ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS(Review)
Fluorine-containing heterocycles play a crucial role in the pharmaceutical, agrochemical, and materials industries. The pursuit of effective and sustainable synthesis methods has driven the development of electrochemistry as a compelling alternative to conventional chemical transformations. Among t...
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| author | Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim |
| author_facet | Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim |
| author_institution_txt_mv | [
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25-406 Kielce, Poland"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology, 463-8560, Nagoya, Japan"
},
{
"author": "Daniel Baecker",
"institution": "Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany"
},
{
"author": "Wei Zhang",
"institution": "Department of Chemistry, University of Massachusetts Boston, Boston MA 02125, Unites States;"
},
{
"author": "Vadim Soloshonok",
"institution": "University of Basque Country"
}
] |
| author_sort | Wzorek, Alicja |
| baseUrl_str | https://ucj.org.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-22T08:23:56Z |
| description | Fluorine-containing heterocycles play a crucial role in the pharmaceutical, agrochemical, and materials industries. The pursuit of effective and sustainable synthesis methods has driven the development of electrochemistry as a compelling alternative to conventional chemical transformations. Among these approaches, electrochemistry has emerged as a particularly promising technique for orchestrating multibond-forming processes under mild, environmentally benign conditions. This review highlights key advances over the past decade in the electrochemical synthesis of fluorinated heterocyclic compounds, encompassing bimolecular, trimolecular, and tetramolecular reactions. Emphasis is placed on multicomponent cascade strategies, radical-mediated couplings, and oxidant-free cyclizations that afford broad functional group tolerance and fluorine incorporation flexibility. Collectively, this work serves as a resource for researchers developing next-generation sustainable synthetic platforms tailored to fluorinated heterocycles with diverse structural and biological profiles. |
| doi_str_mv | 10.33609/2708-129X.91.11.2025.35-62 |
| first_indexed | 2026-03-12T15:49:41Z |
| format | Article |
| fulltext |
35
UDC 546.26-162: 541.13:549.21 doi: 10.33609/2708-129X.91.11.2025.35-62
ELECTROCHEMICAL SYNTHESIS OF FLUORINATED
HETEROCYCLIC COMPOUNDS (review).
Alicja Wzorek1, Taizo Ono2, Daniel Baecker3, Wei Zhang4, Vadim A. Soloshonok5*
1 Institute of Chemistry, Jan Kochanowski University in Kielce,
Uniwersytecka 7, 25–406 Kielce, Poland;
2 National Institute of Advanced Industrial Science and Technology (AIST),
2266–98, Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463–8560, Japan;
5 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy,
Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany;
4 Department of Chemistry, University of Massachusetts Boston,
Boston MA 02125, Unites States of America;
5 IKERBASQUE, Basque Foundation for Science,
María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain
e-mail: vadimsoloshonok@gmail.com
Fluorine-containing heterocycles play a crucial role in the pharmaceutical, agrochemical,
and materials industries. The pursuit of effective and sustainable synthesis methods has dri
ven the development of electrochemistry as a compelling alternative to conventional chemi-
cal transformations. Among these approaches, electrochemistry has emerged as a particularly
promising technique for orchestrating multibond-forming processes under mild, environ-
mentally benign conditions. This review highlights key advances over the past decade in the
electrochemical synthesis of fluorinated heterocyclic compounds, encompassing bimolecular,
trimolecular, and tetramolecular reactions. Emphasis is placed on multicomponent cascade
strategies, radical-mediated couplings, and oxidant-free cyclizations that afford broad func-
tional group tolerance and fluorine incorporation flexibility. Collectively, this work serves as a
resource for researchers developing next-generation sustainable synthetic platforms tailored
to fluorinated heterocycles with diverse structural and biological profiles.
Keywords: Electrochemistry, Heterocyclic Compounds, Fluorine, Fluorinated Pharma-
ceuticals, Green Chemistry, Sustainable Synthesis.
36 ISSN 2708-129X. Укр. хім. журн., 2025
ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS. (review)PHISICAL CHEMISTRY
INTRODUCTION. Electrochemistry is a
fascinating interdisciplinary branch of chemist
ry that studies the relationship between electri-
cal energy and chemical reactions. At its core,
it investigates processes where chemical ener-
gy is converted into electrical energy or where
electrical energy is used to drive non-sponta-
neous chemical reactions. These transforma-
tions occur through redox reactions where
electrons are transferred, typically at the inter-
face between an electrode (an electrical con-
ductor) and an electrolyte (an ion-conducting
medium). The principles of electrochemistry
underpin a vast array of modern technologies,
from power sources like batteries and super-
capacitors, to industrial processes such as the
production of aluminum and chlorine, and
analytical techniques like pH measurement
and biosensors. [1–6].
Electrochemistry offers a powerful and in-
creasingly vital approach to organic synthe-
sis, enabling chemists to drive a wide range of
transformations through the controlled trans-
fer of electrons rather than relying solely on
traditional chemical reagents. This method, of-
ten termed electrosynthesis, leverages the pre-
cise control of electrical potential to effect se-
lective oxidations and reductions, allowing for
the formation of C-C bonds, functional group
interconversions, and the synthesis of complex
molecules under remarkably mild conditions.
Key advantages include enhanced selectivi-
ty (chemo-, regio-, and stereoselectivity), the
elimination of hazardous or stoichiometric
redox reagents, and the generation of cleaner
reaction profiles with fewer byproducts. From
sustainable anodic oxidations and cathodic re-
ductions to electro-initiated radical reactions
and the precise functionalization of sensitive
substrates, electrosynthesis is revolutionizing
synthetic routes, making complex organic
transformations more efficient, environmen-
tally friendly, and scalable. [7–16].
Electrochemistry offers compelling advan
tages over conventional organic synthesis
methods, particularly in its alignment with
green chemistry principles [17]. Foremost
among these benefits is the replacement of
stoichiometric chemical oxidants and reduc
tants with electricity, which serves as a clean,
tunable, and inexpensive reagent. This elimi-
nates the need for often hazardous and costly
reagents, significantly reducing waste gene
ration and simplifying downstream purifica-
tion processes. Furthermore, electrochemical
reactions frequently proceed under milder
conditions, such as ambient temperature and
pressure, minimizing energy consumption and
enabling the synthesis of sensitive compounds
that might degrade under harsher thermal or
chemical routes. The precise control over elect
ron transfer at the electrode surface allows for
unparalleled selectivity (chemo-, regio-, and
stereoselectivity), leading to higher yields of
desired products and fewer unwanted bypro
ducts, thus contributing to greater efficiency
and sustainability in modern organic synthe-
sis. [18–21].
As part of our ongoing commitment to the
design of modern pharmaceuticals [22–28]—
particularly those incorporating residues of
tailor-made amino acids [29–36] and fluori-
nated motifs [37–45]—we are strongly focused
on developing innovative synthetic methodo
logies for their preparation [46–56]. Given that
heterocyclic compounds and amino acids con-
stitute the structural backbone of over 85% and
35% of contemporary drugs, respectively, these
domains remain central to pharmaceutical
research [57–65]. Notably, heterocyclic scaf-
37https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 11 / Vol. 91
folds serve as indispensable building blocks
in medicinal chemistry, owing to their broad
spectrum of biological activity and remarkable
structural versatility, making them essential
for rational drug design [66–71].
Recently, we presented a comprehensive
overview of advancements in the synthesis of
fluorinated heterocyclic compounds, highligh
ting innovative directions such as the use of
carbon nanotubes as catalysts [72] and the ap-
plication of mechanochemical principles [73].
In the present work, we extend this exploration
by providing a detailed treatment of electro-
chemical methodologies for the synthesis of
fluorinated heterocyclic compounds.
Electrochemistry is an emerging field with
significant synthetic potential, offering sus-
tainable and efficient alternatives to traditional
chemical processes. Here, we summarize data
published over the past decade on the electro-
chemical synthesis of fluorine-containing he
terocycles. The material is organized according
to the number of reacting species, focusing
on reaction dynamics rather than mechanis-
tic principles such as the molecularity of the
rate-determining step. Accordingly, reactions
involving three structural components—two
of which are identical—are classified based on
effective molecularity and treated as bimolecu-
lar in terms of structural diversity.
We believe this compilation will serve as a
valuable resource for researchers and practi-
tioners in synthetic and medicinal chemistry,
as well as for those pursuing advances in green
and sustainable methodologies.
Bimolecular reactions.
In 2020, Yang et al. [74] introduced an ef-
ficient electrochemical strategy for synthe-
sizing 1,2,4-trisubstituted (1H)-imidazoles 3
(Scheme 1), .utilizing readily available starting
materials and carbon rod electrodes in an undi-
vided cell under metal- and oxidant-free con-
ditions The approach involves the electrooxi-
dative tandem cyclization of acetophenones 1
and substituted benzylamines 2, proceeding
via in situ generation of 2-iodoacetophenone
through anodic oxidation of molecular iodine,
which subsequently engages with the ketone
1. This protocol stands out for its broad func-
tional group tolerance and consistent deli
very of moderate to excellent yields. Notably,
both starting materials—highly electrophilic
ketones 1 [75, 76] and benzylamines 2—can
incorporate fluorinated substituents, enabling
a high degree of fluorination and structural
versatility in the resulting products 3. Further-
more, this electrochemical protocol eliminates
the need for external metal catalysts or chemi-
cal oxidants, making it a simple, cost-effective,
and environmentally sustainable alternative.
While the primary focus is on nitrogen-con-
taining heterocycles, the methodology also
holds promise for the synthesis of related scaf-
folds across diverse heterocyclic systems.
Scheme 1. Electrochemical strategy for synthesizing 1,2,4-trisubstituted (1H)-imidazoles.
38 ISSN 2708-129X. Укр. хім. журн., 2025
ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS. (review)PHISICAL CHEMISTRY
Elinson and co-workers developed highly
stereoselective electrocatalytic approach for
synthesizing substituted (R*,R*)-bis-(spiro-
2,4-dihydro-3H-pyrazol-3-one)cyclopropa
nes 6 (Scheme 2) [77] via an electrochemical
multi-step cyclization reaction. This one-pot
strategy employs fluoro-aldehydes 4 and pyra-
zolin-5-ones 5 as starting materials, proceed-
ing through a direct electrochemical transfor-
mation to access functionally rich cyclopro-
pane scaffolds. The process utilizes sodium
iodide or bromide as a redox mediator in an
undivided cell, with methanol as the solvent,
and is conducted at ambient temperature.
By circumventing conventional halogena-
tion reagents and leveraging mild electrolysis
conditions, the method delivers good yields
(65–80%) with high current efficiency and vir-
tually complete diastereoselectivity of relative
(R*,R*) configuration. The underlying mecha-
nism follows a typical mediator system: iodine
is generated anodically, while methanol is de-
protonated cathodically to produce methoxide
anions and evolve hydrogen gas.
Qian et al. have recently introduced a novel
electrochemical cascade cyclization strategy
for the synthesis of bis-pyrazolo[3,4-b:4’,3’-e]
pyridines 9 (Scheme 3) [78]. Leveraging the
enhanced electrophilicity of fluorinated alde
hydes 7 [74, 79, 80], this method exploits their
high reactivity in nucleophilic addition reac-
tions. The transformation between fluoroal-
dehydes 7 and pyrazol-5-amines 8 proceeds
smoothly under metal- and oxidant-free con-
ditions. This electrochemical approach affords
a diverse array of mono- and trifluoromethyl-
substituted bis-pyrazolo[3,4-b:4’,3’-e]pyridines
9 in moderate yields (50–70%). Key advantages
of the protocol include its operational simplici-
ty, broad substrate scope, and environmentally
benign character, making it a promising alter-
native to conventional multistep syntheses.
Scheme 3. Electrochemical approach for preparation of bis-pyrazolo[3,4-b:4’,3’-e]pyridines.
Scheme 2. Synthesis of (R*,R*)-bis-(spiro-2,4-dihydro-3H-pyrazol-3-one)cyclopropanes.
39https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 11 / Vol. 91
A highly effective and operationally conve
nient electrochemical method has been deve
loped for the synthesis of fluoro-spirocyclopro-
panes 11 (Scheme 4) [81], achieved by reacting
indan-1,3-dione 10 with aromatic fluoro-alde-
hydes 4. The reaction is conducted at 50 °C in a
mixture of propanol and sodium bromide un-
der constant current electrolysis. This method
offers several significant advantages, including
mild halogen production, the use of low-con-
centration currents, a neutral reaction solution
pH, no need for by-product isolation, synthe
tically attractive yields (>75%), inexpensive re-
agents, environmental sustainability, and easy
product isolation.
Scheme 4. Electrochemically aided synthesis of fluoro-spirocyclopropanes.
A straightforward and green electrochemi
cal method for synthesizing CF₃-containing
benzazepines has been developed by Zhang
et al. via the radical cascade cyclization of
alkynes. Starting compounds 12 (Scheme 5)
[82], bearing an acetylenic residue properly
positioned relative to the aromatic ring, were
subjected to electrochemical conditions in an
undivided cell with sodium trifluorometha
nesulfinate 13 in acetonitrile at ambient tem-
perature, yielding cyclized products 14 with a
trifluoromethyl group bonded to the olefinic
moiety. This transformation provides a novel
approach to synthesizing seven-membered
heterocycles without requiring any external
catalyst or oxidant, operating under mild re-
action conditions. A gram-scale experiment
further demonstrated the practicality of this
method. Benzazepines are an important class
of seven-membered nitrogen-containing he
terocyclic compounds, widely present in natu-
ral products and pharmaceuticals. They exhibit
diverse biological activities, making them va
luable in medicinal chemistry [83].
Scheme 5. Electrochemical synthesis of fluorinated benzazepines.
40 ISSN 2708-129X. Укр. хім. журн., 2025
ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS. (review)PHISICAL CHEMISTRY
Lei et al. described a one-pot electroche
mical oxidation-induced intermolecular annu-
lation reaction for the synthesis of tetrasubsti-
tuted pyrroles 16 (Scheme 6) [84]. The reac-
tion was conducted in an undivided cell at a
constant current of 10 mA, using simple and
readily available fluorinated ketones 15 and
tert-butyl amine in the presence of tetrabu-
tylammonium tetrafluoroborate (n-Bu4NBF₄)
as an electrolyte. Tetrasubstituted pyrroles 16
were obtained with yields ranging from 42% to
79%. Substituting tert-butyl amine with other
amines led to complications due to the insta-
bility of intermediate imines, thereby limiting
the synthetic utility of this method.
Scheme 6. Electrochemical preparation of tetrasubstituted pyrroles.
Ackermann et al. describe a rhodium-cata-
lyzed cascade C–H activation and alkyne
annulation for the novel synthesis of nitro-
gen-doped polycyclic aromatic hydrocarbons
(aza- nanographenes) 19 (Scheme 7) [85],
demonstrating high chemo- and regioselecti
vity. The method employs a specially designed
multifunctional O-methylamidoxime direct-
ing group, using amidoxime 17 and various
disubstituted 18 for the envisioned rhoda-elec-
trocatalyzed cascade C–H annulation. The re-
action is conducted with KOAc as the base,
[Cp*RhCl₂]₂ (Cp* = C₅Me₅) as the catalyst pre-
cursor, MeOH as the solvent, and a constant
current of 4.0 mA, yielding the desired pro
ducts 19 in 42–94% yield. Through the identi-
fication of two key rhodacyclic intermediates,
the authors determined the precise sequence in
which the three steps of C–H activation occur.
The metalla-electrocatalyzed multiple C–H
transformations exhibit a unique functional
group tolerance, accommodating even highly
reactive iodo and azido groups. This innova-
tive approach holds promising applications in
materials science.
Scheme 7. Electrochemical synthesis of fluorine-containing aza-nanographene derivatives.
41https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 11 / Vol. 91
Trimolecular reactions.
Yao et al. demonstrated the synthesis of
fluorine-containing 4-thiocyanato-1H-pyra-
zoles 23 (Scheme 8) [86] under mild, metal-
and oxidant-free conditions, using fluorinated
arylhydrazines 20, 1,3-diketones 21, and am-
monium thiocyanate 22 in an undivided elect
rochemical cell. The reaction was performed at
room temperature for 4 hours in an undivid-
ed cell equipped with graphite felt (GF) as the
anode, a platinum plate (Pt) as the cathode, and
LiBF₄ as the electrolyte, maintaining a constant
current of 10 mA. This process afforded fluo
rinated phenyl-4-thiocyanato-1H-pyrazole 23
in moderate to excellent yields (41–94%).
Mechanistic studies revealed that anodic
oxidation generates SCN• radicals, which sub-
sequently undergo electrophilic substitution
with the pyrazole intermediate adduct. The
practicality and scalability of this thiocyana-
tion protocol make it both cost-effective and
environmentally friendly. Given its simplicity,
mild reaction conditions, and neutral medium,
this electrochemical multicomponent tandem
approach is highly appealing for applications
in the pharmaceutical and fine chemical in
dustries, offering high scalability and func-
tional group tolerance. Notably, fluorination in
products 23 can manifest as a single fluorine
atom, two fluorine atoms, or trifluoromethyl
and trifluoromethoxy groups on the aromatic
ring.
Scheme 8. Electrochemical approach to fluorinated 1-phenyl-4-thiocyanato-1H-pyrazoles.
Elinson et al. reported the synthesis of spi
ro-indole-3,4’-pyrano-pyranones 27 via elect
rochemical cascade trimolecular cyclization,
using fluoro-isatins 24, pyran-4-one 25, and
malonic acid derivatives 26 (Scheme 9) [87].
The reaction is conducted under reflux condi-
tions in undivided cells, with potassium iodi
de as the electrolyte and n-propanol as the
solvent, achieving high yields (~80%) of the
spiro-heterocyclic system 27. This catalytically
efficient procedure requires no complex equip-
ment, is easily executable, and allows straight-
forward product isolation. As a result, this
novel approach provides significant advanta
ges for large-scale processes, supporting envi-
ronmentally friendly synthesis while enabling
high molecular diversity.
Scheme 9. Electrochemical approach to fluorinated spiro-indole-3,4’-pyrano- pyranones.
42 ISSN 2708-129X. Укр. хім. журн., 2025
ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS. (review)PHISICAL CHEMISTRY
Scheme 10. Electrocatalytic trimolecular reaction affording fluorinated isoxazol-5(2H)-ones.
Fluorinated derivatives of 4H-pyran-2yl-
(aryl)methyl-isoxazol-5(2H)-one 30 (Sche
me 10) [88] can be synthesized electroche
mically in propanol, heating at 97 oC, via a
one-pot, three-component reaction involving
aromatic aldehydes 28, fluorinated 3-aryl-
substituted isoxazol-5(4H)-one 29, and pyran-
4-one 25. This method represents a significant
achievement, performed in an undivided elect
rochemical cell using graphite as the anode
and iron as the cathode.
Fluorine-containing carbonyl compounds
are highly effective reagents in various addi-
tion reactions performed under conventional
conditions [89, 90]. A similar reactivity is ob-
served for aldehydes 4 (Scheme 11) [91] in an
electrochemical assembly with 6-methyl-3H-
pyran-2,4-dione 30 and barbituric acid 31. The
reaction is carried out in an undivided electro-
chemical cell using sodium iodide as a mediator
in methanol. The process yields fluorine-con-
taining spiro[furo[3,2-b]-pyran-2,5’-pyrimi-
dines 32 with high efficiency, achieving 73–
82% yields.
Scheme 11. Electrochemical synthesis of fluorine-containing
spiro[furo[3,2-b]-pyran-2,5’-pyrimidines.
Indoles serve as a fundamental scaffold in
drug design, valued for their versatile biologi-
cal activity and capacity to interact with diverse
molecular targets. They are widely present in
both natural and synthetic pharmaceuticals,
playing critical roles in anticancer, antimicro-
bial, anti-inflammatory, and neuroprotective
therapies. Their structural adaptability enables
medicinal chemists to optimize potency, selec-
tivity, and bioavailability, making them indis-
pensable in modern drug discovery [92–95].
Various strategies have been developed for syn-
thesizing indole derivatives [96–99], including
fluorine-containing variants [100–103].
Singh et al. developed an electrocatalytic
tandem condensation method for synthesi
zing tri-substituted indoles 35 (Scheme 12)
[104]. The process involves an electrocatalytic
43https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 11 / Vol. 91
conversion of fluorinated aldehydes 4, indole
33, and malononitrile 34, conducted in EtOH
at a current density of 10–15 mA/cm², using
LiClO₄ as the electrolyte. Fluorinated benzal-
dehydes exhibit high reactivity and distinct re-
activity patterns, which vary depending on the
number and position of fluorine atoms on the
aromatic ring [105, 106].
Scheme 12. Electrochemical synthesis of fluorine-containing indoles.
Triazoles and their derivatives exhibit a wide
range of biological activities, making them va
luable in medicinal chemistry. They are known
for their antimicrobial, antiviral, antitubercu-
lar, anticancer, anticonvulsant, analgesic, an-
tioxidant, anti-inflammatory, and antidepres-
sant properties [107, 108].
Zhao et al. developed an electrochemical
multicomponent [3+1+1] annulation reaction
for the synthesis of fluoro-substituted 1,2,4-tri
azoles 37 (Scheme 13) [109], without the use
of transition metals, acids, bases, or external
oxidants. The electrolysis was conducted in an
undivided cell, equipped with a graphite car-
bon anode, a platinum cathode, and 20 mol%
LiClO₄ as the electrolyte, under constant cur-
rent conditions. Substituted 1,2,4-triazoles 37
were obtained through the reaction of 1-ben-
zylidene-2-phenylhydrazine 36 (derived from
fluorinated benzaldehydes), aromatic alde-
hydes, and ammonium acetate. Given the ready
availability of raw materials, reasonable yields
(~75%), feasible scalability, and experimental
convenience, this protocol offers a practical
and efficient approach to triazole synthesis.
Scheme 13. Electrochemical preparation of fluorinated 1,2,4-triazole derivatives.
Imidazolines and oxazolidines exhibit di-
verse biological activities, making them valu-
able in medicinal chemistry [110–113]. Claraz
et al. reported a one-pot, eco-friendly elect
rochemical method for synthesizing oxazo-
lidine 39 (Scheme 13) [114] and imidazoline
derivatives 40, incorporating trifluoromethyl
groups and aromatic fluorine substitutions un-
der mild, environmentally benign conditions.
The method involves electrochemical tandem
44 ISSN 2708-129X. Укр. хім. журн., 2025
ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS. (review)PHISICAL CHEMISTRY
radical trifluoromethylation of allylamines 38,
followed by a formal (3+2)-cycloaddition with
Alk-CN or aliphatic ketones. The starting al-
lylamines are typically tosyl-protected, facili-
tating the reaction. The electrochemical reac-
tion of tosyl-amines 38 with Langlois reagent
(CF₃SO₂Na) is carried out in acetonitrile and
dichloromethane using LiClO₄ as the suppor
ting electrolyte, enabling the one-pot electro
synthesis of fluorinated 1,3-oxazolidines 39
and 2-imidazolines 40.
Scheme 14. Three-component synthesis of fluorinated imidazolines and oxazolidines.
Selenium-containing heterocyclic com
pounds exhibit a range of biological activities,
making them valuable in medicinal chemistry
and materials science [115, 116]. The reaction
reported by He et al. involves the electrochemi
cal transformation of fluoro-phenylhydrazine
41 (Scheme 15) [117], diketone 42, and di-
phenyl diselenide 43. Using readily available
starting materials, the approach outlined in
Scheme 15 provides a versatile method for
synthesizing a broad range of fluorinated 4-se-
lanylpyrazole derivatives 44, achieving high
yields (71–96%). Notably, fluorine atoms are
both on the phenyl ring of the starting hydra-
zine 41 and on the selenide 43. The reaction
is conducted in an undivided electrochemical
cell with reticulated vitreous carbon (RVC) as
the anode, a platinum plate as the cathode, and
LiBF₄ (20 mol%) as the electrolyte. Under mild
conditions, at ambient temperature for 9 hours
with a constant current of 6 mA, the desired
fluorinated 4-phenylselanyl-pyrazoles 44 are
obtained in MeCN, without the need for cata-
lysts or chemical oxidants.
Scheme 15. Electrochemical approach to fluorinated 4-selanylpyrazoles.
45https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 11 / Vol. 91
Weimin et al. reported a mechanistically
similar method to Scheme 15 for the synthesis
of various 4-bromopyrazoles 46 (Scheme 16)
[118], employing a three-component reaction
involving fluorinated aryl-hydrazine 41, dike-
tone 42, and bromomalonate 45 in an environ-
mentally friendly approach. The reaction was
conducted in an undivided electrochemical
cell for 10 hours, using n-Bu4NBF₄ (20 mol%)
as the electrolyte in MeCN at ambient tempe
rature. Mechanistically, hydrazine 41 under-
goes condensation with diketone 42, forming
the pyrazole ring, which is subsequently bro-
minated to yield 4-bromopyrazole 46. This
method can be generalized for the bromina-
tion of heterocyclic compounds, offering a sus-
tainable and efficient synthetic strategy.
Scheme 16. Electrochemical approach to fluorinated 4-bromopyrazoles.
As emphasized throughout this review,
fluorine-containing carbonyl compounds are
highly valuable synthetic building blocks ex-
hibiting significantly enhanced reactivity com-
pared to their non-fluorinated counterparts
[119–122]. Mohammadi et al. employed an
electrochemical approach for the successful
synthesis of fluorinated phthalazine derivatives
48 (Scheme 17) [123]. The reaction was con-
ducted in an undivided electrochemical cell at
a current density of 12 mA/cm², using NaBr as
the electrolyte. This one-pot, three-component
reaction involved fluorinated benzaldehydes 4,
phthalhydrazide 47, and malononitrile, carried
out in propanol. The method efficiently yiel
ded fluorine-containing pyrazolo[1,2-b]phtha
lazines 48 in good to excellent yields (75–92%).
Scheme 17. Electrochemical synthesis of fluorinated pyrazolo[1,2-b]phthalazines.
Mechanistically and strategically similar to
the electrochemical transformations described
in Schemes 15 and 16, the method reported
by He et al. enables the synthesis of 4-thio-
cyanato-1H-pyrazoles 49 (Scheme 18) [124].
Under mild, metal- and oxidant-free condi-
tions, fluorinated arylhydrazines 41, 1,3-dike-
tones 42, and ammonium thiocyanate under-
go electrochemical coupling in an undivided
cell, affording fluorine-containing products
46 ISSN 2708-129X. Укр. хім. журн., 2025
ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS. (review)PHISICAL CHEMISTRY
49 in moderate to excellent yields (41–94%).
Optimal results were obtained using graphite
felt (GF) as the anode, a platinum plate as the
cathode, and LiBF₄ as the electrolyte, at room
temperature for 4 hours under a constant cur-
rent of 10 mA. This setup efficiently produced
fluorinated phenyl-4-thiocyanato-1H-pyra-
zole scaffolds 49. Mechanistic investigations
suggest that anodic oxidation generates an
SCN• radical, which subsequently reacts with
a pyrazole intermediate via electrophilic sub-
stitution. Owing to its cost-effectiveness, prac-
ticality, and scalability, this electrochemical
thiocyanation protocol is not only environ-
mentally benign but also highly appealing for
applications in the pharmaceutical and fine
chemical industries, thanks to its operational
simplicity, mild reaction conditions, and broad
functional group tolerance.
Scheme 18. Electrochemical synthesis of fluorinated phenyl-4-thiocyanato-1H-pyrazoles.
Benzylamines and their derivatives, such as
pyridoxamine, play a significant role in biologi
cal enzymatic transamination, facilitating the
interconversion of α-keto and α-amino acids
[125–127]. Inspired by this natural process,
biomimetic synthetic approaches have largely
focused on the reductive amination of carbonyl
compounds, employing benzylamines both as
a nitrogen source and as a self-oxidizing agent
through oxidative deamination [128–133]. Re-
markably, both α-hydrogens of the CH₂–NH₂
moiety in benzylamine can participate in the
reductive amination of carboxylic acids, yiel
ding the corresponding amine products, while
the benzylamine itself is oxidized to the cor-
responding carboxylic acid (Scheme 19) [134].
Scheme 19. Reductive amination of trifluoroacetic acid to 2,2,2-trifluoroethylamine
via ‘double’ biomimetic transamination.
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Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 11 / Vol. 91
A comparable transformation—oxidation
of benzylamine to a formal benzoic acid resi-
due—was reported by Wang et al. via an elect
rochemical three-component reaction invol
ving quinoline derivatives 50, benzylamines,
and trimethylsilyl cyanide, yielding imida-
zo-fused N-heterocycles 51 with good to ex-
cellent efficiency (Scheme 20) [135]. Fluorine
substituents, either as a single fluorine atom
or a trifluoromethyl group, can be introduced
on both the quinoline derivatives 50 and the
benzylamine substrates, expanding the scope
of this methodology. This anodic oxidation–
driven cyclization proceeds under metal- and
chemical oxidant-free conditions in an un
divided cell, employing readily available star
ting materials. The method is notable for its
substrate generality, environmental friendli-
ness, mild reaction conditions, and excellent
scalability, making it particularly appealing for
applications in complex heterocycle synthesis.
Scheme 20. Electrochemical synthesis of fluorinated imidazo-fused N-heterocycles.
Analogous to biomimetic transamination
involving reduction of carbonyl compounds
and the oxidation of benzylamine [136–138],
the electrochemical reaction reported by Yang
et al. describes the synthesis of 1,2,4-trisubsti-
tuted imidazoles 53 via a three-component cou-
pling of fluorine-containing ketones 52, ben-
zylamine, and alkyl amines (Scheme 21) [139].
The reaction employs readily available starting
materials in an undivided electrochemical cell
equipped with carbon rod electrodes, procee
ding under metal- and oxidant-free condi-
tions. This electrochemical strategy offers a
practical and scalable approach to the synthe-
sis of fluorinated heterocycles 53, with mode
rate to excellent yields across a broad substrate
scope. Owing to its functional group tolerance,
simplicity, and environmental compatibility,
the method holds significant promise for large-
scale applications in heterocyclic and medici-
nal chemistry.
Scheme 21. Electrochemical synthesis of fluorinated 1,2,4-trisubstituted-(1H)imidazoles.
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ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS. (review)PHISICAL CHEMISTRY
Another compelling example of electro-
chemical oxidation of benzylamine derivati
ves, analogous to biomimetic transamination
processes [140–142], was developed by Chen
et al. (Scheme 22) [143]. Their strategy enables
the efficient synthesis of imidazole derivatives
54 under undivided electrolytic conditions,
demonstrating the effectiveness of electro
chemical-oxidation-induced three-component
condensation. The methodology is notably
metal- and peroxide-free, rendering it envi-
ronmentally benign and sustainable. It also
exhibits broad substrate compatibility, allow-
ing for the introduction of fluorine substitu-
ents into the imidazole ring with consistently
high yields. A particularly noteworthy ap-
plication involves the reaction of di-trifluo-
romethylacetylene (perfluorobut-2-yne) with
fluorinated benzylamine and trimethylsilyl
azide (TMS-N₃), affording imidazole products
54 bearing two trifluoromethyl groups and a
fluorinated phenyl ring—a valuable structu
ral motif for pharmaceutical and agrochemical
development.
Scheme 22. Electrochemical synthesis of fluorinated imidazoles.
Mohammedi et al. reported the synthesis
of a novel tetrahydroimidazo[1,2-a]pyridine-
5(1H)-one derivative 56 (Scheme 23) [144]
via a one-pot electrochemical strategy, com-
bining fluoro-aldehydes 4, Meldrum’s acid 54,
and 2-(nitromethylene)imidazolidine 55. The
reaction proceeds in propanol using sodium
bromide as the electrolyte within an undivid-
ed cell, maintained under a constant current of
50 mA, yielding the target heterocyclic com-
pounds in good to excellent yields (70–96%).
This green protocol demonstrates significant
potential for the construction of fused polycyc
lic frameworks relevant to bioactive heterocyc
les. It offers several advantages, including high
product yields, simple experimental setup, and
environmentally benign conditions, making it
an attractive approach for sustainable synthetic
chemistry.
Scheme 23. Electrochemical preparation of fluorine-containing imidazo-pyridines.
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Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 11 / Vol. 91
Gao et al. demonstrated that an electro-
chemical strategy can be effectively employed
to construct complex biologically relevant
molecules bearing trifluoromethyl-substituted
quinoline scaffolds 60 (Scheme 24) [145]. The
method relies on a paired electrolysis–driven
cascade annulation, designed to achieve two
key objectives simultaneously: the direct syn-
thesis of quinolines and their convergent incor-
poration into bioactive molecular frameworks.
The transformation involves the electro-reduc-
tion–induced reaction of fluoro-substituted
isatin 57, methyl 4,4,4-trifluorobut-2-ynoate
58, and alcohol-containing substrates 59.
Conducted in CH₃CN within an undivided
cell equipped with a graphite rod anode and
platinum cathode, and using KI (20 mol%) as
the electrolyte, the reaction proceeds under a
constant current of 5 mA, affording the desired
quinoline derivatives 60 in moderate to excel-
lent yields (40–99%). The reaction exhibits
broad substrate tolerance—the R group in al-
cohol 59 can encompass virtually any organic
residue: from simple aliphatic alcohols to he
terocycles, fluorinated side chains, natural and
tailor-made amino acids [146–148], as well
as peptides, peptidomimetics, steroids, and
small-molecule drugs. Of over sixty examples
explored, only a few representative cases are
shown in Scheme 24.
Importantly, the stereochemical integrity
of chiral centers is preserved under the mild
electrochemical conditions. Fluorine incorpo
ration is also highly tunable, occurring as
monofluoroaryl, aryl–CF₃, or aliphatic–CF₃
functionalities, providing access to a structu
rally diverse library of fluorinated quinolines
with pharmaceutical potential.
Scheme 24. Application of electrochemical approach for preparation of various
quinoline-substituted bioactive molecules.
Sharma et al. developed a novel electroche
mically induced oxidative cascade cyclization
for the synthesis of fluorinated quinazolinone-
and quinoline-decorated indolizine derivatives
64 (Scheme 25) [149]. This transformation pro-
ceeds in an undivided cell under metal- and
oxidant-free conditions, showcasing an envi-
ronmentally friendly approach. The reaction in-
volves a three-component coupling of substitut-
ed pyridines 61, fluorobenzyl-containing quina-
zolinone 62, and fluoro-chalcones 63. Conduct-
ed at 90 °C using two platinum plate electrodes,
50 ISSN 2708-129X. Укр. хім. журн., 2025
ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS. (review)PHISICAL CHEMISTRY
with NH₄I/n-Bu₄NPF₆ as the electrolyte and
dimethylacetamide (DMA) as the solvent, the
method enables efficient construction of hete
rocycle-rich molecular frameworks.
A gram-scale synthesis was performed to
demonstrate the scalability and practical ap-
plicability of the protocol. The study highlights
the potential to expand this strategy toward the
synthesis of more complex polycyclic architec-
tures, offering broad utility in medicinal che
mistry and materials science.
Scheme 25. Electrochemical synthesis of complex fluorinated quinazolin-indolizines.
Tetramolecular reactions.
Yang et al. developed a tetramolecular elec-
trochemical strategy for the synthesis of fluo-
rine-substituted 1,2,4-triazoles 66 (Scheme 26)
[150]. The reaction combines fluorinated aryl
hydrazines 41, benzyl alcohols 65, paraform-
aldehyde (HCHO)n, and ammonium acetate
(NH₄OAc) in a single pot. Electrolysis was
performed under constant current conditions
in an undivided cell equipped with a graphite
rod anode and a nickel plate cathode. Notably,
benzyl alcohol serves both as solvent and re-
actant, while n-Bu₄NI (TBNI) acts as a redox
mediator and t-BuOK as the base. The reaction
proceeds under mild, metal- and oxidant-free
conditions at room temperature, reflecting
its practicality and environmental appeal. In
the resulting triazole derivatives 66, fluorine
atoms are introduced on both aromatic rings,
allowing for structural diversification and the
potential to fine-tune biological properties of
the synthesized compounds.
Scheme 26. Electrochemical synthesis of fluoro-substituted substituted 1,2,4-triazoles.
CONCLUSIONS. This review has showcased
the breadth and sophistication of electrochemi-
cal strategies for synthesizing fluorine-contain-
ing heterocycles, highlighting their relevance
to modern pharmaceutical, agrochemical, and
materials-oriented research. Across a wide ar-
ray of reaction classes, the recurring theme is
the ability of electrochemical methods to drive
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Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 11 / Vol. 91
complex, multibond-forming transformations
under sustainable, operationally simple, and
transition-metal-free conditions.
Electrooxidative multicomponent reacti
ons—including two-, three-, and four-compo-
nent assemblies—have proven highly effective
for constructing structurally rich heterocycles
such as pyrazoles, imidazoles, triazoles, quino
lines, and fused polycyclic systems. Many
of these transformations rely on fluorinated
building blocks (e.g., fluorinated aryl hydra-
zines, benzylamines, or fluoroalkynes) to de-
liver final products that possess both high syn-
thetic value and tunable biological properties.
These methodologies also provide remar
kable flexibility in fluorine incorporation, en-
abling the installation of fluorine in diverse
chemical environments. Substituents may in-
clude single or multiple fluoroaromatic rings,
aromatic CF₃ groups, aliphatic trifluoromethyl
moieties, or combinations thereof, offering
wide-ranging opportunities for structural de-
sign and biological fine-tuning. This versatility
significantly enhances the utility of electro-
chemical platforms in the discovery and deve
lopment of functional fluorinated heterocycles.
Several reactions capitalize on the oxida-
tive transformations of benzylamine moieties,
drawing biomimetic parallels to enzymatic
transamination processes. These processes
enable carbon–nitrogen bond construction
via in situ formation of reactive imine inter-
mediates, thus opening pathways to reductive
amination and tandem heterocycle formation
from simple precursors such as carboxylic
acids, aldehydes, and ketones.
Noteworthy contributions include anodic
SCN• radical generation for thiocyanation
of fluorinated pyrazoles under mild, scalable
conditions; electrosynthesis of imidazoles and
triazoles from benzyl alcohols, fluorinated ke-
tones, and amines in metal- and oxidant-free
systems; cascade annulations involving comp
lex bio-derived alcohols and trifluoromethyl
alkynes, preserving stereochemical integrity
during quinoline ring construction; and elect
rochemically induced ring-forming conden-
sation of fluoroaryl fragments with isatins,
azides, and heteroaromatic substrates, giving
rise to heterocycle-rich molecular frameworks
with structural and functional diversity.
The methodologies described herein emp
loy commonly available electrodes (e.g., gra
phite felt, platinum, nickel), green solvents,
and electrochemical mediators (such as tetra
butylammonium iodide), supporting both
environmental and synthetic economy. Mild
temperatures, functional group tolerance, and
gram-scale validations further underscore the
practical potential of these approaches.
In conclusion, the reviewed strategies
demonstrate that electrochemistry is not
merely a replacement for traditional oxidants
and catalysts, but a powerful platform capable
of orchestrating molecular complexity with
precision—particularly in the realm of fluori
nated heterocyclic synthesis. Future research
is expected to further integrate paired redox
processes, flow electrolysis, and computatio
nally guided design, expanding the boundaries
of what is synthetically and environmentally
possible in this field.
ACKNOWLEDGMENTS: We gratefully
acknowledge the financial support from
IKERBASQUE, Basque Foundation for
Science, (for Soloshonok). The authors
acknowledge the assistance of Microsoft
Copilot and Google Gemini for their
support in translating to Ukrainian.
52 ISSN 2708-129X. Укр. хім. журн., 2025
ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS. (review)PHISICAL CHEMISTRY
ЕЛЕКТРОХІМІЧНИЙ СИНТЕЗ ФТОРОВАНИХ
ГЕТЕРОЦИКЛІЧНИХ СПОЛУК (огляд)
Аліція Взорек,1 Таїзо Оно,2
Даніель Беккер3, Вей Чжан4,
Вадим А. Солошонок5*
1 Хімічний інститут, Університет Яна
Кохановського в Кельці,
вул. Університетська 7, Кельце25–406,
Польща;
2 Національний інститут передової науки
та технологій (AIST),
2266–98, Анагахора, Шімошідамі, район
Моріяма, Нагоя 463–8560, Японія;
3 Відділ фармацевтичної та лікарської
хімії, Фармацевтичний інститут,
Вільний університет Берліна,
Кьоніґін-Луїзе-Штрасе 2+4, Берлін 14195,
Німеччина;
4 Хімічний факультет, Університет
Массачусетса в Бостоні,
Бостон, Массачусетс 02125, Сполучені
Штати Америки;
5 ІКЕРБАСКЕ, Баскська наукова фундація,
вул. Марія Діас де Харо 3, площа Бізкая,
Більбао 48013, Іспанія
e-mail: vadimsoloshonok@gmail.com
Фторвмісні гетероцикли відіграють клю-
чову роль у фармацевтичній, агрохімічній
та матеріалознавчій промисловості. Праг-
нення до ефективних та сталих методів
синтезу сприяло розвитку електрохімії як
привабливої альтернативи традиційним
хімічним перетворенням. Серед цих підхо-
дів електрохімія виявилася особливо перс
пективною технікою для здійснення бага-
тозв’язкових процесів у м’яких, екологічно
чистих умовах.
Цей огляд висвітлює ключові досягнен-
ня за останнє десятиліття в електрохіміч-
ному синтезі фторованих гетероциклічних
сполук, що охоплюють бімолекулярні, три-
молекулярні та чотиримолекулярні реак-
ції. Особливу увагу приділено багатоком
понентним каскадним стратегіям, ради-
кально-опосередкованим сполученням та
безокиснювальним циклізаціям, які забез-
печують широку толерантність до функціо
нальних груп та гнучкість введення фтору.
Сукупно ця робота слугує ресурсом для
дослідників, які розробляють стійкі синте-
тичні платформи нового покоління, адап-
товані до фторованих гетероциклів із різ-
номанітними структурними та біологічни-
ми профілями.
Ключові слова: електрохімія, гетероцик
лічні сполуки, фтор, фторовані фармацев
тичні препарати, зелена хімія, сталий син-
тез.
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Стаття надійшла 06.08.2025.
|
| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-757 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:13:54Z |
| publishDate | 2025 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
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| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-7572026-07-22T08:23:56Z ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS(Review) Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim Electrochemistry, Heterocyclic Compounds, Fluorine, Fluorinated Pharmaceuticals, Green Chemistry, Sustainable Synthesis. Fluorine-containing heterocycles play a crucial role in the pharmaceutical, agrochemical, and materials industries. The pursuit of effective and sustainable synthesis methods has driven the development of electrochemistry as a compelling alternative to conventional chemical transformations. Among these approaches, electrochemistry has emerged as a particularly promising technique for orchestrating multibond-forming processes under mild, environmentally benign conditions. This review highlights key advances over the past decade in the electrochemical synthesis of fluorinated heterocyclic compounds, encompassing bimolecular, trimolecular, and tetramolecular reactions. Emphasis is placed on multicomponent cascade strategies, radical-mediated couplings, and oxidant-free cyclizations that afford broad functional group tolerance and fluorine incorporation flexibility. Collectively, this work serves as a resource for researchers developing next-generation sustainable synthetic platforms tailored to fluorinated heterocycles with diverse structural and biological profiles. V.I.Vernadsky Institute of General and Inorganic Chemistry 2025-12-25 Article Article Physical chemistry Физическая xимия Фізична xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/757 10.33609/2708-129X.91.11.2025.35-62 Ukrainian Chemistry Journal; Vol. 91 No. 11 (2025): Ukrainian Chemistry Journal; 35-62 Украинский химический журнал; ##issue.vol## 91 ##issue.no## 11 (2025): Ukrainian Chemistry Journal; 35-62 Український хімічний журнал; Том 91 № 11 (2025): Ukrainian Chemistry Journal; 35-62 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/757/392 Copyright (c) 2025 Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS(Review) |
| title | ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS(Review) |
| title_full | ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS(Review) |
| title_fullStr | ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS(Review) |
| title_full_unstemmed | ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS(Review) |
| title_short | ELECTROCHEMICAL SYNTHESIS OF FLUORINATED HETEROCYCLIC COMPOUNDS(Review) |
| title_sort | electrochemical synthesis of fluorinated heterocyclic compounds(review) |
| topic_facet | Electrochemistry Heterocyclic Compounds Fluorine Fluorinated Pharmaceuticals Green Chemistry Sustainable Synthesis. |
| url | https://ucj.org.ua/index.php/journal/article/view/757 |
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