Direct and Regioselective Monofluorination of N-Protected Pyridone Derivatives using N-Fluorobenzenesulfonimide (NFSI)

Article abstract of DOI:10.1021/acs.orglett.9b02482

The direct monofluorination of N-protected pyridone derivatives has been developed using a stable electrophilic fluorinating reagent, N-fluorobenzenesulfonimide (NFSI). Interestingly, the fluorine atom is regioselectively introduced at the position opposite the carbonyl group in the pyridone substrate during the reaction. This method is applicable to a wide range of substrates and allows the regioselective late-stage monofluorination of pyridone scaffolds.

Full text of DOI:10.1021/acs.orglett.9b02482

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct and Regioselective Monofluorination of N‑Protected Pyridone
Derivatives using N‑Fluorobenzenesulfonimide (NFSI)
Fumie Sakurai,* Takafumi Yukawa, and Takahiko Taniguchi
Drug Discovery Chemistry Laboratories, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1,
Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
S
* Supporting Information
ABSTRACT: The direct monofluorination of N-protected pyridone
derivatives has been developed using a stable electrophilic fluorinating
reagent, N-fluorobenzenesulfonimide (NFSI). Interestingly, the fluorine
atom is regioselectively introduced at the position opposite the carbonyl
group in the pyridone substrate during the reaction. This method is
applicable to a wide range of substrates and allows the regioselective late-
stage monofluorination of pyridone scaffolds.
he regioselective introduction of fluorine atoms to
recovered starting material (Figure 1b).4b Very recently, the
Torganic molecules has attracted much attention in the regioselective monofluorination of 4-aryl- or methyl-substi-
tuted pyridin-2(1H)-ones using Selectfluor was reported by
Zhou et al. (Figure 1c).4d This procedure can provide the
corresponding 3-monoflorinated pyridone products with high
regioselectivity. On the contrary, the highly regioselective
monofluorination of monocyclic 2-pyridone derivatives at the
five-position has not been reported to date to the best of our
knowledge (Figure 1d). Herein we report the direct
monofluorination of N-protected pyridones under mild
conditions using a bench-stable and easily handled electro-
philic fluorinating reagent, N-fluorobenzenesulfonimide
(NFSI), focusing on the difference in the reactivity of the
fluorinating reagents shown in Figure 1a. This method enables
the regioselective introduction of a fluorine atom at the
position opposite to the carbonyl group.
To investigate the optimized reaction conditions for the
monofluorination of pyridone derivatives, a number of
fluorinating reagents were initially investigated in the
fluorination of N-methylisoquinolone (1a), which contains a
bicyclic pyridone scaffold (Table 1). When the fluorination
reaction of 1a was performed in acetonitrile (MeCN) for 1 h
using Selectfluor, a commonly used electrophilic fluorinating
reagent, a complex mixture of products was obtained
containing trace amounts of the desired 4-monofluoro-
substituted product (2a) (entry 1). The reaction was also
conducted at rt for 16 h, which resulted in 2a being formed in
5% yield along with significant amounts of byproducts (entry
2). These results suggest that Selectfluor shows extremely high
reactivity toward 1a and that controlling its reactivity is
difficult. The previous report shown in Figure 1a encouraged
us to explore other less reactive electrophilic fluorinating
reagents such as Synfluor, NFSI, and FP-T300 to suppress the
overreaction observed when using Selectfluor.
field of drug discovery because of the resulting improvement in
biological activity and physicochemical properties (e.g.,
bioavailability, lipophilicity, and metabolic stability).1 Electro-
philic fluorination is a simple and convenient method to
introduce fluorine atoms to organic compounds.2 Although
this reaction enables the fluorination of various heterocyclic
compounds, few processes are applicable to the direct
fluorination of pyridone derivatives.3,4 Pyridone scaffolds are
commonly found in pharmaceutical compounds and are
rapidly gaining importance in the development of new drug
candidates.5 Therefore, the direct and regioselective introduc-
tion of a fluorine atom to such scaffolds will allow researchers
not only to rapidly obtain structure−activity relationships but
also to improve the physicochemical profiles in the drug
discovery process.
In 1982, Kobayashi et al. demonstrated the first mono-
fluorination reaction of pyridone derivatives using gaseous
fluorine, which required specialized equipment to be safely
handled.3a These days, a variety of electrophilic fluorinating
reagents have been developed that are less toxic and easier to
handle than the conventional fluorinating reagents.6−9 More-
over, the comparison of the reactivity of such fluorinating
reagents was investigated by Rozatian et al. (Figure 1a).10 1-
(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane di-
(tetrafluoroborate) (Selectfluor)6 has often been used in the
fluorination of pyridone derivatives as a bench-stable electro-
philic fluorinating reagent. However, this procedure still has
limitations in regard to its substrate scope due to the
difficulties in controlling its reactivity in the reaction. For
example, the direct monofluorination of monocyclic pyridin-
2(1H)-ones with Selectfluor results in a highly complex
product mixture, which is difficult to separate.4a
Whereas the fluorination of cytisine derivatives bearing a
bicyclic pyridone scaffold has also been reported, the reaction
affords several fluorinated products with a large amount of
Received: July 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02482
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Letter
T300 did not proceed at all due to its lower reactivity
compared with the other electrophilic fluorinating reagents
studied (entry 6). When a common nucleophilic fluorinating
reagent, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluo-
lead),11 was used in the reaction, no reaction occurred, even
after 12 h (entry 7). Consequently, screening of the reaction
conditions was carried out (Table 2). The reaction of 1a with
Table 2. Optimization of the Reaction Conditions Used for
the Monofluorination of 1a with NFSI
a
entry
solvent
temp (°C)
time (h)
yield of 2a (%)
1
2
3
4
5
6
7
8
MeCN
DMF
DMA
MeOH
HFIP
EtOAc
DME
THF
toluene
DCE
MeCN
MeCN
MeCN
MeCN
60
60
60
60
60
60
60
60
60
60
90
rt
1
1
1
1
1
1
1
1
1
1
1
16
2
3
50
45
27
b
ND
48
35
38
31
39
34
9
10
11
12
13
14
15
c
−
trace
51
60
60
60
42
c
MeCN
16
−
a
b
Isolated yield. LC−MS analysis of the reaction mixture revealed
that compound 3 appeared to be obtained instead of 2a. Reaction
afforded a complex mixture of products.
c
Figure 1. Direct monofluorination of pyridone scaffolds.
Table 1. Screening of the Fluorinating Reagents Used for
the Monofluorination of 1a
2.0 equiv of NFSI using an aprotic polar solvent such as N,N′-
dimethylformamide (DMF) and N,N′-dimethylacetoamide
(DMA) gave the 4-monofluorinated product (2a) in lower
yield when compared with the reaction performed in MeCN
(entries 2 and 3). When using an alcohol solvent such as
methanol, LC−MS analysis of the reaction mixture revealed a
peak corresponding to the methanol adduct (3) instead of the
target product (2a) (entry 4).4a The use of 1,1,1,3,3,3-
hexafluoroisopropyl alcohol (HFIP), which is a more acidic
alcohol with weak nucleophilicity, provided 2a in 48% yield,
and the alcohol adduct obtained when using methanol as the
solvent was not observed (entry 5).
Solvent screening was further conducted using EtOAc, 1,2-
dimethoxyethane (DME), THF, toluene, and 1,2-dichloro-
ethane (DCE) (entries 6−10). Although the yield of 2a was
not improved when using these solvents, it confirmed that
various types of solvent are tolerated in the reaction.
Subsequently, screening of the reaction temperature was
conducted using MeCN as the reaction solvent. The reaction
was performed at high temperature (90 °C) to improve the
yield of 2a (entry 11). However, the as-obtained mono-
fluorinated product was decomposed during the reaction.
Lowering the temperature to rt for 16 h afforded a trace
amount of 2a with recovered starting material obtained as the
main product (entry 12). When the reaction time was
prolonged to 2 h, 2a was obtained in 51% yield without
generating any byproducts (entry 13). However, the yield of 2a
a
entry
1
2
3
4
5
6
7
fluorinating reagent (equiv)
time (h)
yield (%)
b
Selectfluor (1.1)
Selectfluor (1.1)
Synfluor (1.1)
NFSI (1.1)
NFSI (2.0)
FP-T300 (1.1)
1
16
1
1
1
−
c
5
−
b
33
50
12
12
NR
NR
d
Fluolead (1.1)
a
b
Isolated yield. Complex mixture of products containing trace
c
d
amounts of 2a. Reaction was performed at rt. Toluene was used as
the reaction solvent instead of MeCN.
Whereas the reaction of 1a with Synfluor gave a complex
mixture of products, NFSI was found to be the better
fluorinating reagent in regard to the efficiency and
regioselectivity of the reaction, providing the corresponding
4-monofluorinated product (2a) in 33% yield and as a single
regioisomer (entry 3 vs 4). Furthermore, the use of 2.0 equiv
of NFSI improved the yield of 2a to 50% without the
generation of any byproducts (entry 5). The reaction using FP-
B
DOI: 10.1021/acs.orglett.9b02482
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Letter
slightly decreased after the reaction was conducted for 3 h
(entry 14). The longer reaction time resulted in a complex
mixture of products, suggesting that product 2a was
decomposed during the reaction (entry 15).
Table 3. Substrate Scope in the Monofluorination of
Pyridones Using NFSI
With the optimized reaction conditions in hand, the
monofluorination of various pyridone derivatives 1 was
investigated (Table 3). N-Methyl-substituted thieno[2,3-c]-
pyridin-7(6H)-one 1b and thieno[3,2-c]pyridin-4(5H)-one 1c
also underwent the monofluorination reaction with 2.0 equiv
of NFSI in MeCN at 60 °C, providing their corresponding
monofluorinated products (2b and 2c) in 49 and 32% yield,
respectively, and were formed as a single regioisomer (entries 2
and 3). The versatility of the reaction could be confirmed using
N-methylated bicyclic pyridone compounds. Unfortunately,
the reaction of isoquinolin-1(2H)-one 1d in MeCN resulted in
a highly complex mixture of products (entry 4). Because of the
poor solubility of 1a in MeCN, DMA was used in the reaction
to improve its solubility (entry 5). Although 1a completely
dissolved in DMA, only a trace amount of the desired product
was generated during the reaction. We then expanded this
methodology to the monofluorination of monocyclic pyr-
idones. The reaction of N-methylpyridone 1e bearing a phenyl
group at the three-position also proceeded to give the
corresponding monofluorinated product 2e in 37% yield and
as a single regioisomer (entry 6). In the reaction of 1f bearing
an electron-withdrawing group (−CF3), a higher reaction
temperature and longer reaction time were required to provide
2f in moderate yield (entry 7). The reaction of pyridones 1g
and 1h bearing a 3-halo substituent also gave monofluorinated
products 2g and 2h in 22 and 36% yield, respectively (entries 8
and 9). An electron-donating group, such as a methyl group at
the three-position of the pyridone moiety, was also tolerated in
the reaction, and the corresponding monofluorinated product
2i was obtained in 43% yield (entry 10). Finally, this method
was also applied to N-protected monocyclic pyridones 1j−m
without any substituents at the three-position. When 4-
methylpyridone 1j was reacted with NFSI for 5 h, 5-
fluoropyridone 2j was obtained in 42% yield with high
regioselectivity (entry 11). Interestingly, the 3-fluorinated
regioisomer of 1j was not formed during the reaction. In
entry 12, the reaction of 6-methyl-substituted pyridone 1k also
gave the monofluorinated product (2k) in 43% yield without
generating the 3-monofluorinated product. Furthermore,
nonsubstituted N-benzylpyridone (1l) underwent the reaction
to provide the corresponding monofluorinated products 2l in
46% yield as a single regioisomer (entry 13). Pirphenidone
analogue 1m without the 5-methyl group was also
regioselectively monofluorinated at the five-position, providing
2m in 42% yield (entry 14).
As shown in Figure 1b, the previously reported fluorination
of N-protected pyridones using Selectfluor revealed that
controlling the regioselectivity of the reaction was difficult.4b
On the contrary, when using our method with NFSI, it was
notable that no fluorine atom was introduced at any other
position except that opposite the carbonyl group in the N-
protected pyridone derivatives studied, even in the case of
sterically hindered pyridones such as 1k. A mechanistic insight
into the excellent regioselectivity observed under our reaction
conditions is currently under investigation in our laboratory
and will be reported in due course.
a
b
Isolated yield. DMA was used as the reaction solvent instead of
c
d
MeCN. Reaction afforded a complex mixture of products. Reaction
was performed at 120 °C in a sealed tube.
strated in the reaction. In addition, the reaction is highly
regioselective with monofluorination only occurring at the
position opposite to the carbonyl group of the pyridone
substrate. This method allows the regioselective late-stage
In conclusion, we have developed the direct monofluorina-
tion of N-protected pyridone derivatives using NFSI under
mild conditions. A wide substrate scope has been demon-
C
DOI: 10.1021/acs.orglett.9b02482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. Sci. 2018, 9, 5608. (f) Bora, P. P.; Bihani, M.; Plummer, S.;
Gallou, F.; Handa, S. ChemSusChem 2019, 12, 3037.
introduction of a fluorine atom to pyridone scaffolds and is
expected to contribute to further advances in drug discovery.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02482.
■
S
General information, synthetic procedures and charac-
terization, and NMR spectra of all characterized
compounds (PDF)
(8) Differding, E.; Ofner, H. Synlett 1991, 1991, 187.
(9) (a) Umemoto, T.; Tomita, K. Tetrahedron Lett. 1986, 27, 3271.
(b) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada,
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(10) Rozatian, N.; Ashworth, I. W.; Sandford, G.; Hodgson, D. R.
Chem. Sci. 2018, 9, 8692.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail fumie.sakurai@takeda.com
ORCID
Fumie Sakurai: 0000-0002-2447-7669
Notes
(11) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc.
2010, 132, 18199.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are very grateful to Dr. Makoto Kamata (Takeda
Pharmaceutical Co. Ltd.) for scientific discussions and his
helpful advice.
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DOI: 10.1021/acs.orglett.9b02482
Org. Lett. XXXX, XXX, XXX−XXX