Transformations of 3-acyl-4H-polyfluorochromen-4-ones under the action of amino acids and biogenic amines

Article abstract of DOI:10.1016/j.jfluchem.2019.109354

For the first time 6,7,8-trifluoro- and 5,6,7,8-tetrafluorinated 3-benzoylflavones have been obtained. Their reactions with amino acids and biogenic amines were studied in comparison with polyfluorinated 3-acetyl-2-methylchromones. For chromones, reactions at the C-2 are preferred, which lead to the pyrone ring opening to form N-substituted aminoenketones. Whereas in the case of flavones the main route is the nucleophilic aromatic substitution of the fluorine atom at the C-7. Flavones and chromones react in the same way both with dopamine to give aminoenketones, and with proline to form 7-amino-substituted chromen-4-ones. All the reactions of chromen-4-ones are accompanied by deacylation, except ones of flavones with proline. Among the synthesized aminoenketones, compounds with high antimycotic and antibacterial action were found.

Full text of DOI:10.1016/j.jfluchem.2019.109354

Accepted Manuscript
Title: Transformations of
3-acyl-4H-polyfluorochromen-4-ones under the action of
amino acids and biogenic amines
Authors: Konstantin V. Shcherbakov, Mariya A. Artemyeva,
Yanina V. Burgart, Natalya P. Evstigneeva, Natalya A.
Gerasimova, Natalia V. Zilberberg, Nicolai V. Kungurov,
Victor I. Saloutin, Oleg N. Chupakhin
PII:
DOI:
Article Number:
S0022-1139(19)30195-2
https://doi.org/10.1016/j.jfluchem.2019.109354
109354
Reference:
FLUOR 109354
To appear in:
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Received date:
Revised date:
Accepted date:
7 June 2019
30 July 2019
30 July 2019
Please cite this article as: Shcherbakov KV, Artemyeva MA, Burgart YV, Evstigneeva
NP, Gerasimova NA, Zilberberg NV, Kungurov NV, Saloutin VI, Chupakhin
ON, Transformations of 3-acyl-4H-polyfluorochromen-4-ones under the action
of amino acids and biogenic amines, Journal of Fluorine Chemistry (2019),
https://doi.org/10.1016/j.jfluchem.2019.109354
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Transformations of 3-acyl-4H-polyfluorochromen-4-ones under the action of amino acids and
biogenic amines
Konstantin V. Shcherbakova, *, Mariya A. Artemyevaa, b, Yanina V. Burgarta, b, Natalya P. Evstigneevac,
Natalya A. Gerasimovac, Natalia V. Zilberbergc, Nicolai V. Kungurovc, Victor I. Saloutina,b and Oleg N.
Chupakhina, b
a
Postovsky Institute of Organic Synthesis UD RAS, 22 Kovalevskoy str., Yekaterinburg 620990, Russian
Federation
b Ural Federal University, 19 Mira str., Yekaterinburg 620002, Russian Federation
c Ural Research Institute of Dermatovenereology and Immunopathology, 8 Shcherbakova str., Yekaterinburg
620076, Russian Federation
 Corresponding author. Tel.: +7-343-362-3229; e-mail: kvshcherbakov@gmail.com
Graphical abstract
Highlights
 Synthesis of the new 3-benzoylpolyfluoroflavones
 The alternative routes for modification of 3-acylpolyfluorochromones with amino acids and
biogenic amines
 New functionalized polyfluorinated chromones, flavones and aminoenketones
 N-substituted 3-amino-1-(2-hydroxypolyfluorophenyl)prop-2-en-1-ones as potential antimycotic
agents
Abstract
For the first time 6,7,8-trifluoro- and 5,6,7,8-tetrafluorinated 3-benzoylflavones have been obtained. Their
reactions with amino acids and biogenic amines were studied in comparison with polyfluorinated 3-acetyl-
2-methylchromones. For chromones, reactions at the C-2 are preferred, which lead to the pyrone ring opening
to form N-substituted aminoenketones. Whereas in the case of flavones the main route is the nucleophilic
aromatic substitution of the fluorine atom at the C-7. Flavones and chromones react in the same way both
with dopamine to give aminoenketones, and with proline to form 7-amino-substituted chromen-4-ones. All
the reactions of chromen-4-ones are accompanied by deacylation, except ones of flavones with proline.
Among the synthesized aminoenketones, compounds with high antimycotic and antibacterial action were
found.

Keywords
3-acyl-4H-polyfluorochromen-4-ones; amines; nucleophilic aromatic substitution; pyrone ring opening;
deacylation; antimycotic and antibacterial activity
1. Introduction
Chromen-4-ones (1,4-benzopyrones) are important scaffold in medicinal chemistry,[1] as there are
numerous examples of natural and synthetic derivatives with diverse biological activities (antithrombotic,[2]
antimicrobial[3] antitumor[4] vasodilating activity[5] etc.), some of which are successfully used as modern
drugs (flacoside, alvocidib, intal, quercetin, etc.). In addition, because of their multifunctional nature
сhromen-4-ones are widely used in organic synthesis as block-synthons to form new open-chain and
heterocyclic compounds.[6] Current studies show wide possibilities for the modification of chromone-based
structures by amino acids that allow obtaining a new type of hybrid multifunctional compounds, which
combine biological activity with high stability and bioavailability.[7]
Transformations of fluorine-containing compounds is of growing interest. It is well known that the
presence of electron-withdrawing fluorine atoms in the organic molecules not only significantly changes their
physical and chemical properties, offering new synthetic possibilities, but also leads to the spectrum variety
of biological activity.[8] Polyfluorinated 3-acylchromen-4-ones are the promising multifunctional
compounds, having several nonequivalent electrophilic centers, that make them convenient substrates for
modification in reactions with nucleophilic reagents. Previously, we have found[9] that the main reaction route
of 3-acetylpolyfluorochromones with highly basic aliphatic amines and esters of α-amino acids, similar to
non-fluorinated substrates,[10] is pyrone ring opening, accompanied by deacylation, leading to formation of
the corresponding substituted aminovinyl ketones. In contrast, 3-ethoxycarbonyl-substituted
polyfluoroflavones are able not only to the pyrone ring opening, but also to formation of SNAr-substitution
products depending on the nature of the amine reagent.[11]
In this work, the interaction features of 3-acylpolyfluorochromen-4-ones with amino acids (β-alanine, γ-
aminobutyric acid (GABA) and proline) and biogenic amines (dopamine and pyrrolidine) were studied. A
wide range of their biological effect determined the aim of modifying of chromones and flavones with such
amines. Based on amino acids the effective antihypertensive, hormonal drugs were designed. Dopamine is
known to play an important role in the activity of the central and peripheral nervous system. The pyrrolidine
fragment is a part of the natural alkaloids, for example, nicotine and hygrin, in drugs, such as procyclidine
and bepridil.[12]
2. Results and discussion
Trifluoro- and tetrafluoro-substituted 3-acetylchromones 4a,b and 3-benzoylflavones 5a,b were selected
as objects for the modification. For their synthesis the previously proposed method was used[13] based on
acylation of 1,3-diketones 2, 3, activated with magnesium alkoxides, with polyfluorobenzoyl chlorides 1a,b.
It should be noted that 6,7,8-trifluoro- and 5,6,7,8-tetrafluoro-substituted 3-benzoyl-2-phenyl-4H-chromen-
4-ones 5a,b were synthesized for the first time using dibenzoylmethane 3 as a diketone component (Scheme
1). The formation of polyfluorinated chromones 4a,b and flavones 5a,b is caused by spontaneous cyclization
of the intermediate triketones B, obtained by acid hydrolysis of their magnesium salts A. The cyclization
proceeds through the intramolecular nucleophilic substitution of the ortho-fluorine atom of the
polyfluorophenyl ring by hydroxyl group of the enolized diketone fragment.
However, to improve the yields of the compounds 4a,b and 5a,b, the previously used reaction conditions[13]
were optimized. Necessity for the optimization was caused by the formation of asymmetric polyfluorinated
1,3-diketones 6a, 7a in reactions of acetylacetone 2 and dibenzoylmethane 3 with tetrafluorobenzoyl chloride
1a as a result of deacylation of intermediates B, as by-products in addition to the target chromene-4-ones 4a,
5a (Scheme 1). Only 1,3-diketone 6a was isolated, while its phenyl analogue 7a was obtained only in a
mixture with flavone 5a. According to 1H, 19F NMR spectra, compound 6a exists in (CD3)2SO as a mixture
of keto-enol tautomers in a ratio of 1÷3.

It was found that for more efficient synthesis of polyfluorinated chromen-4-ones 4a,b, 5a,b, it is necessary
to remove excess of alcohol from the reaction mixture immediately after the activation of 1,3-diketones 2, 3
with magnesium methoxide to prevent the esterification of polyfluorobenzoyl chlorides 1a,b. Subsequent
neutralization of magnesium salts A preferably should be proceeded by using of 0.5M HCl at room
temperature, instead of 10% aqueous H2SO4 at heating, to prevent the deacylation of the intermediate
triketones B. For the cyclization of triketones B to target chromen-4-ones 4a,b, 5a,b N,N-
diisopropylethylamine (DIPEA) was used. As a result of the synthetic method optimization, the yields of
products 4a,b, 5a,b were increased up to 80–84% (Scheme 1).
Scheme 1. Synthesis of polyfluorinated 3-acyl-4H-chromen-4-ones
Further, it was found that the result of the interaction of polyfluorinated chromones 4a,b and flavones 5a,b
with aliphatic amino acids depends on the reaction conditions. Amino acids are well known to exist
predominantly in a zwitter-ionic form in an acidic or neutral media in low polar solvents.[14] In this regard, at
first the reactions of compounds 4a,b, 5a,b with β-alanine and GABA were carried out in ethanol in the
presence of AcONa and DIPEA at room temperature. However, under these conditions deacylated chromones
8a,b, 9a,b were obtained as the main products (50–56%) while N-substituted aminoenketones 10a,b–13a,b
were formed as minor products (11–20%), resulted from the subsequent pyrone ring opening of compounds
8a,b, 9a,b under the action of amino acids (Scheme 2). To increase the yields of open-chain products 10a,b–
13a,b, reactions of chromen-4-ones 4a,b, 5a,b with β-alanine and GABA were performed in a mixture of
ethanol and 0.5M carbonate buffer (Na2CO3/NaHCO3, pH 9.4) at 80˚C in a microwave reaction module at
discrete power, limited up to 20 W. As a result, the yield of the target aminoenketones 10a,b, 11a,b was
significantly increased up to 55% (Scheme 2).
In contrast to chromones 4a,b, reactions of polyfluoroflavones 5a,b with β-alanine and GABA proceeded
an alternative pathway under these conditions. Trifluoroflavone 5a reacted with β-alanine and GABA to give
flavones 14a, 15a, having the amino acid fragment, as a result of the SNAr mono-substitution of the fluorine
atom at the C-7. Under similar conditions, tetrafluoroflavone 5b formed a mixture of N-substituted 7-amino-
5,6,8-trifluoroflavones 14b, 15b and 7-amino-6,8-difluoro-5-hydroxyflavones 14c, 15c (Scheme 2) in a ratio
of 2÷1 (for 14b, 14c) and 3÷1 (for 15b, 15c). In the case of GABA, by ramping the reaction temperature and
pressure (130°C, 0.9–1.0 MPa) it was succeeded to synthesize the mono-substituted flavone 15b almost
19
selectively, since its content in a mixture increased up to 10÷1, according to F NMR spectroscopy data.
However, we did not manage to find conditions for the selective synthesis of flavones 14b, 14c, and 15b,
15c, as well as to isolate them individually because of their joint crystallization and elution. The structure of
compounds 14b,c, 15b,c was confirmed by 1H, 19F NMR and HRMS data of their mixtures.

Scheme 2. Reactions of 3-acyl-4H-cromen-4-ones with amino acids
Polyfluorochromen-4-ones 4a,b, 5a,b reacted with dopamine in ethanol at room temperature forming N-
substituted aminoenketones 16a,b, 17a,b as a result of the pyrone ring opening and deacylation (Scheme 3).
The transformations of flavones 5a,b with dopamine were accompanied by a significant resinification of the
reaction mass; therefore these reactions were carried out in absolute ethanol under argon atmosphere.
Scheme 3. Reactions of 3-acyl-4H-cromen-4-ones with dopamine hydrochloride
According to 1H, 19F NMR spectra, aminobutenones 10a,b, 11a,b, 16a,b exist as mixtures of (E,Z)-isomers
in (CD3)2SO with a predominance of (Z)-form. While 1H, 19F NMR spectra of phenyl analogues 12a,b, 13a,b,
17a,b contain the only one set of signals of the (Z)-isomer. (Z)-Aminobutenones 10a,b, 11a,b, 16a,b are
characterized by the low-field shift of a proton signal of the amino group ( 10.83–11.08 ppm) that
determined by intramolecular H-bonding with the carbonyl group, in contrast to the analogous signal of (E)-
isomer ( 7.68–8.48 ppm). Moreover, methylene proton of the (Z)-isomer, existing in pseudo-aromatic enol
form, was registered in the low-field region, compared to the CH-signal of the (E)-isomer (see Supplementary
material for full NMR data).
Structure of aminoenketones 10b and 17a in the solid state was confirmed by XRD. It was turned out that
crystals of aminobutenone 10b, having an acidic fragment, were isolated as the sodium salt 10b.Na.
According to XRD data (Fig. 1, 2), compounds 10b.Na, 17a exist in (Z)-aminoenketone form, stabilized by
the two pairs of intramolecular hydrogen bonds О2–H2∙∙∙O1 and N1–H1…O1 (17a, Fig. 1), and О4–H4∙∙∙O1

and N1–H1…O1 (10b.Na, Fig. 2) (see Supplementary material for parameters of the hydrogen bond of
compounds 10b.Na and 17a). Due to the stabilization, atoms of the aminoenketone fragment of the
compounds 17a ({N1,C15,C16,C17,O1}, Fig. 1) and 10b.Na ({N1,C5,C6,C7,O1}, Fig. 2) are located in the
plane of the fluoroaromatic ring. The molecules of compound 17a are bound into dimers by intermolecular
contacts between the amino and carbonyl groups of the aminoenketone fragment of one molecule and the
hydroxyl group of the dopamine moiety of another one (Fig. 3). Zig zag layers with an interplanar distance
of 3.333 Å are formed in the molecular packing of compound 17a due to the π–π interaction of the
fluoroaromatic fragment and the σ–π interaction of the dopamine moiety of the molecules (Fig. 3). The
crystals of 10b.Na are polymer structures, in which sodium ions are linked with each another through the two
molecules of water; at the same time, each sodium ion binds another water molecule. Water molecules link
dimers into polymer chains in direction to the b-axis due to the formation of intermolecular contacts, in which
oxygen atoms of the carboxylate fragment are involved (Fig. 4).
Figure 1. Molecular structure of compound 17a
with atoms represented as thermal ellipsoids of
thermal vibrations with a 50% probability
Figure 2. Molecular structure of compound 10b.Na
with atoms represented as thermal ellipsoids of
thermal vibrations with a 50% probability

Figure 3. Molecular packaging of compound 17a Figure 4. Molecular packaging of compound
10b.Na along the b-axis
It was found that transformations of polyfluorinated chromen-4-ones 4a,b, 5a,b with the
secondary heterocyclic amines (such as pyrrolidine and its 2-carboxylated analogue proline) under
similar reaction conditions depend on the nature of fluorinated substrates and nucleophiles used
(Schemes 4, 5). In ethanol (ε 24.3)[15] under the action of pyrrolidine, chromones 4a,b undergo
pyrone ring opening and deacylation, forming 3-(pyrrolidin-1-yl)-1-(polyfluorophenyl)but-2-en-
1-ones 18a,b. In more polar dimethylsulfoxide (ε 49)[15] these transformations are accompanied
by substitution of a fluorine atom to form compounds 19a,b, having two pyrrolidine fragments
(Scheme 4). However, interaction of chromones 4a,b with proline in the same reaction conditions
had no significant conversion, therefore a mixture of EtOH and 0.5M carbonate buffer was used.
Ar
Only 7-[2-(carboxy)pyrrolidin-1-yl]-substituted 4H-chromen-4-ones 20a,b as products of SN
substitution of fluorine atoms were isolated in an individual form (Scheme 4).
Scheme 4. Reactions of 3-acetyl-4H-chromen-4-ones with pyrrolidine and proline

According to XRD data, 3-(pyrrolidinyl)buthenone 18b is in (E)-aminoenketone form in the
solid state, in contrast to aminoenketones 10a,b–13a,b, 16a,b, 17a,b having an NH-group, which
stabilizes the (Z)-isomer (Fig. 5). The molecules of 18b are characterized by one intramolecular
1
19
hydrogen bond O5–H5А…O1. Besides, the only one set of signals was registered in the H, F
NMR spectra of compounds 18a,b, 19a,b in (CD3)2SO, corresponding to the (E)-form, obviously.
Figure 5. Molecular structure of compound 18b with atoms represented as thermal ellipsoids of thermal
vibrations with a 50% probability
Only 7-substituted 3-benzoylflavones 21a,b, 22a,b were isolated from the reaction of
polyfluoroflavones 5a,b with pyrrolidine and proline as products of nucleophilic aromatic
substitution of fluorine atoms (Scheme 5). It should be noted that the isolated products 21a,b,
22a,b have retained benzoyl function in contrast to chromones 4a,b.
Scheme 5. Reactions of 3-benzoyl-4H-chromen-4-ones with pyrrolidine and proline
We have studied antimycotic and antibacterial activities of some synthesized compounds.
Antimycotic evaluations were carried out against eight fungal strains (Table 1). Terbinafine was
used as a positive control. N-Substituted aminoenketones showed an antimycotic effect from
moderate (compounds 10b, 11b, 12a, 16a,b) to high values (compounds 13b, 17b).
Tetrafluorinated 3-phenylpropenones 13b, 17b revealed the highest activity of the tested
compounds. 3-Phenylpropenone 17b having dopamine moiety showed the elevated antimycotic
activity against T. rubrum and M. canis (MIC 1.56 µg/mL), T. tonsurans and T. violaceum (MIC
3.12 µg/mL) along with the moderate activity against E. floccosum and C. albicans (MIC 12.5
µg/mL). 3-Phenylpropenone 13b, involving 4-aminobutanoic acid fragment, had the same activity
against T. rubrum and M. canis (MIC 1.56 µg/mL). In contrast to tetrafluorinated compounds 13b,
17b, their trifluorinated analogues 13а, 17а exhibited the low antimycotic action. Change of
phenyl substituent in the aminoenketones 13b, 17b to methyl group decreased the antimycotic
avtivity of compounds 11a,b, 16a,b. We did not observe the clear correlation between fungicidal
action and the number of the fluorine atoms in the case of compounds 11a,b, 16a,b In this series
trifluorinated butenone 16a containing dopamine moiety was more effective, suppressing T.
violaceum strains at MIC of 12.5 µg/mL. In contrast to N-substituted aminoenketones, chromone
derivatives 14a, 15a, 20a, 21b, 22a, as well as diaminosubstituted aminoenketone 19b, did not
show antimycotic activity. Most antimicrobial drugs act by a non-enzymatic mechanism,
accompanied by a destruction of the microbial cell membrane.[16] It is possible that chromones

14a, 15a, 20a, 21b, 22a possess the less adsorption on the surface of microbial cells, unlike open-
chain products 13b, 16a, 17b, having aminoenediketone fragment.
Table 1. Antimycotic activity of synthesized compounds.
Minimum inhibitory concentration (MIC), µg/mL
1
50
100
50
50
50
100
100
50
100
10a
10b
11a
11b
12a
12b
13a
13b
14a
15a
16a
16b
17a
17b
19b
20a
21b
22a
2
25
50
50
50
50
25
100
3
50
100
>200
200
200
50
100
>200
200
200
50
100
100
100
50
100
4
>200
25
>200
>200
>200
>200
200
50
25
25
>200
>200
>200
>200
>200
>200
>200
100
5
>200
200
>200
200
25
6
12.5
25
200
200
1.56
>200
>200
50
7
200
200
8
1.56
>200
>200
25
25
50
200
50
9
>200
>200
100
25
>200
>200
50
>200
>200
12.5
25
>200
>200
100
>200
>200
50
10
11
12
13
14
15
16
17
18
25
25
100
100
100
100
1.56
>200
>200
>200
200
0.02
>200
>200
12.5
>200
>200
>200
>200
6.25
50
100
25
100
3.12
>200
>200
>200
>200
–
>200
3.12
>200
200
>200
200
>200
12.5
>200
>200
>200
>200
0.01
1.56
>200
>200
>200
200
0.002
>200
>200
>200
>200
0.001
>200
>200
>200
>200
0.01
>200
100
0.01
Terbinafine
Testing of synthesized compounds against eight strains of conditionally pathogenic
microorganisms and N. gonorrhoeae revealed a higher activity of N-substituted aminoenketones
12a, 16b against St. aureus and St. aureus MRSA (MIC 15.6 mg/mL), compared to Spectinomycin.
Table 2. Antibacterial activity of synthesized compounds.
Minimum inhibitory concentration, MIC, µg/mL
1
2
3
4
125
62.5
125
n.d.
125
125
250
125
250
>250
250
250
125
125
250
250
250
250
250
250
250
250
250
125
>250
>250
250
250
62.5
250
62.5
250
62.5
250
62.5
10a
10b
11a
11b
>250

5
62.5
62.5
62.5
62.5
31.2
250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
15.6
>250
>250
>250
>250
>250
>250
250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
31.25
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
15.6
>250
>250
>250
>250
>250
>250
>250
250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
250
15.6
15.6
>250
>250
31.2
>250
>250
>250
15.6
>250
>250
>250
>250
>250
125
12a
12b
13a
13b
14a
15a
16a
16b
17a
17b
19b
20a
21b
22a
6
>250
>250
>250
>250
>250
62.5
7
8
9
10
11
12
13
14
15
16
17
18
125
n.d.
250
15.6
62.5
250
>250
>250
>250
>250
>250
>250
15.6
>250
>250
>250
>250
>250
>250
7.8
>250
>250
>250
>250
>250
>250
31.25
>250
62.5
31.2
250
15.6
n.a.
Spectinomycin
n.d. – not determined, n.a. – data not available
3. Conclusion
The present study has demonstrated that multifunctional character of polyfluorinated 3-
acylchromen-4-ones 4a,b, 5a,b determines the different routes for their interaction with biogenic
amines and amino acids, depending on the structure of the fluorine-containing substrate and
nucleophilic reagent as well as reaction conditions. Chromones 4a,b react with the primary amines
(amino acids and dopamine) to give N-substituted aminoenketones as a result of nucleophilic
attack at the C-2 with the subsequent pyron ring opening. In addition, flavones 5a,b can react with
amino acids with retention of the pyrone ring, forming products of the fluorine atom substitution.
The SNAr process becomes the main route for the reactions of flavones 5a,b with secondary amines
and an alternative for the similar transformations of chromones 4a,b. At the same time, all these
transformations are accompanied by deacylation, even under mild conditions, except for the
interaction of flavones 5a,b with secondary amines. Deacylation of acyl-functionalized derivatives
is known to easily carry out under the basic conditions.[10,17] Differences in the reactivity of
chromones 4a,b and flavones 5a,b when interacting with primary and secondary amines can be
explained by the steric factors of an amine attack on the C-2 of the chromenone cycle. In the case
of a difficult attack on C-2, an alternative path of transformations along the activated C-7 position
of the aromatic cycle is realized. The presence of fluorine atoms in the aromatic part of the studied
chromenones 4a,b, 5a,b provides the additional opportunities for their transformations. The case
of simultaneous SNAr substitution, pyrone ring opening and deacylation in the reaction of chromone
4a,b with pyrrolidine was found. Among the synthesized aminoenketones, compounds with high
antimycotic and antibacterial action were found. Moreover, 7-substituted flavones may reveal
angioprotective activity, as well as GABA-modified aminoenketones may be of interest as
neurotransmitters. Chromenes and aminoenketones, having dopamine fragment, can be the
promising effectors of the corresponding dopamine receptors.
Acknowledgements
The work was supported by the State project AAAA-A19-119012290115-2.
The equipment of the CCU “Spectroscopy and analysis of organic compounds” of the Postovsky
Institute of Organic Synthesis UD RAS was used in this work. Microbiological assay of the

synthesized compounds was performed at the Ural Research Institute of Dermatovenereology and
Immunopathology.
4. Experimental section
4.1. General information
All the reagents except fluorine-containing benzoyl chlorides, chromones and flavones are
commercially available and used without further purification. Solvents were prepared according
to standard methods of purification. Synthesis under microwave irradiation was carried out in a
CEM Discover SP Explorer Hybrid microwave reaction module in closed reaction vessels. The
Nuclear magnetic resonance spectra (NMR) of the synthesized compounds were recorded on a
Bruker DRX-400 and Bruker AVANCE III 500 spectrometers (1H, 400 (DRX400) and 500
(AV500) MHz, 13C, 100.6 MHz, SiMe4 as an internal standart, 19F, 376 (DRX400) and 470
(AV500) MHz, C6F6 as internal standart (chemical shifts were converted to CCl3F)). IR spectra
were recorded on a Perkin Elmer Spectrum One FT-IR spectrometer using a diffuse reflectance
attachment (DRA) in the range of 4000–400 cm– 1. High-resolution mass spectra (HRMS) were
recorded on a Bruker MaXis Impact HD mass spectrometer (ESI). Elemental (C, H, N) analysis
was performed on a Perkin Elmer PE 2400 Series II CHNS-O EA 1108 elemental analyzer.
Melting points were measured on a Stuart SMP3 in open capillaries and are uncorrected. The
reaction progress was monitored by TLC on ALUGRAM SIL G/ UV254 plates. Column
chromatography was performed on Alfa Aesar silica gel 60 (0.063–0.2 mm).
4.2. General procedure of synthesis of 3-acyl-4H-polyfluorochromen-4-ones 4a,b, 5a,b.
In a three-necked flask, equipped with a reflux condenser and a drop funnel, several iodine
crystals and 1.2 g (50 mmol) of magnesium turnings were added, heated with stirring until the
vigorous sublimation of iodine, then 10 mL (250 mmol) of MeOH and a few drops of CCl4 were
added. While vigorous hydrogen evoluation, 25 mL of absolute toluene was added to the mixture.
Then 50 mmol of corresponding diketone 2, 3 was added in portions while stirring. The mixture
was refluxed until the magnesium turnings were completely dissolved, and then cooled to room
temperature. The solvent was removed in vacuo till the mass thickening, then 25 mL of absolute
toluene was added. Polyfluorobenzoyl chloride 1a,b (50 mmol) in 20 mL of absolute toluene was
added to the mixture dropwise with stirring at the room temperature. The mixture was stirred for
6 h at room temperature, then poured into 150 mL 0.5M HCl. An organic layer was separated and
dried over anhydrous Mg2SO4. To the mixture, separated from Mg2SO4, 0.6 g (5 mmol) of DIPEA
was added, and then refluxed for 2 h. The solvent was removed in vacuo, and the residue was
crystallized fractionally from toluene.
4.2.1. 3-Benzoyl-6,7,8-trifluoro-2-phenyl-4H-chromen-4-one (5a) was synthesized
from 11.2 g (50 mmol) of dibenzoylmethane 3 and 10.6 g (50 mmol) of tetrafluorobenzoyl chloride
1a. Yield 15.2 g (80%), white powder, mp 181–182˚С. IR (DRA): ν 1676 (Bz), 1632 (C=O), 1523,
1496, 1447 (C=C, С–Н), 1006, 927 (C–F) cm–1. 1H NMR (400.13 MHz, (CD3)2SO+CCl4): δ 7.39–
7.91 (10Н, m, 2 Ph), 7.79 (1Н, m, Н, С-5). 19F NMR (376.44 MHz, (CD3)2SO+CCl4): δ -152.11
(1F, d, J = 18.8 Hz), -150.48, -136.65 (2F, both m). Anal. calcd. for С22Н11F3O3: C, 69.48; H, 2.92;
found: C, 69.57; H, 3.18.
4.2.2. 3-Benzoyl-5,6,7,8-tetrafluoro-2-phenyl-4H-chromen-4-one (5b) was
synthesized from 11.2 g (50 mmol) of dibenzoylmethane 3 and 11.5 g (50 mmol) of
pentafluorobenzoyl chloride 1b. Yield 16.7 g (84%), white powder, mp 178–180˚С. IR (DRA): ν
1674 (Bz), 1645 (C=O), 1522, 1502, 1448 (C=C, С–Н), 994 (C–F) cm–1. 1H NMR (400.13 MHz,

(CD3)2SO+CCl4): δ 7.39–7.95 (10Н, m, 2 Ph). 19F NMR (376.44 MHz, (CD3)2SO+CCl4): δ -
162.17, -159.21, -148.87, -144.13 (4F, all m). Anal. calcd. for С22Н10F4O3: C, 66.34; H, 2.53;
found: C, 66.00; H, 2.66.
4.2.3. 1-(2,3,4,5-Tetrafluorophenyl)butane-1,3-dione (6a) was synthesized from 1.0
g (10 mmol) of acetylacetone 2 and 2.1 g (10 mmol) of tetrafluorobenzoyl chloride 1a under
1
reaction conditions.[13] Yield 585 mg (25%), orange powder, mp 82–85˚С (CHCl3/C6H14). Н
NMR (500.13 MHz, (CD3)2SO) spectrum of keto-enol mixture, 3÷1, enol form: δ 2.23 (3Н, s,
СН3), 6.34 (1Н, s, СН), 7.79–7.84 (1Н, m, Н, C6HF4), 15.82 (1Н, br.s, ОН); keto form: δ 2.23
(3Н, s, СН3), 4.25 (2Н, d, J = 3.1 Hz, СН2), 7.78–7.84 (1Н, Н, C6HF4). 19F NMR (470.52 MHz,
(CD3)2SO) spectrum of keto-enol mixture, enol form: δ -154.96, -150.28, -138.71, -137.57 (4F, all
m), keto form: δ -155.02, -148.42, -138.60, -137.70 (4F, all m). Anal. calcd. for С10Н6F4O2: C,
51.30; H, 2.58; found: C, 51.19; H, 2.65.
4.2.4. 1-Phenyl-3-(2,3,4,5-tetrafluorophenyl)propane-1,3-dione (7a) in a mixture
with 5a was synthesized from 11.2 g (50 mmol) of dibenzoylmethane 3 and 10.6 g (50 mmol) of
tetrafluorobenzoyl chloride 1a under reaction conditions. [13] 1Н NMR (500.13 MHz, (CD3)2SO):
δ 7.08, (1Н, s, СН), 7.57–8.18 (5Н, m, Ph), 7.67 (1H, m, H, C-5). 19F NMR (470.52 MHz,
(CD3)2SO): δ -154.99, -149.97, -138.85, -137.54 (4F, all m).
4.3. General procedures for the synthesis of compounds 8–22.
Method A. 3-Acyl-4H-polyfluorochromen-4-one 4a,b, 5a,b (1 mmol), amino acid (2 mmol) and
sodium acetate trihydrate (2 mmol) were suspended in 10 mL of EtOH, then 65 mg (0.5 mmol) of
DIPEA were added to a mixture. Reaction mixture was stirred at room temperature for 96 hrs. At
the end of the reaction, the mixture was poured onto 50 mL of 0.5M HCl, extracted with AcOEt,
3×10 mL. Organic layer was dried with Mg2SO4. Then mixture was separated from Mg2SO4, the
solvent was removed in vacuo. The residue was purified by crystallization from a suitable solvent
or by column chromatography on silica gel, using suitable eluent.
Method B. 3-Acyl-4H-polyfluorochromen-4-one 4a,b, 5a,b (1 mmol), nucleophile reagent (2
mmol) were suspended in a mixture of 5 mL of EtOH and 5 mL of 0.5M carbonate buffer. The
mixture was placed in a reaction vessel and irradiated in a microwave reactor at a discrete power
(10–20 W) and a constant temperature (80 °C) for 4 hrs while stirring. At the end of the reaction,
the mixture was poured onto 50 mL of 0.5M HCl, extracted with AcOEt, 3×10 mL. Organic layer
was dried with Mg2SO4. Then the mixture was separated from Mg2SO4, the solvent was removed
in vacuo. The residue was purified by crystallization from a suitable solvent or by column
chromatography on silica gel, using suitable eluent.
Method C. 3-Acyl-4H-polyfluorochromen-4-one 4a,b, 5a,b (1 mmol) was suspended in 10 mL
of solvent, an excess of amine (2 or 4 mmol) was added to the mixture. The mixture was stirred at
room temperature for 8 hrs. At the end of the reaction, the mixture was poured onto 50 mL of 0.5M
HCl, the precipitate was filtered off, washed with water, and crystallized from a suitable solvent.
4.3.1. 6,7,8-Trifluoro-2-methyl-4H-chromen-4-one (8a) was synthesized according
to the method A from 256 mg (1 mmol) of chromone 4a and 2 mmol of the corresponding amino
1
acid (β-alanine, GABA). White powder, mp 107–109˚С (EtOH). Н NMR (400.13 MHz,
(CD3)2SO): δ 2.44 (3Н, s, СН3), 6.37 (1Н, s, Н, С-3), 7.80 (1Н, d.d.d, JHF = 10.2, 8.0, 2.3 Hz, Н,
С-5). 19F NMR (376.44 MHz, (CD3)2SO): δ -152.14, -151.70, -137.74 (3F, all m). Anal. calcd. for
С10Н5F3O2: C, 56.09; H, 2.35; found: C, 56.44; H, 2.40.
4.3.2. 5,6,7,8-Tetrafluoro-2-methyl-4H-chromen-4-one (8b) was synthesized
according to method A from 274 mg (1 mmol) of chromone 4b and 2 mmol of the corresponding
amino acid (β-alanine, GABA). White powder, mp 102–104°C (EtOH), (lit.[13a] 102–104°C). 1Н
NMR (500.13 MHz, (CD3)2SO): δ 2.41 (3Н, s, СН3), 6.30 (1Н, s, Н, С-3). 19F NMR (470.52 MHz,
(CD3)2SO): δ -172.90, -164.97, -154.99, -139.67 (4F, all m).

4.3.3. 6,7,8-Trifluoro-2-phenyl-4H-chromen-4-one (9a) was synthesized according
to method A from 380 mg (1 mmol) of flavone 5a and 2 mmol of the corresponding amino acid
(β-alanine, GABA). White powder, mp 203–206°C (EtOH). 1Н NMR (500.13 MHz, (CD3)2SO):
δ 7.18 (1Н, s, Н, С-3), 7.61–8.09 (5Н, m, Ph), 7.87 (1Н, d.d.d, JHF = 10.0, 8.0, 2.3 Hz, Н, С-5).
19F NMR (470.52 MHz, (CD3)2SO): δ -152.02, -151.31, -137.38 (3F, all m). Anal. calcd. for
С15Н7F3O2: C, 65.23; H, 2.55; found: C, 65.28; H, 2.57.
4.3.4. 5,6,7,8-Tetrafluoro-2-phenyl-4H-chromen-4-one (9b) was synthesized
according to method A from 398 mg (1 mmol) of flavone 5b and 2 mmol of the corresponding
1
amino acid (β-alanine, GABA). White powder, mp 224-226°C (EtOH). Н NMR (400.13 MHz,
(CD3)2SO): δ 7.13 (1Н, s, Н, С-3), 7.59–8.07 (5Н, m, Ph). 19F NMR (376.44 MHz, (CD3)2SO): δ
-162.64, -159.10, -149.72, -145.42 (4F, all m). Anal. calcd. for С15Н6F4O2: C, 61.24; H, 2.06;
found: C, 61.72; H, 2.43.
4.3.5. N-[1-Methyl-3-oxo-3-(3,4,5-trifluoro-2-hydroxyphenyl)prop-1-enyl]-3-
aminopropanoic acid, hydrate (10a) was synthesized from 256 mg (1 mmol) of chromone
4a and 179 mg (2 mmol) of β-alanine. Yield 45 mg (14% method A), 179 mg (55% method B),
yellow powder, mp 135–140˚С (CHCl3). IR (DRA): ν 3545, 3466 (N–H), 2970, 2924 (О–Н), 1713
(СО2H), 1596, 1566 (С=О), 1509, 1437, 1364, 1258 (С–N, C=C, С–Н), 1032, 1010 (C–F) cm–1.
1Н NMR (500.13 MHz, (CD3)2SO) spectrum of (E,Z)-isomer mixture, 10÷1, (Z)-isomer: δ 2.18
(3Н, s, СН3), 2.59 (2Н, t, 3JHH = 6.4 Hz, СН2, C-2), 3.58 (2Н, q, 3JHH = 6.4 Hz, СН2, C-3), 5.88
(1Н, s, H, С-6), 7.79 (1Н, d.d.d, JHF = 11.6, 9.0, 2.0 Hz, Н, С-9), 10.87 (1Н, t, 3JHH = 6.1 Hz, NH),
14.50 (1Н, br.s, ОН); (E)-isomer: δ 2.40 (3Н, s, СН3), 2.88 (2Н, t, 3JHH = 6.3 Hz, СН2, C-2), 3.49
(2Н, m, СН2, C-3), 5.74 (1Н, s, H, С-6), 7.98 (1Н, d.d.d, JHF = 11.5, 8.9, 2.1 Hz, Н, С-9), 8.34
(1Н, br.s, NH). 13C NMR (125.76 MHz, (CD3)2SO) spectrum of (Z)-isomer: δ 19.21 (s, С-4), 34.26
(s, С-2), 39.40 (m, С-3+(CD3)2SO), 90.80 (s, С-6); 109.33 (br.s, С-9), 115.97 (br.s, С-8), 139.84
(m, С-12), 141.52 (m, С-10), 141.96 (m, С-11), 148.30 (m, С-13), 168.40 (m, С-5), 172.64 (s, С-
1), 184.84 (br.s, С-7). 19F NMR (470.52 MHz, (CD3)2SO) spectrum of (E,Z)-isomer mixture, 10÷1,
(Z)-isomer: δ -159.33, -154.81, -149.45 (3F, all m); (E)-isomer: δ -160.01, -154.91, -150.22 (3F,
.
all m). Anal. calcd. for С13Н12F3NO4 H2O: C, 48.60; H, 4.39; N, 4.36; found: C, 48.60; H, 4.15;
N, 3.73.
4.3.6.
N-[1-Methyl-3-oxo-3-(2,3,4,5-tetrafluoro-6-hydroxyphenyl)prop-1-
enyl]-3-aminopropanoic acid, hemihydrate (10b) was synthesized from 274 mg (1
mmol) chromone 4b and 178 mg (2 mmol) β-alanine. Yield 66 mg (20% method A), 185 mg (54%
method B), yellow powder, mp 239–240°C (CHCl3). IR (DRA): ν 3117, 3007 (N–H), 2959 (О–
Н), 1719 (СО2H), 1595, 1578 (С=О), 1513, 1433, 1363, 1285 (С–N, C=C, С–Н), 1005, 981 (C–
F) cm–1. 1Н NMR (400.13 MHz, (CD3)2SO) spectrum of (E,Z)-isomer mixture, 12÷1, (Z)-isomer:
δ 2.12 (3Н, s, СН3), 2.46 (2Н, t, 3JHH = 6.4 Hz, СН2, C-2); 3.53 (2Н, q, 3JHH = 6.4 Hz, СН2, C-3),
5.49 (1Н, s, H, С-6), 11.06 (1Н, br.s, NH); (E)-isomer: δ 2.09 (3Н, s, СН3), 2.53 3.26 (4Н, both
m, 2 СН2, C-2,3), 5.55 (1Н, s, H, С-6), 8.52 (1Н, br.s, NH). 19F NMR (376.44 MHz, (CD3)2SO)
spectrum (E,Z)-isomer mixture, 12÷1, (Z)-isomer: δ -179.94, -166.62, -159.05, -143.09 (4F, all
m); (E)-isomer: δ -177.10, -166.12, -157.65, -141.55 (4F, all m). Anal. calcd. for
.
С13Н11F4NO4 ½H2O: C, 47.28; H, 3.66; N, 4.24; found: C, 47.35; H, 3.51; N, 4.12.
4.3.7. N-[1-Methyl-3-oxo-3-(3,4,5-trifluoro-2-hydroxyphenyl)prop-1-enyl]-4-
aminobutanoic acid (11a) was synthesized from 256 mg (1 mmol) of chromone 4a and 206

mg (2 mmol) of GABA. Yield 35 mg (11% method A), 171 mg (54% method B), yellow powder,
mp 160–161˚С (CHCl3, EtOHaq). IR (DRA): ν 3066, 3011 (N–H), 2945 (О–Н), 1704 (СО2Н),
1590, 1563 (С=О), 1506, 1445, 1349, 1247 (С–N, C=C, С–Н), 1003 (C–F) cm–1. 1Н NMR (400.13
MHz, (CD3)2SO) spectrum of (E,Z)-isomer mixture, 5÷1, (Z)-isomer: δ 1.81 (2Н, qnt, 3JHH = 7.2
Hz, СН2, C-3), 2.16 (3Н, s, СН3), 2.32 (2Н, m, СН2, C-2), 3.42 (2Н, m, СН2, C-4), 5.90 (1Н, s,
H, С-7), 7.79 (1Н, d.d.d, JHF = 11.6, 9.0, 2.0 Hz, Н, С-10), 10.83 (1Н, t, 3JHH = 6.1 Hz, NH), 12.24,
14.69 (2Н, both br.s, 2 ОН); (E)-isomer: δ 1.81 (2Н, m, СН2, C-3), 2.42 (3Н, s, СН3), 2.37, 3.29
(4Н, both m, СН2, C-2, C-4), 5.76 (1Н, s, H, С-7), 7.94 (1Н, m, Н, С-10), 8.32 (1Н, m, NH), 12.24
(1Н, br.s, ОН). 13C NMR (125.76 MHz, (CD3)2SO) spectrum of (Z)-isomer: δ 19.13 (s, С-5), 24.74
(s, С-3), 30.69 (s, С-2), 42.59 (s, С-4), 90.79 (s, С-7), 109.37 (m, С-10), 115.96 (m, С-9), 139.66
(m, С-13), 141.72 (m, С-11), 141.99 (m, С-12), 148.19 (m, С-14), 168.73 (s, С-6), 173.74 (s, С-
1), 184.85 (br.s, С-8). 19F NMR (376.44 MHz, (CD3)2SO) spectrum of (E,Z)-isomer mixture, 5÷1,
(Z)-isomer: δ -159.30, -154.80, -149.38 (3F, all m); (E)-isomer: δ -159.97, -154.93, -150.10 (3F,
all m). Anal. calcd. for С14Н14F3NO4: C, 53.00; H, 4.45; N, 4.41; found: C, 53.05; H, 4.38; N, 4.58.
4.3.8.
N-[1-Methyl-3-oxo-3-(2,3,4,5-tetrafluoro-6-hydroxyphenyl)prop-1-
enyl]-4-aminobutanoic acid (11b) was synthesized from 274 mg (1 mmol) chromone 4b
and 206 mg (2 mmol) of GABA. Yield 60 mg (18% method A), 157 mg (47% method B), yellow
powder, mp 161–163˚С (CHCl3). IR (DRA): ν 3012 (N–H), 2944 (О–Н), 1712 (СО2Н), 1602,
1567 (С=О), 1509, 1450, 1340, 1245 (С–N, C=C, С–Н), 998, 969 (C–F) cm–1. 1Н NMR (400.13
MHz, (CD3)2SO) spectrum of (E,Z)-isomer mixture, 5÷1, (Z)-isomer: δ 1.82 (2Н, qnt, 3JHH = 7.3
Hz, СН2, C-3), 2.16 (3Н, s, СН3), 2.32 (2Н, t, 3JHH = 7.3 Hz, СН2, C-2), 3.45 (2Н, m, СН2, C-4),
5.59 (1Н, s, H, С-7), 11.05 (1Н, br.s, NH), 12.44, 14.07 (2Н, both br.s, 2 ОН); (E)-isomer: δ 1.83,
2.33 (4Н, both m, СН2, C-3, C-2), 2.43 (3Н, s, СН3), 3.18 (2Н, m, СН2, C-4), 5.61 (1Н, s, H, С-
7), 8.48 (1Н, m, NH). 19F NMR (376.44 MHz, (CD3)2SO) spectrum of (E,Z)-isomer mixture, 5÷1,
(Z)-isomer: δ -172.96, -165.00, -154.91, -139.61 (4F, all m); (E)-isomer: δ -173.53, -165.46, -
155.20, -139.06 (4F, all m). Anal. calcd. for С14Н13F4NO4: C, 50.16; H, 3.91; N, 4.18; found: C,
50.18; H, 4.09; N, 4.03.
4.3.9. N-[3-Oxo-1-phenyl-3-(3,4,5-trifluoro-2-hydroxyphenyl)prop-1-enyl]-3-
aminopropanoic acid, hydrochloride hydrate (12a) was synthesized from 380 mg (1
mmol) flavone 5a and 178 mg (2 mmol) β-alanine. Yield 59 mg (14% method A), yellow powder,
mp 198–200˚С (CHCl3). IR (DRA): ν 3002, 2928 (О–Н), 1698 (СО2H), 1565 (С=О), 1512, 1447,
1360, 1263 (С–N, C=C, С–Н), 1005, 998 (C–F) cm–1. 1Н NMR (500.13 MHz, (CD3)2SO): δ 2.57
(2Н, t, 3JHH = 6.2 Hz, СН2, C-2), 3.42 (2Н, m, СН2, C-3), 5.86 (1Н, s, H, C-5), 7.54 (5Н, m, Ph),
7.92 (1Н, m, Н С-8), 11.09 (1Н, t, 3JHH = 5.2, NH), 14.18 (1Н, br.s, ОН). 13C NMR (125.76 MHz,
(CD3)2SO): δ 34.34 (s, С-2), 40.91 (s, С-3), 91.97 (s, С-5), 110.15 (m, С-7), 116.25 (m, С-8),
127.73 (s, С-14), 128.65 (s, С-15), 130.08 (s, С-16), 134.23 (s, С-13), 139.72 (m, С-11), 141.83
(m, С-9), 142.35 (m, С-10), 148.03 (m, С-12), 168.59 (s, С-4), 172.59 (s, С-1), 186.30 (m, С-6).
19F NMR (470.52 MHz, (CD3)2SO): δ -159.06, -154.09, -149.07 (3F, all m). Anal. calcd. for
.
С18Н14F3NO4 HCl.H2O: C, 51.50; H, 4.08; N, 3.34; found: C, 51.27; H, 3.59; N, 3.61.

4.3.10.
N-[3-Oxo-1-phenyl-3-(2,3,4,5-tetrafluoro-6-hydroxyphenyl)prop-1-
enyl]-3-aminopropanoic acid (12b) was synthesized from 398 mg (1 mmol) flavone 5b and
178 mg (2 mmol) β-alanine. Yield 45 mg (11% method A), yellow powder, mp 210–211˚С
(CHCl3). IR (DRA): ν 3964 (N–H), 2927 (О–Н), 1699 (СО2H), 1603, 1582 (С=О), 1516, 1451,
1355 (С–N, C=C, С–Н), 996 (C–F) cm–1. 1Н NMR (400.13 MHz, (CDCl3): δ 2.59 (2Н, t, 3JHH
=
6.2 Hz, СН2, C-2), 3.45 (2Н, m, СН2, C-3), 5.53 (1Н, s, Н С-5), 7.51–7.55 (5Н, m, Ph), 11.17 (1Н,
br.s, NH), 12.51, 13.73 (2Н, both br.s, 2 ОН). 19F NMR (376.44 MHz, (CDCl3): δ -172.35, -164.31,
-154.42, -140.09 (4F, all m). Anal. calcd. for С18Н13F4NO4: C, 56.40; H, 3.42; N, 3.65; found: C,
56.35; H, 3.61; N, 3.36.
4.3.11. N-[3-Oxo-1-phenyl-3-(3,4,5-trifluoro-2-hydroxyphenyl)prop-1-enyl]-4-
aminobutanoic acid (13a) was synthesized from 380 mg (1 mmol) flavone 5a and 206 mg (2
mmol) of GABA. Yield 76 mg (20% method A), yellow powder, mp 175–178˚С (CHCl3, EtOHaq).
IR (DRA): ν 2952 (О–Н), 1704 (СО2Н), 1586, 1564 (С=О), 1511, 1448, 1368 (С–N, C=C, С–Н),
1025, 1008 (C–F) cm–1. 1Н NMR (400.13 MHz, (CD3)2SO): δ 1.75 (2Н, qnt, 3JHH = 7.1 Hz, СН2,
C-3), 2.21 (2Н, t, 3JHH = 7.1 Hz, СН2, C-2), 3.30 (2Н, m, СН2, C-4), 5.88 (1Н, s, H, C-6), 7.51–
7.55 (5Н, m, Ph), 7.92 (1Н, m, Н, С-9), 11.00 (1Н, t, 3JHH = 6.1 Hz, NH), 12.13, 14.27 (2Н, both
19
br.s, 2 ОН). F NMR (376.44 MHz, (CD3)2SO): δ -159.04, -154.13, -149.04 (3F, all m). Anal.
calcd. for С19Н16F3NO4: C, 60.16; H, 4.25; N, 3.69; found: C, 60.32; H, 4.57; N, 3.45.
4.3.12.
N-[3-Oxo-1-phenyl-3-(2,3,4,5-tetrafluoro-6-hydroxyphenyl)prop-1-
enyl]-4-aminobutanoic acid, hydrate (13b) was synthesized from 398 mg (1 mmol) of
flavone 5b and 206 mg (2 mmol) of GABA. Yield 67 mg (17% method A), yellow powder, mp
159–161˚С (CHCl3). IR (DRA): ν 3172 (N–H), 2955 (О–Н), 1737, 1715 (СО2Н), 1652, 1583
1
(С=О), 1515, 1452, 1349, 1288 (С–N, C=C, С–Н), 997 (C–F) cm–1. Н NMR (500.13 MHz,
(CD3)2SO): δ 1.76 (2Н, qnt, 3JHH = 7.2 Hz, СН2, C-3), 2.22 (2Н, t, 3JHH = 7.2 Hz, СН2, C-2), 3.32
(2Н, m, СН2, C-4), 5.54 (1Н, s, H, C-6), 7.48–7.55 (5Н, m, Ph), 11.08 (1Н, t, 3JHH = 5.4 Hz, NH),
12.14, 13.65 (2Н, both br.s, 2 ОН). 19F NMR (470.52 MHz, (CD3)2SO): δ -172.36, -164.30, -
.
154.54, -140.16 (4F, all m). Anal. calcd. for С19Н15F4NO4 H2O: C, 54.94; H, 4.13; N, 3.37; found:
C, 55.59; H, 3.95; N, 3.56.
4.3.13. N-(6,8-Difluoro-4-oxo-2-phenyl-4H-chromen-7-yl)-3-aminopropanoic
acid (14a) was synthesized according to method B from 380 mg (1 mmol) flavone 5a and 178
mg (2 mmol) β-alanine. Yield 197 mg (57%), yellow powder, mp 235–238˚С (CHCl3, EtOHaq).
IR (DRA): ν 3292 (N–H), 2965, 2921 (О–Н), 1712 (СО2Н), 1641, 1632 (С=О), 1547, 1471, 1409,
1370 (С–N, C=C, С–Н), 1017 (C–F) cm–1. 1Н NMR (500.13 MHz, (CD3)2SO): δ 2.59 (2Н, t, 3JHH
= 7.1 Hz, СН2, C-10), 3.67 (2Н, q, 3JHH = 7.1 Hz, СН2, C-11), 6.43 (1Н, br.s, NH), 6.95 (1Н, s, Н,
С-3), 7.44 (1Н, d.d, JHF = 12.0, 1.5 Hz, Н, С-5), 7.58–8.04 (5Н, m, Ph), 12.31 (1Н, br.s, ОН). 19F
NMR (470.52 MHz, (CD3)2SO): δ -154.65, -130.48 (2F, both m). Anal. calcd. for С18Н13F2NO4:
C, 62.61; H, 3.79; N, 4.06; found: C, 62.83; H, 3.59; N, 4.00.

4.3.14.
N-(5,6,8-Trifluoro-4-oxo-2-phenyl-4H-chromen-7-yl)-3-
aminopropanoic acid (14b) in a mixture with 14c was synthesized according to method B
1
from 398 mg (1 mmol) of flavone 5b and 356 mg (4 mmol) β-alanine. Н NMR (400.13 MHz,
(CD3)2SO): δ 2.58, 3.67 (4Н, both m, 2 СН2, C-10, C-11), 6.77 (1Н, br.s, NH), 6.86 (1Н, s, Н, С-
3), 7.56–8.03 (5Н, m, Ph), 12.32 (1Н, br.s, ОН). 19F NMR (376.44 MHz, (CD3)2SO): δ -160.00, -
159.68, -148.52 (3F, all m). HRMS (ESI), m/z: calcd. for [C18H11F3NO4]- 362.0646; found
362.0639.
4.3.15.
N-(6,8-Difluoro-5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)-3-
aminopropanoic acid (14c) in a mixture with 14b was synthesized according to method B
1
from 398 mg (1 mmol) of flavone 5b and 356 mg (4 mmol) β-alanine. Н NMR (400.13 MHz,
(CD3)2SO): δ 2.66, 3.68 (4Н, both m, 2 СН2, C-10, C-11), 6.62 (1Н, br.s, NH), 6.99 (1Н, s, Н, С-
3), 7.56–8.03 (5Н, m, Ph), 12.41 (1Н, br.s, ОН). 19F NMR (376.44 MHz, (CD3)2SO): δ -167.35, -
161.84 (2F, both m). HRMS (ESI), m/z: calcd. for [C18H12F2NO5]-: 360.0689; found 360.0684.
4.3.16.
N-(6,8-Difluoro-4-oxo-2-phenyl-4H-chromen-7-yl)-4-aminobutanoic
acid, hemihydrate (15a) was synthesized according to method B from 380 mg (1 mmol)
flavone 5a and 206 mg (2 mmol) GABA. Yield 182 mg (50%), yellow powder, mp 204–207˚С
(CHCl3, EtOHaq). IR (DRA): ν 3296 (N–H), 2977, 2941 (О–Н), 1721 (СО2Н), 1641, 1622 (С=О),
1545, 1480, 1370 (С–N, C=C, С–Н), 1022 (C–F) cm–1. 1Н NMR (500.13 MHz, (CD3)2SO): δ 1.83
(2Н, qnt, 3JHH = 7.1 Hz, СН2, C-11), 2.32 (2Н, t, 3JHH = 7.1 Hz, СН2, C-10), 3.45 (2Н, q, 3JHH
=
6.1 Hz, СН2, C-12), 6.54 (1Н, br.s, NH), 6.93 (1Н, s, Н, С-3), 7.40 (1Н, d.d, JHF = 11.9, 1.6 Hz,
Н, С-5), 7.58–8.02 (5Н, m, Ph), 12.11 (1Н, s, ОН). 13C NMR (125.76 MHz, (CD3)2SO): δ 25.65
(s, С-11), 30.87 (s, С-10), 43.60 (m, С-12), 104.18 (m, С-5), 106.33 (s, С-3), 111.34 (m, С-4a),
125.99 (s, С-14), 129.12 (s, С-15), 131.00 (s, С-13), 131.41 (m, С-7), 131.63 (s, С-16), 137.86 (m,
19
С-8a), 143.06 (m, С-8), 149.02 (m, С-6), 161.31 (s, С-2), 174.22 (s, С-9), 174.93 (m, С-4). F
NMR (470.52 MHz, (CD3)2SO): δ -154.96, -130.44 (2F, both m). Anal. calcd. for
.
С19Н15F2NO4 ½H2O: C, 61.96; H, 4.38; N, 3.80; found: C, 62.41; H, 4.27; N, 3.95.
4.3.17. N-(5,6,8-Trifluoro-4-oxo-2-phenyl-4H-chromen-7-yl)-4-aminobutanoic
acid (15b) in a mixture with 15c was synthesized according to method B from 398 mg (1 mmol)
of flavone 5b and 412 mg (4 mmol) of GABA. 1Н NMR (400.13 MHz, (CD3)2SO): δ 1.83, 2.31,
3.45 (6Н, all m, 3 СН2, C-10, C-11, C-12), 6.85 (1Н, s, Н, С-3), 6.92 (1Н, br.s, NH), 7.55–8.04
(5Н, m, Ph), 12.32 (1Н, br.s, ОН). 19F NMR (376.44 MHz, (CD3)2SO): δ -160.25, -159.81, -148.58
(3F, all m). HRMS (ESI), m/z: calcd. for [C19H13F3NO4]-: 376.0802; found 376.0798.
4.3.18.
N-(6,8-Difluoro-5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)-4-
aminobutanoic acid (15c) in a mixture with 15b was synthesized according to method B from
1
398 mg (1 mmol) of flavone 5b and 412 mg (4 mmol) of GABA. Н NMR (400.13 MHz,
(CD3)2SO): δ 1.83, 2.28, 3.42 (2Н, m, СН2, C-10, C-11, C-12), 6.78 (1Н, br.s, NH), 6.98 (1Н, s,
Н, С-3), 7.55–8.04 (5Н, m, Ph). 19F NMR (376.44 MHz, (CD3)2SO): δ -167.46, -161.85 (2F, both
m). HRMS (ESI), m/z: calcd. for [C19H14F2NO5]-: 374.0846; found 374.0840.
4.3.19.
3-{[2-(3,4-Dihydroxyphenyl)ethyl]amino}-1-(3,4,5-trifluoro-2-
hydroxyphenyl)but-2-en-1-one (16а) was synthesized according to method A from 256 mg

(1 mmol) of chromone 4а, 379 mg (2 mmol) of dopamine hydrochloride and 168 mg (2 mmol)
NaHCO3. Yield 180 mg (49%), yellow powder, mp 154–156˚С (CHCl3/C6H14). IR (DRA): ν 3458
(N–H), 2930, 2870 (О–Н), 1595 (С=О), 1509, 1437, 1370 (С–N, C=C, С–Н), 1001 (C–F) cm–1.
1Н NMR (400.13 MHz, (CD3)2SO+CCl4) spectrum of (E,Z)-isomer mixture, 17÷1, (Z)-isomer: δ
2.04 (3Н, s, СН3), 2.74 (2Н, t, 3JHH = 7.0 Hz, СН2, C-12), 3.56 (2Н, q, 3JHH = 6.9 Hz, СН2, C-11),
5.72 (1Н, s, H, C-2), 6.47–6.64 (3Н, m, С6Н3), 7.59 (1Н, m, Н, С-6), 8.51, 8.55 (2Н, both s, 2
ОН), 10.85 (1Н, t, 3JHH = 5.1 Hz, NH), 14.45 (1Н, s, ОН); (E)-isomer: δ 2.66, 3.42 (4Н, m, 2 СН2,
C-11, C-12), 5.60 (1Н, s, H, C-2), 6.47–6.64 (3Н, m, С6Н3), 7.73 (1Н, m, Н, С-6), 8.07 (1Н, m,
NH), 8.46, 8.52 (2Н, both s, 2 ОН), 15.49 (1Н, s, ОН). 13C NMR (125.76 MHz, (CD3)2SO+CCl4)
spectrum of (Z)-isomer: δ 19.16 (s, С-4), 34.65 (s, С-12), 45.11 (s, С-11), 90.61 (s, С-2), 109.32
(m, С-6), 115.51 (s, С-14), 115.93 (m, С-5), 116.18 (s, С-17), 119.44 (s, С-18), 128.98 (s, С-13),
139.70 (m, С-9), 141.63 (m, С-7), 141.95 (m, С-8), 143.79 (s, С-16), 145.16 (s, С-15), 148.27 (m,
19
С-10), 168.55 (s, С-3), 184.71 (s, С-1). F NMR (376.44 MHz, (CD3)2SO+CCl4) spectrum of
(E,Z)-isomer mixture, 17÷1, (Z)-isomer: δ -159.54 (1F, d, J = 19.5 Hz), -155.34, -149.96 (2F, both
m); (E)-isomer: δ -160.19, -155.52, -150.75 (3F, all m). Anal. calcd. for С18Н16F3NO4: C, 58.86;
H, 4.39; N, 3.81; found: C, 58.24; H, 4.59; N, 3.91.
4.3.20.
3-{[2-(3,4-Dihydroxyphenyl)ethyl]amino}-1-(2,3,4,5-tetrafluoro-6-
hydroxyphenyl)but-2-en-1-one (16b) was synthesized according to method A from 274 mg
(1 mmol) of chromone 4b, 379 mg (2 mmol) of dopamine hydrochloride and 168 mg (2 mmol)
NaHCO3. Yield 193 mg (50%), yellow powder, mp 177–179˚С (CHCl3/C6H14). IR (DRA): ν 3405
(N–H), 2954, 2925 (О–Н), 1656, 1595 (С=О), 1511, 1446, 1340 (С–N, C=C, С–Н), 1004 (C–F)
1
cm–1. Н NMR (500.13 MHz, (CD3)2SO+CCl4) spectrum of (E,Z)-isomer mixture, 14÷1, (Z)-
isomer: δ 2.07 (3Н, s, СН3), 2.75 (2Н, t, 3JHH = 7.2 Hz, СН2, C-12), 3.59 (2Н, q, 3JHH = 7.0 Hz,
СН2, C-11), 5.58 (1Н, s, H, C-2), 6.47–6.64 (3Н, m, С6Н3), 8.54, 8.57 (2Н, both s, 2 ОН), 11.08
(1Н, t, 3JHH = 5.5 Hz, NH), 14.60 (1Н, s, ОН); (E)-isomer: δ 2.44 (3Н, s, СН3), 2.72, 3.30 (4Н, m,
2 СН2, C-11, C-12), 5.69 (1Н, s, H, C-2), 6.45–6.59 (3Н, m, С6Н3), 7.68 (1Н, m, NH), 8.47 (2Н,
br.s, 2 ОН), 15.50 (1Н, s, ОН). 19F NMR (470.52 MHz, (CD3)2SO+CCl4) spectrum of (E,Z)-isomer
mixture, 14÷1, (Z)-isomer: δ -173.91, -165.71, -155.01, -139.27 (4F, all m); (E)-isomer: δ -174.50,
-166.12, -155.41, -138.94 (4F, all m). Anal. calcd. for С18Н15F4NO4: C, 56.11; H, 3.92; N, 3.64;
found: C, 56.04; H, 4.05; N, 3.80.
4.3.21. 3-{[2-(3,4-Dihydroxyphenyl)ethyl]amino}-3-phenyl-1-(3,4,5-trifluoro-
2-hydroxyphenyl)prop-2-en-1-one (17а) was synthesized according to method B in inert
atmosphere of argon, using EtOH as solvent from 380 mg (1 mmol) of flavone 5а 379 mg (2
mmol) of dopamine hydrochloride and 202 mg (2 mmol) of Et3N. The reaction vessel was filled
with argon, dopamine hydrochloride 379 mg (2 mmol) was added to a mixture. Yield 159 mg
(37%), yellow powder, mp 159–161˚С (column chromatography on silica gel, using CHCl3). IR
(DRA): ν 3535, 3223 (N–H), 2949, 2935 (О–Н), 1590 (С=О), 1511, 1441, 1269 (С–N, C=C, С–
Н), 1021, 1003 (C–F) cm–1. 1Н NMR (400.13 MHz, (CD3)2SO): δ 2.64 (2Н, t, 3JHH = 7.0 Hz, СН2,
3
C-15), 3.39 (2Н, q, JHH = 6.7 Hz, СН2, C-14), 5.83 (1Н, s, H, C-2), 6.35–6.62 (3Н, m, С6Н3),
7.40–7.54 (5Н, m, Ph), 7.89 (1Н, m, H, C-9), 8.72, 8.75 (2Н, both s, 2 ОН), 10.99 (1Н, t, 3JHH
=
6.0 Hz, NH), 14.35 (1Н, s, ОН). 13C NMR (125.76 MHz, (CD3)2SO): δ 35.31 (s, С-15), 46.75 (s,
С-14), 91.68 (s, С-2), 110.02 (m, С-8), 115.47 (s, С-17), 116.05 (s, С-21), 116.21 (m, С-9), 119.32
(s, С-22), 127.53 (s, С-5), 128.49 (s, С-6), 128.71 (s, С-7), 129.94 (s, С-16), 134.25 (s, С-4),

139.37 (m, С-12), 141.74 (m, С-10), 142.42 (m, С-11), 143.80 (s, С-20), 145.13 (s, С-19), 148.02
19
(m, С-13), 168.56 (s, С-3), 186.09 (m, С-1). F NMR (376.44 MHz, (CD3)2SO): δ -159.17, -
154.22, -149.12 (3F, all m). Anal. calcd. for С23Н18F3NO4: C, 64.34; H, 4.23; N, 3.26; found: C,
64.52; H, 4.57; N, 3.44.
4.3.22.
3-{[2-(3,4-Dihydroxyphenyl)ethyl]amino}-3-phenyl-1-(2,3,4,5-
tetrafluoro-6-hydroxyphenyl)prop-2-en-1-one (17b) was synthesized according to
method B in inert atmosphere of argon, using EtOH as solvent from 398 mg (1 mmol) of flavone
5b 379 mg (2 mmol) of dopamine hydrochloride and 202 mg (2 mmol) of Et3N. The reaction
vessel was filled with argon, dopamine hydrochloride 379 mg (2 mmol) was added to a mixture.
Yield 170 mg (38%), yellow powder, mp 163–166˚С (column chromatography on silica gel, using
CHCl3). IR (DRA): ν 3443, 3378 (N–H), 2966, 2922 (О–Н), 1653 (С=О), 1515, 1463, 1347 (С-
N, C=C, С–Н), 1002 (C–F) cm–1. 1Н NMR (400.13 MHz, (CD3)2SO): δ 2.66 (2Н, t, 3JHH = 7.0 Hz,
СН2, C-15), 3.41 (2Н, q, 3JHH = 6.8 Hz, СН2, C-14), 5.51 (1Н, s, H, C-2), 6.35–6.63 (3Н, m, С6Н3),
7.40–7.55 (5Н, m, Ph), 8.73, 8.76 (2Н, both s, 2 ОН), 11.07 (1Н, t, 3JHH = 5.8 Hz, NH), 13.88 (1Н,
br.s, ОН). 19F NMR (376.44 MHz, (CD3)2SO): δ -172.46, -164.49, -154.45, -139.97 (4F, all m).
Anal. calcd. for С23Н17F4NO4: C, 61.75; H, 3.83; N, 3.13; found: C, 61.75; H, 3.75; N, 3.03.
4.3.23. 3-(Pyrrolidin-1-yl)-1-(3,4,5-trifluoro-2-hydroxyphenyl)but-2-en-1-one
(18а) was synthesized according to method C from 256 mg (1 mmol) of chromone 4а and 142
mg (2 mmol) of pyrrolidine, using EtOH as solvent. Yield 165 mg (58%), yellow powder, mp
174–177˚С (EtOH). IR (DRA): ν 2984, 2878 (О–Н), 1641, 1539 (С=О), 1445, 1341, 1227 (С–N,
1
C=C, С–Н), 1022, 983 (C–F) cm–1. Н NMR (500.13 MHz, (CD3)2SO+CCl4): δ 2.00 (4Н, m,
(СН2)2, C-6), 2.59 (3Н, s, СН3), 3.56 (4Н, m, (СН2)2, C-5), 5.51 (1Н, s, H, C-2), 7.67 (1Н, d.d.d,
JHF = 11.6, 9.0, 2.2 Hz, H, C-8), 15.47 (1Н, s, ОН). 13C NMR (125.76 MHz, (CD3)2SO): δ 18.54
(s, С-4), 24.25, 24.49 (both s, С-6), 48.90, 49.45 (both s, С-5), 89.66 (s, С-2), 109.69 (m, С-8),
117.08 (m, С-7), 139.90 (m, С-11), 141.44 (m, С-9), 142.40 (m, С-10), 149.42 (m, С-12), 165.21
19
(s, С-3), 185.30 (s, С-1). F NMR (470.52 MHz, (CD3)2SO+CCl4): δ -160.10, -155.65, -150.81
(3F, all m). Anal. calcd. for С14Н14F3NO2: C, 58.95; H, 4.95; N, 4.91; found: C, 58.83; H, 5.12; N,
4.90.
4.3.24. 3-(Pyrrolidin-1-yl)-1-(2,3,4,5-tetrafluoro-6-hydroxyphenyl)but-2-en-1-
one (18b) was synthesized according to method C from 274 mg (1 mmol) chromone 4b and 142
mg (2 mmol) of pyrrolidine, using EtOH as solvent. Yield 200 mg (66%), yellow powder, mp
144–145˚С (EtOH). IR (DRA): ν 2984, 2881 (О–Н), 1650 (С=О), 1449, 1342, 1267 (С–N, C=C,
1
С–Н), 1000, 981 (C–F) cm–1. Н NMR (400.13 MHz, (CD3)2SO): δ 1.94 (4Н, m, (СН2)2, C-6),
2.61 (3Н, s, СН3), 3.50 (4Н, m, (СН2)2, C-5), 5.52 (1Н, s H, C-2), 15.31 (1Н, br.s, ОН). 19F NMR
(376.44 MHz, (CD3)2SO): δ -173.84, -165.61, -155.58, -139.22 (4F, all m). Anal. calcd. for
С14Н13F4NO2: C, 55.45; H, 4.32; N, 4.62; found: C, 55.67; H, 4.56; N, 4.52.

4.3.25. 1-[3,5-Difluoro-2-hydroxy-4-(pyrrolidin-1-yl)phenyl]-3-(pyrrolidin-1-
yl)but-2-en-1-one (19а) was synthesized according to method C from 256 mg (1 mmol) of
chromone 4а and 284 mg (4 mmol) of pyrrolidine, using Me2SO as solvent. Yield 296 mg (88%),
yellow powder, mp 196–198˚С (EtOH). IR (DRA): ν 2972, 2890 (О–Н), 1628 (С=О), 1442, 1355,
1216 (С–N, C=C, С–Н), 1030, 1010 (C–F) cm–1. 1Н NMR (500.13 MHz, (CD3)2SO+CCl4): δ 1.94
(8Н, m, (СН2)4, C-6), 2.56 (3Н, s, СН3), 3.53 (8Н, m, (СН2)4, C-5), 5.40 (1Н, s, H, C-2), 7.17 (1Н,
d.d, JHF = 15.5, 1.5 Hz, H, C-8), 14.86 (1Н, br.s, ОН). 19F NMR (470.52 MHz, (CD3)2SO+CCl4):
δ -152.61, -136.65 (2F, both m). Anal. calcd. for С18Н22F2N2O2: C, 64.27; H, 6.59; N, 8.33; found:
C, 64.53; H, 6.60; N, 8.22.
4.3.26.
3-(Pyrrolidin-1-yl)-1-[2,3,5-trifluoro-6-hydroxy-4-(pyrrolidin-1-
yl)phenyl]but-2-en-1-one (19b) was synthesized according to method C from 274 mg (1
mmol) of chromone 4b and 284 mg (4 mmol) of pyrrolidine, using Me2SO as solvent. Yield 209
mg (59%), yellow powder, mp 178–180˚С (EtOH). IR (DRA): ν 2979, 2885 (О–Н), 1641, 1618
1
(С=О), 1441, 1334, 1248 (С–N, C=C, С–Н), 1027, 990 (C–F) cm–1. Н NMR (500.13 MHz,
(CD3)2SO+CCl4): δ 1.95 (8Н, m, (СН2)4, C-6), 2.59 (3Н, s, СН3), 3.52 (8Н, m, (СН2)4, C-5), 5.57
(1Н, s H, C-2), 15.25 (1Н, s, ОН). 13C NMR (125.76 MHz, (CD3)2SO): δ 18.87 (s, С-4), 24.32,
24.52 (both s, С-6), 25.14 (s, С-6’), 48.62, 48.97 (both s, С-5), 50.99 (t, J = 6.3 Hz, С-5’), 94.62
(d, J = 18.5 Hz, С-2), 100.76 (d, J = 11.8 Hz, С-7), 130.13 (m, С-11), 133.73 (m, С-9), 136.64 (m,
С-8), 146.51 (m, С-10), 148.61 (d.d, J = 12.6, 7.6 Hz, С-12), 164.25 (s, С-3), 183.22 (m, С-1). 19F
NMR (470.52 MHz, (CD3)2SO+CCl4): δ -165.80, -159.33, -140.89 (3F, all m). Anal. calcd. for
С18Н21F3N2O2: C, 61.01; H, 5.97; N, 7.91; found: C, 61.11; H, 6.04; N, 7.87.
4.3.27. 1-(6,8-Difluoro-2-methyl-4-oxo-4H-chromen-7-yl)proline (20а) was
synthesized according to method B from 256 mg (1 mmol) of chromone 4а and 230 mg (2 mmol)
of proline. Yield 105 mg (34%), white powder, mp 221–223˚С (CHCl3, EtOHaq). IR (DRA): ν
2964, 2892 (О–Н), 1742 (СО2Н), 1639, 1616 (С=О), 1524, 1471, 1354, 1314 (С–N, C=C, С–Н),
1035 (C–F) cm–1. 1Н NMR (400.13 MHz, (CD3)2SO): δ 1.92 (4Н, m, (СН2)2, С-10, С-11), 2.37
(3Н, s, СН3), 3.75 (2Н, m, СН2, С-12), 4.70 (1Н, m, Н, С-9), 6.16 (1Н, s, Н, С-3); 7.36 (1Н, d.d,
JHF = 13.9, 2.0 Hz, Н, С-5), 12.70 (1Н, br.s, ОН). 13C NMR (125.76 MHz, (CD3)2SO): δ 19.80 (s,
С-14), 24.10 (s, С-11), 30.41(s, С-10), 52.20 (t, J = 6.4 Hz, C-12), 62.45 (t, J = 5.6 Hz, C-9),
104.94 (m, C-5), 109.30 (s, C-3), 112.93 (d, J = 8.1 Hz, C-4a), 130.31 (d.d, J = 14.6, 8.1 Hz, C-
7), 139.92 (m, C-8), 112.93 (d, J = 11.2 Hz, C-8a), 150.13 (m, C-6), 165.87 (s, C-2), 173.61 (s, C-
4), 174.55 (br.s, C-13). 19F NMR (376.44 MHz, (CD3)2SO): δ -147.05, -124.19 (2F, both m). Anal.
calcd. for С15Н13F2NO4: C, 58.26; H, 4.24; N, 4.53; found: C, 58.10; H, 4.25; N, 4.50.
4.3.28. 1-(5,6,8-Trifluoro-2-methyl-4-oxo-4H-chromen-7-yl)proline (20b) was
synthesized according to method C from 274 mg (1 mmol) of chromone 4b and 230 mg (2 mmol)
of proline. Yield 128 mg (39%), yellow powder, mp 230–232˚С (CHCl3, EtOHaq). IR (DRA): ν
3061 (О–Н), 1693 (СО2Н), 1625 (С=О), 1521, 1480, 1353 (С-N, C=C, С–Н), 1036, 1024 (C–F)
cm–1. 1Н NMR (400.13 MHz, (CD3)2SO): δ 1.93 (4Н, m, (СН2)2, С-10, С-11), 2.33 (3Н, s, СН3),
19
3.78 (2Н, m, СН2, С-12), 4.71 (1Н, m, Н, С-9), 6.07 (1Н, s, Н, С-3), 12.80 (1Н, br.s, ОН). F
NMR (376.44 MHz, (CD3)2SO): δ -154.91, -153.41, -148.08 (3F, all m). Anal. calcd. for
С15Н12F3NO4: C, 55.05; H, 3.70; N, 4.28; found: C, 55.54; H, 4.05; N, 4.01.
4.3.29. 3-Benzoyl-6,8-difluoro-2-phenyl-7-(pyrrolidin-1-yl)-4H-chromen-4-one
(21а) was synthesized according to method C from 380 mg (1 mmol) of flavone 5а and 142 mg
(2 mmol) of pyrrolidine, using EtOH as solvent. Yield 169 mg (39%), yellow powder, mp 210–

214˚С (EtOH). IR (DRA): ν 2978, 2883 (О–Н), 1668, 1615 (С=О), 1479, 1447, 1349 (С–N, C=C,
С–Н), 1036, 1025 (C–F) cm–1. 1Н NMR (500.13 MHz, (CD3)2SO): δ 1.92 (4Н, m, (СН2)2, C-10),
13
3.72 (4Н, m, (СН2)2, C-9), 7.62 (1Н, m, Н, С-5), 7.42–7.92 (10Н, m, 2 Ph). C NMR (125.76
MHz, (CD3)2SO): δ 25.32 (s, С-10), 51.34 (s, С-9), 105.35 (m, С-5), 111.39 (m, С-4a), 121.35 (s,
С-3), 128.17 (s, С-12), 128.85 (s, С-17), 128.94 (s, С-13), 129.13 (s, С-14), 131.30 (s, С-11),
131.48 (s, С-14), 134.08 (s, С-19), 136.46 (s, С-16), 138.34–154.40 (all m, С-6, С-7, С-8, С-8a),
19
160.56 (br.s, С-2), 173.39 (br.s, С-4), 192.97 (s, С-15). F NMR (470.52 MHz, (CD3)2SO): δ -
149.19, -123.75 (2F, both m). Anal. calcd. for С26Н19F2NO3: C, 72.38; H, 4.44; N, 3.25; found: C,
72.96; H, 4.45; N, 3.35.
4.3.30.
3-Benzoyl-5,6,8-trifluoro-2-phenyl-7-pyrrolidin-1-yl-4H-chromen-4-
one (21b) was synthesized according to method C from 398 mg (1 mmol) of flavone 5b and 142
mg (2 mmol) of pyrrolidine, using EtOH as solvent. Yield 153 mg (34%), yellow powder, mp
224–227˚С (EtOH). IR (DRA): ν 2980, 2886 (О–Н), 1669, 1648 (С=О), 1494, 1448, 1352 (С–N,
C=C, С–Н), 1003 (C–F) cm–1. 1Н NMR (400.13 MHz, (CD3)2SO+CCl4): δ 1.98 (4Н, m, (СН2)2,
C-10), 3.77 (4Н, m, (СН2)2, C-9), 7.37–7.89 (10Н, m, 2 Ph). 19F NMR (376.44 MHz,
(CD3)2SO+CCl4): δ -155.68, -155.06 (2F, all m), -146.99 (1F, d.d, J = 17.7, 9.2 Hz). Anal. calcd.
for С26Н18F3NO3: C, 69.49; H, 4.04; N, 3.12; found: C, 69.71; H, 4.25; N, 3.02.
4.3.31.
1-(3-Benzoyl-6,8-difluoro-4-oxo-2-phenyl-4H-chromen-7-yl)proline
(22а) was synthesized according to method B from 380 mg (1 mmol) of flavone 5а and 230 mg
(2 mmol) of proline. Yield 171 mg (35%), yellow powder, mp 230–232˚С (CHCl3). IR (DRA): ν
2979 (О–Н), 1736 (СО2Н), 1674 (С=О), 1522, 1471, 1394 (С–N, C=C, С–Н), 1038, 1019 (C–F)
cm–1. 1Н NMR (500.13 MHz, (CD3)2SO): δ 2.08 (4Н, m, (СН2)2, С-10, С-11), 3.82 (2Н, m, СН2,
С-12), 4.78 (1Н, m, Н, С-9), 7.42–7.94 (10Н, m, 2 Ph), 7.62 (1Н, m, Н, С-5), 12.79 (1Н, br.s,
ОН). 19F NMR (470.52 MHz, (CD3)2SO): δ -147.65 (1F, d, J = 11.9 Hz), -123.14 (1F, m). Anal.
calcd. for С27Н19F2NO5: C, 68.21; H, 4.03; N, 2.95; found: C, 68.30; H, 4.28; N, 2.98.
4.3.32. 1-(3-Benzoyl-5,6,8-trifluoro-4-oxo-2-phenyl-4H-chromen-7-yl)proline
(22b) was synthesized according to method B from 398 mg (1 mmol) of flavone 5b and 230 mg
(2 mmol) of proline. Yield 199 mg (40%), yellow powder, mp 265–268˚С (CHCl3). IR (DRA): ν
2983, 2884 (О–Н), 1748 (СО2Н), 1674 (С=О), 1523, 1479, 1368 (С–N, C=C, С–Н), 1003 (C–F)
cm–1. 1Н NMR (400.13 MHz, (CD3)2SO): δ 2.14 (4Н, m, (СН2)2, С-10, С-11), 3.85 (2Н, m, СН2,
С-12), 4.80 (1Н, m, Н, С-9), 7.43–7.98 (10Н, m, 2 Ph), 12.90 (1Н, br.s, ОН). 19F NMR (376.44
MHz, (CD3)2SO): δ -154.11, -153.97 (2F, both m), -147.71 (1F, d.d, J = 18.3, 9.1 Hz). Anal. calcd.
for С27Н18F3NO5: C, 65.72; H, 3.68; N, 2.84; found: C, 65.91; H, 3.90; N, 3.24.
4.4. The X-ray structural analysis of compounds 10b.Na, 17a, 18b was performed on an
Xcalibur 3 automatic diffractometer (Oxford Diffraction, UK) with a CCD detector (graphite
monochromator, λ (MoKα) 0.71073 Å, ω-scan). Absorption was corrected analytically using a
multi-facet crystal model as implemented in the program CrysAlis RED v.1.171.39.38a. The
structures were solved with the direct method from differential Fourier syntheses and refined by
full-matrix least-squares F2 using the software package SHELXTL.[18] Refinement for non-
hydrogen atoms was performed in the anisotropic approximation. Hydrogen atoms were placed in
geometrically calculated positions and were included in the refinement according to the “rider”
model in an isotropic approximation with thermal parameters dependent on the “parent” atoms.

4.4.1. Crystals of compound 10b. Na (С13Н18F4NNaO8, М 415.27) are monoclinic; spatial
symmetry group P2(1)/ c; a 21.106(2), b 5.1186(4), c 17.0736(19) Å; α 90.00, β 106.223(12), γ
90.00°; V 1771.1(3) Å3; Z 4; dcalc 1.557 g/cm3; μ 0.172 mm–1. 4763 total reflections, 2109
independent reflections, R-factor 0.0555, 289 refinable parameters (measured at 295(2) K).
4.4.2. Crystals of compound 17а (С23Н18F3NO4, М 429.38) are monoclinic; spatial
symmetry group P2(1)/ c; a 19.237(4), b 4.5309(8), c 23.426(5) Å; α 90.00, β 108.76(3), γ 90.00°;
V 1933.4(7) Å3; Z 4; dcalc 1.475 g/cm3; μ 0.120 мм–1. 4735 total reflections, 1736 independent
reflections, R- factor 0.0716, 296 refinable parameters (measured at 295(2) K).
4.4.3. Crystals of compound 18b (С14Н13F4NO2, М 303.25) are triclinic; spatial symmetry
group Р1¯; a 7.6785(16), b 13.215(2), c 13.531(3) Å; α 80.743(16), β 80.049(18), γ 75.127(17)°;
V 1297.2(4) Å3; Z 2; dcalc 1.553 g/cm3; μ 0.142 мм–1. 4394 total reflections, 1417 independent
reflections, R- factor 0.0401, 382 refinable parameters (measured at 295(2) K).
The full set of X-ray structural data for compounds 10b.Na, 17а, 18b were deposited at
Cambridge Crystallographic Data Center (deposits CCDC 1901179, CCDC 1901173, CCDC
1901184).
4.5. Microbiological activity assay. Evaluation of antimicrobial properties (fungistatic and
bactericidal) was performed by the serial dilution method recommended by the Institute of Clinical
and Laboratory Standards (CLSI). Test strains of fungi: Trichophyton rubrum (RCPF F-1408),
Trichophyton mentagrophytes var. gypseum (RCPF F-1425), Trichophyton tonsurans (RCPF F-
1458), Trichophiton violaceum (RCPF F-1393/658), Trichophyton mentagrophytes var.
interdigitale (RCPF F-1229), Epidermophyton floccosum (RCPF F-1174), Microsporum canis
(RCPF F-1403), Candida albicans (RCPF Y-401 / NCTC 885-653) (Table 1), and test strains of
clinically significant obligate and conditionally pathogenic bacteria: Escherichia coli (ATCC
8739), Klebsiella pneumoniae (ATCC 13883 / NCTC9633), Citrobacter braakii (ATCC 101/57),
Serratia marcescens (ATCC 13880 / NCTC 10211), Shigella flexneri (1a8516), Pseudomonas
aeruginosa (ATCC 9027 / NCTC 12924), Staphylococcus aureus (ATCC 25923 / NCTC 12981
(F-49)), Staphylococcus aureus MRSA (NCTC12493) (Table 2).
Fungi were cultivated at 27˚C on Sabouraud Dextrose Agar (SDA) and MIC was determined by
using Sabouraud Dextrose Broth (SDB). The tested compounds and standard were dissolved in
DMSO, 1÷10 and applied in different concentrations (from 1000 till 0.19 μg/mL). DMSO was
used as a negative control and antifungal (Terbinafine) as positive control. The broth dilution test
was performed in test tubes. The inoculum suspension, which gave the final concentration of 1ˣ108
CFU/mL, was prepared. A growth control tube and sterility control tube were used in each test.
After 14 days incubation at 27˚C, the MIC was determined visually as the lowest concentration
that inhibits growth, evidenced by the absence of turbidity.
The Muller-Hinton medium was used for testing antibacterial activity. Adjust the density of the
suspension to contain 1.5ˣ108 CFU/mL by comparison with a 0.5 McFarland turbidity standard.
For suspension, using colonies from an overnight (20 to 24-hour) agar plate incubated in 5% CO2
36±1°C. Dilute this suspension 1÷100 in Muller-Hinton to give 106 CFU/mL. The test compounds
concentrations: 1000, 500, 250, 125, 62.5, 31.25, 15.6, 7.8, 3.9, 1.9, 0.97 μg/mL (solvent – DMSO,
diluent – Н2О and GC agar base).
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