Uncommon fluorination of enones with xenon difluoride

Article abstract of DOI:10.1016/j.jfluchem.2019.109413

Readily available β-alkoxyvinylpolyfluoroalkyl ketones react with XeF₂ to give the products of addition of two Fluorine atoms to the C[dbnd]C double bond - vic-difluoro ketones, which can be easily converted to α-F enones. We demonstrated chemical evaluation of these compounds by formation of new fluorocontaining enaminones and pyrazoles. In order to obtain new precursors for bioactive compounds we performed [4 + 2] hetero Diels-Alder reaction and obtained dihydropyranes which are perspective starting materials for fluorinated carbohydrates.

Full text of DOI:10.1016/j.jfluchem.2019.109413

Journal Pre-proof
Uncommon fluorination of enones with xenon difluoride
Igor I. Gerus, Yury I. Zhuk, Liliya M. Kacharova, Gerd-Volker
Ro¨schenthaler, Elena N. Shaitanova, Alexandr E. Sorochinskii,
Sergey I. Vdovenko, Jacek Wojcik
PII:
S0022-1139(19)30345-8
DOI:
https://doi.org/10.1016/j.jfluchem.2019.109413
FLUOR 109413
Reference:
To appear in:
Journal of Fluorine Chemistry
Received Date:
Revised Date:
Accepted Date:
3 October 2019
5 November 2019
6 November 2019
Please cite this article as: Gerus II, Zhuk YI, Kacharova LM, Ro¨schenthaler G-Volker,
Shaitanova EN, Sorochinskii AE, Vdovenko SI, Wojcik J, Uncommon fluorination of enones
with xenon difluoride, Journal of Fluorine Chemistry (2019),
doi: https://doi.org/10.1016/j.jfluchem.2019.109413
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Uncommon fluorination of enones with xenon difluoride
1
1
1,2
3
Igor I. Gerus* , Yury I. Zhuk , Liliya M. Kacharova , Gerd-Volker Röschenthaler , Elena N.
1
1
1
4
Shaitanova , Alexandr E. Sorochinskii , Sergey I. Vdovenko , Jacek Wojcik
1
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian
Academy of Science, Murmanska Str. 1, Kiev 02094, Ukraine
2
University of Minnesota Duluth Advanced Materials Center, 102 HCAMS, 1038 University
Drive 55812, Duluth, MN USA
3
Jacobs University Bremen gGmbH, Life Sciences and Chemistry, Campus Ring 1, 28759
Bremen, Germany
4
Institute of Biochemistry and Biophysics Polish Academy of Sciences, ul. Pawińskiego 5a, 02-
1
06 Warszawa, Poland
Graphical abstract
H
F
i) XeF2 ii) Py
EtO
CF3
EtO
CF3
CH CN, BF xEt O
3
3
2
E
t
O
H
O
H
O
X
=
C
H 2
H
N
H 2
N
H
=
,
C
F
H
2
,
C
l,
B
r
F3C
F
CF3
O
OEt
H
N
X
EtO
N
H
H

2
Highlights

The fluorination of readily available β-alkoxy-enones using the commercial reagent XeF
and BF ·Et O as catalyst gives the vic-difluoro ketones
2
3
2

α-Fluoro-β-alkoxy-enones can be obtained as Z-isomers under farther
dehydrofluorination



The synthesis is based on fluorination by XeF
2
The chemical evaluation of synthesized α-fluoro-β-alkoxy-enones was investigated
New fluorinated dihydropyranes were obtained which are perspective precursors for
fluorocontaining hexoses
Abstract
Readily available β-alkoxyvinylpolyfluoroalkyl ketones react with XeF to give the products of
2
addition of two Fluorine atoms to the C=C double bond - vic-difluoro ketones, which can be
easily converted to α-F enones. We demonstrated chemical evaluation of these compounds by
formation of new fluorocontaining enaminones and pyrazoles. In order to obtain new precursors
for bioactive compounds we performed [4+2] hetero Diels-Alder reaction and obtained
dihydropyranes which are perspective starting materials for fluorinated carbohydrates.
Keywords: Halogenation; Enones; Heterocyclic compounds; XeF ; [4+2] Cyclization;
2
Fluorinated synthons
1
. Introduction
The current interest to fluoroorganic compounds connected with its unique
beneficial properties [1] used in pharmaceuticals [2-5], agrochemicals [6], medical
imaging and as radio labels [7, 8]. There are two major processes for the synthesis
of fluoroorganic compounds:


Replacement of an atom or group by a fluorine atom
Using a fluorinated synthon as a building block.

3
Of course, the second approach is more common and convenient. In our group, we
work with readily available (E)-β-alkoxyvinylpolyfluoroalkyl ketones A - enones,
that may be considered as a synthetic equivalent of 1,3-ketoaldehydes B) and are
an useful precursors with fluoroalkyl groups, see Fig. 1 [9-14].
Fig. 1. Enones A are a synthetic equivalent of 1,3-ketoaldehydes B.
Although the first reactions of trifluoromethyl-containing enone 1 were
published 30 years ago, but abiding interest to β-alkoxyvinylpolyhaloalkyl ketones
compounds is not reduced due to their high functionality and attractive reactivity.
We have modified this useful synthon by adding one more reaction center to obtain
a series of α-halogen enones that generally have reactivity similar to starting enone
1
(Scheme 1) [15, 16].
O
H
O
Y
O
H
XY
Rf
OEt
Rf
OEt
Rf
OEt
-HY
H
X
X
XY = Cl , Br , ICl
3
2
2
2
1
Scheme 1. Halogenation of β-alkoxyvinylpolyhaloalkyl ketones 1.
The presence of a halogen atom at the α-position gives more reaction
opportunities for α-halogeno enones 3, which are obviously impossible for enone
1
. Only α-Br, Cl, I derivatives [15-17] were synthesized, the literature contains no
reports about the synthesis of α-F enones 3 (X=F). There are few reports about α-
fluoro-β-alkoxyvinyl ketones showing that synthetic routes are unique for each
compound. For example, 3-fluoro-4-methoxybut-3-en-2-one was obtained as a
result of a rearrangement of gem-chlorofluorocyclopropanes under basic

4
conditions. 5-Fluorodioxinones were synthesized from readily available 1,3-
dioxin-4-ones using molecular fluorine followed by treatment with an organic base
in yields of 5% and 10%, respectively [18]. Introduction of the fluorine into α-
position of enones 1 is difficult. It could be achieved by using molecular fluorine
or other electrophilic fluorinating reagents. Reaction with molecular Fluorine is
complicated and suffers difficulties of handling, therefore the development of new
methods for the introduction of fluorine remains important. We have been studying
the fluorination of β-alkoxyenones 1 with different fluoroalkyl groups using
®
commercially available reagents such as: NFSI, Selectfluor , XeF with the aim to
2
obtain α-fluoroenones and study their reactivity, as well.
2
. Results and discussion
2
.1. Synthesis of α-F enones
Elecrophilic halogenation of olefins is widely used for the synthesis of a
variety useful vinyl halide building blocks and fluorine containing compounds, as
well [19, 20]. Notable, fluorination of olefins is not convenient because of the high
likelihood of polymerization. In order to achieve α-fluoroenones we used
polyfluoroalkyl enones 1 as our starting materials which are push-pull compounds
with highly polarized C=C double bond.
Our goal was to develop a convenient method for direct fluorination of enones
1
, as we previously have reported for the halogenation of enones 1 with Br , Cl2
2
[15,16]. It could be easily achieved by using commercially available reagents:
®
NFSI, Selectfluor and XeF . We started our fluorination studies reacting enone 1a
2
®
with Selectfluor in CH Cl at room temperature. But this reagent as well, as NFSI
2
2
in CH CN (the temperature was increased in some cases to 80 °C) did not lead to
3
19
the respective difluorides or products with α-F-vinyl group. F NMR data showed
only the starting compound 1a was recovered from the reaction mixtures.

5
Next, we investigated the reaction of trifluoromethyl enone 1a with xenon
difluoride. XeF was first described in 1962 [21] and since then it has received
2
wide attention as an “easy to handle” reagent for introduction of fluorine in to
organic molecules instead of aggressive elemental fluorine [22]. Reactions of
aliphatic alkenes with XeF have been reported, especially with phenylalkenes
2
[23]. Generally, complex reaction mixtures were formed containing, among others,
germinal difluorides, along with lower amount of vicinal difluorides. As
exceptions, individual examples showed formation of vicinal difluorides in high
yields [24]. It is known that in the absence of catalyst reactions with XeF are
2
going slow or even not observed and depend on substituents on the C=C double
bond and nature of the solvent [25].
We studied the reaction of enone 1a with the XeF in different conditions to
2
achieve an efficient fluorination method. Various solvents (CH CN, CH Cl ) were
3
2
2
tested. We used HF, CF COOH as catalysts but did not receive the corresponding
3
products. We choose BF ·Et O as a catalyst because it was frequently used in
3
2
fluorination reaction of alkenes and dienes [26], and it was effective. But the
addition of a small amount of BF ·Et O to the mixture of enone 1a and XeF in
3
2
2
CH Cl resulted a violent reaction with evolution of Xe gas and rapid reaction
2
2
mixture heating. The complex mixture of products containing the corresponding
1
9
difluoro ketone 2a was obtained (by F NMR) (Scheme 2).
H
F
F
H
XeF , BF ·Et O
Py
2
3
2
EtO
CF3
EtO
CF3
EtO
CF3
CH CN
68%
3
H
F
H
O
O
H
O
1a
3a
2a
Scheme 2. The fluorination of enone 1a with XeF2.
The reaction conditions were modified by optimizing the temperature (starting
with −10 °C with a slow increase to room temperature), by using acetonitrile

6
instead of CH Cl and addition of XeF in small portions (to keep the temperature
2
2
2
range from −10 to −5 °C). Under the optimized reaction conditions enone 1a gives
vic-difluoro ketones 2a as a major products with 100% conversion. We also
investigated the product formation and their conversion in the reaction mixture by
19
integration of signals ratio to internal standard using F NMR spectroscopy (the
results are summarized in Table 1). Thus, to the mixture of enone 1a in acetonitrile
catalytic amount of BF ·Et O and XeF were added in portions at −10 °C. Each
3
2
2
19
portion (0.25 eq.) was added after the end of gas evolution. In the F NMR spectra
two sets of dual signals at: −133.2 and −136.2 ppm (doublet of multiplets,
2
EtOCHF, J ~62 Hz), and −210.7 and −213.1 ppm (doublet of multiplets,
FH
2
OC−CHF, J ~50 Hz) were observed corresponding to two diastereomeric vic-
FH
difluoroketones 2a in a 55% to 45% ratio. The formation of the diastereomeric
mixture is a result of both syn- and anti-addition of fluorine to the C=C double
bond of (E)-enone 1a. In comparison, the halogenation of enone 1a with chlorine
gives predominantly syn-adducts in a 80:20 ratio. Bromination gives anti-adducts
in a 80:20 ratio, respectively [15].
The ketones 2a are rather unstable for being isolated in pure form in contrast
to similar dibromo and dichloro ketones (which are more stable and can be isolated
by vacuum distillation). Addition of one equivalent of water to difluoroketones 2a
gave hydrates 4a with 100% conversion. Structure of hydrates 4a was determined
1
9
by F NMR data: CF groups have characteristic assignment at −82.68 and −84.51
3
ppm, respectively (Table 1, Entry 5) (Scheme 3) [27].
Scheme 3. Formation of hydrates 4a.

7
During the water work up and vacuum distillation of difluoroketons 2a the
partial HF elimination was observed with formation of the β-alkoxy-α-fluorovinyl
trifluoromethyl ketone 3a (Scheme 2). The elimination of HF is more effective in
the presence of the base. Some bases (NEt , DBU, Py, and Hunig base) were
3
tested. We found that pyridine is the most suitable base for HF elimination (Table
1
, Entry 6) and under the protocol α-fluoroenone 3a was obtained in gram quantity
with 68% yield.
Scheme 4. Fluorination of enones 1b-e with XeF2.
We applied the optimized procedure of the fluorination with XeF to enones
2
1
b-e bearing different fluorocontaining groups (Scheme 4). The formation of
1
9
corresponding ketones 2b-e was detected by F NMR without their isolation.
Thus, the α-fluoropolyfluoromethyl-containing enone 3b was isolated with 71%
yield, and 3c with 70%, respectively. Whereas enones 3d,e were synthesized with
low purity and low yield. Despite the formation of the diastereomeric mixture of
intermediate difluoroketones 2 the final α-F-enones 3a-c were obtained as a single
Z-isomers regarding NMR data. Thus, α-fluorine of enone 3a has characteristic
3
coupling constant J = 19 Hz. We assigned the Z-configuration of the C=C
HF
double bond (trans-position between ethoxy and trifluoroacetyl groups) with two
broad signals (with ratio 3:1) at −73.0 and −161.2 ppm (with a half-width 0.6 and
19
1
.0 ppm) of CF and =CF fragments in F NMR, respectively. It is a result of
3
restricted rotation around formally C−C single bond in the heterodiene system
O=C–C=C.

8
Using NMR data of compound 3a at low temperature (−22.3 °C) we
assigned the separate signals of =CF and CF groups of Z- and E-conformers
3
which confirms our hypothesis (Fig. 2). At the same time the comparison of FTIR
spectra (in CCl ) of the previously studied enone 1a [28] and α-fluoro containing
4
enone 3a demonstrates that 3a also has three stereoisomeric structures.
Characteristic vibrations of the carbonyl(C=O) and carbon-carbon double bond
(C=C) for all three isomers were confirmed by FTIR data: E-s-Z-s-cis [ν(C=O)
-
1
-1
-1
-1
1
719 cm , ν(C=C) 1594 cm ], E-s-E-s-cis [ν(C=O) 1714 cm , ν(C=C) 1614 cm ]
-
1
-1
and E-s-E-s-trans [ν(C=O) 1698 cm , ν(C=C) 1638 cm ]. Nevertheless, the ratio
of isomers 1a and α-fluoroenone 3a is significantly different: cf. 4% (E-s-E-s-
trans), 39% (E-s-E-s-cis), 57% (E-s-Z-s-cis) for 1a and 36% (E-s-E-s-trans), 55%
19
(
E-s-E-s-cis), 9% (E-s-Z-s-cis) for 3a. In the F NMR spectra of α-fluoroenones
b-g all fluorine signals are also broad just like in enone 3a. It is worth to mention
3
that in the NMR data of the corresponding α-Cl- and α-Br-enones with CF -group,
3
the broad signals of the CF -group were not observed, because of the bulkier
3
chlorine and bromine atoms the rotation around C−C single bond is restricted.
19
Fig. 2. Low temperature F NMR spectra of 4-ethoxy-1,1,1,3-tetrafluorobut-3-
en-2-one 3a.

9
We observed the differences in the reaction of XeF with
2
trifluoromethylenone 1f, containing a CH group in β-position under the same
3
1
9
reaction conditions. The reaction was started at −20 °C and F NMR analysis of
the reaction mixture showed very complex mixture of products. Obviously,
difluoroketones 2f are more unstable compared to all investigated difluoroketones
2
a-e, and partially HF elimination took place without base and gave the complex
mixture of fluorinated products. About 17% of starting enone 1f was left unreacted
Scheme 5).
(
Scheme 5. Reaction of enones 1f,g with XeF2.
Since enones 3f,g are involved into subsequent fluorination with XeF and
2
following HF release, the addition of base to the reaction mixture leads to
19
formation of a complex mixture of products. The results of F NMR study show
that the reaction mixture contains compounds with CH F-group (product of
2
fluorination of methyl group), as well as products with CHF C=O fragment in their
2
structures. Unfortunately, the corresponding products were detected only by NMR.
In contrast to enones 3a-c the signals of -CF and =CF groups of enone 3f
3
19
are sharp in F NMR. This is a result of the rotation restriction between bulky
methyl group at β-position and trifluoromethyl group, when rotation around single
C=C−C=O bond is not possible. So, the most stable structure for α-fluoro-β-

1
0
methylenone 3f is Z-s-Z configuration which confirms with F-F coupling constant
0 MHz (Fig. 3).
2
Fig. 3. Two conformers of α-fluoro-β-methylenone 3f
Both the polyfluoroalkyl chain length and the electrononegativity decrease
of the C(=O)R acyl group lead to spontaneous HF elimination which gives
complicated mixtures of products.
2
.2. Synthesis of α-halogen containing enaminones
Previously we showed that α-halogen ketones 3 (where R=Cl, Br, I) easily
react with methyl- or dimethylamines and give corresponding α-halogen
enaminones [15]. As was mentioned above, there are three stereoisomeric forms of
enone 3a, each form having different reactivity. Detailed investigation of the
stereochemistry of α-fluorine-β-N,N-dimethylaminovinyl trifluoromethyl ketones
(Scheme 6) was done earlier [29, 30] and kinetic study of reaction of 3a with
amines is in progress and the results will be published later.
Scheme 6. Synthesis of α-halogen-containing enaminones 4-8.

1
1
The presence of halogen atom in α-position of enone 3 leads to a number
of significant changes in the stereochemistry of enaminones 5-7 in comparison to
unsubstituted enaminon 4 (trans-position between amino and trifluoroacetyl
groups). N,N-Dimethyl enaminones α-H, Cl, Br exist predominantly in a Z-
configuration (trans-position between the trifluoroacetyl and amino groups) which
was determined directly by IR and NMR spectra. Since the relatively small size
difference between hydrogen and fluorine α-F enaminone 5b also gives two
conformers of Z-isomer: Z-s-Z and Z-s-E in equilibrium as α-H enaminone 4b [13-
5,29,30].
In order to evaluate the effect of α-substituents (H, F, Cl, Br) in N-
monomethyl enaminones on their spatial forms, we synthesized α-F-substituted N-
1
19
1
Me enaminone 5a. Based on F and H NMR data enaminone 5а exists as a
mixture of 4 conformers (Fig. 4). The ratio of conformers slightly depends on the
nature of the solvent: less polar (CDCl ) or polar (DMSO-d ). Two conformers
3
6
4
have J = 5.7 Hz (Z-s-E and Z-s-Z), the other two (E-s-Z, E-s-E) have J about
FF
FF
1
1
7 Hz. In the H NMR spectra we observed different shifts for conformers with
hydrogen bonding between C=O···HN-groups and with unbound NH group.
Fig. 4. Possible conformers of enaminone 5a.
2
.3. Synthesis of fluoro containing pyrazole and dihydropyranes
Pyrazoles attract biochemical community because some of them have a
pesticide activity [31, 32]. Also 4-fluoropyrazole is a part of bioavailable Hsp90
inhibitors which displays a good efficacy in a melanoma A2058 tumor model [33].

1
2
However, the number of convenient methods to these compounds is limited
mostly due to the difficulty of introducing a fluorine atom into heterocycles. That
is why the synthesis of pyrazoles with different fluoro-containing groups is still of
great interest, and new methods for preparing pyrazoles are required [34]. Thus,
the condensation of α-fluoro-β-ethoxytrifluoromethyl enone 3a with N H ·H O
2
4
2
gives F- and CF -substituted pyrazole 9 with a high yield (Scheme 7).
3
Scheme 7. Synthesis of pyrazole 9.
Fluorinated carbohydrates play an important role in organic chemistry. They
increase the bioavailability of drugs. In this context, the carbohydrate units are
good components for synthesis of bioactive analogs. One of the most suitable
methods to obtain dihydropyrans is [4+2] hetero Diels-Alder reaction [35-38].
Dihydropyrans are a key intermediates in the synthesis of carbohydrates [39,40]
which are the part of bioactive compounds with antitumor activity [40], also they
are a fragments of macrolides antibiotics and a cardiac glycoside digitoxin [41].
The synthesis of carbohydrates which contain not only trifluoromethyl group but
also Halogen atom is a very attractive way of developing new routes to bioactive
compounds.
With the aim to obtain new fluorinated dihydropyranes and to compare the
reactivity of trifluoromethyl enone 1a with α-halogeno-substituted enones 3a,h,i
[4+2] Diels-Alder approach was used. The first reaction with enone 1a, as a
precursor for the dihydropyrans synthesis, was performed at similar conditions

1
3
more than 30 years ago [37,38]. α-Halogenoenones 3 react with vinyl ether and
give the corresponding dihydropyrans 10 in a very good yields (Scheme 8).
Scheme 8. [4+2] Hetero Diels-Alder reaction of enones with vinyl ether.
[4+2] Hetero Diels-Alder reaction of enones 1a and 3a,h,i with vinyl ethers
and a small amount of hydroquinone was run at 80 °C for 24-30 hrs and 2,4-
disubstituted-5-(hydrogen,halogen)-6-(trifluoromethyl)-3,4-dihydro-2H-pyranes
1
0 were obtained [38]. α-Halogen enones contain some insignificant amount of
acid after prolonged storing. Therefore freshly distilled enone was used or a small
amount of Et N was added to prevent the polymerization of the vinyl ether. In the
3
cycloaddition we observed a stereoselective reaction for enone 1a and for 3a,h,i.
Unsubstituted enone 1a gave a mixture of diastereomeric adducts 10a in a 70:30
ratio with δ = ‒73.51 and ‒73.45 respectively. The diastereoselectivity of
F
1
19
cycloadditions was estimated by H and F NMR data of the crude product
mixtures. Using literature data (both chemical shifts of characteristic protons and
constants, and CF group shifts) for adducts 10a we assigned the cis-configuration
3
for predominant diastereomers 10b,h,i [36,40]. The diastereomeric ratio is 76:24
for 10b (X = F), 82:18 for 10h (X = Cl), 80:20 for 10i (X = Br).
3
. Conclusions
The fluorination of readily available polyfluoroalkyl enones 1 using XeF2
and BF ·Et O as a catalyst, gives the vic-difluoro ketones. α-Fluoroenones 3 can be
3
2

1
4
obtained as a Z-isomers under further dehydrofluorination with pyridine as a base.
The yield of α-fluoroenones 3 strongly depends from the nature of R CO group or
f
substituents in β-position of enone 1. New fluoro containing enaminones 4,5 and
pyrazole 9 were obtained from α-fluoroenones 3. Also α-fluoroenones 3 are a
useful dienophiles in [4+2] hetero Diels-Alder cycloaddition and it is a convenient
route to synthesis of fluorinated hexose.
4
. Experimental
4
.1. General
All reagents were commercially available and used as received. Solvents were
purified according to standard procedures. Starting materials were purchased from
Acros, Merck, Fluka, and Enamine. Melting points are uncorrected.
1
13
19
Characterization of intermediates and final compounds was done by H, C, F
1
19
13
NMR and IR spectroscopies. H, F and C NMR spectra were recorded on
Varian VXR at 300 MHz, Varian Unity Plus at 400 MHz and Bruker DRX-500 at
2
5 °C. Low temperature NMR spectra of enone 3a were recorded on Varian Unity
1
13
Plus at 500 MHz. Chemical shifts are reported in ppm from TMS (for H and C
1
9
NMR) and CCl F (for F NMR), coupling constants are in Hz. Multiplicity is: (s)
3
for singlet, (br.s) for broad singlet, (d) for doublet, (t) for triplet, (q) for quartet,
(dd) for doublet of doublets, and (m) for multiplet. Infrared spectra were recorded
on a Bruker Vertex 70 FTIR spectrometer with KBr beamsplitter and RT-DLaTGS
detector at ambient temperature (20±1 °C). The progress of reactions was
monitored by using TLC (silica gel 60 F254, Merck). The purification by column
chromatography was carried out on silica gel 60 (Merck, particle size 0.040–0.063
mm).
4
.2. Experimental procedures

1
5
4
.2.1. General procedure for α-fluoroenones (3a-c) synthesis
To a 50 mL round-bottom flask under argon 4-ethoxy-1,1,1-trifluorobut-3-en-
2
-one 1a (8.2 g, 48.8 mmol) in dry acetonitrile (20 mL) and BF ·Et O (50 mg)
3
2
were added. To the stirring solution the xenon difluoride (8.42 g, 49.8 mmol) was
added in portions to keep the reaction temperature at -10 to -5°C. After the
completion of the gas evolution the pyridine (3.86 g, 49.8 mmol) was added at
0
3
°C. Reaction mixture was poured in 50 mL of dichloromethane and washed with
0 mL of 5% water solution of citric acid and 2×30 mL of H O. Organic layer was
2
separated and dried with sodium sulfate. Dry solution was filtered and the solvent
was removed under reduced pressure. The residue was purified by vacuum
distillation (10 mm Hg) to give 3a.
4
6
.2.1.1. 4-Ethoxy-1,1,1,3-tetrafluorobut-3-en-2-one (3а). Pale yellow oil, yield
1
8% (6.17 g), bp = 62 °C (10 mmHg). H NMR (500 MHz, CDCl ): δ 1.42 (t, 3H,
3
J = 7.1 Hz, CH ), 4.26 (q, 2H, J = 7.1 Hz, CH ), 7.24 (d, J = 19.2 Hz, 1H, OCH=);
3
2
1
9
F NMR (376 MHz, CDCl ): δ ‒73.49 (br. s, 3F, CF ), ‒162.08 (br. s, 1F, =CF);
3
3
1
3
1
3
C NMR (126 MHz, CDCl ):  15.1, 73.2, 116.1 (qd, J = 289.2 Hz, J = 2.0
3
CF
CF
1
2
2
Hz, CF ), 140.3 (d, J = 244.4 Hz, =CF), 148.9, 172.8 (dq, J = 37.0 Hz, J =
3
CF
CF
CF
2
3
4
3.0 Hz, CO). Anal.calcd. for C H F O : C, 38.72; H, 3.25; found: C, 38.45; H,
6
6
4
2
.32.
.2.1.2. 4-Ethoxy-1,1,3-trifluorobut-3-en-2-one (3b). Pale yellow oil, yield 68%
1
(
2.7 g), bp = 75 °C (10 mm Hg). H NMR (500 MHz, CDCl ): δ 1.44 (t, 3H, J =
3
2
7
.1 Hz, CH ), 4.26 (q, 2H, J = 7.1 Hz, CH ), 6.03 (t, J = 56.3 Hz, CHF ), 7.3 (d,
3
2
HF
2
3
19
J = 20 Hz, 1H, OCH=); F NMR (376 MHz, CDCl ): ‒123.41 (br. s, 2F, CF H),
HF
3
2
‒
4
4
161.33 (br. s, 1F, =CF) Anal. calcd. for C H F O : C, 42.87; H, 4.20; found: C,
6
7
3
2
2.98; H, 4.27;
.2.1.3. 1-Chloro-4-ethoxy-1,1,3-trifluorobut-3-en-2-one (3c). Pale yellow oil,
1
yield 70% (3.9 g), bp = 74° C (0.5 mm.Hg). H NMR (500 MHz, CDCl ): δ 1.45 (t,
3

1
6
3
3
H, J = 7.1 Hz, CH ), 4.29 (q, 2H, J = 7.1 Hz, CH ), 7.31 (d, J = 19 Hz, 1H,
3
2
HF
1
9
OCH=); F NMR (376 MHz, CDCl ): δ ‒63.46 (br. s, 2F, CF Cl), ‒160.45 (br. s,
3
2
1
3
4
4
8
F, =CF). Anal. calcd. for C H ClF O : C, 35.58; H, 2.89; found: C, 35.42; H,
6
6
3
2
.02.
.2.2 General procedure for enamonones (4-8) synthesis [15]
.2.2.1. 1,1,1,3-Tetrafluoro-4-(methylamino)but-3-en-2-one (5a) crystals, yield
1
5%, (0.96 g), mp = 83-85 °C. H NMR (400 MHz, CDCl ): δ 3.14 (m, 3H), 5.58
3
3
3
(
br. s, 0.16H, NH), 5.86 (br. s, 0.7H, NH), 7.20 (dd, 0.68H, J = 13.7 Hz, J =
HH
HF
3
3
2
3.3 Hz, OCH=), 7.32 (dd, 0.32H, J = 10.7 Hz, J = 13.5 Hz, OCH=), 8.79
HH
HF
1
9
(
br. s, 0.14H, NH); F NMR (376 MHz, CDCl , {H}): δ ‒69.28 (br. m, 0.04F),
3
4
4
‒
‒
‒
0
8
4
69.79 (br. d, J = 6.3 Hz, 1.95F, CF ), ‒75.49 (d, 0.55F, J = 16.9 Hz, CF ),
FF
3
FF
3
4
4
75.68 (br. d, 0.46F, J = 16.3 Hz, CF ), ‒169.14 (q, 0.64F, J = 6.5 Hz, =CF),
FF
3
FF
4
170.79 (br. m, 0.04F, =CF), ‒179.08 (q, 0.18F, J = 16.5 Hz, =CF), ‒186.64 (q,
FF
4
.14F, J = 17.0 Hz, =CF). Anal. calcd. for C H F NO: C, 35.10; H, 2.95; N,
FF
5
5 4
.19; found: C, 35.42; H, 3.01; N, 8.01.
.2.2.2 4-(Dimethylamino)-1,1,1,3-tetrafluorobut-3-en-2-one (5b) [29]
Pale yellow oil, yield 76% (0.8 g), bp = 71°C (1 mm).
.2.3 4-Fluoro-3-(trifluoromethyl)-1H-pyrazole (9)
4
To the stirred solution of H SO (1.32 g, 13.43 mmol) in toluene (5 mL) the
2
4
hydrazine hydrate (134.5 mg, 2.69 mmol) and 4-ethoxy-1,1,1,3-tetrafluorobut-3-
en-2-one (3а) (500 mg, 2.69 mmol) were added at 0 °C. The mixture was heated
and stirred for 24 h at 80 °C. Then the reaction mixture was cooled to rt and treated
with aq. KOH solution (0.84 g, 15 mmol). CH Cl (20 mL) was added and the
2
2
organic layer was separated and washed with water (2х15 mL). The solvent was
evaporated under reduced pressure and residue was crystallized from hexane to
1
give 355.9 mg of 9. Pale yellow crystals, yield 86%, mp = 89 °C. H NMR (500
3
19
MHz, CDCl ): δ 7.56 (br. d, 1H, J = 4.4 Hz, CH), 10.87 (br. s. 1H, NH); F
3
HF

1
7
NMR (376 MHz, CDCl , {H}): ‒62.02 (d, 3F, J = 6.6 Hz, CF ), ‒174.60 (q, 1F,
3
FF
3
4
13
2
J = 6.6 Hz, CF); C NMR (126 MHz, CDCl ):  116.5 (d, J = 25.6 Hz, CH),
FF
3
CF
1
3
2
2
1
19.9 (qd, J = 268.6 Hz, J = 3.4 Hz, CF ), 128.6 10/2(qq, J = 38.8 Hz, J
CF
CF
3
CF
CF
1
=
10.2 Hz, C-CF ), 145.7 (br. d, J = 254.6 Hz, CF). Anal. calcd. for C H F N : C,
3
4
2
4
2
3
4
1.18; H, 1.31; N, 18.18; found: C, 31.38; H, 1.61; N, 18.16.
.2.4. General procedure for dihydropyranes (10) synthesis
The mixture of enone 3 (2.5 mmol), ethylvinyl ether (7.5 mmol), trimethylamine
0.15 mmol) and hydrohinone (0.15 mmol) was heated in closed pressure tube for
4 h at 70 °C in argon atmosphere. The reaction was monitored by GLC. Then the
(
2
reaction mixture was cooled to rt and hexane (25 mL) was added. The solution was
filtered and the filtrate was evaporated under reduced pressure.
4
.2.4.1. 2,4-Diethoxy-5-fluoro-6-(trifluoromethyl)-3,4-dihydro-2H-pyran (10b)
Colorless oil, yield of crude product 78% (0.5 g), yield after column
chromatography 65% (0.42 g) (eluents Hexane : EtOAc 6:1), major diastereomer:
1
H NMR (400 MHz, CDCl ): 1.21 (t, J = 7 Hz, 6H, 2CH ), 2.14 (m, 1H, CH ), 2.28
3
3
2
(
(
m, 1H, CH ), 3.59 (m, 1H, CH ), 3.65 (m, 2H, OCH ), 3.84 (m, 1H, CH ), 4.14
2
2
2
2
19
br.t. 1H, J = 7.2 Hz, CH), 5.12 (s, 1H, CH); F NMR (376 MHz, CDCl , {H}): ‒
3
6
8.01 (d, J = 23.7 Hz, 3F, CF ), ‒ 147.10 (qt, J = 23.6 and 4.2 Hz, 1F, CF);
FF
3
FF
1
9
minor diastereomer F NMR (376 MHz, CDCl , {H}): ‒ 68.10 (d, J = 22.9 Hz,
3
FF
3
4
F, CF ), ‒ 149.39 (qt, J = 23.3 and 3.7 Hz, 1F, CF);
3
FF
.2.4.2. 5-Chloro-2,4-diethoxy-6-(trifluoromethyl)-3,4-dihydro-2H-pyran (10h)
Yield of crude product 97% (0.66 g), yield after distillation 67% (0.46 g), bp = 84
1
°
C (0.5 mm.Hg); major diastereomer: H NMR (300 MHz, CDCl ): δ 1.24 (t, J =
3
7
.0 Hz, 3H, CH ) 1.26 (t, J = 7.0 Hz, 3H, CH ), 2.26 (m, 1H, CH ), 2.10 (m, 1H,
3
3
2
1
2
CH ), 3.65 (m, 3H, OCH ), 4.01 (m, 1H, CH), 5.21 (dd, J = 3.0 Hz, J = 4.5 Hz,
2
2
19
1
H, CH); F NMR (282 MHz, CDCl ): ‒66.96 (s, 3F, CF ); minor diastereomer:
3
3
1
H NMR (300 MHz, CDCl ): δ 1.24 (t, J = 7.0 Hz, 3H, CH ) 1.26 (t, J = 7.0 Hz,
3
3

1
8
3
1
H, CH ), 2.10 (m, 1H, CH ), 2.22 (m, 1H, CH ), 3.91 (m, 3H, OCH ), 3.99 (m,
3
2
2
2
1
2
19
H, CH), 5.11 (dd, J = 2.3 Hz, J = 7.8 Hz, 1H, CH); F NMR (282 MHz,
CDCl ): ‒67.14 (s, 3F, CF ).
3
3
4
.2.4.3. 5-Bromo-2,4-diethoxy-6-(trifluoromethyl)-3,4-dihydro-2H-pyran (13i)
Yield of crude product 93% (0.74 g), yield after distillation 60% (0.48 g), bp = 94
1
°
C (0.5 mm.Hg); major diastereomer: H NMR (400 MHz, CDCl ): 1.24 (m, 6H,
3
2
CH ), 2.11 (m, 1H, CH ), 2.28 (m, 1H, CH ), 3.63 (m, 3H, OCH ), 3.88 (m, 1H,
3
2
2
2
1
9
OCH ), 4.04 (m, 1H, CH), 5.24 (m, 1H, CH); F NMR (282 MHz, CDCl ): ‒66.80
2
3
1
(
s, 3F, CF ); minor diastereomer: H NMR (400 MHz, CDCl ): 1.24 (m, 6H,
3
3
2
CH ), 2.11 (m, 1H, CH ), 2.28 (m, 1H, CH ), 3.66 (m, 3H, OCH ), 3.88 (m, 1H,
3
2
2
2
1
9
OCH ), 4.04 (m, 1H, CH), 5.12 (m, 1H, CH); F NMR (282 MHz, CDCl ): ‒66.97
2
3
(s, 3F, CF3).
Acknowledgments Financial support by the Deutsche Forschungsgemeinschaft
Grant 436 UKR 113/101/0 is gratefully acknowledged.

1
9
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2
2
1
9
Table 1. Products ratio in the reaction of enone 1a with XeF by F NMR data.
2
a
Entry Reagents
Ratio of the products (%)
1
100
74
45
10
a
2a
-
11
19
80
3a
-
15
28
10
4a
-
1
2
3
4
5
Starting pointb
0.25 eq XeF
0.5 eq XeF
1 eq XeF
1eq H
1 eq Py
2
2
2
2
O
100
6
100
was used;
a
by 19F NMR, as internal standard 1 equivalents of C
F
6 6
b
5
0 mg (0.27 mmol) 1a, 4 mg BF ·Et O in CH CN 1mL.
3 2 3