Solid-State Radical C?H Trifluoromethylation Reactions Using Ball Milling and Piezoelectric Materials

Article abstract of DOI:10.1002/anie.202009844

The application of piezoelectricity for the generation of trifluoromethyl (CF₃) radicals is reported together with the development of a method for the mechanochemical C?H trifluoromethylation of aromatic compounds. As compared to conventional solution-based approaches, this mechanoredox C?H trifluoromethylation enables cleaner and more sustainable access to a wide range of trifluoromethylated N-heterocycles and peptides, which are important structural motifs in modern drug discovery. This study thus represents an important milestone for future applications of mechanoredox systems to medicinal and pharmaceutical science.

Full text of DOI:10.1002/anie.202009844

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Accepted Article
Title: Solid-State Radical C–H Trifluoromethylation Reactions Using
Ball Milling and Piezoelectric Materials
Authors: Yadong Pang, Joo Won Lee, Koji Kubota, and Hajime Ito
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009844
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10.1002/anie.202009844
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Solid-State Radical C−H Trifluoromethylation Reactions Using
Ball Milling and Piezoelectric Materials
Yadong Pang,[a] Joo Won Lee,[b] Koji Kubota,*[a,b] and Hajime Ito*[a,b]
Abstract: The first application of piezoelectricity for the generation of
studies revealed that ultrasonic agitation of BaTiO3 in solution can
also be used in water splitting,[11a] the piezocatalytic degradation
of model pollutants such as rhodamine B,[11b] and via the reduction
of a Cu(II) catalyst precursor to an active Cu(I) compound, in
controlled atom transfer radical polymerizations.[11c,d] Shortly after
our report on the first BaTiO3/ball milling system,[8] Bolm and
Hernández reported a mechanochemical radical cyclization
based on the reduction of a Cu(II) salt via a similar ball milling
reaction with BaTiO3.[12] Although the use of piezoelectric
materials as charge-transfer catalysts offers great potential in
organic chemistry, its application to the synthesis of small organic
molecules still remains very limited.[8,12]
trifluoromethyl (CF3) radicals is reported together with the
development of
a
method for the mechanochemical C–H
trifluoromethylation of aromatic compounds. Compared to
conventional solution-based approaches, this mechanoredox C–H
trifluoromethylation enables cleaner and more sustainable access to
a wide range of trifluoromethylated N-heterocycles and peptides,
which are important structural motifs in modern drug discovery. This
study thus represents an important milestone for future applications
of mechanoredox systems to medicinal and pharmaceutical science.
During the last few years, mechanochemical synthesis
using ball milling has become a practical and sustainable
technique that enables solvent-free organic transformations.[1-3]
The advantages of mechanochemical approaches, i.e., the
avoidance of potentially harmful organic solvents, shorter reaction
times, and operational simplicity, have created a significant
demand for their application to pharmaceutical synthesis.[4]
Fluorinated compounds continue to be of major interest for the
design of new pharmaceuticals.[5] In this context, the
trifluoromethyl (CF3) group plays a crucial role in the realm of
medicinal chemistry given that its incorporation into drug
molecules can dramatically improve the metabolic stability and
other pharmacokinetic properties of drug molecules.[5] Therefore,
the development of new mechanochemical methods for the
efficient and selective introduction of a CF3 group into a diverse
array of skeletons could provide medicinal chemical solutions that
are both cleaner and safer than those currently available.[4,5]
Despite the recent progress of mechanochemical transformations,
there have been no reports in the literature pertaining to
trifluoromethylation reactions under solid-state mechanochemical
conditions.[1,2,6,7]
We have recently discovered a conceptually new redox
system, in which electrons are transferred from distorted
piezoelectric materials in the solid-state to trigger organic
transformations.[8] In these reactions, the agitation of BaTiO3 via
ball milling generates particles that are temporarily highly
polarized and can thus act as charge-transfer catalysts[9] to
reduce aryl diazonium salts to generate aryl radicals (Scheme 1A).
This mechanoredox system represents a unique solid-state
approach that can be applied to arylation and borylation reactions
in a manner analogous to photoredox catalysts.[10] Prior to the
development of our solid-state ball milling approach, pioneering
Scheme 1. Radical C−H Trifluoromethylation of Aromatic Compounds Using
Ball Milling and Piezoelectric Materials.
In this study, we envisioned that the piezoelectric reduction
of electrophilic trifluoromethylation reagents via a single electron
transfer (SET) pathway could produce a CF3 radical. This could
potentially enable, via the use of ball milling, the development of
[a] Dr. Y. Pang, Prof. Dr. K. Kubota, Prof. Dr. H. Ito
Institute for Chemical Reaction Design and Discovery (WPI-ICReDD),
Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
E-mail: kbt@eng.hokudai.ac.jp, hajito@eng.hokudai.ac.jp
a
solid-state radical C–H trifluoromethylation of aromatic
compounds 1 (Scheme 1B). To this end, we selected easily
available Umemoto reagents 2 as the CF3 radical source.[13] This
choice was motivated by the strong electron-accepting character
of these reagents. For example, Umemoto reagent 2a has a
reduction potential of –0.26 V (versus SCE; Figure S3)[12c] which
[b] J. W. Lee, Prof. Dr. K. Kubota, Prof. Dr. H. Ito
Division of Applied Chemistry, Graduate School of Engineering,
Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
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10.1002/anie.202009844
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COMMUNICATION
Table 1. Initial Optimization Study.[a]
would, when subjected to ball milling, undergo piezoelectric
reduction to generate
a
CF3 radical (Scheme 1C).[13b,14]
Subsequent radical addition to aromatic 1 would provide
trifluoromethylated intermediate A, which would then be oxidized
by the hole in the agitated BaTiO3 (B).
A subsequent
deprotonation would give the trifluoromethylated product 3
(Scheme 1C).[7]
CF3
Piezoelectric material
Yield
Entry
1
reagent
(Particle size)
BaTiO3 (<3 μm)
BaTiO3 (<3 μm)
BaTiO3 (<3 μm)
BaTiO3 (<3 μm)
BaTiO3 (<3 μm)
BaTiO3 (<3 μm)
BaTiO3 (<75 μm)
LiNbO3 (<70 μm)
ZnO (<10 μm)
none
Liquid
none
(%)[b]
<1
1
We initially conducted
a
study to optimize the
mechanoredox C–H trifluoromethylation reaction conditions using
3-methyl indole (1a) and various electrophilic trifluoromethylation
reagents in the presence of commercially available piezoelectric
materials (Table 1). All reactions were carried out in a Retch
MM400 mixer mill (1.5 mL stainless-steel milling jar using a 5 mm
diameter stainless-steel ball; Table 1). Unfortunately, the reaction
with Umemoto reagent 2a in the presence of piezoelectric
tetragonal BaTiO3 (particle size: <3 μm at 30 Hz for 90 minutes
did not generate the desired product 3a (entry 1). However, trace
amounts of 3a were obtained when the reaction was performed
with the difluorinated Umemoto reagent 2b. This reagent is a
more electrophilic trifluoromethylation reagent than 2a[13b]
(reduction potential: –0.23 V versus SCE; Figure S3) (entry 2).
Next, we attempted liquid-assisted grinding (LAG), which uses a
substoichiometric liquid additive to improve the reactivity (entries
3−6).[15] In the LAG reactions, we used 0.20 μL of liquid per mg of
solid reactant. To our delight, polar solvents such as N,N-
dimethylformamide (DMF), acetonitrile (MeCN), or acetone
improved the reactivity and provided 3a in good yield (58%, 58%,
and 62% NMR yield, respectively). Conversely, in hexane, the
reaction did not proceed (1%). The use of cubic BaTiO3 (particle
size: <75 μm), which is highly symmetric and generates less
polarized particles in response to mechanical impact, significantly
decreased the yield of 3a (8%; entry 7).[8,11] Using other
piezoelectric materials, such as LiNbO3 (particle size: <70 μm) or
ZnO (particle size: <10 μm), also afforded 3a, albeit in lower yield
(43% and 18%, respectively; entries 8 and 9). When the reaction
was carried out in the absence of BaTiO3, only a very small
amount of 3a was obtained (2%; entry 10). Reactions using non-
piezoelectric ceramic materials, such as TiO2 (particle size: <2
μm), BaCO3 (particle size: <5 μm), or Al2O3 (particle size: <1 μm)
only yielded trace amounts of 3a (entries 11−13). These results
suggest that piezoelectric materials are essential for the success
of this C–H trifluoromethylation reaction. When the reaction was
performed in acetone (0.3 M) with a stirring bar at room
temperature for 24 h, the formation of 3a was not observed (entry
14). This result indicates that mechanical agitation by ball milling
is essential for the generation of a piezoelectric potential that is
sufficient to reduce 2b. In addition, the reaction that was carried
out with ultrasonic sonication in acetone provided trace amounts
of 3a (entry 15). This suggests that the use of ball milling to
generate a piezoelectric potential may have a different reactivity
profile compared to a solution-based approach using ultrasonic
agitation.[8,9,11,12] Next we investigated other types of Umemoto
reagents such as 2c (reduction potential: –0.13 V versus SCE;
Figure S3) (entry 16).[13b] However, the yield did not improve
(61%). The use of 4, which is a widely employed CF3 radical
precursor in solution-based photoredox-catalyzed reactions,[16]
did not provide 3a under mechanoredox conditions (entry 17).
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2c
4
2
none
3
DMF
58
58
1
4
MeCN
5
hexane
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
6
62
8
7[c]
8
43
18
2
9
10
11
12
13
14[d]
15[e]
16
17
TiO2 (<2 μm)
<1
1
BaCO3 (<5 μm)
Al2CO3 (<1 μm)
BaTiO3 (<3 μm)
BaTiO3 (<3 μm)
BaTiO3 (<3 μm)
BaTiO3 (<3 μm)
<1
<1
1
61
<1
[a] Conditions: 1a (0.6 mmol), trifluoromethylation reagent (0.3 mmol),
piezocatalyst (1.5 mmol), and liquid additive (0.20 μL/mg) in a stainless-steel
milling jar (1.5 mL) with a stainless-steel ball (5 mm). [b] Determined by 19F NMR
analysis of the crude reaction mixture using an internal standard. [c] Cubic
BaTiO3 (particle size: <75 μm) was used instead of tetragonal BaTiO3 (particle
size: <3 μm). [d] The reaction was carried out in acetone (0.3 M) with a stirring
bar at room temperature for 24 h. [e] The reaction was carried out in acetone
(0.3 M) under ultrasonic agitation at room temperature for 1.5 h.
To improve the reaction further, we investigated the effect
of different mechanochemical parameters on this mechanoredox
C–H trifluoromethylation (Table 2). We found that conducting the
reaction with a smaller ball (3 mm diameter) or at a lower ball-
milling frequency (25 Hz and 20 Hz), which subjects BaTiO3 to
lower-impact mechanical collisions than under the standard
conditions, substantially decreased the yield of 3a (4%, 19%, and
2%, respectively; entries 1−4). These results are consistent with
our hypothesis that the piezoelectric potential required for a
successful reaction is generated by the mechanical force induced
by the ball milling. The use of a larger ball and a larger jar
improves the yield of 3a (73%, entry 5). Finally, we found that
prolonging the reaction time and increasing the number of balls
used provided the desired product 3a in high yield (80%; entry 6).
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Table 2. Investigation of the Effect of Varying the Mechanochemical
Parameters.[a]
investigate the substrate scope of this mechanoredox C–H
trifluoromethylation reaction (Table 3). The reactions proceeded
efficiently to furnish the corresponding CF3-substituted products
in moderate to good yield. N-Methyl-, N-ethyl-, and N-benzyl-
substituted indoles (1b–1d) reacted with 2b to afford the
corresponding C–H trifluoromethylation products (3b–3d) in good
yield. Additionally, the C–H trifluoromethylation proceeded at the
3-position of 2-substituted indole 1e to provide 3e in moderate
yield. Next, we turned our attention to the substrate scope with
respect to the pyrrole derivatives. Pyrrole 1f, which bears a linear
alkyl-chain on the nitrogen atom, provided 3f in a good yield. It is
noteworthy that the use of trifluoromethylation reagent 2c, which
has a lower reduction potential than 2b,[13b] is crucial for
successful reactions involving pyrroles that bear electron-
withdrawing groups on the five-membered ring (1g–1j). When 2c
was used, 3g–3j were produced in good yield. Substrates that
contain a ring-fused structure (1k) or a chlorine group (1l) did not
hamper the reaction. Pleasingly, the desired CF3-substituted
Melatonin 3m was also obtained in good yield. Despite the fact
that solution-based photoredox systems can be applied to other
substrate classes, other heteroaromatic derivatives such as furan
and thiophene did not provide the desired products under the
applied mechanoredox conditions (for details, see the Supporting
Information).[7,16]
Jar size
(mL)
Ball size
(mm)
Frequency
(Hz)
Time
(h)
Yield
(%)[b]
Entry
1
2
1.5
1.5
1.5
1.5
5
5
3
30
30
25
20
30
30
1.5
1.5
1.5
1.5
1.5
3
62
4
19
3
5
4
5
2
5
7.5
7.5
73
6[c]
5
80 (76)
[a] Conditions: 1a (0.6 mmol), 2b (0.3 mmol), tetragonal BaTiO3 (<3 μm) (1.5
mmol), and acetone (0.20 μL/mg) in a stainless-steel milling jar with a stainless-
steel ball. [b] Determined by 19F NMR analysis of the crude reaction mixture
using an internal standard. Isolated yields are shown in parenthesis. [c] Two
balls were used.
With the optimal reaction conditions in hand (Table 2, entry
6), a series of indole and pyrrole derivatives were tested to
Table 3. Mechanoredox Radical C−H Trifluoromethylation Reactions of Aromatic Compounds in the Solid State.[a]
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[a] Conditions: 1 (0.6 mmol), 2 (0.3 mmol), tetragonal BaTiO3 (<3 μm) (1.5 mmol), and acetone (0.20 μL/mg) in a stainless-steel milling jar (5 mL) with two stainless-
steel balls. Isolated yields are shown. 19F NMR yields are shown in parenthesis.
We found that this method is also applicable to electron-rich
arenes (Table 3). The reaction of benzene molecules that bear
three methoxy groups, such as 1n and 1o, proceeded efficiently
to give the corresponding products (3n and 3o) in high yield.
However, when 1,4-dimethoxy-substituted benzene 1p was used
as the substrate, the yield of 3p decreased dramatically. When
substrates that do not bear electron-donating groups on the
aromatic ring were employed in this mechanoredox C–H
trifluoromethylation, the reaction did not proceed (for details, see
the Supporting Information).
Scheme 2. Site-selective Mechanoredox C−H Trifluoromethylation of 1u.[a,b]
Tryptophan (Trp) is an ideal platform to test post-synthetic
transformations of peptide-based bioactive compounds.[17] To
demonstrate the applicability of the newly developed method for
the post-functionalization of peptides, tryptophan-containing
peptides were tested under the previously established standard
reaction conditions (Table 3). Pleasingly, both protected
tryptophan and several dipeptides (1q–1t) reacted smoothly to
afford the corresponding 2-CF3-substituted tryptophan-containing
peptides in a site-selective manner.[18]
Given that the mechanoredox system shows significantly
higher reactivity toward the C–H trifluoromethylation of indoles
and pyrroles than other classes of substrates, we envisioned that
the present method could be used for the site-selective C–H
trifluoromethylation of aromatic compounds that contain multiple
reactive C–H bonds. To this end, we investigated the C–H
trifluoromethylation of substrate 1u, which contains pyrrole and
furan rings that are both potentially reactive (Scheme 2). Under
the applied mechanoredox conditions, we observed excellent
site-selectivity for the C–H trifluoromethylation of the pyrrole
moiety in 1u. In contrast, a mixture of products (3u–3w) was
obtained when the photoredox catalyst fac-Ir(ppy)3 was used
under conventional solution-based photoredox conditions.[19] The
observed site-selectivity under mechanoredox conditions may be
due to the poor reactivity of the gaseous CF3 radical,[20] generated
in the solid-state reaction mixture, which can only react with the
highly nucleophilic pyrrole ring.[1j] These results suggest that this
mechanoredox system has great potential for the selective
installation of CF3 groups that are otherwise difficult to install via
conventional solution-based photoredox reactions, into complex
molecules in the solid state.
[a] Conditions for the mechanoredox C–H trifluoromethylation: 1u (0.3 mmol),
2b (0.36 mmol), tetragonal BaTiO3 (<3 μm) (1.5 mmol), and DMF (0.20 μL/mg)
in a stainless-steel milling jar (5 mL) with a stainless-steel ball at 30 Hz for 3 h.
[b] Conditions for the photoredox C–H trifluoromethylation: 1u (0.2 mmol), 2b
(0.24 mmol), fac-Ir(ppy)3 (2 mol %) in MeCN under irradiation from blue LEDs
for 3 h.
Scheme 3. Exploration of BaTiO3 Recycling.[a]
[a] For experimental details, see the Supporting Information.
We believe that the mechanoredox C–H trifluoromethylation
reaction involves two SET events, in which a CF3 radical is
generated via piezoelectric reduction (Scheme 1). This
hypothesis is supported by the results of our preliminary
mechanistic investigations (Scheme 4). When the reaction of
To demonstrate the practical utility of this protocol, we
investigated the recycling of BaTiO3 (Scheme 3). After separation
from the crude reaction mixture and washing, BaTiO3 could be re-
used for the mechanoredox C–H trifluoromethylation of 1n under
the same reaction conditions at least three times without declining
the yield of 3n. However, the recovery loss of BaTiO3 would limit
the recycling times (for details, see the Supporting Information).
2,2,6,6-tetramethylpiperidinoxyl
(TEMPO,
5)
with
the
trifluoromethylation reagent 2b was conducted in the absence of
3-methyl indole (1a), the TEMPO-trapped intermediate 6 was
obtained in 25% NMR yield (Scheme 4A). Furthermore, the
addition of 5 to the mechanoredox C–H trifluoromethylation of 1a
terminated the reaction and yielded the same TEMPO-trapped
intermediate 6 (Scheme 4B). In their entirety, these results
suggest that the mechanoredox C–H trifluoromethylation with
BaTiO3 most likely proceeds via the piezoelectric reduction of 2 to
generate a CF3 radical.
To identify the role of ball milling in this transformation, we
conducted the reaction using an alternative form of mechanical
impact (Scheme 4C). First, the reaction mixture was prepared by
gently grinding the components in a mortar. The mixture was then
wrapped in a piece of weighing paper and placed in cotton before
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10.1002/anie.202009844
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COMMUNICATION
being struck with a hammer over 250 times. Even under these
conditions, the mechanoredox C–H trifluoromethylation product
3a was obtained in 14% yield. This suggests that the role of ball
milling is not only to mix the reactants, but also to provide
sufficient mechanical impact to activate the BaTiO3.[8]
Premier International Research Initiative (WPI), MEXT, Japan.
We would like to thank Dr. Yuki Ide for his help analyzing the
results of the cyclic voltammetry experiments. We would also like
to thank Nippon Chemical Industrial Co., Ltd. for the generous
donation of the piezoelectric materials.
Scheme 4. Results of the Preliminary Mechanistic Study.[a]
Conflict of interest
The authors declare no conflict of interests.
Keywords: Mechanochemistry • C−H Trifluoromethylation •
Solid-state reaction • Radical reaction • Synthetic method
[1]
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[a] For experimental details, see the Supporting Information.
In conclusion, we have described the first application of
piezoelectricity for the generation of CF3 radicals, which has
enabled the development of a radical C–H trifluoromethylation
reaction under mechanochemical conditions. This solid-state
mechanoredox C–H trifluoromethylation can be carried out in air
without the use of large amounts of dry and degassed organic
solvents and does not require specific handling techniques. This
operational simplicity suggests that the present strategy may
complement existing solution-based approaches to provide rapid
and sustainable access to a wide range of trifluoromethylated
molecules, privileged structural motifs in modern drug discovery.
This study thus illustrates the outstanding potential of
[3]
For selected examples of mechanochemical organic transformations
from our group, see: a) K. Kubota, T. Seo, K. Koide, Y. Hasegawa, H. Ito,
Nat. Commun. 2019, 10, 111−122; b) Y. Pang, T. Ishiyama, K. Kubota,
H. Ito, Chem. – Eur. J. 2019, 25, 4654−4659; c) K. Kubota, R. Takahashi,
H. Ito, Chem. Sci. 2019, 10, 5837−5842; d) T. Seo, T. Ishiyama, K.
Kubota, H. Ito, Chem. Sci. 2019, 10, 8202−8210; e) R. Takahashi, K.
Kubota, H. Ito, Chem. Commun. 2020, 56, 407−410; f) T. Seo, K. Kubota,
H. Ito, J. Am. Chem. Soc. 2020, 142, 9884−9889.
D. Tan, L. Loots, T. Friščić, Chem. Commun. 2016, 52, 7760−7781.
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systems
for
advancing
medicinal
mechanochemistry.[4]
Acknowledgements
This work was financially supported by the Japanese Society for
the Promotion of Science (JSPS) via KAKENHI grants 18H03907,
17H06370, 19K15547, and 20H04795; by the JST via CREST
grant JPMJCR19R1; by the Institute for Chemical Reaction
Design and Discovery (ICReDD), established by the World
[4]
[5]
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10.1002/anie.202009844
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Yadong Pang, Joo Won Lee, Koji
Kubota*, Hajime Ito*
Page No. – Page No.
Solid-State Radical C–H
Trifluoromethylation Reactions Using
Ball Milling and Piezoelectric
Materials
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