C (lit. mp 98 ◦C [40]). IR (ATR)
ν
1633, 1568, 1511, 1453, 1441, 1420.
3.86 (3H, s, OMe); 6.00 (1H, s, 3-CH); 6.45 (1H,
d, 3J = 15.8 Hz, 5-CH); 6.94 (2H, d, 3J = 8.8 Hz, H-3, H-5 Ar); 7.53 (2H, d, 3J = 8.4 Hz, H-2,
H-6 Ar); 7.74 (1H, d, 3J = 15.8 Hz, 6-CH); 14.45 (1H, s, OH). 19F NMR (471 MHz, CDCl3)
1H NMR (500 MHz, CDCl3) enol form:
δ
δ
84.8 (s, CF3). 13C NMR (101 MHz, CDCl3) 55.5 (OMe); 95.2 (q, 2JCF = 1.2 Hz, C-3); 114.7
δ
(2C Ar); 116.9 (q, 1JCF = 285.1 Hz, CF3); 118.6 (C-5); 126.9 (C Ar); 130.5 (2C Ar); 143.7 (C-6);
2
162.2 (C Ar); 179.7 (q, JCF = 35.9 Hz, C-2); 181.9 (C-4). Anal. Calcd for C13H11F3O3: C
57.36; H 4.07. Found: C 57.38; H 4.20%. The analytical data are in consistence with the
literature [40].
(E)-6-(4-(Dimethylamino)phenyl)-1,1,1-trifluorohex-5-ene-2,4-dione (2h). Yield 0.76 g (67%),
magenta needles, mp 79–80 ◦C (lit. mp 78–79 ◦C [39]). IR (ATR)
ν 2900, 1556, 1519, 1453,
1
1430, 1360, 1328. H NMR (500 MHz, CDCl3) enol form:
δ 3.07 (6H, s, NMe2); 5.95 (1H, s,
3-CH); 6.35 (1H, d, 3J = 15.6 Hz, 5-CH); 6.68 (2H, d, 3J = 8.9 Hz, H-3, H-5 Ar); 7.47 (2H, d,
3
3J = 8.9 Hz, H-2, H-6 Ar); 7.74 (1H, d, J = 15.6 Hz, 6-CH); 14.69 (1H, s, OH). 19F NMR
(471 MHz, CDCl3)
δ 85.0 (s, CF3). Anal. Calcd for C14H14F3NO2: C 58.95; H 4.95; N
4.91. Found: C 58.92; H 4.94; N 4.79%. The analytical data are in consistence with the
literature [39].
(E)-1,1,1-Trifluoro-6-(thiophen-2-yl)hex-5-ene-2,4-dione (2i). Yield 0.83 g (84%), yellow rectan-
1
gular prisms, mp 94–95 ◦C. IR (ATR)
enol form:
ν
1577, 1503, 1437, 1416. H NMR (400 MHz, CDCl3)
δ
5.99 (1H, s, 3-CH); 6.36 (1H, d, 3J = 15.5 Hz, 5-CH); 7.11 (1H, dd, 3J = 4.9 Hz,
3J = 3.8 Hz, H-4 Th); 7.35 (1H, d, 3J = 3.5 Hz, H-3 Th); 7.48 (1H, d, 3J = 5.0 Hz, H-5 Th);
7.88 (1H, d, 3J = 15.5 Hz, 6-CH); 14.28 (1H, s, OH). 19F NMR (376 MHz, CDCl3)
δ
84.8 (s,
CF3). 13C NMR (101 MHz, CDCl3)
δ
95.5 (unresolved q, C-3); 116.8 (q, JCF = 285.3 Hz,
1
CF3); 119.8 (C-5); 128.6; 130.2; 132.4; 136.2; 139.8; 180.1 (q, 2JCF = 36.0 Hz, C-2); 180.8 (C-4).
Anal. Calcd for C10H7F3O2S: C 48.39; H 2.84. Found: C 48.36; H 2.75%.
(E)-1,1-Difluoro-6-phenylhex-5-ene-2,4-dione (2j). Yield 0.39 g (43%), yellow crystals, mp
◦
85–87 C. IR (ATR)
ν
3030, 1647, 1495, 1341, 1180, 1105, 867, 757. 1H NMR (500 MHz,
2
CDCl3) enol form:
δ
5.91 (1H, t, JHF = 54.3 Hz, CF2H); 6.04 (1H, s, 3-CH); 6.58 (1H, d,
J = 15.9 Hz, 5-CH); 7.39–7.44 (3H, m, H Ph); 7.51–7.62 (2H, m, H-2, H-6 Ph); 7.72 (1H, d,
J = 15.9 Hz, 6-CH); 14.58 (1H, s, OH). 19F NMR (471 MHz, CDCl3) 35.0 (dd, 2JHF = 54.4 Hz,
96.0 (t, 3JCF = 1.9 Hz, C-4); 109.6 (t,
δ
4JHF = 0.5 Hz, CF2H). 13C NMR (126 MHz, CDCl3)
δ
1JCF = 249.0 Hz, CF2H); 121.8 (C-6); 128.4 (2C Ph); 129.1 (2C Ph); 130.8 (C Ph); 134.4 (C Ph);
142.7 (C-7); 181.0 (C-5); 186.5 (t, 2JCF = 25.7 Hz, C-3). Anal. Calcd for C12H10F2O2: C 64.29;
H 4.50. Found: C 64.69; H 4.35.
(E)-6,6,7,7-Tetrafluoro-1-phenylhept-1-ene-3,5-dione (2k). Yield 0.47 g (43%), yellow liquid.
IR (ATR)
form: 6.10 (tt, JHF = 52.9 Hz, JHF = 5.1 Hz, CF2H); 6.13 (1H, s, 4-CH); 6.58 (1H, d,
J = 15.9 Hz, 6-CH); 7.40–7.45 (3H, m, H Ph); 7.53–7.61 (2H, m, H-2, H-6 Ph); 7.77 (1H, d,
J = 15.9 Hz, 7-CH); 14.45 (1H, s, OH). 19F NMR (376 MHz, CDCl3) 23.4 (dt, 2JHF = 52.9 Hz,
3JFF = 6.9 Hz, CF2H); 35.8 (tdd, 3JFF = 6.9 Hz, 3JHF = 5.1 Hz, 4JHF = 0.8 Hz, CF2). 13C NMR
ν
3028, 1633, 1580, 1449, 1244, 1110, 700. 1H NMR (400 MHz, CDCl3) enol
2
3
δ
δ
1
2
(126 MHz, CDCl3)
δ 96.8 (unresolved t, C-4); 109.1 (tt, JCF = 251.2 Hz, JCF = 34.1 Hz,
CF2H); 109.5 (tt, 1JCF = 258.5 Hz, 2JCF = 27.8 Hz, CF2); 121.3 (C-6); 128.4 (2C Ph); 129.1 (2C
Ph); 131.0 (C Ph); 134.3 (C Ph); 143.6 (C-7); 180.1 (q, 2JCF = 26.7 Hz, C-3); 180.9 (C-5). HRMS
(ESI) m/z [M + H]+. Calcd for C13H11F4O2: 275.0695. Found: 275.0694.
(E)-6,6,7,7,8,8,9,9-Octafluoro-1-phenylnon-1-ene-3,5-dione (2l). Yield 0.76 g (51%), yellow liq-
1
uid. IR (ATR)
ν
2929, 1633, 1580, 1450, 1172, 1034, 972, 787. H NMR (500 MHz, CDCl3)

Molecules 2021, 26, 4415
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δ
enol form (88%): 6.08 (1H, s, 4-CH); 6.12 (1H, tt, 2JHF = 52.0 Hz, 3JHF = 5.5 Hz, CF2H);
6.58 (1H, d, J = 15.8 Hz, 2-CH); 7.39–7.47 (3H, m, H Ph); 7.54–7.61 (2H, m, H-2, H-6 Ph);
7.79 (1H, d, J = 15.8 Hz, 1-CH); 14.33 (1H, s, OH); keto form (12%): 2.77 (2H, s, CH2); 6.08
2
3
(1H, tt, JHF = 52.0 Hz, JHF = 5.5 Hz, CF2H); 6.46 (1H, d, J = 15.9 Hz, 2-CH); 7.39–7.47
(3H, m, H Ph); 7.54–7.61 (2H, m, H-2, H-6 Ph); 7.81 (1H, d, J = 15.9 Hz, 1-CH). 19F NMR
2
(471 MHz, CDCl3)
δ
enol form (88%): 24.4 (dm, JHF = 51.9 Hz, CF2H); 32.0 –32.1 (m,
8-CF2); 37.0 (t, 3JFF = 8.2 Hz, 7-CF2); 40.5 (t, 3JFF = 9.9 Hz, 6-CF2); keto form (12%): 24.4 (dm,
2JHF = 51.9 Hz, CF2H); 31.9–32.0 (m, 8-CF2); 36.9 (t, JFF = 8.2 Hz, 7-CF2); 42.3 (t,
3
3JFF = 9.6 Hz, 6-CF2). 13C NMR (126 MHz, CDCl3)
δ 97.2 (unresolved m, C-6); 107.6
(tt, 1JCF = 254.7 Hz, 2JCF = 30.9 Hz, CF2H); 107.7–113.5 (m, 3CF2); 121.0 (C-8); 128.5 (2C Ph);
129.1 (2C Ph); 131.2 (C Ph); 134.2 (C Ph); 144.0 (C-9); 180.5 (C-7); 182.5 (t, 2JCF = 26.7 Hz,
C-5). HRMS (ESI) m/z [M + H]+. Calcd for C15H11F8O2: 375.0631. Found: 375.0627.
3.2. Synthesis of Compounds 3a,g
General procedure. A solution of Br2 (3.20 g, 0.020 mol) in glacial AcOH (5.7 mL) was
added dropwise to enedione 2 (0.020 mol) in glacial AcOH (18 mL) cooled by a water bath.
After that, the reaction mixture was stirred for 1 h at room temperature. The resulting
solution was diluted by water (30 mL). The precipitate that formed was filtered. If it is
needed, the pure product can be obtained by recrystallization from heptane.
(5S,6R)-5,6-Dibromo-1,1,1-trifluoro-6-phenylhexane-2,4-dione (3a). Yield 5.71 g (71%), beige
◦
1
powder, mp 119–120 C. IR (ATR)
DMSO-d6) enol form:
5.56 (1H, d, 3J = 11.7 Hz, CHBr); 6.08 (1H, d, 3J = 11.7 Hz, CHBr);
6.30 (1H, s, 3-CH); 7.29–7.46 (3H, m, H Ph); 7.49–7.54 (2H, m, H-2, H-6 Ph). 1H NMR
(400 MHz, CDCl3)
4.96 (1H, d, 3J = 11.6 Hz, CHBr); 5.39 (1H, d, 3J = 11.6 Hz, CHBr); 6.24
(1H, s, 3-CH); 7.38–7.50 (5H, m, H Ph). 19F NMR (471 MHz, CDCl3) 86.0 (s, CF3). 13C
ν 1665, 1629, 1604, 1497, 1458, 1434. H NMR (400 MHz,
δ
δ
δ
NMR (126 MHz, CDCl3) δ 48.8; 51.2; 96.5; 117.1 (q, J = 280.4 Hz, CF3); 128.0; 129.0; 129.6;
137.4; 171.9 (q, J = 37.2 Hz, C-2); 190.6. HRMS (ESI) m/z [M – H]–. Calcd for C12H8Br2F3O2:
398.8843. Found: 398.8835.
(5S,6R)-5,6-Dibromo-1,1,1-trifluoro-6-(4-methoxyphenyl)hexane-2,4-dione (3g). Yield 2.42 g
1
(28%), yellow powder, mp 124–125 ◦C. IR (ATR)
(500 MHz, CDCl3) enol form:
ν
1665, 1607, 1514, 1462, 1443. H NMR
δ
3.84 (3H, s, OMe); 4.93 (1H, d, 3J = 11.6 Hz, CHBr); 5.37
(1H, d, 3J = 11.6 Hz, CHBr); 6.21 (1H, s, 3-CH); 6.92 (2H, d, 3J = 8.6 Hz, H-3, H-5 Ar); 7.35
(2H, d, 3J = 8.6 Hz, H-2, H-6 Ar); 13.50 (1H, s, OH). 19F NMR (376 MHz, CDCl3)
δ 86.0 (s,
CF3). Anal. Calcd for C13H11Br2F3O3: C 36.14; H 2.57. Found: C 36.48; H 2.73%.
3.3. Synthesis of Compound 4c
A solution of Br2 (400 mg, 2.5 mmol) in CH2Cl2 (2 mL) was added to enedione 2c
(277 mg, 1 mmol) in CH2Cl2 (8 mL) under cooling on an ice-bath. The reaction mixture was
left at room temperature for 15 h, and then the solvent was evaporated without heating.
The residue is a mixture of diastereoisomeres (dr = 80:20), which was recrystallized from
hexane to obtain single isomer in pure form for analysis.
(1R0,2S0)-1,2,4-Tribromo-1-(4-chlorophenyl)-6,6,6-trifluoro-5,5-dihydroxyhexan-3-one (4c). Yield
0.44 g (82%), white powder, mp 125–128 ◦C (toluene-hexane). After recrystallization from
◦
hexane, mp 154–155 C (for the major diastereoisomer in pure form). IR (ATR)
ν 3015, 1714,
1
1597, 1493, 1295, 1207, 990, 830, 715. H NMR (500 MHz, CDCl3)
δ major diastereomer
(80%): 4.38 (1H, s, OH); 4.74 (1H, s, OH); 4.95 (1H, s, 4-CHBr); 5.24 (1H, d, 3J = 11.3 Hz,
2-CHBr); 5.35 (1H, d, 3J = 11.3 Hz, 1-CHBr); 7.32–7.43 (4H, m, H Ar); minor diastereomer
(20%): 3.94 (1H, s, OH); 4.58 (1H, s, OH); 4.98 (1H, s, 4-CHBr); 5.19 (1H, d, 3J = 11.3 Hz,
2-CHBr); 5.27 (1H, d, 3J = 11.3 Hz, 1-CHBr); 7.34–7.41 (4H, m, H Ar). 19F NMR (471 MHz,
CDCl3)
δ major diastereomer: 79.7 (s, CF3). Anal. Calcd for C12H9Br3ClF3O3: C 27.02; H
1.70. Found: C 27.32; H 1.79%.

Molecules 2021, 26, 4415
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3.4. Synthesis of Compound A’
A solution of dibromide 3i, which was prepared by reaction of enedione 2i (248 mg,
1 mmol) with Br2 (160 mg, 1 mmol) in CH2Cl2 (3.4 mL) without additional purification,
and DIPEA (323 mg, 2.5 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 15 h.
The reaction mixture was then quenched with aqueous HCl (10 mL, 0.5 M), the organic
phase was separated, washed with water and brine, dried under Na2SO4, and evaporated.
The crude product was purified by column chromatography (CH2Cl2).
5-Bromo-1,1,1-trifluoro-6-(thiophen-2-yl)hex-5-ene-2,4-dione (A’). Yield 183 mg (56%), dark
1
yellow solid, mp 84–85 ◦C. IR (ATR)
ν
1623, 1573, 1413. H NMR (500 MHz, CDCl3) enol
3
3
form:
δ 6.69 (1H, s, 3-CH); 7.22 (1H, dd, J = 4.9 Hz, J = 3.5 Hz, H-4 Th); 7.65 (1H, d,
3J = 3.5 Hz, H-3 Th); 7.72 (1H, d, J = 4.9 Hz, H-5 Th); 8.53 (1H, s, 6-CH); 14.77 (1H, s,
3
OH). 19F NMR (471 MHz, CDCl3)
δ
85.5 (s, CF3). 13C NMR (126 MHz, CDCl3)
δ
95.0 (q,
3JCF = 2.1 Hz, C-4); 112.4; 117.2 (q, JCF = 283.1 Hz, CF3); 127.6; 133.2; 134.1; 136.9;
1
137.7; 176.2 (q, JCF = 37.1 Hz, C-2); 182.3 (C-4). HRMS (ESI) m/z [M + H]+. Calcd for
2
C10H7BrF3O2S: 326.9302. Found: 326.9315.
3.5. Synthesis of Pyrones 5
General procedure. A solution of Br2 (160 mg, 1.0 mmol) in the solvent (1.7 mL) was
added to enedione 2 (1 mmol) in the solvent (2.7 mL) under cooling on an ice-bath (C6H6
was used for Method A, CH2Cl2 – Method B). After that, the reaction mixture was stirred
at room temperature for 15 h, and then the solvent was evaporated without heating. Then
acetone (4.3 mL) was added to the residue, and the solution was treated with Et3N (0.253 g,
2.5 mmol) under cooling on an ice-bath. After that, the reaction mixture was stirred at room
temperature for 3 days and was diluted with H2O (15 mL). The precipitate was filtered,
washed with water, and recrystallized from hexane.
2-Phenyl-6-(trifluoromethyl)-4H-pyran-4-one (5a). Method B. Yield 115 mg (48%), pale-yellow
◦
fine crystals, mp 85–86 C. Procedure from dibromide 3a: Solutions of dibromide 3a (2.00 g,
5.0 mmol) in acetone (20 mL) was treated with Et3N (1.26 g, 12.5 mmol) under cooling on
an ice bath. After that, the reaction mixture was stirred at room temperature for 3 days
and diluted with H2O (75 mL). The precipitate was filtered, washed with water, and
recrystallized from hexane. Yield 51% (0.60 g), pale-yellow fine crystals, mp 85–86 ◦C. IR
1
(ATR)
ν
3068, 1668, 1632, 1605, 1579, 1498, 1451, 1415. H NMR (400 MHz, CDCl3)
δ
6.76
(1H, d, 4J = 2.1 Hz, CH); 6.84 (1H, d, 4J = 2.1 Hz, CH); 7.50–7.61 (3H, m, H Ph); 7.76–7.80
(m, 2H, H-2, H-6 Ph). 19F NMR (471 MHz, CDCl3) 90.3 (s, CF3). 13C NMR (126 MHz,
δ
CDCl3) δ
112.3; 114.7 (q, 3JCF = 2.3 Hz, C-5); 118.5 (q, 1JCF = 274.8 Hz, CF3); 126.0 (2C Ar);
129.3 (2C Ar); 129.9; 132.2; 152.4 (q, 2JCF = 39.6 Hz, C-6); 163.9; 178.0 (CO). Anal. Calcd for
C12H7F3O2: C 60.01; H 2.94. Found: C 59.63; H 2.56%.
2-(4-Fluorophenyl)-6-(trifluo◦romethyl)-4H-pyran-4-one (5b). Method A. Yield 0.18 g (69%),
ν 3064, 1674, 1637, 1601, 1509, 1291, 1085, 945, 838.
beige powder, mp 109–110 C. IR (ATR)
1H NMR (400 MHz, CDCl3) 6.78 (1H, d, 4J = 2.1 Hz, CH); 6.82 (1H, d, 4J = 2.1 Hz, CH);
δ
7.19–7.25 (2H, m, H-3, H-5 Ar); 7.76–7.85 (2H, m, H-2, H-6 Ar). 19F NMR (471 MHz, CDCl3)
δ
55.8 (tt, 3JFH = 8.2 Hz, 4JFH = 5.1 Hz, F-Ar); 90.3 (s, CF3). 13C NMR (126 MHz, CDCl3)
δ
112.1 (d, 6JCF = 0.8 Hz, C-4); 114.8 (q, 3JCF = 2.6 Hz, C-5); 116.7 (d, 2JCF = 22.3 Hz, C-3, C-5
Ar); 118.3 (q, 1JCF = 273.5 Hz, CF3); 126.1 (d, 4JCF = 3.3 Hz, C-1 Ar); 128.3 (d, 3JCF = 9.0 Hz,
C-2, C-6 Ar); 152.4 (q, 2JCF = 39.4 Hz, C-6); 163.0 (C-2); 164.9 (d, 1JCF = 253.2 Hz, C-4 Ar);
177.9 (CO). Anal. Calcd for C12H6F4O2
·
0.33H2O: C 54.57; H 2.54. Found: C 54.31; H 2.57%.
2-(4-Chlorophenyl)-6-(trifluoromethyl)-4H-pyran-4-one (5c). Method B. Yield 170 mg (62%),
◦
beige crystals, mp 135–137 C. IR (ATR)
NMR (400 MHz, CDCl3)
6.76 (1H, d, 4J = 2.1 Hz, CH); 6.81 (1H, d, 4J = 2.1 Hz, CH); 7.51
(2H, d, 3J = 8.7 Hz, H Ar); 7.72 (2H, d, 3J = 8.7 Hz, H Ar). 19F NMR (376 MHz, CDCl3)
90.3 (s, CF3). 13C NMR (126 MHz, CDCl3) 112.4 (C-3); 114.8 (q, 3JCF = 2.6 Hz, C-5); 118.4 (q,
1JCF = 273.7 Hz, CF3); 127.3 (2C Ar); 128.3 (C Ar); 129.7 (2C Ar); 138.7; 152.4 (q,
ν
3061, 1671, 1632, 1605, 1492, 1416, 1407. 1H
δ
δ
δ

Molecules 2021, 26, 4415
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2JCF = 39.6 Hz, C-6); 162.8; 177.7 (CO). Anal. Calcd for C12H6ClF3O2: C 52.48; H 2.20.
Found: C 52.47; H 2.40%.
2-(4-Bromophenyl)-6-(trifluoromethyl)-4H-pyran-4-one (5d). Method B. Yield 0.207 mg (65%),
◦
colorless powder, mp 161–163 C. IR (ATR)
ν
3059, 1668, 1654, 1645, 1627, 1600, 1590,
1
1488, 1414, 1402. H NMR (500 MHz, CDCl3)
δ
6.76 (1H, d, 4J = 2.1 Hz, H-3); 6.82 (1H, d,
4J = 2.1 Hz, H-5); 7.64 (2H, d, 3J = 8.8 Hz, H Ar); 7.67 (2H, d, 3J = 8.8 Hz, H Ar). 19F NMR
(471 MHz, CDCl3)
δ δ 112.4 (C-3); 114.9 (q,
90.3 (s, CF3). 13C NMR (126 MHz, CDCl3)
3JCF = 2.6 Hz, C-5); 118.4 (q, 1JCF = 273.9 Hz, CF3); 127.1 (C Ar); 127.4 (2C Ar); 128.8 (C
Ar); 132.6 (2C Ar); 152.4 (q, 2JCF = 39.7 Hz, C-6); 162.9 (C-2); 177.7 (CO). Anal. Calcd for
C12H6BrF3O2: C 45.17; H 1.90. Found: C 45.00; H 1.94%.
2-(p-Tolyl)-6-(trifl◦uoromethyl)-4H-pyran-4-one (5f). Method B. Yield 71 mg (28%), colorless
1
needles, 105–107 C. IR (ATR)
ν
1645, 1632, 1608, 1594, 1569, 1511, 1447. H NMR (500 MHz,
CDCl3)
δ 2.44 (3H, s, Me); 6.74 (1H, d, J = 2.1 Hz, H-5); 6.80 (1H, d, J = 2.1 Hz, H-3); 7.32
(2H, d, J = 8.1 Hz, H-3, H-5 Ar); 7.67 (2H, d, J = 8.1 Hz, H-2, H-6 Ar). 19F NMR (471 MHz,
CDCl3)
δ δ 21.5 (CH3); 111.6 (C-3); 114.6 (q,
90.3 (s, CF3). 13C NMR (126 MHz, CDCl3)
3JCF = 2.5 Hz, C-5); 118.5 (q, 1JCF = 273.8 Hz, CF3); 125.9 (2C Ar); 127.0 (C Ar); 130.0 (2C
Ar); 143.1(C Ar); 152.3 (q, 2JCF = 39.5 Hz, C-6); 164.1 (C-2); 178.0 (CO). HRMS (ESI) m/z [M
+ H]+. Calcd for C13H10F3O2: 255.0633. Found: 255.0625.
2-(4-Methoxyphenyl)-6-(trifluoromethyl)-4H-pyran-4-one (5g). Method A. Yield 176 mg (65%),
◦
yellow crystals, mp 106–107 C. IR (ATR)
ν
3019, 1685, 1598, 1522, 1489, 1432. 1H
4
NMR (500 MHz, CDCl3)
δ
3.89 (3H, s, Me); 6.73 (1H, d, J = 2.1 Hz, CH); 6.75 (1H, d,
4J = 2.1 Hz, CH); 7.02 (2H, d, 3J = 8.9 Hz, H-3, H-5 Ar); 7.73 (2H, d, 3J = 8.9 Hz, H-2, H-6
Ar). 19F NMR (376 MHz, CDCl3) 90.3 (s, CF3). 13C NMR (126 MHz, CDCl3)
δ δ 55.5 (CH3);
110.7 (C-3); 114.6 (q, 3JCF = 2.5 Hz, C-5); 114.7 (2C Ar); 118.6 (q, 1JCF = 273.6 Hz, CF3); 122.1
(C Ar); 127.8 (2C Ar); 152.1 (q, 2JCF = 39.4 Hz, C-6); 162.9; 164.0; 178.0 (CO). Anal. Calcd for
C13H9F3O3: C 57.79; H 3.36. Found: C 57.39; H 3.39%.
2-(Thiophen-2-yl)-6-(trifluo◦romethyl)-4H-pyran-4-one (5i). Method A. Yield 153 mg (62%),
1
yellow crystals, mp 87–88 C. IR (ATR)
ν
3042, 1668, 1652, 1630, 1594, 1427, 1408. H NMR
(400 MHz, CDCl3)
δ 6.68 (1H, d, J = 2.1 Hz, H-5); 6.71 (1H, d, J = 2.1 Hz, H-3); 7.19 (1H, dd,
3J = 4.9 Hz, 3J = 3.9 Hz, H-4 Th); 7.60 (1H, d, 3J = 4.9 Hz, H-5 Th); 7.65 (1H, d, 3J = 3.9 Hz,
H-3 Th). 19F NMR (376 MHz, CDCl3) 90.3 (s, CF3). 13C NMR (126 MHz, CDCl3)
δ δ 110.7
(C-3); 114.8 (q, 3JCF = 2.4 Hz, C-5); 118.4 (q, 1JCF = 274.2 Hz, CF3); 128.7 (C Ar); 129.1 (C Ar);
130.9 (C Ar); 132.9 (C Ar); 151.9 (q, 2JCF = 39.7 Hz, C-6); 159.5; 177.4 (CO). HRMS (ESI) m/z
[M + H]+. Calcd for C10H6F3O2S: 247.0041. Found: 247.0031.
2-(Difluoromethyl)-6-phenyl-4H-pyran-4-one (5j). Yield 40% (89 mg), yellow powder, mp
◦
135–136 C. IR (ATR)
(500 MHz, CDCl3)
6.47 (1H, t, 2J = 53.7 Hz, CHF2); 6.63 (1H, d, 4J = 2.2 Hz, H-3); 6.84 (1H,
d, 4J = 2.2 Hz, H-5); 7.49–7.58 (3H, m, H Ph); 7.78 (2H, dd, 3J = 8.1 Hz, 4J = 1.1 Hz, H-2,
H-6 Ph). 19F NMR (471 MHz, CDCl3) 38.3 (d, 2J = 53.7 Hz, CF2H). 13C NMR (126 MHz,
ν
1665, 1616, 1596, 1497, 1358, 1177, 1108, 1055, 925. 1H NMR
δ
δ
CDCl3) δ
109.0 (t, 1JCF = 242.9 Hz, CF2H); 112.2; 114.4 (t, 3JCF = 4.0 Hz, C-3); 126.0 (2C Ar);
129.2 (2C Ar); 130.3; 132.0; 157.0 (t, 2JCF = 27.2 Hz, C-2); 163.9; 178.6 (CO). HRMS (ESI) m/z
[M + H]+. Calcd for C12H9F2O2: 223.0571. Found: 223.0574.
2-Phenyl-6-(1,1,2,2-tetrafluoroethyl)-4H-pyran-4-one (5k). Yield 44% (120 mg), yellow powder,
◦
1
mp 125–126 C. IR (ATR)
CDCl3)
6.10 (1H, tt, 2J = 53.1 Hz, 3J = 2.7 Hz, CHF2); 6.77 (1H, d, 4J = 1.8 Hz, CH); 6.84
(1H, d, 4J = 1.8 Hz, CH); 7.50–7.60 (3H, m, H Ph); 7.76 (2H, dd, 3J = 7.8 Hz, 4J = 1.4 Hz, H-2,
ν 3074, 2924, 1663, 1622, 1452, 1239, 1104, 940. H NMR (500 MHz,
δ
H-6 Ph). 19F NMR (471 MHz, CDCl3)
δ
26.9 (dt, 2JHF = 53.0 Hz, 3JFF = 4.0 Hz, CF2); 41.1
(td, 3JFF = 4.0 Hz, 3JHF = 2.7 Hz, CF2H). HRMS (ESI) m/z [M + H]+. Calcd for C13H9F4O2:
273.0539. Found: 273.0542.
2-(1,1,2,2,3,3,4,4-Octafluorobutyl)-6-phenyl-4H-pyran-4-one (5l). Yield 70% (261 mg), pale-
yellow semi-solid liquid. IR (ATR)
ν 3047, 1660, 1629, 1602, 1497, 1404, 1118, 944, 767.

Molecules 2021, 26, 4415
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1H NMR (500 MHz, CDCl3)
δ
6.08 (1H, tt, 2J = 51.8 Hz, 3J = 5.1 Hz, CHF2); 6.83 (1H, d,
4J = 2.0 Hz, CH); 6.88 (1H, d, 4J = 2.0 Hz, CH); 7.51 (2H, dd, 3J = 7.9 Hz, 3J = 7.3 Hz, H-3,
H-5 Ph); 7.57 (1H, tt, 3J = 7.3 Hz, 4J = 1.3 Hz, H-4 Ph); 7.75 (2H, dd, 3J = 7.9 Hz, 4J = 1.3 Hz,
H-2, H-6 Ph). 19F NMR (376 MHz, CDCl3) 24.8 (dm, 2JHF = 51.8 Hz, CF2H); 32.5–32.7 (m,
δ
3-CF2); 37.75–37.85 (m, 2-CF2); 43.8 (tt, 3JFF = 11.4 Hz, 3JFF = 1.7 Hz, 1-CF2). HRMS (ESI)
m/z [M + H]+. Calcd for C15H9F8O2: 373.0475. Found: 373.0479.
3.6. Synthesis of Pyrones 6
General procedure (Method C). A solution of Br2 (400 mg, 2.5 mmol) in CH2Cl2
(4.25 mL) was added to enedione 2 (1 mmol) in CH2Cl2 (2.7 mL) under cooling on an
ice-bath. After that, the reaction mixture was stirred at room temperature for 15 h, and then
the solvent was evaporated without heating. The residue was refluxed in pyridine (3 mL)
at 100 ◦C for 10 h. The excess of pyridine was evaporated under reduced pressure and the
product was purified by flash-chromatography (EtOAc). The product was hot-extracted
with hexane (3
crystallized from the extract after cooling.
×
5 mL). The solvent was evaporated until 2 mL of hexane, and the product
3-Bromo-6-phenyl-2-(trifluoromethyl)-4H-pyran-4-one (6a). Yield 73 mg (23%), beige solid, mp
1
132–133 ◦C. IR (ATR)
ν
3069, 1646, 1600, 1451, 1146, 973, 769. H NMR (500 MHz, CDCl3)
δ
6.94 (1H, s, H-5); 7.50–7.57 (2H, m, H-3, H-5 Ph); 7.57–7.62 (1H, m, H-4 Ph); 7.79 (2H, d,
3J = 7.4 Hz, H-2, H-6 Ph). 19F NMR (471 MHz, CDCl3) 95.6 (s, CF3). 13C NMR (126 MHz,
δ
CDCl3) δ
109.3; 116.3; 118.8 (q, 1JCF = 276.4 Hz, CF3); 126.0 (2C Ph); 129.3; 129.4 (2C Ph);
132.6; 149.7 (q, 2JCF = 38.0 Hz, C-6); 163.2; 172.8 (CO). Anal. Calcd for C12H6BrF3O2: C
45.17; H 1.90. Found: C 45.36; H 1.86%.
3-Bromo-6-(4-fluorophenyl)-2-(trifluoromethyl)-4H-pyran-4-one (6b). Yield 94 mg (28%), beige
1
solid, mp 156–167 ◦C. IR (ATR)
ν
1667, 1627, 1556, 1412. H NMR (500 MHz, CDCl3)
δ
6.88 (1H, s, H-5); 7.20–7.28 (2H, m, H-3, H-5 Ar); 7.77–7.85 (2H, m, H-2, H-6 Ar). 19F NMR
(471 MHz, CDCl3)
(126 MHz, CDCl3)
δ
56.4 (tt, 3JFH = 8.2 Hz, 4JFH = 5.2 Hz, F-Ar); 95.6 (s, CF3). 13C NMR
3
δ
109.1 (d, 6JCF = 1.1 Hz, H-5); 116.4 (q, JCF = 1.1 Hz, C-3); 116.8 (d,
2JCF = 22.3 Hz, C-3, C-5 Ar); 118.7 (q, 1JCF = 276.6 Hz, CF3); 125.5 (d, 4JCF = 3.4 Hz, C-1
3
2
Ar); 128.4 (d, JCF = 9.1 Hz, C-2, C-6 Ar); 149.6 (q, JCF = 39.6 Hz, C-2); 162.2; 162.3 (d,
1JCF = 255.4 Hz, C-4 Ar); 172.7 (CO). Anal. Calcd for C12H5BrF4O2: C 42.76; H 1.50. Found:
C 42.39; H 1.33%.
3-Bromo-6-(4-chlorophenyl)-2-(trifluoromethyl)-4H-pyran-4-one (6c). Yield 120 mg (34%), beige
◦
solid, mp 149–150 C. Procedure from tribromide 3c: Tribromide 3c (533 mg, 1.0 mmol) was
◦
refluxed in pyridine (3 mL) at 100 C for 10 h. The excess of pyridine was evaporated
under reduced pressure, and the product purified by flash-chromatography (EtOAc). The
product was hot-extracted with hexane (3 5 mL). The solvent was evaporated until 2 mL
×
of hexane, and the produ◦ct crystallized from extract after cooling. Yield 36% (127 mg),
beige solid, mp 149–150 C. IR (ATR)
ν
3069, 1645, 1600, 1577, 1561, 1498, 1451. 1H
NMR (400 MHz, CDCl3)
δ
6.91 (1H, s, H-5); 7.52 (2H, d, 3J = 8.7 Hz, H Ar); 7.72 (2H, d,
95.6 (s, CF3). 13C NMR (126 MHz, CDCl3)
3J = 8.7 Hz, H Ar). 19F NMR (376 MHz, CDCl3)
δ
δ
109.4 (C-5); 116.5 (C-3); 118.7 (q, 1JCF = 276.5 Hz, CF3); 127.3 (2C Ar); 127.7 (C Ar); 129.8
(2C Ar); 139.1; 149.7 (q, 2JCF = 38.1 Hz, C-2); 162.1; 172.7 (CO). HRMS (ESI) m/z [M + H]+.
Calcd for C12H6BrClF3O2: 352.9186. Found: 352.9183.
3-Bromo-6-(3-nitrophenyl)-2-(trifluoromethyl)-4H-pyran-4-one (6e). Yield 15 mg (4%), yellow-
◦
1
ish solid, mp 122–125 C. IR (ATR)
ν 3074, 3055, 1672, 1647, 1615, 1596, 1532, 1442. H
NMR (500 MHz, DMSO-d6) δ
7.58 (1H, s, H-5); 7.90 (1H, t, 3J = 8.1 Hz, H-5 Ar); 8.39 (1H,
ddd, 3J = 7.9 Hz, 4J = 1.7 Hz, 4J = 0.9 Hz, H-6 Ar); 8.46 (1H, ddd, 3J = 8.2 Hz, 4J = 2.2 Hz,
4J = 0.8 Hz, H-4 Ar); 8.68 (1H, dd, 4J = 2.2 Hz, 4J = 1.7 Hz, H-2 Ar). H NMR (400 MHz,
1
3
3
CDCl3)
4J = 1.7 Hz, 4J = 1.0 Hz, H-6 Ar); 8.45 (1H, ddd, 3J = 8.3 Hz, 4J = 2.2 Hz, 4J = 1.0 Hz, H-4 Ar);
8.64 (1H, dd, 4J = 2.2 Hz, 4J = 1.7 Hz, H-2 Ar). 19F NMR (376 MHz, CDCl3)
95.6 (s, CF3).
13C NMR (126 MHz, DMSO-d6) 110.9; 115.8; 118.6 (q, 1JCF = 277.0 Hz, CF3); 120.8; 126.5;
δ 7.04 (1H, s, H-5); 7.78 (1H, t, J = 8.8 Hz, H-5 Ar); 8.12 (1H, ddd, J = 7.9 Hz,
δ
δ

Molecules 2021, 26, 4415
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131.0; 131.2; 132.4; 148.3; 148.9 (q, 2JCF = 36.8 Hz, C-2); 160.2; 172.5 (CO). HRMS (ESI) m/z
[M + H]+. Calcd for C12H6BrF3NO4: 363.9427. Found: 363.9429.
3-Bromo-6-(p-tolyl)-2-(trifluoromethyl)-4H-pyran-4-one (6f). Yield 107 mg (32%), beige solid,
1
mp 170–171 ◦C. IR (ATR)
ν
1644, 1608, 1595, 1569, 1511, 1449. H NMR (500 MHz, CDCl3)
δ
2.44 (3H, s, Me); 6.90 (1H, s, H-5); 7.33 (2H, d, J = 8.1 Hz, H-3, H-5 Ar); 7.67 (2H, d,
J = 8.1 Hz, H-2, H-6 Ar). 19F NMR (471 MHz, CDCl3) 95.6 (s, CF3). 13C NMR (126 MHz,
CDCl3)
δ
δ
21.5 (CH3); 111.6 (C-3); 114.6 (q, 3JCF = 2.5 Hz, C-5); 118.5 (q, 1JCF = 273.8 Hz, CF3);
125.9 (2C Ar); 127.0 (C Ar); 130.0 (2C Ar); 143.1(C Ar); 152.3 (q, 2JCF = 39.5 Hz, C-6); 164.1
(C-2); 178.0 (CO). HRMS (ESI) m/z [M + H]+. Calcd for C13H9BrF3O2: 332.9733. Found:
332.9737.
3-Bromo-2-(difluoromethyl)-6-phenyl-4H-pyran-4-one (6j). Yield 84 mg (28%), beige solid, mp
◦
2
122–123 C. 1H NMR (500 MHz, CDCl3)
δ
6.93 (1H, s, H-5); 7.00 (1H, t, JHF = 52.1 Hz,
CHF2); 7.50–7.61 (3H, m, H Ph); 7.80–7.84 (2H, m, H-2, H-6 Ph). 19F NMR (376 MHz, CDCl3)
δ
39.3 (d, 2JHF = 52.1 Hz, CF2H). 13C NMR (126 MHz, CDCl3) 109.3 (t, 1JCF = 242.3 Hz,
δ
CF2H); 109.5; 116.5 (t, 3JCF = 5.3 Hz, C-3); 126.1 (2C Ph); 129.3 (2C Ph); 129.6; 132.4; 152.9 (t,
2JCF = 23.9 Hz, C-2); 163.6; 172.9 (CO). HRMS (ESI) m/z [M + H]+. Calcd for C13H10F3O2:
255.0633. Found: 255.0629.
3-Bromo-6-phenyl-2-(1,1,2,2-tetrafluoroethyl)-4H-pyran-4-one (6k). Yield 77 mg (24%), beige
solid, mp 122–125 ◦C. IR (ATR)
ν
3074, 3002, 1642, 1452, 1383, 1231, 1213, 1083, 975, 842.
2
1H NMR (500 MHz, CDCl3)
δ
6.32 (1H, tt, JHF = 52.8 Hz, J = 4.0 Hz, CHF2); 6.95 (1H,
s, H-5); 7.51–7.56 (2H, m, H-3, H-5 Ph); 7.57–7.61 (1H, m, H-4 Ph); 7.75–7.79 (2H, m, H-
2, H-6 Ph). 19F NMR (471 MHz, CDCl3)
δ
26.3 (dt, 3JFF = 6.6 Hz, 3JHF = 4.1 Hz, CF2); 44.6 (td,
108.9 (tt,
3
2JFF = 52.8 Hz, JFF = 6.6 Hz, CF2H). 13C NMR (126 MHz, CDCl3)
δ
1JCF = 254.1 Hz, 2JCF = 35.8 Hz, CF2H); 109.2; 111.4 (tt, 1JCF = 256.9 Hz, 2JCF = 28.9 Hz, CF2);
117.6; 126.0 (2C Ph); 129.4 (2C Ph); 130.5; 132.5; 150.9 (t, 2JCF = 27.4 Hz, C-2); 163.6; 172.8
(CO). HRMS (ESI) m/z [M + H]+. Calcd for C13H7BrF4O2: 350.9644. Found: 350.9650.
3-Bromo-2-(1,1,2,2,3,3,4,◦4-octafluorobutyl)-6-phenyl-4H-pyran-4-one (6l). Yield 149 mg (33%),
beige solid, mp 86–88 C. IR (ATR)
ν
3075, 1640, 1499, 1453, 1377, 1145, 943. 1H NMR
(400 MHz, CDCl3)
δ
6.12 (3H, tt, 2JHF = 51.9 Hz, 3JHF = 5.2 Hz, CHF2); 6.95 (1H, s, H-5);
7.51–7.62 (3H, m, H Ph); 7.74–7.78 (2H, m, H-2, H-6 Ph). 19F NMR (376 MHz, CDCl3)
2
δ
24.9 (dm, JHF = 51.9 Hz, CF2H); 32.4 –32.6 (m, 3-CF2); 38.7–38.8 (m, 2-CF2); 49.3 (t,
3JFF = 11.6 Hz, 1-CF2). HRMS (ESI) m/z [M + H]+. Calcd for C15H7BrF8O2: 450.9580.
Found: 450.9590.
3.7. Synthesis of Fluorinated Azaheterocycles 7–9
2-Phenyl-6-(trifluoromethyl)pyridin-4(1H)-one (7). A solution of pyrone 5a (120 mg, 0.5 mmol)
in EtOH (2 mL), saturated with NH3 at room temperature, was heated in an autoclave
at 100 ◦C for 8 h. The reaction mixture was diluted with H2O (10 mL), and the formed
precipitate was filtered and recrystallized from EtOH. Yield 84 mg (70%), colorless crystals,
1
mp 133–134 ◦C. IR (ATR)
ν
1614, 1579, 1481, 1427, 1460, 1429. H NMR (400 MHz, DMSO-
d6)
δ pyridinol form (96%): 7.05 (1H, s, H-3); 7.25 (1H, s, H-5); 7.39–7.48 (3H, m, H Ph);
7.91 (2H, d, J = 6.8 Hz, H-2, H-6 Ph); pyridone form (4%): 6.87 (1H, d, 4J = 2.0 Hz, H-3);
4
6.84 (1H, d, J = 2.0 Hz, H-5); 7.39–7.48 (3H, m, H Ph); 7.87–7.94 (2H, m, H-2, H-6 Ph);
the signals from NH and OH were not observed due to the fast exchange with water. 19F
NMR (376 MHz, CDCl3)
δ
pyridone form (4%): 93.4 (s, CF3); pyridinol form (96%): 93.6
(s, CF3). 13C NMR (126 MHz, CDCl3)
δ
108.3 Hz, 111.2 Hz, 121.2 (q, 1JCF = 274.4 Hz, CF3);
127.1 (2C Ph); 128.9 (2C Ph); 130.0 Hz, 137.2 Hz, 148.1 Hz, 158.9 Hz, 166.5. Anal. Calcd for
C12H8F3NO: C 60.26; H 3.37; N 5.86. Found: C 60.35; H 3.26; N 5.84%.
1-Phenyl-3-(4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl)propane-1,3-dione (8). To a solution of
pyrone 5a (96 mg, 0.4 mmol) in DMSO (1 mL), NaN3 (29 mg, 0.44 mmol) was added, and
◦
the mixture was stirred at 115–120 C for 30 min. The reaction was then diluted with
aqueous HCl (10 mL, 0.1 M), and the formed precipitate was filtered and recrystallized

Molecules 2021, 26, 4415
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◦
from toluene. Yield 65 mg (55%), pale-brown plates, mp 189–190 C. IR (ATR)
ν
3268 (NH),
1
1600, 1575, 1535, 1492, 1460, 1429. H NMR (400 MHz, DMSO-d6)
δ
enol form (82%): 7.19
(1H, s, 2-CH); 7.59 (2H, t, J = 7.6 Hz, H-3, H-5 Ph); 7.68 (1H, t, J = 7.4 Hz, H-4 Ph); 8.05 (2H,
d, J = 7.4 Hz, H-2, H-6 Ph); 14.70–17.9 (2H, broad s, NH, OH); keto form (18%): 4.85 (2H,
s, CH2); 7.58 (2H, t, J = 7.4 Hz, H-3, H-5 Ph); 7.70 (1H, t, J = 7.4 Hz, H-4 Ph); 8.01 (2H, d,
J = 7.4 Hz, H-2, H-6 Ph); 14.70–17.9 (1H, broad s, NH). 19F NMR (376 MHz, DMSO-d6)
δ
keto form (18%): 102.2 (s, CF3); enol form (82%): 103.2 (s, CF3). 13C NMR (126 MHz,
DMSO-d6) δ
enol form: 94.9 (CH=); 120.7 (q, 1JCF = 268.5 Hz, CF3); 127.2 (2C Ar); 129.1 (2C
Ar); 133.2 (C Ar); 133.2 (C Ar); 136.2 (q, 2JCF = 40.1 Hz, C-CF3); 140.9 (C Ar); 179.6; 182.2;
keto form: 50.7 (CH2); 120.2 (q, 1JCF = 267.1 Hz, CF3); 128.5 (2C Ar); 128.9 (2C Ar); 133.9
(C Ar); 136.0 (C Ar); 136.2 (q, 2JCF = 40.5 Hz, C-CF3); 142.4 (C Ar); 187.9 (CO); 194.8 (CO).
Anal. Calcd for C12H8F3N3O2: C 50.89; H 2.85; N 14.84. Found: C 50.90; H 2.78; N 14.85%.
(E)-1,5-Diphenyl-3-(3,3,3-trifluoro-2-(2-phenylhydrazono)propyl)-1H-pyrazole (9). A mixture
of p◦yrone 5a (120 mg, 0.5 mmol) and phenylhydrazine (270 mg, 2.5 mmol) was heated at
120 C for 3 h. The reaction mixture was cooled to room temperature, treated with 1M HCl
solution (10 mL), the formed precipitate was filtered and recrystallized from EtOH. Yield
65 mg (55%), colorless crystals, mp 171–173 ◦C. IR (ATR)
ν 3267 (NH), 1605 (C=N), 1543,
1
1500, 1457. H NMR (500 MHz, CDCl3)
δ
3.84 (2H, s, H-3); 6.40 (1H, s, H-5); 6.91 (1H, t,
3
J = 7.3 Hz, H-4 Ph); 7.11 (2H, d, J = 7.8 Hz, H-2, H-6 Ph); 7.19 (2H, dd, J = 7.7 Hz,
4J = 1.5 Hz, H-2, H-6 Ph); 7.22–7.38 (3H, m, H Ph); 9.99 (1H, s, NH). 19F NMR (376 MHz,
CDCl3)
δ δ 24.6; 107.2; 113.5 (2C); 121.4;
92.8 (s, CF3). 13C NMR (126 MHz, CDCl3)
121.94 (q, 1JCF = 272.0 Hz, CF3); 125.1 (2C); 127.8; 128.5 (2C); 128.6; 128.7 (2C); 128.78 (q,
2JCF = 33.9 Hz, C=N); 129.0 (2C); 129.2 (2C); 129.8; 139.6; 144.1; 144.8; 147.1. Anal. Calcd for
C24H19F3N4: C 68.56; H 4.56; N 13.33. Found: C 68.42; H 4.38; N 13.34%.
Supplementary Materials: The following are available online, Scheme S1. Reaction of (3Z,5E)-6-(4-
(dimethylamino)phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one with Br2 in benzene; Table S1.
Composition of reaction mixtures of bromination of enediones 2; Table S2. Characteristic chemical
shifts in 1H and 19F NMR spectra of compounds 3; Table S3. Characteristic chemical shifts in 1H and
19F NMR spectra of compounds 4; Table S4. Characteristic chemical shifts in 1H and 19F NMR spectra
of dihydropyrone forms of 3; Table S5. Characteristic chemical shifts in 1H and 19F NMR spectra of
dihydropyrone forms of 4; full 1H, 19F, and 13C NMR spectra of all synthesized compounds.
Author Contributions: Conceptualization and methodology were provided by V.Y.S., S.A.U. and
D.L.O. conceived and designed the experiments. The experimental work was conducted by D.I.N.,
D.K.M., N.A.N., and S.A.U. S.A.U. and D.L.O. analyzed the results. S.A.U. studied and systemized the
NMR data. V.Y.S. and D.L.O. wrote the paper. Project administration and funding acquisition were
carried out by V.Y.S. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Russian Science Foundation, grant number 18-13-00186.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data is contained within the article and Supplementary Materials.
Acknowledgments: Analytical studies were carried out using equipment at the Center for Joint Use
‘Spectroscopy and Analysis of Organic Compounds’ at the Postovsky Institute of Organic Synthesis
of the Russian Academy of Sciences (Ural Branch) and the Laboratory of Complex Investigations
and Expert Evaluation of Organic Materials of the Center for Joint Use at the Ural Federal University.
Authors would like to thank Artem Chudinov for his help in the work.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are not available from the authors.

Molecules 2021, 26, 4415
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References
1.
2.
3.
4.
5.
Singh, K.S. Pyrone-derived marine natural products: A review on isolation, bio-activities and synthesis. Curr. Org. Chem. 2020
24, 354–401. [CrossRef]
Rukachaisirikul, V.; Kannai, S.; Klaiklay, S.; Phongpaichit, S.; Sakayaroj, J. Rare 2-phenylpyran-4-ones from the seagrass-derived
fungi Polyporales PSU-ES44 and PSU-ES83. Tetrahedron 2013, 69, 6981–6986. [CrossRef]
,
Zhang, Y.; Zhu, T.; Fang, Y.; Liu, H.; Gu, Q.; Zhu, W. Carbonarones A and B, new bioactive
γ-pyrone and α-pyridone derivatives
from the marine-derived fungus Aspergillus carbonarius. J. Antibiot. 2007, 60, 153–157. [CrossRef] [PubMed]
Ola, A.R.B.; Thomy, D.; Lai, D.; BroJz-Oesterhelt, H.; Proksch, P. Inducing secondary metabolite production by the endophytic
Fungus Fusarium tricinctum through coculture with Bacillus subtilis. J. Nat. Prod. 2013, 76, 2094–2099. [CrossRef] [PubMed]
Kunze, B.; Jansen, R.; Pridzun, L.; Jurkiewicz, E.; Hunsmann, G.; Höfle, G.; Reichenbach, H. Phenoxan, a new oxazole-pyrone
from myxobacteria: Production, antimicrobial activity and its inhibition of the electron transport in complex I of the respiratory
chain. J. Antibiot. 1992, 45, 1549–1552. [CrossRef]
6.
Bejcek, L.P.; Murelli, R.P. Oxidopyrylium [5 + 2] cycloaddition chemistry: Historical perspective and recent advances (2008–2018).
Tetrahedron 2018, 74, 2501–2521. [CrossRef]
7.
8.
Zirak, M.; Eftekhari-Sis, B. Kojic acid in organic synthesis. Turk. J. Chem. 2015, 39, 439–496. [CrossRef]
Zhang, L.; Cao, T.; Jiang, H.; Zhu, S. Deconstructive reorganization: De Novo synthesis of hydroxylated benzofuran. Angew.
Chem. Int. Ed. 2020, 59, 4670–4677. [CrossRef]
9.
Obydennov, D.L.; Khammatova, L.R.; Steben’kov, V.D.; Sosnovskikh, V.Y. Synthesis of novel polycarbonyl Schiff bases by
ring-opening reaction of ethyl 5-acyl-4-pyrone-2-carboxylates with primary mono- and diamines. RSC Adv. 2019, 9, 40072–40083.
[CrossRef]
10. Schreiner, E.; Richter, F.; Nerdinger, S. Development of synthetic routes to dolutegravir. Top. Heterocycl. Chem. 2016, 44, 187–208.
11. Guo, Z.; Zhu, W.; Tian, H. Dicyanomethylene-4H-pyranchromophores for OLED emitters, logic gates and optical chemosensors.
Chem. Commun. 2012, 48, 6073–6084. [CrossRef] [PubMed]
12. Obydennov, D.L.; Suslova, A.I.; Sosnovskikh, V.Y. Synthesis and some chemical properties of 2-cyano-4-pyrone. Chem. Heterocycl.
Compd. 2020, 56, 173–179. [CrossRef]
13. Obydennov, D.L.; Simbirtseva, A.E.; Piksin, S.E.; Sosnovskikh, V.Y. 2,6-Dicyano-4-pyrone as a novel and multifarious building
block for the synthesis of 2,6-bis(hetaryl)-4-pyrones and 2,6-bis(hetaryl)-4-pyridinols. ACS Omega 2020, 5, 33406–33420. [CrossRef]
14. Obydennov, D.L.; Sosnovskikh, V.Y. The reaction of 6-substituted 4-pyrone-2-carboxylic acids with o-phenylenediamine. Synthesis
and structure of 3-(1H-1,5-benzodiazepin-2(3H)-ylidenemethyl)quinoxalin-2(1H)-ones. Chem. Heterocycl. Compd. 2015, 51, 281–290.
[CrossRef]
15. Obydennov, D.L.; Khammatova, L.R.; Eltsov, O.S.; Sosnovskikh, V.Y. A chemo- and regiocontrolled approach to bipyrazoles
and pyridones via the reaction of ethyl 5-acyl-4-pyrone-2-carboxylates with hydrazines. Org. Biomol. Chem. 2018, 16, 1692–1707.
[CrossRef]
16. Obydennov, D.L.; Usachev, B.I.; Sosnovskikh, V.Y. Reactions of 2-mono- and 2,6-disubstituted 4-pyrones with phenylhydrazine as
general method for the synthesis of 3-(N-phenylpyrazolyl)indoles. Chem. Heterocycl. Compd. 2015, 50, 1388–1403. [CrossRef]
17. Politanskaya, L.; Selivanova, G.A.; Panteleeva, E.V.; Tretyakov, E.V.; Platonov, V.E.; Nikul’Shin, P.V.; Vinogradov, A.S.; Zonov, Y.V.;
Karpov, V.M.; Mezhenkova, T.V.; et al. Organofluorine chemistry: Promising growth areas and challenges. Russ. Chem. Rev. 2019
88, 425–569. [CrossRef]
,
18. Usachev, B.I. 2-(Trifluoromethyl)-4H-pyran-4-ones: Convenient, available and versatile building-blocks for regioselective synthe-
ses of trifluoromethylated organic compounds. J. Fluor. Chem. 2015, 172, 80–91. [CrossRef]
19. Usachev, S.A.; Sosnovskikh, V.Y. Synthesis of γ-pyrone precursors by condensation of acetyl ketene dithioacetals with ethyl
polyfluorocarboxylates and diethyl oxalate. Chem. Heterocycl. Compd. 2016, 52, 1005–1011. [CrossRef]
20. Yeates, C.L.; Batchelor, J.F.; Capon, E.C.; Cheesman, N.J.; Fry, M.; Hudson, A.T.; Pudney, M.; Trimming, H.; Woolven, J.; Bueno,
J.M.; et al. Synthesis and structure–activity relationships of 4-pyridones as potential antimalarials. J. Med. Chem. 2008, 51,
2845–2852. [CrossRef] [PubMed]
21. Tyvorskii, V.I.; Bobrov, D.N.; Kulinkovich, O.G.; Aelterman, W.; de Kimpe, N. Synthesis of 3-(trifluoromethyl)benzo[c][1,6]naphthy-
ridines from substituted 4H-pyran-4-ones via 4-amino-5-aryl-2-(trifluoromethyl)pyridines. Tetrahedron 2000, 56, 7313–7318.
[CrossRef]
22. Büttner, S.; Desens, W.; Michalik, D.; Langer, P. Synthesis and structures of fluoroalkylated triketides. Eur. J. Org. Chem. 2011
,
6663–6669. [CrossRef]
23. Serdyuk, R.N.; Sizov, A.Y.; Ermolov, A.F. Polyfluoroalkylthiotrifluoroacetylketenes. Rus. Chem. Bull. 2003, 52, 1854–1858.
[CrossRef]
24. Boivin, J.; El Kaima, L.; Zarda, S.Z. Trifluoromethyl ketones from carboxylic acids. Part II. A versatile access to trifluoromethylated
heterocycles. Tetrahedron 1995, 51, 2585–2592. [CrossRef]
25. Krasnykh, O.P.; Aleksandrov, G.G.; Karpenko, N.S.; Filyakova, V.I.; Charushin, V.N. Formation of fluoroalkyl-containing pyran-4-
one in the reaction of lithium 4,4,4-trifluoro-1-phenylbutane-1,3-dionate with oxalyl chloride. Rus. Chem. Bull. 2007, 56, 178–180.
[CrossRef]
26. Usachev, B.I.; Obydennov, D.L.; Röschenthaler, G.-V.; Sosnovskikh, V.Y. 2-Cyano-6-(trifluoromethyl)-4-pyran-4-one: A novel
versatile CF3-containing building block. J. Fluor. Chem. 2012, 137, 22–26. [CrossRef]

Molecules 2021, 26, 4415
19 of 19
27. Sosnovskikh, V.Y. Synthesis and reactions of halogen-containing chromones. Russ. Chem. Rev. 2003, 72, 489–516. [CrossRef]
28. Sosnovskikh, V.Y.; Korotaev, V.Y.; Chizhov, D.L.; Kutyashev, I.B.; Yachevskii, D.S.; Kazheva, O.N.; Dyachenko, O.A.; Charushin,
V.N. Reaction of polyhaloalkyl-substituted chromones, pyrones, and furanones with salicylaldehydes as a direct route to fused
2H-chromenes. J. Org. Chem. 2006, 71, 4538–4543. [CrossRef] [PubMed]
29. Liu, W.; Fang, L.; Wan, Y.; Zhang, J.; Deng, G.; Wang, J. Synthesis of 2-cyclopropyl-4-pyrones and 5-cyclopropyl-2-alkylene-3(2H)-
furanones based on tandem cyclization-cyclopropanation strategy. Tetrahedron 2019, 75, 855–861. [CrossRef]
30. Wang, F.; Lu, S.; Chen, B.; Zhou, Y.; Yang, Y.; Deng, G. Regioselective reversal in the cyclization of 2-diazo-3,5-dioxo-6-ynoates
(ynones, ynamide): Construction of
6248–6251. [CrossRef] [PubMed]
γ-pyrones and 3(2H)-furanones starting from identical materials. Org. Lett. 2016, 18,
31. Solas, M.; Muñoz, M.A.; Suárez-Pantiga, S.; Sanz, R. Regiodivergent hydration
Lett. 2020, 22, 7681–7687. [CrossRef]
−
cyclization of diynones under gold catalysis. Org.
32. Fürstner, A. Gold catalysis for heterocyclic chemistry: A representative case study on pyrone natural products. Angew. Chem. Int.
Ed. 2018, 57, 4215–4233. [CrossRef]
33. Zhang, J.; Deng, G.; Wang, J. Diastereoselective synthesis of 2-(1,3-dioxolanes-4-yl)-4H-pyran-4-ones from 2-diazo-3,5-dioxo-6-
ynoates (sulfones) and aldehydes based on tandem cyclization-cycloaddition strategy. Eur. J. Org. Chem. 2019, 2019, 3979–3986.
[CrossRef]
34. Usachev, B.I.; Obydennov, D.L.; Kodess, M.I.; Röschenthaler, G.-V.; Sosnovskikh, V.Y. New derivatives of 6-phenylcomanic acid.
Rus. Chem. Bull. 2009, 58, 1248–1252. [CrossRef]
35. Soliman, G.; Rateb, L. Synthesis of heterocyclic compounds from
[CrossRef]
δ-unsaturated 1:3-diketo-esters. J. Chem. Soc. 1956, 3663–3668.
36. Clark, B.P.; Ross, W.J.; Todd, A. 6-Substituted Pyranone Compounds and Their Use as Pharmaceuticals. US Patent 4471129, 1984.
37. Borsche, W.; Peter, W. Über eine neue y-Pyronsynthese. Justus Liebigs Ann. Chem. 1927, 53, 148–162. [CrossRef]
38. Pashkevich, K.L.; Khomutov, O.G. Synthesis of polyfluoroalkyl-containing dienones. Rus. Chem. Bull. 1996, 45, 2169–2171.
[CrossRef]
39. Kim, E.; Felouat, A.; Zaborova, E.; Ribierre, J.-C.; Wu, J.W.; Senatore, S.; Matthews, C.; Lenne, P.-F.; Baffert, C.; Karapetyan, A.;
et al. Borondifluoride complexes of hemicurcuminoids as bio-inspired push-pull dyes for bioimaging. Org. Biomol. Chem. 2016
14, 1311–1324. [CrossRef]
,
40. Sosnovskikh, V.Y.; Ovsyannikov, I.S. Condensation of trichloro- and trfluoroacetonitriles with mesityl oxide and arylideneacetones.
Russ. J. Org. Chem. 1993, 29, 214–219.
41. Leng, D.J.; Black, C.M.; Pattison, G. One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process.
Org. Biomol. Chem. 2016, 14, 1531–1535. [CrossRef]
42. Kobelevskaya, V.A.; Popov, A.V.; Zinchenko, S.V.; Rulev, A.Y. Chemoselective bromination of dienoates. Eur. J. Org. Chem. 2020
2020, 5544–5550. [CrossRef]
,
43. Usachev, S.A.; Usachev, B.I.; Eltsov, O.S.; Sosnovskikh, V.Y. Synthesis of isomerically pure 3-(5-trifluoromethyl-1,2,3-triazol-
4-yl)cinnamic acid derivatives via the reaction of 4-aryl-6-trifluoromethyl-2-pyrones with sodium azide. Tetrahedron 2014, 70,
8863–8871. [CrossRef]
44. He, Y.-H.; He, T.; Guo, J.-T.; Li, R.; Xiang, Y.; Yang, D.-C.; Guan, Z. Enzyme-catalyzed domino reaction: Efficient construction of
spirocyclic oxindole skeleton using porcine pepsin. Catal. Sci. Technol. 2016, 6, 2239–2248. [CrossRef]