Showcasing research from Professor Junichiro Yamaguchi’slaboratory, Department of Applied Chemistry, Waseda
University, Tokyo, Japan.

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Ring-opening fluorination of bicyclic azaarenes
Upon treatment of bicyclic azaarenes with electrophilic
ﬂuorinating agents, ﬂuorination of the aromatic ringis followed by a ring-opening reaction. Although thisoverall transformation can be classiﬁed as an electrophilic
ﬂuorination of an aromatic ring, it is a novel type of
ﬂuorination that results in tertiary carbon–ﬂuorine bonds.

See Junichiro Yamaguchi et al.,Chem. Sci., 2022, 13, 665.

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Ring-opening ﬂuorination of bicyclic azaarenes†
Cite this: Chem. Sci., 2022, 13, 665
All publication charges for this article
have been paid for by the Royal Societyof Chemistry

Masaaki Komatsuda, a Ayane Suto,a Hiroki Kondo, Jr,a Hiroyuki Takada,
Kenta Kato, a Bunnai Saitob and Junichiro Yamaguchi *ab

We have discovered a ring-opening ﬂuorination of bicyclic azaarenes. Upon treatment of bicyclic azaarenes
such as pyrazolo[1,5-a]pyridines with electrophilic ﬂuorinating agents, ﬂuorination of the aromatic ring isfollowed by a ring-opening reaction. Although this overall transformation can be classiﬁed as an

Received 12th November 2021
Accepted 21st December 2021

electrophilic ﬂuorination of an aromatic ring, it is a novel type of ﬂuorination that results in constructionof tertiary carbon–ﬂuorine bonds. The present protocol can be applied to a range of bicyclic azaarenes,

DOI: 10.1039/d1sc06273e
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tolerating azines and a variety of functional groups. Additionally, mechanistic studies andenantioselective ﬂuorination have been examined.

Introduction
Fluorine is one of the most important elements that could beinstalled onto hydrocarbon frameworks in pharmaceuticals,
agrochemicals, and materials science.1 Particularly, in medicinal chemistry, uorine has been incorporated into drug
molecules to improve their liposolubility and metabolicstability.2 The eﬀect of uorine atoms in molecules has beenwell-studied,3 and in turn, uorination methodology has ourished as well.4 One of the most conventional ways to achieve
uorination is electrophilic uorination. Nucleophiles used inelectrophilic uorinations can be broadly classied into carbanions (e.g., 1,3-dicarbonyls), electron-rich unsaturated bonds(e.g., alkenes and alkynes), and aromatics.5 However, in these
existing methods, uorination proceeds while retaining thecarbon skeleton of the starting material, and uorinations
involving skeletal transformations are rare.
Ring-opening uorination, in which a uorine atom is
introduced onto a cyclic compound with concomitant ringcleavage, has recently attracted attention as a useful method foreﬃciently constructing complex uorine-containing skeletons(Fig. 1A). Although ring-opening uorinations have recently
been reported, most are limited to three- or four-membered ring
starting materials such as epoxides, cyclopropanes/butanes,
and aziridines, which have strained chemical bonds.6 Fluorinations involving bond cleavage in a ring size $5 are rare. The
Lectka, Leonori, and Ma group reported ring-openinguorinations via C–C bond cleavage of carbocycles (Fig. 1B).7,8
Very recently, the Lim group disclosed acyl uoride synthesis
through C–C bond cleavage of carbocycles and cyclic amides.9a

Department of Applied Chemistry, Waseda University, 513, Wasedatsurumakicho,
Shinjuku, Tokyo 169-8555, Japan. E-mail: junyamaguchi@waseda.jpbResearch, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2chome, Fujisawa, Kanagawa, 251-8555, Japan† Electronic supplementary information (ESI) available: CCDC 2113745 (for 10).
For experimental procedures, spectroscopic data for compounds including 1H,
13
C, and 19F NMR spectra. CCDC 2113745. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/d1sc06273e© 2022 The Author(s). Published by the Royal Society of ChemistryFig. 1 (A) Ring-opening ﬂuorination. (B) Fluorination of cyclic
compounds via C–C bond cleavage. (C) Fluorination of cyclic
compounds via X–Y bond cleavage.

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In 2018, the Sarpong group reported an elegant ring-openinguorination of cyclic amines (Fig. 1B).9,10
In the heteroatom–heteroatom (X–Y) bond paradigm, theYao group reported a ring-opening uorination using isoxazoline N-oxides via O–N bond cleavage (Fig. 1C).11 However, allthese methods require the use of highly specic substrates, anduorinations involving the ring opening of aromatic rings orasymmetric uorination have not yet been reported. In contrast
to existing methods, we planned to develop a ring-openinguorination of bicyclic azaarenes such as pyrazolo[1,5-a]pyridines. We hypothesized that treating bicyclic azaarenes with anelectrophilic uorinating agent would result in uorination at
the C3 position, followed by deprotonation at the C2 positionand pyrazole ring opening via N–N bond cleavage. Although thiscan be considered as a simple electrophilic uorination using
an electron-rich heteroaromatic system as a nucleophile, theresulting compound is an sp3-uorinated compound (C(sp3)–Fbond) instead of a uorine-substituted heteroarene (C(sp2)–Fbond). In other words, we thought that this would be a novel
type of uorination reaction with accompanying skeletaltransformation.

Results and discussion
First, we selected 3-phenylpyrazolo[1,5-a]pyridine (1A) as themodel substrate (which was readily prepared in three steps froma commercially available compound) to examine electrophilic
uorinating agents and reaction conditions (Table 1). When Nuoropyridinium salts (F1–F3) were used in MeCN at 80  C,
ring-opening uorinated product 2A was successfully obtained,

Table 1

Screening of reaction conditionsa

Entry

F+ source

Temp/ C

Solvent

2A/%

1A/%

1
2
3
4
5
6
7
8
9
10
11

F1
F2
F3
NFSI
Selectuor®
Selectuor®
Selectuor®
Selectuor®
Selectuor®
Selectuor®
Selectuor®

80
80
80
80
80
50
60
70
80
80
80

MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Acetone
DMF
MeOH

39
27
5
94
>99
68
74
87
65
64
58

37
43
3
0
0
0
0
0
0
0
0

a
Conditions: 1A (0.20 mmol), F+ source (1.0 equiv.), solvent (1.0 mL),
50–80  C, 24 h. NFSI ¼ N-uorobenzenesulfonimide.

666 | Chem. Sci., 2022, 13, 665–670

albeit in low yields (entries 1–3).12 The use of other nonpyridinium based electrophilic uorinating agents such as
NFSI and Selectuor® gave uorinated products in high yields(entries 4 and 5).13
As for the reaction temperature, the yield of 2A was 68% evenat 50  C. The yield increased as the temperature was increased,
and the uorinated product was obtained quantitatively at 80  C(entries 6–8 vs. entry 5). The reaction proceeded in polar
solvents such as acetone and DMF (which is able to dissolve
Selectuor®), and gave the uorinated product 2A (entries 9–11). Finally, we conformed the optimal conditions: Selectuor®
(1.0 equiv.) at 80  C in MeCN for 24 h. With the optimal
conditions in hand, the substrate scope was investigated(Scheme 1). Various 3-arylpyrazolo[1,5-a]pyridines were examined: Methyl (1B), tert-butyl (1C), and phenyl (1D) at the paraposition on the aryl group gave the ring-opening uorinatedproducts 2B–2D in moderate yields. It should be noted thatuorination of these aryl groups was detected. When using
trimethylphenyl (1E) and naphthyl (1F) starting materials, thecorresponding products 2E and 2F were obtained in moderate
yields, and occurred decomposition of 1E or uorinated the arylgroup of 1F (less than 10% yields). The reaction showed goodfunctional group tolerance in the presence of formyl (1G), acetyl(1H), cyano (1I), triuoromethyl (1J), nitro (1K), and chloro (1L)groups, as the reaction worked to give the corresponding
products 2G–2L in excellent yields. Next, 3-alkylpyrazolo[1,5-a]pyridines were investigated. The uorination using bicyclic
azaarenes bearing alkyl groups (1M and 1N) or acetal (1O)
proceeded smoothly to give the corresponding uorinatedproducts 2M–2O in moderate to excellent yields. Pyrazolo[1,5-a]pyridines with alkyl acetate (1P), cyano (1Q), and ethylcarboxylate (1R) aﬀorded the corresponding products (2P–2R)
in good yields. Pyrazolo[1,5-a]pyridine carboxylates were also
examined. Substrates with alkyl groups including alkene (1U)
and alkyne (1W) remained intact to give products 2S–2X in highyields. Carboxylic acid 1Y also reacted well, but the product wasdiﬃcult to purify, resulting in a low yield of 2Y. In the case ofcompounds with amides such as 1Z, deamidation occurred togive 3-uoropyrazolo[1,5-a]pyridine as a byproduct. Therefore,the uorinated product 2Z was obtained in moderate yield(39%) by reacting at a lower temperature (30  C). Furthermore,azaarenes 1AA and 1AB derived from probenecid and estrone
also gave uorinated compounds 2AA and 2AB in high yields. Of
note, in the case of an unsaturated ester or iodine at the C3
position, the desired uorinated product could not be obtained,
giving a complex mixture.
Substituted bicyclic arenes gave uorination products 2AC–
2AF, however, for some substrates such as 1AC and 1AE, theuorination reactions were more diﬃcult. Aer extensive
screening of additives, we found that NaClO4 (1.0 equiv.) was
eﬀective for increasing yields (see the ESI† for details). For
example, without this additive, 1AC gave 2AC in only 51% yield,
but with the additive, the yield improved to 87%. The role of theadditive remains unclear, but we hypothesize that the counter
anion exchange in the intermediate might aﬀect the acidity ofthe proton at the C3 position.14© 2022 The Author(s). Published by the Royal Society of ChemistryView Article Online

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Substrate Scope. a Conditions. 1 (0.20 mmol), Selectﬂuor® (1.0 equiv.), MeCN (1.0 mL), 80  C, 24 h. b Selectﬂuor® (5.0 equiv.) was
added. The reaction was performed at 30  C. d NaClO4 (1.0 equiv.) was added.
Scheme 1cThis uorination was also applicable to other azaarenes:
pyrazolo[1,5-a]pyrimidine with a phenyl group at the C3 position gave uorinated compounds 2AG–2AI in high yields. 6Bromopyrazolo[1,5-a]pyrimidine with various aryl groups at theC3 position gave uorinated compounds 2AJ–2AL as well. The
ring-opening uorination proceeded well even when using
zaleplon, a hypnotic agent, for which the desired product 2AM
was obtained. The reaction was also applicable to pyrazolopyrazine, triazine, quinoline, and quinazoline, giving uorinatedproducts 2AN–2AQ in moderate yields.
In order to elucidate the reaction mechanism, we performed
reaction tracking by 1H NMR analysis using 1M (Fig. 2A). When
Selectuor® was added to 1M in an NMR tube without stirring,
1M was immediately consumed at room temperature to
produce tetrauoroborate 3 as the intermediate, which isthought to be the result of electrophilic uorination at the C3© 2022 The Author(s). Published by the Royal Society of Chemistry

position. Aer 2 to 4 hours of reaction time at 80  C, 1M almost
entirely disappeared, and NMR peaks showed a mixture of 2M
and 3; nally, practically only 2M resulted in the 1H NMR
spectrum. This experiment indicated that the uorination andthe cleavage of the N–N bond proceeds in a stepwise fashion.
When the reaction was stirred in a ask, 1M disappeared aer
10 min at room temperature, giving intermediate 3 and theresidue 4 of Selectuor® (Fig. 2B). Upon removal of 4 from theresulting mixture, further reaction did not procced by heating at
80  C for 24 h (see the ESI† for experimental details). Therefore,
triethylamine (1.0 equiv.) was added, and the reaction proceeded quickly to give the desired 2M quantitatively. This
supports the role of Selectuor® as the uorinating agent in thereaction and the conjugate base of 4 as the base that promotes
the N–N bond cleavage. These results also suggested that thebasicity of the conjugate base of the uorinating agent was

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Edge Article(A) Reaction tracking by 1H NMR. (B) The role of Selectﬂuor®. (C) Reactions using C2-substituted azaarene 5 and C3-unsubstituted
azaarene 7. (D) Studies toward asymmetric ﬂuorination.
Fig. 2

crucial for this ring-opening uorination. In the case of F1–F3,
the consumption of 1A was increased as the electrophilicity ofthe uorinating agents was higher (F3 > F2 z F1), but the yieldof 2A was proportional to the basicity of the conjugate base (F1 >F2 > F3). Furthermore, the reaction proceeded eﬃciently withthe use of base with higher pKa such as triethylamine and 4.
Next, the uorination reaction was carried out with 5, where theC2 position was substituted (Fig. 2C). As a result, only triuoroborate salt 6 was obtained in a good yield, with no ringopened product was obtained upon heating. When the uorination reaction was attempted using 7, which is unsubstituted
at the C3 position, one equivalent of Selectuor® gave theuorinated compound 8 as the main product (50%) and thering-opened compound 9 as a byproduct, demonstrating
further uorination. When the amount of Selectuor® wasincreased to two equivalents, 9 became the main product (58%).
These results indicated that a substituent is required at the C3
position because deprotonation of an acidic C–H (adjacent to F)

668 | Chem. Sci., 2022, 13, 665–670

to regain aromaticity occurs preferentially over deprotonation/
ring-opening.
We then studied the enantioselective version of this uorination reaction (Fig. 2D).15 We attempted asymmetric uorinations using chiral uorinating agents. Shibata reported thata chiral uorinating agent, NF–(DHQD)2PHAL, can be preparedby mixing (DHQD)2PHAL and Selectuor® at room temperature.16 A reaction using stoichiometric amounts of these agentswith 3-phenyl-6-bromopyrazolo[1,5-a]pyrimidine 1AJ in MeCN
at 50  C gave the corresponding product in 68 : 32 e. r., albeit ina low yield. However, when (DHQD)2PHAL was reduced tocatalytic amount, enantioselectivity was dropped whereas theyield was increased. The substrate without a bromo atom at theC6 position (1AG) gave the uorinated product in moderate
yield (44%) and 65 : 35 e. r. By lowering the temperature,changing the uorinating agent, and changing the solvent, wenally succeeded in obtaining the uorinated compound 2AJ
with an enantioselectivity of 84 : 16 e. r.

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Chemical Scienceuorinating reagent functioned not only as the uorine source,
but also as the base required for ring opening. Expanding therange of substrates and other electrophiles for this type oftransformation is currently underway in our laboratory.19

Data availability
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All experimental data is available in the ESI.†

Author contributions

Scheme 2 Derivatization of the products. Conditions: (i) pyrrolidine(5.0 equiv.), MeCN, RT, 12 h; (ii) Pd(PPh3)4 (5.0 mol%), toluene, RT, 1 h;(iii) Pd2(dba)3 (5.0 mol%), PPh3 (20 mol%), pyridine (3.0 equiv.), MeCN,
RT, 1 h; (iv) TMSCl (5.0 equiv.), MeOH, 50  C, 6 h; (v) Pd(OAc)2(4.0 mol%), acetaldoxime (10 equiv.), 1,4-dioxane, reﬂux, 1 h; (vi)t
BuOAc (6.0 equiv.), conc. H2SO4 (10 mL), 40  C, 2 h; (vii) BH3$SMe2 (3.0
equiv.), THF, 0  C to RT, 19 h.

B. S. and J. Y. conceived and designed the study. M. K., A. S. and
H. K. performed the chemical experiments and analyzed thedata. K. K. performed the X-ray crystallography experiments andanalyzed the obtained data. H. T. performed the preliminary
experimental studies. J. Y. wrote the manuscript and all authors
discussed the results and commented on the nal manuscript.

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

Acknowledgements
The absolute stereochemical conguration was determinedby derivatization to give optically pure amide 10, recrystallization, and then X-ray structural analysis. In the crystal structure,
the C]O bond of amide 10 is align antiparallel to the C–F bond,a conformation in which the amide dipole opposes the C–F
dipole due to a dipole minimization eﬀect. The enantioselectivity of this asymmetric uorination could be explainedusing the proposed transition state model. Although thedirection in which the substrate reacts with the chiral uorinating agent determines the enantioselectivity, we believe thatthe transition state of the desired compound has a p–p interaction between the substrate and the methoxyquinoline moietyof (DHQD)2PHAL, which xes the conformation.16c,17 Finally, theobtained uorinated compounds were derivatized into various
compounds (Scheme 2). The ring-opened uorinated productsof pyrazolo[1,5-a]pyridine 2U (R ¼ CO2allyl) were condense withamines to give amide 11 in 41% yield. Palladium-catalyzed
decarboxylative allylation and removal of allyl esters proceeded to give derivatives 12 and 13 in high yields. Furthermore,
we attempted to convert the cyano group of the product of theuorination reaction. Fluorinated product 2A (R ¼ Ph) wasconverted to methyl ester 14 by methanolysis. 2A was also
converted to amides 15 and 16 by hydrolysis and Ritter reaction.18 Furthermore, borane reduction gave amine 17. In thisway, we have succeeded in synthesizing a variety of uorinecontaining compounds by orthogonal functional group transformations following ring-opening uorination.

Conclusions
In summary, we developed a ring-opening uorination of bicyclic azaarenes leading to sp3-uorinated compounds via N–Nbond cleavage. Studies revealed that the electrophilic© 2022 The Author(s). Published by the Royal Society of ChemistryThis work was supported by JSPS KAKENHI Grant Number
JP19H02726, JP21H05213, JP21K18966, JST ERATO Grant
Number JPMJER1901 (to J. Y.), and JP20J14905 and a Waseda
Research Institute for Science and Engineering Grant in Aid forYoung Scientists (Early Bird) (to M. K.). We thank Kota Ishitobi
for preparation of several starting materials. We also thank Prof.
Masahiro Terada (Tohoku University) for supplying chiral
phosphoric acids. We also thank Iwatani Corporation for
supplying Cs2CO3. The Materials Characterization Central
Laboratory in Waseda University is acknowledged for the
support of HRMS measurement.

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© 2022 The Author(s). Published by the Royal Society of Chemistry