1,1-Дифлуоро-2-(бромо, азидо)етилзаміщені β-алкоксієнони: синтез та реакції гетероциклізації
New 5-bromo- and 5-azido-1-ethoxy-4,4-difluoropent-1-en-3-ones were synthesized and their reactivity was studied by nucleophilic substitution reactions and heterocyclizations with various binucleophiles
Saved in:
| Date: | 2024 |
|---|---|
| Main Authors: | , , |
| Format: | Article |
| Language: | English |
| Published: |
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2024
|
| Subjects: | |
| Online Access: | https://bioorganica.com.ua/index.php/journal/article/view/85 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Journal Title: | Ukrainica Bioorganica Acta |
| Download file: |  |
Institution
Ukrainica Bioorganica Acta| _version_ | 1871193611895308288 |
|---|---|
| author | Agunovych, Volodymyr A. Bugera, Maksym Ya. Gerus, Igor I. |
| author_facet | Agunovych, Volodymyr A. Bugera, Maksym Ya. Gerus, Igor I. |
| author_institution_txt_mv | [
{
"author": "Volodymyr A. Agunovych",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Maksym Ya. Bugera",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Igor I. Gerus",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Agunovych, Volodymyr A. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:55Z |
| description | New 5-bromo- and 5-azido-1-ethoxy-4,4-difluoropent-1-en-3-ones were synthesized and their reactivity was studied by nucleophilic substitution reactions and heterocyclizations with various binucleophiles |
| doi_str_mv | 10.15407/bioorganica2024.01.044 |
| first_indexed | 2025-07-17T12:20:01Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
UDC 577.1:547.321
DOI: https://doi.org/10.15407/bioorganica2024.01.044
44
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
1,1-Difluoro-2-(bromo, azido)ethyl-substituted β-alkoxyenones: synthesis
and heterocyclizations
Volodymyr A. Agunovych, Maksym Ya. Bugera, Igor I. Gerus*
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: New 5-bromo- and 5-azido-1-ethoxy-4,4-difluoropent-1-en-3-ones were synthesized and their reactivity was studied by
nucleophilic substitution reactions and heterocyclizations with various binucleophiles.
Keywords: organic chemistry; fluorine; enones; nucleophilic substitution; heterocyclizations.
Introduction
Introducing fluorine atoms and fluorinated groups into
organic molecules is a powerful and valuable instrument for
purposefully adjusting of their chemical and physical
properties purposefully especially in the search for new
biologically active compounds. Though direct fluorination
or polyfluoroalkylation methods are very attractive tools for
constructing fluorinated compounds, fluorine-containing
building blocks are often the more convenient starting
reagents. One of such synthons is readily available
β-alkoxyvinyl polyfluoroalkyl ketones 1 which may be
considered as the chemical equivalent of 1,3-diketones (R2
= Alk, Ar) or 1,3-ketoaldehydes (R2 = H) (Figure 1) [1].
RF
O
R1, R2 = H, Alk, Ar
1
RF R2
O O
OAlk
R2
R1
R1
Figure 1. β-Alkoxyvinyl polyfluoroalkyl ketones 1 are the
chemical equivalent of 1,3-dicarbonyl compounds.
Received:
Revised:
Accepted:
Published online:
21.02.2024
15.03.2024
02.04.2024
30.06.2024
Corresponding author. Tel.: +380-44-296-0409;
e-mail: gerus@nas.gov.ua (I.I. Gerus)
ORCID: 0000-0001-5086-9466
The enones 1 are easily afforded in a one-step reaction of
alkyl vinyl ethers with polyfluoroacylating reagents [2] and
widely used in organic synthesis as reactive and useful
polyfluoroalkyl-containing building blocks for obtaining
various fluorinated aliphatic and (hetero)aromatic
compounds: enaminones [3], hydroxy [4] and amino acids
[5-7], carbo- [8, 9] and heterocycles [10-15], etc. The
variating R1, R2, and OAlk substituents at vinyl group
allows to get a lot of different enones bearing various
functional groups. One more way to get new perspective
fluorinated building blocks is the modifying RF group both
the quantity of fluorine atoms and the structure of its
skeleton. Previously we reported that the enones 1 with
CF2CO fragment can be synthesized by the reaction of alkyl
vinyl ethers with acylating reagents bearing at last two
fluorine atoms at α-position to carbonyl group, as example:
XCF2COCl (X = RF, H, Cl, Br) [1], and ArCF2COCl [16]. It
is worth to mention that the enones 1 bearing CH2CF2CO
fragment are not synthesized till now although incor-
poration of the CH2CF2 linker instead of CH2CH2 between
functional groups and (hetero)aromatic rings improved
activity and/or pharmacokinetic properties of the
compounds as compared to their non-fluorinated
counterparts. In addition to that, the NHCH2CF2 fragment
can be found in several experimental drugs (Figure 2) [17].
In this work, we explored a new approach to gem-
difluoroethane bearing compounds, which also relied on
the use of 1,1-difluoro-2-(bromo, azido) ethyl-substituted
building blocks, namely, β-alkoxyenones 1 [RF =
(Br,N3)CH2CF2, R1 = R2 = H, Figure 1], which were not.
© Agunovych V.A. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
V.A. Agunovych et al.
45
F
F
N
H
Cl
F
O
HN
O
HN
HN NH2
N NH
N
N
Cl
OH
N
H
NH
NH2
F
F
F F
NH
N
O
N
N
N
N
N+
F
F
NH
O-
N+
Cl
NH
O
Cl O-
Figure 2. Examples of experimental drugs bearing 1-amino-2,2-difluoroethyl unit.
reported to date and can be good starting materials for the
synthesis of various heterocyclic compounds containing
1-amino-2,2-difluoroethyl unit - NH2CH2CF2.
Results and Discussion
First, we synthesized bromodifluoroethyl bearing enone
5 in good yield under the usual reaction conditions [1] by
the reaction of ethyl vinyl ether with 3-bromo-2,2-
difluoropropanoyl chloride 4, which was obtained in 3 steps
from readily available ethyl bromopyruvate by slightly
modified method [18] – we used oxalyl chloride instead of
phthaloyl chloride (Scheme 1).
Enone 5 is relatively stable; it can be distilled in vacuum
and stored at +4 °C for months without changes. The
structure of the enone 5 was confirmed by 1H, 13C, and 19F
NMR spectroscopy. Thus, in the 19F NMR spectra, the CF2
group appeared as a triplet at -107.13 ppm (3JHF 13.8 Hz).
In the 1H NMR spectra of 5, the CH2 group appeared at
3.72 ppm as triplet (3JHF 13.8 Hz) and trans-vinyl protons as
two doublets at 6.01 and 7.86 ppm (3JHH 12.5 Hz). These
chemical shifts of the signals were similar to that reported
for previously synthesized enones with –CH=CH–CO–
fragment [1, 16].
There are three electrophilic carbon atoms in the
structure of the enone 5: β-position of vinyl group, carbonyl
group, and bromomethyl group (Figure 3).
O
OEtNu:
F
Br
F
Figure 3. The possible pathways of nucleophilic attack on the
enone 5.
We found that enone 5 easily reacts with ammonia and
morpholine afforded corresponding enaminones 6a,b in
high yield and no products of the bromine substitution were
observed even at large excess of amines and elevated
temperature (Scheme 2).
Also, no products of the bromine substitution were
observed in the reaction of enone 5 with 1,2- and 1,3-bi-
nucleophiles such as hydrazines, hydroxylamine, urea, and
thiourea (Scheme 3). In particular, the reaction of enone 5
with hydrazine hydrate in AcOH proceeded smoothly at r.t.
and led to corresponding pyrazole 7, whereas methyl-
hydrazine provided a mixture of isomeric pyrazoles 8a and
8b in 9 : 2 ratio (the designation of isomers was approved
by its NMR data as in reference [19]). The reaction of
enone 5 with hydroxylamine led to dihydroisoxazoline 9
which was dehydrated to isoxazole 10. Unfortunately the
reaction of enone 5 with urea and thiourea afforded very
complex reaction mixtures and pyrimidines 11a and 11b
were not isolated in pure form. However the formation of
pyrimidine 11b was firmly detected by 1H and 19F NMR
spectroscopy: the signals of CF2 group as two triplets
(3JHF ~14 Hz) are downfield shifted to -100.6 ppm and two
pairs of doublets of CH protons of pyrimidine ring are
observed at 9.11, 7.84 and 8.98, 7.71 ppm (3JHH ~4.8 Hz).
The signal doubling can be explained by thione-thiol
tautomerism.
The low reactivity of bromine atom in BrCH2CF2
fragment towards substitution reaction with N-nucleophiles
is explained by electron withdrawing effect of neighboring
difluoromethylene group. The azide anion is an excellent
nucleophile and SN2 displacement of primary bromide with
sodium azide gives the corresponding alkyl azide which can
be reduced into a primary alkyl amine by a wide variety of
reagents or reaction systems [20]. Unfortunately, the
reactions of enone 5 and heterocycles 9 and 10 with sodium
azide in DMSO at 110 °C did not afford to the
corresponding azides, we observed only a destruction of
starting compounds. However azide 12 was obtained in
good yield from pyrazole 7 after heating for 48 h in DMSO
(Scheme 4).
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
46
2
COOEt
F F
Br
COOEt
Br
O
COOLi
F F
Br
F F
Br
O
OEt
60%
LiOHSF4
100%
95%
, PyOEt
40%
(COCl)2
3
COCl
F F
Br
4 5
Scheme 1. Synthesis of 5-bromo-1-ethoxy-4,4-difluoropent-1-en-3-one 5.
O
OEt
F
Br
F NHR2
O
NR2
F
Br
F
5 6a,b
79-82%
CH2Cl2
NR2 = NH2 (a), N(CH2CH2)2O (b)
Scheme 2. Synthesis of 5-bromo-1-amino-4,4-difluoropent-1-en-3-ones 6a,b.
Br
F
F
O
OEt
N2H4 x H2O
Py, SOCl2
N2H3Me
5
7
8a 8б
9 10
Br
F
F
NHN
Br
F
F
NN
Br
F
F
NN
+
Br
F
F
NO
OH
Br
F
F
NO
N
NH
F
F
Br
79%
75%
83% 55%
(NH2)2CX
EtOH, HCl
AcOH
Na2CO3, H2O
AcOH
CH2Cl2, 0 oC
NH2OH x HCl
X = O (11a), S (11b)X
X
Scheme 3. Synthesis of 2-bromo-1,1-difluoroethyl substituted heterocycles 7-11.
NaN3
Br
F
F
NHN
N3
F
F
NHN
DMSO, 110 oC
7 12
72%
Scheme 4. Synthesis of 2-azido-1,1-difluoroethyl substituted pyrazole 12.
F
Br
F
13
75%
NaN3
F
N3
F
OEt
O
OEt
O
DMSO, 60 oC
N3
F
F
N3
F
F
OLi
O
Cl
O
LiOH x H2O
100%
THF-H2O
95%
(COCl)2
Et2O, 0 oC
F F
N3
O
OEt
60%
CH2=CHOEt
Py, CH2Cl2
16
2
14 15
Scheme 5. Synthesis of 2-azido-1,1-difluoroethyl substituted enone 16.
V.A. Agunovych et al.
47
N3
F
F
O
OEt
Py, SOCl2
16
12
17 18
N3
F
F
NHN
N3
F
F
NO
OH
N3
F
F
NO
N
NH
F
F
N3
75%
81% 53%
(NH2)2CO
EtOH, HCl
Na2CO3, H2O
AcOH
CH2Cl2, 0 oC
NH2OH x HCl
19
O
N2H4 x H2O
62%
Scheme 6. Synthesis of 2-azido-1,1-difluoroethyl substituted heterocycles 12, 17-19.
Next another way to obtain 2-amino-1,1-difluoroethyl
substituted heterocycles was investigated. The most
effective approach was the use of 1,1-difluoro-2-azidoethyl-
substituted β-ethoxyenone 1 (RF = N3CH2CF2, R1 = R2 = H,
Figure 1) as promising building block in the synthesis of
aimed heterocycles after the reducing azido group into
amino one. The most challenging was validation of the
synthesis of 3-azido-2,2-difluoropropanoyl chloride 15.
Finally, after the substitution of bromine atom on azido
group in ethyl 3-bromo-2,2-difluoropropanoat 2 by sodium
azide at the heating in DMSO and the sequence of reactions
we obtained enone 16 in good yield (Scheme 5).
Enone 16 is yellowish liquid with low stability even if it
was stored at +4 °C and the best to use immediately after
isolation. The structure of the enone 16 was confirmed by
1H, 13C, and 19F NMR spectroscopy and the data are very
similar to ones for enone 5. Synthetic utility of enone 16 as
the CCC bis-electrophiles was demonstrated by
condensation with common 1,2- and 1,3-binucleophiles
such as hydrazine, hydroxylamine, urea, and thiourea
(Scheme 6). Pyrazole 12 and isoxazole 18 were obtained in
good yields at the same reaction conditions as for enone 5.
The reaction of enone 16 with thiourea was unsuccessful in
the contrast with urea that afforded pyrimidinone 19 after
column chromatography.
Next we used the reduction of azido-bearing compounds
to synthesize some heterocyclic compounds with 1-amino-
2,2-difluoroethyl unit – NH2CH2CF2. Thus the catalytic
hydrogenation or the reduction under Staudinger reaction of
enone 16 can afforded enone 20 which is interesting
polyfuntionalized fluorocontaining building block (Scheme
7). Unfortunately, in both cases we obtained only very
complex mixture of unidentified products with, possible,
polymeric nature.
Surprisingly, we obtained a complex mixture of products
under the catalytic hydrogenation of pyrazole 12 (Scheme
8).
The catalytic hydrogenation of pyrimidinone 19 afforded
the compound 22 – the product of the reduction both azido
group and pyrimidine ring in good yield and selective
reduction of azido group in pyrimidinone 19 was successful
under Staudinger reaction (Scheme 9). The structure of the
compounds 22 and 23 was confirmed by 1H and 19F NMR
spectroscopy.
Conclusions
We demonstrated several approaches to the synthesis of
heterocyclic compounds with 1-(bromo,azido,amino)-2,2-
difluoroethyl unit – (Br,N3,NH2)CH2CF2 based on new
promising fluorocontaining building blocks – enones 5 and
16 for further applications in drug discovery, material
science and agrochemistry.
Notes
Acknowledgments and finances. The work was
supported by Enamine Ltd. The authors thank Prof. Andriy
Tolmachev for his encouragement and support, and all the
brave people of Ukraine for making this publication
possible.
The authors declare no conflict of interest. The
authors declare that there is no conflict of interest regarding
the publication of this paper.
Experimental section
The solvents were purified according to the standard
procedures. Column chromatography was performed using
Kieselgel Merck 60 (230-400 mesh) as the stationary phase.
1H, 13C, and 19F NMR spectra were recorded on Bruker 170
Avance 500 spectrometer (at 500 MHz for 1H NMR, 126
MHz for 13C NMR and 470 MHz for 19F NMR) and Varian
Unity Plus 400 spectrometer (at 400 MHz for 1H NMR, 101
MHz for 13C NMR and 376 MHz for 19F NMR). NMR
chemical shifts are reported in ppm (δ scale) downfield
from TMS as an internal standard and are referenced using
residual NMR solvent peaks at 7.26 and 77.16 ppm for 1H
and 13C in CDCl3, 2.50 and 39.52 ppm for 1H and 13C in
DMSO-d6; fluorine signals from CFCl3 as an internal
standard. Coupling constants (J) are given in Hz. Spectra
are reported as follows: chemical shift (δ, ppm),
multiplicity, integration, coupling constants (Hz). Elemental
analyses were performed at the Analytical Chemistry
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
48
Laboratory of the V.P. Kukhar Institute of Bioorganic
Chemistry and Petrochemistry, National Academy of
Sciences of Ukraine.
Synthesis
Ethyl 3-bromo-2,2-difluoropropanoate (2).
The solution of ethyl bromopyruvate (120.0 g, 0.615
mol) in 100 mL of CH2Cl2 was placed in 1000 mL
autoclave made of Hastelloy nickel alloy and water
(5.55 mL, 0.307 mol) was added. The reaction vessel was
cooled down by liquid nitrogen and SF4 (232.0 g, 2.15 mol)
was condensed into a reaction vessel. Cooling bath was
removed, and the mixture was allowed to warm up to a
room temperature. It was then stirred for 18 h. The gaseous
products were vented off into a trap with aqueous solution
of NaOH (1M). To the residue 516.5 g (6.15 mol) of
NaHCO3 was added by portions. The organic faze was
separated by filtration and concentrated under reduced
pressure to afford the desired product. The final product
was purified by distillation. Yield: 80.1 g, 60%, yellowish
liquid, b.p. 85 °C, 60 mmHg. 1H NMR (400 MHz, CDCl3)
δ 4.36 (q, J = 7.1 Hz, 2H), 3.59 (t, J = 14.6 Hz, 2H), 1,36 (t,
J = 7.1 Hz, 3H) [18].
Lithium 3-bromo-2,2-difluoropropanoate (3).
The solution of propanoate 2 (45 g, 0.207 mol) and
LiOH·H2O (8.7 g, 0.207 mol) in the mixture of THF
(400 mL) and water (50 mL) was stirred at rt overnigth. The
reaction mixture was concentrated under reduced pressure
to afford the desired product. Yield: 40.37 g, 100%, white
crystals which was used in the next step without further
purification. 1H NMR (400 MHz, DMSO-d6) δ 3.85 (t, J =
15.8 Hz); 19F {H} NMR (376 MHz, DMSO-d6) δ -103.44
(s).
3-Bromo-2,2-difluoropropanoyl chloride (4).
To a stirred suspension of Lithium salt 3 (40.37 g, 0.207
mol) in diethyl ether (400 mL) the solution of oxalyl
chloride (78.87 g, 0.621 mol) was added dropwise at 0 °C.
After stirring at rt overnight the reaction mixture was
filtered, an inorganic precipitate was washed with diethyl
ether (100 mL) and the ethereal solution was concentrated
under reduced pressure without heating to afford the desired
product. Yield: 40.88 g, 95%, colorless liquid which was
used in the next step without further purification. 1H NMR
(400 MHz, CDCl3) δ 3.79 (t, J = 12.6 Hz); 19F {H} NMR
(376 MHz, CDCl3) δ -101.27 (s).
(E)-5-Bromo-1-ethoxy-4,4-difluoropent-1-en-3-one (5).
To the solution of ethyl vinyl ether (28.4 g, 0.394 mol)
and pyridine (31.2 g, 0.394 mol) in 200 mL of CH2Cl2
propanoyl chloride 4 (40.8 g, 0.197 mol) was added
dropwise at 0 °C. After stirring at rt overnight the reaction
mixture was quenched with water (200 mL). Organic phase
was washed with water (2x100 mL), and 2% solution of
citric acid (50 mL), was dried over Na2SO4, and
concentrated under reduced pressure to afford the desired
product. The final product was purified by distillation.
Yield: 19.15 g, 40%, yellowish liquid, b.p. 95 °C, 10
mmHg. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 12.4 Hz,
1H), 6.01 (d, J = 12.4 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H),
3.72 (t, J = 13.9 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ 187.15 (t, J = 29.1 Hz), 167.15,
114.30 (t, J = 255.7 Hz), 98.44, 68.61, 28.46 (t, J = 29.2
Hz), 14.37; 19F {H} NMR (376 MHz, CDCl3) δ -107.13 (s).
Anal. Calcd for C7H9BrF2O2: C, 34.59; H, 3.73. Found:
C, 34.81; H, 3.55.
(Z)-1-Amino-5-bromo-4,4-difluoropent-1-en-3-one (6a).
To the solution of enone 5 (0.5 g, 0.002 mol) in MeOH
(3 mL) 20% solution of ammoniac in MeOH (0.17 g, 0.002
mol) was added at 0 °C. After stirring at rt overnight the
reaction mixture and concentrated under reduced pressure to
afford the desired product. Yield: 0.36 g, 82%, yellow oil.
1H NMR (400 MHz, CDCl3) δ 9.79-9.20 (br.s, 1H), 7.14
(m, 1H), 6.10-5.70 (br.s, 1H), 5.53 (dm, J = 7.5 Hz, 1H),
3,71 (t, J = 13.9 Hz, 2H); 19F {H} NMR (376 MHz, CDCl3)
δ -107.42 (s). Anal. Calcd for C5H6BrF2NO: C, 28.06;
H, 2.83; N, 6.55. Found: C, 27.91; H, 2.98; N, 6.41.
(E)-5-Bromo-4,4-difluoro-1-morpholinopent-1-en-3-one
(6b).
To the solution of enone 5 (0.5 g, 0.002 mol) in CH2Cl2
(5 mL) morpholine (0.18 g, 0.002 mol) was added at 0 °C.
After stirring at rt overnight the reaction mixture was
concentrated under reduced pressure to afford the desired
product. Yield: 0.46 g, 79%, yellow lowmelting solid. 1H
NMR (400 MHz, CDCl3) δ 7.77 (d, J = 12.5 Hz, 1H), 5.55
(d, J = 12.5 Hz, 1H), 3.71-3.66 (m, 2H), 3.49 (m, 2H), 3.40
(m, 2H); 19F {H} NMR (376 MHz, CDCl3) δ -107.21 (s).
Anal. Calcd for C9H12BrF2NO2: C, 38.05; H, 4.26; N, 4.93.
Found: C, 37.78; H, 4.41; N, 4.82.
3-(2-Bromo-1,1-difluoroethyl)-1H-pyrazole (7).
To the solution of enone 5 (5.0 g, 0.02 mol) in acetic acid
(100 mL) hydrazine hydrate (1.05 g, 0.021 mol) was added
dropwise under stirring at rt. After stirring at rt overnight
the reaction mixture was concentrated under reduced
pressure. The rest was resolved in MTBE (50 mL), the
organic phase was washed with 2% solution of NaHCO3
(50 mL), was dried over Na2SO4, and concentrated under
reduced pressure to afford the desired product. Yield:
3.56 g, 82%, yellow lowmelting solid. 1H NMR (400 MHz,
CDCl3) δ 13.85-12.89 (br.s, 1H), 7.69 (br.s, 1H), 6.54 (br.s,
1H), 3.88 (t, J = 13.7 Hz, 2H); 13C NMR (101 MHz, CDCl3)
δ 145.97 (t, J = 30.8 Hz), 130.36, 116.33 (t, J = 240.2 Hz),
103.82 (t, J = 2.6 Hz), 32.67 (t, J = 33.4 Hz); 19F {H} NMR
(376 MHz, CDCl3) δ -95.47 (s). Anal. Calcd for
C5H5BrF2N2: C, 28.46; H, 2.39; N, 13.28. Found: C 28.72;
H 2.65; N, 13.02.
3-(2-Bromo-1,1-difluoroethyl)-1-methyl-1H-pyrazole and
5-(2-bromo-1,1-difluoroethyl)-1H-pyrazole (8a) and (8b).
Analogously as for pyrazole 7 from enone 5 (1.0 g,
0.004 mol) and methylhydrazine (0.19 g, 0.004 mol). Yield:
0.70 g, 75%, yellow oil. Major pyrazole 8a: 1H NMR (400
MHz, CDCl3) δ 7.38 (br.d, J = 1.2 Hz, 0.82H), 6.48 (br.d,
V.A. Agunovych et al.
49
J = 1.2 Hz, 0.82H), 3.94 (t, J = 13.8 Hz, 1.64H); 19F {H}
NMR (376 MHz, CDCl3) δ -94.52 (s, 2.46F).
Minor pyrazole 8b: 1H NMR (400 MHz, CDCl3) δ 7.46
(br.s, 0.18H), 6.49 (br.s, 0.18H), 4.02 (s, 0.54), 3.88 (t, J =
13.3 Hz, 0.36H); 19F {H} NMR (376 MHz, CDCl3) δ -92.77
(s, 0.36F). Anal. Calcd for C6H7BrF2N2: C, 32.02; H, 3.14;
N, 12.45. Found: C 32.31; H 3.05; N, 12.62.
5-(2-Bromo-1,1-difluoroethyl)-4,5-dihydroisoxazol-5-ol (9).
To the solution of enone 5 (5.0 g, 0.02 mol) and
H2NOH·HCl (1.43 g, 0.02 mol) in water (50 mL) Na2CO3
(2.22 g, 0.021 mol) was added by portions. After stirring at
rt overnight the reaction mixture was extracted with CH2Cl2
(2x50 mL). Organic phase was dried over Na2SO4, and
concentrated under reduced pressure to afford the desired
product. Yield: 3.93 g, 83%, yellow lowmelting solid which
was used in the next step without further purification. 1H
NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 3.97-3.57 (m, 3H),
3.52 (d, J = 19.1 Hz, 1H), 3.08 (d, J = 19.1 Hz, 1H); 19F
{H} NMR (376 MHz, CDCl3) δ -111.07 (d, J = 252.2 Hz,
1F), -112.14 (d, J = 252.2 Hz, 1F).
5-(2-Bromo-1,1-difluoroethyl)isoxazole (10).
To the solution of dihydroisoxazolol 9 (3.82 g, 0.017
mol) and pyridine (1.60 g, 0.02 mol) in CH2Cl2 (50 mL)
SOCl2 (2.41 g, 0.02 mol) was added dropwise at 0 °C. After
stirring at rt overnight the reaction mixture was quenched
with water (50 mL), organic phase was dried over Na2SO4,
and concentrated under reduced pressure to afford the
desired product. Yield: 1.95 g, 55%, yellow liquid. 1H NMR
(400 MHz, CDCl3) δ 8.32 (s, 1H), 6.62 (s, 1H), 3.89 (t, J =
13.1 Hz, 2H); 19F {H} NMR (376 MHz, CDCl3) δ -97.09
(s). Anal. Calcd for C5H4BrF2NO: C, 28.33; H, 1.90;
N, 6.61. Found: C 28.01; H 1.75; N, 6.48.
3-(2-Azido-1,1-difluoroethyl)-1H-pyrazole (12).
A. The solution of pyrazole 7 (1.0 g, 0.0058 mol) and
NaN3 (0.92 g, 0.014 mol) in DMSO (5 mL) was stirred at
110 °C for 48 h. The reaction mixture was quenched with
water (50 mL), extracted with MTBE (2x30 mL), organic
phase was dried over Na2SO4, and concentrated under
reduced pressure to afford the desired product. Yield:
0.72 g, 72%, braun oil.
B. Analogously as for pyrazole 7 from enone 16 (0.5 g,
0.0024 mol) and hydrazine hydrate (0.122 g, 0.0024 mol).
Yield: 0.39 g, 75%, yellow oil. 1H NMR (400 MHz, CDCl3)
δ 12.3-11.3 (br.s, 1H), 7.67 (s, 1H), 6.60 (s, 1H), 3.89 (t, J =
13.4 Hz, 2H); 19F {H} NMR (376 MHz, CDCl3) δ -98.61
(s). Anal. Calcd for C5H5F2N5: C, 34.69; H, 2.91; N, 40.45.
Found: C 34.91; H 2.65; N, 40.18.
Ethyl 3-azido-2,2-difluoropropanoate (13).
The solution of ester 2 (20.0 g, 0.092 mol) and NaN3 (9.0
g, 0.138 mol) in DMSO (150 mL) was stirred overnight at
60 °C. The reaction mixture was quenched with water (500
mL), extracted with MTBE (2x80 mL), organic phase was
dried over Na2SO4, and concentrated under reduced
pressure to afford the desired product. Yield: 12.41 g, 75%,
yellow liquid which was used in the next step without
further purification. 1H NMR (400 MHz, CDCl3) δ 4.36 (q,
J = 7.1 Hz, 2H), 3.73 (t, J = 12.7 Hz, 2H), 1.36 (t, J = 7.1
Hz, 3H); 19F {H} NMR (376 MHz, CDCl3) δ -110.81 (s).
Lithium 3-azido-2,2-difluoropropanoate (14).
Analogously as for Li salt 3 from propanoate 13 (12 g,
0.067 mol) and LiOH·H2O (2.81 g, 0.067 mol). Yield:
10.5 g, 100%, yellowish crystals which was used in the next
step without further purification. 1H NMR (400 MHz,
DMSO-d6) δ 3.66 (t, J = 14.9 Hz); 19F {H} NMR (376
MHz, DMSO-d6) δ -108.34 (s).
3-Azido-2,2-difluoropropanoyl chloride (15).
Analogously as for chloro anhydride 4 from Lithium salt
14 (10.0 g, 0.064 mol) and oxalyl chloride (22.0 g, 0.191
mol). Yield: 10.3 g, 95%, yellow liquid which was used in
the next step without further purification. 1H NMR (500
MHz, CDCl3) δ 3.84 (t, J = 12.3 Hz); 19F {H} NMR (376
MHz, CDCl3) δ -110.70 (s).
(E)-5-Azido-1-ethoxy-4,4-difluoropent-1-en-3-one (16).
Analogously as for enone 5 from chloro anhydride 15
(1.0 g, 0.0059 mol), ethyl vinyl ether (0.85 g, 0.012 mol)
and pyridine (0.94 g, 0.012 mol). Yield: 0.91 g, 75%,
yellow oil which was used in the next step without further
purification. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 12.4
Hz, 1H), 5.99 (d, J = 12.4 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H),
3.72 (t, J = 13.5 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ 187.55 (t, J = 28.5 Hz), 167.15,
115.39 (t, J = 256.9 Hz), 98.36, 68.59, 51.38 (t, J = 27.3
Hz), 14.29; 19F {H} NMR (376 MHz, CDCl3) δ -111.60 (s).
Anal. Calcd for C7H9F2N3O2: C, 40.98; H, 4.42; N, 20.48.
Found: C, 41.21; H, 4. 25; N, 20.13.
5-(2-Azido-1,1-difluoroethyl)-4,5-dihydroisoxazol-5-ol (17).
Analogously as for dihydroisoxazolol 9 from enone 16
(1.0 g, 0.0049 mol), H2NOH·HCl (0.37 g, 0.0054 mol), and
Na2CO3 (0.57 g, 0.0054 mol). Yield: 0.76 g, 81%, yellow
oil which was used in the next step without further
purification. 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H),
5.00-4.50 (br.s, 1H), 3.95-3.69 (m, 2H), 3.48 (d, J = 19.0
Hz, 1H), 3.03 (dm, J = 19.1 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 147.16, 117.74 (t, J = 251.5 Hz), 104.01 (t, J =
30.0 Hz), 50.88 (t, J = 27.7 Hz), 43.15; 19F {H} NMR (376
MHz, CDCl3) δ -115.16 (s). Anal. Calcd for C5H6F2N4O2:
C, 31.26; H, 3.15; N, 29.16. Found: C, 31.52; H, 3.37;
N, 28.88.
5-(2-Azido-1,1-difluoroethyl)isoxazole (18).
Analogously as for isoxazole 9 from dihydroisoxazolol
19 (0.74 g, 0.0038 mol), pyridine (0.31 g, 0.0039 mol), and
SOCl2 (0.46 g, 0.0039 mol). Yield: 0.30 g, 62%, yellow oil.
1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 6.65 (s, 1H),
3.91 (t, J = 13.2 Hz, 2H); 19F {H} NMR (376 MHz, CDCl3)
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
50
δ -97.09 (s). Anal. Calcd for C5H4F2N4O: C, 34.49; H, 2.32;
N, 32.18. Found: C, 34.27; H, 2.49; N, 31.79.
4-(2-Azido-1,1-difluoroethyl)pyrimidin-2(1H)-one (19).
To the solution of enone 16 (0.5 g, 2.4 mmol) and urea
(0.146 g, 2.4 mmol) in ethanol (5 mL) conc. HCl (0.5 g,
5.9 mmol) was added and stirred for 48 h at rt. The reaction
mixture was concentrated under reduced pressure and the
desired product was purified by column chromatography
with eluent CHCl3 : MeOH (50 : 1). Yield: 0.36 g, 53%,
yellow lowmelting compound. 1H NMR (400 MHz, DMSO-
d6) δ 12.8-12.3 (br.s, 1H), 8.24 (d, J = 6.3 Hz, 1H), 6.68 (d,
J = 6.3 Hz, 1H), 4.11 (t, J = 14.6 Hz, 2H); 13C NMR (126
MHz, DMSO-d6) δ 168.10 (t, J = 28.6 Hz), 156.53, 151.71,
118.13 (t, J = 246.5 Hz), 100.01, 52.34 (t, J = 26.8 Hz); 19F
{H} NMR (376 MHz, DMSO-d6) δ -105.63 (s). Anal. Calcd
for C6H5F2N5O: C, 35.83; H, 2.51; N, 34.82. Found:
C, 35.97; H, 2.42; N, 35.11.
4-(2-Amino-1,1-difluoroethyl)tetrahydropyrimidin-2(1H)-
one (22).
To the solution of pyrimidinone 19 (0.12 g, 0.6 mmol) in
ethyl acetate (5 mL) 10% Pd/C (0.15 g) was added and the
reaction mixture was stirred under hydrogen for 48 h at rt.
The catalyst was filtered off and washed with ethyl acetate
(5 mL). The solution was concentrated under reduced
pressure to afford the desired product. Yield: 0.082 g, 77%,
yellow lowmelting compound. 1H NMR (400 MHz, CDCl3)
δ 5.84 (br.s, 1H), 5.14 (br.s, 1H), 3.88 (m, 1H), 3.41 (m,
1H), 3,30 (m, 1H), 3.25-2.98 (m, 2H), 2.02 (m, 2H); 19F
{H} NMR (470 MHz, CDCl3) δ -115.58 (dm, J = 250.6
Hz), -118.64 (dm, J = 250.6 Hz). Anal. Calcd for
C6H11F2N3O: C, 40.22; H, 6.19; N, 23.45. Found: C, 40.01;
H, 6.32; N, 23.19.
4-(2-Amino-1,1-difluoroethyl)pyrimidin-2(1H)-one (23).
To the solution of pyrimidinone 19 (0.33 g, 1.6 mmol) in
THF (5 mL) triphenylphosphine (0.47 g, 1.8 mmol) and
water (0.15 g, 8 mmol) were added and stirred overnight at
rt. The reaction mixture was concentrated under reduced
pressure and the desired product was purified by
crystallization from benzene. Yield: 0.232 g, 81%,
yellowish crystals, mp 86-88 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.15 (d, J = 6.2 Hz, 1H), 6.60 (d, J = 6.2 Hz,
1H), 3.45-3.15 (br.s, 2H), 3.17 (t, J = 14.7 Hz, 2H); 19F {H}
NMR (376 MHz, DMSO-d6) δ -107.74 (s). Anal. Calcd for
C6H7F2N3O: C, 41.15; H, 4.03; N, 23.99. Found: C, 41.38;
H, 3.81; N, 23.87.
References
1. Gerus, I.I.; Gorbunova, M.G.; Kukhar, V.P. β-Ethoxyvinyl
polyfluoroalkyl ketones - versatile synthones in fluoroorganic
chemistry. J. Fluorine Chem. 1994, 69, 195-198.
2. Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo, S.
Electrophilic substitutions of olefinic hydrogens ii. acylation of
vinyl ethers and n-vinyl amides. Chem. Lett. 1976, 5, 499-502.
3. Vdovenko, S.I.; Gerus, I.I.; Zhuk, Yu.I.; Kukhar, V.P.; Pagacz-
Kostrzewab, M.; Wierzejewskab, M.; Daniliuc, C.-G. The
conformational analysis of push-pull enaminones using FTIR and
NMR spectroscopy, and quantum chemical calculations. VI. β-N-
Methyl-aminovinyl trifluoromethyl ketone and α-methyl-β-N-
methylaminovinyl trifluoromethyl ketone. J. Mol. Struct. 2017,
1128, 741-753.
4. Kondratov, I.S.; Gerus, I.I.; Kukhar, V.P.; Manoilenko, O.V. New
synthetic approach to mevalonate and mevaldate fluoroanalogues.
Tetrahedron: Asymmetry 2007, 18, 1918-1925.
5. Shaitanova E.N.; Gerus I.I.; Belik M.Yu.; Kukhar V.P. Synthesis of
optically active β-hydroxy-β-polyfluoromethyl GABAs.
Tetrahedron: Asymmetry 2007, 18, 192-198.
6. Tolmacheva, N.A.; Gerus, I.I.; Dolovanyuk, V.G.; Kondratov, I.S.;
Haufe, G. Synthesis of New δ-(Polyfluoroalkyl)-δ-hydroxy-α-amino
Acids. Eur. J. Org. Chem. 2009, 2009, 5012-5019.
7. Kondratov, I.S.; Dolovanyuk, V.G.; Tolmachova, N.A.; Gerus, I.I.;
Bergander, K.; Fröhlich, R.; Haufe, G. Reactions of β-alkoxyvinyl
polyfluoroalkyl ketones with ethyl isocyanoacetate and its use for
the synthesis of new polyfluoroalkyl pyrroles and pyrrolidines. Org.
Biomol. Chem. 2012, 2012, 8778-8785.
8. Kondratov, I.S.; Tolmachova, N.A.; Dolovanyuk, V.G.; Gerus, I.I.;
Daniliuc, C.-G.; Haufe G. Synthesis of Trifluoromethyl-Containing
Polysubstituted Aromatic Compounds by Diels-Alder Reaction of
Ethyl 3-Benzamido-2-oxo-6-(trifluoromethyl)-2H-pyran-5-
carboxylate. Eur. J. Org. Chem. 2015, 2015, 2482-2491.
9. Shaitanova, E.N.; Gerus, I.I.; Balabon, O.A.; Ivasyshyn, V.E.;
Tarasenko, K.V.; Daniliuc, C.G.; Haufe, G. Synthesis of Fluorine-
Containing 3-Aminocyclopent-2-enones via Intramolecular
Cyclization. Eur. J. Org. Chem. 2020, 2020, 7156-7163.
10. Shaitanova, E.N.; Balabon, O.A.; Rybakova, A.N.; Khlebnicova,
T.S.; Lakhvich, F.А.; Gerus, I.I. Synthesis of functionalized
fluoroalkyl pyrimidines and pyrazoles from fluoroalkyl enones. J.
Fluorine Chem., 2021, 252, 109905.
11. Gerus, I.I.; Mironetz, R.V.; Kondratov, I.S.; Bezdudny, A.V.;
Dmytriv, Y.V.; Shishkin, O.V.; Starova, V.S.; Zaporozhets, O.A.;
Tolmachev, A.A.; Mykhailiuk, P.K. “Reported, but Still Unknown.”
A Closer Look into 3,4-Bis- and 3,4,5-
Tris(trifluoromethyl)pyrazoles. J. Org. Chem. 2012, 77, 47-56.
12. Tolmachova, N.A.; Gerus, I.I.; Vdovenko, S.I.; Haufe, G.; Kirzhner,
Y.A. Synthesis of New Polyfluoroalkyl-Containing Pyrones,
Pyridones and Pyrido[1,2-a]benzazoles from Fluorinated β-
Alkoxyenones. Synthesis, 2007, 3797-3806.
13. Kacharova, L.M.; Gerus, I.I.; Kacharov, A.D. Reaction of α-halogen
substituted β-ethoxyvinyl trifluoromethyl ketones with 2-
aminopyridine: new route to trifluoroacetyl-containing heterocycles.
J. Fluorine Chem., 2002, 117, 193-197.
14. Lyutenko, N.V.; Gerus, I.I. aza-Annulation of β-aminovinyl
trifluoromethyl ketones with acryloyl chloride: an efficient synthesis
of 5-(trifluoroacetyl)-3,4-dihydro-2(1H)-pyridinones. Tetrahedron
Lett. 2013, 94, 4091-4093.
15. Klipkov, A.A.; Sorochinsky, A.E.; Tarasenko, K.V.; Rusanova,
J.A.; Gerus I.I. Synthesis of trifluoromethyl and trifluoroacetyl
substituted dihydropyrrolizines and tetrahydroindolizines.
Tetrahedron Lett. 2020, 61, 151633.
16. Bugera, M.Ya.; Tarasenko, K.V.; Kondratov, I.S.; Gerus, I.I.;
Vashchenko, B.V.; Ivasyshyn, V.E.; Grygorenko, O.O. (Het)aryl
Difluoromethyl-Substituted β-Alkoxyenones: Synthesis and
Heterocyclizations. Eur. J. Org. Chem. 2020, 2020, 1069-1077.
17. Meanwell, N.A. Fluorine and Fluorinated Motifs in the Design and
Application of Bioisosteres for Drug Design. J. Med. Chem. 2018,
61, 5822-5880.
18. Joyeau, R.; Molines, H.; Labia, R.; Wakselman, M. N-Aryl 3-
halogenated azetidin-2-ones and benzocarbacephems, inhibitors of
.beta.-lactamases. J. Med. Chem. 1988, 31, 370-374.
19. Sevenard, D.V., Khomutov, O.G., Kodess, M.I., Pashkevich, K.I.,
Loop, I., Lork, E., Röschenthaler, G.-V. Novel polyfluoroalkylated
pyrazoles from 2-polyfluoroacylcycloalkanones and hydrazines:
syntheses and unequivocal molecular structure assignment. Can. J.
Chem. 2001, 79, 183-194.
20. Mitsunobu, O. Synthesis of Amines and Ammonium Salts. In
Comprehensive Organic Synthesis, Editors: Trost, B. M., Fleming,
I. 1991, 6, 65-101.
V.A. Agunovych et al.
51
1,1-Дифлуоро-2-(бромо, азидо)етилзаміщені β-алкоксиенони: синтез та реакції
гетероциклізації
В.А. Агунович, М.Я. Бугера, І.І. Герус*
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: Синтезовано нові 5-бромо- та 5-азидо-1-етокси-4,4-дифлуоропент-1-ен-3-они та досліджено їх реакційну здатність за допомогою реакцій
нуклеофільного заміщення та гетероциклізації з різними бінуклеофілами.
Ключові слова: органічна хімія; флуор; енони; нуклеофільне заміщення; реакції гетероциклізації.
|
| id | oai:ojs2.bioorganica.com.ua:article-85 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:28Z |
| publishDate | 2024 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/68/acd872a72ae9394420dcdc45c711df68.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-852026-07-19T14:56:55Z 1,1-Difluoro-2-(bromo, azido) ethyl-substituted β-alkoxyenones: synthesis and heterocyclizations 1,1-Дифлуоро-2-(бромо, азидо)етилзаміщені β-алкоксієнони: синтез та реакції гетероциклізації Agunovych, Volodymyr A. Bugera, Maksym Ya. Gerus, Igor I. organic chemistry fluorine enones nucleophilic substitution heterocyclizations органічна хімія флуор енони нуклеофільне заміщення реакції гетероциклізації New 5-bromo- and 5-azido-1-ethoxy-4,4-difluoropent-1-en-3-ones were synthesized and their reactivity was studied by nucleophilic substitution reactions and heterocyclizations with various binucleophiles Синтезовано нові 5-бромо- та 5-азидо-1-етокси-4,4-дифлуоропент-1-ен-3-они та досліджено їх реакційну здатність за допомогою реакцій нуклеофільного заміщення та гетероциклізації з різними бінуклеофілами V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2024-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/85 10.15407/bioorganica2024.01.044 Ukrainica Bioorganica Acta; Vol. 19 No. 1 (2024): Ukrainica Bioorganica Acta; 44-51 Ukrainica Bioorganica Acta; Том 19 № 1 (2024): Ukrainica Bioorganica Acta; 44-51 1814-9766 1814-9758 10.15407/bioorganica2024.01 en https://bioorganica.com.ua/index.php/journal/article/view/85/82 Copyright (c) 2024 Volodymyr A. Agunovych, Maksym Ya. Bugera, Igor I. Gerus https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | органічна хімія флуор енони нуклеофільне заміщення реакції гетероциклізації Agunovych, Volodymyr A. Bugera, Maksym Ya. Gerus, Igor I. 1,1-Дифлуоро-2-(бромо, азидо)етилзаміщені β-алкоксієнони: синтез та реакції гетероциклізації |
| title | 1,1-Дифлуоро-2-(бромо, азидо)етилзаміщені β-алкоксієнони: синтез та реакції гетероциклізації |
| title_alt | 1,1-Difluoro-2-(bromo, azido) ethyl-substituted β-alkoxyenones: synthesis and heterocyclizations |
| title_full | 1,1-Дифлуоро-2-(бромо, азидо)етилзаміщені β-алкоксієнони: синтез та реакції гетероциклізації |
| title_fullStr | 1,1-Дифлуоро-2-(бромо, азидо)етилзаміщені β-алкоксієнони: синтез та реакції гетероциклізації |
| title_full_unstemmed | 1,1-Дифлуоро-2-(бромо, азидо)етилзаміщені β-алкоксієнони: синтез та реакції гетероциклізації |
| title_short | 1,1-Дифлуоро-2-(бромо, азидо)етилзаміщені β-алкоксієнони: синтез та реакції гетероциклізації |
| title_sort | 1,1-дифлуоро-2-(бромо, азидо)етилзаміщені β-алкоксієнони: синтез та реакції гетероциклізації |
| topic | органічна хімія флуор енони нуклеофільне заміщення реакції гетероциклізації |
| topic_facet | organic chemistry fluorine enones nucleophilic substitution heterocyclizations органічна хімія флуор енони нуклеофільне заміщення реакції гетероциклізації |
| url | https://bioorganica.com.ua/index.php/journal/article/view/85 |
| work_keys_str_mv | AT agunovychvolodymyra 11difluoro2bromoazidoethylsubstitutedbalkoxyenonessynthesisandheterocyclizations AT bugeramaksymya 11difluoro2bromoazidoethylsubstitutedbalkoxyenonessynthesisandheterocyclizations AT gerusigori 11difluoro2bromoazidoethylsubstitutedbalkoxyenonessynthesisandheterocyclizations AT agunovychvolodymyra 11difluoro2bromoazidoetilzamíŝeníbalkoksíênonisinteztareakcíígeterociklízacíí AT bugeramaksymya 11difluoro2bromoazidoetilzamíŝeníbalkoksíênonisinteztareakcíígeterociklízacíí AT gerusigori 11difluoro2bromoazidoetilzamíŝeníbalkoksíênonisinteztareakcíígeterociklízacíí |