Showcasing research from Professor Shibata’s Laboratory,
Department of Nanopharmaceutical Sciences, Departmentof Life Science and Applied Chemistry, Nagoya Institute ofTechnology, Country.

As featured in:

Halo-perfluoroalkoxylation of gem-difluoroalkenes withshort-lived alkali metal perfluoroalkoxides in triglyme
This cover image, crafted by the Japanese artist Mami
Shibata, depicts the Taisho Sanshoku, a vibrant carp
coloured red, white and black on a delicate paper fan. These
images bring peace and eco-friendly worlds in which purewater flourishes. The varied carp seem to be ready to jumpfrom the fan and reflect vitality and hope. Our perfluoroalkyl
ethers, like these vivid creatures, promise to become friendly
materials for tomorrow and to coordinate with the eleganceof nature.

See Norio Shibata et al.,Chem. Sci., 2024, 15, 9574.

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Halo-perﬂuoroalkoxylation of gemdiﬂuoroalkenes with short-lived alkali metal
perﬂuoroalkoxides in triglyme†‡
Koki Kawai,a Yoshimitsu Kato,b Taichi Araki,b Sota Ikawa,b Mai Usui,bNaoyuki Hoshiya,c Yosuke Kishikawa,c Jorge Escorihuela d and Norio Shibata*abAlkali metal alkoxides play a pivotal role in nucleophilic alkoxylation reactions, oﬀering pathways for thesynthesis of ethers, including the increasingly sought-after triﬂuoromethyl ethers. However, the synthesisof long-chain perﬂuoroalkyl ethers remains a substantial challenge in this ﬁeld. Through the innovativeuse of triglyme to encapsulate potassium ions, we enhanced the stability of short-lived, longer-chain
perﬂuoroalkoxy anions, thereby facilitating eﬃcient nucleophilic perﬂuoroalkoxylation reactions. This
Received 29th March 2024
Accepted 16th May 2024

method provides a new precedent for the halo-perﬂuoroalkoxylation of gem-diﬂuoroalkenes and oﬀers
a versatile tool for the design of perﬂuoroalkyl ethers, including those containing complex moieties of

DOI: 10.1039/d4sc02084g

heterocycles and drug molecules. We also demonstrated the utility of the resulting halo-perﬂuoroalkoxyl

rsc.li/chemical-scienceadducts through various chemical transformations to valuable diverse perﬂuoroalkyl ethers.

Introduction
Alkali metal alkoxides are recognized as key reagents in organic
synthesis, especially for nucleophilic alkoxylation reactions that
establish carbon–oxygen (C–O) bonds and produce ethers.1
Recent breakthroughs have thrusted this area into new territories, especially in the synthesis of triuoromethyl ethers (ROCF3),2 promising exciting developments in agrochemicals andpharmaceuticals.3 Traditionally, the production of alkali metaltriuoromethoxides [M][OCF3] requires uorophosgene(carbonyl uoride, F2C]O) and alkali metal uorides (M–F,
Fig. 1a),4 and the recent introduction of safer shelf-stablereagents for nucleophilic triuoromethylation has advanced
signicantly (Fig. 1b).5 Peruoroalkyl ethers are prized for theirhigh lipophilicity, improved metabolic stability, and unparalleled thermal and chemical resilience, and they can be used invarious industries.6–8 Most of the unique properties are due tothe ether oxygens inserted between the peruorinated carbon
backbones.7b For example, compared to peruoroalkylaDepartment of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso,
Showa-ku, Nagoya 466-8555, Japan. E-mail: nozshiba@nitech.ac.jpbDepartment of Life Science and Applied Chemistry, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya 466-8555, Japanc
Technology Innovation Center, DAIKIN Industries, Ltd, 1-1 Nishi-Hitotsuya, Settsu,
Osaka 566-8585, Japand

Departamento de Quı́mica Orgánica, Universitat de València, Avda. Vicente AndrésEstellés S/N, Burjassot 46100, Valencia, Spain† Dedicated to Professor Santos Fustero and Professor Günter Haufe on the
Occasion of their 75th Birthday.
‡ Electronic supplementary information
https://doi.org/10.1039/d4sc02084g

9574 | Chem. Sci., 2024, 15, 9574–9581(ESI)

available.

See

DOI:

carboxylic acids, peruoropolyether carboxylic acids allow easy
formation of non-covalent hydrogen bonds with water, resulting
in increased hydrophilicity.8a The presence of ether linkages in
peruoroalkyl ether carboxylic acids results in increased bonddissociation energies for the adjacent carbon-uorine bonds,
which aﬀects their reactivity and degradation results.8b This
structural feature generally promotes more eﬀective degradation under reductive conditions than non-oxygenated variants
by facilitating the cleavage of carbon–oxygen bonds andenhancing deuorination. There are also reports that peruoroalkylether sulfonates degrade more eﬀectively than peruoroalkyl sulfonates in subcritical water in the presence ofoxygen8c due to their ether linkages. In addition, peruoroalkyl
compounds with long peruorinated chains consisting of morethan 10 peruorinated carbons exhibit a crystalline nature,9which would also be an additional advantage of peruoroalkyl
ethers.10 Despite rapid progress in nucleophilic triuoromethoxylation, the synthesis of longer peruoroalkyl
ethers remains a signicant challenge,11,12 particularly for
ethers with peruoroalkyl moieties on both sides, represented
by RCF2–O–CF2R0 .12 To understand the diﬃculty of nucleophilic
longer-chain peruoroalkoxylation reactions, our investigation
began with density functional theory (DFT) calculations toassess the feasibility of generating peruoroalkoxides fromtheir precursors, represented by two critical reactions: thetraditional generation of [K][OCF3] from O]CF2 and potassium
uoride (KF) and the formation of potassium peruorohexanolate [K][OCF2C5F11] from peruorohexanoyl uoride (O]CF(C5F11)) and KF (Fig. 1c). Our results reveal a stark
contrast in the reaction Gibbs free energy (DGR) between theseprocesses (see ESI‡ for details). The formation of [K][OCF3] had© 2024 The Author(s). Published by the Royal Society of ChemistryView Article Online

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Chemical ScienceFig. 1 Background and strategy of nucleophilic perﬂuoroalkoxylations. (a) Traditional method for the preparation of alkali metal triﬂuoromethoxides. (b) Shelf-stable reagents for nucleophilic triﬂuoromethoxylation. (c) DFT-calculated reaction Gibbs free energy B3LYP-D3/6311+G(d,p) in ether (SMD), in kcal mol−1 for the reactions of KF with F2C]O (−10.8 kcal mol−1), C5F11CF]O (−1.8 kcal mol−1) and C5F11CF]O
with triglyme (−30.8 kcal mol−1) (this work). (d) Halo-perﬂuoroalkoxylation of oleﬁns (this work).

a DGR of −10.9 kcal mol−1, indicating a favorable reaction
pathway. In contrast, the generation of [K][OCF2C5F11] hada DGR of −1.8 kcal mol−1, suggesting a less favorable process.
To overcome this discrepancy and enhance the synthetic feasibility of long-chain peruoroalkyl ethers, we introduced a novel
method that involves encapsulating K+ ions with two moleculesof triglyme (G3). This approach signicantly increases thestability of the OCF2C5F11 anion, facilitating the eﬃcientsynthesis of this complex molecule, [K(G3)2][OCF2C5F11], witha DGR of −33.9 kcal mol−1, indicating a highly favorable reaction process. This result not only deepens our understanding of
the stability of alkali metal peruoroalkoxides but also realizes
the halo-peruoroalkoxylation of gem-diuoroalkenes 1 using[K(G3)2][OCF2Rf] generated in situ from peruoroalkanoyl
uorides 2 (O]CFRf) with KF, yielding valuable diuoroalkyl
peruoroalkyl ethers 3 (X = I), 4 (X = Br) or 6 (X = Cl) with chain
lengths from C3 to C6 (Fig. 1d). This halo-peruoroalkoxylation
reaction was achieved with regioselectivity, and various peruoroalkyl ethers with functional groups relevant to materials
and medicines were obtained in high yields. Finally, we
explored the various chemical transformations of the resulting© 2024 The Author(s). Published by the Royal Society of Chemistryhalo-peruoroalkoxy products to demonstrate their potential asbuilding blocks.

Results and discussion
The halo-peruoroalkoxylation reaction was optimized using
gem-diuoroalkene 1a and alkali metal peruoroalkoxide
generated in situ from undecauorohexanoyl uoride 2a andinorganic uoride as model substrates in the presence of
halogen sources (Table 1). Glymes were used as the solvent tostabilize the labile peruoroalkoxide by encapsulating metal
cations, based on our previous research on triuoromethylation
reactions involving the labile triuoromethyl anion.13 Initially,
2a was treated with sodium uoride (NaF), KF, or cesium uoride (CsF) in triglyme for 15 min at room temperature to
generate metal peruoroalkoxides. Aer uoroalkene 1a wasadded to the peruoroalkoxide solution, I2 was added to thereaction mixture. NaF treatment did not yield the desired
product (entry 1), KF treatment produced 3aa in 38% yield(entry 2), and CsF treatment resulted in 25% yield (entry 3). A
lower yield (4%) was obtained when N-iodosuccinimide (NIS)

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Table 1

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Optimization of reaction conditions for halo-perﬂuoroalkoxylation of gem-diﬂuoroalkenea

Entry

2a (Y equiv.)

MF

Halogen source (Z equiv.)

Solvent (0.1 M)

Yieldb 3aa (%)

1
2
3
4
5
6
7
8
9c
10
11
12
13
14
15
16
17d
18f

1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
3.0
1.0
2.0
3.0
3.0

NaF
KF
CsF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF

I2 (1.0)I2 (1.0)I2 (1.0)
NIS (1.0)I2 (1.0)I2 (1.0)I2 (1.0)I2 (1.0)I2 (1.0)
I2 (2.0)
I2 (2.0)I2 (1.0)
I2 (2.0)I2 (3.0)
Br2 (1.0)Br2 (2.0)
Br2 (3.0)
Br2 (3.0)

Triglyme
Triglyme
Triglyme
Triglyme
MeCN
DMF
Et2O
THF
THF
Triglyme
Triglyme/THF (1/2)
Triglyme
Triglyme
Triglyme
Triglyme
Triglyme
Triglyme
Triglyme

0
38
25
4
18
9
0
0
7
38
22
31
70
89

Yieldb 4aa (%)

48
70
88e
56

a

Reaction conditions: 1a (0.1 mmol), 2a, MF, halogen source, solvent (1.0 mL), room temperature for 18 h. b 19F NMR yields were determined using
C6F6 as an internal standard. c 18-C-6 (1.0 equiv.) was added. d 1a (0.3 mmol) was used for 6 h e Isolated yield. f 1a was added aer stirring Br2 withthe peruoroalkoxide generated for 15 min.

was used instead of I2 (entry 4). Switching the solvent to MeCN,
DMF, Et2O, or THF using KF did not increase the yield (entries
5–8), even in the presence of 18-crown-6-ether (18-C-6, entry 9).
Subsequently, we varied the equivalents of acyl uorides 2a, KF,
and I2. A yield of 38% was obtained when using 2.0 equiv. of I2(entry 10). Using triglyme/THF solved (entry 11) and increasing
the number of equivalents of 2a and KF to 2.0 equiv. (entry 12)
led to decrease in yields. Remarkably, employing 2.0 equivalents of 2a, KF, and I2 substantially improved the yield to 70%(entry 13), with further enhancement to an outstanding 89%
yield achieved by increasing the equivalents to 3.0 (entry 14).
Encouraged by the success of iodo-peruoroalkoxylation andsubsequent bromo-peruoroalkoxylation of 1a with 2a using
bromine in the triglyme, we noted the signicant impact ofreactant quantities (entries 15–17). Notably, a high yield of thedesired compound 4aa (88%) was obtained by employing 3.0
equivalents of reagents (entry 17). The addition of reagents is
critical for successful transformation. When the generated
alkoxide and Br2 were rst mixed, followed by the addition ofalkene 1a, the yield of the desired uoroalkyl ether 4aa
decreased to 56%, and 1a was recovered in 36% yield (entry 18).
Next, we explored the substrate scope of haloperuoroalkoxylation under optimal reaction conditions (Fig. 2).
To demonstrate the functional tolerance of this method, various
gem-diuoroalkenes with diverse reactive functionalities,

9576 | Chem. Sci., 2024, 15, 9574–9581

including benzyl ether (1b), ether (1c), ester (1d), tosylate (1e),ketone, and amide groups (1f), were selected as substrates for
iodo-peruoro-hexyloxylation. All the reactions proceededsmoothly, furnishing desired a-peruorohexyl a,a-diuoroalkyl
ethers 3 in high yields (82–96%) and regioselectivity, irrespective of the functional group. Notably, chemoselectivity wasobserved in the iodo-peruoro-hexyloxylation of peruoroallylbenzene (1g). The desired peruorinated ether 3ga
was obtained in 81% yield without SNAr reactions at the peruorophenyl moiety. A gram-scale reaction was also conductedusing peruoroalkoxide on 6.0 mmol (1.01 g) of 1a under
optimized conditions, resulting in the isolation of iodoperuoroalkyl ether 3aa in 92% yield (Fig. 2, 3aa: 3.47 g isolated).
We expanded the substrate scope of bromoperuoroalkoxylation using Br2. Gem-diuoroalkenes bearing
benzyloxy and methoxy moieties (1c) and tosylate (1e) reacted
eﬀectively with potassium peruorohexyloxide 2a, which was
generated in situ in the presence of Br2, providing the corresponding peruorohexyloxyl diuoroalkyl ethers in excellent
yields (4aa, 88%; 4ca, 93%; 4ea, 90%). Gem-diuorostyrene
derivatives (1h–1j) with nonsubstituted (H), electron-donating(Me), and electron-withdrawing (CF3) groups also interactedwith peruoroalkoxides under bromination conditions, aﬀording the corresponding bromoperuoroalkyl ethers in moderate
to good yields (4ha: 40%, 4ia: 53%, 4ja: 66%). The bromo-© 2024 The Author(s). Published by the Royal Society of ChemistryView Article Online

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Chemical ScienceFig. 2 Substrate scope of the halo-perﬂuoroalkoxylation of gem-diﬂuoroalkenes 1 using undecaﬂuorohexanoyl ﬂuoride 2a. Isolated yields areshown. Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), KF (0.9 mmol), I2 or Br2 (0.9 mmol) in triglyme (3.0 mL), stirring under atmosphere of N2
at room temperature. (a) Gram scale reaction. 1 (6.0 mmol, 1.01 g) was used. (b) 1 (0.3 mmol), 2a (1.5 mmol), KF (1.5 mmol), Br2 (1.5 mmol) in
triglyme (6.0 mL).

peruoroalkylation of gem-diuoroalkenes with a secondary
alkyl g-position furnished the corresponding ethers (4ka: 88%(1.2 : 1 dr), 4la: 82%). Signicantly, the triuorinated alkene 1m
eﬃciently reacted with 2a, KF, and bromine, yielding bis(a,adiuoro)ether in a high yield (4ma: 92%). Subsequently, reactions involving various gem-diuoroalkenes bearing natural
products or biologically relevant moieties were explored. Gemdiuoroalkenes 1, containing theophylline (1n), indomethacin(1o), an insecticidal agent (1p), lithocholic acid (1q), andthalidomide (1r), underwent iodoperuoroalkoxylation using
1a, KF, and I2 in the triglyme, resulting in the synthesis of drugconjugated peruoroalkyl diethyl ether in high yields and withexcellent regioselectivity (3na: 75%; 3oa: 85%; 3pa: 85%; 3qa:
75%; 3ra: 91%). Biologically attractive molecules with peruoroalkyl chains are expected to be used as decoy molecules indrug discovery.14© 2024 The Author(s). Published by the Royal Society of ChemistryThis methodology was applied to halo-peruoroalkoxylation
reactions with shorter peruoroalkoxy moieties ranging from C3
to C5 to demonstrate a modular approach (Fig. 3a). Peruoroacyl uorides (2b–2d) were generated ex situ from theircorresponding peruorocarboxylic acids (5) via deoxyuorination using Ishikawa's reagent and NaF. The peruoropropoxylation,peruorobutyloxylation,andperuoropentoxylation of uoroolenes proceeded smoothly,
aﬀording the corresponding peruoroalkoxyethers in good tohigh yields (4ab, 76%; 4ac, 65%; 4ad, 99%). Furthermore,peruoro-isopropoxylation was performed using hexauoroacetone and KF in triglyme with diuoroalkene 1a in thepresence of Br2 to aﬀord the desired branched peruorinatedalkyl ether 4ae in 83% yield.
We further investigated the eﬀect of uorine on the reactivityof alkenes in halo-peruoroalkoxylation reactions under standard conditions (Fig. 3b). Notably, the eﬀect of uorine

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Fig. 3 (a) Substrate scope of the halo-perﬂuoroalkoxylation of gem-diﬂuoroalkene 1a using various perﬂuoroacylﬂuorides 2. Isolated yields areshown. Reaction conditions: 1a (0.3 mmol), 2 (excess), KF (1.5 mmol), Br2 (1.5 mmol) in triglyme (6.0 mL), stirring under atmosphere of N2 at room
temperature. (b) Investigation of ﬂuoroalkene selective reaction using undecaﬂuorohexanoyl ﬂuoride 2a under the standard conditions in Fig. 2.

substitution is obvious, and mono- (1s), di- (1t), and triuorinated (1m) alkenes are well accepted as substrates (4sa,
51%; 4ta, 93%; 4ma, 85%), whereas the nonuorinated alkene
1u remains unreactive (4ua, trace). This highly uoroalkeneselective transformation enhances the advantages of thismethodology.
Although I2 and Br2 are eﬀective for this conversion, we did
not investigate the use of chlorine due to its gasueous, highly
oxidative nature, which makes it diﬃcult to optimize the reaction
conditions.
Uponfurther
investigation,
trichloroisocyanuric acid (TCCA) was found to be a suitablechlorine source for chloro-peruoro alkoxylation, allowing the
production of bis(a,a)diuoro ethers 6 from 2a and 1 in yields
ranging from to 40–58%. Chloro-peruoroalkoxylation was also
selective to uorinated alkenes 1, with nonuorinated alkene
1u remaining unreactive (6ua, 0%) (Fig. 4).

Fig. 4 Substrate scope of the chloro-perﬂuoroalkoxylation of gemdiﬂuoroalkenes 1 using undecaﬂuorohexanoyl ﬂuoride 2a. Isolated
yields are shown. Reaction conditions: 1 (0.6 mmol), 2a (0.3 mmol), KF(0.3 mmol), TCCA (0.3 mmol) in triglyme (3.0 mL), stirring underatmosphere of N2 at room temperature.

9578 | Chem. Sci., 2024, 15, 9574–9581

Furthermore, several chemical transformations were performed to demonstrate the synthetic utility of the obtained
halo-peruoroalkyl ether products (Fig. 5). First, radical
coupling of 3aa with TEMPO in the presence of TMS3SiH atroom temperature resulted in the formation of the TEMPO
adduct 7 in 71% yield. Subsequently, the piperidinyl protecting
group of 7 was reductively removed using zinc and acetic acid,yielding oxygenated compound 8 in quantitative yield.
Employing tributyl stannane facilitated the reduction of iodine
in 3aa using AIBN, leading to hydrogenated product 9 in 93%
yield. Additionally, the radical allylation of 3aa using triethylborane provided corresponding allylated product 10 in 77%
yield. The Giese radical addition of 3aa yielded the desiredolen 11 in 58% yield. Finally, HI elimination from 3aa using mCPBA aﬀorded corresponding E-alkene 12 as a single isomer in
67% yield.
DFT calculations were conducted to assess the stabilizationof peruoroalkoxides in the presence of triglymes. The calculations were performed at the B3LYP-D3/6-311+G(d,p) (SDD for

Fig. 5Synthetic applications.

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Mechanistic studies. (a) Formation of perﬂuoroalkoxides without triglyme. (b) Evaluation of the ﬂuoride salt with triglyme. Optimized
structures of ﬂuoride salt with two triglyme molecules. (c) Control experiments. (d) Evaluation of dissociation of ionic species.

Fig. 6

K and Cs) level of theory using Gaussian 16 soware.15 As
indicated in Fig. 1c. Initially, the formation of peruoroalkoxides from KF and acyluoride 2a in ether was calculated to be
exothermic (Fig. 6a, −1.8 kcal mol−1). Complex formation
involving two triglyme molecules (G3) coordinated to alkali
metal cations resulted in complexes [Na(G3)2][OCF2C5F11],[K(G3)2][OCF2C5F11], and [Cs(G3)2][OCF2C5F11], indicating thatthe potassium cation had the greatest stabilizing eﬀect (Fig. 6b,33.9 kcal mol−1). The M+–O(G3) distances in the tetra-dentated
G3 structures, that is, [Na(G3)2][OCF2C5F11], [K(G3)2][OCF2C5F11], and [Cs(G3)2][OCF2C5F11], ranged from 2.80–3.00,
2.90–3.10, and 3.20–3.40 Å, respectively. This implies that the
deformation energy of G3 molecules, which is the energy
increase due to the deformation of G3 geometries when G3
molecules are coordinated to the M+ cation, is less destabilizing
in [K(G3)2][OCF2C5F11].16 Subsequently, a control experiment
was conducted (Fig. 6c). Alkali metal uoride salts werecompared under optimal reaction conditions using triglyme: KF
resulted in 89% yield, CsF yielded a slightly lower yield, and NaF
did not react. The eﬀects of solvents were further investigated.
The yield decreased to 51% when the reaction was conducted in
MeCN with KF, and no reaction occurred in Et2O. The yield of
the CsF/MeCN system was greater than that of the KF/MeCN
system but signicantly lower than that of the CsF/triglyme
system. Based on these calculations and experimental observations, the yields of the larger cation, cesium salt, were greaterin MeCN, and potassium salt exhibited a greater stabilizing
eﬀect than the cesium salt in the presence of triglyme.

© 2024 The Author(s). Published by the Royal Society of Chemistry

In addition, these outcomes might also be attributed to theenhanced reactivity of peruoroalkoxide anions because of thebetter dissociation of the ionic species. We thus performed
additional DFT calculations to evaluate the dissociation of ionicspecies (Fig. 6d). The dissociation of ionic pair [K][OCF2C5F11]
had a DGR of 26.0 kcal mol−1, indicating a not favourable
process; whereas the process involving the encapsulation of K+
ions with two molecules of triglyme facilitates thedissociation of the ionic pair [K(G3)2][OCF2C5F11], with a DGR of
8.9 kcal mol−1. As shown by the DGR values, the process is morefavourable in the presence of triglyme. Based on the results ofFig. 6a, b-ii, and d, both factors, stabilization and reactivity of
the anion, resulted in diglyme playing important roles for the
successful transformation. These two factors were morefavourable in the presence of triglyme as inferred from thecomputed Gibbs energies, despite the dissociation is still anendergonic process. Also, the diﬀerence in Gibbs energies
stabilization in the presence and the absence of triglyime(DDGR = −33.9 − (−1.8) = −32.1 kcal mol−1) is moresignicant than that for the dissociation (DDGR = 26.0–8.9 =17.1 kcal mol−1).

Conclusion
We designed a novel approach to enhance the stability of shortlived, longer-chain peruoroalkoxy anions to facilitate eﬃcient
nucleophilic peruoroalkoxylation reactions. This method
involves regioselective halo-peruoroalkoxylation of gemdiuoroalkenes using potassium peruoroalkoxides generated

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Chemical Sciencein situ from KF and peruoroacyluorides in a triglyme withbromine, iodine, or TCCA at room temperature. This methodology is broadly applicable to substrates containing analogs
derived from bioactive compounds, thus enabling the synthesisof diuoroalkyl peruoroalkyl ethers with C3–C6 peruoroalkyl
chains. The reaction is performed under mild conditions at rt inan environmentally friendly solvent, triglyme.17 Moreover, it
encompasses a wide range of gem-diuoroalkenes as substrates,
producing halo-peruoroalkoxyl adducts that are suitable fordiverse chemical transformations. This methodology is highly
chemoselective toward uorinated alkenes, whereas nonuorinated alkenes remain intact. The extension of this methodology to the synthesis of uorinated polymers consisting ofbis(a,a-diuoro)ethers (–CF2–O–CF2–) is currently underinvestigation.

Data availability
The data that support the ndings of this study are available
within the article and the ESI.‡ Details about materials andmethods, experimental procedures, characterization data, and
NMR spectral are included.

Author contributions
KK optimized the reaction conditions. KK, YK, TA, MU and SI
surveyed the substrate scope, analyzed the data, and then discussed the results with NH, YK and NS. JE performed DFT
calculation and analyzed the data. KK and NS wrote themanuscript. NS supervised the project. All authors contributed
to the manuscript and have approved the nal version of themanuscript.

Conﬂicts of interest
There are no conicts to declare.

Acknowledgements
This study was supported by the CREST program of the Japan
Science and Technology Agency, entitled “Precise Material
Science for Degradation and Stability” (grant number:
JPMJCR21L1). The computational resources from the Servei
d’Informàtica de la Universidad de Valencia (SIUV) are gratefully acknowledged for providing access to the supercomputing
resources. Profs Tsutomu Konno and Shigeyuki Yamada (Kyoto
Institute of Technology) helped with mass spectrometry.

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