5-Трифлуорометоксизаміщена нікотинова кислота, нікотинамід і споріднені сполуки
A practical and convenient method for synthesizing nicotinic acid and nicotinamide with the trifluoromethoxy group in position 5 of the ring has been developed. A series of related compounds, for example, nicotinic aldehyde and nicotinic alcohol, have been synthesized. It has been shown that 3-bromo...
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| Опубліковано в: | Журнал органічної та фармацевтичної хімії |
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| Дата: | 2024 |
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| ISSN: | 2518-1548 |
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Репозитарії
Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874364473301532672 |
|---|---|
| author | Sokolenko, Taras M. Yagupolskii, Yurii L. |
| author_facet | Sokolenko, Taras M. Yagupolskii, Yurii L. |
| author_institution_txt_mv | [
{
"author": "Taras M. Sokolenko",
"institution": "Інститут органічної хімії Національної академії наук України",
"orcid": ""
},
{
"author": "Yurii L. Yagupolskii",
"institution": "Інститут органічної хімії Національної академії наук України; ТОВ НВП «Єнамін»",
"orcid": ""
}
] |
| author_sort | Sokolenko, Taras M. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 30 |
| container_issue | 1 |
| container_start_page | 22 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 22 |
| datestamp_date | 2026-08-23T16:38:16Z |
| description | A practical and convenient method for synthesizing nicotinic acid and nicotinamide with the trifluoromethoxy group in position 5 of the ring has been developed. A series of related compounds, for example, nicotinic aldehyde and nicotinic alcohol, have been synthesized. It has been shown that 3-bromo-5-trifluoromethoxypyridine is a convenient and efficient synthon for palladium-catalyzed coupling reactions. The trifluoromethoxy group has been found to be remarkably stable against hydroiodic acid in contrast to the methoxy group. |
| doi_str_mv | 10.24959/ophcj.24.302435 |
| first_indexed | 2025-07-23T04:43:28Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 22
Original Research
http://ophcj.nuph.edu.ua
UDC 547.821.2+542.06
T. M. Sokolenko1, Yu. L. Yagupolskii1,2
1 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Academician Kukhar str., 02660 Kyiv, Ukraine
2 Enamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine
5-Trifluoromethoxy-substituted Nicotinic Acid, Nicotinamide
and Related Compounds
Abstract
A practical and convenient method for synthesizing nicotinic acid and nicotinamide with the trifluoromethoxy group in posi-
tion 5 of the ring has been developed. A series of related compounds, for example, nicotinic aldehyde and nicotinic alcohol,
have been synthesized. It has been shown that 3-bromo-5-trifluoromethoxypyridine is a convenient and efficient synthon for
palladium-catalyzed coupling reactions. The trifluoromethoxy group has been found to be remarkably stable against hydroi-
odic acid in contrast to the methoxy group.
Keywords: nicotinic acid; nicotinamide; trifluoromethoxy group; antimony trifluoride; fluorination
Т. М. Соколенко1, Ю. Л. Ягупольський1,2
1 Інститут органічної хімії Національної академії наук України,
вул. Академіка Кухаря, 5, м. Київ, 02660, Україна
2 ТОВ НВП «Єнамін», вул. Вінстона Черчилля, 78, м. Київ, 02094, Україна
5-Трифлуорометоксизаміщена нікотинова кислота, нікотинамід і споріднені сполуки
Анотація
Розроблено практичний і зручний метод синтезу нікотинової кислоти та нікотинаміду з трифлуорометоксигрупою
в положенні 5 кільця. Було синтезовано деякі споріднені сполуки, наприклад, нікотиновий альдегід і нікотиновий
спирт. З’ясовано, що 3-бромо-5-трифлуорометоксипіридин є зручним синтоном для каталізованих паладієм реакцій
сполучення. Визначено, що, на відміну від метоксигрупи, трифлуорометоксигрупа є надзвичайно стійка до дії йодо-
водневої кислоти.
Ключові слова: нікотинова кислота; нікотинамід; трифлуорометоксигрупа; стибій трифлуорид; флуорування
Citation: Sokolenko, T. M.; Yagupolskii, Yu. L. 5-Trifluoromethoxy-substituted Nicotinic Acid, Nicotinamide and Related Compounds.
Journal of Organic and Pharmaceutical Chemistry 2024, 22 (1), 22 – 30.
https://doi.org/10.24959/ophcj.24.302435
Supporting information: Copies of 1H, 13C and 19F NMR spectra of the synthesized compounds.
Received: 24 February 2024; Revised: 11 March 2024; Accepted: 15 March 2024
Copyright© 2024, T. M. Sokolenko, Yu. L. Yagupolskii. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0).
Funding: The authors received no specific funding for this work.
Conflict of interests: The authors have no conflict of interests to declare.
■ Introduction
A fluorine atom has a privileged position
within the halogen family for drugs and agro-
chemicals design due to its unique properties –
small size, high electronegativity, and the ability
to form a strong C-F bond. In 2020, about 20 % of
the commercial pharmaceuticals were fluorine-
containing drugs, and their total quantity was
340 compounds. Commonly, they were fluoro-
substituted arenes (167 compounds) or hetero-
cycles (20 compounds), as well as trifluorometh-
ylated arenes and heteroarenes (64 compounds).
Fluorinated ethers were an important group of
pharmaceuticals represented by 18 compounds,
among them four were trifluoromethoxylated are-
nes, namely riluzole (treatment of amyotrophic
lateral sclerosis), pretomanid and delamanid
(treatment of tuberculosis), and sonidegib (treat-
ment of basal cell carcinoma) [1].
ISSN 2308-8303 (Print) / 2518-1548 (Online) 23
Journal of Organic and Pharmaceutical Chemistry 2024, 22 (1)
Nitrogen-containing heterocycles are the most
popular compounds for drug design. At least 85 % of
pharmaceuticals contain such a fragment in their
structure. Therefore, it seems unexpected that a
small number of drugs with a fluorine-containing
heterocyclic ring is known (42 compounds). More-
over, only single fluorine atom or the trifluoro-
methyl group represent fluorinated substituents
[1]. Such circumstances can be explained by the
absence of practical and cheap synthetic ways to
heterocycles with other fluorinated groups, in par-
ticular fluorinated ethers [2]. Methodologies for
the synthesis of fluorinated ethers are signifi-
cantly different from methods for the prepara-
tion of alkyl ethers. It is impossible to use tri-
fluoromethyl iodide or trifluoromethyl triflate for
direct trifluoromethylation of oxygen nucleophi-
les in the same way as methyl iodide or methyl
triflate. This is due to the strong electronegati-
vity of a fluorine atom that results in reverse po-
larity of I-CF3 and TfO-CF3 bonds as compared
to I-CH3 and TfO-CH3 [2, 3]. A few different stra-
tegies can be applied for the preparation of fluo-
rinated ethers. The first method was based on
the ether fluorination. It was incorporated into
organic chemistry by Lev Yagupolskii in 1955 [4].
The main limitation of this method is the harsh
conditions of the fluorination stage. Neverthe-
less, this approach was successfully applied to
the synthesis of trifluromethoxy substituted he-
terocycles [5 – 7]. Pyridines with the trifluoro-
methoxy group in various positions of the ring –
α-, β- and γ-substituted pyridines – were obtained
by this method. However, this reaction success-
fully occurred only when at least one α-position of
the ring was occupied by a chlorine atom. The same
feature was also found to be characteristic for
pyrazine derivatives [7]. The second approach to
trifluoromethoxylated heterocycles is the cycli-
zation of the fluorinated precursors [8, 9]. A novel
route to trifluoromethoxy substituted heterocy-
cles is based on trifluorometylation of the hy-
droxyl group by the action of hypervalent iodine
reagents or direct trifluoromethoxylation [10].
Although the examples of direct trifluoromethoxy-
lation are known from the literature [11], these
methods are promising for preparing the α-substi-
tuted pyridine ring mainly, at the same time, the
synthesis of β-trifluormethoxipyridine in such a
manner is controversial. Direct introduction
of the trifluoromethoxy group occurred under
more mild reaction conditions than fluorination.
Therefore, it can be applied to a wide range of
substrates. From the other hand, these methods
require expensive reagents that are used in a large
excess.
It can be summarized that each of the above-
mentioned strategies – fluorination of ethers, nuc-
leophilic substitution or direct trifluoromethxy-
lation of hydroxy-compounds – requires some im-
provements before it becomes a practical method.
In the current study, we concentrated our atten-
tion on the scalable synthesis of nicotinic acid
and related compounds with the trifluorometh-
oxy group in position 5.
■ Results and discussion
A series of trifluoromethoxysubstituted pyri-
dines was prepared earlier [6]. The method used
in this paper was based on chlorination-fluori-
nation techniques that allowed to obtain a se-
ries of α-chloropyridines with the OCF3-group in
various positions. These compounds were used
for the preparation of pyridines with different
functional groups: amines, aldehydes, acids, si-
lanes, etc. However, 5-trifluoromethoxy substi-
tuted nicotinic acid or any suitable precursors
for its preparation were not described in this
research.
Key compounds for the synthesis of nicotinic
acid 4 and nicotinamide 5 with trifluoromethoxy
substituent are shown in Scheme 1. We found
that transformation of 5-hydroxynicotinic acid 7
(or its methyl ester) into the corresponding chlo-
rothionoformate or methylxanthate with further
chlorination-fluorination gave no positive results
(route 1). Similarly, our attempts to transform
bromopyridinol 6 to 3-bromo-5-trifluoromethoxy-
pyridine in such a manner failed, despite such
transformation was well documented for pyridi-
nes with halogen atoms in α-position (route 2) [5,
6]. Taking into account this feature of the pyri-
dine ring, α-chloro-substituted pyridines 1 and
2 were used as starting compounds (Scheme 1,
route 3).
We tried to prepare pyridines 10 and 11 ac-
cording to [6] and found that this procedure was
suitable for trichloromethoxysubstituted pyri-
dine 10, but gave poor results for pyridine 11.
Modifications of the method (reversed mixing of
the reagents) allowed us to increase the yield of
11 from 15 to 78 % (Scheme 2). It should be not-
ed that chlorothionoformates 8 and 9 were used
for further transformations without isolation in
a pure state. Thus, the methodology proposed is
very attractive in terms of handling such toxic
compounds. Further fluorination of 10 and 11 by
ISSN 2308-8303 (Print) / 2518-1548 (Online) 24
Журнал органічної та фармацевтичної хімії 2024, 22 (1)
antimony trifluoride led to trifluoromethoxysub-
stituted pyridines 12 and 13, respectively, in high
yields.
For hydrodechlorination reaction of 12 and
13, we used “red phosphorus / HI” as a reducing
agent, and 3-bromo-5-trifluoromethoxypyridine
(3) was prepared in a high yield. It is notewor-
thy that the reaction can be performed in a 50 g
scale. It is worth mentioning that this reaction
required the use of hydroiodic acid as a solvent.
However, in contrast to the methoxy group that
easily cleaves under these conditions (Zeisel
determination of ethers [12]), trifluoromethoxy
one remains intact even after prolonged heat-
ing. No evidence of this group destruction was
found in 19F NMR spectra of the reaction mix-
ture. Thus, both isomers 12 and 13 were suc-
cessfully transformed into 3 in the same yields.
With this in mind, we also used the mixture of
chloropyridines 1 and 2 for preparing pyridine 3.
This mixture can be easily obtained by chlorina-
tion of 5-bromopyridin-3-ol (6) with sodium hy-
pochlorite [13] and, as a result, is more avail-
able than individual isomers 1, 2.
We have found that 3-bromo-5-trifluorometh-
oxypyridine (3) is a convenient starting material
for a wide range of 5-trifluoromethoxysubstitut-
ed pyridines (Scheme 3). Bromopyridine 3 can
be readily lithiated by the action of n-buthyllith-
ium, and after the treatment with carbon diox-
ide, nicotinic acid 4 was formed in almost quan-
titative yield. This acid was used for preparing
5-trifluoromethoxynicotinamide (5) by common
methods with a high yield. Lithiated pyridine 3
readily reacted with ethyl formate yielding nico-
tinic aldehyde 14. This aldehyde was reduced to
alcohol 15 with a high yield.
Bromopyridine 3 was also used in palladium-
catalyzed cross-coupling reactions. Bromine was
substituted with boronic ester under Pd(dppf)Cl2
N
OHBr
N
OHBr
N
O F
F
F
H2N
O
N
OH
HO
O
N
O F
F
F
HO
O
N
O F
F
F
Br
Cl
1 2: 2-Cl; : 6-Cl 3 4 5
6 7
12
3
Scheme 1. Potential routes to 5-(trifluoromethoxy)nicotinic acid and nicotinamide
N
OBr
R6 R2
1, 8, 10, 12: R2 = Cl, R6 = H; R2, 9, 11, 13:
2 = H, R6 = Cl
N
O F
F
F
Br
N
OHBr
R6 R2
Cl
S
N
O Cl
Cl
Cl
Br
R6 R2 N
O F
F
F
Br
R6 R2
38, 9 10, 11 12, 131, 2
a b c d
Scheme 2. The synthesis of 3-bromo-5-(trifluoromethoxy)pyridine (3)
Reagents and conditions: (a) CSCl2, NaOH, CHCl3/H2O, 0 °C; (b) Cl2, CHCl3, r.t.; (c) SbF3, SbCl5, 145 – 150 °C; (d) P, aq 57 % HI, reflux
N
O F
F
F
N
O F
F
F
H2N
N
O F
F
F
B
N
O F
F
F
Br
H
O
N
O F
F
F
HO
O
O
O
N
O F
F
F
HO
N
O F
F
F
H2N
O
3
4 51415
16 17
a bcd
e f
N
O F
F
FH
NO
BuOt-
g
17a
Scheme 3. The reactivity of 3-bromo-5-(trifluoromethoxy)pyridine
Reagents and conditions: (a) nBuLi, -90 °C, then CO2, 85 % yield; (b) SOCl2, 70 °C, then NH4OH, 0 °C, 85 % yield; (c) nBuLi, -90 °C,
then EtOCHO, 64 % yield; (d) NaBH4, EtOH, r.t., then aq HCl, r.t., 89 % yield; (e) B2pin2, Pd(dppf)Cl2, KOAc, dioxane, 100 °C, 80 % yield;
(f) tBuOCONH2, Pd2dba3, Xantphos, Cs2CO3, dioxane, 100 °C, 69 % yield; (g) CF3COOH, CH2Cl2, r.t., 72 % yield
ISSN 2308-8303 (Print) / 2518-1548 (Online) 25
Journal of Organic and Pharmaceutical Chemistry 2024, 22 (1)
catalysis to form pyridine 16. Compound 3 readily
reacted with tert-butyl carbamate under Pd2dba3
catalysis yielding Boc-protected amine 17a. After
deprotection, aminopyridine 17 was obtained in
50 % yield in two steps.
Alternatively, we investigated the metalation
of chloro-substituted pyridine 13 using n-butyl-
lithium (Scheme 4). We found that a mixture of
nicotinic and isonicotinic acids was formed af-
ter treating lithium derivatives with carbon di-
oxide. If the reaction mixture was saturated by
gaseous CO2 at -95 – -100°C, a mixture of acids
18 – 19 (1:1) was obtained. When lithiated pyri-
dine was poured onto solid carbon dioxide (-78 °C),
the main product was isonicotinic acid 18 (5:1).
We supposed that the rearrangement of the ini-
tially formed 3-lithium isomer into 4-isomer oc-
curred at temperatures higher than -78 °C due
to a strong α‑effect of the OCF3 group.
In contrast to nicotinic acids 18 and 19, nico-
tinic aldehyde 20 was formed selectively and ob-
tained in a high yield of 79 % by the reaction of
3-bromo-2-chloro-5-trifluoromethoxypyridine (13)
with n-butyllithium and further treatment with
DMF. In this case isomerization did not occur,
probably because the interaction of lithiated py-
ridine with DMF proceeded faster than with car-
bon dioxide.
It was shown that this aldehyde 20 could be
reduced to alcohol 21 by sodium borohydride or
oxidized by potassium permanganate yielding
nicotinic acid 19. In both cases, the target pro-
ducts were obtained in almost quantitative yields.
2-Chloronicotinic acid 19 was used for prepar-
ing 5-trifluoromethoxynicotinic acid (4). A chlo-
rine atom was reduced by Pd catalysed hydro-
genation. This reaction occurred at atmospheric
pressure, and the product was obtained in a high
yield.
■ Conclusion
A synthetic approach based on chlorination-
fluorination of the chlorothionoformate group in
the pyridine core is a convenient and practical
route for trifluoromethoxylated pyridines. The pre-
sence of a chlorine atom in α-position of pyridi-
ne (either 2 or 6) is necessary for successful trans-
formation, and in both cases 2- or 6-chloro-3-bro-
mo-5-trifluoromethoxysubstituted pyridines are
obtained in high yields. In contrast to methoxy
group, the trifluoromethoxy one is stable to the
hydroiodic acid action. This remarkable property
of the trifluoromethoxy group allows to reduce a
chlorine atom in α-position of the pyridine ring
selectively without destruction of the OCF3 group
and reduction of a bromine atom in β-position of
the ring. 3-Bromo-5-trifluoromethoxy pyridine is
a promising building block demonstrated by me-
talation reactions and Pd-catalyzed syntheses.
Using this precursor, analogues of natural prod-
ucts– nicotinic acid and nicotinamide with trif-
luoromethoxy group have been synthesized.
■ Experimental part
1H NMR spectra were recorded using a Var-
ian VXR-300 instrument at 300 MHz, a Bruker
AVANCE DRX 500 spectrometer at 500 MHz, or
a Varian UNITY-Plus 400 instrument at 400 MHz.
13C NMR spectra (proton decoupled) were recor-
ded on a Bruker AVANCE DRX 500 instru-
ment at 125 MHz, or a Varian UNITY-Plus 400
spectrometer at 100 MHz, or a Varian VXR-300
N
O F
F
F
H
O
N
O F
F
F
N
O F
F
F
HO
N
O F
F
F
HO
O
Cl N
O F
F
F
HO
O
Cl
HO O
Cl Cl
+
18 19
20 21
4
a
b c
d
e
N
O F
F
F
HO
O
Cl
19
N
O F
F
F
Br
Cl
13
Scheme 4. The synthetic potential of 3-bromo-2-chloro-5-trifluoromethoxypyridine
Reagents and conditions: (a) nBuLi, -90 °C, then CO2; (b) nBuLi, -90 °C, then DMF, 79 % yield; (c) NaBH4, EtOH, r.t., then HCl aq, r.t.,
94 % yield; (d) KMnO4, H2O, 60 °C, 80 % yield; (e) H2, 10 % Pd/C, HCOONH4, MeOH, r.t., 79 % yield
ISSN 2308-8303 (Print) / 2518-1548 (Online) 26
Журнал органічної та фармацевтичної хімії 2024, 22 (1)
instrument at 75 MHz. 19F NMR spectra were re-
corded at 376 MHz using a Varian UNITY-Plus
400 spectrometer or at 188 MHz using a Mercury
VX 200 Varian instrument. The chemical shifts
are given in ppm relative to TMS and CCl3F,
respectively, as internal or external standards.
The LC-MS spectra were registered on an Agi-
lent 1100 instrument with a diode-matrix and
an Agilent 1100 LS/MSD SL mass-selective de-
tector. The GC-MS spectra were registered on a
Hewlett-Packard HP GC/MS 5890/5972 instru-
ment (EI 70 eV). The melting points were deter-
mined in open capillaries using an SMP3 instru-
ment. The elemental analysis was performed in
the Analytical Laboratory of the Institute of Orga-
nic Chemistry of mass-selective detector NASU.
For the column chromatography, Merck Kie-
selgel 60 silica gel was used. Thin-layer chroma-
tography (TLC) was carried out on aluminium-
backed plates coated with silica gel (Merck Kie-
selgel 60 F254).
Unless otherwise stated, commercially avail-
able reagents were purchased from Enamine Ltd.
(Kyiv, Ukraine) and were used without purifica-
tion. The solvents were purified according to the
standard procedures. Antimony trifluoride was
sublimed immediately prior to use. Chlorination
of 5-bromopyridin-3-ol with sodium hypochlorite
was performed according to [13]. Pure 5-bromo-
2-chloro-pyridin-3-ol (M. p. 188 °C) was obtained by
SiO2 column chromatography with the mixture
of hexane/ethyl acetate (1:4) as an eluent (Rf 0.5).
Trichloromethoxypyridines (10) and (11).
The general procedure
Method A. The solution of thiophosgene
(41.4 g, 0.36 mol) in 300 mL of chloroform was
added dropwise to the vigorously stirred mixtu-
re of hydroxypyridine 1 or 2 (75 g, 0.36 mol) and
sodium hydroxide (15.1 g, 0.38 mol) in 300 mL
of water at 0 °C, and the mixture was stirred for
2 h at the same temperature. The organic layer
was separated, washed with water, and dried over
MgSO4. Prepared in such a manner the chloro-
form solution of chlorothionoformate was satu-
rated with chlorine and stirred for 48 h at room
temperature. The excess of chlorine was then re-
moved with N2 gas stream. The solvent was dis-
tilled off under reduced pressure (300 mbar), and
the residue was distilled in a vacuum yielding the
corresponding trichlorometoxypyridine 10 or 11.
Method B. Sodium hydroxide (15.8 g, 0.40 mol)
in 300 mL of water was added dropwise to the
vigorously stirred mixture of hydroxypyridine 1
or 2 (75 g, 0.36 mol) and thiophosgene (41.4 g,
0.36 mol) in chloroform at 0°C, and the mixture
was stirred for 2 h at the same temperature. The or-
ganic layer was separated, washed with water,
and dried over MgSO4. Prepared in such a man-
ner the chloroform solution of chlorothionoforma-
te was saturated with chlorine and stirred for
48 h at room temperature. The excess of chlo-
rine was removed with N2 gas stream. The sol-
vent was distilled off under reduced pressure
(300 mbar), and the residue was distilled in a va-
cuum yielding the corresponding trichlorometoxy-
pyridine 10 or 11.
5-Bromo-2-chloro-3-trichloromethoxypyridi-
ne (10)
A colorless oil or a low melted solid. Yield –
64.5 g, 55 % (Method A); 72.7 g, 62 % (Method B).
B. p. 115 – 117 °C at 0.5 mbar; M. p. 32 °C. Anal.
Calcd for C6H2BrCl4NO, %: C 22.12, H 0.62, N
4.30. Found, %: C 21.97, H 0.85, N 4.08. 1H NMR
(400 MHz, CDCl3), δ, ppm: 8.15 (1H, d, 3JHH = 2.4 Hz,
4-PyH), 8.41 (1H, d, 3JHH = 2.4 Hz, 6-PyH). 13C NMR
(100 MHz, CDCl3), δ, ppm: 111.5, 117.8, 132.7,
143.7, 144.7, 147.5.
3-Bromo-2-chloro-5-trichloromethoxypyridi-
ne (11)
A colorless oil or a low melted solid. B. p.
120 – 122 °C at 0.5 mbar; M. p. 45 °C. Yield – 17.7 g,
15 % (Method A); 91.5 g, 78 % (Method B). Anal.
Calcd for C6H2BrCl4NO, %: C 22.12, H 0.62,
N 4.30. Found, %: C 22.01, H 0.80, N 4.12. 1H NMR
(400 MHz, CDCl3), δ, ppm: 8.02 (1H, d, 3JHH = 2.4 Hz,
4-PyH), 8.43 (1H, d, 3JHH = 2.4 Hz, 6-PyH). 13C NMR
(100 MHz, CDCl3), δ, ppm: 112.1, 119.9, 136.3,
142.2, 147.0, 149.0.
Trifluoromethoxypyridines (12) and (13).
The general procedure
The corresponding trichloromethoxypyridine
10 or 11 (81.5 g, 0.25 mol) was added in portions
to the mixture of SbF3 (134 g, 0.75 mol) and SbCl5
(7.5 g, 0.025 mol) at 100 °C. The mixture was stir-
red for 5 h at 145 – 150 °C, cooled to room tempe-
rature, mixed with 650 mL of CH2Cl2, and then
quenched with an aqueous solution of K2CO3
(517 g, 3.75 mol in 2.5 L of water) and KF (653 g,
11.25 mol in 1.25 L of water). The precipitate was
filtered off, the organic layer was separated, wash-
ed with water, and dried with MgSO4. The sol-
vent was distilled off, and the residue was dis-
tilled in a vacuum yielding the corresponding
trifluorometoxypyridine 12 or 13.
5-Bromo-2-chloro-3-trifluoromethoxypyridi-
ne (12)
A colorless oil. Yield – 58.1 g (84 %). B. p. 90 – 92 °C
at 20 mbar. Anal. Calcd for C6H2BrClF3NO, %:
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (1)
C 26.07, H 0.73, Cl 12.82. Found, %: C 25.88,
H 0.50, Cl 13.04. 1H NMR (400 MHz, CDCl3), δ,
ppm: 7.78 (1H, s, 4-PyH), 8.41 (1H, s, 6-PyH).
13C NMR (100 MHz, CDCl3), δ, ppm: 118.6, 120.3
(q, 2JCF = 262.5 Hz, OCF3), 133.1, 142.0, 143.5,
148.4. 19F NMR (300 MHz, CDCl3), δ, ppm:
-57.55 (s, OCF3). GC-MS, m/z (Irel, %): 277 (100)
[M(79Br37Cl)/(81Br35Cl)]+, 275 (79) [M(79Br35Cl)]+,
279 (24) [M(81Br37Cl)]+.
3-Bromo-2-chloro-5-trifluoromethoxypyridi-
ne (13)
A colorless oil. Yield – 63.1 g (91 %). B. p. –
105 – 107 °C at 20 mbar. Anal. Calcd for
C6H2BrClF3NO, %: C 26.07, H 0.73, Cl 12.82.
Found, %: C 25.80, H 0.55, Cl 12.49. 1H NMR
(300 MHz, CDCl3), δ, ppm: 7.86 (1H, dd, 3JHH =
2.4 Hz, 4JHF = 1.8 Hz, 4-PyH), 8.32 (1H, dd, 3JHH =
2.4 Hz, 4JHF = 1.8 Hz, 6-PyH). 13C NMR (100 MHz,
CDCl3), δ, ppm: 120.2 (q, 1JCF = 260.5 Hz, OCF3),
120.3, 134.6, 140.7, 144.4, 148.9. 19F NMR (300 MHz,
CDCl3), δ, ppm: -58.93 (s, OCF3). GC-MS, m/z (Irel,
%): 277 (100) [M(79Br37Cl)/(81Br35Cl)]+, 275 (79)
[M(79Br35Cl)]+, 279 (24) [M(81Br37Cl)]+.
The synthesis of 3-bromo-5-trifluoro-
methoxypyridine (3)
The mixture of 3-bromo-2-chloro-5-trifluoro-
methoxypyridine (13) (63.0 g, 0.23 mol) and
red phosphorus (85.0 g, 2.75 mol) in 1 L of 57 %
aqueous HI was refluxed for 48 h. The progress
of the reaction was monitored by 19F NMR spec-
tra. The excess of phosphorus was filtered off
via a glass filter, and the resulting solution was
poured into the solution of Na2CO3 (400 g, 3.8 mol)
in 2.5 L of water. The product was extracted with
CH2Cl2 (6×400 mL), the extract obtained was
washed with water (3×250 mL), and dried with
MgSO4. The solvent was distilled off, and the
residue was distilled in a vacuum yielding pyri-
dine 3 (50.2 g, 90 %).
5-Bromo-2-chloro-3-trifluoromethoxypyridi-
ne (12) (63 g, 0.23 mol) was used for preparing
pyridine 3 (46.2 g, 83 %) by the same procedure.
When the mixture of chlorinated pyridines 12
and 13 in the ratio of 4:1 (50 g, 0.18 mol) was
used for this reaction, bromopyridine 3 was ob-
tained in 83 % yield (36.3 g).
A colorless oil. B. p. 100 – 105 °C at 70 mbar.
Anal. Calcd for C6H3BrF3NO, %: C 29.78, H 1.25,
Br 33.02. Found, %: C 29.88, H 1.53, Br 32.85.
1H NMR (400 MHz, CDCl3), δ, ppm: 7.73 (1H, s,
4-PyH), 8.48 (1H, s, 2/6-PyH), 8.63 (1H, s, 2/6-PyH).
13C NMR (75 MHz, CDCl3), δ, ppm: 120.3 (q, 1JCF
= 260.7 Hz, OCF3), 120.4, 131.4, 141.1, 145.9,
149.4. 19F NMR (300 MHz, CDCl3), δ, ppm:
‑58.74 (s, OCF3). GC-MS, m/z (Irel, %): 241 (100)
[M(79Br)]+, 243 (98) [M(81Br)]+.
The preparation of 5-trifluoromethoxy-
nicotinic acid (4) from bromopyridine (3)
n-Butyllithium (2.5 M solution in hexane, 7 mL,
17.4 mmol) was added to 25 mL of vigorously stir-
red toluene at -70 – -65 °C. After the addition was
completed, bromopyridine 3 (4 g, 16.5 mmol) was
added at the same temperature, and the mixture
was stirred for additional 30 min. Then the mix-
ture was cooled to -85 – -90 °C, and 12 mL of THF
were added. The reaction mixture was stirred for
15 min, then poured into crushed dry ice (ca. 15 g).
The product was extracted with aqueous sodium
hydroxide solution (2 g, 50 mmol in 40 mL of wa-
ter), washed with MTBE, and acidified with 3 %
aqueous hydrochloric acid to pH 5.5. The precipi-
tate was filtered and crystallized (water/ethanol
5-to-1 mixture) yielding nicotinic acid 4 (2.9 g, 85 %).
The preparation of 5-trifluoromethoxy-
nicotinic acid (4) from 2-chloro-5-(trifluo-
romethoxy)nicotinic acid (19)
The mixture of 2-chloronicotinic acid 19 (0.5 g,
2 mmol), ammonium formate (0.2 g, 3 mmol) and
10 % Pd on charcoal (0.2 g) in methanol (10 mL)
was stirred in hydrogen atmosphere for 24 h.
The mixture was filtered, the solvent was evap-
orated in a vacuum, and the residue was diluted
with 3 % hydrochloric acid and extracted with
ethyl acetate. The organic solution was dried
with MgSO4, evaporated in a vacuum yielding
nicotinic acid 4 (0.33 g, 79 %).
5-Trifluoromethoxynicotinic acid (4)
A colorless powder. M. p. 148 – 149 °C. Anal.
Calcd for C7H4F3NO3, %: C 40.60, H 1.95. Found,
%: C 40.48, H 2.13. 1H NMR (500 MHz, DMSO-d6),
δ, ppm: 8.19 (1H, s, 4-PyH), 8.90 (1H, s, 2/6-PyH),
9.08 (1H, s, 2/6-PyH). 13C NMR (125 MHz,
DMSO-d6), δ, ppm: 120.4 (q, 1JCF = 257.7 Hz,
OCF3), 128.6, 129.4, 145.5, 146.8, 149.4, 165.3.
19F NMR (470 MHz, DMSO-d6), δ, ppm: -58.38
(s, OCF3). LC-MS, m/z (CI): 207 [M]+.
The synthesis of 5-(trifluoromethoxy)ni-
cotinamide (5)
Nicotinic acid 4 (1 g, 4.8 mmol) was added in
portions to thionyl chloride (2.9 g, 24 mmol) at
0 °C. The mixture was stirred at 70 °C for 2 h
until the evolution of gas was completed. The ex-
cess of thionyl chloride was distilled off in a va-
cuum, and the residue was dissolved in MTBE
(10 mL). A concentrated aqueous solution of am-
monia (2 mL) was added dropwise to the solution
at 0 °C, and the precipitate formed was filtered
and dried in a vacuum.
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Журнал органічної та фармацевтичної хімії 2024, 22 (1)
A colorless powder. Yield – 0.85 g (85 %). M. p.
147 – 148 °C. Anal. Calcd for C7H5F3N2O2, %: C
40.79, H 2.45, N 13.59. Found, %: C 40.60, H 2.55,
N 13.70. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
7.82 (1H, s, NH2), 8.22 (1H, s, 4-PyH), 8.32 (1H,
s, NH2), 8.83 (1H, s, 2/6-PyH), 9.07 (1H, s, 2/6-
PyH). 13C NMR (125 MHz, DMSO-d6), δ, ppm:
120.4 (q, 1JCF = 257.7 Hz, OCF3), 128.6, 129.4,
145.5, 146.8, 149.4, 165.3. 19F NMR (376 MHz,
DMSO-d6), δ, ppm: -57.68 (s, OCF3). LC-MS, m/z
(CI): 207 [M+H]+.
The procedure for 5-trifluoromethoxy-
nicotinaldehyde (14)
n-Butyllithium (2.5 M solution in hexane, 7 mL,
17.4 mmol) was added to 25 mL of vigorously stir-
red toluene at -70 – -65 °C. After the addition was
completed, the solution of bromopyridine 3 (4 g,
16.5 mmol) in toluene (10 mL) was added to the
mixture at the same temperature, and the mix-
ture was stirred for further 30 min. The reaction
mixture was cooled to -85 – -90 °C, 12 mL of THF
was added, the reaction mixture was stirred for
15 min, ethyl formate (1.5 g, 20 mmol) was add-
ed dropwise at the same temperature. After the
addition was completed, the mixture was warm-
ed to -10 °C, and the solution of NaHSO4 (4 g,
33 mmol) in 10 mL of water was added. The pro-
duct was extracted with MTBE, the extract ob-
tained was washed with a brine, and dried with
MgSO4. The solvent was distilled off, and the
residue was distilled in a vacuum yielding nico-
tinic aldehyde 14 as a colorless oil.
Yield – 2 g (64 %). B. p. 50 – 52 °C at 0.5 mbar.
Anal. Calcd for C7H4F3NO2, %: C 43.99, H 2.11, N
7.33. Found, %: C 42.71, H 2.35, N 7.12. 1H NMR
(300 MHz, CDCl3), δ, ppm: 8.01 (1H, s, 4-PyH),
8.77 (1H, s, 6-PyH), 9.02 (1H, s, 2-PyH), 10.15
(1H, s, CHO). 13C NMR (100 MHz, CDCl3), δ, ppm:
120.3 (q, 2JCF = 260.5 Hz, OCF3), 126.7, 132.3,
146.5, 147.9, 149.9, 189.0. 19F NMR (188 MHz,
CDCl3), δ, ppm: -58.38 (s, OCF3). GC-MS, m/z
(Irel, %): 191 (100) [M]+.
The preparation of 5-trifluoromethoxy-
pyridin-3-yl-methanol (15)
Sodium borohydride (0.6 g, 15 mmol) was add-
ed to the solution of 5‑(trifluoromethoxy)nicoti-
naldehyde (14) (1 g, 5 mmol) in ethanol (30 mL)
at 0 °C, and the mixture was stirred at room tem-
perature for 4 h. The solvent was evaporated in
vacuum, and 10 mL of water was added to the
mixture. The mixture was acidified with 10 %
aqueous HCl to pH 1 – 2, stirred at room tempera-
ture for 12 h, and then neutralized with NaHCO3.
The product was extracted with MTBE, the extract
was dried over MgSO4. The solvent was distilled
off, and the residue was distilled in a vacuum to
give alcohol 15 as a colorless oil.
Yield – 0.85 g (89 %). B. p. 92 – 93 °C at 0.5 mbar.
Anal. Calcd for C7H6F3NO2, %: C 43.53, H 3.13, N
7.25. Found, %: C 43.37, H 3.33, N 7.22. 1H NMR
(300 MHz, CDCl3), δ, ppm: 4.06 (1H, br. s, OH),
4.73 (2H, s, CH2OH), 7.60 (1H, s, 4-PyH), 8.33
(1H, s, 2/6-PyH), 8.40 (1H, s, 2/6-PyH). 13C NMR
(100 MHz, CDCl3), δ, ppm: 61.3 (CH2OH), 120.3
(q, 1JCF = 260.0 Hz, OCF3), 127.0, 138.6, 141.3,
146.0, 146.3. 19F NMR (188 MHz, CDCl3), δ, ppm:
-58.66 (s, OCF3). GC-MS, m/z (Irel, %): 193 (100)
[M]+.
The preparation of 3-(4,4,5,5-Tetramethyl-
1,3,2-dioxaborolan-2-yl)-5-trifluoromethoxy-
pyridine (16)
The mixture of bromopyridine 3 (6 g, 25 mmol),
bis(pinacolato)diboron (8.2 g, 32 mmol), potassium
acetate (9.7 g, 100 mmol) and Pd(dppf)Cl2·CH2Cl2
(1 g, 1.2 mmol) in 90 mL of dioxane was stirred
for 24 h at 95 – 100 °C under argon atmosphere.
The mixture was cooled to room temperature,
filtered through a SiO2 pad, diluted with water
(150 mL), and extracted with MTBE. The pro-
duct was purified by SiO2 column chromatogra-
phy using a mixture of hexane/MTBE in 3:1 as
an eluent (Rf 0.3).
A colorless powder. Yield – 5.8 g (80 %). M. p.
35 – 37 °C. Anal. Calcd for C12H15BF3NO3, %: C
49.86, H 5.23. Found, %: C 50.01, H 5.40. 1H NMR
(300 MHz, CDCl3), δ, ppm: 1.35 (12H, s, 4×CH3),
7.90 (1H, s, 4-PyH), 8.59 (1H, s, 2/6-PyH), 8.86
(1H, s, 2/6-PyH). 13C NMR (150 MHz, CDCl3),
δ, ppm: 24.6 (CH3), 84.6 (C(CH3)2), 118.3, 120.3
(q, 1JCF = 260.1 Hz, OCF3), 133.9, 145.0, 145.8,
153.4. 19F NMR (300 MHz, CDCl3), δ, ppm:
-58.0 (s, OCF3). GC-MS, m/z (Irel, %): 289 (100)
[M(11B)]+, 288 (26) [M(10B)]+.
tert-Butyl 5-(trifluoromethoxy)pyridin-
3-yl-carbamate (17a)
The mixture of bromopyridine 3 (4.8 g, 20 mmol),
tert-butyl carbamate (3.5 g, 30 mmol), caesium
carbonate (13 g, 40 mmol), Pd2dba3 (0.9 g, 1 mmol)
and Xantphos (0.6 g, 1 mmol) in 50 mL of dioxane
were stirred for 24 h at 95 – 100 °C under argon at-
mosphere. The mixture was cooled to room tem-
perature, filtered through a SiO2 pad, diluted
with water (150 mL), and extracted with MTBE.
The product was purified by SiO2 column chro-
matography using the mixture of hexane/ethyl
acetate (5:1) as an eluent (Rf 0.2).
A colorless powder. Yield – 3.8 g (69 %). M. p.
60 – 62 °C. Anal. Calcd for C11H13F3N2O3, %: C 47.49,
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (1)
H 4.71, N 10.07. Found, %: C 47.28, H 4.88, N
10.24. 1H NMR (400 MHz, CDCl3), δ, ppm: 1.55
(9H, s, t-Bu), 7.38 (1H, s, 4-PyH), 8.22 (1H, s,
2/6-PyH), 8.48 (1H, s, NH). 13C NMR (125 MHz,
CDCl3), δ, ppm: 28.2 (C(CH3)3), 81.8 (C(CH3)3),
118.3, 120.4 (q, 1JCF = 260.2 Hz, OCF3), 135.9,
137.2, 137.5, 146.4, 152.7. 19F NMR (300 MHz,
CDCl3), δ, ppm: -58.54 (s, OCF3).
3-Amino-5-trifluoromethoxypyridin (17)
The mixture of compound Boc-17 (3.8 g,
14 mmol) and trifluoroacetic acid in CH2Cl2 were
stirred at room temperature for 20 h. The mixture
was neutralized with sodium carbonate, wash-
ed with water, and dried with MgSO4. The sol-
vent was distilled off, and the residue was dis-
tilled in a vacuum to yield pyridine 17 as a color-
less solid.
Yield – 1.8 g (72 %). B. p. 60 – 62 °C at 1 mbar;
M. p. 35 – 37 °C. Anal. Calcd for C6H5F3N2O, %:
C 40.46, H 2.83, N 15.73. Found, %: C 40.31, H
3.01, N 15.55. 1H NMR (400 MHz, CDCl3), δ, ppm:
4.09 (2H, s, NH), 6.87 (1H, s, 4-PyH), 7.95 (1H,
s, 2/6-PyH), 8.06 (1H, s, 2/6-PyH). 13C NMR
(125 MHz, CDCl3), δ, ppm: 118.0, 120.5 (q, 1JCF
= 260.0 Hz, OCF3), 136.0, 137.0, 137.5, 146.6,
152.7. 19F NMR (300 MHz, CDCl3), δ, ppm: -58.5
(s, OCF3). GC-MS, m/z (Irel, %): 178 (100) [M]+.
2-Chloro-5-trifluoromethoxy-nicotinalde-
hyde (20)
n-Butyllithium (2.5 M solution in hexane,
4.6 mL, 11.5 mmol) was added to 20 mL of vigor-
ously stirred toluene at -70 – -65 °C. After the ad-
dition was complete, the solution of pyridine 13
(3 g, 10.8 mmol) in toluene (10 mL) was added
to the mixture at the same temperature, and the
mixture was stirred for further 30 min. The reac-
tion mixture was cooled to -90 – -85 °C, and 10 mL
of THF was added, the reaction mixture was stir-
red for 15 min, then DMF (2.4 g, 30 mmol) was
added dropwise at the same temperature. After
the addition was completed, the mixture was
warmed to -10 °C, and the solution of NaHSO4
(2.9 g, 20 mmol) in 10 mL of water was added.
The product was extracted with MTBE, the ex-
tract was washed with a brine, dried over MgSO4.
The solvent was distilled off, and the residue
was distilled in a vacuum to give chloronicotinic
aldehyde 20 as a colorless oil.
Yield – 1.9 g (79 %). B. p. 65 – 66 °C at 1 mbar.
Anal. Calcd for C7H3ClF3NO2, %: C 37.28, H
1.34, N 6.21. Found, %: C 37.30, H 1.55, N 6.12.
1H NMR (500 MHz, CDCl3), δ, ppm: 8.05 (1H, s,
4-PyH), 8.51 (1H, s, 6-PyH), 10.37 (1H, s, CHO).
13C NMR (125 MHz, CDCl3), δ, ppm: 120.1 (q,
1JCF = 261.5 Hz, OCF3), 129.2, 129.5, 145.6,
146.9, 150.6, 178.8. 19F NMR (188 MHz, CDCl3),
δ, ppm: -57.92 (s, OCF3). GC-MS, m/z (Irel, %):
225 (100) [M(35Cl)]+, 227 (30) [M(35Cl)]+.
2-Chloro-5-(trifluoromethoxy)pyridin-
3-yl-methanol (21)
Sodium borohydride (0.95 g, 25 mmol) was
added to the solution of 2-chloro-5-(trifluoro-
methoxy)nicotinaldehyde (20) (1.9 g, 8.4 mmol)
in ethanol (40 mL) at 0 °C, and the mixture was
stirred at room temperature for 4 h. The sol-
vent was evaporated in a vacuum, and 10 mL
of water was added to the mixture. The mixture
was acidified with 10 % aqueous HCl to pH 1 – 2,
stirred at room temperature for 12 h, and then
neutralized with NaHCO3. The product was ex-
tracted with MTBE, the extract was dried with
MgSO4. The solvent was distilled off, and the
residue was distilled in a vacuum to give alcohol
23 as a colorless oil.
Yield – 1.8 g (94 %). B. p. 101 – 102 °C at
0.5 mbar. Anal. Calcd for C7H5F3NO2, %: C 36.95,
H 2.21, Cl 15.58. Found, %: C 36.90, H 2.28,
Cl 15.55. 1H NMR (400 MHz, CDCl3), δ, ppm:
2.25 (1H, br. s, OH), 4.78 (2H, s, CH2OH), 7.83
(1H, s, 4-PyH), 8.22 (1H, s, 6-PyH). 13C NMR
(100 MHz, CDCl3), δ, ppm: 61.2 (CH2OH), 120.3
(q, 1JCF = 260.0 Hz, OCF3), 127.0, 138.6, 141.3,
146.0, 146.3. 19F NMR (188 MHz, CDCl3), δ,
ppm: -58.84 (s, OCF3). GC-MS, m/z (Irel, %): 227
(100) [M(35Cl)]+, 225 (30) [M(35Cl)]+.
2-Chloro-5-(trifluoromethoxy)nicotinic
acid (19)
Potassium permanganate (0.46 g, 3 mmol) was
added to a mixture of aldehyde 20 (1 g, 4.4 mmol)
and potassium carbonate (0.11 g, 0.8 mmol) in
water (10 mL) at 50 – 60 °C. The mixture was
stirred for 1 h at 60 °C, cooled to room tempera-
ture, filtered, and the water solution was acidi-
fied to pH 6 with 3 % aqueous hydrochloric acid.
The product was filtered off, washed with water,
and dried in a vacuum.
A colorless powder. Yield – 0.85 g (80 %).
M. p. 142 – 143 °C. Anal. Calcd for C7H3ClF3NO3,
%: C 34.81, H 1.25, Cl 14.68. Found, %: C 34.50,
H 1.55, Cl 14.82. 1H NMR (300 MHz, DMSO-d6),
δ, ppm: 8.24 (1H, s, 4-PyH), 8.89 (1H, s, 6-PyH),
13.76 (1H, br. s, COOH). 13C NMR (75 MHz,
DMSO-d6), δ, ppm: 116.4 (q, 1JCF = 260.5 Hz, OCF3),
125.2, 128.1, 131.7, 147.0, 148.8, 164.2. 19F NMR
(188 MHz, DMSO-d6), δ, ppm: -57.34 (s, OCF3).
LC-MS, m/z (CI): 241 [M(35Cl)+H]+, 243 [M(35Cl)+H]+.
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Журнал органічної та фармацевтичної хімії 2024, 22 (1)
The metalation of 3-bromo-2-chloro-5-
trifluoromethoxy-pyridine (13) using n-bu-
tyllithium with the formation of the mix-
ture of isonicotinic (18) and nicotinic acids
(19)
n-Butyllithium (2.5 M solution in hexane,
4.6 mL, 11.5 mmol) was added to 20 mL of vi-
gorously stirred toluene at -70 – -65 °C. After the
addition was completed, the solution of pyridine
13 (3 g, 10.8 mmol) in toluene (10 mL) was added
to the mixture at the same temperature, and the
resulting mixture was stirred for further 30 min.
The reaction mixture was cooled to -90 – -85 °C,
and 10 mL of THF was added, the reaction mix-
ture was stirred for 15 min, then gaseous CO2
(4.8 g, 0.11 mol) was bubbled through the reac-
tion mixture at -90 – -85 °C. After the addition was
completed, the mixture was warmed to room
temperature, washed with MTBE, acidified
with 5 % hydrochloric acid to pH 2. The products
were filtered off, washed with water, and dried
in a vacuum.
The yield of the mixture of isonicotinic 18 and
nicotinic 19 acids (1:1) was 1.95 g (75 %). In the
case when the reaction mixture after the addi-
tion of THF and stirring for 15 min at -90 – -85 °C
was poured into crushed dry ice, the yield of the
mixture of acids 18 and 19 (5:1) was 2.2 g (84 %).
The structures of products were determined by
1H and 19F NMR and LC-MS methods. They were
in good agreement with [6] for 2-chloro-5-(trifluo-
romethoxy)isonicotinic acid (18), and the sample
of pure 2-chloro-5-(trifluoromethoxy)nicotinic
acid (19) prepared by oxidation of aldehyde 20.
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9. Davydova, Y. A.; Sokolenko, T. M.; Yagupolskii, Y. L. Polyfluoro- and perfluoroalkoxyenaminones in syntheses of nitrogen containing
heterocycles. J. Fluorine Chem. 2014, 157, 58 – 62. https://doi.org/10.1016/j.jfluchem.2013.11.007.
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Information about the authors:
Taras M. Sokolenko (corresponding author), Ph.D. in Chemistry, Senior Researcher, Organofluorine Compounds Chemistry Department,
Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; https://orcid.org/0000-0002-3944-5571; e-mail for
correspondence: taras_sk@ukr.net.
Yurii L. Yagupolskii, Dr.Sci. in Chemistry, Professor, Chief of Organofluorine Compounds Chemistry Department, Institute of Organic
Chemistry of the National Academy of Sciences of Ukraine; Scientific advisor, Enamine Ltd.; https://orcid.org/0000-0002-5179-4096.
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| id | oai:ojs.journals.uran.ua:article-302435 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-24T01:00:57Z |
| publishDate | 2024 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/5e/e40bd45e83043e39b9718da9fc3e955e.pdf |
| spelling | oai:ojs.journals.uran.ua:article-3024352026-08-23T16:38:16Z 5-Trifluoromethoxy-substituted Nicotinic Acid, Nicotinamide and Related Compounds 5-Трифлуорометоксизаміщена нікотинова кислота, нікотинамід і споріднені сполуки Sokolenko, Taras M. Yagupolskii, Yurii L. нікотинова кислота нікотинамід трифлуорометоксигрупа стибій трифлуорид флуорування nicotinic acid nicotinamide trifluoromethoxy group antimony trifluoride fluorination A practical and convenient method for synthesizing nicotinic acid and nicotinamide with the trifluoromethoxy group in position 5 of the ring has been developed. A series of related compounds, for example, nicotinic aldehyde and nicotinic alcohol, have been synthesized. It has been shown that 3-bromo-5-trifluoromethoxypyridine is a convenient and efficient synthon for palladium-catalyzed coupling reactions. The trifluoromethoxy group has been found to be remarkably stable against hydroiodic acid in contrast to the methoxy group. Розроблено практичний і зручний метод синтезу нікотинової кислоти та нікотинаміду з трифлуорометоксигрупою в положенні 5 кільця. Було синтезовано деякі споріднені сполуки, наприклад, нікотиновий альдегід і нікотиновий спирт. З’ясовано, що 3-бромо-5-трифлуорометоксипіридин є зручним синтоном для каталізованих паладієм реакцій сполучення. Визначено, що, на відміну від метоксигрупи, трифлуорометоксигрупа є надзвичайно стійка до дії йодоводневої кислоти. National University of Pharmacy 2024-06-18 Article Article application/pdf application/pdf https://ophcj.nuph.edu.ua/article/view/302435 10.24959/ophcj.24.302435 Journal of Organic and Pharmaceutical Chemistry; Vol. 22 No. 1 (2024); 22-30 Журнал органической и фармацевтической химии; Том 22 № 1 (2024); 22-30 Журнал органічної та фармацевтичної хімії; Том 22 № 1 (2024); 22-30 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/302435/297037 https://ophcj.nuph.edu.ua/article/view/302435/297038 Copyright (c) 2024 Taras M. Sokolenko, Yurii L. Yagupolskii http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | нікотинова кислота нікотинамід трифлуорометоксигрупа стибій трифлуорид флуорування Sokolenko, Taras M. Yagupolskii, Yurii L. 5-Трифлуорометоксизаміщена нікотинова кислота, нікотинамід і споріднені сполуки |
| title | 5-Трифлуорометоксизаміщена нікотинова кислота, нікотинамід і споріднені сполуки |
| title_alt | 5-Trifluoromethoxy-substituted Nicotinic Acid, Nicotinamide and Related Compounds |
| title_full | 5-Трифлуорометоксизаміщена нікотинова кислота, нікотинамід і споріднені сполуки |
| title_fullStr | 5-Трифлуорометоксизаміщена нікотинова кислота, нікотинамід і споріднені сполуки |
| title_full_unstemmed | 5-Трифлуорометоксизаміщена нікотинова кислота, нікотинамід і споріднені сполуки |
| title_short | 5-Трифлуорометоксизаміщена нікотинова кислота, нікотинамід і споріднені сполуки |
| title_sort | 5-трифлуорометоксизаміщена нікотинова кислота, нікотинамід і споріднені сполуки |
| topic | нікотинова кислота нікотинамід трифлуорометоксигрупа стибій трифлуорид флуорування |
| topic_facet | нікотинова кислота нікотинамід трифлуорометоксигрупа стибій трифлуорид флуорування nicotinic acid nicotinamide trifluoromethoxy group antimony trifluoride fluorination |
| url | https://ophcj.nuph.edu.ua/article/view/302435 |
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