MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING(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 mechanochemistry as a solvent-free, energy-efficient alternative to conventional chemical trans...
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Ukrainian Chemistry Journal| _version_ | 1871466151188365312 |
|---|---|
| author | Han, Jianlin Wzorek, Alicja Ono, Taizo Klika, Karel Soloshonok, Vadim |
| author_facet | Han, Jianlin Wzorek, Alicja Ono, Taizo Klika, Karel Soloshonok, Vadim |
| author_institution_txt_mv | [
{
"author": "Jianlin Han",
"institution": "Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China"
},
{
"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": "Karel Klika",
"institution": "Molecular Structure Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 280, 69120 Heidelberg, Germany"
},
{
"author": "Vadim Soloshonok",
"institution": "University of Basque Country"
}
] |
| author_sort | Han, Jianlin |
| 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 mechanochemistry as a solvent-free, energy-efficient alternative to conventional chemical transformations. Among these approaches, ball milling has emerged as a particularly promising technique for facilitating chemical reactions. This review covers key achievements over the past decade in the mechanochemical synthesis of fluorinated heterocyclic compounds for bimolecular, trimolecular, and tetramolecular reactions as well as transformations classified as peripheral functionalization of the heterocyclic framework. This work serves as a valuable resource for researchers and practitioners seeking to develop sustainable and efficient catalytic systems for fluorinated heterocyclic synthesis. |
| doi_str_mv | 10.33609/2708-129X.91.7.2025.35-55 |
| first_indexed | 2025-10-23T01:32:48Z |
| format | Article |
| fulltext |
35
UDC 546.26-162: 541.13:549.21 doi: 10.33609/2708-129X.91.7.2025.35-55
MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING
HETEROCYCLES VIA BALL MILLING.
Jianlin Han1, Alicja Wzorek2, Taizo Ono3, Karel D. Klika4, Vadim A. Soloshonok5,6*
1 Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources,
College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China;
2 Institute of Chemistry, Jan Kochanowski University in Kielce,
Uniwersytecka 7, 25-406 Kielce, Poland;
3 National Institute of Advanced Industrial Science and Technology (AIST),
2266-98, Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463-8560, Japan;
4 Research & Development Center, Archer Daniels Midland,
1001 N Brush College Rd., Decatur, IL 62521, USA;
5 Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country
UPV/EHU, Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain;
6 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 driven
the development of mechanochemistry as a solvent-free, energy-efficient alternative to con-
ventional chemical transformations. Among these approaches, ball milling has emerged as a
particularly promising technique for facilitating chemical reactions. This review covers key
achievements over the past decade in the mechanochemical synthesis of fluorinated hetero-
cyclic compounds for bimolecular, trimolecular, and tetramolecular reactions as well as trans-
formations classified as peripheral functionalization of the heterocyclic framework. This work
serves as a valuable resource for researchers and practitioners seeking to develop sustainable
and efficient catalytic systems for fluorinated heterocyclic synthesis.
Keywords: Fluorine, Heterocyclic Compounds, Fluorinated Pharmaceuticals, Mechanoche
mistry, Ball Milling, Green Chemistry, Sustainable Synthesis.
36 ISSN 2708-129X. Укр. хім. журн., 2025
MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING.ORGANIC CHEMISTRY
INTRODUCTION. Mechanochemistry, a
subdiscipline of chemistry, instigates chemi
cal transformations initiated by the direct
application of mechanical energy in contrast
to conventional thermal, photochemical, or
electrochemical activation. These reactions
are typically induced through techniques such
as grinding, milling, and the exertion of me-
chanical force to instigate molecular transfor-
mations. Particularly effective in solid-state
chemistry, mechanochemical forces can over-
come activation energies by disrupting crystal
lattices, breaking bonds, and enhancing reac-
tant contact, frequently enabling solvent-free
reactions and aligning with green chemistry
principles. The unique activation mechanisms
of mechanochemistry are finding growing uti
lity in materials science, pharmaceuticals, and
catalysis providing sustainable alternatives to
traditional synthetic methodologies [1–7].
Ball milling, an innovative mechanochemi
cal strategy in organic synthesis, involves the
high-energy grinding of reactants within a ro-
tating reactor, typically a cylindrical chamber
charged with milling media such as ceramic,
steel, or zirconia spheres, which provides the
mechanical energy required for bond activa-
tion. Reaction progression is efficiently de-
livered through impact and frictional forces
generated by the movement of the milling me-
dia, instigating molecular transformations. By
significantly reducing or eliminating the use of
hazardous organic solvents, ball milling offers
enhanced substrate reactivity as the application
of mechanical force effectively activates reac-
tant molecules, often facilitating transforma-
tions that exhibit sluggish kinetics or require
harsh conditions in traditional solution-phase
methodologies. This can unlock unique reac-
tion pathways, enabling challenging transfor-
mations such as carbon–carbon bond forma-
tion, oxidation reactions, and the selective func-
tionalization of heterocyclic compounds with
potentially enhanced regioselectivity [8–15].
Scaling up mechanochemical processes,
particularly ball milling techniques, from la
boratory to industrial settings presents several
challenges. Reactor design must ensure uni-
form energy distribution and effective mix-
ing across larger volumes, a task complicated
by the risk of uneven reactions and increased
equipment wear at industrial scales. Addi-
tionally, mechanochemical systems lack the
precise monitoring and control mechanisms
found in solution-phase reactions, making it
more difficult to regulate key parameters such
as temperature, pressure, and reaction kine
tics–especially in larger setups. Consequently,
optimizing reaction conditions requires meti
culous experimentation and refinement. Given
these complexities, synthetically useful data
reported in the literature serve as invaluable
resources for practitioners seeking to advance
mechanochemical methodologies [16–20].
As part of our expertise in modern pharma-
ceutical development [21–25], particularly in
fluorine-containing drugs [26–31] and those
derived from tailor-made amino acids [32–37],
we continuously explore and assess innovative
synthetic methodologies [38–42]. Given that
heterocyclic compounds and amino acids form
the structural foundation of over 85% and 35%
of modern pharmaceutical drugs, respectively,
we place special emphasis on advancements in
these synthetic domains [43–52]. Heterocyclic
compounds, in particular, serve as fundamen-
tal building blocks in medicinal chemistry with
their broad biological activity and exceptional
structural versatility making them indispen
sable for rational drug design [53–56].
37https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 7 / Vol. 91
As previously noted, mechanochemistry is
an emerging research field with significant syn-
thetic potential. In this review, we summarize
the data published over the past decade on the
mechanochemical synthesis of fluorine-con-
taining heterocyclic compounds under ball
milling conditions. The content is organized
based on the number of reacting species cover-
ing bi-, tri-, and tetramolecular reactions with
a final section dedicated to examples classified
as peripheral functionalization of the hetero-
cyclic framework. We believe this compilation
will serve as a valuable resource and inspiration
for researchers and practitioners in the fields
of synthetic and medicinal chemistry as well as
those interested in sustainable methodologies.
Bimolecular reactions.
The synthesis of trifluoromethyl derivatives
of 7-phenylpyrazolo[1,5-a]pyrimidine 3 is
presented in Scheme 1. Using nanosized, pow-
dered magnesium oxide as catalyst, unsatura
ted amino ketone 1 reacted with 1H-pyrazol-
5-amine 2 under ball milling. For optimized
conditions, the reaction proceeded at relatively
high rates affording the target 7-phenylpyra-
zolo[1,5-a]pyrimidines 3 with excellent chem-
ical yields. This mechanochemical process has
a high degree of generality as 1H-pyrazol-5-
amines 2 can carry various alkyl and aryl sub-
stituents.
Scheme 1. Synthesis of trifluoromethyl derivatives of 7-phenylpyrazolo[1,5-a]pyrimidine 3
under ball milling (BM).
It is interesting to note that these structural-
ly new fluorinated 7-phenylpyrazolo[1,5-a]py-
rimidines 3 show promising antibacterial and
anticancer properties [57].
The one-pot, two-step mechanochemical
synthesis of fluorinated pyrazolones 6 and 7 is
illustrated in Scheme 2. Trifluoromethyl-sub-
stituted β-keto ester 4 reacts with phenylhy-
drazines 5 under ball milling in the presence of
NaCl (6 eq.) and acetic acid (0.5 eq.) yielding
trifluoromethylated pyrazolones 6 in yields in
excess of 90% [58]. Furthermore, the authors
demonstrated that fluorination of 6 with Se-
lectfluor [59] can also be achieved under me
chanochemical conditions affording deriva-
tives 7 in yields ranging from 40% to 60% fea-
turing multiple fluorination patterns.
After meticulous optimization, the final
protocol has been successfully applied to the
synthesis of a library of 12 difluorinated pyra-
zolones 7 highlighting the synthetic versatility
of ball milling. Due to their enhanced electro-
philicity, fluorinated 1,3-dicarbonyl compounds
exhibit high reactivity toward nucleophilic
and inspiration for researchers and practitioners in the fields of synthetic and
medicinal chemistry as well as those interested in sustainable methodologies.
Bimolecular reactions.
The synthesis of trifluoromethyl derivatives of
7-phenylpyrazolo[1,5-a]pyrimidine 3 is presented in Scheme 1. Using nanosized,
powdered magnesium oxide as catalyst, unsaturated amino ketone 1 reacted with
1H-pyrazol-5-amine 2 under ball milling. For optimized conditions, the reaction
proceeded at relatively high rates affording the target
7-phenylpyrazolo[1,5-a]pyrimidines 3 with excellent chemical yields. This
mechanochemical process has a high degree of generality as 1H-pyrazol-5-amines 2
can carry various alkyl and aryl substituents.
Scheme 1. Synthesis of trifluoromethyl derivatives of 7-phenylpyrazolo[1,5-a]pyrimidine 3
under ball milling (BM).
It is interesting to note that these structurally new fluorinated
7-phenylpyrazolo[1,5-a]pyrimidines 3 show promising antibacterial and anticancer
properties [57].
The one-pot, two-step mechanochemical synthesis of fluorinated pyrazolones 6
and 7 is illustrated in Scheme 2. Trifluoromethyl-substituted β-keto ester 4 reacts with
phenylhydrazines 5 under ball milling in the presence of NaCl (6 eq.) and acetic acid
(0.5 eq.) yielding trifluoromethylated pyrazolones 6 in yields in excess of 90% [58].
Furthermore, the authors demonstrated that fluorination of 6 with Selectfluor [59] can
also be achieved under mechanochemical conditions affording derivatives 7 in yields
ranging from 40% to 60% featuring multiple fluorination patterns.
Scheme 2. Synthesis of fluorinated pyrazolones 6 and 7.
38 ISSN 2708-129X. Укр. хім. журн., 2025
MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING.ORGANIC CHEMISTRY
reagents [60], often posing challenges in con-
trolling reaction selectivity. Consequently, the
development of this mechanochemical proto-
col marks a significant achievement offering
an efficient and reproducible method for the
preparation of fluorinated pyrazolones 6 and 7.
Scheme 2. Synthesis of fluorinated pyrazolones 6 and 7.
Indoles are a crucial scaffold in drug design
due to their versatile biological activity and
ability to interact with various molecular tar-
gets. They are found in numerous natural and
synthetic pharmaceuticals playing key roles in
anticancer, antimicrobial, anti-inflammatory,
and neuroprotective therapies. Their structur-
al adaptability allows medicinal chemists to
modify them for enhanced potency, selectivity,
and bioavailability making them indispensable
in modern drug discovery [61–64]. Numerous
approaches have been developed for the prepa-
ration of variously substituted indole deriva-
tives [65–67], including fluorine-containing
variants [68–71].
Scheme 3 presents a mechanochemical ap-
proach to Fischer indolization under ball mill-
ing conditions [72]. In this method, 1-naph-
thylhydrazine 8 reacts with fluorinated ketone
9 in the presence of oxalic acid and dimethy-
lurea as catalysts together with a trace amount
of acetic acid serving as a liquid-assisted grin
ding agent. The reaction is conducted in a ball
mill at 30 Hz for two hours at ambient tempe
rature providing fluoroindoles 10 in excellent
yields of ~90%. Besides fluorine at the para po-
sition, ketones 9 can also accommodate other
halogens and alkyl groups—including ben-
zyl—highlighting the structural versatility of
this mechanochemical approach for the syn-
thesis of indole derivatives relevant to medi
cinal chemistry studies.
Scheme 3. Synthesis of fluoroindoles 10.
and inspiration for researchers and practitioners in the fields of synthetic and
medicinal chemistry as well as those interested in sustainable methodologies.
Bimolecular reactions.
The synthesis of trifluoromethyl derivatives of
7-phenylpyrazolo[1,5-a]pyrimidine 3 is presented in Scheme 1. Using nanosized,
powdered magnesium oxide as catalyst, unsaturated amino ketone 1 reacted with
1H-pyrazol-5-amine 2 under ball milling. For optimized conditions, the reaction
proceeded at relatively high rates affording the target
7-phenylpyrazolo[1,5-a]pyrimidines 3 with excellent chemical yields. This
mechanochemical process has a high degree of generality as 1H-pyrazol-5-amines 2
can carry various alkyl and aryl substituents.
Scheme 1. Synthesis of trifluoromethyl derivatives of 7-phenylpyrazolo[1,5-a]pyrimidine 3
under ball milling (BM).
It is interesting to note that these structurally new fluorinated
7-phenylpyrazolo[1,5-a]pyrimidines 3 show promising antibacterial and anticancer
properties [57].
The one-pot, two-step mechanochemical synthesis of fluorinated pyrazolones 6
and 7 is illustrated in Scheme 2. Trifluoromethyl-substituted β-keto ester 4 reacts with
phenylhydrazines 5 under ball milling in the presence of NaCl (6 eq.) and acetic acid
(0.5 eq.) yielding trifluoromethylated pyrazolones 6 in yields in excess of 90% [58].
Furthermore, the authors demonstrated that fluorination of 6 with Selectfluor [59] can
also be achieved under mechanochemical conditions affording derivatives 7 in yields
ranging from 40% to 60% featuring multiple fluorination patterns.
Scheme 2. Synthesis of fluorinated pyrazolones 6 and 7.
After meticulous optimization, the final protocol has been successfully applied to
the synthesis of a library of 12 difluorinated pyrazolones 7 highlighting the synthetic
versatility of ball milling. Due to their enhanced electrophilicity, fluorinated
1,3-dicarbonyl compounds exhibit high reactivity toward nucleophilic reagents [60],
often posing challenges in controlling reaction selectivity. Consequently, the
development of this mechanochemical protocol marks a significant achievement
offering an efficient and reproducible method for the preparation of fluorinated
pyrazolones 6 and 7.
Indoles are a crucial scaffold in drug design due to their versatile biological
activity and ability to interact with various molecular targets. They are found in
numerous natural and synthetic pharmaceuticals playing key roles in anticancer,
antimicrobial, anti-inflammatory, and neuroprotective therapies. Their structural
adaptability allows medicinal chemists to modify them for enhanced potency,
selectivity, and bioavailability making them indispensable in modern drug discovery
[61–64]. Numerous approaches have been developed for the preparation of variously
substituted indole derivatives [65–67], including fluorine-containing variants [68–71].
Scheme 3 presents a mechanochemical approach to Fischer indolization under
ball milling conditions [72]. In this method, 1-naphthylhydrazine 8 reacts with
fluorinated ketone 9 in the presence of oxalic acid and dimethylurea as catalysts
together with a trace amount of acetic acid serving as a liquid-assisted grinding agent.
The reaction is conducted in a ball mill at 30 Hz for two hours at ambient temperature
providing fluoroindoles 10 in excellent yields of ~90%. Besides fluorine at the para
position, ketones 9 can also accommodate other halogens and alkyl
groups—including benzyl—highlighting the structural versatility of this
mechanochemical approach for the synthesis of indole derivatives relevant to
medicinal chemistry studies.
Scheme 3. Synthesis of fluoroindoles 10.
Quinazolinones exhibit a broad spectrum of biological activities, including
anticancer, antimicrobial, anti-inflammatory, antihypertensive, and antiviral properties.
Their structural versatility makes them valuable scaffolds in drug design with many
derivatives showing promising therapeutic effects [73–75]. Benzothiazoles are widely
studied for their antitumor, antibacterial, antifungal, and neuroprotective properties.
They are frequently explored in medicinal chemistry for their ability to interact with
biological targets making them useful in Alzheimer’s disease research, anticancer
therapies, and antimicrobial drug development [76–79].
Scheme 4 illustrates a mechanochemical approach for the synthesis of fluorinated
quinazolinones 13 and benzothiazoles 15 [80]. In this process, fluorine-containing
39https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 7 / Vol. 91
Quinazolinones exhibit a broad spectrum
of biological activities, including anticancer,
antimicrobial, anti-inflammatory, antihyper-
tensive, and antiviral properties. Their struc-
tural versatility makes them valuable scaffolds
in drug design with many derivatives showing
promising therapeutic effects [73–75]. Benzo
thiazoles are widely studied for their antitumor,
antibacterial, antifungal, and neuroprotective
properties. They are frequently explored in
medicinal chemistry for their ability to interact
with biological targets making them useful in
Alzheimer’s disease research, anticancer the
rapies, and antimicrobial drug development
[76–79].
Scheme 4 illustrates a mechanochemical ap-
proach for the synthesis of fluorinated quina-
zolinones 13 and benzothiazoles 15 [80]. In
this process, fluorine-containing α-keto acids
11 react with 2-aminobenzamides 12 under
ball milling at 30 Hz and ambient temperature
for 3 hours. Upon completion, the reaction
mixture is quenched with NaHCO₃ and the
target fluorinated quinazolinones 13 are puri-
fied either by recrystallization or column chro-
matography yielding products in good-to-ex-
cellent yields of 74–92%. Ball milling has been
successfully scaled to gram quantities, though
extended reaction times of up to 5 hours were
required. Notably, fluorine substitution is
well-tolerated on both starting compounds 11
and 12 enabling the design of quinazolinones
13 with varying degrees and positions of fluo-
rine atoms and trifluoromethyl groups.
Scheme 4. Synthesis of fluorinated quinazolinones 13 and benzothiazoles 15.
The synthesis of fluorinated benzothiazole
derivatives 15 is carried out under the same
ball milling conditions substituting 2-amino
thiophenol 14 for 2-aminobenzamides 12. The
reactions proceed in similarly high yields of
80–90% yields providing a convenient and reli-
able route to fluorinated benzothiazoles 15 [82].
Both fluorine and trifluoromethyl groups can
be incorporated into the starting compounds 11
and 12, further highlighting the synthetic versa-
tility of this mechanochemical approach.
The benzopyrone class of heterocyclic com-
pounds, including chromones and coumarins,
comprises naturally occurring biologically ac-
tive molecules with diverse pharmacological
properties. These compounds exhibit antioxi
dant, anti-inflammatory, antimicrobial, anti-
cancer, and neuroprotective activities making
them valuable in drug discovery. Their ability
to regulate enzymatic pathways, oxidative
stress, and inflammatory responses has driven
their exploration for potential treatments of
α-keto acids 11 react with 2-aminobenzamides 12 under ball milling at 30 Hz and
ambient temperature for 3 hours. Upon completion, the reaction mixture is quenched
with NaHCO₃ and the target fluorinated quinazolinones 13 are purified either by
recrystallization or column chromatography yielding products in good-to-excellent
yields of 74–92%. Ball milling has been successfully scaled to gram quantities,
though extended reaction times of up to 5 hours were required. Notably, fluorine
substitution is well-tolerated on both starting compounds 11 and 12 enabling the
design of quinazolinones 13 with varying degrees and positions of fluorine atoms and
trifluoromethyl groups.
Scheme 4. Synthesis of fluorinated quinazolinones 13 and benzothiazoles 15.
The synthesis of fluorinated benzothiazole derivatives 15 is carried out under the
same ball milling conditions substituting 2-aminothiophenol 14 for
2-aminobenzamides 12. The reactions proceed in similarly high yields of 80–90%
yields providing a convenient and reliable route to fluorinated benzothiazoles 15 [82].
Both fluorine and trifluoromethyl groups can be incorporated into the starting
compounds 11 and 12, further highlighting the synthetic versatility of this
mechanochemical approach.
The benzopyrone class of heterocyclic compounds, including chromones and
coumarins, comprises naturally occurring biologically active molecules with diverse
pharmacological properties. These compounds exhibit antioxidant, anti-inflammatory,
antimicrobial, anticancer, and neuroprotective activities making them valuable in drug
discovery. Their ability to regulate enzymatic pathways, oxidative stress, and
inflammatory responses has driven their exploration for potential treatments of
neurological disorders, infections, and metabolic diseases [81–83].
Scheme 5 illustrates the mechanochemical synthesis of fluorinated
3-acylchromones 18 [84]. The reaction of enaminones 16 with fluorine-containing
benzoic acids 17 is efficiently catalyzed by FeCl₃ supported on nanocellulose under
ball milling. The process exhibits a relatively fast reaction rate reaching completion
within approximately 1.5 hours and in excellent yield.
40 ISSN 2708-129X. Укр. хім. журн., 2025
MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING.ORGANIC CHEMISTRY
neurological disorders, infections, and meta-
bolic diseases [81–83].
Scheme 5 illustrates the mechanochemical
synthesis of fluorinated 3-acylchromones 18
[84]. The reaction of enaminones 16 with fluo
rine-containing benzoic acids 17 is efficiently
catalyzed by FeCl₃ supported on nanocellulose
under ball milling. The process exhibits a re
latively fast reaction rate reaching completion
within approximately 1.5 hours and in excel-
lent yield.
Scheme 5. Synthesis of fluorine-containing chromones 18.
This mechanochemical approach is straight-
forward and accommodates a wide range of
substitutions on the benzoic acid moiety. Spe-
cifically, one or two fluorine atoms, trifluo-
romethyl, and trifluoromethoxy groups can
be introduced at the ortho, meta, or para posi-
tions within the target chromones 18. Particu-
larly noteworthy are derivatives containing the
trifluoromethoxy group which is commonly
found in the structures of successful pharma-
ceutical drugs and agrochemicals [85, 86].
Scheme 6 presents a compelling example
of the mechanochemical synthesis of fluorina
ted 1,2-disubstituted benzimidazole 21 [87].
The reaction of benzene-1,2-diamine 19 with
two equivalents of o-fluorobenzaldehyde 20
is catalyzed by FeCl₃·6H₂O under ball milling
and involves the oxidation of one aldehyde re
sidue together with the reduction of the other.
This internal redox process is likely to proceed
via transition state TS 1 featuring a key biomi-
metic 1,3-hydrogen transfer [88]. Fluorinated
benzaldehydes are highly reactive and exhibit
distinct reactivity patterns depending on the
number and position of fluorine atoms on the
aromatic ring [89, 90].
Scheme 6. Synthesis of fluorinated benzimidazole 21.
Scheme 5. Synthesis of fluorine-containing chromones 18.
This mechanochemical approach is straightforward and accommodates a wide
range of substitutions on the benzoic acid moiety. Specifically, one or two fluorine
atoms, trifluoromethyl, and trifluoromethoxy groups can be introduced at the ortho,
meta, or para positions within the target chromones 18. Particularly noteworthy are
derivatives containing the trifluoromethoxy group which is commonly found in the
structures of successful pharmaceutical drugs and agrochemicals [85, 86].
Scheme 6 presents a compelling example of the mechanochemical synthesis of
fluorinated 1,2-disubstituted benzimidazole 21 [87]. The reaction of
benzene-1,2-diamine 19 with two equivalents of o-fluorobenzaldehyde 20 is catalyzed
by FeCl₃·6H₂O under ball milling and involves the oxidation of one aldehyde residue
together with the reduction of the other. This internal redox process is likely to
proceed via transition state TS 1 featuring a key biomimetic 1,3-hydrogen transfer
[88]. Fluorinated benzaldehydes are highly reactive and exhibit distinct reactivity
patterns depending on the number and position of fluorine atoms on the aromatic ring
[89, 90].
Scheme 6. Synthesis of fluorinated benzimidazole 21.
Scheme 7 illustrates examples of mechanochemical fluorination-cyclization
reactions. The treatment of unsaturated carboxylic acid 22 with fluoroiodane under
ball milling leads to the clean formation of fluorinated dihydrofuranone 23 in a good
yield of 80%. Similarly, the reaction of aromatic acid 24 under identical
mechanochemical conditions affords the corresponding benzofuranone 25 with
comparable efficiency. Notably, both heterocyclic compounds 23 and 25 incorporate
fluorine substitution at both aromatic and aliphatic positions, highlighting the
Scheme 5. Synthesis of fluorine-containing chromones 18.
This mechanochemical approach is straightforward and accommodates a wide
range of substitutions on the benzoic acid moiety. Specifically, one or two fluorine
atoms, trifluoromethyl, and trifluoromethoxy groups can be introduced at the ortho,
meta, or para positions within the target chromones 18. Particularly noteworthy are
derivatives containing the trifluoromethoxy group which is commonly found in the
structures of successful pharmaceutical drugs and agrochemicals [85, 86].
Scheme 6 presents a compelling example of the mechanochemical synthesis of
fluorinated 1,2-disubstituted benzimidazole 21 [87]. The reaction of
benzene-1,2-diamine 19 with two equivalents of o-fluorobenzaldehyde 20 is catalyzed
by FeCl₃·6H₂O under ball milling and involves the oxidation of one aldehyde residue
together with the reduction of the other. This internal redox process is likely to
proceed via transition state TS 1 featuring a key biomimetic 1,3-hydrogen transfer
[88]. Fluorinated benzaldehydes are highly reactive and exhibit distinct reactivity
patterns depending on the number and position of fluorine atoms on the aromatic ring
[89, 90].
Scheme 6. Synthesis of fluorinated benzimidazole 21.
Scheme 7 illustrates examples of mechanochemical fluorination-cyclization
reactions. The treatment of unsaturated carboxylic acid 22 with fluoroiodane under
ball milling leads to the clean formation of fluorinated dihydrofuranone 23 in a good
yield of 80%. Similarly, the reaction of aromatic acid 24 under identical
mechanochemical conditions affords the corresponding benzofuranone 25 with
comparable efficiency. Notably, both heterocyclic compounds 23 and 25 incorporate
fluorine substitution at both aromatic and aliphatic positions, highlighting the
41https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 7 / Vol. 91
Scheme 7 illustrates examples of mechano
chemical fluorination-cyclization reactions.
The treatment of unsaturated carboxylic acid
22 with fluoroiodane under ball milling leads
to the clean formation of fluorinated dihydro-
furanone 23 in a good yield of 80%. Similarly,
the reaction of aromatic acid 24 under iden-
tical mechanochemical conditions affords the
corresponding benzofuranone 25 with com-
parable efficiency. Notably, both heterocyclic
compounds 23 and 25 incorporate fluorine
substitution at both aromatic and aliphatic po-
sitions, highlighting the versatility of this ap-
proach [91].
Scheme 7. Synthesis of fluorinated dihydrofuranone 23 and benzofuranone 25.
Trimolecular reactions.
Fluorine-containing benzaldehydes are
highly reactive compounds widely utilized in
the synthesis of various five-membered he
terocyclic structures, either as final products
or key intermediates [92, 93]. Benzaldehyde
26, activated by a trifluoromethyl group in
the para position, rapidly reacts with dimethyl
acetylenedicarboxylate 27 and diverse anilines
28 under ball milling at ambient temperature
yielding highly functionalized pyrrolidinones
29 in 25 minutes and in excellent 80–90%
yields (Scheme 8). The reactions under ball
milling are catalyzed by 1,1’-butylene bis(3-
sulfo-3H-imidazol-1-ium) hydrogen sulfate
(BBSIHSO₄), a reusable Brønsted acid ionic
liquid catalyst [94].
Scheme 8. Synthesis of trifluoromethyl-containing pyrrolidinones 29.
versatility of this approach [91].
Scheme 7. Synthesis of fluorinated dihydrofuranone 23 and benzofuranone 25.
Trimolecular reactions.
Fluorine-containing benzaldehydes are highly reactive compounds widely utilized
in the synthesis of various five-membered heterocyclic structures, either as final
products or key intermediates [92, 93]. Benzaldehyde 26, activated by a
trifluoromethyl group in the para position, rapidly reacts with dimethyl
acetylenedicarboxylate 27 and diverse anilines 28 under ball milling at ambient
temperature yielding highly functionalized pyrrolidinones 29 in 25 minutes and in
excellent 80–90% yields (Scheme 8). The reactions under ball milling are catalyzed
by 1,1'-butylene bis(3-sulfo-3H-imidazol-1-ium) hydrogen sulfate (BBSIHSO₄), a
reusable Brønsted acid ionic liquid catalyst [94].
Scheme 8. Synthesis of trifluoromethyl-containing pyrrolidinones 29.
A catalyst-free, solvent-free trimolecular reaction between fluorobenzaldehyde 30,
6-aminouracil 31, and 2,2-dimethyl-1,3-dioxane-4,6-dione 32 is performed under ball
milling yielding fluoropyridopyrimidine 33 in excellent yields of 90% [95]. Due to
the highly electrophilic nature of the malonic residue in diester 32, it undergoes ring
opening followed by decarboxylation, contributing only two carbon atoms to the
structure of pyridopyrimidine 33. Alternatively, employing more stable diamides (e.g.,
barbituric acid) or 1,3-diketones (e.g., dimedone), 34 results in a distinct chemical
transformation enabling the synthesis of fluorinated tricyclic pyrimidoquinolines 35
(Scheme 9) in high yields of 90–97%.
versatility of this approach [91].
Scheme 7. Synthesis of fluorinated dihydrofuranone 23 and benzofuranone 25.
Trimolecular reactions.
Fluorine-containing benzaldehydes are highly reactive compounds widely utilized
in the synthesis of various five-membered heterocyclic structures, either as final
products or key intermediates [92, 93]. Benzaldehyde 26, activated by a
trifluoromethyl group in the para position, rapidly reacts with dimethyl
acetylenedicarboxylate 27 and diverse anilines 28 under ball milling at ambient
temperature yielding highly functionalized pyrrolidinones 29 in 25 minutes and in
excellent 80–90% yields (Scheme 8). The reactions under ball milling are catalyzed
by 1,1'-butylene bis(3-sulfo-3H-imidazol-1-ium) hydrogen sulfate (BBSIHSO₄), a
reusable Brønsted acid ionic liquid catalyst [94].
Scheme 8. Synthesis of trifluoromethyl-containing pyrrolidinones 29.
A catalyst-free, solvent-free trimolecular reaction between fluorobenzaldehyde 30,
6-aminouracil 31, and 2,2-dimethyl-1,3-dioxane-4,6-dione 32 is performed under ball
milling yielding fluoropyridopyrimidine 33 in excellent yields of 90% [95]. Due to
the highly electrophilic nature of the malonic residue in diester 32, it undergoes ring
opening followed by decarboxylation, contributing only two carbon atoms to the
structure of pyridopyrimidine 33. Alternatively, employing more stable diamides (e.g.,
barbituric acid) or 1,3-diketones (e.g., dimedone), 34 results in a distinct chemical
transformation enabling the synthesis of fluorinated tricyclic pyrimidoquinolines 35
(Scheme 9) in high yields of 90–97%.
42 ISSN 2708-129X. Укр. хім. журн., 2025
MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING.ORGANIC CHEMISTRY
A catalyst-free, solvent-free trimolecular re-
action between fluorobenzaldehyde 30, 6-ami-
nouracil 31, and 2,2-dimethyl-1,3-dioxane-
4,6-dione 32 is performed under ball milling
yielding fluoropyridopyrimidine 33 in excel-
lent yields of 90% [95]. Due to the highly elec-
trophilic nature of the malonic residue in di-
ester 32, it undergoes ring opening followed by
decarboxylation, contributing only two carbon
atoms to the structure of pyridopyrimidine
33. Alternatively, employing more stable di-
amides (e.g., barbituric acid) or 1,3-diketones
(e.g., dimedone), 34 results in a distinct che
mical transformation enabling the synthesis
of fluorinated tricyclic pyrimidoquinolines 35
(Scheme 9) in high yields of 90–97%.
Scheme 9. Synthesis of fluorine-containing pyridopyrimidines 33 and pyrimidoquinolines 35.
Ethyl 4,4,4-trifluoro-3-oxobutanoate 36
(Scheme 10) is a highly reactive keto-ester
widely utilized in the synthesis of fluorinated
β-amino acids and their derivatives [96–98].
Under ball milling at ambient temperature,
the trimolecular reaction of keto-ester 36 with
aromatic aldehyde 37 and urea 38 proceeds at
an exceptionally high rate reaching completion
in approximately 10 minutes. The resulting
multicomponent product, dihydropyrimidi-
none 39, is isolated in yields of over 90% [99].
Scheme 10. Synthesis of trifluoromethyl-containing dihydropyrimidinone 39.
30
CHO N
N
O
O
H
H
NH2
O
O
O
O
X
X
O
OY
Y
N
N N X
X
F
F
O
HH
O
O
H
N N
N
F
O
H H
O
O
H
BM
r.t., 30-35 min
Y
Y
31
32
34
33
35
X = CH2, NH; Y = CH3, O
+
up to 80%
65-83%
Scheme 9. Synthesis of fluorine-containing pyridopyrimidines 33 and pyrimidoquinolines 35.
Ethyl 4,4,4-trifluoro-3-oxobutanoate 36 (Scheme 10) is a highly reactive
keto-ester widely utilized in the synthesis of fluorinated β-amino acids and their
derivatives [96–98]. Under ball milling at ambient temperature, the trimolecular
reaction of keto-ester 36 with aromatic aldehyde 37 and urea 38 proceeds at an
exceptionally high rate reaching completion in approximately 10 minutes. The
resulting multicomponent product, dihydropyrimidinone 39, is isolated in yields of
over 90% [99].
Scheme 10. Synthesis of trifluoromethyl-containing dihydropyrimidinone 39.
This variant of the Biginelli reaction [100] is efficiently catalyzed by zeolites.
These porous materials provide both Brønsted and Lewis acid sites, offering key
advantages such as high thermal stability, tunable acidity, and recyclability. Their
compatibility with ball milling conditions further enhances their utility in sustainable
and efficient catalysis.
Scheme 11 demonstrates another application of fluoro-aromatic aldehydes.
p-fluorobenzaldehyde 30 undergoes a trimolecular reaction with
2-hydroxynaphthalene-1,4-dione 40 and malononitrile 41 yielding annulated pyran 43.
This transformation is performed under ball milling at ambient temperature. A key
feature of this reaction is the catalyst tetraethylammonium (carbamoyl)benzoate 42, a
bifunctional organocatalyst that efficiently facilitates the process under ball milling
30
CHO N
N
O
O
H
H
NH2
O
O
O
O
X
X
O
OY
Y
N
N N X
X
F
F
O
HH
O
O
H
N N
N
F
O
H H
O
O
H
BM
r.t., 30-35 min
Y
Y
31
32
34
33
35
X = CH2, NH; Y = CH3, O
+
up to 80%
65-83%
Scheme 9. Synthesis of fluorine-containing pyridopyrimidines 33 and pyrimidoquinolines 35.
Ethyl 4,4,4-trifluoro-3-oxobutanoate 36 (Scheme 10) is a highly reactive
keto-ester widely utilized in the synthesis of fluorinated β-amino acids and their
derivatives [96–98]. Under ball milling at ambient temperature, the trimolecular
reaction of keto-ester 36 with aromatic aldehyde 37 and urea 38 proceeds at an
exceptionally high rate reaching completion in approximately 10 minutes. The
resulting multicomponent product, dihydropyrimidinone 39, is isolated in yields of
over 90% [99].
Scheme 10. Synthesis of trifluoromethyl-containing dihydropyrimidinone 39.
This variant of the Biginelli reaction [100] is efficiently catalyzed by zeolites.
These porous materials provide both Brønsted and Lewis acid sites, offering key
advantages such as high thermal stability, tunable acidity, and recyclability. Their
compatibility with ball milling conditions further enhances their utility in sustainable
and efficient catalysis.
Scheme 11 demonstrates another application of fluoro-aromatic aldehydes.
p-fluorobenzaldehyde 30 undergoes a trimolecular reaction with
2-hydroxynaphthalene-1,4-dione 40 and malononitrile 41 yielding annulated pyran 43.
This transformation is performed under ball milling at ambient temperature. A key
feature of this reaction is the catalyst tetraethylammonium (carbamoyl)benzoate 42, a
bifunctional organocatalyst that efficiently facilitates the process under ball milling
43https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 7 / Vol. 91
This variant of the Biginelli reaction [100] is
efficiently catalyzed by zeolites. These porous
materials provide both Brønsted and Lewis
acid sites, offering key advantages such as high
thermal stability, tunable acidity, and recyc
lability. Their compatibility with ball milling
conditions further enhances their utility in
sustainable and efficient catalysis.
Scheme 11 demonstrates another applica-
tion of fluoro-aromatic aldehydes. p-fluoro
benzaldehyde 30 undergoes a trimolecular
reaction with 2-hydroxynaphthalene-1,4-di-
one 40 and malononitrile 41 yielding annu-
lated pyran 43. This transformation is per-
formed under ball milling at ambient tem-
perature. A key feature of this reaction is the
catalyst tetraethylammonium (carbamoyl)
benzoate 42, a bifunctional organocatalyst
that efficiently facilitates the process under
ball milling [101].
Scheme 11. Synthesis of fluorine-containing pyran 43.
Scheme 12 presents a variant of the Biginel-
li-type multicomponent reaction employing
p-fluorobenzaldehyde 30, sulfonimidamides
44, and β-keto esters 45 to efficiently synthe-
size 2,3-dihydro-1,2,6-thiadiazine 1-oxides 46
in high yields [102]. The reaction is carried out
under solvent-free ball milling at ambient tem-
perature using acetic acid as a catalyst.
Scheme 12. Synthesis of fluoro-substituted thiadiazine 46.
Tetramolecular reactions.
Tetramolecular reactions, while syntheti
cally valuable, are rare. These transformations
resemble a finely tuned orchestra where each
component harmonizes perfectly with all
others. As a result, successfully executing te-
tramolecular reactions evokes a sense of awe,
particularly when they proceed with high ef-
ficiency. Accordingly, mechanochemical tetra-
molecular reactions hold both practical and
aesthetic significance in synthetic chemistry.
The mechanochemical synthesis of fluo
rinated pyranopyrazoles 47 (Scheme 13) was
successfully achieved by ball milling a mixture
[101].
Scheme 11. Synthesis of fluorine-containing pyran 43.
Scheme 12 presents a variant of the Biginelli-type multicomponent reaction
employing p-fluorobenzaldehyde 30, sulfonimidamides 44, and β-keto esters 45 to
efficiently synthesize 2,3-dihydro-1,2,6-thiadiazine 1-oxides 46 in high yields [102].
The reaction is carried out under solvent-free ball milling at ambient temperature
using acetic acid as a catalyst.
Scheme 12. Synthesis of fluoro-substituted thiadiazine 46.
Tetramolecular reactions.
Tetramolecular reactions, while synthetically valuable, are rare. These
transformations resemble a finely tuned orchestra where each component harmonizes
perfectly with all others. As a result, successfully executing tetramolecular reactions
evokes a sense of awe, particularly when they proceed with high efficiency.
Accordingly, mechanochemical tetramolecular reactions hold both practical and
aesthetic significance in synthetic chemistry.
The mechanochemical synthesis of fluorinated pyranopyrazoles 47 (Scheme 13)
was successfully achieved by ball milling a mixture of p-fluorobenzaldehyde 30,
malononitrile 41, β-keto esters 45, and hydrazine hydrate at ambient temperature [103,
104]. The key to this success is a specially designed nanocatalyst, synthesized using
silica/aminoethylpiperazine, which significantly enhances reaction efficiency.
[101].
Scheme 11. Synthesis of fluorine-containing pyran 43.
Scheme 12 presents a variant of the Biginelli-type multicomponent reaction
employing p-fluorobenzaldehyde 30, sulfonimidamides 44, and β-keto esters 45 to
efficiently synthesize 2,3-dihydro-1,2,6-thiadiazine 1-oxides 46 in high yields [102].
The reaction is carried out under solvent-free ball milling at ambient temperature
using acetic acid as a catalyst.
Scheme 12. Synthesis of fluoro-substituted thiadiazine 46.
Tetramolecular reactions.
Tetramolecular reactions, while synthetically valuable, are rare. These
transformations resemble a finely tuned orchestra where each component harmonizes
perfectly with all others. As a result, successfully executing tetramolecular reactions
evokes a sense of awe, particularly when they proceed with high efficiency.
Accordingly, mechanochemical tetramolecular reactions hold both practical and
aesthetic significance in synthetic chemistry.
The mechanochemical synthesis of fluorinated pyranopyrazoles 47 (Scheme 13)
was successfully achieved by ball milling a mixture of p-fluorobenzaldehyde 30,
malononitrile 41, β-keto esters 45, and hydrazine hydrate at ambient temperature [103,
104]. The key to this success is a specially designed nanocatalyst, synthesized using
silica/aminoethylpiperazine, which significantly enhances reaction efficiency.
44 ISSN 2708-129X. Укр. хім. журн., 2025
MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING.ORGANIC CHEMISTRY
of p-fluorobenzaldehyde 30, malononitrile 41,
β-keto esters 45, and hydrazine hydrate at am-
bient temperature [103, 104]. The key to this
success is a specially designed nanocatalyst,
synthesized using silica/aminoethylpiperazine,
which significantly enhances reaction efficiency.
Scheme 13. Synthesis of fluorinated pyranopyrazoles 47.
Peripheral functionalization of the heterocy-
clic framework.
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
[105–107]. Consequently, their preparation
via mechanochemistry is of particular interest.
Scheme 14 illustrates the synthesis of α-keto
esters 50 under ball milling [108]. The process
involves an anaerobic oxidation of aryl diazo
esters 48 with pyridine N-oxide 49 catalyzed
by CuI under ball milling to afford α-keto es-
ters 50. Mechanistic studies highlighted the
role of CuI in forming a copper–carbenoid
intermediate which facilitates the oxygenation
process. The scalability of this method was va
lidated by gram-scale reactions and its utility
was demonstrated in the synthesis of various
natural product and pharmaceutical interme-
diates.
Scheme 14. Synthesis of fluorinated α-keto esters 50.
Scheme 15 illustrates the synthesis of in-
doylchalcones 53 under ball milling [109]. The
reaction between fluorine-containing aromatic
ketones 51 and 1-methylindole-3-carboxalde-
hyde 52 was optimized for Claisen–Schmidt
condensation under high-energy ball milling.
The optimal protocol, utilizing KOH as a cata
lyst and ethanol (100 μL) as a liquid-assisted
grinding additive, proceeds efficiently at am-
bient temperature and is completed within
15 minutes. Under these conditions, a series
of indoylchalcones 53 incorporating fluorine
atoms and/or trifluoromethyl groups were
synthesized in yields of 50–92%. Notably, the
[101].
Scheme 11. Synthesis of fluorine-containing pyran 43.
Scheme 12 presents a variant of the Biginelli-type multicomponent reaction
employing p-fluorobenzaldehyde 30, sulfonimidamides 44, and β-keto esters 45 to
efficiently synthesize 2,3-dihydro-1,2,6-thiadiazine 1-oxides 46 in high yields [102].
The reaction is carried out under solvent-free ball milling at ambient temperature
using acetic acid as a catalyst.
Scheme 12. Synthesis of fluoro-substituted thiadiazine 46.
Tetramolecular reactions.
Tetramolecular reactions, while synthetically valuable, are rare. These
transformations resemble a finely tuned orchestra where each component harmonizes
perfectly with all others. As a result, successfully executing tetramolecular reactions
evokes a sense of awe, particularly when they proceed with high efficiency.
Accordingly, mechanochemical tetramolecular reactions hold both practical and
aesthetic significance in synthetic chemistry.
The mechanochemical synthesis of fluorinated pyranopyrazoles 47 (Scheme 13)
was successfully achieved by ball milling a mixture of p-fluorobenzaldehyde 30,
malononitrile 41, β-keto esters 45, and hydrazine hydrate at ambient temperature [103,
104]. The key to this success is a specially designed nanocatalyst, synthesized using
silica/aminoethylpiperazine, which significantly enhances reaction efficiency.
Scheme 13. Synthesis of fluorinated pyranopyrazoles 47.
Peripheral functionalization of the heterocyclic framework.
As emphasized throughout this review, fluorine-containing carbonyl compounds
are highly valuable synthetic building blocks exhibiting significantly enhanced
reactivity compared to their non-fluorinated counterparts [105–107]. Consequently,
their preparation via mechanochemistry is of particular interest. Scheme 14 illustrates
the synthesis of α-keto esters 50 under ball milling [108]. The process involves an
anaerobic oxidation of aryl diazo esters 48 with pyridine N-oxide 49 catalyzed by CuI
under ball milling to afford α-keto esters 50. Mechanistic studies highlighted the role
of CuI in forming a copper–carbenoid intermediate which facilitates the oxygenation
process. The scalability of this method was validated by gram-scale reactions and its
utility was demonstrated in the synthesis of various natural product and
pharmaceutical intermediates.
Scheme 14. Synthesis of fluorinated α-keto esters 50.
Scheme 15 illustrates the synthesis of indoylchalcones 53 under ball milling [109].
The reaction between fluorine-containing aromatic ketones 51 and
1-methylindole-3-carboxaldehyde 52 was optimized for Claisen–Schmidt
condensation under high-energy ball milling. The optimal protocol, utilizing KOH as
a catalyst and ethanol (100 μL) as a liquid-assisted grinding additive, proceeds
efficiently at ambient temperature and is completed within 15 minutes. Under these
conditions, a series of indoylchalcones 53 incorporating fluorine atoms and/or
trifluoromethyl groups were synthesized in yields of 50–92%. Notably, the presence
of electron-withdrawing trifluoromethyl groups significantly enhanced reactivity.
Additionally, ball milling considerably reduced reaction time compared to
conventional solution-based approaches, highlighting its efficiency and practicality.
Scheme 15. Synthesis of fluorine-containing indoylchalcones 53.
Scheme 16 presents a synthetically valuable mechanochemical procedure for the
preparation of sulfonyl quinolines 56 [110]. This method involves the coupling of
haloquinolines 54 with sulfonic acids 55 showcasing the advantages of
45https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 7 / Vol. 91
presence of electron-withdrawing trifluorome-
thyl groups significantly enhanced reactivity.
Additionally, ball milling considerably reduced
reaction time compared to conventional solu-
tion-based approaches, highlighting its effi-
ciency and practicality.
Scheme 15. Synthesis of fluorine-containing indoylchalcones 53.
Scheme 16 presents a synthetically valuable
mechanochemical procedure for the prepa-
ration of sulfonyl quinolines 56 [110]. This
method involves the coupling of haloquino-
lines 54 with sulfonic acids 55 showcasing the
advantages of mechanochemistry over conven-
tional approaches that typically rely on metal
catalysts, solvents, and harsh reaction condi-
tions. Notably, this procedure eliminates the
need for metals, solvents, or additives making
it a more sustainable and efficient alternative.
Fluorine atoms incorporated into the aroma
tic sulfonic acid residues, either as fluorine di-
rectly attached to the aromatic ring or as tri-
fluoromethyl groups attached to the aromatic
ring at various positions, further demonstrate
structural diversity and potential applications
of the methodology.
Scheme 16. Synthesis of fluorine-containing sulfonyl quinolines 56.
Aromatic trifluoromethylation is a funda-
mental transformation in fluorine chemistry
widely employed in the synthesis of key build-
ing blocks and bioactive compounds [111–
113]. Accordingly, the development of a me
chanochemical version of this reaction holds
significant synthetic value. Scheme 17 presents
a notable example of this approach [114] rep-
resenting the first instance of using piezoelec-
tricity to generate trifluoromethyl radicals. In
this method, Umemoto reagent 58 [115] and
piezoelectric tetragonal BaTiO₃ are utilized
in a ball milling trifluoromethylation reac-
tion of indole 57 yielding fluorinated indole
59. Compared to conventional solution-phase
methodologies, this mechano-redox C–H
Scheme 13. Synthesis of fluorinated pyranopyrazoles 47.
Peripheral functionalization of the heterocyclic framework.
As emphasized throughout this review, fluorine-containing carbonyl compounds
are highly valuable synthetic building blocks exhibiting significantly enhanced
reactivity compared to their non-fluorinated counterparts [105–107]. Consequently,
their preparation via mechanochemistry is of particular interest. Scheme 14 illustrates
the synthesis of α-keto esters 50 under ball milling [108]. The process involves an
anaerobic oxidation of aryl diazo esters 48 with pyridine N-oxide 49 catalyzed by CuI
under ball milling to afford α-keto esters 50. Mechanistic studies highlighted the role
of CuI in forming a copper–carbenoid intermediate which facilitates the oxygenation
process. The scalability of this method was validated by gram-scale reactions and its
utility was demonstrated in the synthesis of various natural product and
pharmaceutical intermediates.
Scheme 14. Synthesis of fluorinated α-keto esters 50.
Scheme 15 illustrates the synthesis of indoylchalcones 53 under ball milling [109].
The reaction between fluorine-containing aromatic ketones 51 and
1-methylindole-3-carboxaldehyde 52 was optimized for Claisen–Schmidt
condensation under high-energy ball milling. The optimal protocol, utilizing KOH as
a catalyst and ethanol (100 μL) as a liquid-assisted grinding additive, proceeds
efficiently at ambient temperature and is completed within 15 minutes. Under these
conditions, a series of indoylchalcones 53 incorporating fluorine atoms and/or
trifluoromethyl groups were synthesized in yields of 50–92%. Notably, the presence
of electron-withdrawing trifluoromethyl groups significantly enhanced reactivity.
Additionally, ball milling considerably reduced reaction time compared to
conventional solution-based approaches, highlighting its efficiency and practicality.
Scheme 15. Synthesis of fluorine-containing indoylchalcones 53.
Scheme 16 presents a synthetically valuable mechanochemical procedure for the
preparation of sulfonyl quinolines 56 [110]. This method involves the coupling of
haloquinolines 54 with sulfonic acids 55 showcasing the advantages of
mechanochemistry over conventional approaches that typically rely on metal catalysts,
solvents, and harsh reaction conditions. Notably, this procedure eliminates the need
for metals, solvents, or additives making it a more sustainable and efficient alternative.
Fluorine atoms incorporated into the aromatic sulfonic acid residues, either as fluorine
directly attached to the aromatic ring or as trifluoromethyl groups attached to the
aromatic ring at various positions, further demonstrate structural diversity and
potential applications of the methodology.
Scheme 16. Synthesis of fluorine-containing sulfonyl quinolines 56.
Aromatic trifluoromethylation is a fundamental transformation in fluorine
chemistry widely employed in the synthesis of key building blocks and bioactive
compounds [111–113]. Accordingly, the development of a mechanochemical version
of this reaction holds significant synthetic value. Scheme 17 presents a notable
example of this approach [114] representing the first instance of using piezoelectricity
to generate trifluoromethyl radicals. In this method, Umemoto reagent 58 [115] and
piezoelectric tetragonal BaTiO₃ are utilized in a ball milling trifluoromethylation
reaction of indole 57 yielding fluorinated indole 59. Compared to conventional
solution-phase methodologies, this mechano-redox C–H trifluoromethylation
technique offers a more environmentally sustainable and efficient route for
synthesizing a broad range of trifluoromethylated N-heterocycles and peptides which
serve as essential scaffolds in modern drug discovery. This advancement marks a
significant step forward in the application of mechano-redox systems for
pharmaceutical and biomedical research [114].
Scheme 17. Mechanochemical trifluoromethylation of indole 57 to yield fluorinated indole
59.
Scheme 18 illustrates the mechanochemical synthesis of
2-(trifluoromethyl)quinolines featuring an aryl-1,2,3-triazole moiety at O-4 in 61
[116]. The reaction is performed under ball milling in the presence of Cu(II) [117],
46 ISSN 2708-129X. Укр. хім. журн., 2025
MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING.ORGANIC CHEMISTRY
trifluoromethylation technique offers a more
environmentally sustainable and efficient
route for synthesizing a broad range of tri
fluoromethylated N-heterocycles and peptides
which serve as essential scaffolds in modern
drug discovery. This advancement marks a
significant step forward in the application of
mechano-redox systems for pharmaceutical
and biomedical research [114].
Scheme 17. Mechanochemical trifluoromethylation of indole 57 to yield fluorinated indole 59.
Scheme 18 illustrates the mechanochemi-
cal synthesis of 2-(trifluoromethyl)quinolines
featuring an aryl-1,2,3-triazole moiety at O-4
in 61 [116]. The reaction is performed under
ball milling in the presence of Cu(II) [117],
Cu(I), and Cu(0) as catalysts for azide–alkyne
cycloaddition in the presence of Hünig’s base
[118]. Notably, this mechanochemical ap-
proach yields significantly higher efficiencies
compared to conventional solution-based
methods [116, 117].
Scheme 18. Mechanochemical azide-alkyne cycloaddition.
CONCLUSIONS. The scalability of mecha-
nochemical methods, particularly ball milling
processes, offers significant potential for in-
dustrial applications but presents key challen
ges. Their ability to eliminate solvents reduces
environmental impact and costs while aligning
with green chemistry principles. High efficien-
cy and rapid reaction rates further enhance
their appeal, potentially lowering energy de-
mands and shortening processing times. How-
ever, scaling up requires overcoming hurdles
such as ensuring uniform energy distribution,
preventing uneven reactions, and mitigating
equipment wear at larger volumes. Mechano-
chemical processes also lack the precise con-
trol mechanisms of solution-based reactions
rendering parameters like temperature and ki-
netics harder to regulate. Most systems still op-
erate in batch mode, limiting throughput com-
pared to continuous processing that is favored
in industry. Additionally, high-energy milling
may degrade sensitive reactants or produce
mechanochemistry over conventional approaches that typically rely on metal catalysts,
solvents, and harsh reaction conditions. Notably, this procedure eliminates the need
for metals, solvents, or additives making it a more sustainable and efficient alternative.
Fluorine atoms incorporated into the aromatic sulfonic acid residues, either as fluorine
directly attached to the aromatic ring or as trifluoromethyl groups attached to the
aromatic ring at various positions, further demonstrate structural diversity and
potential applications of the methodology.
Scheme 16. Synthesis of fluorine-containing sulfonyl quinolines 56.
Aromatic trifluoromethylation is a fundamental transformation in fluorine
chemistry widely employed in the synthesis of key building blocks and bioactive
compounds [111–113]. Accordingly, the development of a mechanochemical version
of this reaction holds significant synthetic value. Scheme 17 presents a notable
example of this approach [114] representing the first instance of using piezoelectricity
to generate trifluoromethyl radicals. In this method, Umemoto reagent 58 [115] and
piezoelectric tetragonal BaTiO₃ are utilized in a ball milling trifluoromethylation
reaction of indole 57 yielding fluorinated indole 59. Compared to conventional
solution-phase methodologies, this mechano-redox C–H trifluoromethylation
technique offers a more environmentally sustainable and efficient route for
synthesizing a broad range of trifluoromethylated N-heterocycles and peptides which
serve as essential scaffolds in modern drug discovery. This advancement marks a
significant step forward in the application of mechano-redox systems for
pharmaceutical and biomedical research [114].
Scheme 17. Mechanochemical trifluoromethylation of indole 57 to yield fluorinated indole
59.
Scheme 18 illustrates the mechanochemical synthesis of
2-(trifluoromethyl)quinolines featuring an aryl-1,2,3-triazole moiety at O-4 in 61
[116]. The reaction is performed under ball milling in the presence of Cu(II) [117],
Cu(I), and Cu(0) as catalysts for azide–alkyne cycloaddition in the presence of
Hünig’s base [118]. Notably, this mechanochemical approach yields significantly
higher efficiencies compared to conventional solution-based methods [116, 117].
Scheme 18. Mechanochemical azide-alkyne cycloaddition.
CONCLUSIONS. The scalability of mechanochemical methods, particularly ball
milling processes, offers significant potential for industrial applications but presents
key challenges. Their ability to eliminate solvents reduces environmental impact and
costs while aligning with green chemistry principles. High efficiency and rapid
reaction rates further enhance their appeal, potentially lowering energy demands and
shortening processing times. However, scaling up requires overcoming hurdles such
as ensuring uniform energy distribution, preventing uneven reactions, and mitigating
equipment wear at larger volumes. Mechanochemical processes also lack the precise
control mechanisms of solution-based reactions rendering parameters like temperature
and kinetics harder to regulate. Most systems still operate in batch mode, limiting
throughput compared to continuous processing that is favored in industry.
Additionally, high-energy milling may degrade sensitive reactants or produce
unintended by-products, necessitating careful material selection. To address these
challenges, researchers are exploring advanced reactor designs, real-time monitoring
technologies, and hybrid approaches integrating mechanochemistry with techniques
like microwave or ultrasound assistance.
The presented data clearly demonstrates that fluorine-containing compounds
serve as versatile starting materials for all types of mechanochemical reactions.
Notably, fluorinated carbonyl compounds are favored due to their significantly
enhanced reactivity compared to their non-fluorinated counterparts. In particular,
fluorinated aromatic aldehydes and keto acid derivatives frequently appear as key
starting materials in numerous examples throughout this review, highlighting their
strategic importance in mechanochemical synthesis.
Given the critical role of fluorinated heterocyclic compounds in the pharmaceutical,
agrochemical, and materials industries, along with the benefits of mechanochemical
reactions, research in this field is expected to expand significantly.
ACKNOWLEDGMENTS. We gratefully acknowledge the financial support from
the National Natural Science Foundation of China (No. 21761132021) and the
Qing-Lan Project of Jiangsu Province (for Han) and 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.
МЕХАНОХІМІЧНИЙ СИНТЕЗ ФТОРВМІСНИХ ГЕТЕРОЦИКЛІВ ЗА ДОПОМОГОЮ
47https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 7 / Vol. 91
unintended by-products, necessitating careful
material selection. To address these challeng-
es, researchers are exploring advanced reactor
designs, real-time monitoring technologies,
and hybrid approaches integrating mechano
chemistry with techniques like microwave or
ultrasound assistance.
The presented data clearly demonstrates
that fluorine-containing compounds serve
as versatile starting materials for all types of
mechanochemical reactions. Notably, fluori
nated carbonyl compounds are favored due to
their significantly enhanced reactivity com-
pared to their non-fluorinated counterparts.
In particular, fluorinated aromatic aldehydes
and keto acid derivatives frequently appear
as key starting materials in numerous examp
les throughout this review, highlighting their
strategic importance in mechanochemical
synthesis.
Given the critical role of fluorinated hetero-
cyclic compounds in the pharmaceutical, agro-
chemical, and materials industries, along with
the benefits of mechanochemical reactions,
research in this field is expected to expand sig-
nificantly.
ACKNOWLEDGMENTS. We grate-
fully acknowledge the financial
support from the National Natu-
ral Science Foundation of China
(No. 21761132021) and the Qing-Lan
Project of Jiangsu Province (for Han)
and IKERBASQUE, Basque Founda-
tion for Science, (for Soloshonok).
The authors acknowledge the assis-
tance of Microsoft Copilot and Goog-
le Gemini for their support in trans-
lating to Ukrainian.
МЕХАНОХІМІЧНИЙ СИНТЕЗ ФТОРВМІСНИХ
ГЕТЕРОЦИКЛІВ ЗА ДОПОМОГОЮ
КУЛЬОВОЇ МЛИНАРКИ
Дзяньлінь Хань,¹ Аліція Взорек,²
Таїзо Оно,3 Карел Д. Кліка,4
Вадим А. Солошонок5,6*
1 Цзянсу, Центр співінновацій ефективного
оброблення та використання лісових
ресурсів, Хімічний факультет,
Лісотехнічний університет Нанкіна,
Нанкін 210037, Китай;
2 Хімічний інститут, Університет Яна
Кохановського в Кельці,
вул. Університетська 7, 25–406 Кельце,
Польща;
3 Національний інститут передової науки
та технологій (AIST),
2266–98, Анагахора, Шімошідамі, район
Моріяма, Нагоя, 463–8560, Японія;
4 Центр досліджень і розробок, Арчер
Деніелс Мідленд, вулиця Північна Браш
Коледж, 1001. Декатур, IL 62521, США;
5 Відділ органічної хімії I, Хімічний
факультет, Університет Країни Басків
UPV/EHU, проспект Мануэля Лардісабаля,
3, 20018 Сан-Себастьян, Іспанія;
6 ІКЕРБАСКЕ, Баскська наукова фундація,
вул. Марія Діас де Харо 3, Площа Бізкая,
48013 Більбао, Іспанія.
e-mail: vadimsoloshonok@gmail.com
Фторвмісні гетероцикли відіграють ви-
рішальну роль у фармацевтичній, агрохі-
мічній та промисловості матеріалів. Пошук
ефективних та екологічно сталих методів
синтезу стимулював розвиток механохімії
як безрозчинникової та енергоефективної
48 ISSN 2708-129X. Укр. хім. журн., 2025
MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING.ORGANIC CHEMISTRY
альтернативи традиційним хімічним пе-
ретворенням. Серед цих підходів кульова
млинарка стала особливо перспективною
технікою для сприяння хімічним реакціям.
Цей огляд охоплює ключові досягнення
останнього десятиліття в механохімічному
синтезі фторованих гетероциклічних спо-
лук для бімолекулярних, тримолекулярних
та тетрамолекулярних реакцій, а також пе-
ретворень, класифікованих як периферійна
функціоналізація гетероциклічного карка-
су. Ця робота слугує цінним ресурсом для
дослідників та практиків, які прагнуть роз-
робляти екологічно сталі та ефективні ка-
талітичні системи для синтезу фторованих
гетероциклів.
Ключові слова: фтор, гетероциклічні
сполуки, фторовані фармацевтичні препа-
рати, механохімія, кульова млинарка, зеле-
на хімія, екологічно сталий синтез.
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Стаття надійшла 17.05.2025.
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| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-738 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:13:22Z |
| publishDate | 2025 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
| record_format | ojs |
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| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-7382026-07-22T08:23:56Z MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING(Review) Han, Jianlin Wzorek, Alicja Ono, Taizo Klika, Karel Soloshonok, Vadim Fluorine, Heterocyclic Compounds, Fluorinated Pharmaceuticals, Mechanochemistry, Ball Milling, 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 mechanochemistry as a solvent-free, energy-efficient alternative to conventional chemical transformations. Among these approaches, ball milling has emerged as a particularly promising technique for facilitating chemical reactions. This review covers key achievements over the past decade in the mechanochemical synthesis of fluorinated heterocyclic compounds for bimolecular, trimolecular, and tetramolecular reactions as well as transformations classified as peripheral functionalization of the heterocyclic framework. This work serves as a valuable resource for researchers and practitioners seeking to develop sustainable and efficient catalytic systems for fluorinated heterocyclic synthesis. V.I.Vernadsky Institute of General and Inorganic Chemistry 2025-08-25 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/738 10.33609/2708-129X.91.7.2025.35-55 Ukrainian Chemistry Journal; Vol. 91 No. 7 (2025): Ukrainian Chemistry Journal; 35-55 Украинский химический журнал; ##issue.vol## 91 ##issue.no## 7 (2025): Ukrainian Chemistry Journal; 35-55 Український хімічний журнал; Том 91 № 7 (2025): Ukrainian Chemistry Journal; 35-55 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/738/376 Copyright (c) 2025 Jianlin Han, Alicja Wzorek, Taizo Ono, Karel Klika, Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Han, Jianlin Wzorek, Alicja Ono, Taizo Klika, Karel Soloshonok, Vadim MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING(Review) |
| title | MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING(Review) |
| title_full | MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING(Review) |
| title_fullStr | MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING(Review) |
| title_full_unstemmed | MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING(Review) |
| title_short | MECHANOCHEMICAL SYNTHESIS OF FLUORINE-CONTAINING HETEROCYCLES VIA BALL MILLING(Review) |
| title_sort | mechanochemical synthesis of fluorine-containing heterocycles via ball milling(review) |
| topic_facet | Fluorine Heterocyclic Compounds Fluorinated Pharmaceuticals Mechanochemistry Ball Milling Green Chemistry Sustainable Synthesis. |
| url | https://ucj.org.ua/index.php/journal/article/view/738 |
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