Synthesis of polyfluorinated 4?hydroxyquinolin-2(1H)?ones based on the cyclization of 2-alkynylanilines with carbon dioxide

Article abstract of DOI:10.1016/j.jfluchem.2020.109720

Convenient and efficient synthesis of polyfluorinated 4-hydroxyquinolin-2(1H)-ones from the corresponding o-alkynylaniline derivatives and CO₂ (1 atm), mediated by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and AgNO₃ in acetonitrile wa

Full text of DOI:10.1016/j.jfluchem.2020.109720

Journal of Fluorine Chemistry 242 (2021) 109720
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of polyfluorinated 4‑hydroxyquinolin-2(1H)‑ones based on the
cyclization of 2-alkynylanilines with carbon dioxide
,
,
Larisa Politanskayaa *, Evgeny Tretyakova b, Chanjuan Xic
a N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Ac. Lavrentiev Ave., 9, Novosibirsk, 630090, Russia
b Novosibirsk State University, Pirogova Street, 2, Novosibirsk, 630090, Russia
c MOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Convenient and efficient synthesis of polyfluorinated 4-hydroxyquinolin-2(1H)-ones from the corresponding o-
alkynylaniline derivatives and CO2 (1 atm), mediated by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and AgNO3
in acetonitrile was performed. This synthetic methodology may be used to prepare fluorinated heterocycles
containing peripheral alkynyl and amino groups but is not suitable for silylethynyl derivatives that give indoles
as the main products. The reaction takes place under mild conditions (60 ◦C) and involves readily available
starting materials that include cheap and renewable carbon dioxide.
Polyfluorinated alkynylanilines
Polyfluorinated heterocycles
Carbon dioxide incorporation
Intermolecular heterocyclization reaction
1. Introduction
derivatives, efficient synthesis of these compounds has attracted much
attention. Various approaches to obtaining this class of compounds are
Fluorine-containing compounds are of great interest in organic
chemistry in that they have found a wide range of applications in
pharmaceuticals, medicine, agrochemicals and material science [1]. Due
to fluorine atom has high electronegativity and a small atomic radius,
introducing a fluorine atom or fluoride group into functional molecules
tends to change chemical, physical, and physiologic properties (such as
metabolic stability and fat) of the parent molecule [2]. Much effort of
researchers is aimed at finding new synthetic strategies for fluorine
incorporation into organic molecules. The objective of our study was to
find universal and efficient approaches to the synthesis of new fluori-
nated benzoheterocycles [3]. Today a large number of fluorinated
bioactive heterocycles are known [4]. A special place among them be-
longs to fluoroquinolones [5–7]. Numerous representatives of biologi-
cally active compounds have also been found among
4‑hydroxyquinolin-2(1H)‑one derivatives (Fig. 1); furthermore, some of
them have been isolated from natural products [8,9]. In particular,
4‑hydroxyquinolin-2(1H)‑ones have been reported to be selective 5-HT3
[10] and GnRH [11] receptor antagonists and NMDA [12–16] and HIV
[9] inhibitors. Besides some representatives of this class of compounds
possess antimicrobial [16,17], antibacterial [8,17–19], anticancer [7],
antifungal [16–18], antimalarial [16], molluscicidal [20], antiparasitic
[21], antioxidant [18] and antiallergic [22] activities.
known today, e.g., the synthesis from o-X-substituted anilines (X = H [7,
23,24], COOMe [11,14,15], COMe [25]) or their congeners [22,26],
from 4‑cloroquinolin-2(1H)‑one or 3-bromoquinolin-4(1H)-one [27],
and from 2-methyl-3,1-benzoxazin-4-ones [28,29].
An alternative method of 4‑hydroxyquinolin-2(1H)‑one synthesis is
based on the 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) – promoted
intramolecular rearrangement reaction of 2-alkynylanilines with carbon
dioxide in DMSO in the presence of AgNO3 [30] or CuI [31]. We were
inspired by this highly efficient and convenient synthetic method
because the fixation of carbon dioxide into valuable organic compounds
is an environmentally friendly and sustainable process [32] and CO2 is
an economical, renewable, noncorrosive, inflammable and nontoxic
carbon source [33]. Moreover, chemical utilization of carbon dioxide
could also help to reduce its concentration in the atmosphere, since it is
assumed that the increasing levels of CO2 has a detrimental effect on the
climate and is the major contributing factor to recent global warmingеhe
[34].
In present work we investigated the synthetic usefulness of carbon
dioxide incorporation into polyfluorinated o-alkynylanilines to obtain
new potentially biologically active fluorine-contained 4‑hydrox-
yquinolin-2(1H)‑ones.
Because of the importance of 4‑hydroxyquinolin-2(1H)‑one
* Corresponding author.
E-mail address: plv@nioch.nsc.ru (L. Politanskaya).
https://doi.org/10.1016/j.jfluchem.2020.109720
Received 12 November 2020; Received in revised form 23 December 2020; Accepted 26 December 2020
Available online 31 December 2020
0022-1139/© 2020 Elsevier B.V. All rights reserved.

L. Politanskaya et al.
Journal of Fluorine Chemistry 242 (2021) 109720
2. Results and discussion
conditions: bis(triphenylphosphine) palladium dichloride (8 mol.%),
copper(I) iodide (18 mol.%) and triethylamine as catalysts in dry MeCN
as a solvent (Scheme 1). The reaction was carried out at 60 ◦C in a tightly
closed Schlenk flask in an argon atmosphere for 4 h.
Given that CO2 is highly thermodynamically and kinetically stable,
organic reactions with CO2 usually require a relatively high-energy
reactant and transition metal catalysts [35]. The application of cata-
lysts that can activate CO2 or starting materials and accelerate the re-
action by lowering the energy barrier of the transition state is the key to
implementing a thermodynamically favored reaction. It is well known
that carbon dioxide easily combines with amines at ambient tempera-
ture and atmospheric pressure to produce carbamic acids [36].
Comparing synthetic methods for obtaining of 4‑hydroxyquinolin-2
(1H)‑one based on the cyclization of o-alkynylanilines with carbon di-
oxide [30,31], we chose the method developed by Yamada and co-
authors, in which the conversion of reagents is carried out at
atmospheric pressure of CO2 owing to silver salt catalysis [30]. It should
be noted that there are other examples of the interaction of o-alkyny-
lanilines with carbon dioxide, leading to the heterocyclic products, for
example, palladium-catalyzed multicomponent reactions between
o-alkynylanilines, aryl iodides and atmospheric pressure of CO2, giving a
number of 3,3-diaryl 2,4-quinolinediones [37].
Silylethynyl derivatives 1n and trimethyl((perfluorophenyl)ethynyl)
silane (4) [42] were synthesized under similar but milder reaction
conditions (Scheme 2).
The synthesis of p-alkynylaniline 1k was based on transformations of
4 (Scheme 3). The action of K2CO3 in MeOH led not only to the removal
of the TMS group but also to nucleophilic substitution of the p-fluorine
atom on the aromatic ring of the polyfluorinated substrate. The rela-
tively low yield of 1-ethynyl-2,3,5,6-tetrafluoro-4-methoxybenzene (5)
is due to the high volatility of this compound. Next, the resulting ethynyl
derivative was reacted with 2,3,4-trifluoro-6-iodoaniline [3c] under
Sonogashira reaction conditions (Scheme 3).
In accordance with the purpose of our work, the obtained fluorinated
o-alkynylanilines 1 were next subjected to the interaction with carbon
dioxide in the presence of DBU and AgNO3. The reaction was allowed to
proceed in CO2 atmosphere (at normal pressure) in MeCN at 60 ◦C in a
Schlenk apparatus for 25 h, and the results are summarized in Table 1.
The analysis of data in Table 1 indicates that most of the poly-
fluorinated o-alkynylanilines reacted smoothly with carbon dioxide in
the presence of DBU and AgNO3, thereby giving rise to the cyclized
products (4‑hydroxyquinolin-2(1H)‑ones 2) in 80–92% yields (entries
As starting materials, we used polyfluorinated o-alkynylaniline 1a–i
synthesized according to previously described methods [35,39,40].
o-Alkynylaniline 1j was obtained by cross-coupling of 3,6-difluoro-2,
4-diiodoaniline [40] with terminal alkynes under Sonogashira
Fig. 1. Examples of some biologically active 4‑hydroxyquinolin-2(1H)‑ones.
2

L. Politanskaya et al.
Journal of Fluorine Chemistry 242 (2021) 109720
Scheme 1. Synthesis of fluorinated alkynylaniline 1 j.
in CO2 must be broken to form carbamic acid (B). Next, by action of the
–
–
transition metal (M), the triple C C bond is transformed, and a cyclic
–
transition state (C) is formed, similar to that previously assumed for the
reaction of 2-aminobenzonitrile and CO2 in the presence of [WO4]2–
[42]. It should be noted that the interaction of N-alkyl substituted de-
rivatives of o-alkynylanilines with CO2 under similar conditions
(M = AgNO3) stopped at the stage of the corresponding
benzoxazine-2-ones formation, which were the final reaction products
[43]. In contrast, the DBU-promoted cleavage of N–H bond in the in-
termediate C produced the heterocyclic structure D, which is then
transformed into an isocyanate derivative E via breaking the single C–O
bond. The resulting enol product F undergoes an intramolecular cycli-
zation reaction to form a quinoline-2,4-diol (G), which is next trans-
Scheme 2. Synthesis of fluorinated alkynylaniline 1n.
1–5, 10, 11 in Table 1).
The newly developed procedure for isolation of the target reaction
products includes dilution of the reaction mixture with 1 M aqueous
NaOH and subsequent obligatory filtration of the resulting solution
through a dense paper filter under normal pressure. This procedure was
used for mechanical removal of catalyst residues and of contamination
with the initial compounds, which stayed on the surface of the paper in
film form. Then, the filtered solution was acidified with 2 M HCl
(aqueous solution), and the precipitate was separated and dried in
vacuum to a constant weight. These manipulations allowed to obtain
polyfluorinated 4‑hydroxyquinolin-2(1H)‑ones in pure form without
additional purification such as extraction (compare with [30]). This is
important, given the extremely low solubility of polyfluorinated com-
pounds 2.
formed into
a thermodynamically more stable final product –
4‑hydroxyquinolin-2(1H)‑one 2.
It is noteworthy that in none of our reactions of polyfluorinated
anilines with CO2 in the presence of DBU, were the products detectable
that correspond to nucleophilic substitution of the fluorine atom at o-
positions relative to the amino group (H). Such transformations were
observed previously in reactions of polyfluorinated anilines and hy-
drazines with CS2 in the presence of DBU. The reaction products were
the respective polyfluorinated benzothiazolethione [3e,44]. The reac-
tion with CS2 proceeded via a nucleophilic attack on the carbon atom of
CS2 by the nitrogen atom of the NH2 group in an arene followed by
selective intramolecular fluorine atom substitution at the o-position
toward the amino group. Nonetheless, as our experiments showed, the
nucleophilic activity of O– is not sufficient (in comparison with S–) for
such a transformation in the reaction of polyfluorinated anilines with
CO2, at least when the reaction is carried out under normal CO2
pressure.
Alkynes 1a–f, 1j, 1k, containing an aromatic substituent at the triple
bond give reaction products in a higher yield than do those with an
aliphatic n-Bu moiety. The presence of fluorine atoms and electron-
donating groups (OMe, NH2) in the aromatic part at a triple bond does
not significantly affect the course of the reaction, and the yields of the
corresponding 4‑hydroxyquinolin-2(1H)‑ones in these cases are com-
parable to those for Ph-substituted substrates (entries 3 and 11, 1 and 5
in Table 1). It was found that the additional triple bond located at a
distance from the reaction center of the molecule 1j remained un-
changed in the reaction product 2j (entry 10, Table 1).
The maintaining of 2,3,5-trifluoro-6-(phenylethynyl)-4-(trifluoro-
methyl)aniline [38] under standard reaction conditions led to the for-
mation of indole 3a (Scheme 5). Apparently, due to the strong acceptor
effect of the p-trifluoromethyl group (in combination with that of the
four fluorine atoms present on the ring), the amino group of substrates
could not interact effectively with the CO2 molecule to form a carbamic
acid (structure B in Scheme 4). Nevertheless, by action of a transition
metal catalyst, the triple bond was transformed, which led to the closure
of the pyrrole heterocycle as a result of an intramolecular reaction
(product 3, Scheme 4) [3a].
Our analysis of the experimental and literature data [30,31] allows
us to interpret the mechanism of interaction of polyfluorinated o-alky-
nylanilines 1 with CO2 in the presence of DBU and transition metal
catalysts (M) as follows in Scheme 4.
Activated by the action of DBU the amino group of the substrate (A)
A similar indole skeleton 3b [45] was detected after the interaction
of silylethynyl derivatives 1m and 1n with AgNO3 in presence of DBU
–
–
interacts with the CO molecule. In this reaction, one of the C O bond
2
Scheme 3. Synthesis of fluorinated o-alkynylaniline 1k.
3

L. Politanskaya et al.
Journal of Fluorine Chemistry 242 (2021) 109720
Table 1
Synthesis of fluorinated 4‑hydroxyquinolin-2(1H)‑one derivatives.
Entry
1
Substrate 1
Product
Yield (%)
80
2
3
4
5
6
92
85
91
87
57
7
8
60
78
(continued on next page)
4

L. Politanskaya et al.
Journal of Fluorine Chemistry 242 (2021) 109720
Table 1 (continued)
Entry
Substrate 1
Product
Yield (%)
9
25
90
82
10
11
1 j
1k
Scheme 4. The mechanism proposed for the DBU and transition metal (M) catalyzed reaction of polyfluorinated o-alkynylaniline 1 with carbon dioxide.
and CO2 (Scheme 6). Apparently, 6-ethynyl-2,3,4-trifluoroaniline [45]
was formed by action of the base (DBU) at the first stage of the reaction
in both cases. This mechanism follows from the finding that the yield of
the reaction product does not depend on the nature of the alkyl moieties
in the substituent at the triple bond (TMS or TIPS). After that, the
transformation typical for polyfluorinated o-alkynylanilines was carried
out in the presence of transition metal salts, namely, cyclization to the
indole.
Thus, polyfluorinated o-alkynylanilines reacted with AgNO3 in the
presence of DBU and CO2 to produce heterocyclic products. In most
cases, 4‑hydroxyquinolin-2(1H)‑ones are formed, i.e., products of
incorporation of the CO2 molecule into the heterocycle. On the other
hand, polyfluorinated o-[(trialkylsilyl)ethynyl]anilines give rise to in-
doles unsubstituted on the pyrrole ring: the result of an intramolecular
5

L. Politanskaya et al.
Journal of Fluorine Chemistry 242 (2021) 109720
Scheme 5. Synthesis of fluorinated indole 3a.
Scheme 6. Synthesis of fluorinated indole 3b.
cyclization reaction. The direction of the reaction is influenced not only
by the substituent at the triple bond but also by the combined effect of
the substituents on the aromatic ring of polyfluorinated substrates.
spectrometer (KBr or thin film).
The structures of all new polyfluorinated compounds prepared here
were corroborated by their 19F, H, and 13C NMR spectroscopy, high-
1
resolution mass spectrometry, and IR-spectroscopy data (see Supple-
mentary data).
3. Conclusion
We demonstrated the possibility of a simple and efficient AgNO3- and
DBU-promoted one-pot transformation of polyfluorinated o-alkynylani-
lines into 4‑hydroxyquinolin-2(1H)‑one derivatives via an interaction
with CO2 in MeCN. The protocol involves utilization of simple and
readily available starting materials and affords the corresponding pol-
yfluorinated heterocycles under mild conditions (1 atm) in good yields.
Polyfluorinated TIPS- and TMS-acetylene derivatives are transformed
into indoles unsubstituted at position 2. Therefore, this work can be
useful for researchers interesting in preparing and studying of fluori-
nated analogs of biologically active 4‑hydroxyquinolin-2(1H)‑ones.
4.2. Synthetic procedures
4.2.1. 3,6-Difluoro-2,4-bis(phenylethynyl)aniline (1 j)
To
a solution of 3,6-difluoro-2,4-diiodoaniline [40] (0.51 g,
1.34 mmol) and phenylacetylene (0.55 g, 5.39 mmol) in MeCN (15 mL)
Pd(PPh3)2Cl2 (73 mg, 0.10 mmol), CuI (45 mg, 0.24 mmol) and Et3N
(4 mL) were added in a Schlenk flask under argon. The reaction mixture
was stirred at 60 ◦C for 6.5 h. Then, the mixture was placed directly onto
a chromatography plate (silica gel) and air-dried. The alkynylaniline 1j
were isolated by TLC using EtOAc/hexane as the eluent.
White solid; yield: 0.42 g (96%); Rf = 0.80 (EtOAc/hexane, 1:10);
mp 84.2–84.7 ◦C. IR (KBr): 3500, 3396, 3057, 3020, 2927, 2854, 2212,
1635, 1599, 1574, 1500, 1481, 1444, 1387, 1323, 1302, 1194, 1128,
4. Experimental section
1
4.1. General
1097, 1070, 1026, 904, 862, 756, 688, 567, 524, 503 cm–1. H NMR
(300 MHz, Acetone-d6): 7.68–7.64 (m, 2 H, Hm), 7.57–7.54 (m, 2 H,
H’m), 7.46–7.41 (m, 6 H, Ho + Hp), 7.23 (d, J (H3,F2) = 11.3 Hz, J (H3,F5)
= 6.3 Hz, 1 H, H3), 5.87 (br s, 2 H, NH2). 13C NMR (100 MHz, Acetone-
d6): δ = 159.5 (d, 1J (C5,F5) = 248.7 Hz, C5), 146.1 (d, 1J (C2,F2) =
236.0 Hz, C2), 140.0 (dd, 2J (C1,F2) = 15.3 Hz, 3J (C1,F5) = 3.9 Hz, C1),
131.6 (s, C10), 131.2 (s, C10’), 129.0 (s, C12), 128.6 (s, C11 + C11’), 128.5
(s, C12’), 123.1 (s, C9), 122.6 (s, C9’), 117.9 (d, 2J (C3,F2) = 21.5 Hz, C3),
100.1 (s, C7), 97.8 (dd, 2J (C4,F5) = 21.2 Hz, 3J (C4,F2) = 6.2 Hz, C4),
All solvents were purified by standard procedures. Acetonitrile and
triethylamine were kept over CaH2 before use. The starting materials
were synthesized according to previously described methods [3c,40–43,
45]. Other chemicals were obtained from commercial sources and were
used without further purification. Preparative TLC was performed on
Merck precoated silica gel 60 PF254 containing gypsum. Visualization of
the developed chromatograms was performed by means of UV light.
NMR spectra were recorded on Bruker Avance-300 (300.13 MHz for
1H and 282.37 MHz for 19F), Avance-400 (400.13 MHz for 1H and
2
3
96.9 (dd, J (C6,F5) = 18.2 Hz, J (C6,F2) = 9.7 Hz, C6), 92.3 (s, C7’),
82.1 (s, C8), 78.1 (s, C8’). 19F NMR (282 MHz, Acetone-d6): δ = –110.6
(dd, J (F5,F2) = 14.1 Hz, J (F5,H3) = 6.3 Hz, 1 F, F5), –137.8 (dd, J (F2,
F5) = 14.1 Hz, J (F2,H3) = 11.3 Hz, 1 F, F2). HRMS (EI): m/z [M]+ calcd
for C22H13F2N: 329.1011; found: 329.1007.
1
100.62 MHz for 13C), and DRX-500 (500.13 MHz for H, 125.76 MHz
for 13C) spectrometers. CDCl3, Acetone-d6 and DMSO-d6 were served as
solvents, with residual CHCl3 (δH = 7.26), CDCl3 (δC = 77.0) and
acetone (δH = 2.15), acetone-d6 (δC = 28.6 and 205.0) or DMSO-d6
(δC = 39.5) acting as internal standards, C6F6 (δF = 163.0) was used as
an external reference for recording 19F NMR spectra. 13C NMR spectra
were recorded with C–H spin decoupling. Masses of molecular ions were
determined by HRMS on a DFS Thermoscientific instrument (EI, 70 eV).
Melting points were recorded on a Mettler-Toledo FP81 Thermosystem
apparatus. The IR spectra were recorded on a Bruker Vector 22
4.2.2. 2,3,4-Trifluoro-6-((triisopropylsilyl)ethynyl)aniline (1n)
To
a
solution of 2,3,4-trifluoro-6-iodoaniline [3c] (1.00 g,
3.66 mmol) and ethynyltriisopropylsilane (1.00 g, 5.50 mmol) in Et3N
(20 mL) Pd(PPh3)2Cl2 (128 mg, 0.18 mmol) and CuI (70 mg,
0.36 mmol) were added in a Schlenk flask under argon. The reaction
mixture was stirred at r. t. for 70 h. Then, the mixture was placed
6

L. Politanskaya et al.
Journal of Fluorine Chemistry 242 (2021) 109720
directly onto a chromatography plate (silica gel) and air-dried. The
alkynylaniline 1n were isolated by TLC using hexane as the eluent.
Yellowish oil; yield: 1.03 g (86%); Rf = 0.68 (hexane). IR (thin):
3494, 3392, 2945, 2893, 2866, 2148, 1587, 1520, 1481, 1371, 1300,
1163, 1072, 1018, 997, 918, 883, 858, 733, 679, 567, 519, 472 cm–1. 1H
NMR (500 MHz, CDCl3): 6.92 (m, J (H3,F4) = 10.4 Hz, J (H3,F5) =
7.7 Hz, J (H3,F6) = 2.3 Hz, 1 H, H3), 4.20 (br s, 2 H, NH2), 1.11–1.10 (m,
F
14) ≈ 24 Hz, 2 F, F11 + F13). HRMS (EI): m/z [M]+ calcd for
C
15H6F7NO: 349.0332; found: 349.0324.
4.2.5. 4‑Hydroxyquinolin-2(1 H)‑ones 2; General Procedure
A 25 mL Schlenk flask containing a stir bar was purged with CO2
from a balloon three times. A solution of substrate 1 (1.0 mmol) in
MeCN (10 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (152 mg,
1.0 mmol) were added in a Schlenk flask under CO2 atmosphere. Then a
bubbler was lowered into the resulting solution in a Schlenk flask and
CO2 was bubbled with intensive stirring at r. t. for 15 min. After that, the
bubbler was removed, AgNO3 (74 mg, 0.2 mmol) was added, and the
reaction vessel was quickly and tightly closed. The reaction mixture was
stirred at 60 ◦C for 25 h. Then 1 M aqueous NaOH (3 × 15 mL) was
added in a Schlenk flask, reaction flack was closed again and shaken
intensely. The combined aqueous extract was filtered through a dense
paper under normal pressure and acidified with 2 M aqueous HCl
(~5 mL). After cooling at 5 ◦C for 2 h the precipitate was separated,
washed with H2O (10 mL) and dried in vacuum to a constant weight.
1
21 H, i-Pr). 13C NMR (126 MHz, CDCl3): δ = 142.6 (ddd, J (C4,F4) =
239.5 Hz, 2J (C4,F5) = 10.8 Hz, C4), 140.9 (ddd, 1J (C5,F5) = 251.9 Hz,
2J (C5,F4) = 16.5 Hz, 2J (C5,F6) = 13.2 Hz, C5), 139.8 (ddd, 1J (C6,F6) =
2
2
242.5 Hz, J (C6,F5) = 12.4 Hz, C6), 134.8 (dm, J (C1,F6) = 10.6 Hz,
C1), 114.1 (dd, 2J (C3,F4) = 19.1 Hz, 3J (C3,F5) = 3.5 Hz, C3), 103.3 (m,
C2), 100.2 (m, C7), 98.1 (m, C8), 18.5 (s, C9), 11.0 (s, C10). 19F NMR
(282 MHz, CDCl3): δ = –151.2 (dd, J (F4,F5) = 21.4 Hz, J (F4,H3) =
10.4 Hz, 1 F, F4), –156.6 (dd, J (F6,F5) = 19.5 Hz, J (F6,H3) = 2.3 Hz,
1 F, F6), –159.2 (m, J (F5,F4) = 21.4 Hz, J (F5,F6) = 19.5 Hz, J (F5,H3) =
7.7 Hz, 1 F, F5). HRMS (EI): m/z [M]+ calcd for C17H24F3NSi: 327.1625;
found: 327.1623.
4.2.3. 1-Ethynyl-2,3,5,6-tetrafluoro-4-methoxybenzene (5)
4.2.5.1. 6,7-Difluoro-4-hydroxy-3-phenylquinolin-2(1 H)-one
(2a).
To a solution of trimethyl((perfluorophenyl)ethynyl)silane [41]
(0.72 g, 2.73 mmol) in MeOH (15 mL) K2CO3 (0.75 g, 5.43 mmol) was
added. The reaction mixture was stirred at r. t. for 20 h, then placed
directly onto a chromatography plate (silica gel), and air-dried. Ethy-
nylarene 5 was isolated by TLC with hexane as the eluent.
White solid; yield: 218 mg (80%); mp undefined (decomp. without
melting). IR (KBr): 3082, 2926, 2860, 1653, 1616, 1523, 1454, 1370,
1352, 1300, 1269, 1250, 1186, 1171, 1097, 885, 791, 779, 750, 704,
694, 580, 540, 509 cm–1. 1H NMR (500 MHz, DMSO-d6): δ = 11.57 (s, 1
H, H1), 10.35 (s, 1 H, H4), 7.91 (dd, J (H5,F6) = 11.6 Hz, J (H5,F7) =
8.6 Hz, 1 H, H5), 7.41 – 7.30 (m, 5 H, 2 Hm + 2 Ho + Hp), 7.23 (dd, J (H8,
F7) = 11.4 Hz, J (H8,F6) = 7.1 Hz, 1 H, H8). 13C NMR (125 MHz, DMSO-
d6): δ = 162.5 (s, C2), 156.3 (s, C4), 151.0 (dd, 1J (C7,F7) = 249.5 Hz, 2J
White solid; yield: 0.32 g (57%); Rf = 0.45 (hexane); mp 55.7 ◦C
(decomp.). IR (KBr): 3288, 2960, 2123, 1643, 1491, 1448, 1425, 1298,
1196, 1136, 983, 908, 704, 650, 420 cm–1. 1H NMR (300 MHz, CDCl3):
4.09 (s, 3 H, OCH3), 3.51 (s, 1 H, CCH). 13C NMR (126 MHz, CDCl3):
δ = 148.0 (dddd, 1J (C2,F2) = 1J (C6,F6) = 252.4 Hz, 2J (C2,F3) = 2J (C6,
F5) =13 Hz, C2 + C6), 140.3 (ddt, 1J (C3,F3) = 1J (C5,F5) = 247.3 Hz, 2J
(C3,F2) = 2J (C5,F6) = 14.2 Hz, C3 + C5), 96.3 (t, 2J (C1,F2) = 2J (C1,F6) =
18.1 Hz, C1), 88.3 (t, C8), 68.5 (t, C7), 62.0 (t, C9). 19F NMR (282 MHz,
CDCl3): δ = –136.0 (dm, J (F2,F3) = J (F6,F5) ≈ 23 Hz, 2 F, F2 + F6),
–156.2 (dm, J (F3,F2) = J (F5,F6) ≈ 23 Hz, 2 F, F3 + F5). HRMS (EI): m/z
[M]+ calcd for C9H4F4: 204.0193; found: 204.0196.
1
(C7,F6) = 14.7 Hz, C7), 144.7 (dd, J (C6,F6) = 240.2 Hz, 2J (C6,F7) =
13.8 Hz, C6), 135.1 (d, 3J (C8a,F7) = 9.9 Hz, C8a), 132.7 (s, C9), 131.0 (s,
C10), 127.6 (s, C11), 127.0 (s, C12), 113.0 (m, C3), 112.1 (dm, 3J (C4a,F6)
= 5.6 Hz, C4a), 111.2 (d, 2J (C5,F6) = 20.0 Hz, C5), 103.0 (d, 2J (C8,F7) =
21.1 Hz, C8). 19F NMR (282 MHz, DMSO-d6): δ = –134.0 (m, J (F7,F6) =
23.4 Hz, J (F7,H8) = 11.3 Hz, J (F7,H5) = 8.7 Hz, 1 F, F7), –146.2 (m, J
(F6,F7) = 23.4 Hz, J (F6,H5) = 11.5 Hz, J (F6,H8) = 7.1 Hz, 1 F, F6).
HRMS (EI): m/z [M-H]+ calcd for C15H8F2NO2: 272.0518; found:
272.0512.
4.2.4. 2,3,4-Trifluoro-6-((2,3,5,6-tetrafluoro-4-methoxyphenyl)ethynyl)
aniline (1k)
4.2.5.2. 6,8-Difluoro-4-hydroxy-3-phenylquinolin-2(1 H)-one
(2b).
White solid; yield: 251 mg (92%); mp 267.2 ◦C (decomp.). IR (KBr):
3145, 3053, 2983, 1655, 1626, 1599, 1508, 1469, 1413, 1336, 1298,
1263, 1192, 1169, 1113, 997, 897, 866, 793, 702, 631, 592, 546, 532,
494 cm–1. 1H NMR (300 MHz, DMSO-d6): δ = 11.50 (br s, 1 H, H1), 7.56
(dm, J (H5,F6) = 9.7 Hz, J (H5,H7) = 2.8 Hz, 1 H, H5), 7.47 (m, J (H7,F8)
= 11 Hz, J (H7,F6) = 8.8 Hz, J (H7,H5) = 2.8 Hz, 1 H, H7), 7.43 – 7.38
(m, 4 H, 2 Hm + 2 Ho), 7.34 – 7.30 (m, 1 H, Hp). 13C NMR (125 MHz,
DMSO-d6): δ = 162.6 (s, C2), 156.8 (t, C4), 156.0 (dd, 1J (C6,F6) =
239.1 Hz, 3J (C6,F8) = 11.0 Hz, C6), 149.0 (dd, 1J (C8,F8) = 248.5 Hz, 3J
(C8,F6) = 12.7 Hz, C8), 133.3 (s, C9), 131.4 (s, C10), 128.0 (s, C11), 127.4
(s, C12), 124.4 (d, 2J (C8a,F8) = 14.8 Hz, C8a), 118.3 (dd, 3J (C4a,F6) =
9.7 Hz, 3J (C4a,F8) = 4.7 Hz, C4a), 114.9 (s, C3), 105.5 (dd, 2J (C7,F6) =
28.6 Hz, 2J (C7,F8) = 21.7 Hz, C7), 104.6 (dd, 2J (C5,F6) = 24.2 Hz, C5).
19F NMR (282 MHz, DMSO-d6): δ = –118.1 (tm, J (F6,H5) ≈ J (F6,H8) =
9.5 Hz, 1 F, F6), –125.0 (dm, J (F8,H7) = 10 Hz, 1 F, F8). HRMS (EI): m/z
[M-H]+ calcd for C15H8F2NO2: 272.0518; found: 272.0519.
To
a
solution of 2,3,4-trifluoro-6-iodoaniline [3c] (0.27 g,
1.00 mmol) 5 (0.20 g, 1.00 mmol) in MeCN (10 mL) Pd(PPh3)2Cl2
(35 mg, 0.05 mmol), CuI (19 mg, 0.10 mmol) and Et3N (2 mL) were
added in a Schlenk flask under argon. The reaction mixture was stirred
at r. t. (30 ◦C) for 18 h. Then, the mixture was placed directly onto a
chromatography plate (silica gel) and air-dried. The alkynylaniline 1k
were isolated by TLC using EtOAc/hexane as the eluent.
Yellowish solid; yield: 0.26 g (77%); Rf = 0.83 (EtOAc/hexane, 1:7,
four times); mp 89.1–91.8 ◦C. IR (KBr): 3494, 3396, 2966, 2218, 1647,
1597, 1525, 1489, 1456, 1431, 1375, 1300, 1205, 1159, 1107, 1022,
985, 924, 860, 609 cm–1. 1H NMR (300 MHz, CDCl3): 7.00 (m, J (H3,F4)
= 10.1 Hz, J (H3,F5) = 7.7 Hz, J (H3,F6) =2.3 Hz, 1 H, H3), 4.12 (t, 3 H,
OCH3), 3.83 (br s, 2 H, NH2). 13C NMR (126 MHz, CDCl3): δ = 146.8
(dddd, 1J (C10,F10) = 1J (C14,F14) = 251.2 Hz, 2J (C10,F11) = 2J (C14,F13
)
= 13.2 Hz, C10 + C14), 142.9 (ddd, 1J (C4,F4) =240.3 Hz, 2J (C4,F5) =
11.0 Hz, C4), 141.4 (ddd, 1J (C5,F5) = 253.7 Hz, 2J (C5,F4) = 16.7 Hz, 2J
(C5,F6) = 13.2 Hz, C5), 140.6 (ddt, 1J (C11,F11) = 1J (C13,F13) =
252.4 Hz, 2J (C11,F10) = 2J (C13,F14) = 14.4 Hz, C11 + C13), 139.7 (ddd,
4.2.5.3. 6,7,8-Trifluoro-4-hydroxy-3-phenylquinolin-2(1 H)-one
(2c).
1J (C6,F6) = 243.1 Hz, 2J (C6,F5) = 12.5 Hz, C6), 139.2 (tm, 2J (C12,F11
)
White solid; yield: 247 mg (85%); mp 305.3–306.5 ◦C. IR (KBr): 3130,
3020, 2980, 2848, 1743, 1631, 1597, 1522, 1458, 1437, 1369, 1346,
1309, 1288, 1213, 1186, 1103, 1041, 1026, 874, 827, 793, 744, 706,
690, 598, 532, 501 cm–1. 1H NMR (500 MHz, DMSO-d6): δ = 11.72 (br s,
1 H, H1), 7.72 (m, J (H5,F6) = 11 Hz, J (H5,F7) = 7.9 Hz, 1 H, H5), 7.42 –
7.39 (m, 2 H, Hm), 7.34 – 7.31 (m, 3 H, Hp+ 2 Ho). 13C NMR (125 MHz,
DMSO-d6): δ = 162.4 (s, C2), 156.2 (t, C4), 144.8 (dd, 1J (C8,F8) =
241.2 Hz, 2J (C8,F7) = 11.2 Hz, C8), 140.1 (ddd, 1J (C7,F7) = 250.7 Hz,
2
2
= J (C12,F13) = 11.6 Hz, C12), 134.9 (dm, J (C1,F6) = 11.0 Hz, C1),
113.7 (dd, 2J (C3,F4) = 19.4 Hz, 3J (C3,F5) = 3.5 Hz, C3), 101.4 (m, C2),
97.1 (t, 2J (C9,F10) = 2J (C9,F14) = 18.0 Hz, C9), 93.8 (m, C7), 80.7 (m,
C8), 62.1 (t, C15). 19F NMR (282 MHz, CDCl3): δ = –136.2 (dm, J (F10
,
F11) = J (F14,F13) ≈ 24 Hz, 2 F, F10 + F14), –147.4 (dd, J (F4,F5) =
21.5 Hz, J (F4,H3) = 10.2 Hz, 1 F, F4), –153.0 (dd, J (F6,F5) = 19.4 Hz, J
(F6,H3) = 2.3 Hz, 1 F, F6), –154.3 (m, J (F5,F4) = 21.4 Hz, J (F5,F6) =
19.4 Hz, J (F5,H3) = 7.7 Hz, 1 F, F5), –155.9 (dm, J (F11,F10) = J (F13
,
7

L. Politanskaya et al.
Journal of Fluorine Chemistry 242 (2021) 109720
2
2
2J (C7,F6) = 17.7 Hz, 2J (C7,F8) = 12.8 Hz, C7), 137.5 (ddd, 1J (C6,F6) =
251.0 Hz, 2J (C6,F7) = 13.8 Hz, C6), 132.6 (s, C9), 131.0 (s, C10), 127.8
(s, C11), 127.2 (s, C12), 125.1 (d, 2J (C8a,F8) = 11.4 Hz, C8a), 113.8 (s,
C3), 111.9 (dm, 3J (C4a,F6) = 7.6 Hz, C4a), 105.5 (dd, 2J (C5,F6) =
19.8 Hz, C5). 19F NMR (282 MHz, DMSO-d6): δ = –142.0 (dd, J (F6,F7) =
23.0 Hz, J (F6,H5) = 11.3 Hz, 1 F, F6), –149.0 (dd, J (F8,F7) = 20 Hz, 1 F,
F8), –155.6 (ddd, J (F7,F6) = 23.0 Hz, J (F7,F8) = 20.1 Hz, J (F7,H5) =
7.9 Hz, 1 F, F7). HRMS (EI): m/z [M-H]+ calcd for C15H7F3NO2:
290.0423; found: 290.0420.
237.3 Hz, J (C6,F5) = 12.9 Hz, C6), 136.7 (t, J (C12,F13) = 12.8 Hz,
C12), 12524 (d, J (C8a,F8) = 13.8 Hz, C8a), 119.3 (dd, J (C14,F13) =
2
2
19.8 Hz, 3J (C14,F10) = 6.3 Hz, C14), 111.1 (m, C4a), 109.5 (m, C3), 106.1
(m, C9), 105.9 (t, 2J (C7,F6) ≈ J (C7,F8) = 23.1 Hz, C7), 102.8 (dd, 2J
2
(C11,F10) = 28.5 Hz, 3J (C11,F13) = 4.2 Hz, C11). 19F NMR (282 MHz,
DMSO-d6): δ = –115.2 (m, 1 F, F10), –131.4 (m, 1 F, F8), –139.9 (m, J
(F13,F10) = 14.2 Hz, 1 F, F13), –145.7 (m, 1 F, F6). HRMS (EI): m/z [M]+
calcd for C15H7F5NO2: 342.0422; found: 342.0415.
4.2.5.7. 3-Butyl-6,8-difluoro-4-hydroxyquinolin-2(1 H)-one (2 g). White
solid; yield: 152 mg (60%); mp 192.6 ◦C (decomp.). IR (KBr): 3419,
3365, 3095, 2960, 2931, 2873, 1657, 1627, 1612, 1581, 1500, 1466,
1400, 1338, 1296, 1201, 1176, 1149, 1120, 1078, 1012, 995, 908, 848,
781, 766, 731, 704, 631, 598, 575, 550, 532, 482, 413 cm–1. 1H NMR
(500 MHz, DMSO-d6): δ = 11.36 (br s, 1 H, H1), 7.48 – 7.43 (m, 2 H, H5
4.2.5.4. 5,6,7,8-Tetrafluoro-4-hydroxy-3-phenylquinolin-2(1 H)-one
(2d). White solid; yield: 281 mg (91%); mp 296.2 ◦C (decomp.). IR
(KBr): 3425, 3139, 3022, 2852, 1666, 1635, 1523, 1508, 1462, 1435,
1415, 1356, 1296, 1261, 1211, 1080, 1036, 935, 821, 764, 735, 694,
638, 561, 530, 463 cm–1. 1H NMR (500 MHz, DMSO-d6): δ = 11.91 (br s,
1 H, H1), 7.43 – 7.31 (m, 5 H, 2 Hm+ 2 Ho+ Hp). 13C NMR (125 MHz,
DMSO-d6): δ = 162.1 (s, C2), 156.3 (t, C4), 143.8 (dm, 1J (C5,F5) =
255 Hz, 2J (C5,F6) = 11 Hz, C5), 140.6 (dt, 1J (C7,F7) = 250 Hz, 2J (C7,
F6) ≈ 2J (C7,F8) = 14 Hz, C7), 134.8 (dt, 1J (C6,F6) = 241.5 Hz, 2J (C6,F5)
≈ 2J (C6,F7) = 15 Hz, C6), 134.1 (dm, 1J (C8,F8) = 245 Hz, 2J (C8,F7) =
11 Hz, C8), 131.9 (s, C9), 131.2 (s, C10), 128.2 (s, C11), 127.7 (s, C12),
124.8 (d, 2J (C8a,F8) = 11.5 Hz, C8a), 114.9 (s, C3), 102.8 (dm, 2J (C4a,F5)
= 7.2 Hz, C4a). 19F NMR (282 MHz, DMSO-d6): δ = –141.7 (m, 1 F, F5),
–154.6 (t, J (F7,F6) ≈ J (F7,F8) = 20.4 Hz, 1 F, F7), –156.0 (m, 1 F, F8),
–167.4 (t, J (F6,F7) ≈ J (F6,F5) = 21.1 Hz, 1 F, F6). HRMS (EI): m/z [M-
H]+ calcd for C15H6F4NO2: 308.0329; found: 308.0331.
+ H7), 2.55 (t, J (H9,H10) = 7.3 Hz, 2 H, H9), 1.41 – 1.27 (m, 4 H, 2 H10
+
2 H11), 0.88 (t, J (H12,H11) = 7.2 Hz, 3 H, H12). 13C NMR (125 MHz,
DMSO-d6): δ = 163.1 (s, C2), 156.0 (t, C4), 155.5 (dd, 1J (C6,F6) =
238.7 Hz, 3J (C6,F8) = 11.1 Hz, C6), 148.6 (dd, 1J (C8,F8) = 248.1 Hz, 3J
(C8,F6) = 12.9 Hz, C8), 123.2 (dd, 2J (C8a,F8) = 14.4 Hz, C8a), 117.7 (dd,
3J (C4a,F6) = 9.7 Hz, 3J (C4a,F8) = 4.8 Hz, C4a), 114.2 (s, C3), 104.7 (dd,
2J (C7,F6) = 28.6 Hz, 2J (C7,F8) = 21.7 Hz, C7), 103.8 (dd, 2J (C5,F6) =
24.0 Hz, C5), 30.3 (s, C9), 23.1 (s, C10), 22.3 (s, C11), 14.1 (s, C12). 19
F
NMR (282 MHz, DMSO-d6): δ = –119.6 (tm, J (F6,H5) ≈ J (F6,H8) =
9.4 Hz, 1 F, F6), –126.9 (dm, J (F8,H7) = 10 Hz, 1 F, F8). HRMS (EI): m/z
[M]+ calcd for C13H13F2NO2: 253.0909; found: 253.0905.
4.2.5.5. 3-(4-Amino-2,5-difluorophenyl)-6,7-difluoro-4-hydroxyquinolin-
2(1 H)-one (2e). White solid; yield: 282 mg (87%); mp undefined
(decomp.). IR (KBr): 3483, 3421, 3078, 2947, 1647, 1618, 1523, 1475,
1448, 1431, 1371, 1352, 1296, 1246, 1190, 1169, 883, 830, 792, 702,
667, 561, 530 cm–1. 1H NMR (500 MHz, DMSO-d6 + Acetone-d6):
δ = 11.57 (s, 1 H, H1), 10.49 (br s, 1 H, H4), 7.82 (dd, J (H5,F6) =
11.4 Hz, J (H5,F7) = 8.6 Hz, 1 H, H5), 7.21 (dd, J (H8,F7) = 11.5 Hz, J
(H8,F6) = 7.1 Hz, 1 H, H8), 6.88 (dd, J (H14,F13) = 11.7 Hz, J (H14,F10) =
6.5 Hz, 1 H, H14), 6.55 (dd, J (H11,F1◦) = 11.2 Hz, J (H11,F13) = 7.8 Hz, 1
H, H11). 13C NMR (125 MHz, DMSO-d6 + Acetone-d6): δ = 162.4 (s, C2),
157.5 (s, C4), 157.1 (d, 1J (C10,F10) = 238.1 Hz, C10), 151.0 (dd, 1J (C7,
F7) = 249.4 Hz, 2J (C7,F6) = 15.0 Hz, C7), 146.5 (dd, 1J (C13,F13) =
232.1 Hz, C13), 144.9 (dd, 1J (C6,F6) = 240.1 Hz, 2J (C6,F7) = 13.9 Hz,
C6), 137.7 (dd, 2J (C12,F13) = 15.2 Hz, 3J (C12,F1◦) = 12.1 Hz, C12),
135.4 (d, 3J (C8a,F7) = 10.4 Hz, C8a), 118.3 (dd, 2J (C14,F13) = 20.3 Hz,
3J (C14,F10) = 6.3 Hz, C14), 111.9 (dm, 3J (C4a,F6) = 5.6 Hz, C4a), 111.2
(d, 2J (C5,F6) = 19.4 Hz, C5), 106.6 (s, C3), 105.9 (dd, 2J (C9,F10) =
19.9 Hz, 3J (C9,F13) = 6.9 Hz, C9), 103.1 (d, 2J (C8,F7) = 21.1 Hz, C8),
102.0 (dd, 2J (C11,F10) = 28.1 Hz, 3J (C11,F13) = 5.0 Hz, C11). 19F NMR
(282 MHz, DMSO-d6 + Acetone-d6): δ = –116.2 (m, J (F10,F13) =
14.8 Hz, J (F10,H11) = 11.2 Hz, J (F10,H14) = 6.6 Hz, 1 F, F10), –132.0
(m, J (F7,F6) = 23.2 Hz, J (F7,H8) = 11.5 Hz, J (F7,H5) = 8.7 Hz, 1 F, F7),
–140.0 (m, J (F13,F10) = 14.8 Hz, J (F13,H14) = 11.8 Hz, J (F13,H11) =
7.7 Hz, 1 F, F13), –144.4 (m, J (F6,F7) = 23.3 Hz, J (F6,H5) = 11.5 Hz, J
(F6,H8) = 7.1 Hz, 1 F, F6). HRMS (EI): m/z [M]+ calcd for C15H8F4NO2:
324.0516; found: 324.0514.
4.2.5.8. 3-Butyl-6,7,8-trifluoro-4-hydroxyquinolin-2(1 H)-one
(2 h).
White solid; yield: 211 mg (78%); mp 193.9 ◦C (decomp.). IR (KBr):
3416, 3319, 3091, 2964, 2927, 1662, 1630, 1593, 1523, 1496, 1433,
1394, 1367, 1304, 1267, 1215, 1184, 1163, 1132, 1057, 1030, 972, 914,
864, 831, 764, 729, 632, 582, 472 cm–1. 1H NMR (300 MHz, DMSO-d6 +
Acetone-d6): δ = 7.65 (m, J (H5,F6) = 11.3 Hz, J (H5,F7) = 7.9 Hz, 1 H,
H5), 2.55 (t, J (H9,H10) = 7 Hz, 2 H, H9), 1.44 – 1.25 (m, 4 H, 2 H10 + 2
H11), 0.87 (t, J (H12,H11) = 7 Hz, 3 H, H12). 13C NMR (125 MHz, DMSO-
d6 + Acetone-d6): δ = 163.5 (s, C2), 155.7 (t, C4), 144.9 (dd, 1J (C8,F8) =
240.5 Hz, 2J (C8,F7) = 10.9 Hz, C8), 139.8 (ddd, 1J (C7,F7) = 249.5 Hz,
2J (C7,F6) = 17.3 Hz, 2J (C7,F8) = 12.5 Hz, C7), 137.8 (ddd, 1J (C6,F6) =
249.2 Hz, 2J (C6,F7) = 12.6 Hz, C6), 124.4 (d, 2J (C8a,F8) = 11.4 Hz, C8a),
113.5 (d, C3), 111.9 (m, 3J (C4a,F6) = 7.9 Hz, C4a), 105.1 (dd, 2J (C5,F6)
= 19.7 Hz, C5), 30.4 (s, C9), 23.0 (s, C10), 22.4 (s, C11), 14.0 (s, C12). 19
F
NMR (282 MHz, DMSO-d6): δ = –143.1 (dd, J (F6,F7) = 22.5 Hz, J (F6,
H5) = 11.4 Hz, 1 F, F6), –149.9 (dd, J (F8,F7) = 19.6 Hz, 1 F, F8), –157.7
(ddd, J (F7,F6) = 22.5 Hz, J (F7,F8) = 19.6 Hz, J (F7,H5) = 7.9 Hz, 1 F,
F7). HRMS (EI): m/z [M]+ calcd for C13H12F3NO2: 271.08153; found:
271.0813.
4.2.5.9. 3-Butyl-5,6,7,8-tetrafluoro-4-hydroxyquinolin-2(1 H)-one (2i).
White solid; yield: 72 mg (25%); mp 180.3 ◦C (decomp.). IR (KBr):
3346, 3136, 2960, 2933, 2862, 1666, 1618, 1591, 1523, 1498, 1452,
1423, 1383, 1292, 1253, 1213, 1180, 1130, 1039, 982, 816, 710, 629
cm–1. 1H NMR (300 MHz, DMSO-d6 + Acetone-d6): δ = 11.56 (br s, 1 H,
H1), 2.53 (t, J (H9,H10) = 7.1 Hz, 2 H, H9), 1.39 – 1.27 (m, 4 H, 2 H10 + 2
H11), 0.87 (t, J (H12,H11) = 7.1 Hz, 3 H, H12). 13C NMR (125 MHz,
DMSO-d6 + Acetone-d6): δ = 162.8 (s, C2), 156.6 (m, C4), 143.3 (ddm, 1J
(C5,F5) = 254.1 Hz, 2J (C5,F6) = 10.7 Hz, C5), 139.7 (dtm, 1J (C7,F7) =
246.7 Hz, 2J (C7,F6) ≈ 2J (C7,F8) = 12 Hz, C7), 134.5 (dtm, 1J (C6,F6) =
241.2 Hz, 2J (C6,F5) ≈ 2J (C6,F7) = 16 Hz, C6), 133.9 (ddm, 1J (C8,F8) =
244.6 Hz, 2J (C8,F7) = 10 Hz, C8), 124.1 (dm, 2J (C8a,F8) = 10.3 Hz, C8a),
113.6 (s, C3), 103.1 (d, 2J (C4a,F5) = 8.0 Hz, C4a), 30.2 (s, C9), 22.6 (s,
4.2.5.6. 3-(4-Amino-2,5-difluorophenyl)-5,6,8-trifluoro-4-hydrox-
yquinolin-2(1 H)-one (2f). White solid; yield: 195 mg (57%); mp
302.7 ◦C (decomp.). IR (KBr): 3402, 3234, 2981, 2929, 1599, 1556,
1525, 1435, 1410, 1336, 1257, 1169, 1136, 1026, 999, 877, 841, 821,
767, 731, 677, 631, 600, 509, 447 cm–1. 1H NMR (300 MHz, DMSO-d6):
δ = 7.56 (m, J (H7,F6) ≈ J (H7,F8) = 10.8 Hz, J (H7,F5) = 6.9 Hz, 1 H,
H7), 6.82 (dd, J (H14,F13) = 12.2 Hz, J (H14,F10) = 6.5 Hz, 1 H, H14),
6.50 (dd, J (H11,F10) = 11.5 Hz, J (H11,F13) = 8.1 Hz, 1 H, H11). 13C NMR
C10), 22.3 (s, C11), 13.9 (s, C12). 19F NMR (282 MHz, DMSO-d6
+
Acetone-d6): δ = –146.0 (ddd, J (F5,F6) = 21.4 Hz, J (F5,F8) = 12 Hz, 1 F,
F5), –159.2 (t, J (F7,F6) ≈ J (F7,F8) = 22 Hz, 1 F, F7), –159.6 (ddd, J (F8,
F7) = 21.2 Hz, J (F8,F5) = 12 Hz, J (F8,F6) = 3.7 Hz, 1 F, F8), –171.2 (td,
J (F6,F7) ≈ J (F6,F5) = 21.7 Hz, J (F6,F8) = 3.7 Hz, 1 F, F6). HRMS (EI):
(125 MHz, DMSO-d6): δ = 173.5 (s, C4), 162.7 (s, C2), 157.6 (d, 1J (C10
,
1
F10) = 237.9 Hz, C10), 147.0 (d, J (C13,F13) = 231.8 Hz, C13), 144.1
(dm, 1J (C5,F5) ≈ 1J (C8,F8) ≈ 250 Hz, C5 + C8), 143.2 (dt, 1J (C6,F6) =
8

L. Politanskaya et al.
Journal of Fluorine Chemistry 242 (2021) 109720
m/z [M]+ calcd for C13H11F4NO2: 289.0720; found: 289.0717.
(b) E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N.A. Meanwell, Applications
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4.2.5.10. 5,8-Difluoro-4-hydroxy-3-phenyl-6-(phenylethynyl)quinolin-2
(1 H)-one (2 j). White solid; yield: 336 mg (90%); mp 276.6 – 277.2 ◦C.
IR (KBr): 3568, 3477, 3396, 3134, 2993, 2850, 2212, 1643, 1599, 1510,
1444, 1410, 1323, 1257, 1230, 1157, 1115, 1070, 1028, 978, 870, 771,
756, 717, 690, 625, 544, 528, 440 cm–1. 1H NMR (300 MHz, DMSO-d6 +
Acetone-d6): δ = 11.24 (br s, 1 H, H1), 7.16 (dd, J (H7,F8) = 10.3 Hz, J
(H7,F5) = 5.5 Hz, 1 H, H6), 7.09 – 7.07 (m, 2 H, Hm), 6.97 – 6.83 (m, 8 H,
(d) T. Fujiwara, D. O’Hagan, Successful fluorine-containing herbicide
agrochemicals, J. Fluorine Chem. 167 (2014) 16–29.
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aspects of fluorinated compounds, J. Med. Chem. 63 (2020) 6315–6386.
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P. Ovchinnikova, O.D. Zakharova, G.A. Nevinsky, An effective two-step synthesis,
fluorescent properties, antioxidant activity and cytotoxicity evaluation of benzene
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(2015) 142–153;
2 H’m + 2 Ho + 2 H’o + Hp + H’p). 13C NMR (125 MHz, DMSO-d6
+
Acetone-d6): δ = 162.2 (s, C2), 156.9 (m, C4), 155.7 (dm, 1J (C5,F5) =
258 Hz, C5), 144.7 (dm, 1J (C8,F8) = 242.1 Hz, C8), 132.6 (s, C9), 131.5
(s, C10), 131.3 (s, C11), 129.3 (s, C20), 129.0 (s, C18), 128.1 (s, C19), 127.5
(s, C12), 126.1 (s, C8a), 122.1 (s, C17), 118.0 (d, 2J (C7,F8) = 22.2 Hz, C7),
115.5 (s, C3), 107.4 (d, 2J (C4a,F5) = 9.6 Hz, C4a), 102.5 (dd, 2J (C6,F5) =
19.1 Hz, 3J (C6,F8) = 7.9 Hz, C6), 94.2 (d, 3J (C15,F5) = 4.5 Hz, C15), 82.0
(s, C16). 19F NMR (282 MHz, DMSO-d6 + Acetone-d6): δ = –113.6 (dd, J
(F5,F8) = 17.2 Hz, J (F5,H7) = 5.5 Hz, 1 F, F5), –134.7 (t, J (F8,H7) ≈ J
(F8,F5) ≈ 12 Hz, 1 F, F8). HRMS (EI): m/z [M]+ calcd for C23H13F2NO2:
373.0909; found: 373.0907.
(c) O. Zakharova, G. Nevinsky, L. Politanskaya, D. Baev, L. Ovchinnikova,
E. Tretyakov, Evaluation of antioxidant activity and cytotoxicity of polyfluorinated
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(2019), 109353;
(d) L. Politanskaya, T. Rybalova, O. Zakharova, G. Nevinsky, E. Tretyakov, p-
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evaluation of polyfluorinated 2-aryl-2,3-dihydroquinolin-4-ones and their
derivatives, J. Fluorine Chem. 211 (2018) 129–140;
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214 (2018) 48–57;
4.2.5.11. 6,7,8-Trifluoro-4-hydroxy-3-(2,3,5,6-tetrafluoro-4-methox-
yphenyl)quinolin-2(1 H)-one (2k). White solid; yield: 322 mg (82%); mp
278.0 ◦C (decomp.). IR (KBr): 3410, 3138, 2970, 2846, 1631, 1603,
1525, 1489, 1446, 1427, 1367, 1344, 1317, 1215, 1203, 1161, 1091,
1049, 1001, 985, 874, 829, 634, 615, 544, 472 cm–1. 1H NMR (400 MHz,
DMSO-d6): δ = 12.06 (br s, 1 H, H1), 7.80 (m, J (H5,F6) = 11 Hz, J (H5,
F7) = 8 Hz, 1 H, H5), 4.10 (s, 3 H, H15). 13C NMR (125 MHz, DMSO-d6):
δ = 161.1 (s, C2), 159.7 (s, C4), 145.2 (dm, 1J (C8,F8) ≈ 1J (C10,F10) ≈ 1J
(C14,F14) ≈ 243 Hz, C8 + C10 + C14), 141.0 (ddd, 1J (C7,F7) = 252.2 Hz,
2J (C7,F6) = 17.2 Hz, 2J (C7,F8) = 12.5 Hz, C7), 140.7 (ddt, 1J (C11,F11) =
(g) L. Politanskaya, N. Troshkova, E. Tretyakov, C. Xi, Synthesis of polyfluorinated
benzofurans, Journal of Fluorine Chemistry 227 (2019), 109371;
(h) L. Politanskaya, E. Tretyakov, C. Xi, Synthesis of polyfluorinated o-
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phenylchroman-4-ones, J. Fluorine Chem. 229 (2020), 109435;
(i) L. Politanskaya, E. Tretyakov, Directed synthesis of fluorine containing 2,3-
dihydrobenzo[b][1,4]oxathiine derivatives from polyfluoroarenes, J. Fluorine
Chem. 236 (2020), 109592.
[4] J. Wang, M. Sanchez-Rosello, J.L. Acen, C. del Pozo, A.E. Sorochinsky, S. Fustero,
V.A. Soloshonok, H. Liu, Fluorine in pharmaceutical industry: fluorine-containing
drugs introduced to the market in the last decade (2001ꢀ 2011), Chem. Rev. 114
(2014) 2432–2506.
2
2
1J (C13,F13) = 244.8 Hz, J (C11,F10) = J (C13,F14) = 15.8 Hz, C11
+
[5] P. Ball, Adverse drug reactions: implications for the development of
fluoroquinolones, J. Antimicrob. Chemoth. 51 (2003) 21–27, https://doi.org/
10.1093/jac/dkg209).
C13), 138.0 (ddm, 1J (C6,F6) = 246 Hz, 2J (C6,F7) = 13.3 Hz, C6), 137.8
(tm, 2J (C12,F13) ≈ 2J (C12,F11) = 12.9 Hz, C12), 126.1 (dm, 2J (C8a,F8) =
8.7 Hz, C8a), 111.0 (dm, 3J (C4a,F6) = 7 Hz, C4a), 106.1 (dd, 2J (C5,F6) =
19.9 Hz, C5), 106.0 (t, 2J (C9,F10) ≈ 2J (C9,F14) = 20 Hz, C9), 99.2 (s, C3),
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62.5 (t, C15). 19F NMR (282 MHz, DMSO-d6): δ = –140.4 (dm, J (F10,F11
)
= J (F14,F13) ≈ 23 Hz, 2 F, F10 + F14), –143.6 (dd, J (F6,F7) = 22.2 Hz, J
(F6,H5) = 10.9 Hz, 1 F, F6), –150.1 (d, J (F8,F7) = 19.8 Hz, 1 F, F8),
–155.9 (td, J (F7,F6) ≈ J (F7,F8) = 22.3 Hz, J (F7,H5) = 7.9 Hz, 1 F, F7),
–159.5 (dd, J (F11,F10) = J (F13,F14) ≈ 23 Hz, 2 F, F11 + F13). HRMS (EI):
m/z [M]+ calcd for C16H6F7NO3: 393.0230; found: 393.0235.
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Declaration of Competing Interest
[11] R.J. DeVita, M.T. Goulet, M.J. Wyvratt, M.H. Fisher, J.-L. Lo, Y.T. Yang, K. Cheng,
R.G. Smith, Investigation of the 4-O-alkylamine substituent of non-peptide
quinolone GnRH receptor antagonists, Bioorg. Med. Chem. Lett. 9 (1999)
2621–2624.
The authors report no declarations of interest.
Acknowledgements
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J. O’Malley, 3-Phenyl-4-hydroxyquinolin-2(lH)-ones: potent and selective
antagonists at the strychnine-insensitive glycine site on the N-methyl-d-aspartate
receptor complex, J. Med. Chem. 35 (1992) 3423–3425.
The authors thank the Russian Foundation for Basic Research (grant
◦
◦
19-53-53003) and NSFC (grant N 21911530097) for financial
[13] T. Fuchigami, T. Haradahira, N. Fujimoto, Y. Nojiri, T. Mukai, F. Yamamoto,
T. Okauchi, J. Maeda, K. Suzuki, T. Suhara, H. Yamaguchi, M. Ogawa, Y. Magata,
M. Maeda, Development of N-[11C]methylamino 4-hydroxy-2(1H)-quinolone
derivatives as PET radioligands for the glycine-binding site of NMDA receptors,
Bioorg. Med. Chem. 17 (2009) 5665–5675.
N
support and the Chemical Service Center SB RAS for spectral and
analytical measurements.
[14] M. Rowley, J.J. Kulagowski, A.P. Watt, D. Rathbone, G.I. Stevenson, R.W. Carling,
R. Baker, G.R. Marshall, J.A. Kemp, A.C. Foster, S. Grimwood, R. Hargreaves,
C. Hurley, K.L. Saywell, M.D. Tricklebank, P.D. Leeson, Effect of plasma protein
binding on in vivo activity and brain penetration of glycine/NMDA receptor
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Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.jfluchem.2020.109720
.
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